Elsevier

Tuberculosis

Volume 95, Issue 3, May 2015, Pages 217-228
Tuberculosis

Review
Cytokines for monitoring anti-tuberculous therapy: A systematic review

https://doi.org/10.1016/j.tube.2015.01.003Get rights and content

Summary

The ability to monitor response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The low reversion rate of interferon-gamma based assays means that they are unlikely to be useful for monitoring therapy. Several exploratory studies have evaluated the diagnostic potential of cytokine biomarkers other than interferon-gamma for monitoring anti-tuberculous therapy. A systematic review of these studies was performed to identify the most promising candidate biomarkers. TNF-α, IL-2, IL-6, IL-10 and IL-12 were the most extensively investigated cytokines. There was significant heterogeneity between studies in relation to study design and laboratory methodology, complicating direct comparisons. There was marked variation between studies in the observed changes during treatment for many of the biomarkers. Further longitudinal studies in sufficiently large patient cohorts with rigorous methodology are needed to determine the true potential of individual cytokine biomarkers, or combinations, for monitoring TB treatment.

Introduction

Mycobacterium tuberculosis (MTB) infection remains a major challenge globally. It is one of the leading infectious causes of death worldwide [1], responsible for an estimated 1.7 million deaths each year [2]. Adequate therapy requires prolonged treatment resulting in significant cost and use of medical resources. In addition, studies suggest that patients' adherence to treatment declines with extended courses [3].

The ability to monitor the response to treatment for tuberculosis (TB) and confirm adequate treatment would be a major advance with a number of significant benefits. In particular, it would allow comparisons of different antibiotic regimens and evaluation of shorter treatment durations. Currently, TB drug treatment trials are difficult and expensive because the absence of reliable surrogate markers of treatment success means trials require prolonged follow up to detect the small proportion of participants who subsequently develop TB. The ability to confirm adequate treatment would also help reduce transmission from subsequent reactivation following inadequate treatment. Moreover, a robust biomarker would be particularly useful to confirm adequate therapy of latent TB, for which there are currently no diagnostic tools. Finding biomarkers of successful treatment might also provide insights into surrogate markers of protective immunity against TB.

There has been recent interest in the possibility of using interferon-gamma (IFN-γ) release assays (IGRAs) for monitoring TB treatment. Existing studies, however, have yielded conflicting results [4], [5], [6], [7], [8], [9]. A recent systematic review by Chiappini et al. highlighted the considerable inconsistency in the reported effect of anti-tuberculous treatment on the kinetics of IGRA results, and estimated that the overall reversion rate (ie change in categorical results from ‘positive’ to ‘negative’) of the QuantiFERON Gold in-Tube (QFT-G-IT) assay at the end of TB treatment was only 30% [10]. This low reversion rate suggests that IFN-γ-based assays are unlikely to be useful for monitoring the response to treatment.

In recent years, several exploratory studies have evaluated the diagnostic potential of cytokine biomarkers other than IFN-γ for monitoring anti-tuberculous treatment. We did a systematic review of these studies to identify the most promising candidate biomarkers, and provide a critical analysis of the supporting data for each.

Section snippets

Search strategy

This review was conducted 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 (1947 to June 2014), EMBASE (to June 2014), and the Cochrane Central Register of Controlled Trials (CENTRALL). The following search terms were used: (exp *Mycobacterium tuberculosis/an, ch, im, ph or exp *Tuberculosis/bl, di, im, mi, ph, pp) and (exp

Results

Of the 5033 articles screened by title and abstract, 4985 were excluded. This left 49 potentially relevant articles. A further 17 articles that did not meet the inclusion criteria were excluded [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], leaving 32 publications [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57],

Discussion

Identification of a biomarker (or a combination of biomarkers) correlating with successful anti-tuberculous treatment would be a major advance for the management of patients with both active and latent TB infection. Such a biomarker could identify patients with TB disease at risk of failing first line treatment, confirm adequacy of treatment of latent TB infection (ensuring that reactivation will not occur), and potentially revolutionise clinical trials of novel anti-tuberculous drugs.

This

Conclusions

In summary, several candidate cytokine biomarkers that have the potential to be used for monitoring anti-tuberculous treatment have been identified. However, no single cytokine or combination of cytokines has been shown to provide a sufficiently robust correlate of treatment success. The findings of this review highlight the relative paucity of research in this area, and the significant limitations of existing studies.

Future research would benefit from rigorous study design. Future studies

Funding

The study was partially supported by a grant from the John Burge Trust 1203 (2013); MT is supported by a Clinical Lectureship provided by the U.K. National Institute for Health Research.

Competing interests

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

Ethical approval

Not required.

Author contribution statement

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

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