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Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome.

Russell, A; Hepgul, N; Nikkheslat, N; Borsini, A; Zajkowska, Z; Moll, N; Forton, D; Agarwal, K; Chalder, T; Mondelli, V; et al. Russell, A; Hepgul, N; Nikkheslat, N; Borsini, A; Zajkowska, Z; Moll, N; Forton, D; Agarwal, K; Chalder, T; Mondelli, V; Hotopf, M; Cleare, A; Murphy, G; Foster, G; Wong, T; Schütze, GA; Schwarz, MJ; Harrison, N; Zunszain, PA; Pariante, CM (2019) Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology, 100. pp. 276-285. ISSN 1873-3360 https://doi.org/10.1016/j.psyneuen.2018.11.032
SGUL Authors: Forton, Daniel Michael

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Abstract

The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p =  0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.

Item Type: Article
Additional Information: © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).
Keywords: Chronic fatigue syndrome, Cytokines, Fatigue, Inflammation, Kynurenine, Tryptophan, 11 Medical And Health Sciences, 17 Psychology And Cognitive Sciences, Psychiatry
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: Psychoneuroendocrinology
ISSN: 1873-3360
Language: eng
Dates:
DateEvent
February 2019Published
17 December 2018Published Online
23 November 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MR/J002739/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 30567628
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/110522
Publisher's version: https://doi.org/10.1016/j.psyneuen.2018.11.032

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