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Diagnostic performance of a seven-marker serum protein biosignature for the diagnosis of active TB disease in African primary healthcare clinic attendees with signs and symptoms suggestive of TB
  1. Novel N Chegou1,
  2. Jayne S Sutherland2,
  3. Stephanus Malherbe1,
  4. Amelia C Crampin3,
  5. Paul L A M Corstjens4,
  6. Annemieke Geluk5,
  7. Harriet Mayanja-Kizza6,
  8. Andre G Loxton1,
  9. Gian van der Spuy1,
  10. Kim Stanley1,
  11. Leigh A Kotzé1,
  12. Marieta van der Vyver7,
  13. Ida Rosenkrands8,
  14. Martin Kidd9,
  15. Paul D van Helden1,
  16. Hazel M Dockrell10,
  17. Tom H M Ottenhoff5,
  18. Stefan H E Kaufmann11,
  19. Gerhard Walzl1
  20. on behalf of the AE-TBC consortium
    1. 1Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa
    2. 2Vaccines and Immunity, Medical Research Council Unit, Fajara, The Gambia
    3. 3Karonga Prevention Study, Chilumba, Malawi
    4. 4Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands
    5. 5Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands
    6. 6Department of Medicine, Makerere University, Kampala, Uganda
    7. 7Faculty of Health Sciences, School of Medicine, University of Namibia, Windhoek, Namibia
    8. 8Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark
    9. 9Department of Statistics and Actuarial Sciences, Centre for Statistical Consultation, Stellenbosch University, Cape Town, South Africa
    10. 10Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK
    11. 11Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
    1. Correspondence to Dr Novel N Chegou, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, P. O. Box 241, Cape Town 8000, South Africa; novel{at}sun.ac.za/novel01{at}gmail.com

    Abstract

    Background User-friendly, rapid, inexpensive yet accurate TB diagnostic tools are urgently needed at points of care in resource-limited settings. We investigated host biomarkers detected in serum samples obtained from adults with signs and symptoms suggestive of TB at primary healthcare clinics in five African countries (Malawi, Namibia, South Africa, The Gambia and Uganda), for the diagnosis of TB disease.

    Methods We prospectively enrolled individuals presenting with symptoms warranting investigation for pulmonary TB, prior to assessment for TB disease. We evaluated 22 host protein biomarkers in stored serum samples using a multiplex cytokine platform. Using a pre-established diagnostic algorithm comprising of laboratory, clinical and radiological findings, participants were classified as either definite TB, probable TB, questionable TB status or non-pulmonary TB.

    Results Of the 716 participants enrolled, 185 were definite and 29 were probable TB cases, 6 had questionable TB disease status, whereas 487 had no evidence of TB. A seven-marker biosignature of C reactive protein, transthyretin, IFN-γ, complement factor H, apolipoprotein-A1, inducible protein 10 and serum amyloid A identified on a training sample set (n=491), diagnosed TB disease in the test set (n=210) with sensitivity of 93.8% (95% CI 84.0% to 98.0%), specificity of 73.3% (95% CI 65.2% to 80.1%), and positive and negative predictive values of 60.6% (95% CI 50.3% to 70.1%) and 96.4% (95% CI 90.5% to 98.8%), respectively, regardless of HIV infection status or study site.

    Conclusions We have identified a seven-marker host serum protein biosignature for the diagnosis of TB disease irrespective of HIV infection status or ethnicity in Africa. These results hold promise for the development of a field-friendly point-of-care screening test for pulmonary TB.

    • Tuberculosis

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