ReviewCytokines for monitoring anti-tuberculous therapy: A systematic review
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.
References (65)
- et al.
Tuberculosis
Lancet
(2011) - et al.
Do results of the T-SPOT.TB interferon-gamma release assay change after treatment of tuberculosis?
Respir Med
(2009) - et al.
Utility of interferon-gamma release assay results to monitor anti-tubercular treatment in adults and children
Clinical therapeutics
(2012) - et al.
Correlation between interleukin-10 and in situ necrosis and fibrosis suggests a role for interleukin-10 in the resolution of the granulomatous response of tuberculous pleurisy patients
Microbes Infect
(2006) - et al.
CCL2, CCL18 and sIL-4R in renal, meningeal and pulmonary TB; a 2 year study of patients and contacts
Tuberculosis
(2011) - et al.
Plasma granulysin levels and cellular interferon-gamma production correlate with curative host responses in tuberculosis, while plasma interferon-gamma levels correlate with tuberculosis disease activity in adults
Tuberculosis
(2007) - et al.
IFN/TNFalpha specific-cells and effector memory phenotype associate with active tuberculosis
Journal of Infection
(2013) - et al.
IFN-gamma-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in Mycobacterium tuberculosis infection
Microbes Infect
(2005) - et al.
Cytokine secretion in vivo and ex vivo following chemotherapy of Mycobacterium tuberculosis infection
Trans R Soc Trop Med Hyg
(1996) - et al.
Efficacy of IP-10 as a biomarker for monitoring tuberculosis treatment
The Journal of infection
(2014)
Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease
Lancet
Pediatric tuberculosis: new guidelines and recommendations
Curr Opin Pediatr
The effectiveness of a 9-month regimen of isoniazid alone versus 3- and 4-month regimens of isoniazid plus rifampin for treatment of latent tuberculosis infection in children: results of an 11-year randomized study
Clin Infect Dis
Latent tuberculosis infection treatment and T-cell responses to Mycobacterium tuberculosis-specific antigens
Am J Respir Crit Care Med
Interferon-gamma responses after isoniazid chemotherapy for latent tuberculosis
Respirology
Reversion of the ELISPOT test after treatment in Gambian tuberculosis cases
BMC Infect Dis
Reversion and conversion of Mycobacterium tuberculosis IFN-gamma ELISpot results during anti-tuberculous treatment in HIV-infected children
BMC Infect Dis
Serial testing of health care workers for tuberculosis using interferon-gamma assay
American journal of respiratory and critical care medicine
Association of increased mycobacterium growth inhibitory factor with antituberculous immunity
Eur Respir J
Analysis of tuberculin-specific CD4 T-cell cytokine profiles by flow cytometry distinguishes active tuberculosis from successfully treated disease
European Journal of Immunology
Soluble markers of the Toll-like receptor 4 pathway differentiate between active and latent tuberculosis and are associated with treatment responses
PLoS One
Longitudinal tracking of cytokines after acute exposure to tuberculosis: association of distinct cytokine patterns with protection and disease development
Clin Vaccine Immunol
Lapa e Silva JR. Interleukin-10 and interferon-gamma patterns during tuberculosis treatment: possible association with recurrence
Int J Tuberc Lung Dis
Elevated serum concentrations of soluble CD14 in HIV- and HIV+ patients with tuberculosis in Africa: prolonged elevation during anti-tuberculosis treatment
Clin Exp Immunol
Ex vivo responses for interferon-gamma and proinflammatory cytokine secretion to low-molecular-weight antigen MTB12 of Mycobacterium tuberculosis during human tuberculosis
Scandinavian Journal of Immunology
Mycobacterium tuberculosis-specific cellular immune profiles suggest bacillary persistence decades after spontaneous cure in untreated tuberculosis
Journal of Infectious Diseases
A mycolic acid-specific CD1-restricted T cell population contributes to acute and memory immune responses in human tuberculosis infection
Journal of Clinical Investigation
Mediators of innate and adaptive immune responses differentially affect immune restoration disease associated with Mycobacterium tuberculosis in HIV patients beginning antiretroviral therapy
Journal of Infectious Diseases
T cells activation and cytokines balance in active and cured tuberculosis
Journal of Immunology
Longitudinal trends in serum levels of mycobacterial secretory (30 kD) and cytoplasmic (65 kD) antigens during chemotherapy of pulmonary tuberculosis patients
Scandinavian Journal of Infectious Diseases
Clinical significance of interleukin-2/gamma interferon ratios in Mycobacterium tuberculosis-specific T-cell signatures
Clin Vaccine Immunol
[Changes and significance of peripheral blood T cell subsets, soluble interleukin-2 receptor and interferon-gamma in patients with retreatment pulmonary tuberculosis and initial treatment tuberculosis]
Chung Hua Chieh Ho Ho Hu Hsi Tsa Chih
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