Improved Diagnostic Evaluation of Suspected Tuberculosis

  1. Davinder P.S. Dosanjh, DPhil;
  2. Timothy S.C. Hinks, MD;
  3. John A. Innes, MD;
  4. Jonathan J. Deeks, PhD;
  5. Geoffrey Pasvol, DPhil;
  6. Sarah Hackforth, RGN;
  7. Hansa Varia, RGN;
  8. Kerry A. Millington, DPhil;
  9. Rubamalar Gunatheesan, MD;
  10. Valerie Guyot-Revol, PhD; and
  11. Ajit Lalvani, DM
  1. From Tuberculosis Immunology Group, Imperial College London, London; University of Oxford, Oxford; Birmingham Heartlands Hospital and University of Birmingham, Birmingham; and Northwick Park Hospital, Harrow, United Kingdom.

    Abstract

    Background: The role of new T-cell–based blood tests for tuberculosis in the diagnosis of active tuberculosis is unclear.

    Objective: To compare the performance of 2 interferon-γ assays and tuberculin skin testing in adults with suspected tuberculosis.

    Design: Prospective study conducted in routine practice.

    Setting: 2 urban hospitals in the United Kingdom.

    Patients: 389 adults, predominantly of South Asian and black ethnicity, with moderate to high clinical suspicion of active tuberculosis.

    Intervention: Tuberculin skin testing, the enzyme-linked immunospot assay (ELISpot) incorporating early secretory antigenic target-6 and culture filtrate protein-10 (standard ELISpot), and ELISpot incorporating a novel antigen, Rv3879c (ELISpotPLUS) were performed during diagnostic assessment by independent persons who were blinded to results of the other test.

    Measurements: Sensitivity, specificity, predictive values, and likelihood ratios.

    Results: 194 patients had a final diagnosis of active tuberculosis, of which 79% were culture-confirmed. Sensitivity for culture confirmed and highly probable tuberculosis was 89% (95% CI, 84% to 93%) with ELISpotPLUS, 85% (CI, 79% to 90%) with standard ELISpot, 79% (CI, 72% to 85%) with 15-mm threshold tuberculin skin testing, and 83% (CI, 77% to 89%) with stratified thresholds of 15 and 10 mm in vaccinated and unvaccinated patients, respectively. The ELISpotPLUS assay was more sensitive than tuberculin skin testing with 15-mm cutoff points (P = 0.01) but not with stratified cutoff points (P = 0.10). The ELISpotPLUS assay had 4% higher diagnostic sensitivity than standard ELISpot (P = 0.02). Combined sensitivity of ELISpotPLUS and tuberculin skin testing was 99% (CI, 95% to 100%), conferring a negative likelihood ratio of 0.02 (CI, 0 to 0.06) when both test results were negative.

    Limitations: Local standards for tuberculin skin testing differed from others used internationally. The study sample included few immunosuppressed patients.

    Conclusion: The ELISpotPLUS assay is more sensitive than standard ELISpot and, when used in combination with tuberculin skin testing, enables rapid exclusion of active infection in patients with moderate to high pretest probability of tuberculosis.

    Article and Author Information

    • Note: Drs. Dosanjh and Hinks contributed equally to this work.

    • Acknowledgment: The authors thank the study participants; Sarah Gooding, for collection and processing of some samples; and Muhunthan Thillai, for critical appraisal and revision of the final manuscript.

    • Grant Support: By the Wellcome Trust (Dr. Lalvani is a Wellcome Senior Research Fellow in Clinical Science), the Sir Halley Stewart Trust (Dr. Dosanjh's studentship), a Wellcome Trust PhD Prize Studentship (Dr. Millington), and a United Kingdom Department of Health Senior Fellowship in Evidence Synthesis (Dr. Deeks).

    • Potential Financial Conflicts of Interest:Consultancies: A. Lalvani (Oxford Immunotec Ltd. [nonexecutive director from 2003 to 2007]). Honoraria: G. Pasvol (Transactions of the Royal Society of Tropical Medicine). Stock ownership or options (other than mutual funds): D.P.S. Dosanjh (Oxford Immunotec Ltd.), A Lalvani (Oxford Immunotec Ltd.), University of Oxford (Oxford Immunotech Ltd.). Patents received: A. Lalvani (T-cell–based diagnosis of tuberculous infection), University of Oxford (T-cell–based diagnosis of tuberculous infection). Patents pending: D.P.S. Dosanjh (T-cell–based diagnosis of tuberculous infection), A. Lalvani (T-cell–based diagnosis of tuberculous infection, University of Oxford (T-cell–based diagnosis of tuberculous infection).

    • Reproducible Research Statement: The analytic data set of all participants' diagnoses, tuberculin skin test results, ELISpot results, and ELISpotPLUS results can be made available to academic investigators on request by written agreement.

    • Requests for Single Reprints: Ajit Lalvani, DM, Tuberculosis Immunology Group, Department of Respiratory Medicine, Faculty of Medicine, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom; e-mail, a.lalvani{at}imperial.ac.uk.

    • Current Author Addresses: Dr. Dosanjh: University of Oxford Medical School, William Osler House, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.

    • Dr. Hinks: Allergy, Inflammation, and Repair Group, Level D, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.

    • Dr. Innes and Ms. Hackforth: Department of Infection & Tropical Medicine, Birmingham Heartlands Hospital, Bordsley Green East, Birmingham B9 5SS, United Kingdom.

    • Dr. Deeks: Department of Public Health and Epidemiology, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

    • Dr. Pasvol and Ms. Varia: Department of Infection and Tropical Medicine, Northwick Park Hospital, Imperial College London, Watford Road, Harrow HA1 3UJ, United Kingdom.

    • Drs. Millington and Lalvani: Department of Respiratory Medicine, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom.

    • Dr. Gunatheesan: University of Melbourne Medical School, Melbourne, Australia.

    • Dr. Guyot-Revol: Genopoietic, 1390 rue Centrale-Beynost, 01708 Miribel Cedex, France.

    • Author Contributions: Conception and design: J.A. Innes, A. Lalvani. Analysis and interpretation of the data: D.P.S. Dosanjh, T.S.C. Hinks, J.J. Deeks, K.A. Millington, A. Lalvani.

    • Drafting of the article: D.P.S. Dosanjh, T.S.C. Hinks, G. Pasvol, A. Lalvani.

    • Critical revision of the article for important intellectual content: D.P.S. Dosanjh, T.S.C. Hinks, J.A. Innes, J.J. Deeks, G. Pasvol, K.A. Millington, A. Lalvani.

    • Final approval of the article: D.P.S. Dosanjh, J.J. Deeks, G. Pasvol, V. Guyot-Revol, A. Lalvani.

    • Provision of study materials or patients: J.A. Innes, G. Pasvol, S. Hackforth, H. Varia, A. Lalvani.

    • Statistical expertise: D.P.S. Dosanjh, J.J. Deeks.

    • Obtaining of funding: A Lalvani.

    • Administrative, technical, or logistic support: D.P.S. Dosanjh, G. Pasvol, S. Hackforth, K.A. Millington, A. Lalvani.

    • Collection and assembly of data: D.P.S. Dosanjh, T.S.C. Hinks, S. Hackforth, K.A. Millington, V. Guyot-Revol.

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    1. Ann Intern Med March 4, 2008 vol. 148 no. 5 325-336
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