TGI Friday! Our weekly round-up of recently published research abstracts | 28 April 2017

From Microbiome (open access), 26 April 2017.

Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome

Dorottya Nagy-Szakal(1)†, Brent L. Williams(1)†, Nischay Mishra(1), Xiaoyu Che(1), Bohyun Lee(1), Lucinda Bateman(2), Nancy G. Klimas(3,4), Anthony L. Komaroff(5), Susan Levine(6), Jose G. Montoya, Daniel L. Peterson(7), Devi Ramanan(8), Komal Jain(1), Meredith L. Eddy(1), Mady Hornig(1) and W. Ian Lipkin(1).
1. Center for Infection and Immunity, Columbia University Mailman School of Public Health
2. Fatigue Consultation Clinic
3. Institute for Neuro-Immune Medicine, College of Osteopathic Medicine, Nova Southeastern University
4. Miami VA Medical Center
5. Brigham and Women’s Hospital, Harvard Medical School
6. Levine Clinic
7. Stanford University
8. Ayasdi, Inc.

†Contributed equally

Abstract

BACKGROUND

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.

RESULTS

Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.

CONCUSIONS

Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.


Cochrane Database Systematic Review, 25 April 2017 (e-published ahead of print).

Exercise therapy for chronic fatigue syndrome.

Larun L(1), Brurberg KG(2) , Odgaard-Jensen J(3), Price JR(4).
1) Norwegian Insitute of Public Health, Postboks 4404 Nydalen, Oslo, Norway, N-0403.
2) Unit for Primary Care and Clinical Procedures, Norwegian Institute of Public Health, PO Box 4404, Nydalen, Oslo, Norway, 0403.
3) Biometrics, Link Medical Research AS, Box 4382 Nydalen, Oslo, Norway, N-0402.
4) Department of Psychiatry, University of Oxford, The Warneford Hospital, Headington, Oxford, UK, OX3 7JX.

Abstract

BACKGROUND

Chronic fatigue syndrome (CFS) is characterised by persistent, medically unexplained fatigue, as well as symptoms such as musculoskeletal pain, sleep disturbance, headaches and impaired concentration and short-term memory. CFS presents as a common, debilitating and serious health problem. Treatment may include physical interventions, such as exercise therapy, which was last reviewed in 2004.

OBJECTIVES

The objective of this review was to determine the effects of exercise therapy (ET) for patients with CFS as compared with any other intervention or control.

• Exercise therapy versus ‘passive control’ (e.g. treatment as usual, waiting-list control, relaxation, flexibility).

• Exercise therapy versus other active treatment (e.g. cognitive-behavioural therapy (CBT), cognitive treatment, supportive therapy, pacing, pharmacological therapy such as antidepressants).

• Exercise therapy in combination with other specified treatment strategies versus other specified treatment strategies (e.g. exercise combined with pharmacological treatment vs pharmacological treatment alone).

SEARCH METHODS

We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL) and SPORTDiscus up to May 2014 using a comprehensive list of free-text terms for CFS and exercise.

We located unpublished or ongoing trials through the World Health Organization (WHO) International Clinical Trials Registry Platform (to May 2014). We screened reference lists of retrieved articles and contacted experts in the field for additional studies

SELECTION CRITERIA

Randomised controlled trials involving adults with a primary diagnosis of CFS who were able to participate in exercise therapy. Studies had to compare exercise therapy with passive control, psychological therapies, adaptive pacing therapy or pharmacological therapy.

DATA COLLECTION AND ANALYSIS

Two review authors independently performed study selection, risk of bias assessments and data extraction. We combined continuous measures of outcomes using mean differences (MDs) and standardised mean differences (SMDs). We combined serious adverse reactions and drop-outs using risk ratios (RRs). We calculated an overall effect size with 95% confidence intervals (CIs) for each outcome.

MAIN RESULTS

We have included eight randomised controlled studies and have reported data from 1518 participants in this review. Three studies diagnosed individuals with CFS using the 1994 criteria of the Centers for Disease Control and Prevention (CDC); five used the Oxford criteria. Exercise therapy lasted from 12 to 26 weeks.

Seven studies used variations of aerobic exercise therapy such as walking, swimming, cycling or dancing provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, whilst one study used anaerobic exercise. Control groups consisted of passive control (eight studies; e.g. treatment as usual, relaxation, flexibility) or CBT (two studies), cognitive therapy (one study), supportive listening (one study), pacing (one study), pharmacological treatment (one study) and combination treatment (one study).

Risk of bias varied across studies, but within each study, little variation was found in the risk of bias across our primary and secondary outcome measures.

Investigators compared exercise therapy with ‘passive’ control in eight trials, which enrolled 971 participants. Seven
studies consistently showed a reduction in fatigue following exercise therapy at end of treatment, even though the fatigue scales used different scoring systems: an 11-item scale with a scoring system of 0 to 11 points (MD -6.06, 95% CI -6.95 to -5.17; one study, 148 participants; low-quality evidence); the same 11-item scale with a scoring system of 0 to 33 points (MD -2.82, 95% CI -4.07 to -1.57; three studies, 540 participants; moderate-quality evidence); and a
14-item scale with a scoring system of 0 to 42 points (MD -6.80, 95% CI -10.31 to -3.28; three studies, 152 participants; moderate-quality evidence).

Serious adverse reactions were rare in both groups (RR 0.99, 95% CI 0.14 to 6.97; one study, 319 participants; moderate-quality evidence), but sparse data made it impossible for review authors to draw conclusions. Study authors reported a positive effect of exercise therapy at end of treatment with respect to sleep (MD -1.49, 95% CI -2.95 to -0.02; two studies, 323 participants), physical functioning (MD 13.10, 95% CI 1.98 to 24.22; five studies, 725 participants) and self-perceived changes in overall health (RR 1.83, 95% CI 1.39 to 2.40; four studies, 489 participants).

It was not possible for review authors to draw conclusions regarding the remaining outcomes.Investigators compared exercise therapy with CBT in two trials (351 participants). One trial (298 participants) reported little or no difference in fatigue at end of treatment between the two groups using an 11-item scale with a scoring system of 0 to 33 points (MD 0.20, 95% CI -1.49 to 1.89). Both studies measured differences in fatigue at follow-up, but neither found differences between the two groups using an 11-item fatigue scale with a scoring system of 0 to 33 points (MD 0.30, 95% CI -1.45 to 2.05) and a nine-item Fatigue Severity Scale with a scoring system of 1 to 7 points (MD 0.40, 95% CI
-0.34 to 1.14).

Serious adverse reactions were rare in both groups (RR 0.67, 95% CI 0.11 to 3.96). We observed little or no difference in physical functioning, depression, anxiety and sleep, and we were not able to draw any conclusions with regard to pain, self-perceived changes in overall health, use of health service resources and drop-out rate.

With regard to other comparisons, one study (320 participants) suggested a general benefit of exercise over adaptive pacing, and another study (183 participants) a benefit of exercise over supportive listening. The available evidence was too sparse to draw conclusions about the effect of pharmaceutical interventions.

AUTHORS’ CONCLUSIONS

Patients with CFS may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed, but no conclusions for the outcomes of pain, quality of life, anxiety, depression, drop-out rate and health service resources were possible.

The effectiveness of exercise therapy seems greater than that of pacing but similar to that of CBT. Randomised trials with low risk of bias are needed to investigate the type, duration and intensity of the most beneficial exercise intervention.

4 thoughts on “TGI Friday! Our weekly round-up of recently published research abstracts | 28 April 2017”

  1. “Exercise therapy for chronic fatigue syndrome.” (1994 CDC and Oxford criteria)

    “The effectiveness of exercise therapy seems greater than that of pacing but similar to that of CBT. Randomised trials with low risk of bias are needed to investigate the type, duration and intensity of the most beneficial exercise intervention.”

    “Serious adverse reactions were rare in both groups but sparse data made it impossible for review authors to draw conclusions.” – Given that serious adverse reactions and participant drop outs were just bundled together as one phenomenon – is that surprising? … or for that matter valid?

    A mixture, without differentiation (or apparent understanding?), of a very wide spectrum (walking to anaerobic sports!) of Graded Exercise Therapy studies compared with other therapy/~ies or “passive” therapy controls including Adaptive Pacing Therapy? As ME sufferers are well aware, many of the best intentioned ‘placebos’ or ‘helps’ from the medical and scientific community are far from benign, and can be quite damaging, or disabling, both physically, emotionally and psychologically. Comparing the apparent “low” to “moderate” quality evidence of marginal to slight improvement (in terms of; sleep, physical function and self-perceived general health) in the “Exercise” arms of these studies, to the “control” arms of these studies, could well be representing the benefits of placebo verses the benefits of placebo minus the deleterious effects of mis-presumed beneficial or benign controls, thus giving the appearance of efficacy to an ineffective or simply less damaging intervention.

    “no conclusions for the outcomes of pain, quality of life, anxiety, depression, drop-out rate and health service resources were possible”

    There would appear, again, to be some scientific difficulty in determining the difference between people who simply drop out of the studies and those who have been damaged or disabled by it.
    Again for some reason, included in the net search of studies included in this review, (despite all scientific evidence now pointing to a very elusive but definite physical/physiological cause of this illness) the authors trawled “The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register”, amongst others, for reviewable studies.

    It is interesting to note that this review has already appeared to ignore peer review criticisms and suggested corrections of factual errors (sound familiar). In particular “As no study has yet assessed exercise for classic ME, one can not generalise any conclusion about efficacy from the trials in the review to patients with this disease.” -Ellen M Goudsmit plus other comments regarding the selection criteria of ‘CFS’.

    Personally, if it wasn’t so sad I would find it entertaining, but regarding the criteria for an individual’s inclusion in these studies being reviewed as being; “adults with a primary diagnosis of CFS who were able to participate in exercise therapy” is signal enough to me to treat any results from such studies as highly suspect. In my own limited experience of sufferers who I have observed, working as a doctor in general practice and psychiatry, people eventually receive a diagnosis of ME long after they have lost the ability to participate in exercise therapy! It is only as they are well on the way to a recovery or remission that such therapy can be contemplated, or reconsidered when the early signs of a relapse start cropping up.

    Any conclusions related to any exercise therapy study, that I have seen, never seem to refer to the investigation of any value (to the sufferers) of exercise therapy on those ME/CFS sufferers in the latter stages of recovery or remission of symptoms or those experiencing the early signs of a relapse! Such a title or claim of a study (or review) might carry more weight and interest with sufferers and those truly interested in identifying a way to help based on real evidence related to the reality of this illness!

  2. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome….

    This is a very exciting insight into the picture of “What does ME look like and why?” field of research. It might seem like it is just about a pile of ‘poo’, but this research has some very big ‘who’s whos’ in genuine immunology, metabolomic and physiological researchers into ME. Interesting that there is a suggestion of Vitamin B6, Zinc, Iron and Riboflavin (B2) endobacterial metabolic change…. well, interesting to me anyway. Not a psycho’, psychi’ or ‘sports’ medic/ scientist or establishment amongst the authors, so promising there too!

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