Interferon-Gamma Release Assays in Tuberculosis Diagnosis

Interferon-gamma release assays (IGRAs) have emerged as pivotal immunodiagnostic tools for the detection of Mycobacterium tuberculosis infection. By measuring interferon-gamma released by sensitised T lymphocytes in response to specific M. tuberculosis antigens, IGRAs overcome many limitations of the traditional tuberculin skin test, notably cross-reactivity with Bacillus Calmette–Guérin vaccination and environmental mycobacteria. Two commercial formats predominate: an enzyme-linked immunosorbent assay that quantifies interferon-gamma in whole blood and an enzyme-linked immunospot assay that enumerates individual cytokine-secreting cells. IGRAs are routinely employed to screen high-risk groups, guide preventive therapy in latent infection and support the evaluation of active disease when microbiological confirmation is lacking. However, sensitivity may be reduced in immunocompromised hosts, young children and individuals with advanced age or lymphocytopenia, leading to indeterminate or false-negative outcomes. Operational enhancements such as optimising antigen panels, re-examination of control wells and integration with machine-learning algorithms promise to refine assay accuracy. Globally, IGRAs contribute to targeted case finding, reduce overtreatment and inform public health strategies aimed at tuberculosis elimination.

Research from Nature Portfolio

Recent systematic analyses have identified key host factors associated with false-negative IGRA results. Advanced age and low peripheral lymphocyte counts were consistently implicated across diverse epidemiological settings, emphasising the need for cautious interpretation in elderly or immunosuppressed patients. Risk stratification frameworks now incorporate these variables to guide follow-up testing and clinical decision-making. In parallel, comparative evaluations of next-generation interferon-gamma assays have demonstrated that the new-generation whole-blood test maintains diagnostic accuracy equivalent to its predecessor despite a reduced antigen repertoire. Optimisation of the assay cut-off improved sensitivity in older subjects without compromising specificity. These studies collectively underscore the importance of assay calibration and patient-centred thresholds to enhance detection of both latent and active tuberculosis.

Interferon-Gamma Release Assays in Tuberculosis Diagnosis publication trend

The graph below shows the total number of articles in interferon-gamma release assays in tuberculosis diagnosis across all publications each year (not limited to Nature Index journals).

Technical terms

Interferon-gamma release assay (IGRA): An immunological test measuring interferon-gamma released by T cells after stimulation with M. tuberculosis–specific antigens.

QuantiFERON-TB Gold Plus (QFT-Plus): A whole-blood IGRA platform that quantifies interferon-gamma using two antigen tubes and controls.

T-SPOT.TB: An enzyme-linked immunospot-based IGRA that counts individual T cells secreting interferon-gamma in response to M. tuberculosis antigens.

Nil tube: A control tube in IGRA assays containing no antigen, used to assess background interferon-gamma levels.

Mitogen tube: A positive control tube containing a nonspecific mitogenic stimulus, used to verify T-cell functionality.

Latent tuberculosis infection (LTBI): A state in which M. tuberculosis resides in the host without causing active disease symptoms.

Active tuberculosis (ATB): Clinical disease resulting from replicating M. tuberculosis, typically accompanied by symptoms and transmissibility.

References

1. From immunology to artificial intelligence: revolutionizing latent tuberculosis infection diagnosis with machine learning. Military Medical Research (2023).
2. Plasma immune profiling combined with machine learning contributes to diagnosis and prognosis of active pulmonary tuberculosis. Emerging Microbes & Infections (2024).
3. Antigen-specific chemokine profiles as biomarkers for detecting Mycobacterium tuberculosis infection. Frontiers in Immunology (2024).
4. Enhancing the interferon-γ release assay through omission of nil and mitogen values. Respiratory Research (2023).
5. Evaluation of QuantiFERON-TB Gold Plus for Detection of Mycobacterium tuberculosis infection in Japan. Scientific Reports (2016).
6. Factors associated with false negative interferon-γ release assay results in patients with tuberculosis: A systematic review with meta-analysis. Scientific Reports (2020).
7. A borderline range for Quantiferon Gold In-Tube results. PLOS ONE (2017).