MicrobiologyTier 1Medical Sciences concept

Interferon-gamma release assays for TB - mechanism and interpretation

Core concept

IGRA (e.g. QuantiFERON-TB Gold, T-SPOT.TB): patient's blood T cells are exposed ex vivo to TB-specific antigens (ESAT-6, CFP-10) -- if the patient has been sensitised by prior TB exposure (latent or active), memory T cells release interferon-gamma, which is measured
Purpose: detect evidence of prior TB infection (sensitisation) -- cannot distinguish latent infection from active disease, and cannot localise disease
Key advantage over tuberculin skin test (TST/Mantoux): the antigens used (ESAT-6, CFP-10) are absent from BCG vaccine strain and most non-tuberculous mycobacteria -- not confounded by prior BCG vaccination, unlike TST

IGRA does not distinguish latent TB infection (LTBI) from active TB disease -- a positive result requires clinical/radiological/microbiological assessment to determine which is present
False negatives occur in significant immunosuppression (HIV with low CD4, high-dose steroids, other T-cell-depleting states) -- test relies on an intact T-cell response to generate signal; anergy causes indeterminate/false-negative results
IGRA is generally preferred over TST in BCG-vaccinated individuals (avoids false positives from vaccine cross-reactivity) but offers no advantage over TST for serial/repeated testing programmes in some settings and can show more inter-test variability ("conversions/reversions") than expected biologically

Trap: using a positive IGRA alone to diagnose active TB -- a positive result only indicates immune sensitisation (past or present infection); active disease requires supporting clinical/radiological findings and microbiological confirmation (culture, NAAT)
An indeterminate IGRA result in an immunosuppressed patient should not be interpreted as "no TB exposure" -- the test may simply be failing due to poor T-cell function; consider repeat testing or alternative assessment
Used for pre-biologic/immunosuppressive therapy LTBI screening (e.g. before anti-TNF therapy) specifically because a positive result changes management (prophylactic treatment) before immunosuppression unmasks latent disease

Directly contrasts with tuberculin skin test -- same underlying principle (memory T-cell response to mycobacterial antigen) but TST uses PPD (shared antigens with BCG/NTM, more false positives) vs IGRA's specific antigens
Same T-cell-dependent test-failure principle explains reduced IGRA reliability in profound immunosuppression -- parallels other cell-mediated immunity tests losing sensitivity in T-cell deficiency
Pairs with the broader multidrug-resistant TB and TB treatment notes once active disease (rather than latent infection) is confirmed

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