Hilary S Whitworth1, Amarjit Badhan2, Aime A Boakye2, Yemisi Takwoingi3, Melanie Rees-Roberts4, Christopher Partlett3, Heather Lambie5, John Innes6, Graham Cooke7, Marc Lipman8, Christopher Conlon9, Derek Macallan10, Felix Chua11, Frank A Post12, Martin Wiselka13, Gerrit Woltmann14, Jonathan J Deeks3, Onn Min Kon2, Ajit Lalvani15. 1. Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK; Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK. 2. Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK; National Institute for Health Research Health Protection Research Unit in Respiratory Infections, Imperial College London, London, UK. 3. Institute of Applied Health Research, University of Birmingham, Birmingham, UK. 4. Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK; National Institute for Health Research Health Protection Research Unit in Respiratory Infections, Imperial College London, London, UK; Centre for Health Services Studies, University of Kent, Canterbury, UK. 5. Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK. 6. Heart of England National Health Service (NHS) Foundation Trust, Birmingham, UK. 7. Department of Infectious Diseases, St Mary's Hospital, Imperial College Healthcare Trust, London, UK. 8. Department of Respiratory Medicine, Royal Free London NHS Foundation Trust, London, UK; University College London Respiratory, Division of Medicine, University College London, London, UK. 9. Nuffield Department of Medicine, Oxford University Hospitals NHS Trust, Oxford, UK. 10. Infection Care Group, St George's University Hospitals NHS Foundation Trust, London, UK; Institute of Infection and Immunity, St George's, University of London, London, UK. 11. Department of Respiratory Medicine, St George's University Hospitals NHS Foundation Trust, London, UK. 12. Department of Sexual Health and HIV, King's College Hospital NHS Foundation Trust, London, UK. 13. Department of Infection and Tropical Medicine, University Hospitals of Leicester NHS Trust, Leicester, UK. 14. Department of Infection, Immunity and Inflammation, Respiratory Biomedical Research Centre, Institute for Lung Health, University of Leicester, Leicester, UK. 15. Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK; National Institute for Health Research Health Protection Research Unit in Respiratory Infections, Imperial College London, London, UK. Electronic address: a.lalvani@imperial.ac.uk.
Abstract
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.
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.
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