Madhukar Pai, MD, PhD; Alice Zwerling, MSc; Dick Menzies, MD, MSc
Grant Support: By the Canadian Institutes of Health Research (grant MOP-81362). Dr. Pai is a recipient of a New Investigator Career Award from the Canadian Institutes of Health Research. Dr. Menzies is a recipient of a career award from the Fonds de la recherche en santé du Québec.
Potential Financial Conflicts of Interest:Other: Dr. Pai serves as an external consultant for the Foundation for Innovative New Diagnostics, Geneva, a nonprofit agency that collaborates with several industry partners, including Cellestis, Carnegie, Australia, for the development of new diagnostics for neglected infectious diseases. No industry partner was involved in the preparation of this manuscript.
Corresponding Author: Madhukar Pai, MD, PhD, Department of Epidemiology, Biostatistics & Occupational Health, McGill University, 1020 Pine Avenue West, Montreal, Quebec H3A 1A2, Canada; e-mail, email@example.com.
Current Author Addresses: Dr. Pai: Department of Epidemiology, Biostatistics & Occupational Health, McGill University, 1020 Pine Avenue West, Montreal, Quebec H3A 1A2, Canada.
Ms. Zwerling and Dr. Menzies: Montreal Chest Institute, 3650 St. Urbain Street, Montreal, Quebec H2X 2P4, Canada.
Interferon-γ–release assays (IGRAs) are alternatives to the tuberculin skin test (TST). A recent meta-analysis showed that IGRAs have high specificity, even among populations that have received bacille Calmette–Guérin (BCG) vaccination. Sensitivity was suboptimal for TST and IGRAs.
To incorporate newly reported evidence from 20 studies into an updated meta-analysis on the sensitivity and specificity of IGRAs.
PubMed was searched through 31 March 2008, and citations of all original articles, guidelines, and reviews for studies published in English were reviewed.
Studies that evaluated QuantiFERON-TB Gold, QuantiFERON-TB Gold In-Tube (both from Cellestis, Victoria, Australia), and T-SPOT.TB (Oxford Immunotec, Oxford, United Kingdom) or its precommercial ELISpot version, when data on the commercial version were lacking. For assessing sensitivity, the study sample had to have microbiologically confirmed active tuberculosis. For assessing specificity, the sample had to comprise healthy, low-risk individuals without known exposure to tuberculosis. Studies with fewer than 10 participants and those that included only immunocompromised participants were excluded.
One reviewer abstracted data on participant characteristics, test characteristics, and test performance from 38 studies; these data were double-checked by a second reviewer. The original investigators were contacted for additional information when necessary.
A fixed-effects meta-analysis with correction for overdispersion was done to pool data within prespecified subgroups. The pooled sensitivity was 78% (95% CI, 73% to 82%) for QuantiFERON-TB Gold, 70% (CI, 63% to 78%) for QuantiFERON-TB Gold In-Tube, and 90% (CI, 86% to 93%) for T-SPOT.TB. The pooled specificity for both QuantiFERON tests was 99% among non–BCG-vaccinated participants (CI, 98% to 100%) and 96% (CI, 94% to 98%) among BCG-vaccinated participants. The pooled specificity of T-SPOT.TB (including its precommercial ELISpot version) was 93% (CI, 86% to 100%). Tuberculin skin test results were heterogeneous, but specificity in non–BCG-vaccinated participants was consistently high (97% [CI, 95% to 99%]).
Most studies were small and had limitations, including no gold standard for diagnosing latent tuberculosis and variable TST methods and cutoff values. Data on the specificity of the commercial T-SPOT.TB assay were limited.
The IGRAs, especially QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube, have excellent specificity that is unaffected by BCG vaccination. Tuberculin skin test specificity is high in non–BCG-vaccinated populations but low and variable in BCG-vaccinated populations. Sensitivity of IGRAs and TST is not consistent across tests and populations, but T-SPOT.TB appears to be more sensitive than both QuantiFERON tests and TST.
Tuberculin skin tests (TSTs) and new interferon-γ–release assays (IGRAs) are alternative tests for detecting latent tuberculosis.
This updated meta-analysis of 38 studies found that sensitivity of IGRAs and TST was not consistent across tests and populations, but TSPOT.TB seemed to be more sensitive than QuantiFERON tests and TST. Both the TST and IGRAs had high specificity (>95%) for tuberculosis in populations not vaccinated with bacille Calmette–Guérin (BCG). The specificity of IGRAs was also high in populations vaccinated with BCG, whereas TST specificity was low and highly variable.
The studies had many limitations, including small sample sizes and no reference standard test for diagnosing latent tuberculosis.
The specificity of IGRAs for detecting latent tuberculosis is good and seems unaffected by BCG vaccination status.
Appendix Table 1. Sensitivity of QuantiFERON-TB Gold (QFT) among Patients with Active Tuberculosis (TB)
Appendix Table 2. Sensitivity of T-SPOT.TB among Patients with Active Tuberculosis (TB)
Appenix Table 3. Specificity of QuantiFERON-TB Gold (QFT) in Bacille Calmette–Guérin (BCG)–Vaccinated and Non–BCG-Vaccinated Patients with an Expected Low Prevalence of Tuberculous Infection*
Appendix Table 4. Specificity of Enzyme-Linked Immunospot (ELISpot) and T-SPOT.TB in Bacille Calmette–Guérin (BCG)–Vaccinated and Non–BCG-Vaccinated Participants with an Expected Low Prevalence of Tuberculous Infection*
Forest plot of studies estimating sensitivity of interferon-γ–release assays in patients with active tuberculosis as a surrogate for latent tuberculous infection.
Point estimates for sensitivity and 95% CIs are shown along with pooled estimates. Top. QuantiFERON-TB Gold (16 studies). Middle. QuantiFERON-TB Gold In-Tube (6 studies). Bottom. T-SPOT.TB (13 studies).
Appendix Table 5. Head-to-Head Comparisons of Sensitivity of QuantiFERON-TB (QFT) Gold versus T-SPOT.TB among Patients with Active Tuberculosis (TB)
Forest plot of studies estimating specificity of interferon-γ–release assays in populations at very low risk for latent tuberculous infection.
Point estimates for specificity and 95% CIs are shown along with pooled estimates. Top. QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube (braille Calmette–Guérin [BCG] nonvaccinated; 8 studies). Middle. QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube (BCG vaccinated; 8 studies). Bottom. T-SPOT.TB (predominantly BCG vaccinated; 6 studies).
Forest plot of studies estimating sensitivity and specificity of the tuberculin skin test.
Point estimates for sensitivity and specificity and 95% CIs are shown along with pooled estimates. Top. Sensitivity (20 studies). Middle. Specificity in non–bacille Calmette–Guérin-vaccinated populations (6 studies). Bottom. Specificity in bacille Calmette–Guérin-vaccinated populations (6 studies).
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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;149:177–184. doi: https://doi.org/10.7326/0003-4819-149-3-200808050-00241
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Published: Ann Intern Med. 2008;149(3):177-184.
Infectious Disease, Mycobacterial Infections, Prevention/Screening.
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