Interferon Gamma Release AssayEdit

Interferon gamma release assays (IGRAs) are a set of blood tests used to detect infection with Mycobacterium tuberculosis, the bacteria that cause tuberculosis (TB). By measuring the release of interferon-gamma from T cells after exposure to MTB-specific antigens, these tests aim to identify people who have been infected, either latently or in some cases active TB. IGRAs are presented as alternatives to the traditional tuberculin skin test (Mantoux test), with particular advantages for individuals who have received the BCG vaccine or have had prior BCG exposure. The tests most commonly in use today include the QuantiFERON family (QuantiFERON-TB Gold Plus and related products) and the T-SPOT.TB assay. The practical appeal of IGRA tests lies in a single blood draw and laboratory processing, in contrast to the Mantoux test, which requires a return visit to read the result.

IGRAs are part of a broader strategy to diagnose MTB infection and to guide decisions about preventive treatment in people at risk of tuberculosis progressing to active disease. They are not a substitute for clinical assessment, radiography, microbiological testing, or public health surveillance, but they are an important tool in targeted screening and in settings where skin testing is less reliable due to prior vaccination or cross-reactivity concerns. In populations where BCG vaccination is common, IGRAs can reduce false-positive results compared with the Mantoux test, which helps avoid unnecessary preventive therapy in individuals who are not truly infected. The tests are discussed in guidelines by major public health bodies and are used by clinics, hospitals, and occupational health programs that screen people at risk for MTB infectionCenters for Disease Control and Prevention and World Health Organization.

Mechanism and types

Interferon gamma release assays detect T cell responses to MTB-specific antigens not present in most BCG strains or in the majority of non-tuberculous mycobacteria. The antigens commonly used include substances like ESAT-6 and CFP-10, among others, which helps distinguish MTB infection from prior BCG vaccination or exposure to many environmental mycobacteria. See for example ESAT-6 and CFP-10 in the MTB literature.
The main commercial families are:
- QuantiFERON-TB Gold Plus (QFT-Plus) and related QuantiFERON assays, which use whole blood stimulated with MTB antigens and quantify the amount of interferon-gamma released.
- T-SPOT.TB (T-SPOT.TB), an enzyme-linked assay that enumerates individual reactive T cells producing interferon-gamma.
No test is perfect, and the choice between IGRA formats may depend on local laboratory capability, cost considerations, and population characteristics.

Performance and interpretation

A positive IGRA result suggests MTB infection but does not distinguish latent TB infection from active TB disease. Positive results are interpreted in the context of exposure history, risk factors, radiographic findings, and microbiologic testing. For latent TB infection, a positive IGRA supports treatment decisions to reduce progression to active TB.
A negative IGRA result does not completely rule out infection, particularly in the very early stage after exposure, in young children, or in people with immune suppression. In such cases, clinicians may consider repeat testing or alternative diagnostic approaches.
Indeterminate IGRA results can occur when the immune system fails to respond in the assay, often due to sample handling issues, low lymphocyte counts, or immunosuppressive states. Indeterminate results generally prompt repeat testing or assessment by alternative methods.
In serial testing, especially among healthcare workers, fluctuations in IGRA results can occur due to assay variability. Guidelines emphasize interpreting serial results cautiously and in the context of exposure history and risk.

Uses and indications

Latent TB infection (LTBI) screening: IGRAs are used to identify LTBI in adults and older children, particularly in individuals who have received BCG vaccination or who have had prior TST cross-reactions. See latent tuberculosis infection.
Targeted testing in high-risk groups: close contacts of people with active TB, immigrants from high-prevalence regions, people starting certain immunosuppressive therapies, and others with risk factors for progression to disease.
Active TB evaluation: while IGRA can support the assessment, it is not sufficient on its own to diagnose active TB. Microbiological confirmation (e.g., culture or molecular tests) and radiographic evaluation remain essential. See tuberculosis diagnosis for the diagnostic pathway.
Pediatric use: IGRA performance in young children is variable and guidelines differ by jurisdiction. Clinicians weigh age, risk of exposure, and feasibility when choosing testing strategies. See pediatric tuberculosis for age-specific considerations.

Advantages and limitations

Advantages:
- Higher specificity than the Mantoux test in BCG-vaccinated populations, reducing unnecessary treatment for those not truly infected.
- Single-visit testing with no need for a return visit to read a result.
- Not confounded by prior BCG vaccination in most cases.
Limitations:
- Requires laboratory infrastructure and timely blood processing, which can limit access in some settings.
- More expensive per test than the Mantoux test, though cost-effectiveness depends on population risk and vaccine practices.
- Sensitivity can be reduced in immunocompromised persons and in very young children, and results can be indeterminate.
- Cannot distinguish latent infection from active TB disease on its own and should be integrated with clinical evaluation.

Controversies and debates

Cost and resource allocation: Critics argue that the higher upfront cost and laboratory requirements of IGRA testing may not be justified in low TB prevalence settings or for broad population screening. Proponents contend that IGRA testing improves specificity, reduces overtreatment in BCG-vaccinated populations, and targets preventive therapy to those most likely to benefit. The balance between upfront costs and downstream savings remains a live policy question in many health systems.
Serial testing and variability: In groups requiring repeated testing (such as healthcare workers), IGRA results can fluctuate over time, leading to conversions or reversions that complicate decision-making. Some guidelines emphasize using a single approach consistently and interpreting changes with awareness of assay variability.
Sensitivity in special populations: In immunosuppressed individuals (for example, those on certain biologic therapies or with advanced HIV), IGRA sensitivity may be reduced, potentially missing true infections. Critics worry about reliance on a test that may under-detect infection in these groups, while supporters emphasize using the test as part of a broader diagnostic workup rather than in isolation.
Public health strategy and personal responsibility: Debates around how aggressively to pursue MTB testing reflect broader views on public health interventions, individual risk assessment, and the optimal mix of government programs, private-sector delivery, and clinician judgment. In jurisdictions with strong private health sectors, some stakeholders argue for targeted, focused testing rather than universal or broad-based screening, to align with principles of cost containment and personal accountability.

History and development

IGRAs emerged in the late 20th and early 21st centuries as laboratories sought assays that could bypass limitations of the Mantoux test, especially in BCG-vaccinated populations. The first commercially available IGRAs entered clinical use in the 2000s, with ongoing refinements in assay formats, antigen selection, and interpretation guidelines. The evolving body of evidence continues to shape recommendations by national health authorities and international organizations.