[Critical approach to the use of blood tests measuring gamma-interferon when suspecting active tuberculosis: clinical cases].
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Abstract:
Assays measuring gamma-interferon (INGA) produced by peripheral lymphocytes exposed to antigens specific of Mycobacterium tuberculosis have a very high specificity, thus avoiding false positive results of the tuberculin skin test (TST) such as the BCG or atypical mycobacteria, and allowing a better targeting of treatments for latent tuberculosis infection (LTBI). Their sensitivity is superior to that of the TST in immuno-compromised and elderly subjects, and probably in immuno-competent individuals. They do not allow however to make the distinction between LTBI and active tuberculosis. Furthermore, their sensitivity, although superior to that of the TST, is not sufficient to exclude active TB specially in immuno-compromised subjects. Their main indication remains the detection of LTBI in screening or contact tracing, or in immuno-compromised subjects.Keywords:
Active tuberculosis
Contact tracing
Tuberculosis diagnosis
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The diagnosis of active and latent tuberculosis infection (LTBI) remains a challenge, especially in light of the fact that the tuberculin skin test (TST), which has been used to diagnose LTBI for over a century, has many well-known drawbacks. This study aimed to compare the diagnostic performance of the T-cell-based interferon-gamma releasing assay (IGRA) T-SPOT.TB with the TST for the diagnosis of LTBI in an intermediate tuberculosis (TB)-burden country with high BCG coverage. For this purpose, a total of 91 participants, including culture-confirmed TB patients, healthy contacts known to have been exposed to Mycobacterium tuberculosis, and healthy volunteers, selected from a BCG-vaccinated population were recruited. The sensitivities of the T-SPOT.TB and TST were 79.3 and 25.8%, and the specificities were 75.9 and 56.7%, respectively. The negative- and positive-predictive values for T-SPOT.TB and TST were 78.6 and 76.7% and 42.5 and 38.1%, respectively. The diagnostic performance of the TST in LTBI diagnosis is therefore severely diminished in BCG-vaccinated populations, with the sensitivity and specificity of the T-SPOT.TB assay being markedly higher. IGRAs have been reported to have higher diagnostic sensitivity and specificity in low TB-incidence settings than those seen here. Further larger scale studies in high and intermediate TB-incidence settings are therefore warranted.
Interferon γ
Tuberculosis diagnosis
Active tuberculosis
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Tuberculosis diagnosis
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The measurement of Interferon gamma or Interferon gamma inducible protein (IP)-10 in antigen stimulated blood samples is suggested as an alternative method for latent tuberculosis (TB) diagnosis. Nonetheless, their role in active TB diagnosis, particularly in TB endemic settings is yet to be defined. In this study, the sensitivities and specificities of Interferon gamma release assay (IGRA), IP-10 assay and tuberculin skin test (TST) in detecting active TB cases were assessed in human immunodeficiency virus (HIV) sero-negative TB patients and healthy controls respectively.A total of 177 adult TB patients and 100 healthy controls were included for this study. QuantiFERON-TB Gold In-tube (QFT-IT) method was used to analyze the sensitivity and specificity of IGRA. QFT-IT, IP-10 and TST yielded the diagnostic sensitivities of 90.6% (95%CI: 86.3%-94.9%), 92.5% (95%CI: 88.6%-96.4%) and 68.9% (95%CI: 60.6%-77.2%) and specificities of 55% (95% CI: 35.2%-54.8%), 48% (95% CI: 38.2%-57.8%) and 75.5% (95% CI: 66.8%-84.2%), respectively. The extent of pulmonary involvement or presence of diabetes mellitus did not appear to influence the sensitivities of any of these tests. The combination of any of the two tests among QFT-IT, IP-10 and TST showed >98% sensitivity among smear negative cases and particularly the combination of IP-10, TST and smear microscopy showed 100% sensitivity, however, the specificity was decreased to 44.8%.QFT-IT and IP-10 were highly sensitive in detecting active TB cases. The combination with TST improved the sensitivity of QFT-IT and IP-10 significantly. Although the higher sensitivity of combination of QFT-IT/IP-10 and TST may be useful in active TB diagnosis, they are limited by their poor specificity due to the high prevalence of latent TB in our settings.
QuantiFERON
Tuberculosis diagnosis
Gold standard (test)
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Medical microbiology
Active tuberculosis
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Until recently, the basic test to identify latent tuberculosis infection (LTBI) was the tuberculin skin test, despite its limitations in the form of low sensitivity and specificity. Currently, Interferon Gamma Release Assays from peripheral blood are used for a rapid diagnosis of LTBI and measurement of the interferon gamma (IFN-g) levels secreted by specific T cells stimulated with Mycobacterium tuberculosis antigens. Detection of LTBI is important in the control of people potentially at risk of TB disease, such as people remaining in close contact with BK (+) tb patient and for patients evaluated for biological treatment. The paper presents the value of IGRA in three selected clinical situations: in two cases of latent tuberculosis infection and in one case of active tuberculosis.
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Assays measuring gamma-interferon (INGA) produced by peripheral lymphocytes exposed to antigens specific of Mycobacterium tuberculosis have a very high specificity, thus avoiding false positive results of the tuberculin skin test (TST) such as the BCG or atypical mycobacteria, and allowing a better targeting of treatments for latent tuberculosis infection (LTBI). Their sensitivity is superior to that of the TST in immuno-compromised and elderly subjects, and probably in immuno-competent individuals. They do not allow however to make the distinction between LTBI and active tuberculosis. Furthermore, their sensitivity, although superior to that of the TST, is not sufficient to exclude active TB specially in immuno-compromised subjects. Their main indication remains the detection of LTBI in screening or contact tracing, or in immuno-compromised subjects.
Active tuberculosis
Contact tracing
Tuberculosis diagnosis
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The tuberculin skin test, now over a century old, is prone to reader variability, and outcomes are influenced by cross-reactivity with environmental mycobacteria, previous bacillus Calmette-Guerin (BCG) vaccination, and anergy in immunosuppressed individuals. More recently, T-cell-based interferon-gamma responses to Mycobacterium tuberculosis - specific antigens have been investigated for their role in diagnosing latent tuberculosis infection.We review the evidence supporting the utility of the interferon-gamma assay for the diagnosis of latent tuberculosis infection (LTBI) in low-prevalence countries. We discuss the principle of the test, technical factors related to performance, and its utility in active tuberculosis, in specialised subgroups such as immunocompromised patients, and its applicability in developing countries.Compared with the tuberculin skin test, the antigen-specific interferon-gamma assay, when used in a standardised protocol (overnight incubation assay using a combination of two antigens) for the diagnosis of LTBI, has greater specificity in BCG-vaccinated individuals, displays a stronger association with exposure, and is less biased by environmental mycobacteria such as Mycobacterium avium. Prospective studies are required, however, to confirm that treating LTBI, as defined by the interferon-gamma assay, will reduce the tuberculosis burden in low-prevalence countries and whether interferon-gamma responses are predictive of those who have a high risk of progression to active tuberculosis. Further studies are required to address the utility of the interferon-gamma assay in specialised subgroups of patients, in developing countries, and as a marker of disease activity.
BCG vaccine
Tuberculosis diagnosis
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Interferon-gamma release assays (IGRAs) represent the first new tool to diagnose latent tuberculosis infection for more than 100 years. They have advantages over the traditional tuberculin skin test which has a poor specificity due to false-positive responses in people who are BCG vaccinated as there is a cross-reactivity of proteins present in both BCG and the tuberculin skin test. IGRAs rely on the concept of detecting the ex vivo release of the cytokine IFN-γ, a key anti-Mycobacterium tuberculosis cytokine, from T cells which react specifically to antigens from M. tuberculosis. T cells are sensitized to the antigens in vivo, and then react when they encounter the same proteins ex vivo. The readouts are used to determine presence of sensitized cells, acting as a surrogate for latent tuberculosis infection. IGRAs are now being incorporated into national guidance for diagnosis and research is ongoing into next-generation versions of the test.
Ex vivo
Tuberculosis diagnosis
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