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Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study

Whitworth, Hilary S.; Badhan, Amarjit; Boakye, Aime A.; Takwoingi, Yemisi; Rees-Roberts, Melanie; Partlett, Christopher; Lambie, Heather; Innes, John; Cooke, Graham; Lipman, Marc; Conlon, Christopher; Macallan, Derek; Chua, Felix; Post, Frank A.; Wiselka, Martin; Woltmann, Gerrit; Deeks, Jonathan J.; Kon, Onn Min; Lalvani, Ajit; Abdoyeku, David; Davidson, Robert; Dedicoat, Martin; Kunst, Heinke; Loebingher, Michael R.; Lynn, William; Nathani, Nazim; O'Connell, Rebecca; Pozniak, Anton; Menzies, Sarah


Hilary S. Whitworth

Amarjit Badhan

Aime A. Boakye

Yemisi Takwoingi

Melanie Rees-Roberts

Assistant Professor of Medical Statistics and Clinical Trials

Heather Lambie

John Innes

Graham Cooke

Marc Lipman

Christopher Conlon

Derek Macallan

Felix Chua

Frank A. Post

Martin Wiselka

Gerrit Woltmann

Jonathan J. Deeks

Onn Min Kon

Ajit Lalvani

David Abdoyeku

Robert Davidson

Martin Dedicoat

Heinke Kunst

Michael R. Loebingher

William Lynn

Nazim Nathani

Rebecca O'Connell

Anton Pozniak

Sarah Menzies


© 2019 Elsevier Ltd Background: The clinical utility of interferon-γ release assays (IGRAs) for diagnosis of active tuberculosis is unclear, although they are commonly used in countries with a low incidence of tuberculosis. We aimed to resolve this clinical uncertainty by determining the accuracy and utility of commercially available and second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in a low-incidence setting. Methods: We did a prospective cohort study of adults with suspected tuberculosis in routine secondary care in England. Patients were tested for Mycobacterium tuberculosis infection at baseline with commercially available (T-SPOT.TB and QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel M tuberculosis antigens) IGRAs and followed up for 6–12 months to establish definitive diagnoses. Sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests were determined. Findings: Of the 1060 adults enrolled in the study, 845 were included in the analyses and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis, including culture-confirmed and highly probable cases, was 81·4% (95% CI 76·6–85·3), which was higher than QFT-GIT (67·3% [62·0–72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0–96·4) for culture-confirmed tuberculosis and 89·2% (85·2–92·2) when including highly probable tuberculosis, giving a negative likelihood ratio for all tuberculosis cases of 0·13 (95% CI 0·10–0·19). Specificity ranged from 86·2% (95% CI 82·3–89·4) for T-SPOT.TB to 80·0% (75·6–83·8) for second-generation IGRAs. Interpretation: Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negative predictive value in low-incidence settings to facilitate prompt rule-out of tuberculosis. Funding: National Institute for Health Research.


Whitworth, H. S., Badhan, A., Boakye, A. A., Takwoingi, Y., Rees-Roberts, M., Partlett, C., …Menzies, S. (2019). Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study. Lancet Infectious Diseases, 19(2), 193-202.

Journal Article Type Article
Acceptance Date Oct 5, 2018
Online Publication Date Jan 14, 2019
Publication Date Feb 1, 2019
Deposit Date Apr 9, 2019
Publicly Available Date Jul 15, 2019
Journal The Lancet Infectious Diseases
Print ISSN 1473-3099
Electronic ISSN 1474-4457
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 19
Issue 2
Pages 193-202
Public URL
Publisher URL


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