What is the scope of IGRA (Interferon-Gamma Release Assay) in the diagnosis of tuberculosis?

Scope of IGRA in the Diagnosis of Tuberculosis

Interferon-Gamma Release Assays (IGRAs) are valuable diagnostic tools for detecting Mycobacterium tuberculosis infection, but they cannot distinguish between latent tuberculosis infection (LTBI) and active tuberculosis disease. 1

Overview of IGRAs

• IGRAs detect sensitization to M. tuberculosis by measuring interferon-gamma (IFN-γ) release in response to antigens representing M. tuberculosis 1
• Two FDA-approved commercial IGRAs are currently available:
  • QuantiFERON-TB Gold In-Tube test (QFT-GIT) by Cellestis Limited 1, 2
  • T-SPOT.TB test (T-Spot) by Oxford Immunotec 1, 2
• IGRAs measure host immune response to M. tuberculosis, similar to the tuberculin skin test (TST), but with improved specificity 3

Advantages of IGRAs over TST

• IGRAs are not affected by prior BCG vaccination, improving specificity in vaccinated populations 4
• They require only one patient visit, eliminating the need for return visits for test reading 4
• No reader bias or placement errors as with TST 4
• IGRAs use M. tuberculosis-specific antigens (ESAT-6 and CFP-10) that are absent from BCG vaccine strains and most nontuberculous mycobacteria 1

Limitations of IGRAs

• IGRAs cannot differentiate between active TB and latent TB infection 3, 2
• They cannot distinguish between current or past M. tuberculosis infection 3
• Sensitivity and specificity vary across different clinical contexts and populations 1
• IGRAs have not demonstrated clear superiority to TST as a diagnostic test in children 3

Recommended Uses of IGRAs

• IGRAs may be used as aids in diagnosing M. tuberculosis infection, both latent infection and infection manifesting as active tuberculosis 1
• They are particularly useful for surveillance purposes and to identify persons likely to benefit from treatment 1
• IGRAs are preferred for individuals ≥5 years old who have received BCG vaccination or are unlikely to return for TST reading 4
• In immunocompromised patients, using both TST and IGRA can increase sensitivity for detecting LTBI 4

Approaches to IGRA Implementation

Guidelines recommend four main approaches to IGRA use:

1. Two-step approach: TST first, followed by IGRA either when:

   • TST is negative (to increase sensitivity, mainly in immunocompromised individuals) 1
   • TST is positive (to increase specificity, mainly in BCG-vaccinated individuals) 1

2. Either TST or IGRA, but not both 1

3. IGRA and TST together (to increase sensitivity) 1

4. IGRA only, replacing the TST 1

Role in Active TB Diagnosis

• The gold standard for diagnosis of active TB remains microbiological confirmation by culture of M. tuberculosis 3
• IGRAs do not have sufficient sensitivity or specificity to exclude or confirm active TB disease 3
• Recent research has explored combining IGRAs with other biomarkers (like TNF-α release assay) to better differentiate active TB from LTBI 5
• QFT results do not offer much value for treatment monitoring of TB disease 6

Special Considerations

• In high TB incidence settings, IGRAs are most useful for screening high-risk groups such as HIV-infected individuals and child contacts of people with TB 1
• In low TB incidence countries, detection and management of LTBI using IGRAs is a key component of TB control 1
• The CDC recommends that IGRAs may be used in all situations where TST is recommended, including contact investigations and evaluation of recent immigrants 1

Pitfalls and Caveats

• Most current guidelines on IGRAs do not use objective, transparent methods to grade evidence and recommendations 1
• IGRA results can be affected by the presence of M. kansasii, M. szulgai, and M. marinum, which contain ESAT-6 and CFP-10 antigens, potentially causing false-positive results 1
• Discordant results between TST and IGRA are common, with poor agreement observed in some studies 7
• High-dose steroids can suppress TST reactions, and IGRA testing may be less affected by steroid therapy 4