Evaluation of cytokine responses against novel Mtb antigens as diagnostic markers for TB disease - 08/08/16

Doi : 10.1016/j.jinf.2016.04.036

Dolapo O. Awoniyi ^a, Andrea Teuchert ^a, Jayne S. Sutherland ^b, Harriet Mayanja-Kizza ^c, Rawleigh Howe ^d, Adane Mihret ^d, Andre G. Loxton ^a, Jacob Sheehama ^e, Desta Kassa ^f, Amelia C. Crampin ^g,^h, Hazel M. Dockrell ^h, Martin Kidd ⁱ, Ida Rosenkrands ^j, Annemieke Geluk ^k, Tom H.M. Ottenhoff ^k, P.L.A.M. Corstjens ^l, Novel N. Chegou ^a, Gerhard Walzl ^a,^⁎
the AE-TBC Consortium
Gerhard Walzl ^m, Novel N. Chegou ^m, Magdalena Kriel ^m, Gian van der Spuy ^m, Andre G. Loxton ^m, Kim Stanley ^m, Stephanus Malherbe ^m, Shirley Mcanda ^m, Belinda Kriel ^m, Khutso G. Phalane ^m, Paulin Essone ^m, Jayne S. Sutherland ⁿ, Olumuyiwa Owolabi ⁿ, Abdou Sillah ⁿ, Joseph Mendy ⁿ, Awa Gindeh ⁿ, Simon Donkor ⁿ, Toyin Togun ⁿ, Martin Ota ⁿ, Amelia C. Crampin ^o, Felanji Simukonda ^o, Alemayehu Amberbir ^o, Femia Chilongo ^o, Rein Houben ^o, Desta Kassa ^p, Atsbeha Gebrezgeabher ^p, Getnet Mesfin ^p, Yohannes Belay ^p, Gebremedhin Gebremichael ^p, Yodit Alemayehu ^p, Marieta van der Vyver ^q, Faustina N. Amutenya ^q, Josefina N. Nelongo ^q, Lidia Monye ^q, Jacob A. Sheehama ^q, Scholastica Iipinge ^q, Harriet Mayanja-Kizza ^r, Ann Ritah Namuganga ^r, Grace Muzanye ^r, Mary Nsereko ^r, Pierre Peters ^r, Rawleigh Howe ^s, Adane Mihret ^s, Yonas Bekele ^s, Bamlak Tessema ^s, Lawrence Yamuah ^s, Tom H.M. Ottenhoff ^t, Annemieke Geluk ^t, Kees Franken ^t, Paul L.A.M. Corstjens ^t, Elisa M. Tjon Kon Fat ^t, Claudia J. de Dood ^t, Jolien J. van der Ploeg-van Schip ^t, Ida Rosenkrands ^u, Claus Aagaard ^u, Stefan H.E. Kaufmann ^v, Maria M. Esterhuyse ^v, Jacqueline M. Cliff ^w, Hazel M. Dockrell ^w
^m Stellenbosch University, South Africa
ⁿ MRC Unit, Gambia
^o Karonga Prevention Study, Malawi
^p Ethiopian Health and Nutrition Research Institute, Ethiopia
^q University of Namibia, Namibia
^r Makerere University, Uganda
^s Armauer Hansen Research Institute, Ethiopia
^t Leiden University Medical Centre, The Netherlands
^u Statens Serum Institut, Copenhagen, Denmark
^v Max Planck Institute for Infection Biology, Berlin, Germany
^w London School of Hygiene and Tropical Medicine, London, UK

^a Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, Cape Town, South Africa
^b Medical Research Council Unit, Fajara, Gambia
^c Department of Medicine, Makerere University, Kampala, Uganda
^d Armauer Hansen Research Institute, Addis Ababa, Ethiopia
^e University of Namibia, Faculty of Health Sciences, School of Medicine, Namibia
^f Ethiopian Health and Nutrition Research Institute, Addis Ababa, Ethiopia
^g Karonga Prevention Study, Chilumba, Malawi
^h London School of Hygiene and Tropical Medicine, London, UK
ⁱ Centre for Statistical Analysis, Stellenbosch University, South Africa
^j Statens Serum Institut, Copenhagen, Denmark
^k Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands
^l Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands

^∗Corresponding author. Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, P. O. Box 19063, Francie van Zijl drive, Tygerberg 7505, South Africa. Tel.: +27 21 938 9158; fax: +27 21 938 9863.Division of Molecular Biology and Human GeneticsDepartment of Biomedical SciencesFaculty of Medicine and Health SciencesStellenbosch UniversityP. O. Box 19063Francie van Zijl driveTygerberg7505South Africa

Summary

Objective

We investigated the accuracy of host markers detected in Mtb antigen-stimulated whole blood culture supernatant in the diagnosis of TB.

Methods

Prospectively, blood from 322 individuals with presumed TB disease from six African sites was stimulated with four different Mtb antigens (Rv0081, Rv1284, ESAT-6/CFP-10, and Rv2034) in a 24 h whole blood stimulation assay (WBA). The concentrations of 42 host markers in the supernatants were measured using the Luminex multiplex platform. Diagnostic biosignatures were investigated through the use of multivariate analysis techniques.

Results

17% of the participants were HIV infected, 106 had active TB disease and in 216 TB was excluded. Unstimulated concentrations of CRP, SAA, ferritin and IP-10 had better discriminating ability than markers from stimulated samples. Accuracy of marker combinations by general discriminant analysis (GDA) identified a six analyte model with 77% accuracy for TB cases and 84% for non TB cases, with a better performance in HIV uninfected patients.

Conclusions

A biosignature of 6 cytokines obtained after stimulation with four Mtb antigens has moderate potential as a diagnostic tool for pulmonary TB disease individuals and stimulated marker expression had no added value to unstimulated marker performance.

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Highlights

•	We evaluated the utility of host markers elicited after overnight stimulation of whole blood with Mtb antigens.
•	We identified a six analyte biosignature that showed promise in the diagnosis of active TB.
•	The identified host markers may be useful in improving the sensitivity of immunodiagnostic assays for TB disease.
•	Stimulation with Mtb antigens may not add value to unstimulated marker levels in the diagnosis of TB disease.

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Keywords : Biosignature, Host markers, Antigen

Plan

Introduction

Materials and methods

Study participants

Reference standard for classification of study participants

Whole blood culture assay (WBA)

Luminex multiplex immunoassay

Statistical analysis

Results

Study participants

Potential of host markers produced by unstimulated supernatants in discriminating between individuals with TB and non TB disease

Utility of host markers detected in overnight antigen-stimulated culture supernatants in the diagnosis of TB disease

Ability of cytokine responses to discriminate between LTBI and uninfected controls

Abilities of combinations of analytes in the general discriminant analysis models in discriminating between TB and non TB

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Vol 73 - N° 3

P. 219-230 - septembre 2016 Retour au numéro

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Evaluation of cytokine responses against novel Mtb antigens as diagnostic markers for TB disease - 08/08/16

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Methods

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Plan

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