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2. Utility of a novel lipoarabinomannan assay for the diagnosis of tuberculous meningitis in a resource-poor high-HIV prevalence setting

Author

Ndung'u Thumbi, Connolly Cathy, Meldau Richard, Singh Ravesh, Paruk Hoosain F, Bhigjee Ahmed I, Patel Vinod B, and Dheda Keertan

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background In Africa, tuberculous meningitis (TBM) is an important opportunistic infection in HIV-positive patients. Current diagnostic tools for TBM perform sub-optimally. In particular, the rapid diagnosis of TBM is challenging because smear microscopy has a low yield and PCR is not widely available in resource-poor settings. Methods We evaluated the performance outcome of a novel standardized lipoarabinomannan (LAM) antigen-detection assay, using archived cerebrospinal fluid samples, in 50 African TBM suspects of whom 68% were HIV-positive. Results Of the 50 participants 14, 23 and 13 patients had definite, probable and non-TBM, respectively. In the non-TB group there were 5 HIV positive patients who were lost to follow-up and in whom concomitant infection with Mycobacterium tuberculosis could not be definitively excluded. The test sensitivities and specificities were as follows: LAM assay 64% and 69% (cut-point 0.22), smear microscopy 0% and 100% and PCR 93% and 77%, respectively. Conclusion In this preliminary proof-of-concept study, a rapid diagnosis of TBM could be achieved using LAM antigen detection. Although specificity was sub-optimal, the estimates provided here may be unreliable because of a classification bias inherent in the study design where it was not possible to exclude TBM in the presumed non-TBM cases owing to a lack of clinical follow-up. As PCR is largely unavailable, the LAM assay may well prove to be a useful adjunct for the rapid diagnosis of TBM in high HIV-incidence settings. These preliminary results justify further enquiry and prospective studies are now required to definitively establish the place of this technology for the diagnosis of TBM.

Published
2009
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3. Utility of Cerebrospinal Fluid Unstimulated Interferon-Gamma (IRISA-TB) as a Same-Day Test for Tuberculous Meningitis in a Tuberculosis-Endemic, Resource-Poor Setting.

Author

Randall, Philippa, Mutsvangwa, Junior, Nliwasa, Marriott, Wilson, Lindsay, Makamure, Beauty, Makambwa, Edson, Meldau, Richard, Dheda, Keertan, Munyati, Shungu, Siddiqi, Omar, Corbett, Elizabeth, and Esmail, Ali

Subjects
TUBERCULOUS meningitis, HIV, INTERFERON gamma, CEREBROSPINAL fluid, POLYMERASE chain reaction
Abstract

Background Tuberculous meningitis (TBM) mortality is high and current diagnostics perform suboptimally. We evaluated the diagnostic performance of a DNA-based assay (GeneXpert Ultra) against a new same-day immunodiagnostic assay that detects unstimulated interferon-gamma (IRISA-TB). Methods In a stage 1 evaluation, IRISA-TB was evaluated in biobanked samples from Zambia (n = 82; tuberculosis [TB] and non-TBM), and specificity in a South African biobank (n = 291; non-TBM only). Given encouraging results, a stage 2 evaluation was performed in suspected TBM patients from Zimbabwe and Malawi (n = 668). Patients were classified as having definite, probable or possible TBM, or non-TBM based on their microbiological results, cerebrospinal fluid (CSF) chemistry, and whether they received treatment. Results In the stage 1 evaluation, sensitivity and specificity of IRISA-TB were 75% and 87% in the Zambian samples, and specificity was 100% in the South African samples. In the stage 2 validation, IRISA-TB sensitivity (95% confidence interval [CI]) was significantly higher than Xpert Ultra (76.2% [55.0%–89.4%] vs 25% [8.9%–53.3%]; P =.0048) when trace readouts were considered negative. Specificity (95% CI) was similar for both assays (91.4% [88.8%–93.4%] vs 86.9% [83.4%–89.8%]). When the Xpert Ultra polymerase chain reaction product was verified by sequencing, the positive predictive value of trace readouts in CSF was 27.8%. Sensitivity of IRISA-TB was higher in human immunodeficiency virus (HIV)–infected versus uninfected participants (85.8% vs 66.7%). Conclusions As a same-day rule-in test, IRISA-TB had significantly better sensitivity than Xpert Ultra in a TB/HIV-endemic setting. An immunodiagnostic approach to TBM is promising, and further studies are warranted. [ABSTRACT FROM AUTHOR]

Published
2024
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5. SARS-CoV-2 Viral Replication Persists in the Human Lung for Several Weeks after Symptom Onset

Author

Tomasicchio, Michele, primary, Jaumdally, Shameem, additional, Wilson, Lindsay, additional, Kotze, Andrea, additional, Semple, Lynn, additional, Meier, Stuart, additional, Pooran, Anil, additional, Esmail, Aliasgar, additional, Pillay, Komala, additional, Roberts, Riyaadh, additional, Kriel, Raymond, additional, Meldau, Richard, additional, Oelofse, Suzette, additional, Mandviwala, Carley, additional, Burns, Jessica, additional, Londt, Rolanda, additional, Davids, Malika, additional, van der Merwe, Charnay, additional, Roomaney, Aqeedah, additional, Kühn, Louié, additional, Perumal, Tahlia, additional, Scott, Alex J., additional, Hale, Martin J., additional, Baillie, Vicky, additional, Mahtab, Sana, additional, Williamson, Carolyn, additional, Joseph, Rageema, additional, Sigal, Alex, additional, Joubert, Ivan, additional, Piercy, Jenna, additional, Thomson, David, additional, Fredericks, David L., additional, Miller, Malcolm GA, additional, Nunes, Marta C., additional, Madhi, Shabir A., additional, and Dheda, Keertan, additional

Published
2024
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12. A Human Lung Challenge Model to Evaluate the Safety and Immunogenicity of PPD and Live Bacillus Calmette-Guérin

Author

Davids, Malika, primary, Pooran, Anil, additional, Hermann, Clemens, additional, Mottay, Lynelle, additional, Thompson, Fawziyah, additional, Cardenas, Jacob, additional, Gu, Jinghua, additional, Koeuth, Thearith, additional, Meldau, Richard, additional, Limberis, Jason, additional, Gina, Phindile, additional, Srivastava, Shashikant, additional, Calder, Bridget, additional, Esmail, Aliasgar, additional, Tomasicchio, Michele, additional, Blackburn, Jonathan, additional, Gumbo, Tawanda, additional, and Dheda, Keertan, additional

Published
2020
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16. A Human Lung Challenge Model to Evaluate the Safety and Immunogenicity of PPD and Live Bacillus Calmette-Guérin

Author

Davids, Malika, Pooran, Anil, Hermann, Clemens, Mottay, Lynelle, Thompson, Fawziyah, Cardenas, Jacob, Gu, Jinghua, Koeuth, Thearith, Meldau, Richard, Limberis, Jason, Gina, Phindile, Srivastava, Shashikant, Calder, Bridget, Esmail, Aliasgar, Tomasicchio, Michele, Blackburn, Jonathan, Gumbo, Tawanda, and Dheda, Keertan

Abstract

Rationale: A human model to better understand tuberculosis immunopathogenesis and facilitate vaccine development is urgently needed.Objectives: We evaluated the feasibility, safety, and immunogenicity of live bacillus Calmette-Guérin (BCG) in a lung-oriented controlled human infection model.Methods: We recruited 106 healthy South African participants with varying degrees of tuberculosis susceptibility. Live BCG, sterile PPD, and saline were bronchoscopically instilled into separate lung segments (n = 65). A control group (n = 34) underwent a single bronchoscopy without challenge. The primary outcome was safety. Cellular and antibody immune signatures were identified in BAL before and 3 days after challenge using flow cytometry, ELISA, RNA sequencing, and mass spectrometry.Measurements and Main Results: The frequency of adverse events was low (9.4%; n = 10), similar in the challenge versus control groups (P = 0.8), and all adverse events were mild and managed conservatively in an outpatient setting. The optimal PPD and BCG dose was 0.5 TU and 104 cfu, respectively, based on changes in BAL cellular profiles (P = 0.02) and antibody responses (P = 0.01) at incremental doses before versus after challenge. At 104 versus 103 cfu BCG, there was a significant increase in number of differentially expressed genes (367 vs. 3; P

Published
2019

17. Same-Day Tools, Including Xpert Ultra and IRISA-TB, for Rapid Diagnosis of Pleural Tuberculosis: a Prospective Observational Study

Author

Meldau, Richard, Randall, Philippa, Pooran, Anil, Limberis, Jason, Makambwa, Edson, Dhansay, Muhammed, Esmail, Aliasgar, and Dheda, Keertan

Abstract

The diagnosis of pleural tuberculosis (TB) is problematic. The comparative performance of newer same-day tools for pleural TB, including Xpert MTB/RIF Ultra (ULTRA), has hitherto not been comprehensively studied. Adenosine deaminase (ADA), IRISA-TB (interferon gamma ultrasensitive rapid immunosuspension assay), Xpert MTB/RIF, and ULTRA performance outcomes were evaluated in pleural fluid samples from 149 patients with suspected pleural TB. The reference standard was culture positivity (fluid, biopsy specimen, or sputum) and/or pleural biopsy histopathology (termed definite TB). Those designated as having non-TB were negative by microbiological testing and were not initiated on anti-TB treatment. To determine the effect of sample concentration, 65 samples underwent pelleting by centrifugation, followed by conventional Xpert MTB/RIF and ULTRA. Of the 149 patients, 49 had definite TB, 16 had probable TB (not definite but treated for TB), and 84 had non-TB. ULTRA sensitivity and specificity (95% confidence intervals [CI]) were similar to those of Xpert MTB/RIF [sensitivity, 37.5% (25.3 to 51.2) versus 28.6% (15.9 to 41.2), respectively; specificity, 98.8% (96.5 to 100) versus 98.8% (96.5 to 100), respectively]. Centrifugation did not significantly improve ULTRA sensitivity (29.5% versus 31.3%, respectively). Adenosine deaminase and IRISA-TB sensitivity were 84.4% (73.9 to 95.0) and 89.8% (81.3 to 98.3), respectively. However, IRISA-TB demonstrated significantly better specificity (96.4% versus 87.5% [P = 0.034]), positive predictive value (93.6% versus 80.9 [P = 0.028]), and positive likelihood ratio (25.1 versus 6.8 [P = 0.032]) than ADA. In summary, Xpert ULTRA has poor sensitivity for the diagnosis of pleural TB. Alternative assays (ADA and IRISA-TB) are significantly more sensitive, with IRISA-TB demonstrating a higher specificity and rule-in value than ADA in this high-TB-burden setting where HIV is endemic.

Published
2019

18. The Injectable Contraceptive Medroxyprogesterone Acetate Attenuates Mycobacterium tuberculosis-Specific Host Immunity Through the Glucocorticoid Receptor

Author

Tomasicchio, Michele, Davids, Malika, Pooran, Anil, Theron, Grant, Smith, Liezel, Semple, Lynn, Meldau, Richard, Hapgood, Janet Patricia, and Dheda, Keertan

Abstract

BACKGROUND: The effects of the widely used progestin-only injectable contraceptives, medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A), on host susceptibility to Mycobacterium tuberculosis (Mtb) are unknown. METHODS: We recruited human immunodeficiency virus-uninfected females, not taking any contraceptives, from Cape Town, South Africa, to evaluate the effect of MPA, NET-A, and dexamethasone on Mtb containment in monocyte-derived macrophages co-incubated with purified protein derivative (PPD)-driven peripheral blood-derived effector cells. RESULTS: MPA (P < .005) and dexamethasone (P < .01), but not NET-A, significantly attenuated Mtb containment in Mtb-infected macrophages co-cultured with PPD-driven effector cells at physiologically relevant concentrations and in a dose-dependent manner. Antagonizing the glucocorticoid receptor with mifepristone (RU486) abrogated the reduction in Mtb containment. In PPD-stimulated peripheral blood mononuclear cells, MPA and dexamethasone, but not NET-A, upregulated (median [interquartile range]) regulatory T cells (5.3% [3.1%-18.2%]; P < .05), reduced CD4+ T-cell interferon-γ (21% [0.5%-28%]; P < .05) and granzyme B production (12.6% [7%-13.5%]; P < .05), and reduced CD8+ perforin activity (2.2% [0.1%-7%]; P < .05). RU486 reversed regulatory T-cell up-regulation and the inhibitory effect on Th1 and granzyme/perforin-related pathways. CONCLUSIONS: MPA, but not NET-A, subverts mycobacterial containment in vitro and downregulates pathways associated with protective CD8+- and CD4+-related host immunity via the glucocorticoid receptor. These data potentially inform the selection and use of injectable contraceptives in tuberculosis-endemic countries.

Published
2018

19. A human lung challenge model to evaluate the safety and immunogenicity of PPD and live BCG.

Author

Pooran, Anil, Hermann, Clemens, Mottay, Lynelle, Thompson, Fawziyah, Cardenas, Jacob, Jinghua Gu, Koeuth, Thearith, Meldau, Richard, Limberis, Jason, Gina, Phindile, Srivastava, Shashikant, Calder, Bridget, Esmail, Aliasgar, Tomasicchio, Michele, Blackburn, Jonathan, Gumbo, Tawanda, and Dheda, Keertan

Subjects
PROTEINS, BCG vaccines, BRONCHOSCOPY, PULMONOLOGISTS, LARYNGEAL masks
Abstract

The article focuses on human lung challenge model to evaluate the safety and immunogenicity of purified protein derivative (PPD) and live Bacille-Calmette-Guerin (BCG) culture. It mentions PPD and BCG dilutions were prepared from GMP-grade pharmaceutical stocks in a Class II bio-safety cabinet under sterile conditions. It also mentions bronchoscopies were performed by the study pulmonologist and laryngeal mask (LMA) was used to protect the airway.

Published
2020

21. An autologous dendritic cell vaccine polarizes a Th-1 response which is tumoricidal to patient-derived breast cancer cells

Author

Tomasicchio, Michele, primary, Semple, Lynn, additional, Esmail, Aliasgar, additional, Meldau, Richard, additional, Randall, Philippa, additional, Pooran, Anil, additional, Davids, Malika, additional, Cairncross, Lydia, additional, Anderson, David, additional, Downs, Jennifer, additional, Malherbe, Francois, additional, Novitzky, Nicolas, additional, Panieri, Eugenio, additional, Oelofse, Suzette, additional, Londt, Rolanda, additional, Naiker, Thurandrie, additional, and Dheda, Keertan, additional

Published
2018
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23. The Injectable Contraceptive Medroxyprogesterone Acetate Attenuates Mycobacterium tuberculosis-Specific Host Immunity Through the Glucocorticoid Receptor.

Author

Tomasicchio, Michele, Davids, Malika, Pooran, Anil, Theron, Grant, Smith, Liezel, Semple, Lynn, Meldau, Richard, Hapgood, Janet Patricia, and Dheda, Keertan

Subjects
GLUCOCORTICOID receptors, MEDROXYPROGESTERONE, ACETATES, MYCOBACTERIUM tuberculosis, PERFORINS, BLOOD cells, MIFEPRISTONE
Abstract

Background: The effects of the widely used progestin-only injectable contraceptives, medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A), on host susceptibility to Mycobacterium tuberculosis (Mtb) are unknown.Methods: We recruited human immunodeficiency virus-uninfected females, not taking any contraceptives, from Cape Town, South Africa, to evaluate the effect of MPA, NET-A, and dexamethasone on Mtb containment in monocyte-derived macrophages co-incubated with purified protein derivative (PPD)-driven peripheral blood-derived effector cells.Results: MPA (P < .005) and dexamethasone (P < .01), but not NET-A, significantly attenuated Mtb containment in Mtb-infected macrophages co-cultured with PPD-driven effector cells at physiologically relevant concentrations and in a dose-dependent manner. Antagonizing the glucocorticoid receptor with mifepristone (RU486) abrogated the reduction in Mtb containment. In PPD-stimulated peripheral blood mononuclear cells, MPA and dexamethasone, but not NET-A, upregulated (median [interquartile range]) regulatory T cells (5.3% [3.1%-18.2%]; P < .05), reduced CD4+ T-cell interferon-γ (21% [0.5%-28%]; P < .05) and granzyme B production (12.6% [7%-13.5%]; P < .05), and reduced CD8+ perforin activity (2.2% [0.1%-7%]; P < .05). RU486 reversed regulatory T-cell up-regulation and the inhibitory effect on Th1 and granzyme/perforin-related pathways.Conclusions: MPA, but not NET-A, subverts mycobacterial containment in vitro and downregulates pathways associated with protective CD8+- and CD4+-related host immunity via the glucocorticoid receptor. These data potentially inform the selection and use of injectable contraceptives in tuberculosis-endemic countries. [ABSTRACT FROM AUTHOR]

Published
2019
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25. In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis

Author

Bell, Lucy C. K., primary, Pollara, Gabriele, additional, Pascoe, Mellissa, additional, Tomlinson, Gillian S., additional, Lehloenya, Rannakoe J., additional, Roe, Jennifer, additional, Meldau, Richard, additional, Miller, Robert F., additional, Ramsay, Alan, additional, Chain, Benjamin M., additional, Dheda, Keertan, additional, and Noursadeghi, Mahdad, additional

Published
2016
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27. Burden of tuberculosis in intensive care units in Cape Town, South Africa, and assessment of the accuracy and effect on patient outcomes of the Xpert MTB/RIF test on tracheal aspirate samples for diagnosis of pulmonary tuberculosis: a prospective burden of disease study with a nested randomised controlled trial

Author

Calligaro, Gregory L, primary, Theron, Grant, additional, Khalfey, Hoosain, additional, Peter, Jonathan, additional, Meldau, Richard, additional, Matinyenya, Brian, additional, Davids, Malika, additional, Smith, Liezel, additional, Pooran, Anil, additional, Lesosky, Maia, additional, Esmail, Aliasgar, additional, Miller, Malcolm G, additional, Piercy, Jenna, additional, Michell, Lancelot, additional, Dawson, Rodney, additional, Raine, Richard I, additional, Joubert, Ivan, additional, and Dheda, Keertan, additional

Published
2015
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28. Determinants of PCR performance (Xpert MTB/RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments

Author

Theron, Grant, primary, Peter, Jonny, additional, Calligaro, Greg, additional, Meldau, Richard, additional, Hanrahan, Colleen, additional, Khalfey, Hoosain, additional, Matinyenya, Brian, additional, Muchinga, Tapuwa, additional, Smith, Liezel, additional, Pandie, Shaheen, additional, Lenders, Laura, additional, Patel, Vinod, additional, Mayosi, Bongani M., additional, and Dheda, Keertan, additional

Published
2014
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29. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: a prospective study

Author

Pandie, Shaheen, primary, Peter, Jonathan G, additional, Kerbelker, Zita S, additional, Meldau, Richard, additional, Theron, Grant, additional, Govender, Ureshnie, additional, Ntsekhe, Mpiko, additional, Dheda, Keertan, additional, and Mayosi, Bongani M, additional

Published
2014
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30. Comparison of same day diagnostic tools including Gene Xpert and unstimulated IFN-γ for the evaluation of pleural tuberculosis: a prospective cohort study

Author

Meldau, Richard, primary, Peter, Jonny, additional, Theron, Grant, additional, Calligaro, Greg, additional, Allwood, Brian, additional, Symons, Greg, additional, Khalfey, Hoosain, additional, Ntombenhle, Gina, additional, Govender, Ureshnie, additional, Binder, Anke, additional, van Zyl-Smit, Richard, additional, and Dheda, Keertan, additional

Published
2014
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31. Bronchoalveolar lavage immunodiagnosis for tuberculosis suspects in Europe and Africa

Author

Lange, Christoph, Bossink, Aik, Eberhardt, Ralf, Goletti, Delia, Jafari, Claudia, Latorre, Irene, Kirsten, Detlef, Losi, Monica, Migliori, Giovanni B., Sotgiu, Giovanni, van Zyl-Smit, Richard N., Meldau, Richard, and Dheda, Keertan

Subjects
Bronchoalveolar lavage -- Usage, Tuberculosis -- Diagnosis, Immunodiagnosis -- Methods, Health
Published
2010

35. Comparison Of Quantitative Techniques Including Xpert MTB/RIF To Evaluate Mycobacterial Burden

Author

Van Zyl-Smit, Richard N., primary, Binder, Anke, additional, Meldau, Richard, additional, Mishra, Hridesh, additional, Semple, Patricia L., additional, Theron, Grant, additional, Peter, Jonathan, additional, Whitelaw, Andrew, additional, Sharma, Surendra K., additional, Warren, Robin, additional, Bateman, Eric D., additional, and Dheda, Keertan U.J., additional

Published
2012
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38. Comparison of Quantitative Techniques including Xpert MTB/RIF to Evaluate Mycobacterial Burden

Author

van Zyl-Smit, Richard N., primary, Binder, Anke, additional, Meldau, Richard, additional, Mishra, Hridesh, additional, Semple, Patricia L., additional, Theron, Grant, additional, Peter, Jonathan, additional, Whitelaw, Andrew, additional, Sharma, Suren K., additional, Warren, Robin, additional, Bateman, Eric D., additional, and Dheda, Keertan, additional

Published
2011
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39. Do adjunct tuberculosis tests, when combined with Xpert MTB/RIF, improve accuracy and the cost of diagnosis in a resource-poor setting?

Author

Theron, Grant, primary, Pooran, Anil, additional, Peter, Jonny, additional, van Zyl-Smit, Richard, additional, Kumar Mishra, Hridesh, additional, Meldau, Richard, additional, Calligaro, Greg, additional, Allwood, Brian, additional, Sharma, Surendra Kumar, additional, Dawson, Rod, additional, and Dheda, Keertan, additional

Published
2011
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44. Incremental Value Of Interferon-Gamma Release Assays For Diagnosis Of Active Tuberculosis In Smear-Negative Patients In A High-Burden Setting: A Multivariable Analysis

Author

Ling, Daphne I., primary, Pai, Madhukar, additional, Davids, Virginia, additional, Brunet, Laurence, additional, Lenders, Laura, additional, Meldau, Richard, additional, van Zyl-smit, Richard N., additional, Peter, Jonny, additional, Dawson, Rodney, additional, Zumla, Alimuddin, additional, and Dheda, Keertan U.J., additional

Published
2010
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47. Clinical Utility of a Commercial LAM-ELISA Assay for TB Diagnosis in HIV-Infected Patients Using Urine and Sputum Samples

Author

Dheda, Keertan, primary, Davids, Virginia, additional, Lenders, Laura, additional, Roberts, Teri, additional, Meldau, Richard, additional, Ling, Daphne, additional, Brunet, Laurence, additional, van Zyl Smit, Richard, additional, Peter, Jonathan, additional, Green, Clare, additional, Badri, Motasim, additional, Sechi, Leonardo, additional, Sharma, Surendra, additional, Hoelscher, Michael, additional, Dawson, Rodney, additional, Whitelaw, Andrew, additional, Blackburn, Jonathan, additional, Pai, Madhukar, additional, and Zumla, Alimuddin, additional

Published
2010
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49. Clinical Diagnostic Utility of IP-10 and LAM Antigen Levels for the Diagnosis of Tuberculous Pleural Effusions in a High Burden Setting

Author

Dheda, Keertan, primary, Van-Zyl Smit, Richard N., additional, Sechi, Leonardo A., additional, Badri, Motasim, additional, Meldau, Richard, additional, Symons, Gregory, additional, Khalfey, Hoosein, additional, Carr, Igshaan, additional, Maredza, Alice, additional, Dawson, Rodney, additional, Wainright, Helen, additional, Whitelaw, Andrew, additional, Bateman, Eric D., additional, and Zumla, Alimuddin, additional

Published
2009
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50. Feasibility and Diagnostic Utility of Antigen-Specific Interferon-c Responses for Rapid Immunodiagnosis of Tuberculosis Using Induced Sputum.

Author

Cashmore, Tamaryn J., Peter, Jonathan G., van Zyl-Smit, Richard N., Semple, Patricia L., Maredza, Alice, Meldau, Richard, Zumla, Alimuddin, Nurse, Barbara, and Dheda, Keertan

Subjects
TUBERCULOSIS research, LUNG diseases, MYCOBACTERIAL diseases, ANTIVIRAL agents, PUBLIC health, ANTIGENS
Abstract

Background: The diagnosis of smear-negative or sputum-scarce tuberculosis (TB) is problematic as culture takes several weeks and representative biological samples are difficult to obtain. RD-1 antigen-specific interferon-c release assays (IGRAs) are sensitive and specific blood-based tests for the diagnosis of M. tuberculosis infection. The feasibility and diagnostic utility of this rapid immunodiagnostic assay, using cells from induced sputum, is unknown. Methodology/Principal Findings: Cells isolated from induced sputum were co-cultured with ESAT-6 and CFP-10 antigens using a standardized enzyme-linked immunospot (ELISPOT) assay (T-SPOT®.TB) in 101 consecutively recruited TB suspects or non-TB controls. An optimization phase using 28 samples was followed by a validation phase using samples from 73 participants (20 with definite or probable TB, and 48 with non-TB). Despite optimization of sputum processing 65/73 (89%) of the IGRAs in the validation phase were inconclusive. 44/73 (60%) tests failed due to sputum induction-related factors [sputum induction-related adverse events (n = 5), inadequate sputum volume (n = 8), non-homogenisable sputum (n = 7), and insufficient numbers of cells to perform the assay (n = 24)], whilst 20/73 (27%) tests failed due T-SPOTH.TB assay-related factors [excessive debris precluding reading of spots in the ELISPOT well (n = 6), failure of the positive control (n = 11), or high spot count in the negative control (n = 3)]. Only 8/73 (11%) of the available samples could therefore be correctly categorized (7 definite or probable TB, and 1 non-TB patient). Thus, 13/20 (65%) of the definite or probable TB cases remained undiagnosed. Conclusions/Significance: Rapid immunodiagnosis of pulmonary TB by antigen-specific IFN-γ ELISPOT responses, using cells from induced sputum, is possible. However, the test, in its current ELISPOT format, is not clinically useful because the majority of the assays are inconclusive. [ABSTRACT FROM AUTHOR]

Published
2010
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