Novel N Chegou1, Jayne S Sutherland2, Stephanus Malherbe1, Amelia C Crampin3, Paul L A M Corstjens4, Annemieke Geluk5, Harriet Mayanja-Kizza6, Andre G Loxton1, Gian van der Spuy1, Kim Stanley1, Leigh A Kotzé1, Marieta van der Vyver7, Ida Rosenkrands8, Martin Kidd9, Paul D van Helden1, Hazel M Dockrell10, Tom H M Ottenhoff5, Stefan H E Kaufmann11, Gerhard Walzl1. 1. 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, Cape Town, South Africa. 2. Vaccines and Immunity, Medical Research Council Unit, Fajara, The Gambia. 3. Karonga Prevention Study, Chilumba, Malawi. 4. Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands. 5. Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands. 6. Department of Medicine, Makerere University, Kampala, Uganda. 7. Faculty of Health Sciences, School of Medicine, University of Namibia, Windhoek, Namibia. 8. Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark. 9. Department of Statistics and Actuarial Sciences, Centre for Statistical Consultation, Stellenbosch University, Cape Town, South Africa. 10. Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK. 11. Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Anouk van Hooij; Debbie M Boeters; Elisa M Tjon Kon Fat; Susan J F van den Eeden; Paul L A M Corstjens; Annette H M van der Helm-van Mil; Annemieke Geluk Journal: Clin Vaccine Immunol Date: 2017-08-04
Authors: Ruvandhi R Nathavitharana; Christina Yoon; Peter Macpherson; David W Dowdy; Adithya Cattamanchi; Akos Somoskovi; Tobias Broger; Tom H M Ottenhoff; Nimalan Arinaminpathy; Knut Lonnroth; Klaus Reither; Frank Cobelens; Christopher Gilpin; Claudia M Denkinger; Samuel G Schumacher Journal: J Infect Dis Date: 2019-10-08 Impact factor: 5.226
Authors: Portia M Manngo; Andrea Gutschmidt; Candice I Snyders; Hygon Mutavhatsindi; Charles M Manyelo; Nonjabulo S Makhoba; Petri Ahlers; Andriette Hiemstra; Kim Stanley; Shirley McAnda; Martin Kidd; Stephanus T Malherbe; Gerhard Walzl; Novel N Chegou Journal: J Infect Date: 2019-07-15 Impact factor: 6.072
Authors: Harriet N Garlant; Kalaiarasan Ellappan; Matthew Hewitt; Prem Perumal; Simon Pekeleke; Nadina Wand; Jo Southern; Saka Vinod Kumar; Harish Belgode; Ibrahim Abubakar; Sanjeev Sinha; Seshadri Vasan; Noyal Mariya Joseph; Karen E Kempsell Journal: Front Immunol Date: 2022-05-20 Impact factor: 8.786
Authors: Artur T L Queiroz; Mariana Araújo-Pereira; Beatriz Barreto-Duarte; Adriano Gomes-Silva; Allyson G Costa; Alice M S Andrade; João Pedro Miguez-Pinto; Renata Spener-Gomes; Alexandra B Souza; Aline Benjamin; Flavia Sant'Anna; Marina C Figueiredo; Vidya Mave; Padmini Salgame; Jerrold J Ellner; Timothy R Sterling; Marcelo Cordeiro-Dos-Santos; Bruno B Andrade; Valeria C Rolla Journal: Front Immunol Date: 2022-06-10 Impact factor: 8.786