Elsevier

Tuberculosis

Volume 95, Issue 6, December 2015, Pages 639-650
Tuberculosis

Review
Interferon gamma release assays for monitoring the response to treatment for tuberculosis: A systematic review

https://doi.org/10.1016/j.tube.2015.07.002Get rights and content

Summary

Introduction

The ability to monitor the response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The utility of interferon gamma assays (IGRA) for this purpose remains uncertain.

Methods

A systematic search of all studies investigating commercial IGRA to monitor anti-tuberculous treatment was done. Studies were included if they included an IGRA before the start of, and at least once during, treatment for active or latent TB.

Results

We identified 30 studies, of which 24 used QuantiFERON-TB (QFT), three used T-SPOT.TB and three used both QFT and T-SPOT.TB. Most studies were done in low TB incidence countries. No uniform pattern was seen in IGRA conversion and reversion rates at the end of treatment for active or latent TB. In most studies, the majority of IGRA results remained positive at the end of treatment. In many studies, the quantitative levels of IFN-γ decreased during treatment, particularly in active TB. There was significant heterogeneity in the included studies.

Conclusion

While quantitative IGRA responses generally fall during treatment for TB, the large degree of variation in results between participants in each study means that IGRAs are unlikely to be useful for monitoring anti-tuberculous treatment in clinical practice for any individual patient.

Introduction

A biomarker to indicate successful tuberculosis (TB) treatment would be a major advance for the management and control of TB globally. In addition to monitoring treatment in individual patients, it would enable the assessment of shorter course regimens for the treatment of both latent TB infection (LTBI) and active TB; currently the absence of a reliable surrogate marker of cure hampers trials of new TB therapies. Biomarkers to confirm adequate TB treatment would also help reduce transmission from subsequent reactivation following failed treatment. Recent research has focused on the use of interferon gamma (IFN-γ) release assays (IGRAs) as a biomarker of treatment success. Animal and human studies have shown a relationship between the Mycobacterium tuberculosis (MTB) bacillary load and the magnitude of IFN-γ responses to MTB antigens [1], [2]. It has therefore been postulated that a decrease in the magnitude of IFN-γ responses to MTB-specific peptides measured by IGRA can be used as a biomarker of cure [3]. To assess the utility of IGRAs for this purpose, a number of studies have investigated the kinetics of IGRA responses during the treatment of TB. We did a systematic review of the use of IGRAs in monitoring the response to treatment of LTBI or active TB.

Section snippets

Search strategy

Our review was done in accordance with the ‘preferred reporting items for systematic reviews and meta-analyses’ (PRISMA) statement. Original articles, letters to the editor and published abstracts were identified by searching MEDLINE (1995 to November 2014), EMBASE (to November 2014) and the Cochrane Central Register of Controlled Trials (CENTRALL). The following search terms were used:

(tuberculosis/or latent tuberculosis/or lung tuberculosis/) and (gamma interferon/or enzyme linked immunospot

Results

A total of 1508 unique references were identified by the initial search. After review of title and abstracts, 75 full text articles were assessed for eligibility. Forty-five articles were excluded after review of the full texts. Of these 45 articles, 14 used an in-house ELISPOT [1], [2], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], five were excluded because they did not use ESAT-6/CFP-10-specific stimulation [16], [17], [18], [19], [20], 4 were cross-sectional [21], [22],

Discussion

To our knowledge, this is the largest systematic review evaluating serial IGRA as a potential tool to monitor treatment in patients with active TB and LTBI. Our systematic review includes nine new studies published subsequent to a previous systematic review by Chiappini et al. (which included a total of 13 studies) [77], as well as several earlier studies not included in their review. This is the first review to address quantitative changes in IFN-γ response in addition to qualitative

Funding

None.

Competing interests

The authors do not have a commercial or other association that might pose a conflict of interest.

Ethical approval

Not required.

Authors' contributions

VC and YH did the literature search. VC, YH and CZ selected the studies for analysis. VC wrote the first draft of the manuscript. YH, CZ, TC and NC assisted with data interpretation, data analysis and writing of the manuscript and figures.

References (80)

  • M. Bocchino et al.

    Limited usefulness of QuantiFERON-TB gold in-tube for monitoring anti-tuberculosis therapy

    Respir Med

    (2010)
  • K. Komiya et al.

    Reversion rates of QuantiFERON-TB gold are related to pre-treatment IFN-gamma levels

    J Infect

    (2011)
  • S.H. Lee et al.

    Serial interferon-gamma release assays after rifampicin prophylaxis in a tuberculosis outbreak

    Respir Med

    (2010)
  • P. Papay et al.

    Retesting for latent tuberculosis in patients with inflammatory bowel disease after exposure to biologics

    J Crohn's Colitis

    (2012)
  • V. Bosshard et al.

    Do results of the T-SPOT.TB interferon-gamma release assay change after treatment of tuberculosis?

    Respir Med

    (2009)
  • Y. Kobashi et al.

    Transitional changes in T-cell responses to Mycobacterium tuberculosis-specific antigens during treatment

    J Infect

    (2009)
  • V. Clifford et al.

    Cytokines for monitoring anti-tuberculous therapy: a systematic review

    Tuberculosis (Edinb)

    (2015 May)
  • S. Carrara et al.

    Use of a T cell-based assay for monitoring efficacy of antituberculosis therapy

    Clin Infect Dis

    (2004)
  • A.A. Pathan et al.

    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

    (2001)
  • A. Lalvani

    Counting antigen-specific T cells: a new approach for monitoring response to tuberculosis treatment?

    Clin Infect Dis

    (2004)
  • I.M. Adetifa et al.

    Interferon-γ ELISPOT as a biomarker of treatment efficacy in latent tuberculosis infection: a clinical trial

    Am J Respir Crit Care Med

    (2013)
  • I.M. Adetifa et al.

    Decay kinetics of an interferon gamma release assay with anti-tuberculosis therapy in newly diagnosed tuberculosis cases

    PLoS ONE

    (2010)
  • A.M. Aiken et al.

    Reversion of the ELISPOT test after treatment in Gambian tuberculosis cases

    BMC Infect Dis

    (2006)
  • X. Chen et al.

    Diagnosis of active tuberculosis in China using an in-house gamma interferon enzyme-linked immunospot assay

    Clin Vac Immunol

    (2009)
  • T.G. Connell et al.

    Reversion and conversion of Mycobacterium tuberculosis IFN-gamma ELISpot results during anti-tuberculous treatment in HIV-infected children

    BMC Infect Dis

    (2010)
  • S.Y. Eum et al.

    Association of antigen-stimulated release of tumor necrosis factor-alpha in whole blood with response to chemotherapy in patients with pulmonary multidrug-resistant tuberculosis

    Respiration

    (2010)
  • K. Ewer et al.

    Dynamic antigen-specific T-cell responses after point-source exposure to Mycobacterium tuberculosis

    Am J Respir Crit Care Med

    (2006)
  • D. Goletti et al.

    Response to M. tuberculosis selected RD1 peptides in Ugandan HIV-infected patients with smear positive pulmonary tuberculosis: a pilot study

    BMC Infect Dis

    (2008)
  • K.A. Wilkinson et al.

    Effect of treatment of latent tuberculosis infection on the T cell response to Mycobacterium tuberculosis antigens

    J Infect Dis

    (2006)
  • A. Lalvani et al.

    Enumeration of T cells specific for RD1-encoded antigens suggests a high prevalence of latent Mycobacterium tuberculosis infection in healthy urban Indians

    J Infect Dis

    (2001)
  • J. Vekemans et al.

    Tuberculosis contacts but not patients have higher gamma interferon responses to ESAT-6 than do community controls in the Gambia

    Infect Immun

    (2001)
  • F. Ameglio et al.

    Post-treatment changes of six cytokines in active pulmonary tuberculosis: differences between patients with stable or increased fibrosis

    Int J Tuberc Lung Dis

    (2005)
  • M. Berktas et al.

    Change in serum concentrations of interleukin-2 and interferon-γ during treatment of tuberculosis

    J Int Med Res

    (2004)
  • R.L. Stuart et al.

    Effect of anti-tuberculosis treatment on the tuberculin interferon-γ response in tuberculin skin test (TST) positive health care workers and patients with tuberculosis

    Int J Tuberc Lung Dis

    (2000)
  • A.M.M. Mattos et al.

    Increased IgG1, IFN-, TNF-alpha and IL-6 responses to Mycobacterium tuberculosis antigens in patients with tuberculosis are lower after chemotherapy

    Int Immunol

    (2010)
  • S. Zhang et al.

    Evaluation of gamma interferon release assays using Mycobacterium tuberculosis antigens for diagnosis of latent and active tuberculosis in Mycobacterium bovis BCG-vaccinated populations

    Clin Vaccine Immunol CVI

    (2010)
  • M. Sester et al.

    Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis

    Eur Respir J

    (2011)
  • R.A. Ferrand et al.

    Interferon-gamma responses to ESAT-6 in tuberculosis patients early into and after anti-tuberculosis treatment

    Int J Tuberc Lung Dis

    (2005)
  • P.C. Hill et al.

    Longitudinal assessment of an ELISPOT test for Mycobacterium tuberculosis infection

    PLoS Med/Public Libr Sci

    (2007)
  • M. Cordero-Coma et al.

    The value of an immune response to Mycobacterium tuberculosis in patients with chronic posterior uveitis revisited: utility of the new IGRAs

    Eye

    (2010)
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    The first two authors have contributed equally and wish to be regarded as joint first authors.

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