Page 385 – American ME and CFS Society

Association of biomarkers with health-related quality of life and history of stressors in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

BACKGROUND: Myalgic encephalomyelitis chronic fatigue syndrome (ME/CFS) is a common debilitating disorder associated with an intense fatigue, a reduced physical activity, and an impaired quality of life. There are no established biological markerof the syndrome. The etiology is unknown and its pathogenesis appears to be multifactorial. Various stressors, including intense physical activity, severe infection, and emotional stress are reported in the medical history of ME/CFS patients which raises the question whether any physiological and biological abnormalities usually found in these patients could be indicative of the etiology and/or the quality-of-life impairment.

METHODS: Thirty-six patients and 11 age-matched healthy controls were recruited. The following variables that appear to address common symptoms of ME/CFS were studied here: (1) muscle fatigue during exercise has been investigated by monitoring the compound muscle action potential (M-wave); (2) the excessive oxidative stress response to exercise was measured via two plasma markers (thiobarbituric acid reactive substances: TBARS; reduced ascorbic-acid: RAA); (3) a potential inflammatory component was addressed via expression of CD26 on peripheral blood mononuclear cells; (4) quality-of-life impairment was assessed using the London Handicap Scale (LHS) and the Medical Outcome Study Short Form-36 (SF-36). The medical history of each patient, including the presence of stressors such as intense sports practice, severe acute infection and/or severe emotional stress was documented.

RESULTS: We observed that: (1) there were striking differences between cases and controls with regard to three biological variables: post-exercise M-wave, TBARS variations and CD26-expression at rest; (2) each of these three variables correlated with the other two; (3) abnormalities in the biomarkers associated with health-related quality of life: the LHS score was negatively correlated with the exercise-induced TBARS increase and positively correlated with CD26-expression while the pain component of SF-36 was negatively correlated with CD26-expression; (4) the TBARS increase and the M-wave decrease were the highest, and the CD26-expression level the lowest in patients who had been submitted to infectious stressors.

CONCLUSION: In ME/CFS patients, severe alterations of the muscle excitability, the redox status, as well as the CD26-expression level are correlated with a marked impairment of the quality-of-life. They are particularly significant when infectious stressors are reported in the medical history.

Source: Fenouillet E, Vigouroux A, Steinberg JG, Chagvardieff A, Retornaz F, Guieu R, Jammes Y. Association of biomarkers with health-related quality of life and history of stressors in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. 2016 Aug 31;14:251. doi: 10.1186/s12967-016-1010-x. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006431/ (Full article)

Metabolic features of chronic fatigue syndrome

Abstract:

More than 2 million people in the United States have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We performed targeted, broad-spectrum metabolomics to gain insights into the biology of CFS.

We studied a total of 84 subjects using these methods. Forty-five subjects (n = 22 men and 23 women) met diagnostic criteria for ME/CFS by Institute of Medicine, Canadian, and Fukuda criteria. Thirty-nine subjects (n = 18 men and 21 women) were age- and sex-matched normal controls. Males with CFS were 53 (±2.8) y old (mean ± SEM; range, 21-67 y). Females were 52 (±2.5) y old (range, 20-67 y). The Karnofsky performance scores were 62 (±3.2) for males and 54 (±3.3) for females.

We targeted 612 metabolites in plasma from 63 biochemical pathways by hydrophilic interaction liquid chromatography, electrospray ionization, and tandem mass spectrometry in a single-injection method. Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism.

Area under the receiver operator characteristic curve analysis showed diagnostic accuracies of 94% [95% confidence interval (CI), 84-100%] in males using eight metabolites and 96% (95% CI, 86-100%) in females using 13 metabolites. Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer.

Source: Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, Gordon E. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5472-80. doi: 10.1073/pnas.1607571113. Epub 2016 Aug 29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027464/ (Full article)

Comment

G L Francis 2016 Sep 19 04:58 a.m.

I have read your publication in PNAS titled ‘Metabolic features of chronic fatigue syndrome’ with much interest, this significant contribution has at last provided a definitive publication of a realistic evidence based diagnostic test based on a panel of blood metabolites – this could provide a more robust diagnostic base for future rational treatment studies in ‘CFS’.

Athough there are many more complex and critical questions to be asked, I will keep mine simple. I took particular note of the authors comments “When MTHFD2L is turned down in differentiated cells, less mitochondrial formate is produced and one-carbon units are directed through Methylene-THF toward increased SAM synthesis and increased DNA methylation” (from Figure S6. Mitochondrial Control of Redox, NADPH, Nucleotide, and Methylation Pathways legend). I recently read the paper, ‘Association of Vitamin B12 Deficiency with Homozygosity of the TT MTHFR C677T Genotype, Hyperhomocysteinemia, and Endothelial Cell Dysfunction’ Shiran A et al. IMAJ 2015; 17: 288–292, and wondered whether the gene variations in the individuals described within that publication, could be over represented in your subjects, mind you the size of your study population probably answers my own question; and no doubt many mechanisms that lead to a perturbation of this pathway exist, of which this could conceivable be just one of many, even if a minor contributor. Moreover, there does seem to be a difference between the two papers in terms of the particular pertubations on incidence of cardiovascular disease and outcomes?

Chronic fatigue syndrome in women assessed with combined cardiac magnetic resonance imaging

Abstract:

OBJECTIVE: In chronic fatigue syndrome (CFS), only a few imaging and histopathological studies have previously assessed either cardiac dimensions/function or myocardial tissue, suggesting smaller left ventricular (LV) dimensions, LV wall motion abnormalities and occasionally viral persistence that may lead to cardiomyopathy. The present study with cardiac magnetic resonance (CMR) imaging is the first to use a contrast-enhanced approach to assess cardiac involvement, including tissue characterisation of the LV wall.

METHODS: CMR measurements of 12 female CFS patients were compared with data of 36 age-matched, healthy female controls. With cine imaging, LV volumes, ejection fraction (EF), mass, and wall motion abnormalities were assessed. T2-weighted images were analysed for increased signal intensity, reflecting oedema (i. e. inflammation). In addition, the presence of contrast enhancement, reflecting fibrosis (i. e. myocardial damage), was analysed.

RESULTS: When comparing CFS patients and healthy controls, LVEF (57.9 ± 4.3 % vs. 63.7 ± 3.7 %; p < 0.01), end-diastolic diameter (44 ± 3.7 mm vs. 49 ± 3.7 mm; p < 0.01), as well as body surface area corrected LV end-diastolic volume (77.5 ± 6.2 ml/m2 vs. 86.0 ± 9.3 ml/m2; p < 0.01), stroke volume (44.9 ± 4.5 ml/m2 vs. 54.9 ± 6.3 ml/m2; p < 0.001), and mass (39.8 ± 6.5 g/m2 vs. 49.6 ± 7.1 g/m2; p = 0.02) were significantly lower in patients. Wall motion abnormalities were observed in four patients and contrast enhancement (fibrosis) in three; none of the controls showed wall motion abnormalities or contrast enhancement. None of the patients or controls showed increased signal intensity on the T2-weighted images.

CONCLUSION: In patients with CFS, CMR demonstrated lower LV dimensions and a mildly reduced LV function. The presence of myocardial fibrosis in some CFS patients suggests that CMR assessment of cardiac involvement is warranted as part of the scientific exploration, which may imply serial non-invasive examinations.

Source: Olimulder MA, Galjee MA, Wagenaar LJ, van Es J, van der Palen J, Visser FC, Vermeulen RC, von Birgelen C. Chronic fatigue syndrome in women assessed with combined cardiac magnetic resonance imaging. Neth Heart J. 2016 Dec;24(12):709-716. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120006/ (Full article)

Deconstructing post-exertional malaise: An exploratory factor analysis

Abstract:

Post-exertional malaise is a cardinal symptom of myalgic encephalomyelitis and chronic fatigue syndrome. There are two differing focuses when defining post-exertional malaise: a generalized, full-body fatigue and a muscle-specific fatigue. This study aimed to discern whether post-exertional malaise is a unified construct or whether it is composed of two smaller constructs, muscle fatigue and generalized fatigue. An exploratory factor analysis was conducted on several symptoms that assess post-exertional malaise. The results suggest that post-exertional malaise is composed of two empirically different experiences, one for generalized fatigue and one for muscle-specific fatigue.

Source: McManimen SL, Sunnquist ML, Jason LA. Deconstructing post-exertional malaise: An exploratory factor analysis. J Health Psychol. 2016 Aug 24. pii: 1359105316664139. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27557649

Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment.

Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p = 0.011). There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab.

A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up. Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab.

Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p = 0.03). In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6-9.5 g/L, IgA 1.8-1.5 g/L, and IgM 0.97-0.70 g/L.

Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B-cell regulatory effects on T-cell or NK-cell subsets are not the main mechanisms for the observed improvements in ME/CFS symptoms observed in the two previous trials. The modest increase in serum BAFF levels at baseline may indicate an activated B-lymphocyte system in a subgroup of ME/CFS patients.

Source: Lunde S, Kristoffersen EK, Sapkota D, Risa K, Dahl O, Bruland O, Mella O, Fluge Ø. Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome. PLoS One. 2016 Aug 18;11(8):e0161226. doi: 10.1371/journal.pone.0161226. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990178/ (Full article)

Stressful Events in the Onset of Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a complex and multifactorial disease. Stressful situations experienced could be related to the presentation of the disease. Few studies have determined which factors could trigger CFS. The main objective of this study was to explore the stressful situations which can be associated with CFS presentation.

METHODS: Retrospective observational case-control study with CFS diagnosed patients according to the Fukuda’s criteria. Controls were matched to cases by sex, age and educational level with a 1:1 ratio. Participants aged between 18 and 75 years from the province of Lleida. Information was obtained through personal questionnaires. The measure of association was the odds ratio.

RESULTS: In total, 77 cases and 77 controls were included. Association found between stressful life events and presentation of disease were pregnancy ORa=31.7 (CI95%:2.2-456.7), spousal abuse ORa= 10.2 (CI95%:1.2-88.4) and mobbing ORa=6.9 (CI95%:1.3-36.9), eating disorders=7.5 (CI95%:1.3-42.1), car accident ORa=5.5 (CI95%:1.7-17 9), economic problems ORa=5.1 (CI95%:2.1-12.6) and changes in sleep habits ORa=2.8 (CI95%:1.1-7.5).

CONCLUSIONS: Stressful life events as pregnancy, spousal abuse, mobbing, eating disorders, car accident, economic problems and changes in sleep habits felt by those affected must be taken into consideration when compiling background information related to the onset of Chronic Fatigue Syndrome. Adequate identification of these stressful life events in risk people could contribute to early diagnosis of Chronic Fatigue Syndrome.

Source: Gimeno Pi I, Guitard Sein-Echaluce ML, Rosselló Aubach L, Torres Puig-Gros J, Fernández Solà J. Stressful Events in the Onset of Chronic Fatigue Syndrome. Rev Esp Salud Publica. 2016 Aug 18;90:e1-7. [Article in English, Spanish; Abstract available in Spanish from the publisher] https://www.ncbi.nlm.nih.gov/pubmed/27535808

Genetic evaluation of AMPD1, CPT2, and PGYM metabolic enzymes in patients with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a disease that can seriously impair one’s quality of life; patients complain of excessive fatigue and myalgia following physical exertion. This disease may be associated with abnormalities in genes affecting exercise tolerance and physical performance. Adenosine monophosphate deaminase (AMPD1), carnitine palmitoyltransferase II (CPT2), and the muscle isoform of glycogen phosphorylase (PYGM) genes provide instructions for producing enzymes that play major roles in energy production during work.

The aim of this study was to look for evidence of genotype-associated excessive muscle fatigue. Three metabolic genes (AMPD1, CPT2, and PYGM) were therefore fully sequenced in 17 Italian patients with CFS. We examined polymorphisms known to alter the function of these metabolic genes, and compared their genotypic distributions in CFS patients and 50 healthy controls using chi-square tests and odds ratios. One-way analysis of variance with F-ratio was carried out to determine the associations between genotypes and disease severity using CF scores.

No major genetic variations between patients and controls were found in the three genes studied, and we did not find any association between these genes and CFS. In conclusion, variations in AMPD1, CPT2, and PGYM genes are not associated with the onset, susceptibility, or severity of CFS.

Source: Maltese PE, Venturini L, Poplavskaya E, Bertelli M, Cecchin S, Granato M, Nikulina SY, Salmina A, Aksyutina N, Capelli E, Ricevuti G, Lorusso L. Genetic evaluation of AMPD1, CPT2, and PGYM metabolic enzymes in patients with chronic fatigue syndrome. Genet Mol Res. 2016 Jul 29;15(3). doi: 10.4238/gmr.15038717. https://www.ncbi.nlm.nih.gov/pubmed/27525900

Do evidence based interventions for chronic fatigue syndrome improve sleep? A systematic review and narrative synthesis

Abstract:

Cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are recommended evidence based treatments for chronic fatigue syndrome (CFS), with research supporting their effectiveness in reducing fatigue and functional impairment. However, little research has focussed on the effect of these treatments on sleep, despite high reported sleep disturbance in CFS.

Using a narrative synthesis approach, we aimed to 1) systematically identify and summarise the current evidence for the effectiveness of CBT and GET in improving sleep; 2) consider factors influencing treatment effectiveness, including incorporation of sleep management techniques; and 3) consider the appropriateness of sleep outcome measures used within evaluations. Studies evaluating CBT and/or GET for CFS, and including a sleep outcome were eligible for inclusion. Eight studies were identified.

We found that GET interventions can improve sleep but this effect is inconsistent across studies. For CBT the evidence is limited with only one of two evaluations demonstrating sleep-related improvements.

We conclude from existing research that we know little about the effects of including sleep management components within CBT and GET interventions. We suggest that future research should explore the effectiveness of sleep components within interventions, and sleep specific interventions, using comprehensive outcome measures that fully capture the range of sleep difficulties experienced in CFS.

Source: Russell C, Kyle SD, Wearden AJ. Do evidence based interventions for chronic fatigue syndrome improve sleep? A systematic review and narrative synthesis. Sleep Med Rev. 2016 May 13. pii: S1087-0792(16)30012-0. doi: 10.1016/j.smrv.2016.05.001. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27524207

Enhanced psychological flexibility and improved quality of life in chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

OBJECTIVE: Psychological Flexibility (PF) is a relatively new concept in physical health. It can be defined as an overarching process of being able to accept the presence of wanted/unwanted experiences, choosing whether to change or persist in behaviour in response to those experiences. Associations between processes of PF and quality of life (QoL) have been found in long-term health conditions such as chronic pain, PF has not yet been applied to Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).

METHODS: Changes in PF, fatigue severity and QoL were examined in one hundred and sixty-five patients with CFS/ME engaged in a six-week outpatient interdisciplinary group treatment programme. Participants were assessed using a series of self-report measures at the start of the start (T1) and end of a six-week programme (T2) and at six months follow up (T3).

RESULTS: Significant changes in PF and QoL were observed from pre-treatment (T1) to post treatment follow-up (T2 and T3); changes in fatigue severity were observed from T1 to T3 only. Controlling for fatigue severity, changes in the PF dimension of activity/occupational engagement were associated with improvement in QoL at six month follow up (T3) but not at six weeks post programme (T2).

CONCLUSION: Findings indicate an interdisciplinary group treatment approach for people with CFS/ME may be associated with improved QoL, processes of PF and fatigue severity, supporting a link between PF and long term health conditions. Results highlight links between PF and patient QoL in CFS/ME and the value of interdisciplinary treatment approaches in this patient population.

Source: Densham S, Williams D, Johnson A, Turner-Cobb JM. Enhanced psychological flexibility and improved quality of life in chronic fatigue syndrome/myalgic encephalomyelitis. J Psychosom Res. 2016 Sep;88:42-7. doi: 10.1016/j.jpsychores.2016.07.009. Epub 2016 Jul 19. https://www.ncbi.nlm.nih.gov/pubmed/27521652

A UK based review of recommendations regarding the management of chronic fatigue syndrome

Abstract:

OBJECTIVES: Chronic fatigue syndrome (CFS) is a controversial illness, with apparent disagreements between medical authorities and patient support organisations regarding safe and effective treatments. The aim of this study was to measure the extent of different views regarding treatments, comparing patient support organisations and medical authorities in the UK.

METHODS: Two independent raters analysed two groups of resources: UK patient support websites and both medical websites and textbooks. A 5-point Likert scale was developed with the question ‘With what strength does the source recommend these treatments?’ The various treatments were divided into the following four groups: complementary and alternative medicine (CAM), pharmacological, rehabilitative, and pacing therapies.

RESULTS: There were significant differences between the scores for patient support organisations and medical sources for all 4 treatment groups. The results for supporting CAM were 74% (patient group) vs 16% (medical source) (p<0.001), 71% vs 42% for pharmacological (p=0.01), 28% vs 94% for rehabilitative (p<0.001) and 91% vs 50% for pacing treatments (p=0.001).

CONCLUSIONS: There were substantially different treatment recommendations between patient support organisations and medical sources. Since expectations can determine response to treatment, these different views may reduce the engagement in and effectiveness of rehabilitative therapies recommended by national guidelines and supported by systematic reviews.

Source: Mallet M, King E, White PD. A UK based review of recommendations regarding the management of chronic fatigue syndrome. J Psychosom Res. 2016 Sep;88:33-5. doi: 10.1016/j.jpsychores.2016.07.008. Epub 2016 Jul 17. https://www.ncbi.nlm.nih.gov/pubmed/27521650

Comment

Ellen M Goudsmit 2016 Aug 16 12:55 p.m.

It should be noted that the PACE trial did not assess pacing as recommended by virtually all patient groups. This behavioural strategy is based on the observation that minimal exertion tends to exacerbate symptoms, plus the evidence that many with ME and CFS cannot gradually increase activity levels for more than a few days because of clinically significant adverse reactions [1]. It does not make any assumptions about aetiology.

The authors state that “It should be remembered that the moderate success of behavioural approaches does not imply that CFS/ME is a psychological or psychiatric disorder.” I submit that this relates to CBT and GET and not to strategies such as pacing. It might be helpful here to remind readers that the GET protocol for CFS/ME (as tested in most RCTs) is partly based on an operant conditioning theory, which is generally regarded as psychological [2]. The rehabilitative approaches promoted in the UK, i.e. CBT and GET, tend to focus on fatigue and sleep disorders, both of which may be a result of stress and psychiatric disorders e.g. depression. A review of the literature from the ‘medical authorities’ in the UK shows that almost without exception, they tend to limit the role of non-psychiatric aetiological factors to the acute phase and that somatic symptoms are usually attributed to fear of activity and the physiological effects of stress.

I informed the editor that as it read, the paper suggests that 1. patients have no sound medical source to support their preference for pacing and that 2. the data from the PACE trial provides good evidence against this strategy. I clarified that the trial actually evaluated adaptive pacing therapy (a programme including advice on stress management and a version of pacing that permits patients to operate at 70% of their estimated capability.) The editor chose not to investigate this issue in the manner one expects from an editor of a reputable journal. In light of the above issues, the information about pacing in this paper may mislead readers.

Interested scientists may find an alternative analysis of the differing views highly illuminating [3].

[1]. Goudsmit, EM., Jason, LA, Nijs, J and Wallman, KE. Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: A consensus document. Disability and Rehabilitation, 2012, 34, 13, 1140-1147. doi: 10.3109/09638288.2011.635746.]

[2]. Goudsmit, E. The PACE trial. Are graded activity and cognitive-behavioural therapy really effective treatments for ME? Online 18th March 2016. http://www.axfordsabode.org.uk/me/ME-PDF/PACE trial the flaws.pdf

[3]. Friedberg, F. Cognitive-behavior therapy: why is it so vilified in the chronic fatigue syndrome community? Fatigue: Biomedicine, Health & Behavior, 2016, 4, 3, 127-131. http://www.tandfonline.com/doi/full/10.1080/21641846.2016.1200884