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1
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Sadeghi MH, Radmehr S, Mohagheghzadeh N, Fathi J, Malekzadegan Y, Moghadam HZ. Innovative electrochemical biosensors for tuberculosis detection. Clin Chim Acta 2025; 574:120327. [PMID: 40286897 DOI: 10.1016/j.cca.2025.120327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Revised: 04/19/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
Tuberculosis (TB) continues to pose a significant global health threat, highlighting the urgent need for the development of rapid, precise, and accessible diagnostic tools to effectively manage its transmission. Conventional diagnostic techniques, such as sputum microscopy and culture-based assays, face several drawbacks, including lengthy processing times, limited sensitivity, and the requirement for specialized laboratory facilities. In this landscape, electrochemical biosensors have emerged as promising alternatives, offering improved sensitivity, specificity, and rapid detection capabilities. This review presents a thorough overview of recent advancements in the development and application of innovative electrochemical biosensors for TB detection. It explores the integration of nanomaterials such as graphene, gold nanoparticles, and carbon nanotubes, focusing on their contributions to enhanced sensor performance in terms of signal amplification and biorecognition efficacy. By synthesizing current research and technological developments, this review emphasizes the considerable potential of electrochemical biosensors to transform TB diagnostics, ultimately assisting in better disease management and control strategies worldwide.
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Affiliation(s)
- Mohammad Hassan Sadeghi
- Medical Student, School of Medicine,Zahedan University of Medical Science, Sistanbaluchestan, Iran
| | - Safa Radmehr
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Neda Mohagheghzadeh
- Department of Bacteriology & Virology, School of Medicine, Shiraz University of Medical Sciences, Iran
| | - Javad Fathi
- Department of Bacteriology & Virology, School of Medicine, Shiraz University of Medical Sciences, Iran
| | - Yalda Malekzadegan
- Department of Microbiology and Parasitology, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Hesam Zendehdel Moghadam
- Research and Technology Department, Iranian Academic Center for Education Culture and Research Kerman Branch, Iran.
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2
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Strzelak A, Komorowska-Piotrowska A, Borowa A, Krasińska M, Feleszko W, Kulus M. IP-10 for the Diagnosis and Treatment Monitoring of Tuberculosis in Children. Diagnostics (Basel) 2024; 14:177. [PMID: 38248054 PMCID: PMC10814829 DOI: 10.3390/diagnostics14020177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/03/2024] [Accepted: 01/10/2024] [Indexed: 01/23/2024] Open
Abstract
PURPOSE To determine the utility of interferon-gamma-inducible protein 10 (IP-10) for identifying active tuberculosis (TB) and TB infection (TBI) in children in BCG-vaccinated populations, establish its diagnostic performance characteristics, and evaluate changes in IP-10 level during anti-TB chemotherapy. METHODS Concentrations of IP-10 and IFN-γ were measured in QuantiFERON-TB Gold (QFT) supernatants in children with suspected TB or due to recent TB contact. A total of 225 children were investigated: 33 with active TB, 48 with TBI, 83 TB contacts, 20 with suspected TB but other final diagnoses, and 41 controls. In 60 children, cytokine responses were evaluated at a follow-up visit after 2 months of anti-TB treatment. RESULTS IP-10 expression was significantly higher in infected children (active TB and TBI cases) than in uninfected individuals. IP-10 proved effective in identifying TB infection at its optimal cut-off (>1084.5 pg/mL) but was incapable of differentiating between children with active TB and TBI. Combining IP-10 and IFN-γ increased the QFT sensitivity. IP-10 but not IFN-γ decreased significantly during anti-TB treatment in children with active TB (p = 0.003). CONCLUSION IP-10 identifies TB infection and declines during anti-TB chemotherapy in children. Incorporating IP-10 into new immunodiagnostic assays could improve TB diagnosis and allow for treatment monitoring.
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Affiliation(s)
- Agnieszka Strzelak
- Department of Pediatric Pulmonology and Allergy, Medical University of Warsaw, 63A Zwirki i Wigury Street, 02-091 Warsaw, Poland
| | - Anna Komorowska-Piotrowska
- Department of Pediatric Pulmonology and Allergy, Medical University of Warsaw, 63A Zwirki i Wigury Street, 02-091 Warsaw, Poland
| | - Agnieszka Borowa
- Department of Lung Diseases and Tuberculosis for Children and Adolescents, Mazovian Center for Treatment of Lung Diseases and Tuberculosis, Reymonta 83/91 Street, 05-400 Otwock, Poland
| | - Maria Krasińska
- Department of Lung Diseases and Tuberculosis for Children and Adolescents, Mazovian Center for Treatment of Lung Diseases and Tuberculosis, Reymonta 83/91 Street, 05-400 Otwock, Poland
| | - Wojciech Feleszko
- Department of Pediatric Pulmonology and Allergy, Medical University of Warsaw, 63A Zwirki i Wigury Street, 02-091 Warsaw, Poland
| | - Marek Kulus
- Department of Pediatric Pulmonology and Allergy, Medical University of Warsaw, 63A Zwirki i Wigury Street, 02-091 Warsaw, Poland
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3
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Imoto S, Suzukawa M, Takeda K, Motohashi T, Nagase M, Enomoto Y, Kawasaki Y, Nakano E, Watanabe M, Shimada M, Takada K, Watanabe S, Nagase T, Ohta K, Teruya K, Nagai H. Evaluation of tuberculosis diagnostic biomarkers in immunocompromised hosts based on cytokine levels in QuantiFERON-TB Gold Plus. Tuberculosis (Edinb) 2022; 136:102242. [PMID: 35944309 DOI: 10.1016/j.tube.2022.102242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 07/11/2022] [Accepted: 07/26/2022] [Indexed: 11/19/2022]
Abstract
Tuberculosis (TB) remains a serious health concern globally. QuantiFERON-TB (QFT) is a diagnostic tool for TB detection, and its sensitivity is reduced in immunocompromised hosts with low T lymphocyte counts or abnormal T cell function. This study aimed to evaluate the correlation between T cell and cytokine levels in patients with active TB using QFT-Plus. Forty-five patients with active TB were enrolled, and the cytokines in QFT-Plus tube supernatants were quantified using the MAGPIX System. CD4+ T cell count negatively correlated with patient age (p < 0.001, r = -0.51). The levels of TB1-responsive interleukin-1 receptor antagonist (IL-1Ra) and IL-2 correlated with CD4+ T cell count, whereas the levels of TB2-responsive IL-1Ra and IFN-γ-induced protein 10 correlated with both CD4+ and CD8+ T cell counts. Cytokines that correlated with CD4+ and CD8+ T cell counts might not be suitable TB diagnostic biomarkers in immunocompromised hosts. Notably, cytokines that did not correlate with the T cell counts, such as monocyte chemoattractant protein-1, might be candidate biomarkers for TB in immunocompromised hosts. Our findings might help improve TB diagnosis, which could enable prompt treatment and minimize poor disease outcomes.
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Affiliation(s)
- Sahoko Imoto
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Maho Suzukawa
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan.
| | - Keita Takeda
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Takumi Motohashi
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Maki Nagase
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Yu Enomoto
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Yuichiro Kawasaki
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Eri Nakano
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Masato Watanabe
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Masahiro Shimada
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Kazufumi Takada
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan; Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shizuka Watanabe
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Takahide Nagase
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Ken Ohta
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan; Japan Anti-Tuberculosis Association, Fukujuji Hospital, Tokyo, 193-0834, Japan
| | - Katsuji Teruya
- National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Hideaki Nagai
- National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
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4
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Meier NR, Sutter TM, Jacobsen M, Ottenhoff THM, Vogt JE, Ritz N. Machine Learning Algorithms Evaluate Immune Response to Novel Mycobacterium tuberculosis Antigens for Diagnosis of Tuberculosis. Front Cell Infect Microbiol 2021; 10:594030. [PMID: 33489933 PMCID: PMC7820115 DOI: 10.3389/fcimb.2020.594030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/24/2020] [Indexed: 12/20/2022] Open
Abstract
Rationale Tuberculosis diagnosis in children remains challenging. Microbiological confirmation of tuberculosis disease is often lacking, and standard immunodiagnostic including the tuberculin skin test and interferon-γ release assay for tuberculosis infection has limited sensitivity. Recent research suggests that inclusion of novel Mycobacterium tuberculosis antigens has the potential to improve standard immunodiagnostic tests for tuberculosis. Objective To identify optimal antigen–cytokine combinations using novel Mycobacterium tuberculosis antigens and cytokine read-outs by machine learning algorithms to improve immunodiagnostic assays for tuberculosis. Methods A total of 80 children undergoing investigation of tuberculosis were included (15 confirmed tuberculosis disease, five unconfirmed tuberculosis disease, 28 tuberculosis infection and 32 unlikely tuberculosis). Whole blood was stimulated with 10 novel Mycobacterium tuberculosis antigens and a fusion protein of early secretory antigenic target (ESAT)-6 and culture filtrate protein (CFP) 10. Cytokines were measured using xMAP multiplex assays. Machine learning algorithms defined a discriminative classifier with performance measured using area under the receiver operating characteristics. Measurements and main results We found the following four antigen–cytokine pairs had a higher weight in the discriminative classifier compared to the standard ESAT-6/CFP-10-induced interferon-γ: Rv2346/47c- and Rv3614/15c-induced interferon-gamma inducible protein-10; Rv2031c-induced granulocyte-macrophage colony-stimulating factor and ESAT-6/CFP-10-induced tumor necrosis factor-α. A combination of the 10 best antigen–cytokine pairs resulted in area under the curve of 0.92 ± 0.04. Conclusion We exploited the use of machine learning algorithms as a key tool to evaluate large immunological datasets. This identified several antigen–cytokine pairs with the potential to improve immunodiagnostic tests for tuberculosis in children.
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Affiliation(s)
- Noëmi Rebecca Meier
- Mycobacterial Research Laboratory, University of Basel Children's Hospital, Basel, Switzerland.,Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Thomas M Sutter
- Department of Computer Science, Medical Data Science, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland
| | - Marc Jacobsen
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinreich Heine University, Düsseldorf, Germany
| | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
| | - Julia E Vogt
- Department of Computer Science, Medical Data Science, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland
| | - Nicole Ritz
- Mycobacterial Research Laboratory, University of Basel Children's Hospital, Basel, Switzerland.,Faculty of Medicine, University of Basel, Basel, Switzerland.,Pediatric Infectious Diseases and Vaccinology Unit, University of Basel Children's Hospital, Basel, Switzerland.,Department of Pediatrics, Royal Children's Hospital Melbourne, University of Melbourne, Parkville, VIC, Australia
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5
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Qiu X, Wang H, Tang Y, Su X, Ge L, Qu Y, Mu D. Is interleukin-2 an optimal marker for diagnosing tuberculosis infection? A systematic review and meta-analysis. Ann Med 2020; 52:376-385. [PMID: 32700645 PMCID: PMC7877967 DOI: 10.1080/07853890.2020.1800073] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Latent tuberculosis infection (LTBI) is a huge reservoir for the deadlier TB disease. Accurate identification of LTBI is a key strategy to eliminate TB. Therefore, a systematic review and meta-analysis approach was used to assess diagnostic potential of IL-2 for LTBI. METHODS PubMed, Web of Science, the Cochrane Library and Embase were searched. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), area under the summary receiver operating characteristic curve (AUROC) and hierarchical summary receiver operating characteristic curve (HSROC) were estimated by bivariate and HSROC models. RESULTS Twenty-seven studies including 1404 participants and 1986 samples met the inclusion criteria. The pooled sensitivity, specificity, PLR, NLR, DOR and AUROC of IL-2 were separately as 87%, 98%, 34.78, 0.14, 256.41 and 0.98, indicating a very powerful differentiating ability of IL-2 for LTBI from non-TB controls. For differentiating ATB from LTBI, the pooled sensitivity, specificity, PLR, NLR, DOR and AUROC of IL-2 were 83%, 76%, 3.41, 0.22, 15.47 and 0.87, respectively, suggesting a good differentiating ability of IL-2. CONCLUSIONS These findings showed that IL-2 is a powerful marker for differentiating LTBI from non-TB controls and a good marker for differentiating ATB from LTBI individuals.
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Affiliation(s)
- Xia Qiu
- Department of Pediatrics, West China Second University Hospital, Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, China
| | - Huiqing Wang
- Department of Pediatrics, West China Second University Hospital, Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, China
| | - Ying Tang
- Department of Ultrasonic, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Xiaojuan Su
- Department of Pediatrics, West China Second University Hospital, Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, China
| | - Long Ge
- Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
| | - Yi Qu
- Department of Pediatrics, West China Second University Hospital, Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, China
| | - Dezhi Mu
- Department of Pediatrics, West China Second University Hospital, Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, China
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6
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Xia A, Xu Z, Hu T, Li X, Zhu Z, Chen X, Jiao X. Development of a flow cytometry assay for bovine interleukin-2 and its preliminary application in bovine tuberculosis detection. Vet Immunol Immunopathol 2020; 228:110112. [PMID: 32892112 DOI: 10.1016/j.vetimm.2020.110112] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 07/28/2020] [Accepted: 08/14/2020] [Indexed: 10/23/2022]
Abstract
Mycobacterium bovis, the causative agent of bovine tuberculosis (bTB), poses a risk of infection for livestock, humans, and wildlife. An interferon (IFN)-γ release assay has been used with tuberculin skin tests to detect bTB; however, infected animals may still be missed. Previous studies have suggested that bovine interleukin-2 (BoIL-2) may act as a potential biological marker for the diagnosis of bovine infectious diseases. However, a detailed evaluation of IL-2 as a diagnostic target for bTB is lacking. Therefore, we established hybridoma cell lines that produced monoclonal antibodies (mAbs) recognizing the native BoIL-2 and developed a flow cytometry assay, based on the BoIL-2 mAbs, for detecting M. bovis-specific IL-2. Subsequently, the method was utilized for a preliminary investigation of bTB in cattle; significantly (P < 0.0001) more CD4+IL-2+ T cells were detected in infected cattle than in healthy animals when a specific mycobacterial antigen CFP-10-ESAT-6 fusion protein was used. Moreover, our method demonstrated high coincidence rates with the BOVIGAM® test and an IFN-γ flow cytometry assay for the diagnosis of bTB. These findings show that the present method may be useful for detecting bTB.
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Affiliation(s)
- Aihong Xia
- Jiangsu Key Laboratory of Zoonosis/Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
| | - Zhengzhong Xu
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture and Rural Affairs, Yangzhou University, Yangzhou 225009, China
| | - Ting Hu
- Jiangsu Key Laboratory of Zoonosis/Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
| | - Xin Li
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture and Rural Affairs, Yangzhou University, Yangzhou 225009, China
| | - Zhaocheng Zhu
- Jiangsu Key Laboratory of Zoonosis/Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
| | - Xiang Chen
- Jiangsu Key Laboratory of Zoonosis/Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China.
| | - Xinan Jiao
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture and Rural Affairs, Yangzhou University, Yangzhou 225009, China.
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7
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Yong YK, Tan HY, Saeidi A, Wong WF, Vignesh R, Velu V, Eri R, Larsson M, Shankar EM. Immune Biomarkers for Diagnosis and Treatment Monitoring of Tuberculosis: Current Developments and Future Prospects. Front Microbiol 2019; 10:2789. [PMID: 31921004 PMCID: PMC6930807 DOI: 10.3389/fmicb.2019.02789] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 11/18/2019] [Indexed: 12/22/2022] Open
Abstract
Tuberculosis (TB) treatment monitoring is paramount to clinical decision-making and the host biomarkers appears to play a significant role. The currently available diagnostic technology for TB detection is inadequate. Although GeneXpert detects total DNA present in the sample regardless live or dead bacilli present in clinical samples, all the commercial tests available thus far have low sensitivity. Humoral responses against Mycobacterium tuberculosis (Mtb) antigens are generally low, which precludes the use of serological tests for TB diagnosis, prognosis, and treatment monitoring. Mtb-specific CD4+ T cells correlate with Mtb antigen/bacilli burden and hence might serve as good biomarkers for monitoring treatment progress. Omics-based techniques are capable of providing a more holistic picture for disease mechanisms and are more accurate in predicting TB disease outcomes. The current review aims to discuss some of the recent advances on TB biomarkers, particularly host biomarkers that have the potential to diagnose and differentiate active TB and LTBI as well as their use in disease prognosis and treatment monitoring.
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Affiliation(s)
- Yean K Yong
- Laboratory Center, Xiamen University Malaysia, Sepang, Malaysia
| | - Hong Y Tan
- Laboratory Center, Xiamen University Malaysia, Sepang, Malaysia.,Department of Traditional Chinese Medicine, Xiamen University Malaysia, Sepang, Malaysia
| | - Alireza Saeidi
- Department of Pediatrics, Emory Vaccine Center, Atlanta, GA, United States
| | - Won F Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | | | - Vijayakumar Velu
- Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, GA, United States
| | - Rajaraman Eri
- School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
| | - Marie Larsson
- Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden
| | - Esaki M Shankar
- Division of Infection Biology and Medical Microbiology, Department of Life Sciences, Central University of Tamil Nadu (CUTN), Thiruvarur, India
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8
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Identification of bovine tuberculosis biomarkers to detect tuberculin skin test and IFNγ release assay false negative cattle. Res Vet Sci 2019; 122:7-14. [DOI: 10.1016/j.rvsc.2018.10.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 10/04/2018] [Accepted: 10/29/2018] [Indexed: 12/18/2022]
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9
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Meier NR, Volken T, Geiger M, Heininger U, Tebruegge M, Ritz N. Risk Factors for Indeterminate Interferon-Gamma Release Assay for the Diagnosis of Tuberculosis in Children-A Systematic Review and Meta-Analysis. Front Pediatr 2019; 7:208. [PMID: 31192175 PMCID: PMC6548884 DOI: 10.3389/fped.2019.00208] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 05/08/2019] [Indexed: 12/26/2022] Open
Abstract
Background: Interferon-gamma release assays (IGRA) are well-established immunodiagnostic tests for tuberculosis (TB) in adults. In children these tests are associated with higher rates of false-negative and indeterminate results. Age is presumed to be one factor influencing cytokine release and therefore test performance. The aim of this study was to systematically review factors associated with indeterminate IGRA results in pediatric patients. Methods: Systematic literature review guided by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) searching PubMed, EMBASE, and Web of Science. Studies reporting results of at least one commercially available IGRA (QuantiFERON-TB, T-SPOT.TB) in pediatric patient groups were included. Random effects meta-analysis was used to assess proportions of indeterminate IGRA results. Heterogeneity was assessed using the I2 value. Risk differences were calculated for studies comparing QuantiFERON-TB and T-SPOT.TB in the same study. Meta-regression was used to further explore the influence of study level variables on heterogeneity. Results: Of 1,293 articles screened, 133 studies were included in the final analysis. These assessed QuantiFERON-TB only in 77.4% (103/133), QuantiFERON-TB and T-SPOT.TB in 15.8% (21/133), and T-SPOT.TB only in 6.8% (9/133) resulting in 155 datasets including 107,418 participants. Overall 4% of IGRA results were indeterminate, and T-SPOT.TB (0.03, 95% CI 0.02-0.05) and QuantiFERON-TB assays (0.05, 95% CI 0.04-0.06) showed similar proportions of indeterminate results; pooled risk difference was-0.01 (95% CI -0.03 to 0.00). Significant differences with lower proportions of indeterminate assays with T-SPOT.TB compared to QuantiFERON-TB were only seen in subgroup analyses of studies performed in Africa and in non-HIV-infected immunocompromised patients. Meta-regression confirmed lower proportions of indeterminate results for T-SPOT.TB compared to QuantiFERON-TB only among studies that reported results from non-HIV-infected immunocompromised patients (p < 0.001). Conclusion: On average indeterminate IGRA results occur in 1 in 25 tests performed. Overall, there was no difference in the proportion of indeterminate results between both commercial assays. However, our findings suggest that in patients in Africa and/or patients with immunocompromising conditions other than HIV infection the T-SPOT.TB assay appears to produce fewer indeterminate results.
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Affiliation(s)
- Noëmi R Meier
- Mycobacterial Research Laboratory, University of Basel Children's Hospital, Basel, Switzerland.,Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Thomas Volken
- School of Health Professions, Zürich University of Applied Sciences, Winterthur, Switzerland
| | - Marc Geiger
- Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Ulrich Heininger
- Faculty of Medicine, University of Basel, Basel, Switzerland.,Paediatric Infectious Diseases and Vaccinology Unit, University of Basel Children's Hospital, Basel, Switzerland
| | - Marc Tebruegge
- UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.,Department of Paediatric Infectious Diseases and Immunology, Evelina London Children's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.,Royal Children's Hospital Melbourne, Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
| | - Nicole Ritz
- Mycobacterial Research Laboratory, University of Basel Children's Hospital, Basel, Switzerland.,Faculty of Medicine, University of Basel, Basel, Switzerland.,Paediatric Infectious Diseases and Vaccinology Unit, University of Basel Children's Hospital, Basel, Switzerland.,Royal Children's Hospital Melbourne, Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
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10
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Sousa J, Saraiva M. Paradigm changing evidence that alter tuberculosis perception and detection: Focus on latency. INFECTION GENETICS AND EVOLUTION 2018; 72:78-85. [PMID: 30576838 DOI: 10.1016/j.meegid.2018.12.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 12/12/2018] [Accepted: 12/15/2018] [Indexed: 12/23/2022]
Abstract
Tuberculosis remains a devastating disease to Mankind, ranking as the ninth cause of death worldwide. Eliminating tuberculosis as proven much more difficult than once anticipated. In addition to the delay in diagnosis and drug resistance problems that compromise the efficacy of treatment, the enormous reservoir of latently infected individuals continuously feeds the epidemics. However, targeting latency with prophylactic antibiotic administration is not possible at the populational level. Together, these issues call for a better understanding of latency, as well as for a more precise identification of individuals at high risk of reactivation. For this, recent paradigm changing evidence need to be taken into account, most notably, the existence of a tuberculosis spectrum; the genetic diversity of both humans and tuberculosis-causing bacteria; and the changes in the human population that interfere with tuberculosis. Here we discuss latency in the light of these variables and how that understanding can move forward tuberculosis research and elimination.
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Affiliation(s)
- Jeremy Sousa
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
| | - Margarida Saraiva
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
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11
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Petrone L, Vanini V, Chiacchio T, Petruccioli E, Cuzzi G, Schininà V, Palmieri F, Ippolito G, Goletti D. Evaluation of IP-10 in Quantiferon-Plus as biomarker for the diagnosis of latent tuberculosis infection. Tuberculosis (Edinb) 2018; 111:147-153. [PMID: 30029901 DOI: 10.1016/j.tube.2018.06.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 05/29/2018] [Accepted: 06/05/2018] [Indexed: 11/30/2022]
Abstract
The QuantiFERON-TB Gold Plus (QFT-Plus) is a new test for latent tuberculosis infection (LTBI) diagnosis, in which has been added a new tube containing shorter peptides stimulating CD8 T-cells and CD4-stimulating-peptides. Measurement of alternative biomarkers to Interferon-γ (IFN-γ) in QFT-Plus may improve its sensitivity. Interferon-γ inducible protein 10 (IP-10), has been proposed as a tuberculosis (TB) biomarker. We aimed to evaluate the IP-10 accuracy in QFT-Plus for LTBI diagnosis. QFT-Plus was performed in 36 active TB, 31 LTBI and 16 healthy donors (HD). IP-10 was detected by ELISA. IP-10 is increased in TB1 and TB2 tubes in subjects with active TB and LTBI compared to HD. A ROC analysis comparing active TB and HD was performed and a cut-off of 1174 pg/mL for TB1 and 928.8 pg/mL for TB2 identified active TB with 86% sensitivity (Se) and 94% specificity (Sp). Moreover, increased IP-10 in response to TB1 was found in subjects with LTBI compared to those with active TB. A cut-off point of ≥16,108 pg/mL was chosen to maximize the test performance. However, the test predicted LTBI only with 58% Se and 61% Sp. These results suggest that IP-10 is an alternative biomarker to IFN-γ in the QFT-Plus format.
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Affiliation(s)
- Linda Petrone
- Translational Research Unit, National Institute for Infectious Diseases "L.Spallanzani" (INMI), Via Portuense 292, 00149, Rome, Italy.
| | - Valentina Vanini
- Translational Research Unit, National Institute for Infectious Diseases "L.Spallanzani" (INMI), Via Portuense 292, 00149, Rome, Italy.
| | - Teresa Chiacchio
- Translational Research Unit, National Institute for Infectious Diseases "L.Spallanzani" (INMI), Via Portuense 292, 00149, Rome, Italy.
| | - Elisa Petruccioli
- Translational Research Unit, National Institute for Infectious Diseases "L.Spallanzani" (INMI), Via Portuense 292, 00149, Rome, Italy.
| | - Gilda Cuzzi
- Translational Research Unit, National Institute for Infectious Diseases "L.Spallanzani" (INMI), Via Portuense 292, 00149, Rome, Italy.
| | | | | | | | - Delia Goletti
- Translational Research Unit, National Institute for Infectious Diseases "L.Spallanzani" (INMI), Via Portuense 292, 00149, Rome, Italy.
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Villar-Hernández R, Latorre I, Mínguez S, Díaz J, García-García E, Muriel-Moreno B, Lacoma A, Prat C, Olivé A, Ruhwald M, Mateo L, Domínguez J. Use of IFN-γ and IP-10 detection in the diagnosis of latent tuberculosis infection in patients with inflammatory rheumatic diseases. J Infect 2017; 75:315-325. [PMID: 28751171 DOI: 10.1016/j.jinf.2017.07.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 07/12/2017] [Accepted: 07/13/2017] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Biologic agents are used against rheumatic diseases, however, they increase the risk of developing severe infections and diseases such as tuberculosis. We aimed to determine the benefits of IP-10 detection to diagnose latent tuberculosis infection (LTBI) in patients with inflammatory rheumatic diseases on different immunosuppressive drug regimens, and compare these results with IFN-γ detection. MATERIALS AND METHODS We included 64 patients with inflammatory rheumatic diseases. We used QuantiFERON Gold In-Tube (QFN-G-IT) and T-SPOT.TB to detect IFN-γ production, and an in-house ELISA for IP-10 detection from the previous QFN-G-IT stimulated samples. We assessed the combined use of IFN-γ release assays (IGRAs) and IP-10 test, and analyzed the influence of immunotherapy on the tests performance. RESULTS We obtained 34.9% positive results by T-SPOT.TB, 25.0% by QFN-G-IT and 31.3% by IP-10 test. The combined use of IGRAs and IP-10 detection increased significantly the amount of positive results (p < 0.0001). Treatment intake had no significant effect on in vitro tests (p > 0.05). CONCLUSIONS IP-10 and IFN-γ detection is comparable and their combined use could increase the number of positive results in the diagnosis of LTBI in rheumatic patients. The tested assays were not influenced by rheumatoid immunosuppressive therapy. Thus, IP-10 could be of use in the development of new and improved LTBI diagnostic tools.
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Affiliation(s)
- Raquel Villar-Hernández
- Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - Irene Latorre
- Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - Sonia Mínguez
- Servei de Reumatología, Hospital Germans Trias i Pujol, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - Jéssica Díaz
- Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - Esther García-García
- Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - Beatriz Muriel-Moreno
- Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - Alicia Lacoma
- Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - Cristina Prat
- Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - Alex Olivé
- Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Servei de Reumatología, Hospital Germans Trias i Pujol, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - Morten Ruhwald
- Department of Infectious Disease Immunology Statens Serum Institut, Artillerivej 5, 2300, København S, Copenhagen, Denmark
| | - Lourdes Mateo
- Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Servei de Reumatología, Hospital Germans Trias i Pujol, Carretera del Canyet, 08916, Badalona, Barcelona, Spain
| | - José Domínguez
- Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Carretera del Canyet, 08916, Badalona, Barcelona, Spain; Universitat Autònoma de Barcelona, Carretera del Canyet, 08916, Badalona, Barcelona, Spain.
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Venturini E, Tersigni C, Chiappini E, de Martino M, Galli L. Optimizing the management of children with latent tuberculosis infection. Expert Rev Anti Infect Ther 2017; 15:341-349. [PMID: 28074660 DOI: 10.1080/14787210.2017.1279541] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION The management of latent tuberculosis (LTBI) in children represents an important issue for paediatricians because of the disease burden, the lack of a gold standard for the diagnosis and the high annual risk of progression to active disease. Areas covered: A review of English language articles on LTBI in children, published between the 1st of January 2010 and the 1st of July 2016, was conducted using multiple keywords and standardized terminology in PubMed database. This review provides an updated overview of the available tests for LTBI diagnosis in children, management strategies and treatment options. Expert commentary: Two tests are available for LTBI diagnosis: tuberculin skin test and interferon-gamma release assays, both with a suboptimal specificity and sensitivity, and both with the lack of capability in distinguishing between infection and disease. Several new markers have been identified but further studies are needed. Among all treatment regimes, because of the high safety and efficacy profile showed and to avoid the poor completion rate, the treatment with a three-month course of isoniazid and rifampicin is currently recommended. New vaccines are needed because of the spread of the disease despite BCG vaccination in high risk countries. Currently, 15 new vaccines are in the pipeline.
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Affiliation(s)
- E Venturini
- a Department of Health Sciences , University of Florence, Anna Meyer Children's University Hospital , Florence , Italy
| | - C Tersigni
- a Department of Health Sciences , University of Florence, Anna Meyer Children's University Hospital , Florence , Italy
| | - E Chiappini
- a Department of Health Sciences , University of Florence, Anna Meyer Children's University Hospital , Florence , Italy
| | - M de Martino
- a Department of Health Sciences , University of Florence, Anna Meyer Children's University Hospital , Florence , Italy
| | - L Galli
- a Department of Health Sciences , University of Florence, Anna Meyer Children's University Hospital , Florence , Italy
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Evaluation of IL-2, IL-10, IL-17 and IP-10 as potent discriminative markers for active tuberculosis among pulmonary tuberculosis suspects. Tuberculosis (Edinb) 2016; 99:100-108. [DOI: 10.1016/j.tube.2016.04.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 04/22/2016] [Accepted: 04/24/2016] [Indexed: 11/23/2022]
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Improving T-cell assays for diagnosis of latent TB infection: Confirmation of the potential role of testing Interleukin-2 release in Iranian patients. Allergol Immunopathol (Madr) 2016; 44:314-21. [PMID: 26786720 DOI: 10.1016/j.aller.2015.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 08/20/2015] [Accepted: 09/30/2015] [Indexed: 11/21/2022]
Abstract
BACKGROUND Since gamma interferon release assays (IGRAs) cannot differentiate between active tuberculosis and latent tuberculosis infection (LTBI), development of rapid and specific diagnosis tools are essential for discriminating between active tuberculosis (TB) from LTBI. Both IGRAs are based on Mycobacterium tuberculosis-specific antigens, namely, early secretory antigenic target 6 (ESAT-6) and 10kDa culture filtrate (CFP-10). The aim of this study was to evaluate the potential value of IL-2 secretion by whole blood cells after stimulation with rESAT-6 and rCFP-10 for discriminating between active and latent tuberculosis. METHODS Interleukin-2 and IFN-γ were measured after blood stimulation of 90 cases (30 with active TB, 30 with LTBI and 30 healthy controls) with recombinant ESAT-6 and CFP-10. Receiver operating characteristic (ROC) curve analysis was conducted to determine the best IL-2 and IFN-γ result thresholds in discriminating between cases with active or latent TB, and the corresponding sensitivity and specificity were recorded. RESULTS The IFN-γ release assay demonstrated a good sensitivity and specificity (sensitivity 83-84% and specificity 92%) for diagnosis of tuberculosis. The discrimination performance of IL-2 assay (assessed by the area under ROC curve) between LTBI and patients with active TB were 0.75 and 0.8 following stimulation with rESAT-6 and rCFP-10, respectively. Maximum discrimination was reached at a cut-off of 11.6pg/mL for IL-2 after stimulation with recombinant rESAT-6 with 72% sensitivity and 79% specificity and 10.7pg/mL for IL-2 following stimulation with rCFP-10 with 75% sensitivity and 79% specificity, respectively. CONCLUSION This study demonstrates that rESAT-6 and rCFP-10 can provide a sensitive and specific diagnosis of TB. In addition, it was shown that IL-2 may be serving as a marker for discriminating LTBI and active TB.
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Novel T-cell assays for the discrimination of active and latent tuberculosis infection: the diagnostic value of PPE family. Mol Diagn Ther 2016; 19:309-16. [PMID: 26245995 DOI: 10.1007/s40291-015-0157-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The diagnosis of active and latent tuberculosis remains a challenge. Although a new approach based on detecting Mycobacterium tuberculosis-specific T-cells has been introduced, it cannot distinguish between latent infection and active disease. The aim of this study was to evaluate the diagnostic potential of interleukin-2 (IL-2) as biomarker after specific antigen stimulation with PE35 and PPE68 for the discrimination of active and latent tuberculosis infection (LTBI). METHOD The production of IL-2 was measured in the antigen-stimulated whole-blood supernatants following stimulation with recombinant PE35 and PPE68. RESULTS The discrimination performance (assessed by the area under ROC curve) for IL-2 following stimulation with recombinant PE35 and PPE68 between LTBI and patients with active TB were 0.837 [95 % confidence interval (CI) 0.72-0.97] for LTBI diagnosis and 0.75 (95 % CI 0.63-0.89) for active TB diagnosis, respectively. Applying the 6.4 pg/mL cut-off for IL-2 induced by PE35 in the present study population resulted in sensitivity of 78 %, specificity of 83 %, PPV of 83 % and NPV of 78 % for the discrimination of active TB and LTBI. In addition, a sensitivity of 81 %, specificity of 71 %, PPV of 68 and 83 % of NPV was reported based on the 4.4 pg/mL cut-off for IL-2 induced by PPE68. CONCLUSION This study confirms IL-2 induced by PE35 and PPE68 as a sensitive and specific biomarker and highlights IL-2 as new promising adjunct markers for discriminating of LTBI and active TB disease.
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17
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Goletti D, Petruccioli E, Joosten SA, Ottenhoff THM. Tuberculosis Biomarkers: From Diagnosis to Protection. Infect Dis Rep 2016; 8:6568. [PMID: 27403267 PMCID: PMC4927936 DOI: 10.4081/idr.2016.6568] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 04/29/2016] [Indexed: 12/25/2022] Open
Abstract
New approaches to control tuberculosis (TB) worldwide are needed. In particular, new tools for diagnosis and new biomarkers are required to evaluate both pathogen and host key elements of the response to infection. Non-sputum based diagnostic tests, biomarkers predictive of adequate responsiveness to treatment, and biomarkers of risk of developing active TB disease are major goals. Here, we review the current state of the field. Although reports on new candidate biomarkers are numerous, validation and independent confirmation are rare. Efforts are needed to reduce the gap between the exploratory up-stream identification of candidate biomarkers, and the validation of biomarkers against clear clinical endpoints in different populations. This will need a major commitment from both scientists and funding bodies.
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Affiliation(s)
- Delia Goletti
- Translational Research Unit, Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases, L. Spallanzani , Rome, Italy
| | - Elisa Petruccioli
- Translational Research Unit, Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases, L. Spallanzani , Rome, Italy
| | - Simone A Joosten
- Department of Infectious Diseases, Leiden University Medical Centre , The Netherlands
| | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Centre , The Netherlands
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18
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Biraro IA, Kimuda S, Egesa M, Cose S, Webb EL, Joloba M, Smith SG, Elliott AM, Dockrell HM, Katamba A. The Use of Interferon Gamma Inducible Protein 10 as a Potential Biomarker in the Diagnosis of Latent Tuberculosis Infection in Uganda. PLoS One 2016; 11:e0146098. [PMID: 26771653 PMCID: PMC4714877 DOI: 10.1371/journal.pone.0146098] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 12/14/2015] [Indexed: 12/14/2022] Open
Abstract
Background In the absence of a gold standard for the diagnosis of latent tuberculosis (TB) infection (LTBI), the current tests available for the diagnosis of LTBI are limited by their inability to differentiate between LTBI and active TB disease. We investigated IP-10 as a potential biomarker for LTBI among household contacts exposed to sputum positive active TB cases. Methods Active TB cases and contacts were recruited into a cohort with six months’ follow-up. Contacts were tested for LTBI using QuantiFERON®-TB Gold In-Tube (QFN) assay and the tuberculin skin test (TST). Baseline supernatants from the QFN assay of 237 contacts and 102 active TB cases were analysed for Mycobacterium tuberculosis (MTB) specific and mitogen specific IP-10 responses. Results Contacts with LTBI (QFN+TST+) had the highest MTB specific IP-10 responses at baseline, compared to uninfected contacts (QFN-TST-) p<0.0001; and active cases, p = 0.01. Using a cut-off of 8,239 pg/ml, MTB specific IP-10 was able to diagnose LTBI with a sensitivity of 87.1% (95% CI, 76.2–94.3) and specificity of 90.9% (95% CI, 81.3–96.6). MTB specific to mitogen specific IP-10 ratio was higher in HIV negative active TB cases, compared to HIV negative latently infected contacts, p = 0.0004. Concentrations of MTB specific IP-10 were higher in contacts with TST conversion (negative at baseline, positive at 6-months) than in those that were persistently TST negative, p = 0.001. Conclusion IP-10 performed well in differentiating contacts with either latent or active TB from those who were uninfected but was not able to differentiate LTBI from active disease except when MTB specific to mitogen specific ratios were used in HIV negative adults. In addition, IP-10 had the potential to diagnose ‘recent TB infection’ in persons classified as having LTBI using the TST. Such individuals with strong IP-10 responses would likely benefit from chemoprophylaxis.
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Affiliation(s)
- Irene Andia Biraro
- Makerere University College of Health Sciences, Kampala, Uganda
- Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
- * E-mail:
| | - Simon Kimuda
- Makerere University College of Health Sciences, Kampala, Uganda
- Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - Moses Egesa
- Makerere University College of Health Sciences, Kampala, Uganda
- Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - Stephen Cose
- Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
- Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Emily L. Webb
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Moses Joloba
- Makerere University College of Health Sciences, Kampala, Uganda
| | - Steven G. Smith
- Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Alison M. Elliott
- Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
- Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Hazel M. Dockrell
- Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, United Kingdom
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The effect of HIV coinfection, HAART and TB treatment on cytokine/chemokine responses to Mycobacterium tuberculosis (Mtb) antigens in active TB patients and latently Mtb infected individuals. Tuberculosis (Edinb) 2015; 96:131-40. [PMID: 26631832 DOI: 10.1016/j.tube.2015.05.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 05/25/2015] [Accepted: 05/31/2015] [Indexed: 11/22/2022]
Abstract
Identification of Mtb specific induced cytokine/chemokine host biomarkers could assist in developing novel diagnostic, prognostic and therapeutic tools for TB. Levels of IFN-γ, IL-2, IL-17, IL-10, IP-10 and MIP-1α were measured in supernatants of whole blood stimulated with Mtb specific fusion protein ESAT-6/CFP-10 using xMAP technology. The study groups were HIV positive TB patients (HIV(+)TB(+)), HIV negative TB patients (HIV(-)TB(+)), HIV positive tuberculin skin test positive (TST+) (HIV(+)TST(+)), HIV negative TST+ (HIV(-)TST(+)), and HIV(-)TST(-) individuals. Compared to HIV(-)TST(-), latent TB infection led to increased levels of IP-10, IFN-γ and IL-17, while levels of IL-2 and IP-10 were increased with active TB. Levels of IFN-γ, IL-17, MIP-1α, and IL-10 were increased in HIV(-)TST(+) individuals compared to HIV(-)TB(+) patients. HIV coinfection decreased the level of IFN-γ, IL-17, IP-10 and IL-2. After six months (M6) of anti-TB treatment (ATT) in HIV(-)TB(+) patients, IFN-γ, IL-10, and MIP-1α levels normalized. After M6 and M18 of ATT plus HAART in HIV(+)TB(+) patients, levels of MIP-1α and IL-10 normalized, while this was not the case for IFN-γ, IL-2, IL-17, and IP-10 levels. In HIV(+)TST(+) patients on HAART, levels of IFN-γ, IL-17, IL-10 and MIP-1α normalized, while no change in the levels of IL-2 and IP-10 were observed. In conclusion, the simultaneous measurement of IFN-γ, IL-17 and IP-10 may assist in diagnosing LTBI; IL-2 and IP-10 may assist in diagnosing active TB; while IFN-γ, IL-17, MIP-1α, and IL-10 levels could help to discriminate LTBI and active TB. In addition, IL-10 and MIP-1α levels could help to monitor responses to TB treatment and HAART.
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Blood or Urine IP-10 Cannot Discriminate between Active Tuberculosis and Respiratory Diseases Different from Tuberculosis in Children. BIOMED RESEARCH INTERNATIONAL 2015; 2015:589471. [PMID: 26346028 PMCID: PMC4540955 DOI: 10.1155/2015/589471] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 07/08/2015] [Accepted: 07/14/2015] [Indexed: 01/01/2023]
Abstract
Objectives. Interferon-γ inducible protein 10 (IP-10), either in blood or in urine, has been proposed as a tuberculosis (TB) biomarker for adults. This study aims to evaluate the potential of IP-10 diagnostics in children from Uganda, a high TB-endemic country. Methods. IP-10 was measured in the blood and urine concomitantly taken from children who were prospectively enrolled with suspected active TB, with or without HIV infection. Clinical/microbiological parameters and commercially available TB-immune assays (tuberculin skin test (TST) and QuantiFERON TB-Gold In-Tube (QFT-IT)) were concomitantly evaluated. Results. One hundred twenty-eight children were prospectively enrolled. The analysis was performed on 111 children: 80 (72%) of them were HIV-uninfected and 31 (27.9%) were HIV-infected. Thirty-three healthy adult donors (HAD) were included as controls. The data showed that IP-10 is detectable in the urine and blood of children with active TB, independent of HIV status and age. However, although IP-10 levels were higher in active TB children compared to HAD, the accuracy of identifying “active TB” was low and similar to the TST and QFT-IT. Conclusion. IP-10 levels are higher in children with respiratory illness compared to controls, independent of “TB status” suggesting that the evaluation of this parameter can be used as an inflammatory marker more than a TB test.
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Abstract
The challenge of diagnosing childhood tuberculosis (TB) results from its paucibacillary nature and the difficulties of sputum collection in children. Mycobacterial culture, the diagnostic gold standard, provides microbiological confirmation in only 30% to 40% of childhood pulmonary TB cases and takes up to 6 weeks to result. Conventional drug susceptibility testing requires an additional 2 to 4 weeks after culture confirmation. In response to the low sensitivity and long wait time of the traditional diagnostic approach, many new assays have been developed. These new tools have shortened time to result; however, none of them offer greater sensitivity than culture.
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Affiliation(s)
- Silvia S Chiang
- Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, 1102 Bates Street, Suite 1150, Houston, TX 77030, USA; Department of Global Health and Social Medicine, Harvard Medical School, 641 Huntington Avenue, Boston, MA 02115, USA
| | - Douglas S Swanson
- Division of Infectious Diseases, Department of Pediatrics, University of Missouri-Kansas City School of Medicine, 2401 Gillham Road, Kansas City, MO 64108, USA
| | - Jeffrey R Starke
- Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, 1102 Bates Street, Suite 1150, Houston, TX 77030, USA.
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Venturini E, Remaschi G, Berti E, Montagnani C, Galli L, de Martino M, Chiappini E. What steps do we need to take to improve diagnosis of tuberculosis in children? Expert Rev Anti Infect Ther 2015; 13:907-22. [PMID: 25938981 DOI: 10.1586/14787210.2015.1040764] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Tuberculosis still represents a big global public health challenge. The diagnosis of tuberculosis and the differentiation between active and latent tuberculosis remain difficult, particularly in childhood, because of the lack of a gold standard test for diagnosis. In the last decade, novel diagnostic assays have been developed. Among immunologic tests, new assays based on the measurement of different cytokines released by specific T cells in response to Mycobacterium tuberculosis antigens, other than INF-γ, have been investigated. Promising results rely on nucleic acid amplification techniques, also able to detect drugs resistance. Innovative research fields studied the modifications of CD27 expression in T cells as well as different host gene expression in response to M. tuberculosis. Further studies are needed to assess the diagnostic value and the accuracy of these new assays.
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Affiliation(s)
- Elisabetta Venturini
- Department of Health Sciences, Anna Meyer Children's University Hospital, University of Florence, Florence, Italy
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Romero-Adrian TB, Leal-Montiel J, Fernández G, Valecillo A. Role of cytokines and other factors involved in the Mycobacterium tuberculosis infection. World J Immunol 2015; 5:16-50. [DOI: 10.5411/wji.v5.i1.16] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 11/18/2014] [Accepted: 02/09/2015] [Indexed: 02/05/2023] Open
Abstract
Mycobacterium tuberculosis (Mtb) is a pathogen that is widely distributed geographically and continues to be a major threat to world health. Bacterial virulence factors, nutritional state, host genetic condition and immune response play an important role in the evolution of the infection. The genetically diverse Mtb strains from different lineages have been shown to induce variable immune system response. The modern and ancient lineages strains induce different cytokines patterns. The immunity to Mtb depends on Th1-cell activity [interferon-γ (IFN-γ), interleukin-12 (IL-12) and tumor necrosis factor-α (TNF-α)]. IL-1β directly kills Mtb in murine and human macrophages. IL-6 is a requirement in host resistance to Mtb infection. IFN-γ, TNF-α, IL-12 and IL-17 are participants in Mycobacterium-induced granuloma formation. Other regulating proteins as IL-27 and IL-10 can prevent extensive immunopathology. CXCL 8 enhances the capacity of the neutrophil to kill Mtb. CXCL13 and CCL19 have been identified as participants in the formation of granuloma and control the Mtb infection. Treg cells are increased in patients with active tuberculosis (TB) but decrease with anti-TB treatment. The increment of these cells causes down- regulation of adaptive immune response facilitating the persistence of the bacterial infection. Predominance of Th2 phenotype cytokines increases the severity of TB. The evolution of the Mtb infection will depend of the cytokines network and of the influence of other factors aforementioned.
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IP-10 measured by Dry Plasma Spots as biomarker for therapy responses in Mycobacterium Tuberculosis infection. Sci Rep 2015; 5:9223. [PMID: 25783975 PMCID: PMC4363864 DOI: 10.1038/srep09223] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 02/23/2015] [Indexed: 12/13/2022] Open
Abstract
Tuberculosis (TB) has huge impact on human morbidity and mortality and biomarkers to support rapid TB diagnosis and ensure treatment initiation and cure are needed, especially in regions with high prevalence of multi-drug resistant TB. Soluble interferon gamma inducible protein 10 (IP-10) analyzed from dry plasma spots (DPS) has potential as an immunodiagnostic marker in TB infection. We analyzed IP-10 levels in plasma directly and extracted from DPS in parallel by ELISA from 34 clinically well characterized patients with TB disease before and throughout 24 weeks of effective anti-TB chemotherapy. We detected a significant decline of IP-10 levels in both plasma and DPS already after two weeks of therapy with good correlation between the tests. This was observed both in pulmonary and extrapulmonary TB. In conclusion, plasma IP-10 may serve as an early biomarker for anti-TB chemotherapy responses and the IP-10 DPS method has potential to be developed into a point-of care test for use in resource-limited settings. Further studies must be performed to validate the use of IP-10 DPS in TB high endemic countries.
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Wergeland I, Pullar N, Assmus J, Ueland T, Tonby K, Feruglio S, Kvale D, Damås JK, Aukrust P, Mollnes TE, Dyrhol-Riise AM. IP-10 differentiates between active and latent tuberculosis irrespective of HIV status and declines during therapy. J Infect 2015; 70:381-91. [PMID: 25597826 DOI: 10.1016/j.jinf.2014.12.019] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 12/15/2014] [Accepted: 12/17/2014] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Biomarkers for diagnosis and therapy efficacy in tuberculosis (TB) are requested. We have studied biomarkers that may differentiate between active and latent TB infection (LTBI), the influence of HIV infection and changes during anti-TB chemotherapy. METHODS Thirty-eight plasma cytokines, assessed by multiplex and enzyme immunoassays, were analyzed in patients with active TB before and during 24 weeks of anti-TB chemotherapy (n = 65), from individuals with LTBI (n = 34) and from QuantiFERON-TB (QFT) negative controls (n = 65). The study participants were grouped according to HIV status. RESULTS Plasma levels of the CXC chemokine IP-10 and soluble TNF receptor type 2 (sTNFr2) significantly differentiated active TB from the LTBI group, irrespective of HIV status. In the HIV-infected group the sensitivity and specificity was 100% for IP-10 with a cut-off of 2547 pg/mL. Plasma IP-10 declined gradually during anti-TB chemotherapy (12-24 weeks, p = 0.002) to a level comparable to LTBI and QFT negative control groups. sTNFr2 fluctuated throughout therapy, but was decreased after 12-24 weeks (p = 0.006). CONCLUSIONS IP-10 distinguished with high accuracy active TB from LTBI irrespective of HIV infection and declined during anti-TB chemotherapy. Plasma IP-10 may serve as a diagnostic biomarker to differentiate between the stages of TB infection and for monitoring therapy efficacy.
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Affiliation(s)
- I Wergeland
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway
| | - N Pullar
- Department of Internal Medicine, Section for Infectious Diseases, University Hospital of Northern Norway, N-9038 Tromsø, Norway; Department of Clinical Medicine, University of Tromsø, N-9037 Tromsø, Norway
| | - J Assmus
- Center for Clinical Research, Haukeland University Hospital, N-5020 Bergen, Norway
| | - T Ueland
- Institute of Clinical Medicine and K.G. Jebsen IRC, University of Oslo, N-0424 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital, N-0424 Oslo, Norway
| | - K Tonby
- Institute of Clinical Medicine and K.G. Jebsen IRC, University of Oslo, N-0424 Oslo, Norway
| | - S Feruglio
- Institute of Clinical Medicine and K.G. Jebsen IRC, University of Oslo, N-0424 Oslo, Norway
| | - D Kvale
- Institute of Clinical Medicine and K.G. Jebsen IRC, University of Oslo, N-0424 Oslo, Norway; Department of Infectious Diseases, Oslo University Hospital, N-0424 Oslo, Norway
| | - J K Damås
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Infectious Diseases, St Olav's Hospital, Trondheim, Norway
| | - P Aukrust
- Institute of Clinical Medicine and K.G. Jebsen IRC, University of Oslo, N-0424 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital, N-0424 Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, N-0424 Oslo, Norway
| | - T E Mollnes
- Institute of Clinical Medicine and K.G. Jebsen IRC, University of Oslo, N-0424 Oslo, Norway; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway; Research Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway
| | - A M Dyrhol-Riise
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Institute of Clinical Medicine and K.G. Jebsen IRC, University of Oslo, N-0424 Oslo, Norway; Department of Infectious Diseases, Oslo University Hospital, N-0424 Oslo, Norway.
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Gunluoglu G, Seyhan EC, Kazancioglu R, Gunluoglu Z, Veske NS, Yazar EE, Altin S. Diagnosing latent tuberculosis in immunocompromised patients measuring blood IP-10 production capacity: an analysis of chronic renal failure patients. Intern Med 2015; 54:465-72. [PMID: 25758071 DOI: 10.2169/internalmedicine.54.3245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE Patients undergoing haemodialysis for chronic renal failure-hemodialysis (CRF-HD) are at risk of latent tuberculosis infection (LTBI). The effectiveness of using blood IP-10 production capacity to diagnose LTBI in CRF-HD patients was analysed. METHODS The study enrolled 50 CRF-HD patients. Interferon-γ release assay (IGRA) was done using QuantiFERON-TB Gold In Tube (QFG-IT) system. Blood IP-10 production capacity was measured using the QFG-IT system tubes. Tuberculin skin testing (TST) was performed on the same day and the test results were compared. RESULTS TST turned out to be positive in 36.4% of the patients and QFG-IT in 54% of them. After stimulation with specific tuberculosis antigens, blood IP-10 levels increased noticeably. The antigen-stimulated blood IP-10 level was significantly higher in patients who were either TST or QFG-IT positive than in patients whose tests were negative (p=0.0001). Using 4.02 pg/mL as the threshold for stimulated blood log-transformed IP-10 level, good agreement was observed between IP-10 and QFG-IT results (κ=1). CONCLUSION Blood IP-10 level, which can be measured simply, provides results equivalent to IGRAs for the diagnosis of LTBI in CRF-HD patients.
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Affiliation(s)
- Gulsah Gunluoglu
- Department of Chest Diseases, Yedikule Teaching Hospital for Chest Diseases and Thoracic Surgery, Turkey
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Holm LL, Rose MV, Kimaro G, Bygbjerg IC, Mfinanga SG, Ravn P, Ruhwald M. A comparison of interferon-γ and IP-10 for the diagnosis of tuberculosis. Pediatrics 2014; 134:e1568-75. [PMID: 25422019 DOI: 10.1542/peds.2014-1570] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE Interferon-γ and IP-10 release assays are diagnostic tests for tuberculosis infection. We have compared the accuracy of IP-10 and QuantiFERON-TB Gold In-tube [QFT-IT] in Tanzanian children suspected of having active tuberculosis (TB). METHODS Hospitalized Tanzanian children with symptoms of TB were tested with the QFT-IT and IP-10 tests and retrospectively classified into diagnostic groups. Adults with confirmed TB were assessed in parallel. RESULTS A total of 203 children were included. The median age was 3.0 years (interquartile range: 1.2-7.0), 38% were HIV infected, 36% were aged <2 years, and 58% had a low weight-for-age. IP-10 and QFT-IT test performance was comparable but sensitivity was low: 33% (1 of 3) in children with confirmed TB and 29% (8 of 28) in children with probable TB. Rates of indeterminate responders were high: 29% (59 of 203) for IP-10 and 26% (53 of 203) for QFT-IT. Age <2 years was associated with indeterminate test outcome for both IP-10 (adjusted odds ratio [aOR]: 2.2; P = .02) and QFT-IT (aOR: 2.4; P = .01). TB exposure was associated with positive IP-10 test outcome (aOR: 3.6; P = .01) but not with positive QFT-IT outcome (aOR 1.4; P = .52). In 102 adults, test sensitivity was 80% for both tests (P = .248). CONCLUSIONS Although IP-10 and QFT-IT performed well in Tanzanian adults, the tests exhibited an equally poor performance in diagnosing active TB in children. Test performance was especially compromised in young children. Neither test can be recommended for use in hospitalized children in high-burden settings.
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Affiliation(s)
| | - Michala Vaaben Rose
- Infectious Diseases, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Godfather Kimaro
- Muhimbili Medical Research Centre, National Institute for Medical Research, Dar es Salaam, Tanzania
| | - Ib C Bygbjerg
- Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Sayoki G Mfinanga
- Muhimbili Medical Research Centre, National Institute for Medical Research, Dar es Salaam, Tanzania
| | - Pernille Ravn
- Clinical Research Centre, and Department for Pulmonary and Infectious Diseases, Nordsjaelland Hospital, Hillerød, Denmark; and
| | - Morten Ruhwald
- Department of Infectious Disease Immunology, Statens Serum Institute, Copenhagen, Denmark
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Chung WY, Lee KS, Jung YJ, Lee HL, Kim YS, Park JH, Sheen SS, Park KJ. A TB antigen-stimulated CXCR3 ligand assay for the diagnosis of active pulmonary TB. Chest 2014; 146:283-291. [PMID: 24577604 DOI: 10.1378/chest.13-1855] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
BACKGROUND The ligands for CXC chemokine receptor 3 (CXCR3) recruit T-helper type 1 cells, which play a major role in cell-mediated immunity in TB. METHODS A total of 409 subjects were enrolled. The study population comprised 186 patients with active TB, 58 patients with non-TB pulmonary diseases, 50 control subjects with a positive interferon (IFN)-γ release assay (IGRA) result, and 115 control subjects with a negative IGRA result. Whole-blood samples were collected using IGRA methodology. After incubation, plasma IFN-γ levels and two CXCR3 ligands, IFN-inducible T-cell α-chemoattractant (I-TAC, CXCL11) and monokine induced by IFN-γ (MIG, CXCL9), were measured by enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) analysis was performed. Sensitivity and specificity were based on cutoff values selected to maximize the Youden index. RESULTS The TB antigen-stimulated levels of IFN-γ, I-TAC, and MIG were significantly increased in the active pulmonary TB group compared with all other groups. From ROC analysis, for the diagnosis of active TB, I-TAC and MIG outperformed IFN-γ in all comparisons with the IGRA-positive and -negative control groups and the non-TB pulmonary disease group. The areas under the curve (95% CI) for differentiating active pulmonary TB from all other groups were 0.893 (0.864-0.924) for IFN-γ, 0.962 (0.946-0.978) for I-TAC, and 0.944 (0.922-0.965) for MIG. Sensitivity and specificity were 90.3% and 90.7%, respectively, for I-TAC; 92.5% and 85.2% for MIG; and 84.9% and 79.8% for IFN-γ. CONCLUSIONS TB antigen-stimulated assays of I-TAC and MIG may be useful surrogate markers in the diagnosis of active pulmonary TB.
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Affiliation(s)
- Wou Young Chung
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Keu Sung Lee
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Yun Jung Jung
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Hye Lim Lee
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Young Sun Kim
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Joo Hun Park
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Seung Soo Sheen
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Kwang Joo Park
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea.
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Mamishi S, Pourakbari B, Teymuri M, Rubbo PA, Tuaillon E, Keshtkar AA, Mahmoudi S. Diagnostic accuracy of IL-2 for the diagnosis of latent tuberculosis: a systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis 2014; 33:2111-9. [PMID: 24993150 DOI: 10.1007/s10096-014-2190-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 06/12/2014] [Indexed: 10/25/2022]
Abstract
We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of interleukin-2 (IL-2) as biomarkers for the diagnosis of latent tuberculosis. Related studies were identified through searches of PubMed, Embase, Web of Science, and complementary manual searches up to December 30, 2013. We used standard methods recommended for meta-analyses of diagnostic test evaluations. The analysis was based on a summary receiver operating characteristic (SROC) curve. Meta-regression analysis was used to assess the effects of some confounding factors on the results of the meta-analysis. The potential presence of publication bias was tested using the Deeks' funnel plots. The pooled estimates of IL-2 for latent tuberculosis infection (LTBI) diagnosis were as follows: sensitivity, 0.81 [95 % confidence interval (CI), 0.60 to 0.92]; specificity, 0.95 (95 % CI, 0.90 to 0.97); positive likelihood ratio (PLR), 15.2 (95 % CI, 8.1to 28.4); negative likelihood ratio (NLR), 0.20 (95 % CI, 0.09 to 0.47). We found that the SROC curve is positioned near the upper left corner of the curve and the area under the curve (AUC) was 0.96 (95 % CI, 0.94 to 0.98). In conclusion, according to the meta-analysis, IL-2 is a valid marker for the diagnosis of LTBI. When there is no definite gold standard for the diagnosis of LTBI, IL-2 release assay in addition to interferon-gamma release assays (IGRAs) can improve the ability of IGRAs to identify individuals with LTBI.
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Affiliation(s)
- S Mamishi
- Pediatric Infectious Disease Research Center, Tehran University of Medical Sciences, Children's Medical Center Hospital, Dr. Gharib Street, Keshavarz Boulevard, Tehran, Iran
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Latorre I, Díaz J, Mialdea I, Serra-Vidal M, Altet N, Prat C, Díez N, Escribano A, Casas I, Rodrigo C, Ausina V, Ruhwald M, Domínguez J. IP-10 is an accurate biomarker for the diagnosis of tuberculosis in children. J Infect 2014; 69:590-9. [PMID: 24975172 DOI: 10.1016/j.jinf.2014.06.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 05/14/2014] [Accepted: 06/03/2014] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Performance of IFN-γ assays in children is compromised. Therefore, we investigated the utility of IP-10 for the detection of active tuberculosis (TB) and latent tuberculosis infection (LTBI) diagnosis in children; comparing its positivity with QuantiFERON-TB Gold In-Tube (QFN-G-IT) and T-SPOT.TB. METHODS We studied 230 children from three groups: active TB, screening (healthy children without known exposure to active TB patient screened at school or by their paediatrician) and contact-tracing studies. IFN-γ release was determined by QFN-G-IT and T-SPOT.TB. IP-10 was detected in QFN-G-IT supernatants by ELISA. RESULTS When combining QFN-G-IT and IP-10 assays, positive results improved significantly from 38.3% in QFN-G-IT and 33.9% in IP-10 to 41.3%. Age and type of contact were significant risk factors associated with positive QFN-G-IT and IP-10 results. IP-10 levels after antigen-specific stimulation were significantly higher in comparison to IFN-γ levels. Correlation between the three assays was good (κ = 0.717-0.783). CONCLUSIONS IP-10 cytokine is expressed in response to TB specific-antigens used in QFN-G-IT. In conclusion, the use of IFN-γ T-cell based assays in combination with an additional IP-10 assay detection could be useful for diagnosing active TB and LTBI in children.
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Affiliation(s)
- I Latorre
- Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain; CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain
| | - J Díaz
- Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain; CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain
| | - I Mialdea
- Unidad de Neumología Infantil, Hospital Clínico Universitario Valencia, Universidad de Valencia, Spain
| | - M Serra-Vidal
- Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain; CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain
| | - N Altet
- Unidad de Prevención y Control de la Tuberculosis de Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - C Prat
- Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain; CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain
| | - N Díez
- Unidad de Neumología Infantil, Hospital Clínico Universitario Valencia, Universidad de Valencia, Spain
| | - A Escribano
- Unidad de Neumología Infantil, Hospital Clínico Universitario Valencia, Universidad de Valencia, Spain
| | - I Casas
- Servei de Medicina Preventiva, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - C Rodrigo
- Universitat Autònoma de Barcelona, Bellaterra, Spain; Servei de Pediatria, Hospital Universitari Germans Trias I Pujol, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain
| | - V Ausina
- Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain; CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain
| | - M Ruhwald
- Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark
| | - J Domínguez
- Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain; CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain.
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Discordance of tuberculin skin test and interferon gamma release assay in recently exposed household contacts of pulmonary TB cases in Brazil. PLoS One 2014; 9:e96564. [PMID: 24819060 PMCID: PMC4018294 DOI: 10.1371/journal.pone.0096564] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 04/09/2014] [Indexed: 11/19/2022] Open
Abstract
Interferon-gamma (IFN-γ) release assays (IGRAs) such as the Quantiferon Gold In-tube test are in vitro assays that measure IFN-γ release from T cells in response to M. tuberculosis (Mtb)-specific antigens. Unlike the tuberculin skin test (TST), IGRA is specific and able to distinguish Mtb-infection from BCG vaccination. In this study we evaluated the concordance between TST and IGRA and the efficacy of IGRA in diagnosing new Mtb infection in household contacts (HHC) of pulmonary tuberculosis (PTB) cases. A total of 357 HHC of TB cases in Vitória, Brazil were studied. A TST was performed within 2 weeks following enrollment of the HHC and if negative a second TST was performed at 8-12 weeks. HHC were categorized as initially TST positive (TST+), persistently TST negative (TST-), or TST converters (TSTc), the latter representative of new infection. IGRA was performed at 8–12 weeks following enrollment and the test results were positive in 82% of TST+, 48% of TSTc, and 12% of TST-, indicating poor concordance between the two test results among HHC in each category. Evaluating CXCL10 levels in a subset of IGRA supernatants or lowering the IGRA cutoff value to define a positive test increased agreement between TST and IGRA test results. However, ROC curves demonstrated that this resulted in a trade-off between sensitivity and specificity of IGRA with respect to TST. Together, the findings suggest that until the basis for the discordance between TST and IGRA is fully understood, it may be necessary to utilize both tests to diagnose new Mtb infection in recently exposed HHC. Operationally, in IGRA negative HHC, it may be useful to employ a lower cutoff value for IGRA to allow closer monitoring for potential conversion.
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Guo SJ, Jia LQ, Hu QJ, Long HY, Pang CS, Wen FQ. Diagnostic accuracy of interferon gamma-induced protein 10 for tuberculosis: a meta-analysis. Int J Clin Exp Med 2014; 7:93-100. [PMID: 24482693 PMCID: PMC3902245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 11/21/2013] [Indexed: 06/03/2023]
Abstract
The diagnostic accuracy of tuberculosis (TB) remains a clinical challenge, and a number of studies have used the interferon gamma-induced protein 10 (IP-10) in the diagnosis of TB. The aim of the present meta-analysis was to determine the overall accuracy of IP-10 in the diagnosis of TB. A systematic review of studies published in English from Medline, Embase and Cochrane Library was conducted and the data concerning the accuracy of IP-10 in the diagnosis of TB were pooled. The methodological quality of each study was assessed by QUADAS (quality assessment for studies of diagnostic accuracy). Statistical analysis was performed by employing Meta-Disc 1.4 soft-ware and STATA. The overall test performance was summarized using receiver operating characteristic curves. 14 studies, based on 2075 subjects, met the inclusion criteria. The summary estimates for IP-10 in the diagnosis of TB were: sensitivity 0.73 (95% CI, 0.71-0.76), specificity 0.83 (95% CI, 0.81-0.86), positive likelihood ratio 7.08 (95% CI, 3.94-12.72), negative likelihood ratio 0.26 (95% CI, 0.20-0.35) and diagnostic odds ratio 29.50 (95% CI, 14.43-60.30), and the area under the curve was 0.88. Our findings suggest that IP-10 may improve the accuracy of TB diagnosis, while the results of IP-10 assays should be interpreted in parallel with conventional test results and other clinical findings.
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Chegou NN, Hoek KGP, Kriel M, Warren RM, Victor TC, Walzl G. Tuberculosis assays: past, present and future. Expert Rev Anti Infect Ther 2014; 9:457-69. [DOI: 10.1586/eri.11.23] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Vordermeier M, Jones GJ, Whelan AO. DIVA reagents for bovine tuberculosis vaccines in cattle. Expert Rev Vaccines 2014; 10:1083-91. [DOI: 10.1586/erv.11.22] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Whitworth HS, Aranday-Cortes E, Lalvani A. Biomarkers of tuberculosis: a research roadmap. Biomark Med 2013; 7:349-62. [PMID: 23734796 DOI: 10.2217/bmm.13.53] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Tuberculosis (TB) continues to represent a major public health problem worldwide. Prompt and accurate diagnosis and effective treatment are fundamental to reducing morbidity and mortality and curtailing spread of infection. Furthermore, tackling the large reservoir of latent infection is the cornerstone to TB control in many high income low TB incidence countries. However, our existing toolkit for prevention, diagnosis and treatment remains outdated and inadequate. Here, we discuss the key targets for biomarker research and discovery in TB and recent developments in the field. We focus on host biomarkers, in particular: correlates of vaccine efficacy and sterilizing immunity; biomarkers of latent TB infection, including diagnosis, risk of progression to active TB and response to treatment; and markers of active TB, including diagnosis, response to treatment and risk of relapse. Recent scientific and technological advances have contributed to significant recent progression in biomarker discovery. Although there are clear remaining paucities, continued efforts within scientific, translational and clinical studies are likely to yield a number of clinically useful biomarkers of TB in the foreseeable future.
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Affiliation(s)
- Hilary S Whitworth
- Tuberculosis Research Unit, Department of Respiratory Medicine, National Heart & Lung Institute, Imperial College London, London W2 1PG, UK
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Toll like receptor 2 agonists lipoteichoic acid and peptidoglycan are able to enhance antigen specific IFNγ release in whole blood during recall antigen responses. J Immunol Methods 2013; 396:107-15. [DOI: 10.1016/j.jim.2013.08.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 07/31/2013] [Accepted: 08/06/2013] [Indexed: 01/10/2023]
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Chegou NN, Detjen AK, Thiart L, Walters E, Mandalakas AM, Hesseling AC, Walzl G. Utility of host markers detected in Quantiferon supernatants for the diagnosis of tuberculosis in children in a high-burden setting. PLoS One 2013; 8:e64226. [PMID: 23691173 PMCID: PMC3655018 DOI: 10.1371/journal.pone.0064226] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 04/10/2013] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The diagnosis of childhood tuberculosis (TB) disease remains a challenge especially in young and HIV-infected children. Recent studies have identified potential host markers which, when measured in Quantiferon (QFT-IT) supernatants, show promise in discriminating between Mycobacterium tuberculosis (M.tb) infection states. In this study, the utility of such markers was investigated in children screened for TB in a setting with high TB incidence. METHODOLOGY AND PRINCIPAL FINDINGS 76 children (29% HIV-infected) with or without active TB provided blood specimens collected directly into QFT-IT tubes. After overnight incubation, culture supernatants were harvested, aliquoted and frozen for future immunological research purposes. Subsequently, the levels of 12 host markers previously identified as potential TB diagnostic markers were evaluated in these supernatants for their ability to discriminate between M.tb infection and disease states using the Luminex platform. Of the 76 children included, 19 (25%) had culture confirmed TB disease; 26 (46%) of the 57 without TB had positive markers of M.tb infection defined by a positive QFT-IT test. The potentially most useful analytes for diagnosing TB disease included IFN-α2, IL-1Ra, sCD40L and VEGF and the most useful markers for discriminating between QFT-IT positive children as TB or latent infection included IL-1Ra, IP-10 and VEGF. When markers were used in combinations of four, 84% of all children were accurately classified into their respective groups (TB disease or no TB), after leave-one-out cross validation. CONCLUSIONS Measurement of the levels of IFN-α2, IL-1Ra, sCD40L, IP-10 and VEGF in QFT-IT supernatants may be a useful method for diagnosing TB disease and differentiating between active TB disease and M.tb infection in children. Our observations warrant further investigation in larger well-characterized clinical cohorts.
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Affiliation(s)
- Novel N Chegou
- DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
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Trajman A, Steffen RE, Menzies D. Interferon-Gamma Release Assays versus Tuberculin Skin Testing for the Diagnosis of Latent Tuberculosis Infection: An Overview of the Evidence. Pulm Med 2013; 2013:601737. [PMID: 23476763 PMCID: PMC3582085 DOI: 10.1155/2013/601737] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Accepted: 01/10/2013] [Indexed: 11/18/2022] Open
Abstract
A profusion of articles have been published on the accuracy and uses of interferon-gamma releasing assays. Here we review the clinical applications, advantages, and limitations of the tuberculin skin test and interferon-gamma release assays and provide an overview of the most recent systematic reviews conducted for different indications for the use of these tests. We conclude that both tests are accurate to detect latent tuberculosis, although interferon-gamma release assays have higher specificity than tuberculin skin testing in BCG-vaccinated populations, particularly if BCG is received after infancy. However, both tests perform poorly to predict risk for progression to active tuberculosis. Interferon-gamma release assays have significant limitations in serial testing because of spontaneous variability and lack of a validated definition of conversion and reversion, making it difficult for clinicians to interpret changes in category (conversions and reversions). So far, the most important clinical evidence, that is, that isoniazid preventive therapy reduces the risk for progression to disease, has been produced only in tuberculin skin test-positive individuals.
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Affiliation(s)
- A. Trajman
- Gama Filho University, 20740-900 Rio de Janeiro, RJ, Brazil
- Montreal Chest Institute, McGill University, Montreal, QC, Canada H2X 2P4
| | - R. E. Steffen
- Federal University of Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
| | - D. Menzies
- Montreal Chest Institute, McGill University, Montreal, QC, Canada H2X 2P4
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Aabye MG, Latorre I, Diaz J, Maldonado J, Mialdea I, Eugen-Olsen J, Ravn P, Dominguez J, Ruhwald M. Dried plasma spots in the diagnosis of tuberculosis: IP-10 release assay on filter paper. Eur Respir J 2013; 42:495-503. [PMID: 23349445 PMCID: PMC3729975 DOI: 10.1183/09031936.00129412] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Interferon (IFN)-γ release assays (IGRAs) are probably the most accurate tests for the detection of latent Mycobacterium tuberculosis infection, but IGRAs are labour intensive and the transport of samples over longer distances is difficult. IFN-γ-induced protein (IP)-10 is expressed at 100-fold higher levels than IFN-γ, and IP-10 release assays have comparable performance to IGRAs. The aim of this study was to explore the diagnostic potential of a novel IP-10 release assay based on dried plasma spots (DPS). The presence of IP-10 and IFN-γ was determined in plasma and in DPS by ELISA. Diagnostic algorithms for plasma and DPS tests for IP-10 were developed on a training cohort comprising 60 tuberculosis (TB) patients and 59 healthy controls. Diagnostic accuracy was assessed in a validation cohort comprising 78 TB patients and 98 healthy controls. Plasma was measured in Spain and DPS samples were sent to Denmark using the conventional postal service for analysis. IP-10 was readily detectable in both plasma and DPS, and correlation was excellent (r(2) = 0.95). QuantiFERON-TB Gold In-Tube (QFT-TB) and IP-10 in DPS and plasma rendered comparable sensitivity (78%, 82% and 84%, respectively), specificity (100%, 97% and 97%, respectively) and indeterminate rates (p>0.55). The DPS-based IP-10 test has comparable diagnostic accuracy to the QFT-TB and samples can be sent via conventional mail over long distances for analysis without affecting the results.
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Affiliation(s)
- Martine G Aabye
- Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
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40
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Wang S, Diao N, Lu C, Wu J, Gao Y, Chen J, Zhou Z, Huang H, Shao L, Jin J, Weng X, Zhang Y, Zhang W. Evaluation of the diagnostic potential of IP-10 and IL-2 as biomarkers for the diagnosis of active and latent tuberculosis in a BCG-vaccinated population. PLoS One 2012; 7:e51338. [PMID: 23272100 PMCID: PMC3522729 DOI: 10.1371/journal.pone.0051338] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 11/06/2012] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The Mycobacterium tuberculosis (Mtb)-specific T-cell interferon gamma release assays (IGRAs) are useful in detecting Mtb infection but perform poorly at distinguishing active tuberculosis disease (ATB) and latent tuberculosis infection (LTBI). This study is aimed at evaluating additional cytokines as biomarkers besides interferon-gamma (IFN-γ) to improve the identification of ATB and LTBI. METHODOLOGY/PRINCIPAL FINDINGS Sixty-six patients with ATB, 73 household contacts (HHC) of ATB patients and 76 healthy controls (HC) were recruited to undergo QuantiFERON TB GOLD in-tube assay (QFT) and the enzyme-linked immunosorbent assay (ELISA) where the release of IFN-γ, IFN-γ inducible protein 10 (IP-10), Interleukin 2 (IL-2) and Tumor Necrosis Factor-α (TNF-α) was determined in the whole blood with or without antigen-stimulation. The positive rates of the QFT, IP-10 and IL-2 tests were 86.4%, 89.4% and 86.4% for the ATB group with no difference between them (p>0.05). However, QFT in combination with IP-10 and IL-2 significantly increased the detection rate to 95.5% in the ATB group (p = 0.03) and the indeterminate rate of all samples decreased from 2.3% (5/215) to 0.4% (1/215). The un-stimulated level of IP-10 was significantly higher in the HHC than the ATB and HC groups. The IP-10 responses were strongly associated with extended Mtb exposure time and the degree of smear-positivity of the index cases. The IL-2/IFN-γ ratio in the antigen-stimulated plasma could discriminate LTBI from ATB with a sensitivity of 77.2% and a specificity of 87.2%. CONCLUSION The increased Mtb-specific antigen-stimulated expression of IP-10 and IL-2 may be useful for detecting both ATB and LTBI. Combining the QFT with IP-10 and IL-2 could increase the detection accuracy of active TB over the QFT alone.
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Affiliation(s)
- Sen Wang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Ni Diao
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chanyi Lu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jing Wu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yan Gao
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiazhen Chen
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zumo Zhou
- People’s Hospital of Zhuji, Zhejiang Province, Zhuji, China
| | - Heqing Huang
- People’s Hospital of Zhuji, Zhejiang Province, Zhuji, China
| | - Lingyun Shao
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jialin Jin
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinhua Weng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Ying Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
- MOH and MOE Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- MOH and MOE Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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Immune responses to ESAT-6 and CFP-10 by FASCIA and multiplex technology for diagnosis of M. tuberculosis infection; IP-10 is a promising marker. PLoS One 2012; 7:e43438. [PMID: 23144772 PMCID: PMC3493549 DOI: 10.1371/journal.pone.0043438] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2011] [Accepted: 07/23/2012] [Indexed: 12/05/2022] Open
Abstract
Background There is a need for reliable markers to diagnose active and latent tuberculosis (TB). The interferon gamma release assays (IGRAs) are compared to the tuberculin skin test (TST) more specific, but cannot discriminate between recent or remote TB infection. Here the Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA), which quantifies expanded T-lymphoblasts by flow-cytometric analysis after long-term antigen stimulation of whole blood, is combined with cytokine/chemokine analysis in the supernatant by multiplex technology for diagnosis of Mycobacterium tuberculosis (Mtb) infection. Methods and Findings Consecutive patients with suspected TB (n = 85), with microbiologically verified active pulmonary TB (n = 33), extra pulmonary TB (n = 21), clinical TB (n = 11), presumed latent TB infection (LTBI) (n = 23), patients negative for TB (n = 8) and 21 healthy controls were studied. Blood samples were analyzed with FASCIA and multiplex technology to determine and correlate proliferative responses and the value of 14 cytokines for diagnosis of Mtb infection: IFN- γ, IL-2, TNF-α, IP-10, IL-12, IL-6, IL-4, IL-5, IL-13, IL-17, MIP-1β, GM-CSF, IFN-α2 and IL-10. Cytokine levels for IFN-γ, IP-10, MIP-1β, IL-2, TNF-α, IL-6, IL-10, IL-13 and GM-CSF were significantly higher after stimulation with the Mtb specific antigens ESAT-6 and CFP-10 in patients with active TB compared to healthy controls (p<0.05) and correlated with proliferative responses. IP-10 was positive in all patients with verified TB, if using a combination of ESAT-6 and CFP-10 and was the only marker significantly more sensitive in detecting active TB then IFN-γ (p = 0.012). Cytokine responses in patients with active TB were more frequent and detected at higher levels than in patients with LTBI. Conclusions IP-10 seems to be an important marker for diagnosis of active and latent TB. Patients with active TB and LTBI responded with similar cytokine profiles against TB antigens but proliferative and cytokine responses were generally higher in patients with active TB.
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Abstract
For the last 100 years, the tuberculin skin test (TST) has been the only diagnostic tool available for latent TB infection (LTBI) and no biomarker per se is available to diagnose the presence of LTBI. With the introduction of M. tuberculosis-specific IFN-gamma release assays (IGRAs), a new area of in vitro immunodiagnostic tests for LTBI based on biomarker readout has become a reality. In this review, we discuss existing evidence on the clinical usefulness of IGRAs and the indefinite number of potential new biomarkers that can be used to improve diagnosis of latent TB infection. We also present early data suggesting that the monocyte-derived chemokine inducible protein-10 may be useful as a novel biomarker for the immunodiagnosis of latent TB infection.
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Affiliation(s)
- Morten Ruhwald
- Clinical Research Centre, Copenhagen University, Hvidovre Hospital Kettegaards, Alle 30 2650 Hvidovre, Denmark.
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43
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Ruhwald M, Aabye MG, Ravn P. IP-10 release assays in the diagnosis of tuberculosis infection: current status and future directions. Expert Rev Mol Diagn 2012; 12:175-87. [PMID: 22369377 DOI: 10.1586/erm.11.97] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The current state-of-the-art tests for infection with Mycobacterium tuberculosis - the IFN-γ release assays - rely on accurate measurement of the cytokine IFN-γ. Many other potential biomarkers are expressed in concert with IFN-γ, and IP-10 in particular has shown promising results. IP-10 is produced in large amounts, allowing for the development of new and simplified test platforms, such as lateral flow. In this review, we summarize the results of 22 clinical studies exploring the use of IP-10 as an alternative marker to IFN-γ. The studies report that diagnostic accuracy of IP-10 is on par with IFN-γ, but also that IP-10 may be more robust in young children and in HIV-infected individuals with low CD4 cell counts. We conclude the review by presenting limitations of the published works and outline recent developments and future directions.
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Affiliation(s)
- Morten Ruhwald
- Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.
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44
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Chegou NN, Essone PN, Loxton AG, Stanley K, Black GF, van der Spuy GD, van Helden PD, Franken KL, Parida SK, Klein MR, Kaufmann SHE, Ottenhoff THM, Walzl G. Potential of host markers produced by infection phase-dependent antigen-stimulated cells for the diagnosis of tuberculosis in a highly endemic area. PLoS One 2012; 7:e38501. [PMID: 22693640 PMCID: PMC3367928 DOI: 10.1371/journal.pone.0038501] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 05/10/2012] [Indexed: 11/25/2022] Open
Abstract
Background Recent interferon gamma (IFN-γ)-based studies have identified novel Mycobacterium tuberculosis (M.tb) infection phase-dependent antigens as diagnostic candidates. In this study, the levels of 11 host markers other than IFN-γ, were evaluated in whole blood culture supernatants after stimulation with M.tb infection phase-dependent antigens, for the diagnosis of TB disease. Methodology and Principal Findings Five M.tb infection phase-dependent antigens, comprising of three DosR-regulon-encoded proteins (Rv2032, Rv0081, Rv1737c), and two resucitation promoting factors (Rv0867c and Rv2389c), were evaluated in a case-control study with 15 pulmonary TB patients and 15 household contacts that were recruited from a high TB incidence setting in Cape Town, South Africa. After a 7-day whole blood culture, supernatants were harvested and the levels of the host markers evaluated using the Luminex platform. Multiple antigen-specific host markers were identified with promising diagnostic potential. Rv0081-specific levels of IL-12(p40), IP-10, IL-10 and TNF-α were the most promising diagnostic candidates, each ascertaining TB disease with an accuracy of 100%, 95% confidence interval for the area under the receiver operating characteristics plots, (1.0 to 1.0). Conclusions Multiple cytokines other than IFN-γ in whole blood culture supernatants after stimulation with M.tb infection phase-dependent antigens show promise as diagnostic markers for active TB. These preliminary findings should be verified in well-designed diagnostic studies employing short-term culture assays.
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Affiliation(s)
- Novel N Chegou
- Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa.
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Riazi S, Zeligs B, Yeager H, Peters SM, Benavides GA, Di Mita O, Bellanti JA. Rapid diagnosis of Mycobacterium tuberculosis infection in children using interferon-gamma release assays (IGRAs). Allergy Asthma Proc 2012; 33:217-26. [PMID: 22584190 DOI: 10.2500/aap.2012.33.3574] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Diagnosis of tuberculosis (TB) in children by the tuberculin skin test (TST) poses a diagnostic challenge for physicians due to its low specificity and cross-reactivity with nontuberculous mycobacteria and bacille Calmette-Guerin (BCG). Although interferon-gamma release assays (IGRAs) have been shown as novel TST alternatives for diagnosis of latent TB infection (LTBI) in adults, their effectiveness is less clear in children. The present study examined QuantiFERON-TB Gold (QFT-G) responses and IFN-gamma production capacity of TST-positive children, younger children ≤5 years. A total of 517 children of whom 434 were TST positive ranging in age from 1 month to 18 years were evaluated by the QFT-G. Of the 517 children, 434 (84%) were TST positive, 25 (5.8%) of whom were found to be QFT-G positive and 25 (5.4%) with an indeterminate response. Of the 517 children, 355 (68.7%) were previously BCG immunized and 310/355 (87.3%) were TST positive including 18/27 (66.7%) QFT-positive children. Adequate IFN-gamma production by purified TB peptides or mitogen was observed in 92.8% of children, 29.6% of whom were <5 years. This study shows that the QFT-G assay is useful for diagnosis of LTBI. The finding of 5.8% positive QFT-G in 434 TST-positive children underscores the superior specificity of the QFT-G than the TST and its greater cost effectiveness in preventing unnecessary and potentially toxic treatment in children. The study suggests that the majority of positive TST in children represent false-positive reactions and supports the use of IGRAs for diagnosis of LTBI in children, including those <5 years of age.
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Affiliation(s)
- Shahla Riazi
- International Center for Interdisciplinary Studies of Immunology, Georgetown University Medical Center, Washington, DC, USA
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Kasprowicz VO, Halliday JS, Mitchell J, Klenerman P. MIGRAs: are they the new IGRAs? Development of monokine-amplified IFN-γ release assays. Biomark Med 2012; 6:177-86. [DOI: 10.2217/bmm.12.13] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
IFN-γ release by antigen-specific T cells can be used to track immune responses to infections and vaccines. In recent years, there have been substantial advances in the techniques available to measure IFN-γ release and a generation of such assays are now available for clinical use, as well as in a research setting. Interferon release leads to subsequent release of interferon-responsive chemokines such as MIG and IP-10, thus amplifying the original signal. A number of investigators have assessed whether measurement of these chemokines might provide a sensitive platform for detection of infection and antigen-specific T-cell responses. In this article, we assess the potential of these new approaches. We have termed the new antigen-specific T-cell assays monokine-amplified IFN-γ release assays (MIGRAs). Overall, it seems likely that improvements in the detection threshold could be made by analysis of antigen-triggered chemokines and potentially of other molecules in the future, although whether MIGRAs will provide additional clinical utility still remains to be determined.
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Affiliation(s)
- Victoria O Kasprowicz
- Ragon Institute of MGH, MIT & Harvard, Harvard Medical School, Boston, MA, USA
- Kwazulu-Natal Research Institute for Tuberculosis & HIV (K-RITH), Nelson R Mandela School of Medicine, Durban, South Africa
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, Durban, South Africa
| | - John S Halliday
- Oxford Biomedical Research Centre & James Martin School for 21st Century, Nuffield Department of Medicine, Peter Medawar Building, South Parks Rd, University of Oxford, UK
| | - Jessica Mitchell
- Ragon Institute of MGH, MIT & Harvard, Harvard Medical School, Boston, MA, USA
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, Durban, South Africa
| | - Paul Klenerman
- Oxford Biomedical Research Centre & James Martin School for 21st Century, Nuffield Department of Medicine, Peter Medawar Building, South Parks Rd, University of Oxford, UK
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Multicytokine detection improves latent tuberculosis diagnosis in health care workers. J Clin Microbiol 2012; 50:1711-7. [PMID: 22403417 DOI: 10.1128/jcm.00117-12] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
In a low-incidence setting, health care workers (HCW) are at a higher risk of tuberculosis than the general population. The suboptimal sensitivity of the QuantiFERON-TB Gold In-Tube (QFT) test remains a critical issue when identifying occupational latent tuberculosis infection (LTBI) in HCW. The aim of this study was to identify additional biomarkers in order to overcome the limits of gamma interferon (IFN-γ) release assays (IGRAs) and improve the performance of LTBI diagnosis within this population. Seventy Bacille Calmette-Guérin-vaccinated HCW regularly exposed to Mycobacterium tuberculosis were grouped according to QFT results into an LTBI-positive group (positive QFT, n = 8), an LTBI-negative group (normal QFT and negative tuberculin skin test [TST], n = 21), and an undetermined group (subpositive QFT and/or positive TST, n = 41). The secretion of 22 cytokines in response to QFT-specific stimulation was quantified using a multiparameter-based immunoassay. As a result, thresholds discriminating LTBI-positive from LTBI-negative HCW were established by comparing areas under the receiver operating characteristic curves for interleukin-2 (IL-2), IL-15, IFN-γ-induced protein 10 (IP-10), and the monokine induced by IFN-γ (MIG), which are biomarkers differentially secreted by the two groups. The combination of IL-15 and MIG provided a sensitivity of 100% and a specificity of 94.1% in distinguishing LTBI-positive from LTBI-negative HCW. When using IL-15 and MIG among the undetermined group, 6/45 HCW could be classified in the LTBI-positive group. The use of additional biomarkers after IGRA screening could improve the diagnosis of LTBI. The performance of these biomarkers and their use in combination with TST and/or QFT, as well as the cost-effectiveness of such a diagnostic strategy, should be evaluated in further larger clinical trials.
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Syed Ahamed Kabeer B, Paramasivam P, Raja A. Interferon gamma and interferon gamma inducible protein-10 in detecting tuberculosis infection. J Infect 2012; 64:573-9. [PMID: 22381458 DOI: 10.1016/j.jinf.2012.02.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Revised: 02/09/2012] [Accepted: 02/10/2012] [Indexed: 10/28/2022]
Abstract
OBJECTIVE This study aimed to compare the levels of TB-antigen specific Interferon gamma (IFN-γ) and IFN-γ inducible protein (IP)-10 in culture of whole blood samples from healthy controls (HC) and healthy household contacts (HHC). METHODOLOGY A total of 386 study subjects, which included 186 HC and 200 HHC, were recruited. QuantiFERON-TB Gold in-tube (QFT-IT) assay was employed to measure IFN-γ levels. IP-10 levels were measured in the supernatants collected from QFT-IT tubes. Tuberculin skin test was also performed. RESULTS The levels of TB antigen specific IFN-γ and IP-10 were significantly higher in HHC compared to HC. There was no significant difference observed between positivity of QFT-IT and IP-10 in HC and HHC. The positivity of TST was significantly lower in subjects <17 year, when compared to IP-10 (p<0.005). The reduced cut-off point 0.22IU/ml significantly increased the positivity of QFT-IT among children with high risk for latent TB infection (LTBI). CONCLUSIONS Measurement of TB antigen specific IFN-γ and IP-10 can be potential markers for the detection of LTBI.
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Affiliation(s)
- Basirudeen Syed Ahamed Kabeer
- Department of Immunology, National Institute for Research in Tuberculosis, Mayor V.R. Ramanathan Road, Chetput, Chennai, Tamil Nadu, India
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Aranday-Cortes E, Hogarth PJ, Kaveh DA, Whelan AO, Villarreal-Ramos B, Lalvani A, Vordermeier HM. Transcriptional profiling of disease-induced host responses in bovine tuberculosis and the identification of potential diagnostic biomarkers. PLoS One 2012; 7:e30626. [PMID: 22359547 PMCID: PMC3281027 DOI: 10.1371/journal.pone.0030626] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Accepted: 12/19/2011] [Indexed: 01/21/2023] Open
Abstract
Bovine tuberculosis (bTb) remains a major and economically important disease of livestock. Improved ante-mortem diagnostic tools would help to underpin novel control strategies. The definition of biomarkers correlating with disease progression could have impact on the rational design of novel diagnostic approaches for bTb. We have used a murine bTb model to identify promising candidates in the host transcriptome post-infection. RNA from in vitro-stimulated splenocytes and lung cells from BALB/c mice infected aerogenically with Mycobacterium bovis were probed with high-density microarrays to identify possible biomarkers of disease. In antigen-stimulated splenocytes we found statistically significant differential regulation of 1109 genes early (3 days) after infection and 1134 at a later time-point post-infection (14 days). 618 of these genes were modulated at both time points. In lung cells, 282 genes were significantly modulated post-infection. Amongst the most strongly up-regulated genes were: granzyme A, granzyme B, cxcl9, interleukin-22, and ccr6. The expression of 14 out of the most up-regulated genes identified in the murine studies was evaluated using in vitro with antigen-stimulated PBMC from uninfected and naturally infected cattle. We show that the expression of cxcl9, cxcl10, granzyme A and interleukin-22 was significantly increased in PBMC from infected cattle compared to naïve animals following PPD stimulation in vitro. Thus, murine transcriptome analysis can be used to predict immunological responses in cattle allowing the prioritisation of CXCLl9, CXCL10, Granzyme A and IL-22 as potential additional readout systems for the ante-mortem diagnosis of bovine tuberculosis.
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Affiliation(s)
- Elihu Aranday-Cortes
- TB Research Group, Animal Health & Veterinary Laboratories Agency Weybridge, New Haw, Addlestone, Surrey, United Kingdom
| | - Philip J. Hogarth
- TB Research Group, Animal Health & Veterinary Laboratories Agency Weybridge, New Haw, Addlestone, Surrey, United Kingdom
| | - Daryan A. Kaveh
- TB Research Group, Animal Health & Veterinary Laboratories Agency Weybridge, New Haw, Addlestone, Surrey, United Kingdom
| | - Adam O. Whelan
- TB Research Group, Animal Health & Veterinary Laboratories Agency Weybridge, New Haw, Addlestone, Surrey, United Kingdom
| | - Bernardo Villarreal-Ramos
- TB Research Group, Animal Health & Veterinary Laboratories Agency Weybridge, New Haw, Addlestone, Surrey, United Kingdom
| | - Ajit Lalvani
- Tuberculosis Immunology Group, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - H. Martin Vordermeier
- TB Research Group, Animal Health & Veterinary Laboratories Agency Weybridge, New Haw, Addlestone, Surrey, United Kingdom
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Kasprowicz VO, Churchyard G, Lawn SD, Squire SB, Lalvani A. Diagnosing latent tuberculosis in high-risk individuals: rising to the challenge in high-burden areas. J Infect Dis 2011; 204 Suppl 4:S1168-78. [PMID: 21996699 DOI: 10.1093/infdis/jir449] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
A key challenge to greater progress in tuberculosis (TB) control is the reservoir of latent TB infection (LTBI), which represents a huge long-lived reservoir of potential TB disease. In parts of Africa, as many as 50% of 15-year-olds and 77%-89% of adults have evidence of LTBI. A second key challenge to TB control is the human immunodeficiency virus (HIV)-associated TB epidemic, and Africa alone accounts for one-quarter of the global burden of HIV-associated TB. HIV co-infection promotes both reactivation TB from LTBI and rapidly progressive primary TB following recent exposure to Mycobacterium tuberculosis. Preventing active TB and tackling latent infection in addition to the Directly Observed Treatment, Short-Course (DOTS) strategy could improve TB control in high-burden settings, especially where there is a high prevalence of HIV co-infection. Current strategies include intensified case finding (ICF), TB infection control, antiretroviral therapy (ART), and isoniazid preventive therapy (IPT). Although ART has been widely rolled out, ICF and IPT have not. A key factor limiting the rollout and effectiveness of IPT and ICF is the limitations of existing tools to both diagnose LTBI and identify those persons most at risk of progressing to active TB. In this review, we examine the obstacles and consider current progress toward the development of new tools to address this pressing global problem.
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Affiliation(s)
- Victoria O Kasprowicz
- Ragon Institute of MGH, MIT, and Harvard, Harvard Medical School, Boston, Massachusetts, USA
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