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There is no reliable means of detecting latent M. tuberculosis infection, and even in patients with active tuberculosis, infection is
often unconfirmed. We hypothesized that M. tuberculosis antigen-specific T cells might reliably indicate infection. We enumerated peripheral blood-derived interferon 
(IFN-)-secreting T cells responding to epitopes from ESAT-6, an antigen that is highly specific
for M. tuberculosis complex but absent from BCG, in four groups
of individuals. Forty-five of 47 patients with bacteriologically confirmed tuberculosis had ESAT-6-specific IFN--secreting T cells, compared with four of 47 patients with nontuberculous illnesses, indicating that these T cells are an accurate marker of M. tuberculosis infection. This assay thus has a sensitivity of 96% (95% confidence interval [CI] 92-100) for detecting M. tuberculosis infection in this patient population. By comparison, of the 26 patients with
tuberculosis who had a diagnostic tuberculin skin test (TST), only
18 (69%) were positive (p = 0.003). In addition, 22 of 26 (85%)
TST-positive exposed household contacts had ESAT-6-specific T cells,
whereas zero of 26 unexposed BCG-vaccinated subjects responded.
This approach enables rapid detection of M. tuberculosis infection
in patients with active tuberculosis and in exposed asymptomatic individuals at high risk of latent infection; it also successfully distinguishes between M. tuberculosis infection and BCG vaccination.
This capability may facilitate tuberculosis control in nonendemic regions.
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INTRODUCTION |
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INTRODUCTION
METHODS
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DISCUSSION
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There are approximately 8 million new cases of tuberculosis worldwide every year, and it is estimated that one-third of the world's population is latently infected with Mycobacterium tuberculosis (1, 2). The ability to accurately detect M. tuberculosis infection will be crucial for global control of this epidemic (3) and for improved contact tracing and outbreak control, yet there is no accurate and reliable means of detecting infection. A rapid means of detecting M. tuberculosis infection would also help to accelerate initial diagnosis and allow early treatment in patients with clinically suspected tuberculosis.
Mycobacterium tuberculosis is often difficult to recover
from infected subjects; even with good microbiological facilities, as in the United Kingdom, only 50% of tuberculosis cases
are bacteriologically confirmed (4, 5). However, M. tuberculosis infection evokes a strong cell-mediated immune response,
and we reasoned that detection of M. tuberculosis-specific T
cells might reliably signal the presence of infection. This approach has been hampered by the lack of a defined antigen that
is specific for M. tuberculosis. We therefore selected ESAT-6,
a secreted antigen (6), which is expressed in M. tuberculosis
complex (M. tuberculosis, bovis, and africanum), but is absent
from all strains of M. bovis BCG (7) and the majority of environmental mycobacteria (8, 10). In animal models of tuberculosis, ESAT-6 is a target of interferon -secreting CD4+ T
cells (11) and in vitro stimulation of human peripheral
blood mononuclear cells (PBMCs) by ESAT-6 induces interferon (IFN-) detectable by enzyme-linked immunosorbent
assay (ELISA) in the supernatant from about half of tuberculosis patients (14). This T cell immunogenicity, together
with its species specificity, make ESAT-6 a promising candidate antigen.
We hypothesised that circulating ESAT-6-specific T cells
would indicate M. tuberculosis infection. We therefore employed an assay that enumerates IFN--secreting T cells directly from peripheral blood, the ex vivo enzyme-linked immunospot (ELISPOT) assay: one of the most sensitive methods
for detecting antigen-specific T cells (17). First, we studied
subjects known definitively to be overtly infected with M. tuberculosis; that is, patients with bacteriologically confirmed
active disease. To be clinically useful, an assay for M. tuberculosis infection should not cross-react with BCG vaccination
or nontuberculous conditions that cause nonspecific activation of the cellular immune system. We therefore included a
series of control patients with a range of infectious, inflammatory, and granulomatous conditions, the majority of whom
were BCG vaccinated. Finally, to assess whether this approach could identify exposed latently infected individuals
and not just patients with active disease, we also studied a series of tuberculin skin test (TST) positive healthy household
contacts (HHCs) of cases of sputum smear-positive pulmonary
tuberculosis and a series of BCG-vaccinated healthy individuals with no known exposure to M. tuberculosis.
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METHODS
RESULTS
DISCUSSION
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Patients
All participants were recruited prospectively in London and Oxford over a 16-mo period from October 1997 through January 1999. A heparinized blood sample was drawn after obtaining informed consent. Ethical approval for the study was granted by the Harrow and Central Oxford Research Ethics Committees.
Forty-seven tuberculosis patients, bacteriologically confirmed with positive cultures for M. tuberculosis from one or more clinical specimens, were recruited prospectively. The patients were ethnically diverse and represented the broad clinical spectrum of tuberculosis, with 22 cases of extrapulmonary disease (Table 1). Twenty-nine of 47 (62%) had received less than 1 mo of therapy or were untreated at the time of venipuncture for ELISPOT assays; the remaining 18 patients were at later time points in their treatment course.
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Control patients were group matched for ethnicity, age (within 4 yr) and sex and 36 of 47 (77%) were BCG vaccinated (33 had a BCG scar, and three gave a history of BCG vaccination) (Table 1). Control patients had the following diagnoses: pneumonia (n = 6), sarcoidosis (n = 3), infective endocarditis (n = 3). The following diagnoses were present in two control patients each: lymphoma, lung cancer, chronic osteomyelitis, ulcerative colitis, Crohn's disease, infective enterocolitis, malaria, cirrhosis, cellulitis, hemoglobinopathy. The following diagnoses were present in one control patient each: pulmonary Ascaris lumbricoides infection, acute pancreatitis, Dengue fever, urinary schistosomiasis, systemic lupus erythematosus (SLE), acute bronchitis, meningococcemia, tonsillitis, sickle cell crisis, gastric ulcer, dermatitis herpetiformis, venous thrombosis, nephrotic syndrome, cardiac failure. Patients with a past history of tuberculosis or recent contact with a case (n = 2) were excluded. No tuberculosis or control patients had any features of human immunodeficiency virus (HIV) infection.
Twenty-six HHCs were recruited on the basis of the following criteria. All had lived in the same household as an index case of untreated sputum smear-positive pulmonary tuberculosis within the last 6 mo. In addition, all HHCs were asymptomatic, had normal chest X-rays (CXRs), and had a positive tuberculin skin test (Heaf grades 3-4). Over 12 mo of follow-up, no HHCs developed active tuberculosis. Twenty-six healthy unexposed control subjects with no history of tuberculosis and no known contact with a case of tuberculosis were also recruited. All had a BCG scar or history of BCG vaccination.
ESAT-6-derived Peptides
Seventeen peptides spanning the length of the ESAT-6 molecule were purchased (Research Genetics, Huntsville, AL). Each peptide was 15 amino acids long and overlapped its adjacent peptide by 10 residues. A response to one or more of the eight broadly immunogenic peptide epitopes in Table 2 was scored as indicative of M. tuberculosis infection.
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Ex Vivo ELISPOT Assay for Single-Cell IFN- Release: Rapid
Enumeration of Circulating ESAT-6 Peptide-specific T Cells
from Peripheral Blood
The procedure was carried out and scored as previously described (17, 20, 21). See online data supplement at www.atsjournals.org.
Tuberculin Skin Testing
Twenty-six patients with tuberculosis underwent tuberculin skin testing, while being investigated for tuberculosis, with 1 tuberculin unit of PPD (Evans Medical, Liverpool, UK), in accordance with standard UK practice. Cutaneous induration of 5 mm or more at 72 h, measured with a ruler, was scored as positive, as per convention.
All 26 HHCs underwent standardized multiple puncture tuberculin skin testing (Heaf test) with a six-needle disposable head Heaf gun (Bignall 2000; Bignall Surgical Instruments, UK) and concentrated PPD (100,000 tuberculin units/ml; Evans Medical, Liverpool, UK) in accordance with UK guidelines for contacts.
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DISCUSSION
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Rapid Diagnosis of Mycobacterium tuberculosis Infection in Patients with Active Tuberculosis by Detection of ESAT-6-specific T Cells in Peripheral Blood
Eight ESAT-6-derived peptides were frequently recognized
epitopes (Table 2). A response to one or more of the peptides
in this panel was scored as indicative of M. tuberculosis infection, and 45 of 47 (96%) patients with tuberculosis had circulating IFN--secreting T cells specific for one or more of these
eight peptides, with many donors recognizing several peptides. Thus, the sensitivity of the assay in this patient population was 96% (95% confidence interval [CI], 92-100). Frequencies of ESAT-6 peptide-specific IFN--secreting T cells
were generally high, with a median of 200 ESAT-6-specific T
cells per million PBMCs (interquartile range, 105-596) (Figure 1A). Of the 17 tuberculosis patients tested against recombinant ESAT-6 in addition to the ESAT-6 peptides, all responded to the whole antigen, indicating the peptide epitopes
are naturally processed and presented to T cells. For the most
broadly recognized peptides (ES1, ES2, ES11 and ES15), we
used anti-HLA-DR, -DQ, and -DP monoclonal antibodies to
block presentation to CD4+ T cells in ELISPOT assays. In all
patients with tuberculosis and contacts where this was tested
(n = 14), the responses were MHC class II restricted (data not
shown).
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Although 36 of 47 (77%) control patients with nontuberculous illnesses were BCG vaccinated, only four of 47 (8%) responded to one or more of the panel of eight ESAT-6-derived peptides (and only one of these was BCG vaccinated), which gives the assay a specificity of 92% (95% CI, 86-97) in this population. Two had acute pneumonia, one had acute bronchitis and the fourth had cellulitis. All four also responded to PPD by ex vivo ELISPOT. In all remaining controls, there was a complete lack of response to all peptides (Figure 1A). The expanded set of 17 peptides spanning ESAT-6 gave the same results as the panel of eight broadly immunogenic epitopes.
The two of 47 tuberculosis patients who did not respond to
ESAT-6 had advanced pulmonary disease and, interestingly,
were lymphopenic, but both were HIV negative and responded to therapy. Advanced tuberculosis causes depression
of peripheral blood T cell responses, which might account for
the lack of detectable ESAT-6-specific IFN--secreting T cells
in these patients, but all four patients with miliary disease, often associated with cutaneous anergy, nonetheless had ESAT-6-specific T cells by ex vivo ELISPOT.
In contrast to other assays of the cellular immune response in tuberculosis (22, 23), the strength of the ESAT-6-specific ex vivo ELISPOT response did not rise with increasing duration of therapy. Rather, the frequency of ESAT-6 peptide-specific T cells actually declined progressively with treatment in patients who were followed up longitudinally (A. A. Pathan and A. Lalvani, unpublished data, 2000). Thus, one would not expect the sensitivity of the ESAT-6-based ex vivo ELISPOT assay for detecting M. tuberculosis infection to be lower in patients who are untreated or early in the course of therapy.
Comparison of ESAT-6-specific T Cell Responses with Skin Test and ELISPOT Responses to Purified Protein Derivative
Twenty-six patients with tuberculosis underwent tuberculin skin
testing (TST); only 18 of these (69%) were positive. By comparison, one-third more, 24 of 26 (92%), were positive to
ESAT-6 by ex vivo ELISPOT for IFN- and, overall, 45 of 47 (96%) responded to ESAT-6 by ex vivo ELISPOT (p = 0.003, Fisher exact test). Although the control patients were not subjected to TST, 26 of 47 (55%) responded to PPD by ex vivo
IFN- ELISPOT, indicating prior in vivo sensitization to PPD,
probably as a result of BCG vaccination. All 47 tuberculosis
patients responded to PPD by ex vivo IFN- ELISPOT.
Rapid Detection of Latent Mycobacterium tuberculosis Infection in Asymptomatic Healthy Subjects
Twenty-two of 26 tuberculin skin test-positive HHCs had
IFN--secreting T cells specific for one or more of the eight
ESAT-6 peptides (Figure 1B). By contrast, none of 26 healthy
control subjects with no history of exposure to tuberculosis responded to ESAT-6 peptides in the ex vivo ELISPOT assay
(Figure 1B). All unexposed control subjects were BCG vaccinated, indicating that the ESAT-6-based ELISPOT assay for
IFN- successfully distinguishes M. tuberculosis-exposed contacts from unexposed, but BCG-vaccinated, individuals. By
contrast, 11 of 14 unexposed control subjects, and all the household contacts, responded to PPD in the IFN- ELISPOT assay.
The median number of ESAT-6 peptide-specific IFN--secreting T cells in HHCs was 338 per million PBMCs (interquartile
range, 63-634).
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We report a novel approach to accurately and rapidly detect
infection with M. tuberculosis. By studying a series of patients, contacts, and control subjects with a sensitive method for detecting antigen-specific T cells, combined with an immunogenic antigen that is highly specific for M. tuberculosis, we
have identified ESAT-6-specific IFN--secreting T cells as an
accurate marker for M. tuberculosis infection.
The high frequency of T cells specific for this single 6-kD
antigen, given that almost 4,000 open reading frames are
encoded in the M. tuberculosis genome (24), distinguishes
ESAT-6 as a major target of the human immune response to
M. tuberculosis. The genetic diversity of the study population
indicates, moreover, that M. tuberculosis infection induces
ESAT-6-specific CD4+ T cells in the context of a wide variety
of different HLA class II haplotypes. Interestingly, a single
peptide, ES1, is a target of IFN--secreting CD4+ T cells in
more than half the patients with tuberculosis and healthy contacts.
Forty-five of 47 (96%) patients with active tuberculosis had
IFN--secreting ESAT-6-specific T cells, indicating that this assay identifies overtly infected individuals with active tuberculosis with a sensitivity of 96% (95% CI, 92-100). This high
sensitivity was achieved in a patient group that included critically ill patients with disseminated disease and patients with
extrapulmonary tuberculosis, who can be difficult to diagnose
by conventional means. The absence of ESAT-6-specific T
cells in 43 of 47 (92%) control patients indicates that these cells
are highly specific for M. tuberculosis infection. The high specificity of the assay, despite the fact that 77% of control patients
were BCG vaccinated, makes it possible to distinguish successfully between BCG-vaccinated and M. tuberculosis-infected patients. Furthermore, the presence in the control patients of a
variety of infectious, inflammatory, and granulomatous diseases indicates that the assay is not confounded by nonspecific
activation of the cellular immune system, which often accompanies conditions that clinically mimic tuberculosis.
The current method for determining infection status, the TST, measures a delayed-type hypersensitivity response to intradermal inoculation of PPD, a crude precipitate of M. tuberculosis culture supernatant containing more than 200 proteins widely shared among mycobacteria other than M. tuberculosis, including M. bovis BCG and many environmental mycobacteria. This antigenic cross-reactivity accounts for the poor specificity of the TST (25). Sensitivity is also low at 75- 90% (29, 30) and falls to less than 50% in critically ill patients with disseminated tuberculosis (29). Moreover, administration and reading of the TST are both highly operator dependent and patients must make a return visit. The sensitivity of the TST among the 26 tuberculosis patients tested by this method was 69%, significantly less than the 96% sensitivity of the ESAT-6-based ex vivo ELISPOT (p = 0.003), suggesting that the latter may be a superior means for the rapid detection of M. tuberculosis infection.
In this series of patients, sputum microscopy would have detected only 76% (19 of 25) of the pulmonary tuberculosis cases, compared with 92% (23 of 25) for the ex vivo ELISPOT, which also detected all six cases of sputum smear-negative pulmonary tuberculosis. Furthermore, sputum microscopy cannot easily differentiate between M. tuberculosis and atypical mycobacteria. Because the esat-6 gene is restricted to M. tuberculosis complex, M. kansasii, marinum, flavescens and szulgai (8) (of these only M. kansasii can cause disease clinically similar to tuberculosis), this ESAT-6-based test may prove to be more specific, as well as more sensitive, than sputum microscopy.
Interestingly, the four of 47 control patients with nontuberculous illnesses who responded in the ESAT-6-based ex vivo ELISPOT assay had all recently arrived from tuberculosis endemic countries (Kenya and Ethiopia). In contrast, none of the 22 UK-born control patients gave a positive response. These four responders were thus at increased risk of exposure to M. tuberculosis and might have been latently infected.
To determine whether we could detect latent M. tuberculosis infection in asymptomatic subjects, we studied a series of
26 TST-positive HHCs; active tuberculosis was clinically and
radiographically excluded, so M. tuberculosis infection in
these individuals would, by definition, be latent rather than
active. ESAT-6 peptide-specific IFN--secreting T cells were
detected in 22 of 26 (85%) contacts (Figure 1B). By contrast,
none of the 26 BCG-vaccinated healthy unexposed subjects had
ESAT-6 peptide-specific IFN--secreting T cells (Figure 1B),
indicating that ESAT-6 peptide-specific T cells represent an
accurate marker of individuals at high risk of latent M. tuberculosis infection that is not confounded by BCG vaccination.
The four TST-positive contacts who were negative by ex vivo
ELISPOT may not have been infected with M. tuberculosis; their positive TSTs may have resulted from prior BCG vaccination. This possibility cannot be formally tested as there is no
other means of definitively confirming or excluding latent M. tuberculosis infection in asymptomatic exposed contacts.
In conclusion, we have developed a T cell-based assay that accurately detects M. tuberculosis infection in TST-positive healthy exposed contacts, as well as patients with active tuberculosis and that successfully distinguishes M. tuberculosis infection from BCG vaccination. Clearly, the usefulness of the assay will depend on the prevalence of latent M. tuberculosis infection in a given population. In nonendemic regions, this approach could help to improve contact tracing, outbreak control, and targeting of chemoprophylaxis. In addition, for individual patients with clinically suspected tuberculosis in low-prevalence populations, the ESAT-6-based ex vivo ELISPOT assay holds promise as a useful adjunct for the rapid presumptive diagnosis of tuberculosis allowing early initiation of therapy. However, before entering widespread clinical use, the assay will need to be further validated in a double-blind study in which a larger number of patients with clinically suspected tuberculosis is prospectively evaluated, and the results of the assay compared against the final clinical and bacteriological diagnoses; this would also generate positive and negative predictive values pertinent to the participating population. In tuberculosis-endemic regions, the high proportion of latently infected people would preclude application of this assay for the presumptive diagnosis of active tuberculosis, but it could nonetheless facilitate epidemiological studies investigating the basic parameters and pathways of M. tuberculosis transmission and might help to evaluate the impact of tuberculosis control measures (31). The assay generates results in less than 24 h, requires no specialized laboratory facilities or radioisotopes, and is amenable to automation; it is thus potentially well suited to routine diagnostic hospital laboratories. Appropriate application of this novel T cell-based approach could potentially make a significant contribution to tuberculosis control.
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Footnotes |
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Correspondence and requests for reprints should be addressed to A. Lalvani, M.D., Nuffield Department of Clinical Medicine, University of Oxford, Level 7, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail: ajit.lalvani{at}ndm.ox.ac.uk
(Received in original form September 27, 2000 and in revised form December 20, 2000).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.orgAcknowledgments: The authors are grateful to all patients who took part in this study and thank the following for helpful discussions: D. Sackett, D. J. Weatherall, S. Jaffar, D. Lalloo, R. Davidson, J. Watson, C. O'Callaghan, K. Thomson, P. Newton, P. Klenerman, E. Corbett, A. Butterworth, T. Peto, J. Naydler, D. Warrell, and M. Patel. The authors also thank the staff of the hospitals involved, especially D. Shah, R. Davidson, and R. A. Wall, and the following for help with obtaining blood samples: F. Burns, A. Hinton, L. Mayahi, J. Schott, F. Haworth, R. Heyderman, A. Meade, A. Godkin, N. Jones, C. Hemsley, D. Webster, R. Price, J. Short, H. Eagleton, and S. Davies.
Supported by the Wellcome Trust of Great Britain.
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M. Pai, A. Zwerling, and D. Menzies Systematic Review: T-Cell-based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update Ann Intern Med, August 5, 2008; 149(3): 177 - 184. [Abstract] [Full Text] [PDF]
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C. B. E. Chee, S. H. Gan, K. W. KhinMar, T. M. Barkham, C. K. Koh, S. Liang, and Y. T. Wang Comparison of Sensitivities of Two Commercial Gamma Interferon Release Assays for Pulmonary Tuberculosis J. Clin. Microbiol., June 1, 2008; 46(6): 1935 - 1940. [Abstract] [Full Text] [PDF]
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D. P.S. Dosanjh, T. S.C. Hinks, J. A. Innes, J. J. Deeks, G. Pasvol, S. Hackforth, H. Varia, K. A. Millington, R. Gunatheesan, V. Guyot-Revol, et al. Improved Diagnostic Evaluation of Suspected Tuberculosis Ann Intern Med, March 4, 2008; 148(5): 325 - 336. [Abstract] [Full Text] [PDF]
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S. Perry, L. Sanchez, S. Yang, Z. Agarwal, P. Hurst, and J. Parsonnet Reproducibility of QuantiFERON-TB Gold In-Tube Assay Clin. Vaccine Immunol., March 1, 2008; 15(3): 425 - 432. [Abstract] [Full Text] [PDF]
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J. Dominguez, J. Ruiz-Manzano, M. De Souza-Galvao, I. Latorre, C. Mila, S. Blanco, M. A. Jimenez, C. Prat, A. Lacoma, N. Altet, et al. Comparison of Two Commercially Available Gamma Interferon Blood Tests for Immunodiagnosis of Tuberculosis Clin. Vaccine Immunol., January 1, 2008; 15(1): 168 - 171. [Abstract] [Full Text] [PDF]
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M. Losi, A. Bossink, L. Codecasa, C. Jafari, M. Ernst, S. Thijsen, D. Cirillo, M. Ferrarese, U. Greinert, L. M. Fabbri, et al. Use of a T-cell interferon-{gamma} release assay for the diagnosis of tuberculous pleurisy Eur. Respir. J., December 1, 2007; 30(6): 1173 - 1179. [Abstract] [Full Text] [PDF]
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N. P. Harrington, O. P. Surujballi, W. R. Waters, and J. F. Prescott Development and Evaluation of a Real-Time Reverse Transcription-PCR Assay for Quantification of Gamma Interferon mRNA To Diagnose Tuberculosis in Multiple Animal Species Clin. Vaccine Immunol., December 1, 2007; 14(12): 1563 - 1571. [Abstract] [Full Text] [PDF]
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Y. Kobashi, K. Mouri, Y. Obase, M. Fukuda, N. Miyashita, and M. Oka Clinical evaluation of QuantiFERON TB-2G test for immunocompromised patients Eur. Respir. J., November 1, 2007; 30(5): 945 - 950. [Abstract] [Full Text] [PDF]
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Y. A. Kang, H. W. Lee, S. S. Hwang, S.-W. Um, S. K. Han, Y.-S. Shim, and J.-J. Yim Usefulness of Whole-Blood Interferon-{gamma} Assay and Interferon-{gamma} Enzyme-Linked Immunospot Assay in the Diagnosis of Active Pulmonary Tuberculosis Chest, September 1, 2007; 132(3): 959 - 965. [Abstract] [Full Text] [PDF]
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R. Diel, P. Wrighton-Smith, and J-P. Zellweger Cost-effectiveness of interferon-{gamma} release assay testing for the treatment of latent tuberculosis Eur. Respir. J., August 1, 2007; 30(2): 321 - 332. [Abstract] [Full Text] [PDF]
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A. Lalvani Diagnosing Tuberculosis Infection in the 21st Century: New Tools To Tackle an Old Enemy Chest, June 1, 2007; 131(6): 1898 - 1906. [Abstract] [Full Text] [PDF]
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D. Menzies, M. Pai, and G. Comstock Meta-analysis: New Tests for the Diagnosis of Latent Tuberculosis Infection: Areas of Uncertainty and Recommendations for Research Ann Intern Med, March 6, 2007; 146(5): 340 - 354. [Abstract] [Full Text] [PDF]
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R. M. L. van Leeuwen, A. W. J. Bossink, and S. F. T. Thijsen Exclusion of active Mycobacterium tuberculosis complex infection with the T-SPOTTM.TB assay Eur. Respir. J., March 1, 2007; 29(3): 605 - 607. [Abstract] [Full Text] [PDF]
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C. B. E. Chee, K. W. KhinMar, S. H. Gan, T. M. S. Barkham, M. Pushparani, and Y. T. Wang Latent Tuberculosis Infection Treatment and T-Cell Responses to Mycobacterium tuberculosis-specific Antigens Am. J. Respir. Crit. Care Med., February 1, 2007; 175(3): 282 - 287. [Abstract] [Full Text] [PDF]
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C. Granger The specificity of interferon-{gamma}-based blood tests in the identification of latent tuberculosis infection Eur. Respir. J., December 1, 2006; 28(6): 1283 - 1283. [Full Text] [PDF]
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C. Aagaard, M. Govaerts, V. Meikle, A. J. Vallecillo, J. A. Gutierrez-Pabello, F. Suarez-Guemes, J. McNair, A. Cataldi, C. Espitia, P. Andersen, et al. Optimizing Antigen Cocktails for Detection of Mycobacterium bovis in Herds with Different Prevalences of Bovine Tuberculosis: ESAT6-CFP10 Mixture Shows Optimal Sensitivity and Specificity J. Clin. Microbiol., December 1, 2006; 44(12): 4326 - 4335. [Abstract] [Full Text] [PDF]
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C. Jafari, M. Ernst, B. Kalsdorf, U. Greinert, R. Diel, D. Kirsten, K. Marienfeld, A. Lalvani, and C. Lange Rapid Diagnosis of Smear-negative Tuberculosis by Bronchoalveolar Lavage Enzyme-linked Immunospot Am. J. Respir. Crit. Care Med., November 1, 2006; 174(9): 1048 - 1054. [Abstract] [Full Text] [PDF]
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L. Richeldi An Update on the Diagnosis of Tuberculosis Infection Am. J. Respir. Crit. Care Med., October 1, 2006; 174(7): 736 - 742. [Abstract] [Full Text] [PDF]
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K. Ewer, K. A. Millington, J. J. Deeks, L. Alvarez, G. Bryant, and A. Lalvani Dynamic Antigen-specific T-Cell Responses after Point-Source Exposure to Mycobacterium tuberculosis Am. J. Respir. Crit. Care Med., October 1, 2006; 174(7): 831 - 839. [Abstract] [Full Text] [PDF]
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R. Diel, M. Ernst, G. Doscher, L. Visuri-Karbe, U. Greinert, S. Niemann, A. Nienhaus, and C. Lange Avoiding the effect of BCG vaccination in detecting Mycobacterium tuberculosis infection with a blood test Eur. Respir. J., July 1, 2006; 28(1): 16 - 23. [Abstract] [Full Text] [PDF]
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F. Piana, L. R. Codecasa, P. Cavallerio, M. Ferrarese, G. B. Migliori, L. Barbarano, E. Morra, and D. M. Cirillo Use of a T-cell-based test for detection of tuberculosis infection among immunocompromised patients Eur. Respir. J., July 1, 2006; 28(1): 31 - 34. [Abstract] [Full Text] [PDF]
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J. Y. Lee, H. J. Choi, I-N. Park, S-B. Hong, Y-M. Oh, C-M. Lim, S. D. Lee, Y. Koh, W. S. Kim, D. S. Kim, et al. Comparison of two commercial interferon-{gamma} assays for diagnosing Mycobacterium tuberculosis infection Eur. Respir. J., July 1, 2006; 28(1): 24 - 30. [Abstract] [Full Text] [PDF]
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P. Wrighton-Smith and J-P. Zellweger Direct costs of three models for the screening of latent tuberculosis infection Eur. Respir. J., July 1, 2006; 28(1): 45 - 50. [Abstract] [Full Text] [PDF]
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T G Connell, N Curtis, S C Ranganathan, and J P Buttery Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children Thorax, July 1, 2006; 61(7): 616 - 620. [Abstract] [Full Text] [PDF]
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L. Codecasa, P. Mantegani, L. Galli, A. Lazzarin, P. Scarpellini, and C. Fortis An In-House RD1-Based Enzyme-Linked Immunospot-Gamma Interferon Assay Instead of the Tuberculin Skin Test for Diagnosis of Latent Mycobacterium tuberculosis Infection. J. Clin. Microbiol., June 1, 2006; 44(6): 1944 - 1950. [Abstract] [Full Text] [PDF]
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E. M. S. Leyten, B. Mulder, C. Prins, K. Weldingh, P. Andersen, T. H. M. Ottenhoff, J. T. van Dissel, and S. M. Arend Use of Enzyme-Linked Immunospot Assay with Mycobacterium tuberculosis- Specific Peptides for Diagnosis of Recent Infection with M. tuberculosis after Accidental Laboratory Exposure. J. Clin. Microbiol., March 1, 2006; 44(3): 1197 - 1201. [Abstract] [Full Text] [PDF]
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N. Banaiee, E. Z. Kincaid, U. Buchwald, W. R. Jacobs Jr., and J. D. Ernst Potent Inhibition of Macrophage Responses to IFN-{gamma} by Live Virulent Mycobacterium tuberculosis Is Independent of Mature Mycobacterial Lipoproteins but Dependent on TLR2. J. Immunol., March 1, 2006; 176(5): 3019 - 3027. [Abstract] [Full Text] [PDF]
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L Richeldi, K Ewer, M Losi, P Roversi, L M Fabbri, and A Lalvani Repeated tuberculin testing does not induce false positive ELISPOT results. Thorax, February 1, 2006; 61(2): 180 - 180. [Full Text] [PDF]
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F. Piana, L. R. Codecasa, G. Besozzi, G. B. Migliori, and D. M. Cirillo Use of Commercial Interferon-{gamma} Assays in Immunocompromised Patients for Tuberculosis Diagnosis Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 130 - 130. [Full Text] [PDF]
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H. Shams, S. E. Weis, P. Klucar, A. Lalvani, P. K. Moonan, J. M. Pogoda, K. Ewer, and P. F. Barnes Enzyme-linked Immunospot and Tuberculin Skin Testing to Detect Latent Tuberculosis Infection Am. J. Respir. Crit. Care Med., November 1, 2005; 172(9): 1161 - 1168. [Abstract] [Full Text] [PDF]
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K. Dheda, J.-S. Chang, R. A. M. Breen, L. U. Kim, J. A. Haddock, J. F. Huggett, M. A. Johnson, G. A. W. Rook, and A. Zumla In Vivo and In Vitro Studies of a Novel Cytokine, Interleukin 4{delta}2, in Pulmonary Tuberculosis Am. J. Respir. Crit. Care Med., August 15, 2005; 172(4): 501 - 508. [Abstract] [Full Text] [PDF]
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C. C. Whalen Diagnosis of Latent Tuberculosis Infection: Measure for Measure JAMA, June 8, 2005; 293(22): 2785 - 2787. [Full Text] [PDF]
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J. Dietrich, C. Aagaard, R. Leah, A. W. Olsen, A. Stryhn, T. M. Doherty, and P. Andersen Exchanging ESAT6 with TB10.4 in an Ag85B Fusion Molecule-Based Tuberculosis Subunit Vaccine: Efficient Protection and ESAT6-Based Sensitive Monitoring of Vaccine Efficacy J. Immunol., May 15, 2005; 174(10): 6332 - 6339. [Abstract] [Full Text] [PDF]
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K. A. Wilkinson, M. Simsova, E. Scholvinck, P. Sebo, C. Leclerc, H. M. Vordermeier, S. J. Dickson, J. R. Brown, R. N. Davidson, G. Pasvol, et al. Efficient Ex Vivo Stimulation of Mycobacterium tuberculosis-Specific T Cells by Genetically Detoxified Bordetella pertussis Adenylate Cyclase Antigen Toxoids Infect. Immun., May 1, 2005; 73(5): 2991 - 2998. [Abstract] [Full Text] [PDF]
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P. Ravn, M. E. Munk, A. B. Andersen, B. Lundgren, J. D. Lundgren, L. N. Nielsen, A. Kok-Jensen, P. Andersen, and K. Weldingh Prospective Evaluation of a Whole-Blood Test Using Mycobacterium tuberculosis-Specific Antigens ESAT-6 and CFP-10 for Diagnosis of Active Tuberculosis Clin. Vaccine Immunol., April 1, 2005; 12(4): 491 - 496. [Abstract] [Full Text] [PDF]
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D. A. Mitchison The Diagnosis and Therapy of Tuberculosis During the Past 100 Years Am. J. Respir. Crit. Care Med., April 1, 2005; 171(7): 699 - 706. [Abstract] [Full Text] [PDF]
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J Moore-Gillon Tuberculin testing, BCG and tuberculosis today Thorax, February 1, 2005; 60(2): 90 - 91. [Full Text] [PDF]
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H. Rieder Annual risk of infection with Mycobacterium tuberculosis Eur. Respir. J., January 1, 2005; 25(1): 181 - 185. [Abstract] [Full Text] [PDF]
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Pediatric Tuberculosis Collaborative Group Targeted Tuberculin Skin Testing and Treatment of Latent Tuberculosis Infection in Children and Adolescents Pediatrics, October 1, 2004; 114(4/S2): 1175 - 1201. [Abstract] [Full Text] [PDF]
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P. Scarpellini, S. Tasca, L. Galli, A. Beretta, A. Lazzarin, and C. Fortis Selected Pool of Peptides from ESAT-6 and CFP-10 Proteins for Detection of Mycobacterium tuberculosis Infection J. Clin. Microbiol., August 1, 2004; 42(8): 3469 - 3474. [Abstract] [Full Text] [PDF]
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H. Shams, P. Klucar, S. E. Weis, A. Lalvani, P. K. Moonan, H. Safi, B. Wizel, K. Ewer, G. T. Nepom, D. M. Lewinsohn, et al. Characterization of a Mycobacterium tuberculosis Peptide That Is Recognized by Human CD4+ and CD8+ T Cells in the Context of Multiple HLA Alleles J. Immunol., August 1, 2004; 173(3): 1966 - 1977. [Abstract] [Full Text] [PDF]
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L. Richeldi, K. Ewer, M. Losi, B. M. Bergamini, P. Roversi, J. Deeks, L. M. Fabbri, and A. Lalvani T Cell-Based Tracking of Multidrug Resistant Tuberculosis Infection after Brief Exposure Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 288 - 295. [Abstract] [Full Text] [PDF]
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P. F. Barnes Diagnosing Latent Tuberculosis Infection: Turning Glitter to Gold Am. J. Respir. Crit. Care Med., July 1, 2004; 170(1): 5 - 6. [Full Text] [PDF]
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I. Brock, K. Weldingh, E. M. S. Leyten, S. M. Arend, P. Ravn, and P. Andersen Specific T-Cell Epitopes for Immunoassay-Based Diagnosis of Mycobacterium tuberculosis Infection J. Clin. Microbiol., June 1, 2004; 42(6): 2379 - 2387. [Abstract] [Full Text] [PDF]
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L. Richeldi, K. Ewer, M. Losi, D. M. Hansell, P. Roversi, L. M. Fabbri, and A. Lalvani Early Diagnosis of Subclinical Multidrug-Resistant Tuberculosis Ann Intern Med, May 4, 2004; 140(9): 709 - 713. [Abstract] [Full Text] [PDF]
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X.-Q. Liu, D. Dosanjh, H. Varia, K. Ewer, P. Cockle, G. Pasvol, and A. Lalvani Evaluation of T-Cell Responses to Novel RD1- and RD2-Encoded Mycobacterium tuberculosis Gene Products for Specific Detection of Human Tuberculosis Infection Infect. Immun., May 1, 2004; 72(5): 2574 - 2581. [Abstract] [Full Text] [PDF]
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A Lalvani Spotting latent infection: the path to better tuberculosis control Thorax, November 1, 2003; 58(11): 916 - 918. [Full Text]
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G. F. Black, R. E. Weir, S. D. Chaguluka, D. Warndorff, A. C. Crampin, L. Mwaungulu, L. Sichali, S. Floyd, L. Bliss, E. Jarman, et al. Gamma Interferon Responses Induced by a Panel of Recombinant and Purified Mycobacterial Antigens in Healthy, Non-Mycobacterium bovis BCG-Vaccinated Malawian Young Adults Clin. Vaccine Immunol., July 1, 2003; 10(4): 602 - 611. [Abstract] [Full Text] [PDF]
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M. Vordermeier, A. O. Whelan, and R. G. Hewinson Recognition of Mycobacterial Epitopes by T Cells across Mammalian Species and Use of a Program That Predicts Human HLA-DR Binding Peptides To Predict Bovine Epitopes Infect. Immun., April 1, 2003; 71(4): 1980 - 1987. [Abstract] [Full Text]
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P. J. Cockle, S. V. Gordon, A. Lalvani, B. M. Buddle, R. G. Hewinson, and H. M. Vordermeier Identification of Novel Mycobacterium tuberculosis Antigens with Potential as Diagnostic Reagents or Subunit Vaccine Candidates by Comparative Genomics Infect. Immun., December 1, 2002; 70(12): 6996 - 7003. [Abstract] [Full Text] [PDF]
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L. B. Gerald, S. Tang, F. Bruce, D. Redden, M. E. Kimerling, N. Brook, N. Dunlap, and W. C. Bailey A Decision Tree for Tuberculosis Contact Investigation Am. J. Respir. Crit. Care Med., October 15, 2002; 166(8): 1122 - 1127. [Abstract] [Full Text] [PDF]
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D. A. Lewinsohn, R. A. Lines, and D. M. Lewinsohn Human Dendritic Cells Presenting Adenovirally Expressed Antigen Elicit Mycobacterium tuberculosis-Specific CD8+ T Cells Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 843 - 848. [Abstract] [Full Text]
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K. J. Welch, A. Morse, and A. Lalvani Improving tuberculin skin testing in hiv-infected individuals Am. J. Respir. Crit. Care Med., May 15, 2002; 165(10): 1452 - 1452. [Full Text]
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M. J. TOBIN Tuberculosis, Lung Infections, Interstitial Lung Disease, and Socioeconomic Issues in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 631 - 641. [Full Text] [PDF]
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N. W. SCHLUGER Changing Approaches to the Diagnosis of Tuberculosis Am. J. Respir. Crit. Care Med., December 1, 2001; 164(11): 2020 - 2024. [Full Text] [PDF]
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A. A. Pathan, K. A. Wilkinson, P. Klenerman, H. McShane, R. N. Davidson, G. Pasvol, A. V. S. Hill, and A. Lalvani Direct Ex Vivo Analysis of Antigen-Specific IFN-{gamma}-Secreting CD4 T Cells in Mycobacterium tuberculosis-Infected Individuals: Associations with Clinical Disease State and Effect of Treatment J. Immunol., November 1, 2001; 167(9): 5217 - 5225. [Abstract] [Full Text] [PDF]
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