Assessment of a 44 gene classifier for the evaluation of chronic fatigue syndrome from peripheral blood mononuclear cell gene expression

Abstract:

Chronic fatigue syndrome (CFS) is a clinically defined illness estimated to affect millions of people worldwide causing significant morbidity and an annual cost of billions of dollars. Currently there are no laboratory-based diagnostic methods for CFS. However, differences in gene expression profiles between CFS patients and healthy persons have been reported in the literature.

Using mRNA relative quantities for 44 previously identified reporter genes taken from a large dataset comprising both CFS patients and healthy volunteers, we derived a gene profile scoring metric to accurately classify CFS and healthy samples. This metric out-performed any of the reporter genes used individually as a classifier of CFS.

To determine whether the reporter genes were robust across populations, we applied this metric to classify a separate blind dataset of mRNA relative quantities from a new population of CFS patients and healthy persons with limited success. Although the metric was able to successfully classify roughly two-thirds of both CFS and healthy samples correctly, the level of misclassification was high. We conclude many of the previously identified reporter genes are study-specific and thus cannot be used as a broad CFS diagnostic.

 

Source: Frampton D, Kerr J, Harrison TJ, Kellam P. Assessment of a 44 gene classifier for the evaluation of chronic fatigue syndrome from peripheral blood mononuclear cell gene expression. PLoS One. 2011 Mar 30;6(3):e16872. doi: 10.1371/journal.pone.0016872. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068152/ (Full article)

 

Chronic fatigue syndrome–a neuroimmunological model

Abstract:

The aetiological and pathophysiological basis of chronic fatigue syndrome (CFS) remains a controversial field of inquiry in the research community. While CFS and similar disease conditions such as fibromyalgia (FM) and post-infectious encephalopathy have been the focus of intense scrutiny for the past 20 years, results of research were often contradictory and a cohesive pathological model has remained elusive. However, recent developments in understanding the unique immunophysiology of the brain may provide important clues for the development of a truly comprehensive explanation of the pathology of CFS.

We argue that CFS pathogenesis lies in the influence of peripheral inflammatory events on the brain and the unique immunophysiology of the central nervous system. There is also evidence that CFS patients have a relative immunodeficiency that predisposes to poor early control of infection that leads to chronic inflammatory responses to infectious insults.

The neurological and endocrine changes have been described in CFS patients support the view that CFS has an inflammatory pathogenesis when considered as a whole. An inflammatory model of disease also provides an explanation for the marked female sex bias associated with CFS.

This review therefore posits the hypothesis that CFS as a disease of long-term inflammatory processes of the brain. We will also provide an investigative framework that could be used to justify the use of anti-TNF biological agents as a reliable and effective treatment approach to CFS, a syndrome that to date remains frustratingly difficult for both patients and health care professionals to manage.

Copyright © 2011 Elsevier Ltd. All rights reserved.

 

Source: Arnett SV, Alleva LM, Korossy-Horwood R, Clark IA. Chronic fatigue syndrome–a neuroimmunological model. Med Hypotheses. 2011 Jul;77(1):77-83. doi: 10.1016/j.mehy.2011.03.030. Epub 2011 Apr 6. https://www.ncbi.nlm.nih.gov/pubmed/21474251

 

Chronic fatigue syndrome: a qualitative investigation of young patient’s beliefs and coping strategies

Abstract:

PURPOSE: The aim of this pilot study was to explore illness beliefs and coping strategies among adolescent patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), applying a qualitative methodology. Recent studies have explored the illness beliefs and coping strategies of adult patients with CFS/ME as possible contributing factors to the disease aetiology. These studies have mainly used quantitative methods, finding that patients often explain their illness as being due to physical causes, deny psychological causes and make use of passive and avoidant coping strategies.

METHOD:Semi-structured, in-depth interviews were conducted with nine adolescent patients with CFS/ME, thematic analysis was adapted to the material and the results were interpreted in light of theories of attribution and coping.

RESULTS: The qualitative method allowed for more complex and nuanced accounts of illness experience. The findings showed that the adolescents differ from what has previously been reported, applying more varied and flexible illness attributions and coping mechanisms than expected.

CONCLUSIONS: The heterogeneity suggested in the results has implications. We suggest three perspectives should be taken into account, both for further research and in clinical practice: (1) individual differences; (2) a developmental perspective and (3) interactive relational focus.

 

Source: Hareide L, Finset A, Wyller VB. Chronic fatigue syndrome: a qualitative investigation of young patient’s beliefs and coping strategies. Disabil Rehabil. 2011;33(23-24):2255-63. doi: 10.3109/09638288.2011.568663. Epub 2011 Apr 7. https://www.ncbi.nlm.nih.gov/pubmed/21473686

 

Analysis of cerebrospinal fluid from chronic fatigue syndrome patients for multiple human ubiquitous viruses and xenotropic murine leukemia-related virus

Abstract:

Recent reports showed many patients with chronic fatigue syndrome (CFS) harbor a retrovirus, xenotropic murine leukemia-related virus (XMRV), in blood; other studies could not replicate this finding. A useful next step would be to examine cerebrospinal fluid, because in some patients CFS is thought to be a brain disorder. Finding a microbe in the central nervous system would have greater significance than in blood because of the integrity of the blood-brain barrier. We examined cerebrospinal fluid from 43 CFS patients using polymerase chain reaction techniques, but did not find XMRV or multiple other common viruses, suggesting that exploration of other causes or pathogenetic mechanisms is warranted.

Copyright © 2011 American Neurological Association.

Comment in:

Reply to Schutzer et al. [Ann Neurol. 2011]

Extraordinary claims require extraordinary evidence. [Ann Neurol. 2011]

 

Source: Schutzer SE, Rounds MA, Natelson BH, Ecker DJ, Eshoo MW. Analysis of cerebrospinal fluid from chronic fatigue syndrome patients for multiple human ubiquitous viruses and xenotropic murine leukemia-related virus. Ann Neurol. 2011 Apr;69(4):735-8. doi: 10.1002/ana.22389. Epub 2011 Apr 6. https://www.ncbi.nlm.nih.gov/pubmed/21472770

 

Excess of activating killer cell immunoglobulin‑like receptors and lack of HLA-Bw4 ligands: a two‑edged weapon in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is an inflammatory disease of unknown aetiology. Researchers have proposed infectious, neurological and immunological causes of this syndrome. Recently, the xenotropic murine leukemia virus-related virus was detected in 67% of patients with CFS in a US study. This observation is in agreement with one ascertained aspect of the disease: a decreased efficiency in NK cell lytic activity in CFS patients. Here, we analyzed the genomic polymorphism of killer cell immunoglobulin-like receptors (KIRs) and their HLA class I cognate ligands in patients with certified CFS. An excess of KIR3DS1 was found in CFS patients with respect to controls, as well as an increased frequency of the genotype missing KIR2DS5. Forty-four CFS patients and 50 controls also underwent genomic typing for the HLA-ligands. In the patients, a great proportion of KIR3DL1 and KIR3DS1 receptors were found to be missing their HLA-Bw4Ile80 binding motif. We hypothesize that an excess of KIR3DS1, combined with an excess of ligand-free KIR3DL1 and KIR3DS1 receptors, may hamper the clearance of a pathogen via NK cells, thus favouring the chronicity of the infection.

Source: Pasi A, Bozzini S, Carlo-Stella N, Martinetti M, Bombardieri S, De Silvestri A, Salvaneschi L, Cuccia M. Excess of activating killer cell immunoglobulin‑like receptors and lack of HLA-Bw4 ligands: a two‑edged weapon in chronic fatigue syndrome. Mol Med Rep. 2011 May-Jun;4(3):535-40. doi: 10.3892/mmr.2011.447. Epub 2011 Mar 4. https://www.ncbi.nlm.nih.gov/pubmed/21468604

Self-critical perfectionism, stress generation, and stress sensitivity in patients with chronic fatigue syndrome: relationship with severity of depression

Abstract:

Chronic Fatigue Syndrome (CFS) is a highly disabling disorder that is part of a broader spectrum of chronic pain and fatiguedisorders. Although the etiology and pathogenesis of CFS largely remain unclear, there is increasing evidence that CFS shares important pathophysiological disturbances with mood disorders in terms of disturbances in the stress response and the stress system.

From a psycho-dynamic perspective, self-critical perfectionism and related personality factors are hypothesized to explain in part impairments of the stress response in both depression and CFS. Yet, although there is ample evidence that high levels of self-critical perfectionism are associated with stress generation and increased stress sensitivity in depression, evidence supporting this hypothesis in CFS is currently lacking.

This study therefore set out to investigate the relationship between self-critical perfectionism, the active generation of stress, stress sensitivity, and levels of depression in a sample of 57 patients diagnosed with CFS using an ecological momentary assessment approach.

Results showed, congruent with theoretical assumptions, that self-critical perfectionism was associated with the generation of daily hassles, which in turn predicted higher levels of depression. Moreover, multilevel analyses showed that self-critical perfectionism was related to increased stress sensitivity in CFS patients over a 14-day period, and that increased stress sensitivity in turn was related to increased levels of depression. The implications of these findings for future research and particularly for the development of psychodynamic treatment approaches of CFS and related conditions are discussed.

 

Source: Luyten P, Kempke S, Van Wambeke P, Claes S, Blatt SJ, Van Houdenhove B. Self-critical perfectionism, stress generation, and stress sensitivity in patients with chronic fatigue syndrome: relationship with severity of depression. Psychiatry. 2011 Spring;74(1):21-30. doi: 10.1521/psyc.2011.74.1.21. https://www.ncbi.nlm.nih.gov/pubmed/21463167

 

The cerebralization of fatigue: an analysis of the cerebral hypothesis in the case of chronic fatigue syndrome

Abstract:

The article analyzes a number of conditions that allowed the brain to become established as an etiological hypothesis in the case of chronic fatigue syndrome (CFS), together with other hypotheses related to organic causes, such as viruses and immunity. It also addresses the process of cerebralization of personhood, which grew out of the use of neuroimaging for research and diagnostic purposes and according to which the brain constitutes the prime place for looking for the cause of the diseases – including CFS – within the context of a somatic culture, intensified at the end of the twentieth century.

 

Source: Ortega F, Zorzanelli R. The cerebralization of fatigue: an analysis of the cerebral hypothesis in the case of chronic fatigue syndrome. Hist Cienc Saude Manguinhos. 2010 Jun;17(2):289-305. [Article in Portuguese] http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0104-59702010000200002&lng=en&nrm=iso&tlng=en (Full article)

 

Psychopathology and physical activity as predictors of chronic fatigue syndrome in the 1958 british birth cohort: a replication study of the 1946 and 1970 birth cohorts

Abstract:

PURPOSE: In this study, we investigate whether prospective associations between psychopathology, physical activity, and chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) observed in the 1946 and 1970 birth cohorts were replicable in the 1958 British birth cohort.

METHODS: Prospective study using the 1958 British birth cohort, which included 98.7% of births from 1 week in March 1958 in England, Wales, and Scotland. The outcome was self-reported CFS/ME by the age of 42 years, at which point 11,419 participants remained in the study. Psychopathology was assessed by the Rutter scales in childhood and the Malaise Inventory in adulthood. Physical activity was reported by the cohort member, mother and teacher in childhood and adulthood.

RESULTS: The prevalence of CFS/ME was 1.0% (95% confidence interval [CI] = 0.9-1.3) and the median age of onset was 34 years. Premorbid psychopathology at 23 years (odds ratio [OR] = 1.85, 95% CI = 1.06-3.22) and 33 years (OR = 2.81, 95% CI = 1.28-6.18) significantly increased the odds of developing CFS/ME, supporting the 1946 cohort findings. Childhood psychopathology, sedentary behavior in childhood, and persistent exercise in adulthood were not associated with CFS/ME.

CONCLUSIONS: In cohort studies premorbid psychopathology in adulthood is a replicated risk marker for CFS/ME, whereas premorbid extremes of physical activity are not.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: Goodwin L, White PD, Hotopf M, Stansfeld SA, Clark C. Psychopathology and physical activity as predictors of chronic fatigue syndrome in the 1958 British birth cohort: a replication study of the 1946 and 1970 birth cohorts. Ann Epidemiol. 2011 May;21(5):343-50. doi: 10.1016/j.annepidem.2010.12.003. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078325/ (Full article)

 

Factors influencing engagement of patients in a novel intervention for CFS/ME: a qualitative study.

Abstract:

AIM: To establish what factors are important for patients to engage in a new intervention for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and make recommendations to general practitioners (GPs) on preparing a patient for referral to such a service.

BACKGROUND: NICE guidelines recommend a prominent role for primary care in the management of patients with CFS/ME, with prompt diagnosis and appropriate referral for evidence-based treatments.

METHODS: A qualitative study nested within a multi-centre randomised controlled trial of two new nurse therapist delivered interventions. Semi-structured interviews carried out with 19 patients who had received pragmatic rehabilitation (PR) in the trial. Interviews were transcribed verbatim and an iterative approach used to develop themes from the data set.

FINDINGS:Factors that influence whether or not a patient engages with PR for CFS/ME are ensuring that the patient feels accepted and believed, that they accept the diagnosis, and that the model implicated by the treatment offered to the patient matches the model of illness held by the patient. If patients hold a clearly incompatible model of their illness, it is unlikely that they will engage with, and successfully complete, therapy. It is vital that the GP elicits and explores such illness beliefs either before making a referral to maximise patient engagement in therapy, or that an initial session with the therapist explores attitudes to the treatment model offered and then works with the patient’s model.

 

Source: Chew-Graham C, Brooks J, Wearden A, Dowrick C, Peters S. Factors influencing engagement of patients in a novel intervention for CFS/ME: a qualitative study. Prim Health Care Res Dev. 2011 Apr;12(2):112-22. doi: 10.1017/S146342361000037X. https://www.ncbi.nlm.nih.gov/pubmed/21457596

 

Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

BACKGROUND: There is evidence that myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by activation of immune, inflammatory, oxidative and nitrosative stress (IO&NS) pathways. The present study was carried out in order to examine whether ME/CFS is accompanied by increased levels of plasma peroxides and serum oxidized LDL (oxLDL) antibodies, two biomarkers of oxidative stress.

MATERIAL/METHODS: Blood was collected from 56 patients with ME/CFS and 37 normal volunteers. Severity of ME/CFS was measured using the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.

RESULTS: Plasma peroxide concentrations were significantly higher in patients with ME/CFS than in normal controls. There was a trend towards significantly higher serum oxLDL antibodies in ME/CFS than in controls. Both biomarkers contributed significantly in discriminating between patients with ME/CFS and normal controls. Plasma peroxide and serum oxLDL antibody levels were both significantly related to one of the FF symptoms.

CONCLUSIONS: The results show that ME/CFS is characterized by increased oxidative stress.

 

Source: Maes M, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Sci Monit. 2011 Apr;17(4):SC11-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539515/ (Full article)