TGI Friday! Our weekly roundup of recently published research abstracts and related items | 10 July 2015

From Physical Medicine and Rehabilitation International, 9 July (FULL TEXT AVAILABLE HERE).

Progressive Myalgic Encephalomyelitis (ME) or a New Disease? A Case Report.

Howes, S(1) and Goudsmit, EM(2,*).
1) Retired Science Writer, Croydon, UK
2) Retired Health Psychologist, London, UK
*Corresponding author: Goudsmit EM, ellengoudsmit@hotmail.com

Abstract

This is a report on a patient with a history of increasing dizziness and muscle weakness after minimal exertion. In her twenties, the symptoms became more pronounced following glandular fever.

After excluding other diseases, her physician diagnosed myalgic encephalomyelitis (ME), now commonly referred to as chronic fatigue syndrome (CFS). The condition followed a relapsing-remitting course until about five years ago, when she experienced a sudden deterioration and developed new symptoms such as blurred vision in one eye and urinary incontinence.

Whether this is a case of progressive ME or a new disease remains uncertain.

Research is required both to increase diagnostic clarity and to establish whether the recommended behavioural interventions designed for CFS are appropriate for the subset of patients with neurological symptoms and abnormalities on MRI.


From Human Immunology, 24 June 2015

Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome

Mangalathu S. Rajeevan*, Irina Dimulescu, Janna Murray, Virginia R. Falkenberg, Elizabeth R. Unger

Division of High-Consequence Pathogens & Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA
Cortrespondent: mor4@cdc.gov

Abstract

Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS.

Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11 K single nucleotide polymorphisms (SNPs) following the manufacturer’s protocol. Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs.

CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4).

Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5′ UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms.

This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study.


Comment published on 30 June 2015 by the Annals of Internal Medicine with respect to the following article:

Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

PD White, MD(1), DJ Clauw, MD(2), JWM van der Meer, MD (3), R Moss-Morris, PhD (4) RR Taylor, PhD(5)
1) Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University, London, UK
2) Department of Anesthesiology, Medicine and Psychiatry, University of Michigan

Conflict of Interest: PDW, JWMvdM and RMM were principal investigators or co-investigators in some of the trials reviewed. PDW does consultancy work for the UK government and a re-insurance company.

In their systematic review, Smith and colleagues concluded that “trials of counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for .. harms is insufficient.”(1)

While we support the general conclusion of benefit with these treatments, we suggest that some aspects of this review may be misinterpreted. Firstly, the
most frequently tested behavioural intervention has been cognitive behaviour therapy (CBT), which aims to reduce symptoms and improve functioning, and it
would be unusual to consider this as “counselling”, which has different objectives and content. One would not combine different types of medicines in a review; why do this with therapies? A review that combines counselling and CBT simply dilutes the efficacy of CBT, which has been amply demonstrated in several previous meta-analyses (2).

Secondly, there is little evidence of harm caused by graded exercise therapy (GET); a Cochrane systematic review of eight trials of exercise therapy for
chronic fatigue syndrome (CFS), published this year, concluded that “..no evidence suggests that exercise therapy may worsen outcomes.” (3) Suggesting evidence of harm by stating that “one trial reported significantly more serious adverse events ..and more nonserious adverse events . in the GET versus comparison groups,.” without mentioning that serious adverse events were independently judged to be unrelated to the intervention, and that the differences between non-serious adverse events was not statistically significant, is a potentially misleading representation of the evidence.

Adding that “..in a trial of GET, 20% of patients declined to repeat exercise testing because of perceived harm of testing” encourages further misunderstanding by failing to mention that the exercise testing was not part of the therapy and that the proportion of patients in the control intervention who also declined exercise testing was 50% (4). (Incidentally the proportion declining testing in the GET arm was 44%, not 20%.4) There is a world of difference between the effects of maximum exercise testing and graded exercise therapy. It isimportant not to overemphasise the harms associated with an effective treatment when there are so few others available.

Finally, the authors concluded that we need trials with analyses of patients meeting different case definitions; we agree and this has already happened. White and colleagues found no statistically significant differences in the efficacy of CBT and GET in sub-groups of those patients meeting Oxford criteria for CFS who also met either CDC defined CFS or myalgic encephalomyelitis (ME)(5).

Note: Seven other CFS clinical scientists supported and approved this letter.

REFERENCES

1. Smith MEB, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review for a national Institutes of Health pathways to prevention workshop. Ann Intern Med 2015; 162: 841-50.

2. Castell BD, Kazantzis N, Moss-Morris RE. Cognitive behavioral therapy and graded exercise for chronic fatigue syndrome: A meta-analysis Clin Psychol Sci Prac 2011; 18: 311-24.

3. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD003200.

4. Moss-Morris R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol 2005; 10: 245-59.

5. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 2011;377:823-36.


From PLoSOne,6 July 2015. Full text available.

The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS).

Michael Falk Hvidberg, Anne V. Olesen, Karin D. Petersen, Lars Ehlers
Danish Center for Healthcare Improvements, Aalborg University, Aalborg, Denmark
Louise Schouborg Brinth
Coordinating Research-unit, Frederiksberg Hospital, Frederiksberg, Denmark
Email: michael@falkhvidberg.dk

Abstract

INTRODUCTION

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a common, severe condition affecting 0.2 to 0.4 per cent of the population. Even so, no recent international EQ-5D based health-related quality of life (HRQoL) estimates exist for ME/CFS patients.

The main purpose of this study was to estimate HRQoL scores using the EQ-5D-3L with Danish time trade-off tariffs. Secondary, the aims were to explore whether the results are not influenced by other conditions using regression, to compare the estimates to 20 other conditions and finally to present ME/CFS patient characteristics for use in clinical practice.

MATERIAL AND METHODS

All members of the Danish ME/CFS Patient Association in 2013 (n=319) were asked to fill out a questionnaire including the EQ-5D-3L. From these, 105 ME/CFS patients wereidentified and gave valid responses. Unadjusted EQ-5D-3L means were calculated and compared to the population mean as well as to the mean of 20 other conditions. Furthermore, adjusted estimates were
calculated using ordinary least squares (OLS) regression, adjusting for gender, age, education, and co-morbidity of 18 self-reported conditions. Data from the North Denmark Health Profile 2010 was used as population reference in the regression analysis (n=23,392).

RESULTS

The unadjusted EQ-5D-3L mean of ME/CFS was 0.47 [0.41-0.53] compared to a population mean of 0.85 [0.84-0.86]. The OLS regression estimated a disutility of -0.29 [-0.21;-0.34] for ME/CFS patients in this study. The characteristics of ME/CFS patients are different from the population with respect to gender, relationship, employment etc.

CONCLUSION

The EQ-5D-3L-based HRQoL of ME/CFS is significantly lower than the population mean and the lowest of all the compared
conditions. The adjusted analysis confirms that poor HRQoL of ME/CFS is distinctly different from and not a proxy of the other included conditions. However, further studies are needed to exclude the possible selection bias of the current study.


From Brain, Behavior, and Immunity, 3 July 2015.

Chronic fatigue syndrome and circulating cytokines: a systematic review

S. Blundell(a), K.K. Ray(b), M. Buckland©, P.D. White(a)
a) Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
b) East London Foundation NHS Trust, London, UK
c) Barts Health Trust, London, UK

HIGHLIGHTS

• Circulating TGF was raised in CFS versus controls in most studies when measured.
• No overall differences were found for any other cytokines.
• There were no overall differences in cytokine concentrations after exercise.
• The quality of studies published was variable and often limited.

Abstract

There has been much interest in the role of the immune system in the pathophysiology of chronic fatigue syndrome (CFS), as CFS may develop following an infection and cytokines are known to induce acute sickness behaviour, with similar symptoms to CFS.

Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a search was conducted on PubMed, Web of Science, Embase and PsycINFO, for CFS related-terms in combination with cytokine-related terms. Cases had to meet established criteria for CFS and be compared with healthy controls.

Papers retrieved were assessed for both inclusionary criteria and quality. 38 papers met the inclusionary criteria. The quality of the studies varied. 77 serum or plasma cytokines were measured without immune stimulation. Cases of CFS had significantly elevated concentrations of Transforming Growth Factor-beta (TGF-) in five out of eight (63%) studies.

No other cytokines were present in abnormal concentrations in the majority of studies, although insufficient data were available for some cytokines.

Following physical exercise there were no differences in circulating cytokine levels between cases and controls and exercise made no difference to already elevated TGF-β concentrations. The finding of elevated TGF-β concentration, at biologically relevant levels, needs further exploration, but circulating cytokines do not seem to explain the core characteristic of post-exertional fatigue.


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