Chronic fatigue syndrome and circulating cytokines: A systematic review

Blundell, Samkeliso; Ray, Kausik K.; Buckland, Matthew; White, Peter D

doi:10.1016/j.bbi.2015.07.004

Cited by 131 publications

(161 citation statements)

References 80 publications

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“…1 and 2). This dysregulation to extremes of normative range also may explain why several studies, including ours, have reported few or no cytokine levels that distinguish ME/CFS cases from controls (10). Above all, it suggests that severity may be a key variable for subgrouping ME/CFS.…”

Section: Discussionmentioning

confidence: 90%

“…TGF-β has been found to be elevated in ME/CFS patients in five of eight studies (63%), as highlighted in a meta-analysis by Blundell et al (10). TGF-β is a 112-amino acid protein that provides cells with the pleiotropic capacity to affect cell-developmental programs and behavior, including cell proliferation, differentiation, morphogenesis, tissue homeostasis, and regeneration (19).…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, conventional markers of inflammation commonly used in the daily practice of medicine (e.g., erythrocyte sedimentation rate, C-reactive protein) are seldom elevated in ME/CFS patients (9). Tests measuring innate and adaptive immune responses have been reported as abnormal but often yield negative or conflicting results (8,(10)(11)(12). However, in a longitudinal study, fatigue severity was associated with daily fluctuations of the inflammatory adipokine leptin (13).…”

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confidence: 97%

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Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Montoya

Holmes

Anderson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

312

265

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Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

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Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Montoya

Holmes

Anderson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

312

265

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“…A review by Powell et al (2013) could not establish hypocortisolism in chronic fatigue patients, but found evidence for an attenuation of the diurnal variability of the cortisol response. A similar picture arises from review studies on the role of inflammatory, infectious, or autoimmune dysfunction in functional somatic syndromes: few differences are found, and if so, they mostly pertain to different parameters (see Borchers and Gershwin, 2015;Üç eyler et al, 2011;Blundell et al, 2015;Ishihara et al, 2013;Schwille-Kiuntke et al, 2015). Importantly, whenever a dysfunction is observed, few studies test whether the abnormalities actually cause or mediate the symptoms in question.…”

Section: Authorsmentioning

confidence: 99%

Symptoms and the body: Taking the inferential leap

Bergh

Witthöft

Petersen

et al. 2017

Neuroscience & Biobehavioral Reviews

400

354

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a b s t r a c tThe relationship between the conscious experience of physical symptoms and indicators of objective physiological dysfunction is highly variable and depends on characteristics of the person, the context and their interaction. This relationship often breaks down entirely in the case of "medically unexplained" or functional somatic symptoms, violating the basic assumption in medicine that physical symptoms have physiological causes. In this paper, we describe the prevailing theoretical approach to this problem and review the evidence pertaining to it. We then use the framework of predictive coding to propose a new and more comprehensive model of the body-symptom relationship that integrates existing concepts within a unifying framework that addresses many of the shortcomings of current theory. We describe the conditions under which a close correspondence between the experience of symptoms and objective physiology might be expected, and when they are likely to diverge. We conclude by exploring some theoretical and clinical implications of this new account.

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“…We propose that such studies could adapt their sample inclusion criteria in line with these subtypes. For example, it seems plausible that any specific cytokine mediators of fatigue would be more optimally identified within powered samples of patients fulfilling the characteristics of 'inflammatory fatigue' (as defined here) rather than the inclusive approach to sampling which has been commonly applied in other populations (40). More immediate clinical benefits may be derived from longitudinal inspection of these clusters to test their stability (recognising that they may change with therapy) and prognostic capacities.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Clinically Relevant Clusters of Severe Fatigue in Rheumatoid Arthritis

et al. 2017

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Objective The considerable heterogeneity of rheumatoid arthritis (RA)-related fatigue is the greatest challenge to determining pathogenesis. The identification of homogenous subtypes of severe fatigue would inform the design and analysis of experiments seeking to characterize the likely numerous causal pathways that underpin the symptom. This study aimed to identify and validate such fatigue subtypes in patients with RA. Methods Data were obtained from patients recruited to the British Society for Rheumatology Biologics register for RA, as either receiving traditional disease-modifying antirheumatic drugs (DMARD cohort, n = 522) or commencing anti-tumor necrosis factor therapy (anti-TNF cohort, n = 3909). In those reporting severe fatigue (Short-Form 36 vitality ≤ 12.5), this cross-sectional analysis applied hierarchical clustering with weighted-average linkage identified clusters of pain, fatigue, mental health (all Short-Form 36), disability (Health Assessment Questionnaire), and inflammation (erythrocyte sedimentation rate) in the DMARD cohort. K-means clustering sought to validate the solution in the anti-TNF cohort. Clusters were characterized using a priori generated symptom definitions and between-cluster comparisons. Results Four severe fatigue clusters, labeled as basic (46%), affective (40%), inflammatory (4.5%), and global (8.9%) were identified in the DMARD cohort. All clusters had severe levels of pain and disability and were distinguished by the presence/absence of poor mental health and high inflammation. The same symptom clusters were present in the anti-TNF cohort, although the proportion of participants in each cluster differed (basic = 28.7%; affective = 30.2%; global = 24.1%; inflammatory = 16.9%). Conclusions Among RA patients with severe fatigue, recruited to two diverse RA cohorts, clinically relevant clusters were identified and validated. These may provide the basis for future mechanistic studies and ultimately support a stratified approach to fatigue management.

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Chronic fatigue syndrome and circulating cytokines: A systematic review

Cited by 131 publications

References 80 publications

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Symptoms and the body: Taking the inferential leap

Identification and Validation of Clinically Relevant Clusters of Severe Fatigue in Rheumatoid Arthritis

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