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IDCM Issue 1: Interferon Gamma Release Assays (IGRAs)
Natasha Chida, MD, MSPH
CCGHE is pleased to present ID Clinical Minute, by Dr. Natasha Chida. Issued monthly, ID Clinical Minute features evidence-based syntheses of clinical practice issues pertaining to the diagnosis, treatment, and management of infectious diseases, emerging infectious diseases, and disease outbreaks and epidemics as well as reviews of groundbreaking articles. It’s designed for both non-ID and ID practitioners, and is applicable to both the
Interferon Gamma Release Assays (IGRAs)
What is an IGRA? IGRAs are blood tests that measure the amount of interferon gamma released by a person’s T cells when exposed to TB antigens. There are 2 commercially available IGRAs: QuantiFERON®-TB Gold In-Tube (QFT) and TSPOT®.TB (TSTB).
What do IGRAs test?
Like the tuberculin skin test (TST), IGRAs are indirect tests that detect prior exposure to TB by testing the body’s immune response to TB antigens. They do not directly detect the Mycobacterium tuberculosis (MTB) bacillus and cannot differentiate between active and latent TB.1 As their positive predictive value depends on disease prevalence, they should only be used for latent TB testing in persons at risk. They cannot predict who is at risk for progressing from latent to active TB.
How should I interpret the results of an IGRA?
QFT reports results as positive, negative, or indeterminate.2 Positive means likely MTB infection (latent or active). Negative means unlikely MTB infection (latent or active). Indeterminate means uncertain likelihood of MTB—i.e., the test failed; no clinical information can be taken from this result. TSTB reports results as positive, borderline, negative, or indeterminate; these results are interpreted the same way.2 The only difference is the borderline category; these results means there is uncertain likelihood of MTB infection (latent or active).
Discordant results can occur between IGRAs and TSTs. As these tests have similar sensitivities, when discordance occurs there is no way to know which test result is correct. Do not use more than one test, except in special situations.
Do any other mycobacteria make IGRAs turn positive?
Mycobacterium marinum and Mycobacterium kansasii contain the same antigens as IGRAs; these infections will turn IGRAs positive.1
What should I use IGRAs for?
As the sensitivity of IGRAS is not high enough to rule out active TB, their use is primarily for diagnosing latent TB infection. In certain situations, IGRAs may contribute supplementary information as part of a work-up for TB, particularly in low-incidence settings, but they should only be used as adjunct tests.2 Guidance from the World Health Organization (WHO) recommends against using IGRAs or TST to diagnose active TB because of the reasons noted above.3
Many studies have assessed the sensitivity and specificity of IGRAs; results have varied but are similar:
Sensitivity: In one systematic review, QFT’s sensitivity in active TB was 70%; TSTB’s was 90%.4 In another review, the sensitivity of QFT in active TB was 76%, and for TSTB was 88%.5 Another review found QFT’s sensitivity in active TB was 80%, and TSTB’s was 81%.2 In patients with HIV infection in low and middle-income countries, the sensitivity if IGRAs in active TB was 61% for QFT and 72% for TSTB.6 This study found TSTB may be more sensitive than QFT in immune suppressed persons. In another study in persons with HIV and active TB, the pooled sensitivity of QFT and TSTB were 61% and 65%.7
Specificity: In one systematic review, the specificity for LTBI was 99-96% for QFT, and 93% for TSTB.4 Another review found the specificity of QFT for LTBI was 97.7% and 92.5% for TSTB.5 One study examining in HIV/TB co-infection found the specificity of QFT for active TB was 72%; TSTB was 70%.7
When testing for latent TB, are there times when I should use an IGRA instead of a TST?
Studies examining whether IGRAs or TSTs are more sensitive/specific vary. In countries where IGRAs are available, use an IGRA preferentially over TST if the person being tested for latent TB is unlikely to come back to have the TST read, or if the person being tested has received BCG.1 Otherwise, either can be used. In resource-constrained settings, the WHO recommends TST over IGRA because it is less costly and the 2 tests have comparable performance for diagnosing latent TB.3
Bottom Line: IGRAs are indirect tests that do NOT differentiate between active and latent TB. Do NOT use IGRAs to diagnose active TB.
We gratefully acknowledge Dr. Maunank Shah, Assistant Professor of Infectious Diseases, Johns Hopkins Medicine, for his thoughtful review of this work.
Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K; IGRA Expert Committee; Centers for Disease Control and Prevention (CDC). Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR. 2010 Jun 25;59(RR-5):1-25. PMID: 20577159.
European Centre for Disease Prevention and Control. Use of interferon-gamma release assays in support of TB diagnosis. Stockholm: ECDC;2011.
World Health Organization. Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-income countries: policy statement. World Health Organization Website. October 2011. Accessed January 13, 2016.
Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med. 2008 Aug 5;149(3):177-84. Epub 2008 Jun 30. PMID: 18593687.
Menzies D1, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med. 2007 Mar 6;146(5):340-54. PMID: 17339619.
Cattamanchi A1, Smith R, Steingart KR, Metcalfe JZ, Date A, Coleman C, Marston BJ, Huang L, Hopewell PC, Pai M.Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis. J Acquir Immune Defic Syndr. 2011;56(3):230. PMID: 21239993.
Santin M1, Muñoz L, Rigau D. Interferon-γ release assays for the diagnosis of tuberculosis and tuberculosis infection in HIV-infected adults: a systematic review and meta-analysis. PLoS One. 2012;7(3):e32482. PMID: 22403663.
The Johns Hopkins Center for Clinical Global Health Education is a clinical research, education, and leadership development center in the Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine. We conduct clinical research, and we train, support, and empower healthcare providers and researchers working in resource-limited communities who share our commitment to improve health outcomes.