Risk Stratification of Latent Tuberculosis Defined by Combined Interferon Gamma Release Assays

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Abstract

Background

Most individuals infected with Mycobacterium tuberculosis develop latent tuberculosis infection (LTBI). Some may progress to active disease and would benefit from preventive treatment yet no means currently exists to predict who will reactivate. Here, we provide an approach to stratify LTBI based on IFN-γ responses to two antigens, the recombinant Early-Secreted Antigen Target-6 (rESAT-6) and the latency antigen Heparin-Binding Haemagglutinin (HBHA).

Methods

We retrospectively analyzed results from in-house IFN-γ-release assays with HBHA (HBHA-IGRA) and rESAT-6 (rESAT-6-IGRA) performed during a 12-year period on serial blood samples (3 to 9) collected from 23 LTBI subjects in a low-TB incidence country. Both the kinetics of the absolute IFN-γ concentrations secreted in response to each antigen and the dynamics of HBHA/rESAT-6-induced IFN-γ concentrations ratios were examined.

Results

This analysis allowed the identification among the LTBI subjects of three major groups. Group A featured stable HBHA and rESAT-6-IGRA profiles with an HBHA/rESAT-6 ratio persistently higher than 1, and with high HBHA- and usually negative rESAT-6-IGRA responses throughout the study. Group B had changing HBHA/rESAT-6 ratios fluctuating from 0.0001 to 10,000, with both HBHA and rESAT-6 responses varying over time at least once during the follow-up. Group C was characterized by a progressive disappearance of all responses.

Conclusions

By combining the measures of IFN-γ concentrations secreted in response to an early and a latency antigens, LTBI subjects can be stratified into different risk groups. We propose that disappearing responses indicate cure, that persistent responses to HBHA with HBHA/rESAT-6 ratios ≥1 represent stable LTBI subjects, whereas subjects with ratios varying from >1 to <1 should be closely monitored as they may represent the highest-risk group, as illustrated by a case report, and should therefore be prioritized for preventive treatment.

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Most cited references 26

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Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update.

Madhukar Pai, Alice Zwerling, Dick Menzies (2008)

Interferon-gamma-release assays (IGRAs) are alternatives to the tuberculin skin test (TST). A recent meta-analysis showed that IGRAs have high specificity, even among populations that have received bacille Calmette-Guérin (BCG) vaccination. Sensitivity was suboptimal for TST and IGRAs. To incorporate newly reported evidence from 20 studies into an updated meta-analysis on the sensitivity and specificity of IGRAs. PubMed was searched through 31 March 2008, and citations of all original articles, guidelines, and reviews for studies published in English were reviewed. Studies that evaluated QuantiFERON-TB Gold, QuantiFERON-TB Gold In-Tube (both from Cellestis, Victoria, Australia), and T-SPOT.TB (Oxford Immunotec, Oxford, United Kingdom) or its precommercial ELISpot version, when data on the commercial version were lacking. For assessing sensitivity, the study sample had to have microbiologically confirmed active tuberculosis. For assessing specificity, the sample had to comprise healthy, low-risk individuals without known exposure to tuberculosis. Studies with fewer than 10 participants and those that included only immunocompromised participants were excluded. One reviewer abstracted data on participant characteristics, test characteristics, and test performance from 38 studies; these data were double-checked by a second reviewer. The original investigators were contacted for additional information when necessary. A fixed-effects meta-analysis with correction for overdispersion was done to pool data within prespecified subgroups. The pooled sensitivity was 78% (95% CI, 73% to 82%) for QuantiFERON-TB Gold, 70% (CI, 63% to 78%) for QuantiFERON-TB Gold In-Tube, and 90% (CI, 86% to 93%) for T-SPOT.TB. The pooled specificity for both QuantiFERON tests was 99% among non-BCG-vaccinated participants (CI, 98% to 100%) and 96% (CI, 94% to 98%) among BCG-vaccinated participants. The pooled specificity of T-SPOT.TB (including its precommercial ELISpot version) was 93% (CI, 86% to 100%). Tuberculin skin test results were heterogeneous, but specificity in non-BCG-vaccinated participants was consistently high (97% [CI, 95% to 99%]). Most studies were small and had limitations, including no gold standard for diagnosing latent tuberculosis and variable TST methods and cutoff values. Data on the specificity of the commercial T-SPOT.TB assay were limited. The IGRAs, especially QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube, have excellent specificity that is unaffected by BCG vaccination. Tuberculin skin test specificity is high in non-BCG-vaccinated populations but low and variable in BCG-vaccinated populations. Sensitivity of IGRAs and TST is not consistent across tests and populations, but T-SPOT.TB appears to be more sensitive than both QuantiFERON tests and TST.

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The population dynamics and control of tuberculosis.

Christopher Dye, Brian Williams (2010)

More than 36 million patients have been successfully treated via the World Health Organization's strategy for tuberculosis (TB) control since 1995. Despite predictions of a decline in global incidence, the number of new cases continues to grow, approaching 10 million in 2010. Here we review the changing relationship between the causative agent, Mycobacterium tuberculosis, and its human host and examine a range of factors that could explain the persistence of TB. Although there are ways to reduce susceptibility to infection and disease, and a high-efficacy vaccine would boost TB prevention, early diagnosis and drug treatment to interrupt transmission remain the top priorities for control. Whatever the technology used, success depends critically on the social, institutional, and epidemiological context in which it is applied.

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Dominant TNF-α+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease.

Alexandre Harari, Virginie Rozot, Felicitas Bellutti Enders … (2011)

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 17 August 2012

Volume: 7

Issue: 8

Electronic Location Identifier: e43285

Affiliations

[1 ]Laboratory of Vaccinology and Mucosal Immunity, Université Libre de Bruxelles (U.L.B.) Brussels, Belgium

[2 ]Department of Nephrology, Hôpital Erasme, Université Libre de Bruxelles (U.L.B.) Brussels, Belgium

[3 ]Immunodeficiency Unit, Hôpital Erasme, Université Libre de Bruxelles (U.L.B.) Brussels, Belgium

[4 ]INSERM, U1019, Lille, France

[5 ]CNRS, UMR8204, Lille, France

[6 ]Université de Lille Nord de France, Institut Pasteur de Lille, Lille, France

[7 ]Center for Infection and Immunity of Lille, Lille, France

[8 ]Department of Tuberculosis Immunology, Statens Serum Institute, Copenhagen, Denmark

[9 ]Immunobiology Clinic, Hôpital Erasme, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium

University of Palermo, Italy

Author notes

* E-mail: fmascart@ 123456ulb.ac.be

Competing Interests: Co-author, T Mark Doherty, is an editor of PlosOne and currently employed by Glaxosmithkline. There are no patents, products in development or marketed products to declare. All other authors declare no further conflicts. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Conceived and designed the experiments: FM. Performed the experiments: VC GP KS VV. Analyzed the data: VC FM CL. Contributed reagents/materials/analysis tools: SL TMD. Wrote the paper: VC FM CL. In charge of the illustrating TB patient: FB KS.

[¤]

Current address: Glaxosmithkline, Nykær 68, Copenhagen, Denmark

Article

Publisher ID: PONE-D-12-06489

DOI: 10.1371/journal.pone.0043285

PMC ID: 3422279

PubMed ID: 22912846

SO-VID: f864b718-c8ba-42ec-b02e-dc9612c1b3ea

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 29 February 2012

Date accepted : 23 July 2012

Page count

Pages: 10

Funding

This work is supported by the E.C. FP6 program TB-VAC (An integrated project for the design and testing of vaccine candidates against tuberculosis: identification, development, and clinical studies)(LSHP-CT-2003-503367), FP7 program NEWTB-VAC (Discovery and preclinical development of new generation tuberculosis vaccines)(HEALTH-2009-2.3.2–2), and the “Région de Bruxelles Capitale”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Risk Stratification of Latent Tuberculosis Defined by Combined Interferon Gamma Release Assays

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Abstract

Background

Methods

Results

Conclusions

Related collections

PLOS Climate

Most cited references 26

Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update.

The population dynamics and control of tuberculosis.

Dominant TNF-α+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease.

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