IGRA (Interferon-Gamma Release Assay) Test

What Is It?

An IGRA is a blood-based immunological test for detecting infection with Mycobacterium tuberculosis (Mtb). It works by measuring the amount of interferon-gamma (IFN-γ) released by T lymphocytes when a patient's blood is exposed ex vivo to TB-specific peptide antigens - primarily ESAT-6, CFP-10, and TB7.7. These antigens are absent from BCG vaccine strains and most non-tuberculous mycobacteria, which gives IGRA a major advantage over the tuberculin skin test (TST).

Available Tests (US)

Test	Type	Positive Threshold
QuantiFERON-TB Gold Plus (QFT-Plus)	Whole blood ELISA	IFN-γ ≥ 0.35 IU/mL above negative control
T-SPOT.TB	ELISPOT (PBMC-based)	≥ 8 spots above negative control

Result Interpretation

Positive: Probable infection with Mtb complex - does NOT distinguish latent from active TB
Negative: TB infection unlikely (but not ruled out)
Indeterminate / Invalid / Borderline: Uninterpretable - seen when the positive control shows insufficient response or negative control shows excessive spontaneous IFN-γ secretion; requires repeat testing

(Murray & Nadel's Textbook of Respiratory Medicine)

CDC Guidelines: When to Use IGRA vs. TST

Situation	Preferred Test
BCG-vaccinated individuals	IGRA preferred (BCG does not cause false positives)
Groups unlikely to return for TST reading (homeless, active drug users)	IGRA preferred
Children < 5 years	TST preferred (limited IGRA data in young children)
All other situations	Either IGRA or TST acceptable
High-risk contacts or suspected active TB requiring maximum sensitivity	Dual testing (both IGRA + TST) may be considered

Key Advantages Over TST

Single visit required (no 48-72 hour return needed)
Not affected by prior BCG vaccination - fewer false positives
More objective (lab measurement vs. skin induration reading)
No boosting effect with serial testing

Limitations

Cannot distinguish latent TB infection (LTBI) from active TB disease
Can be falsely negative in immunocompromised patients (HIV, immunosuppressants)
Indeterminate results are more common in immunocompromised individuals - a 2023 systematic review (PMID 37422080) found these patients have a meaningful residual risk of TB progression even with indeterminate results
IGRA conversion (negative to positive) and reversion (positive to negative) can occur with serial testing; a 2025 meta-analysis (PMID 38954503) quantified these rates and highlighted challenges in serial testing programs
A positive result does NOT indicate active disease and does not guide treatment in isolation
Should NOT be repeated in someone with a prior documented positive result or prior TB treatment

Clinical Use

Screening for latent TB infection (LTBI) before starting immunosuppressive therapy (e.g., anti-TNF biologics, steroids)
Contact investigation after TB exposure
Pre-employment screening in healthcare workers
Immigration and travel medicine screening
Workup of suspected active TB (alongside sputum culture, chest X-ray, and PCR)

A 2024 Ontario Health Technology Assessment (PMID 39911267) and CDC guidance both support IGRA as a reliable tool for LTBI screening, with QFT-Plus and T-SPOT.TB performing similarly at the population level with no clear advantage of one over the other.

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