Carole Chedid1,2, Eka Kokhreidze3, Nestani Tukvadze3, Sayera Banu4, Mohammad Khaja Mafij Uddin4, Samanta Biswas4, Graciela Russomando5, Chyntia Carolina Díaz Acosta5, Rossana Arenas6, Paulo Pr Ranaivomanana7, Crisca Razafimahatratra7, Perlinot Herindrainy7, Julio Rakotonirina8, Antso Hasina Raherinandrasana8, Niaina Rakotosamimanana7, Monzer Hamze9, Mohamad Bachar Ismail9, Rim Bayaa9, Jean-Luc Berland1, Flavio De Maio10,11, Giovanni Delogu10, Hubert Endtz12, Florence Ader13, Delia Goletti14, Jonathan Hoffmann1. 1. Laboratoire des Pathogènes Emergents, Fondation Mérieux, Centre International de Recherche en Infectiologie, INSERM U1111, Lyon, France. 2. Département de Biologie, Ecole Normale Supérieure de Lyon, Lyon, France. 3. National Center for Tuberculosis and Lung Diseases (NCTBLD), Tbilisi, Georgia. 4. International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh. 5. Instituto de Investigaciones en Ciencias de la Salud, National University of Asunción, Asunción, Paraguay. 6. Hospital General de San Lorenzo, MSPyBS, Asunción, Paraguay. 7. Institut Pasteur de Madagascar, Antananarivo, Madagascar. 8. Centre Hospitalier Universitaire de Soins et Santé Publique Analakely (CHUSSPA), Antananarivo, Madagascar. 9. Laboratoire Microbiologie, Santé et Environnement (LMSE), Doctoral School of Sciences and Technology, Faculty of Public Health, Lebanese University, Tripoli, Lebanon. 10. Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy. 11. Dipartimento di Scienze biotecnologiche di base, cliniche intensivologiche e perioperatorie - Sezione di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy. 12. Fondation Mérieux, Lyon, France. 13. Service des Maladies Infectieuses et Tropicales, Hospices Civils de Lyon, Lyon, France. 14. Translational Research Unit, Department of Epidemiology and Preclinical Research, "L. Spallanzani" National Institute for Infectious Diseases (INMI), IRCCS, Rome, Italy.
Abstract
Background: Tuberculosis (TB) is a leading infectious cause of death. To improve treatment efficacy, quicker monitoring methods are needed. The objective of this study was to monitor the response to a heparin-binding hemagglutinin (HBHA) interferon-γ (IFN-γ) release assay (IGRA) and QuantiFERON-TB Gold Plus (QFT-P) and to analyze plasma IFN-γ levels according to sputum culture conversion and immune cell counts during treatment. Methods: This multicentered cohort study was based in Bangladesh, Georgia, Lebanon, Madagascar, and Paraguay. Adult, non-immunocompromised patients with culture-confirmed pulmonary TB were included. Patients were followed up at baseline (T0), after two months of treatment (T1), and at the end of therapy (T2). Clinical data and blood samples were collected at each timepoint. Whole blood samples were stimulated with QFT-P antigens or recombinant methylated Mycobacterium tuberculosis HBHA (produced in Mycobacterium smegmatis; rmsHBHA). Plasma IFN-γ levels were then assessed by ELISA. Findings: Between December 2017 and September 2020, 132 participants completed treatment, including 28 (21.2%) drug-resistant patients. rmsHBHA IFN-γ increased significantly throughout treatment (0.086 IU/ml at T0 vs. 1.03 IU/ml at T2, p < 0.001) while QFT-P IFN-γ remained constant (TB1: 0.53 IU/ml at T0 vs. 0.63 IU/ml at T2, p = 0.13). Patients with low lymphocyte percentages (<14%) or high neutrophil percentages (>79%) at baseline had significantly lower IFN-γ responses to QFT-P and rmsHBHA at T0 and T1. In a small group of slow converters (patients with positive cultures at T1; n = 16), we observed a consistent clinical pattern at baseline (high neutrophil percentages, low lymphocyte percentages and BMI, low TB1, TB2, and MIT IFN-γ responses) and low rmsHBHA IFN-γ at T1 and T2. However, the accuracy of the QFT-P and rmsHBHA IGRAs compared to culture throughout treatment was low (40 and 65% respectively). Combining both tests improved their sensitivity and accuracy (70-80%) but not their specificity (<30%). Conclusion: We showed that QFT-P and rmsHBHA IFN-γ responses were associated with rates of sputum culture conversion. Our results support a growing body of evidence suggesting that rmsHBHA IFN-γ discriminates between the different stages of TB, from active disease to controlled infection. However, further work is needed to confirm the specificity of QFT-P and rmsHBHA IGRAs for treatment monitoring.
Background: Tuberculosis (TB) is a leading infectious cause of death. To improve treatment efficacy, quicker monitoring methods are needed. The objective of this study was to monitor the response to a heparin-binding hemagglutinin (HBHA) interferon-γ (IFN-γ) release assay (IGRA) and QuantiFERON-TB Gold Plus (QFT-P) and to analyze plasma IFN-γ levels according to sputum culture conversion and immune cell counts during treatment. Methods: This multicentered cohort study was based in Bangladesh, Georgia, Lebanon, Madagascar, and Paraguay. Adult, non-immunocompromised patients with culture-confirmed pulmonary TB were included. Patients were followed up at baseline (T0), after two months of treatment (T1), and at the end of therapy (T2). Clinical data and blood samples were collected at each timepoint. Whole blood samples were stimulated with QFT-P antigens or recombinant methylated Mycobacterium tuberculosis HBHA (produced in Mycobacterium smegmatis; rmsHBHA). Plasma IFN-γ levels were then assessed by ELISA. Findings: Between December 2017 and September 2020, 132 participants completed treatment, including 28 (21.2%) drug-resistant patients. rmsHBHA IFN-γ increased significantly throughout treatment (0.086 IU/ml at T0 vs. 1.03 IU/ml at T2, p < 0.001) while QFT-P IFN-γ remained constant (TB1: 0.53 IU/ml at T0 vs. 0.63 IU/ml at T2, p = 0.13). Patients with low lymphocyte percentages (<14%) or high neutrophil percentages (>79%) at baseline had significantly lower IFN-γ responses to QFT-P and rmsHBHA at T0 and T1. In a small group of slow converters (patients with positive cultures at T1; n = 16), we observed a consistent clinical pattern at baseline (high neutrophil percentages, low lymphocyte percentages and BMI, low TB1, TB2, and MIT IFN-γ responses) and low rmsHBHA IFN-γ at T1 and T2. However, the accuracy of the QFT-P and rmsHBHA IGRAs compared to culture throughout treatment was low (40 and 65% respectively). Combining both tests improved their sensitivity and accuracy (70-80%) but not their specificity (<30%). Conclusion: We showed that QFT-P and rmsHBHA IFN-γ responses were associated with rates of sputum culture conversion. Our results support a growing body of evidence suggesting that rmsHBHA IFN-γ discriminates between the different stages of TB, from active disease to controlled infection. However, further work is needed to confirm the specificity of QFT-P and rmsHBHA IGRAs for treatment monitoring.
Authors: L Liang; R Shi; X Liu; X Yuan; S Zheng; G Zhang; W Wang; J Wang; K England; L E Via; Y Cai; L C Goldfeder; L E Dodd; C E Barry; R Y Chen Journal: Int J Tuberc Lung Dis Date: 2017-10-01 Impact factor: 2.373