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1. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Author

Alba Llibre, Nikaïa Smith, Vincent Rouilly, Munyaradzi Musvosvi, Elisa Nemes, Céline Posseme, Simbarashe Mabwe, Bruno Charbit, Stanley Kimbung Mbandi, Elizabeth Filander, Hadn Africa, Violaine Saint-André, Vincent Bondet, Pierre Bost, Humphrey Mulenga, Nicole Bilek, Matthew L. Albert, Thomas J. Scriba, and Darragh Duffy

Subjects
tuberculosis, IL-1ra, IL-1, immunometabolism, systems immunology, Immunologic diseases. Allergy, RC581-607
Abstract

Tuberculosis (TB) remains a major public health problem and we lack a comprehensive understanding of how Mycobacterium tuberculosis (M. tb) infection impacts host immune responses. We compared the induced immune response to TB antigen, BCG and IL-1β stimulation between latently M. tb infected individuals (LTBI) and active TB patients. This revealed distinct responses between TB/LTBI at transcriptomic, proteomic and metabolomic levels. At baseline, we identified a novel immune-metabolic association between pregnane steroids, the PPARγ pathway and elevated plasma IL-1ra in TB. We observed dysregulated IL-1 responses after BCG stimulation in TB patients, with elevated IL-1ra responses being explained by upstream TNF differences. Additionally, distinct secretion of IL-1α/IL-1β in LTBI/TB after BCG stimulation was associated with downstream differences in granzyme mediated cleavage. Finally, IL-1β driven signalling was dramatically perturbed in TB disease but was completely restored after successful treatment. This study improves our knowledge of how immune responses are altered during TB disease, and may support the design of improved preventive and therapeutic tools, including host-directed strategies.

Published
2022
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2. Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy

Author

Fatoumatta Darboe, Stanley Kimbung Mbandi, Kogieleum Naidoo, Nonhlanhla Yende-Zuma, Lara Lewis, Ethan G. Thompson, Fergal J. Duffy, Michelle Fisher, Elizabeth Filander, Michele van Rooyen, Nicole Bilek, Simbarashe Mabwe, Lyle R. McKinnon, Novel Chegou, Andre Loxton, Gerhard Walzl, Gerard Tromp, Nesri Padayatchi, Dhineshree Govender, Mark Hatherill, Salim Abdool Karim, Daniel E. Zak, Adam Penn-Nicholson, Thomas J. Scriba, and The SATVI Clinical Immunology Team

Subjects
tuberculosis, recurrence, diagnosis, treatment, transcriptomic signature, HIV, Microbiology, QR1-502
Abstract

HIV-infected individuals are at high risk of tuberculosis disease and those with prior tuberculosis episodes are at even higher risk of disease recurrence. A non-sputum biomarker that identifies individuals at highest tuberculosis risk would allow targeted microbiological testing and appropriate treatment and also guide need for prolonged therapy. We determined the utility of a previously developed whole blood transcriptomic correlate of risk (COR) signature for (1) predicting incident recurrent tuberculosis, (2) tuberculosis diagnosis and (3) its potential utility for tuberculosis treatment monitoring in HIV-infected individuals. We retrieved cryopreserved blood specimens from three previously completed clinical studies and measured the COR signature by quantitative microfluidic real-time-PCR. The signature differentiated recurrent tuberculosis progressors from non-progressors within 3 months of diagnosis with an area under the Receiver-operating characteristic (ROC) curve (AUC) of 0.72 (95% confidence interval (CI), 0.58–0.85) amongst HIV-infected individuals on antiretroviral therapy (ART). Twenty-five of 43 progressors (58%) were asymptomatic at microbiological diagnosis and thus had subclinical disease. The signature showed excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94–1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81–0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.

Published
2019
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3. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Author

Nicole Bilek, Violaine Saint-André, Elisa Nemes, Stanley Kimbung Mbandi, Elizabeth Filander, Munyaradzi Musvosvi, Humphrey Mulenga, Matthew L. Albert, Alba Llibre, Vincent Rouilly, Hadn Africa, Céline Posseme, Simba Mabwe, Nikaïa Smith, Vincent Bondet, Thomas J. Scriba, Pierre Bost, Darragh Duffy, Bruno Charbit, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Datactix, University of Cape Town, Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Département de Biologie Computationnelle - Department of Computational Biology, Insitro [San Francisco], This study was funded by the Bill and Melinda Gates Foundation (OPP1114368 and OPP1204624), with additional support from the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01. AL was supported by the Fondation Recherche Médicale (SPF20170938617) and the European Commision (H2020-MSCA-IF 2018, 841729). NS was supported by an Institut Pasteur Roux Cantarini fellowship., We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Nanostring analysis. DD thanks Immunoqure for provision of the mAbs under an MTA for the Simoa IFN-α assay. We are grateful to the study participants and the SATVI clinical and laboratory teams., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Tuberculosis, Immunology, Disease, Mycobacterium tuberculosis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Interleukin 1 (IL-1), Medicine, Immunology and Allergy, Interleukin 1 Receptor antagonist (IL-1ra), 030304 developmental biology, Systems immunology, 0303 health sciences, Immunometabolism, biology, business.industry, biology.organism_classification, medicine.disease, 3. Good health, Granzyme, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, business, 030215 immunology
Abstract

SUMMARYTuberculosis (TB) remains a major public health problem with host-directed therapeutics offering potential as novel treatment strategies. However, their successful development still requires a comprehensive understanding of howMycobacterium tuberculosis(M.tb) infection impacts immune responses. To address this challenge, we applied standardised immunomonitoring tools to compare TB antigen, BCG and IL-1β induced immune responses between individuals with latentM.tbinfection (LTBI) and active TB disease, at diagnosis and after cure. This revealed distinct responses between TB and LTBI groups at transcriptomic, proteomic and metabolomic levels. At baseline, we identified pregnane steroids and the PPARγ pathway as new immune-metabolic drivers of elevated plasma IL-1ra in TB. We also observed dysregulated induced IL-1 responses after BCG stimulation in TB patients. Elevated IL-1 antagonist responses were explained by upstream differences in TNF responses, while for IL-1 agonists it was due to downstream differences in granzyme mediated cleavage. Finally, the immune response to IL-1β driven signalling was also dramatically perturbed in TB disease but was completely restored after successful antibiotic treatment. This systems immunology approach improves our knowledge of how immune responses are altered during TB disease, and may support design of improved diagnostic, prophylactic and therapeutic tools.

Published
2022
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4. Immune Profiling Enables Stratification of Patients With Active Tuberculosis Disease or Mycobacteriu m tuberculosis Infection

Author

Françoise Dromer, Antonio Rausell, Elizabeth Filander, Bruno Charbit, Odile Gelpi, Kalla Astrom, Stanislas Pol, Elisa Nemes, Vincent Rouilly, Mark Hatherill, Hadn Africa, Humphrey Mulenga, Ana Cumano, Hugo Mouquet, Etienne Patin, Lluis Quintana-Murci, Lungisa Jaxa, Laurent Abel, Milena Hasan, James P. Di Santo, Claude Leclerc, Spencer L. Shorte, Vassili Soumelis, Stéphanie Thomas, Caroline Demangel, Mathilde Touvier, Andrés Alcover, Thomas J. Scriba, Matthew L. Albert, Anavaj Sakuntabhai, Hugues Aschard, Nikaïa Smith, Serge Hercberg, Darragh Duffy, Jost Enninga, Olivier Schwartz, Ivo Gomperts-Boneca, Marie-Noëlle Ungeheuer, Simbarashe Mabwe, Ludovic Deriano, Frédéric Tangy, Gérard Eberl, Sandra Pellegrini, Antoine Toubert, Lars Rogge, Stephanus T. Malherbe, Gerhard Walzl, Michele Tameris, Munyaradzi Musvosvi, Alba Llibre, Benno Schwikowski, Olivier Lantz, Nicole Bilek, Philippe Bousso, Pierre Bruhns, Jacques Fellay, and Eric Tartour

Subjects
0301 basic medicine, Microbiology (medical), Tuberculosis, Enzyme-Linked Immunosorbent Assay, Disease, Asymptomatic, QuantiFERON, Mycobacterium tuberculosis, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Antigen, Latent Tuberculosis, medicine, Humans, 030212 general & internal medicine, Online only Articles, Whole blood, biology, business.industry, immune profiling, biomarkers, patient stratification, bacterial infections and mycoses, medicine.disease, biology.organism_classification, cytokines, 3. Good health, AcademicSubjects/MED00290, 030104 developmental biology, Infectious Diseases, Cohort, Immunology, medicine.symptom, business, Interferon-gamma Release Tests
Abstract

Background Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. Methods We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb-specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. Results TruCulture showed discrimination of active TB cases from LTBI (P < .0001, AUC = .81) compared with QFT (P = .45, AUC = .56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC = .89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P < .0001, AUC = .91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. Conclusions TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection., We tested TruCulture, an immunomonitoring tool, to identify active disease from latent Mtb infection. TruCulture showed improved discrimination of tuberculosis cases from LTBI as compared with QuantiFERON. Tuberculosis stratification could be further improved by the Mtb Ag:BCG IFNγ ratio.

Published
2020
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5. Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial

Author

Thomas J Scriba, Andrew Fiore-Gartland, Adam Penn-Nicholson, Humphrey Mulenga, Stanley Kimbung Mbandi, Bhavesh Borate, Simon C Mendelsohn, Katie Hadley, Chris Hikuam, Masooda Kaskar, Munyaradzi Musvosvi, Nicole Bilek, Steven Self, Tom Sumner, Richard G White, Mzwandile Erasmus, Lungisa Jaxa, Rodney Raphela, Craig Innes, William Brumskine, Andriëtte Hiemstra, Stephanus T Malherbe, Razia Hassan-Moosa, Michèle Tameris, Gerhard Walzl, Kogieleum Naidoo, Gavin Churchyard, Mark Hatherill, Kesenogile Baepanye, Tshepiso Baepanye, Ken Clarke, Marelize Collignon, Audrey Dlamini, Candice Eyre, Tebogo Feni, Moogo Fikizolo, Phinda Galane, Thelma Goliath, Alia Gangat, Shirley Malefo-Grootboom, Elba Janse van Rensburg, Bonita Janse van Rensburg, Sophy Kekana, Marietjie Zietsman, Adrianne Kock, Israel Kunene, Aneessa Lakhi, Nondumiso Langa, Hilda Ledwaba, Marillyn Luphoko, Immaculate Mabasa, Dorah Mabe, Nkosinathi Mabuza, Molly Majola, Mantai Makhetha, Mpho Makoanyane, Blossom Makhubalo, Vernon Malay, Juanita Market, Selvy Matshego, Nontsikelelo Mbipa, Tsiamo Mmotsa, Sylvester Modipa, Samuel Mopati, Palesa Moswegu, Primrose Mothaga, Dorothy Muller, Grace Nchwe, Maryna Nel, Lindiwe Nhlangulela, Bantubonke Ntamo, Lawerence Ntoahae, Tedrius Ntshauba, Nomsa Sanyaka, Letlhogonolo Seabela, Pearl Selepe, Melissa Senne, MG Serake, Maria Thlapi, Vincent Tshikovhi, Lebogang Tswaile, Amanda van Aswegen, Lungile Mbata, Constance Takavamanya, Pedro Pinho, John Mdlulu, Marthinette Taljaard, Naydene Slabbert, Sharfuddin Sayed, Tanya Nielson, Ni Ni Sein, Dhineshree Govender, Tilagavathy Chinappa, Mbali Ignatia Zulu, Nonhle Bridgette Maphanga, Senzo Ralph Hlathi, Goodness Khanyisile Gumede, Thandiwe Yvonne Shezi, Jabulisiwe Lethabo Maphanga, Zandile Patrica Jali, Thobelani Cwele, Nonhlanhla Zanele Elsie Gwamanda, Celaphiwe Dlamini, Zibuyile Phindile Penlee Sing, Ntombozuko Gloria Ntanjana, Sphelele Simo Nzimande, Siyabonga Mbatha, Bhavna Maharaj, Atika Moosa, Cara-Mia Corris, Fazlin Kafaar, Hennie Geldenhuys, Angelique Kany Kany Luabeya, Justin Shenje, Natasja Botes, Susan Rossouw, Hadn Africa, Bongani Diamond, Samentra Braaf, Sonia Stryers, Alida Carstens, Ruwiyda Jansen, Simbarashe Mabwe, Roxane Herling, Ashley Veldsman, Lebohgang Makhete, Marcia Steyn, Sivuyile Buhlungu, Margareth Erasmus, Ilse Davids, Patiswa Plaatjie, Alessandro Companie, Frances Ratangee, Helen Veldtsman, Christel Petersen, Charmaine Abrahams, Miriam Moses, Xoliswa Kelepu, Yolande Gregg, Liticia Swanepoel, Nomsitho Magawu, Nompumelelo Cetywayo, Lauren Mactavie, Habibullah Valley, Elizabeth Filander, Nambitha Nqakala, Elizna Maasdorp, Justine Khoury, Belinda Kriel, Bronwyn Smith, Liesel Muller, Susanne Tonsing, Andre Loxton, Andriette Hiemstra, Petri Ahlers, Marika Flinn, Eva Chung, Michelle Chung, and Alicia Sato

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Tuberculosis, Antitubercular Agents, Disease, Tuberculosis preventive therapy, Drug Administration Schedule, law.invention, 03 medical and health sciences, South Africa, Young Adult, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, HIV Seronegativity, medicine, Isoniazid, Humans, Cumulative incidence, 030212 general & internal medicine, Adverse effect, business.industry, Transmission (medicine), Reverse Transcriptase Polymerase Chain Reaction, Incidence, Computational Biology, Articles, Mycobacterium tuberculosis, medicine.disease, RNA, Bacterial, 030104 developmental biology, Infectious Diseases, Treatment Outcome, Biomarker (medicine), Female, Rifampin, business, Transcriptome, Biomarkers
Abstract

Summary Background Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design. Methods Adult volunteers aged 18–59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie

Published
2020

6. Diagnostic performance of an optimized transcriptomic signature of risk of tuberculosis in cryopreserved peripheral blood mononuclear cells

Author

Fatoumatta Darboe, Stanley Kimbung Mbandi, Ethan G. Thompson, Michelle Fisher, Miguel Rodo, Michele van Rooyen, Elizabeth Filander, Nicole Bilek, Simbarashe Mabwe, Mark Hatherill, Daniel E. Zak, Adam Penn-Nicholson, Thomas J. Scriba, Sindile Matiwane, Lungisa Jaxa, Noncedo Xoyana, Constance Schreuder, Janelle Botes, Hadn Africa, Lebohang Makhethe, and Marcia Steyn

Subjects
0301 basic medicine, Microbiology (medical), Pathology, medicine.medical_specialty, Tuberculosis, business.industry, Immunology, medicine.disease, Microbiology, Peripheral blood mononuclear cell, Cryopreservation, Biomarker (cell), Transcriptome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Infectious Diseases, Tuberculosis diagnosis, Area under curve, medicine, 030212 general & internal medicine, business, Whole blood
Published
2018
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7. Immune profiling in M. tuberculosis infection enables stratification of patients with active disease

Author

Alba Llibre, Simbarashe Mabwe, Matthew L. Albert, Nicole Bilek, Elizabeth Filander, Mark Hatherill, Humphrey Mulenga, Stéphanie Thomas, Elisa Nemes, Lungisa Jaxa, Vincent Rouilly, Hadn Africa, Munyaradzi Musvosvi, Thomas J. Scriba, Bruno Charbit, and Darragh Duffy

Subjects
Innate immune system, Tuberculosis, biology, business.industry, Stimulation, Disease, biology.organism_classification, medicine.disease, bacterial infections and mycoses, Asymptomatic, Mycobacterium tuberculosis, Antigen, Immunology, medicine, medicine.symptom, business, Whole blood
Abstract

Tuberculosis (TB) is caused byMycobacterium tuberculosis(Mtb) infection and is a major public health problem with an estimated 1.7 billion persons infected worldwide. Clinical challenges in TB include the lack of a blood-based test for active disease, and the absence of prognostic biomarkers for early treatment response. Current blood based tests, such as QuantiFERON-TB Gold (QFT), are based on an IFNγ readout followingMtbantigen stimulation. However, they do not distinguish active TB disease from asymptomaticMtbinfection. We hypothesized that the use of TruCulture, an improved immunomonitoring method for whole blood collection and immune stimulation, could improve the discrimination of active disease from latentMtbinfection. To test our hypothesis, we stimulated whole blood from active TB patients (before and after successful treatment), comparing them to asymptomatic latently infected individuals.Mtb-specific antigens (ESAT-6, CFP-10, TB7.7) and live bacillus Calmette-Guerin (BCG) were used for TruCulture stimulation conditions, with direct comparison to QFT. Protein analyses were performed on the culture supernatants using ELISA and Luminex multi-analyte profiling. TruCulture showed an ability to discriminate active TB cases from latent controls (p < 0.0001, AUC = 0.81, 95% CI: 0.69-0.93) as compared to QFT (p = 0.47 AUC = 0.56, 95% CI: 0.40-0.72), based on an IFNγ readout afterMtbantigen stimulation. The stratification of the two groups could be further improved by using theMtbAg/BCG IFNγ ratio response (p < 0.0001, AUC = 0.918, 95% CI: 0.84-0.98). We also identified additional cytokines that distinguished latent infection from TB disease; and show that the primary differences between the TruCulture and QFT systems were a result of higher levels of non-specific innate immune activation in QFT tubes, due to the lack of a buffering solution in the latter. We conclude that TruCulture offers a next-generation solution for whole blood stimulation and immunomonitoring with the possibility to discriminate active and latently infected persons.

Published
2019
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8. Optimization and Interpretation of Serial QuantiFERON Testing to Measure Acquisition of Mycobacterium tuberculosis Infection

Author

Elisa Nemes, Virginie Rozot, Hennie Geldenhuys, Nicole Bilek, Simbarashe Mabwe, Deborah Abrahams, Lebohang Makhethe, Mzwandile Erasmus, Alana Keyser, Asma Toefy, Yolundi Cloete, Frances Ratangee, Thomas Blauenfeldt, Morten Ruhwald, Gerhard Walzl, Bronwyn Smith, Andre G. Loxton, Willem A. Hanekom, Jason R. Andrews, Maria D. Lempicki, Ruth Ellis, Ann M. Ginsberg, Mark Hatherill, Thomas J. Scriba, Susan Rossouw, Carolyn Jones, Elisma Schoeman, Yolande Gregg, Elizabeth Beyers, Sandra Kruger, Helen Veltdsman, Sophie Keffers, Sandra Goliath, Mariana Mullins, Michele Tameris, Angelique Luabeya, Ashley Veldsman, Humphrey Mulenga, Angelique Hendricks, Fajwa Opperman, Elma Van Rooyen, Julia Noble, Samentra Braaf, Rose Ockhuis, Emerencia Vermeulen, Alessandro Companie, Xoliswa Kelepu, Maigan Ratangee, Abraham Pretorius, Henry Issel, Phumzile Langata, Ilse Davids, Roxanne Herling, Hadn Africa, Marcia Steyn, Lungisa Nkantso, Noncedo Xoyana, Bongani Diamond, Margareth Erasmus, Jane Hughes, Denise van der Westhuizen, Lydia Makunzi, Natasja Botes, Julia Amsterdam, Clive Maqubela, Portia Dlakavu, Pamela Mangala, Charmaine Abrahams, Petrus Tyambetyu, Diann Gempies, Cindy Elbring, Elizabeth Hamilton, Fadia Alexander, Sindile Wiseman Matiwane, Cashwin September, Christel Petersen, Yulande Herselman, Johanna Hector, Terence Esterhuizen, Lauren Mactavie, Elize van der Riet, Debbie Pretorius, Justin Shenje, Anne Swarts, Eunice Sinandile, Janelle Botes, Constance Schreuder, Jateel Kassiem, Onke Xasa, Boitumelo Mosito, Rodney Raphela, Denis Arendsen, Palesa Dolo, Elizabeth Filander, Hassan Mahomed, Fazlin Kafaar, Leslie Workman, Rodney Ehrlich, Sizulu Moyo, Sebastian Gelderbloem, and Gregory Hussey

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Tuberculosis, Adolescent, Tuberculin, Critical Care and Intensive Care Medicine, QuantiFERON, Mycobacterium tuberculosis, 03 medical and health sciences, Interferon-gamma, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Tuberculosis Disease, Tuberculosis, Pulmonary, biology, business.industry, Tuberculin Test, Reproducibility of Results, Original Articles, Skin test, bacterial infections and mycoses, Control subjects, biology.organism_classification, medicine.disease, 030228 respiratory system, Immunology, Female, business
Abstract

Conversion from a negative to positive QuantiFERON-TB test is indicative of Mycobacterium tuberculosis (Mtb) infection, which predisposes individuals to tuberculosis disease. Interpretation of serial tests is confounded by immunological and technical variability.To improve the consistency of serial QuantiFERON-TB testing algorithms and provide a data-driven definition of conversion.Sources of QuantiFERON-TB variability were assessed, and optimal procedures were identified. Distributions of IFN-γ response levels were analyzed in healthy adolescents, Mtb-unexposed control subjects, and patients with pulmonary tuberculosis.Individuals with no known Mtb exposure had IFN-γ values less than 0.2 IU/ml. Among individuals with IFN-γ values less than 0.2 IU/ml, 0.2-0.34 IU/ml, 0.35-0.7 IU/ml, and greater than 0.7 IU/ml, tuberculin skin test positivity results were 15%, 53%, 66%, and 91% (P 0.005), respectively. Together, these findings suggest that values less than 0.2 IU/ml were true negatives. In short-term serial testing, "uncertain" conversions, with at least one value within the uncertainty zone (0.2-0.7 IU/ml), were partly explained by technical assay variability. Individuals who had a change in QuantiFERON-TB IFN-γ values from less than 0.2 to greater than 0.7 IU/ml had 10-fold higher tuberculosis incidence rates than those who maintained values less than 0.2 IU/ml over 2 years (P = 0.0003). By contrast, "uncertain" converters were not at higher risk than nonconverters (P = 0.229). Eighty-seven percent of patients with active tuberculosis had IFN-γ values greater than 0.7 IU/ml, suggesting that these values are consistent with established Mtb infection.Implementation of optimized procedures and a more rigorous QuantiFERON-TB conversion definition (an increase from IFN-γ0.2 to0.7 IU/ml) would allow more definitive detection of recent Mtb infection and potentially improve identification of those more likely to develop disease.

Published
2017

9. Analysis of prevalent tuberculosis by using oral swab PCR

Author

Lisa Jones-Engel, Angelique Kany Kany Luabeya, Rachel C. Wood, Elizabeth Filander, Mark Hatherill, Alicia K. Wilbur, and Gerard A. Cangelosi

Subjects
Microbiology (medical), Tuberculosis, Infectious Diseases, business.industry, Medicine, lcsh:RC109-216, General Medicine, business, medicine.disease, Virology, lcsh:Infectious and parasitic diseases
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