Marc Tebruegge1,2,3,4, Binita Dutta3, Susan Donath1,5,3, Nicole Ritz1,2,3,6, Benjamin Forbes3, Kattia Camacho-Badilla2, Vanessa Clifford1,3, Christel Zufferey3, Roy Robins-Browne1,7,3, Willem Hanekom8, Stephen M Graham1,3,9, Tom Connell1,2,3, Nigel Curtis1,2,3. 1. 1 Department of Paediatrics and. 2. 2 Infectious Diseases Unit and. 3. 3 Murdoch Children's Research Institute, Parkville, Victoria, Australia. 4. 4 Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. 5. 5 Clinical Epidemiology and Biostatistics Unit, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia. 6. 6 Infectious Diseases Unit, University Children's Hospital Basel, Basel, Switzerland. 7. 7 Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia. 8. 8 Institute of Infectious Diseases and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa; and. 9. 9 Centre for International Child Health, Parkville, Victoria, Australia.
Abstract
RATIONALE: Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-γ release assay (IGRA), have significant limitations, which include their inability to distinguish between latent TB infection (LTBI) and active TB, a distinction critical for clinical management. OBJECTIVES: To identify mycobacteria-specific cytokine biomarkers that characterize TB infection, determine their diagnostic performance characteristics, and establish whether these biomarkers can distinguish between LTBI and active TB. METHODS: A total of 149 children investigated for TB infection were recruited; all participants underwent a tuberculin skin test and QuantiFERON-TB Gold assay. In parallel, whole-blood assays using early secretory antigenic target-6, culture filtrate protein-10, and PPD as stimulatory antigens were undertaken, and cytokine responses were determined by xMAP multiplex assays. MEASUREMENTS AND MAIN RESULTS: IFN-γ, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-α, IL-1ra, IL-2, IL-13, and MIP-1β (macrophage inflammatory protein-1β) responses were significantly higher in LTBI and active TB cases than in TB-uninfected individuals, irrespective of the stimulant. Receiver operating characteristic analyses showed that IP-10, TNF-α, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-α, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-α/IL-1ra and TNF-α/IL-10 achieved correct classification of 95.5% and 100% of cases, respectively. CONCLUSIONS: We identified several mycobacteria-specific cytokine biomarkers with the potential to be exploited for immunodiagnosis. Incorporation of these biomarkers into future immunodiagnostic assays for TB could result in substantial gains in sensitivity and allow the distinction between LTBI and active TB based on a blood test alone.
RATIONALE: Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-γ release assay (IGRA), have significant limitations, which include their inability to distinguish between latent TB infection (LTBI) and active TB, a distinction critical for clinical management. OBJECTIVES: To identify mycobacteria-specific cytokine biomarkers that characterize TB infection, determine their diagnostic performance characteristics, and establish whether these biomarkers can distinguish between LTBI and active TB. METHODS: A total of 149 children investigated for TB infection were recruited; all participants underwent a tuberculin skin test and QuantiFERON-TB Gold assay. In parallel, whole-blood assays using early secretory antigenic target-6, culture filtrate protein-10, and PPD as stimulatory antigens were undertaken, and cytokine responses were determined by xMAP multiplex assays. MEASUREMENTS AND MAIN RESULTS: IFN-γ, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-α, IL-1ra, IL-2, IL-13, and MIP-1β (macrophage inflammatory protein-1β) responses were significantly higher in LTBI and active TB cases than in TB-uninfected individuals, irrespective of the stimulant. Receiver operating characteristic analyses showed that IP-10, TNF-α, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-α, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-α/IL-1ra and TNF-α/IL-10 achieved correct classification of 95.5% and 100% of cases, respectively. CONCLUSIONS: We identified several mycobacteria-specific cytokine biomarkers with the potential to be exploited for immunodiagnosis. Incorporation of these biomarkers into future immunodiagnostic assays for TB could result in substantial gains in sensitivity and allow the distinction between LTBI and active TB based on a blood test alone.
Authors: Edward Barton; Yifang Gao; Darran Ball; Katy Fidler; Nigel Klein; Nigel Curtis; Vanessa Clifford; Ben G Marshall; Andrew Chancellor; Salah Mansour; Paul Elkington; Marc Tebruegge Journal: Ann Am Thorac Soc Date: 2019-06
Authors: Christian Lundtoft; Anthony Afum-Adjei Awuah; Norman Nausch; Anthony Enimil; Ertan Mayatepek; Ellis Owusu-Dabo; Marc Jacobsen Journal: Med Microbiol Immunol Date: 2017-03-15 Impact factor: 3.402
Authors: Bryan Vonasek; Tara Ness; Yemisi Takwoingi; Alexander W Kay; Susanna S van Wyk; Lara Ouellette; Ben J Marais; Karen R Steingart; Anna M Mandalakas Journal: Cochrane Database Syst Rev Date: 2021-06-28