Transformative tools for tackling tuberculosis

Gardiner, Jennifer; Karp, Christopher

doi:10.1084/jem.20151468

Cited by 37 publications

(34 citation statements)

References 84 publications

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“…To develop such predictive tests, we need transformative research that will enable us to identify biomarkers or biosignatures that can resolve the LTBI spectrum (8) and help target those at highest risk of progressing to active disease (51). Some promising biomarkers have been identified, especially gene expression signatures (52), but much more validation work is required.…”

Section: Discussionmentioning

confidence: 99%

Latent Mycobacterium tuberculosis Infection and Interferon-Gamma Release Assays

Pai

Behr

2016

Microbiol Spectr

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The identification of individuals with latent tuberculosis infection (LTBI) is useful for both fundamental understanding of the pathogenesis of disease and for clinical and public health interventions (i.e., to prevent progression to disease). Basic research suggests there is a pathogenetic continuum from exposure to infection to disease, and individuals may advance or reverse positions within the spectrum, depending on changes in the host immunity. Unfortunately, there is no diagnostic test that resolves the various stages within the spectrum of Mycobacterium tuberculosis infection. Two main immune-based approaches are currently used for identification of LTBI: the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). TST can use either the conventional purified protein derivative or more specific antigens. Extensive research suggests that both TST and IGRA represent indirect markers of M. tuberculosis exposure and indicates a cellular immune response to M. tuberculosis . The imperfect concordance between these two tests suggests that neither test is perfect, presumably due to both technical and biological reasons. Neither test can accurately differentiate between LTBI and active TB. Both IGRA and TST have low sensitivity in a variety of immunocompromised populations. Cohort studies have shown that both TST and IGRA have low predictive value for progression from infection to active TB. For fundamental applications, basic research is necessary to identify those at highest risk of disease with a positive TST and/or IGRA. For clinical applications, the identification of such biomarkers can help prioritize efforts to interrupt progression to disease through preventive therapy.

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Section: Discussionmentioning

confidence: 99%

Latent Mycobacterium tuberculosis Infection and Interferon-Gamma Release Assays

Pai

Behr

2016

Microbiol Spectr

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“…However, translation from biomarker discovery to clinical tools has been poor. In this regard, improved detection of the lipoglycan biomarker LAM could lead to a breakthrough in urine‐based antigen detection . Another approach to TB biomarkers is the analysis of mycobacteria‐specific lipid profiles.…”

Section: Challenges and Future Directions For Improving The Diagnosismentioning

confidence: 99%

Diagnosis of Tuberculosis in HIV Co‐infected Individuals: Current Status, Challenges and Opportunities for the Future

Méndez-Samperio¹

2017

Scand J Immunol

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Tuberculosis (TB) remains one of the most important causes of death among people co-infected with human immunodeficiency virus (HIV). The diagnosis of TB remains challenging in HIV co-infected individuals, due to a high frequency of smear-negative disease and high rates of extrapulmonary TB. Accurate, ease of use and rapid diagnosis of active TB are critical to the World Health Organization (WHO) End TB Strategy by 2050. Traditional laboratory techniques do not provide rapid and accurate results to effectively manage HIV co-infected patients. Over the last decade, molecular methods have provided significant steps in the fight against TB. However, many HIV co-infected patients do not have access to these molecular diagnostic tests. Given the costs closely related with confirming a TB diagnosis in HIV patients, an overtreatment for TB is used in this patient population. Nowadays, an estimated US $8 billion a year is required to provide TB treatment, which is very high compared with making an important strategy to improve the current diagnostic tests. This review focuses on current advances in diagnosing active TB with an emphasis on the diagnosis of HIV-associated TB. Also discussed are the main challenges that need to be overcome for improving an adequate initial diagnosis of active TB in HIV-positive patients.

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“…As previously shown (5), in HIV-uninfected persons, HLA-DR, Ki67, and CD38 expression on IFN-g 1 Mtb-specific CD4 1 T cells was significantly higher in aTB participants than in those with LTBI ( Figure 1B). Interestingly, although HLA-DR expression on Mtb-specific CD4 1 T cells in the LTBI/HIV 1 group (median, 41.7%; IQR, 25.7-54.6%) was significantly higher than in the LTBI/HIV 2 group (median, 13.7%; IQR, 8.9-27.5%), HLA-DR expression on these cells was significantly further increased in HIV-infected individuals with aTB (median, 84%; IQR, 73.7-87.9%) ( Figure 1B). Additional analyses showed that in LTBI/HIV 1 individuals, HLA-DR expression on Mtb-specific CD4 1 T cells mirrors HLA-DR expression in the whole CD4 compartment (P = 0.02; r = 0.56), but this association was not apparent in aTB/HIV 1 individuals (data not shown).…”

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confidence: 99%

Activation Profile of Mycobacterium tuberculosis–Specific CD4⁺ T Cells Reflects Disease Activity Irrespective of HIV Status

Wilkinson

Oni

Gideon

et al. 2016

Am J Respir Crit Care Med

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The diagnosis of pulmonary tuberculosis in HIV-infected individuals is particularly challenging as HIV-induced alterations of the immune system lead to reduced cavitation, limiting the sensitivity of sputum-based assays (1). Thus, alternate markers are needed to distinguish between latent tuberculosis infection (LTBI) and active tuberculosis (aTB) in this high-risk group. Several attributes of Mycobacterium tuberculosis (Mtb)-specific CD4 1 T cells have been shown to efficiently delineate LTBI and aTB in HIV-uninfected individuals, including their polyfunctional or memory profiles (2-4). Moreover, Adekambi and colleagues recently demonstrated that the activation profile of Mtb-specific CD4 1 T cells accurately discriminates between LTBI and aTB (5). As chronic HIV infection is characterized by persistent systemic immune activation (6), it is plausible that these blood-based markers may not be relevant for HIV-infected individuals. We, therefore, compared the potential of the activation and polyfunctional profiles of Mtb-specific CD4 1 T cells to distinguish between LTBI and aTB in HIV-uninfected and HIV-infected individuals. We analyzed 76 participants divided in four groups according to their TB and HIV status: LTBI/HIV 2 (n = 17; median age, 22 yr; 47% female), aTB/HIV 2 (n = 17; median age, 27 yr; 29% female), LTBI/HIV 1 (n = 21; median age, 29 yr; 67% female; median CD4 count, 316 cells/mm 3 ; interquartile range [IQR], 231-543 cells/mm 3), and aTB/HIV 1 (n = 21; median age, 35 yr; 57% female; CD4 count, 250 cells/mm 3 ; IQR, 155-295 cells/mm 3). LTBI was defined as tuberculin skin test positive, IFN-g release assay positive, sputum culture negative, and normal chest X-ray. aTB was diagnosed on the basis of symptoms suggestive of tuberculosis and Mtb-positive smear and/or sputum culture, as previously described (7). All HIV-infected participants were antiretroviral therapy-naive. The University of Cape Town ethics committee approved the study, and written consent was obtained from participants. Cryopreserved peripheral blood mononuclear cells were stimulated for 16 hours with early secretory antigenic target-6 (ESAT-6)/culture filtrate protein-10 (CFP-10) peptide pool, and intracellular staining, using a live/dead marker and antibodies toward CD3, CD4, CD8, human leukocyte antigen-DR (HLA-DR), Ki67, CD38, IFN-g, tumor necrosis factor (TNF)-a, and IL-2, was performed. Positive ESAT-6/CFP-10 responses (defined as twice the

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Transformative tools for tackling tuberculosis

Abstract: Better tools are needed for detecting Mycobacterium tuberculosis and defining the dynamic interactions of M. tuberculosis with its human host.

Cited by 37 publications

References 84 publications

Latent Mycobacterium tuberculosis Infection and Interferon-Gamma Release Assays

Latent Mycobacterium tuberculosis Infection and Interferon-Gamma Release Assays

Diagnosis of Tuberculosis in HIV Co‐infected Individuals: Current Status, Challenges and Opportunities for the Future

Activation Profile of Mycobacterium tuberculosis–Specific CD4⁺ T Cells Reflects Disease Activity Irrespective of HIV Status

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Transformative tools for tackling tuberculosis

Abstract: Better tools are needed for detecting Mycobacterium tuberculosis and defining the dynamic interactions of M. tuberculosis with its human host.

Cited by 37 publications

References 84 publications

Latent Mycobacterium tuberculosis Infection and Interferon-Gamma Release Assays

Latent Mycobacterium tuberculosis Infection and Interferon-Gamma Release Assays

Diagnosis of Tuberculosis in HIV Co‐infected Individuals: Current Status, Challenges and Opportunities for the Future

Activation Profile of Mycobacterium tuberculosis–Specific CD4+ T Cells Reflects Disease Activity Irrespective of HIV Status

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Activation Profile of Mycobacterium tuberculosis–Specific CD4⁺ T Cells Reflects Disease Activity Irrespective of HIV Status