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Mycobacteria-specific cytokine responses detect tuberculosis infection and distinguish latent from active tuberculosis

Mycobacteria-specific cytokine responses detect tuberculosis infection and distinguish latent from active tuberculosis
Mycobacteria-specific cytokine responses detect tuberculosis infection and distinguish latent from active tuberculosis
RATIONALE: Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-? 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-?, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-?, IL-1ra, IL-2, IL-13, and MIP-1? (macrophage inflammatory protein-1?) 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-?, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-?, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-?/IL-1ra and TNF-?/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.
tuberculosis, child, diagnosis, cytokines, biomarker
1073-449X
485-499
Tebruegge, Marc
2c3dff22-0b5f-48a7-bb36-ce323705f74a
Dutta, Binita
0621b33e-ae04-427c-ac38-ab40db51174a
Donath, Susan
b1bb69fe-e708-4ec5-b98a-6bdab36e71b1
Ritz, Nicole
ce6604a1-f373-4d76-838a-1ae75f35b20b
Forbes, Benjamin
5a92eda9-33a1-4038-aaed-58ff19b936e4
Camacho-Badilla, Kattia
43e5e267-35fe-41c8-8848-2128b5b1cb6f
Clifford, Vanessa
bf6063da-16e9-4b72-b4e7-ba2582ac3eb5
Zufferey, Christel
5df305e6-0080-4e35-9c70-5fd8006b4740
Robins-Browne, Roy
fa592da6-9054-499a-b0bc-1ce11dda8b5c
Hanekom, Willem
c9ec155b-a8ad-49a2-baf2-f8996b43baf9
Graham, Stephen
6cef519d-25a3-4063-8a0d-0175d10851ac
Connell, Tom
7c1afb37-45bd-44a3-a274-20839e68f2c3
Curtis, Nigel
60e08f70-7ce9-42b3-8074-d5df55131b12
Tebruegge, Marc
2c3dff22-0b5f-48a7-bb36-ce323705f74a
Dutta, Binita
0621b33e-ae04-427c-ac38-ab40db51174a
Donath, Susan
b1bb69fe-e708-4ec5-b98a-6bdab36e71b1
Ritz, Nicole
ce6604a1-f373-4d76-838a-1ae75f35b20b
Forbes, Benjamin
5a92eda9-33a1-4038-aaed-58ff19b936e4
Camacho-Badilla, Kattia
43e5e267-35fe-41c8-8848-2128b5b1cb6f
Clifford, Vanessa
bf6063da-16e9-4b72-b4e7-ba2582ac3eb5
Zufferey, Christel
5df305e6-0080-4e35-9c70-5fd8006b4740
Robins-Browne, Roy
fa592da6-9054-499a-b0bc-1ce11dda8b5c
Hanekom, Willem
c9ec155b-a8ad-49a2-baf2-f8996b43baf9
Graham, Stephen
6cef519d-25a3-4063-8a0d-0175d10851ac
Connell, Tom
7c1afb37-45bd-44a3-a274-20839e68f2c3
Curtis, Nigel
60e08f70-7ce9-42b3-8074-d5df55131b12

Tebruegge, Marc, Dutta, Binita, Donath, Susan, Ritz, Nicole, Forbes, Benjamin, Camacho-Badilla, Kattia, Clifford, Vanessa, Zufferey, Christel, Robins-Browne, Roy, Hanekom, Willem, Graham, Stephen, Connell, Tom and Curtis, Nigel (2015) Mycobacteria-specific cytokine responses detect tuberculosis infection and distinguish latent from active tuberculosis. American Journal of Respiratory and Critical Care Medicine, 192 (4), 485-499. (doi:10.1164/rccm.201501-0059OC). (PMID:26030187)

Record type: Article

Abstract

RATIONALE: Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-? 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-?, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-?, IL-1ra, IL-2, IL-13, and MIP-1? (macrophage inflammatory protein-1?) 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-?, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-?, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-?/IL-1ra and TNF-?/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.

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Tebruegge et al - AJRCCM 2015 - accepted manuscript - Mycobacteria-specific cytokine responses detect TB infection and distinguish LTBI from active TB.pdf - Accepted Manuscript
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Accepted/In Press date: 27 May 2015
Published date: 15 August 2015
Keywords: tuberculosis, child, diagnosis, cytokines, biomarker
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 386360
URI: https://eprints.soton.ac.uk/id/eprint/386360
ISSN: 1073-449X
PURE UUID: e6ad2341-9cea-4c35-b173-5813e0aa6d1e

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Date deposited: 01 Feb 2016 10:14
Last modified: 17 Jul 2017 19:50

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Contributors

Author: Marc Tebruegge
Author: Binita Dutta
Author: Susan Donath
Author: Nicole Ritz
Author: Benjamin Forbes
Author: Kattia Camacho-Badilla
Author: Vanessa Clifford
Author: Christel Zufferey
Author: Roy Robins-Browne
Author: Willem Hanekom
Author: Stephen Graham
Author: Tom Connell
Author: Nigel Curtis

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