Update in

• Exercise therapy for chronic fatigue syndrome. [Cochrane Database Syst Rev. 2016]

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 We located unpublished or ongoing trials through the World Health Organization (WHO) International Clinical Trials Registry Platform (to May 2014).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.

Update of

• Exercise therapy for chronic fatigue syndrome. [Cochrane Database Syst Rev. 2004]

 

Source: Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2015 Feb 10;(2):CD003200. doi: 10.1002/14651858.CD003200.pub3. https://www.ncbi.nlm.nih.gov/pubmed/25674924

Comments

• Tom Kindlon 2016 Apr 18 11:38 a.m.

  James C Coyne PhD has blogged here https://jcoynester.wordpress.com/2016/03/20/why-the-cochrane-collaboration-needs-to-clean-up-conflicts-of-interest/ about my comment:

  “Selective reporting (outcome bias)” and White et al. (2011) I don’t believe that White et al. (2011) (the PACE Trial) (3) should be classed as having a low risk of bias under “Selective reporting (outcome bias)” (Figure 2, page 15). According to the Cochrane Collaboration’s tool for assessing risk of bias (21), the category of low risk of bias is for: “The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way”. This is not the case in the PACE Trial. The three primary efficacy outcomes can be seen in the published protocol (22). None have been reported in the pre-specified way. The Cochrane Collaboration’s tool for assessing risk of bias states that a “high risk” of bias applies if any one of several criteria are met, including that “not all of the study’s pre-specified primary outcomes have been reported” or “one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified”. In the PACE Trial, the third primary outcome measure (the number of “overall improvers”) was never published. Also, the other two primary outcome measures were reported using analysis methods that were not pre-specified (including switching from the bimodal to the Likert scoring method for The Chalder Fatigue Scale, one of the primary outcomes in your review). These facts mean that the “high risk of bias” category should apply.

  and the response I received from one of the authors .

More from Tom Kindlon

• • Tom Kindlon 2015 Sep 14 4:57 p.m.

    (contd.)

    Compliance

    The review doesn’t include any information on compliance. I’m not sure that there is much published information on this but I know there was a measure based on attendance at therapy sessions (which could be conducted over the phone) given for the PACE Trial (3). Ideally, it would be interesting if you could obtain some unpublished data from activity logs, records from heart-rate monitors, and other records to help build up a picture of what exercise was actually performed and the level of compliance. Information on adherence and what exercise was actually done is important in terms of helping clinicians, and indeed patients, to interpret and use the data. I mention patients because patients’ own decisions about their behaviour is likely to be affected by the medical information available to them, both within and outside of a supervised programme of graded exercise; unlike with an intervention like a drug, patients can undertake exercise without professional supervision.

    “Selective reporting (outcome bias)” and White et al. (2011)

    I don’t believe that White et al. (2011) (the PACE Trial) (3) should be classed as having a low risk of bias under “Selective reporting (outcome bias)” (Figure 2, page 15). According to the Cochrane Collaboration’s tool for assessing risk of bias (21), the category of low risk of bias is for: “The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way”. This is not the case in the PACE Trial. The three primary efficacy outcomes can be seen in the published protocol (22). None have been reported in the pre-specified way. The Cochrane Collaboration’s tool for assessing risk of bias states that a “high risk” of bias applies if any one of several criteria are met, including that “not all of the study’s pre-specified primary outcomes have been reported” or “one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified”. In the PACE Trial, the third primary outcome measure (the number of “overall improvers”) was never published. Also, the other two primary outcome measures were reported using analysis methods that were not pre-specified (including switching from the bimodal to the Likert scoring method for The Chalder Fatigue Scale, one of the primary outcomes in your review). These facts mean that the “high risk of bias” category should apply.

    Thank you for taking the time to read my comments.

    Tom Kindlon

    Conflict of Interest statement:

    I am a committee member of the Irish ME/CFS Association and do a variety of unpaid work for the Association.

    (continues)

  More from Tom Kindlon

• Laurie Thomas 2015 Feb 24 11:58 a.m.

  Clinical studies of chronic fatigue syndrome are plagued by serious problems in the inclusion/exclusion criteria. These problems stem from the fact that the syndrome consists of nonspecific symptoms that are “medically unexplained.” However, there is a major difference between medically unexplained and medically inexplicable. The symptoms of chronic fatigue syndrome can result from a serious circulatory problem that is easily overlooked. In 2003, Peckerman and coworkers showed that low cardiac output, as measured by impedance cardiography, predicts the severity of symptoms in CFS patients.[1] Miwa and Fujita found a small left ventricular size leading to low cardiac output in CFS patients with orthostatic intolerance.[2] Porter and coworkers reported that a case of femoral arteriovenous fistula causing high-output cardiac failure was originally misdiagnosed as chronic fatigue syndrome.[3]

  The studies of graded exercise for management of CFS are based on the presumption that CFS is the result of laziness and deconditioning and that the solution to the problem is to persuade the patient to exercise. Yet in many reported cases, the real problem was unrecognized cardiac decompensation. This state of cardiac decompensation could account for the push-crash phenomenon (serious, prolonged adverse events from overexertion) among people with CFS. Thus, a graded exercise program that might be beneficial for the large number of people who are tired and achy because of major depressive disorder could be catastrophic for the relatively small number of people whose problem is due to cardiac decompensation. Unfortunately, the existing studies of exercise for management of CFS do not shed light on this problem. The patients whose exercise intolerance is too severe to allow them to participate in the exercise program might refuse to enroll or might be dismissed as noncompliant if they try but fail to exercise. Yet as a result of the positive results of graded exercise for subjects whose real problem is major depressive disorder, patients with unrecognized cardiac decompensation are being scolded for failing to exercise.

  For ethical and scientific reasons, the protocol for a clinical study of subjects with CFS should be based on the best possible model for clinical management of CFS patients. It would begin with a careful assessment of the subject’s circulatory status. This assessment should include a tilt-table test, or at least a measurement of supine, sitting, and standing pulse and blood pressure. Any circulatory problem should be addressed appropriately. (Note that once the patient’s condition is found to be due to a circulatory problem, the patient no longer fits the inclusion criteria of “medically unexplained” symptoms.)

  As improper diet is the most prevalent cause of chronic ill-health, the cardiology assessment should be followed by a run-in period of at least a week of optimal dietary management. Subjects should be fed a low-fat (<10% of calories), purely plant-based diet that excludes the most common causes of food allergies or intolerance syndromes (i.e., wheat, rye, barley, corn, soy, strawberries, and citrus fruits). To ensure adherence, the diet should be administered in a residential setting. This kind of low-fat, plant-based diet can bring about a significant drop in blood pressure in hypertensive patients within 7 days, even if the patients stop taking blood pressure medication at baseline.[4] This correction of hypertension results from the decrease in systemic resistance. Thus, this diet could lead to a significant improvement in circulation, which would be beneficial to patients whose symptoms are due to poor circulation, even if they are not hypertensive. Note also that the elimination of poorly tolerated foods is the only reliable way to establish that the patient’s problem is due to a food intolerance. Of course, once the subject’s problem has been shown to be dietary in origin, the subject no longer has “medically unexplained” symptoms and thus no longer fits the inclusion criteria for a study of CFS.

  Many patients with a diagnosis of CFS are inactive, but they may be inactive because they are sick, rather than being sick because they are inactive. Thus, any study of exercise and CFS should be structured to establish the direction of causality. If a study of subjects with a diagnosis of CFS involves exercise, the outcome variables must involve some measurement of the subjects’ overall activity levels, not just to assess compliance with the exercise program but to assess whether the subjects are merely wasting their energy on the exercises and thus become less able to perform activities of daily living. In that situation, the exercise program could actually decrease the subject’s quality of life.

  [1] Peckerman A, LaManca JJ, Dahl KA, Chemitiganti R, Qureishi B, Natelson BH. Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome. Am J Med Sci. 2003 Aug;326(2):55-60.

  [2] Miwa K1, Fujita M. Small heart with low cardiac output for orthostatic intolerance in patients with chronic fatigue syndrome.Clin Cardiol. 2011 Dec;34(12):782-6. doi: 10.1002/clc.20962. Epub 2011 Nov 28.

  [3] Porter J1, Al-Jarrah Q1, Richardson S. A case of femoral arteriovenous fistula causing high-output cardiac failure, originally misdiagnosed as chronic fatigue syndrome. Case Rep Vasc Med. 2014;2014:510429. doi: 10.1155/2014/510429. Epub 2014 May 20.

  [4] McDougall J1, Thomas LE, McDougall C, Moloney G, Saul B, Finnell JS, Richardson K, Petersen KM.Effects of 7 days on an ad libitum low-fat vegan diet: the McDougall Program cohort. Nutr J. 2014 Oct 14;13:99. doi: 10.1186/1475-2891-13-99.

• Joan Crawford 2015 Feb 19 07:58 a.m.

  This review states: “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.”

  This is important because the above description of CFS and the addition of trials in the review only requiring chronic fatigue as an inclusionary requirement (Sharpe et al, 1991) makes generalisation of the findings problematic as many patients with major depressive disorder (MDD) would also meet the above description of CFS and Sharpe et al.’s (1991) criteria if their condition was fatiguing – a common feature – along with muscular aches and pains, sleep disturbance, cognitive difficulties and so on. The high percentage of patients included in these trials suffering from depression (Table 1. Study demographics) indicates this may be their primary condition – confounding the results. Exercise, through behavioural activation programs, has a moderately positive impact on patients with depression (Cooney et al., 2013). It is unclear whether the modest improvement seen in some of these trials can be accounted for by an improvement in low mood caused by depression. Moreover, where there is data there is a high usage of antidepressants in patients included in the reviewed trials (Table 1. Study demographics).

  Of the eight exercise trials included in this review, five used broad inclusion criteria (Sharpe et al, 1991) (N=1287) – 85% of all participants. Two of these studies also used a version of the London criteria, which did not exclude patients with depression and other psychiatric conditions as originally specified by the authors making it hard to assess how these criteria were operationalised. Three further trials used the CDC Fukuda (1994) CFS criteria (N=231). While these purport to be more selective, they do not necessary include patients whose primary difficulties include post exertional weakness and debility and flu-like symptoms and so on beyond broadly defined fatigue and other general symptoms which could be attributed to CFS or MDD.

  There is also an issue with lack of evidence of patients’ fidelity to exercise programs using objective measures. We do not know if patients increased their activity as suggested to them by their clinicians. Without using devises such as actimeters or pedometers to track daily activity levels we have no accurate way of assessing whether an increase in activity occurred and whether this helps. Black & McCully’s (2005) study demonstrates objectively the difficulties patients face when trying to increase activity and concluded that they were exercise intolerant, unable to sustain activity targets.

  The report is bold in stating “no evidence suggests that exercise therapy may worsen outcomes“. Many patient surveys from across the world report numerous instances of harm and worsening of symptoms from taking part in exercise programs. For a summary of the difficulties and limitations of the reporting of harms, in and outside of clinical trials, and why these might be underestimated please see Kindlon (2011).

  References

  Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE (2013). Exercise for depression. The Cochrane Library. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004366.pub6/abstract

  Fukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. International chronic fatigue syndrome study group. Annals of Internal Medicine, 121(12), 953-959.

  Kindlon T. (2011). Reporting of harms associated with graded exercise therapy and cognitive behavioural therapy in Myalgic Encephalomyelitis/chronic fatigue syndrome. Bulletin of the IACFS/ME. 19(2): 59-111.

  M, Archard L, Banatvala J, Borysiewicz LK, Clare AW, David A, et al. (1991). Chronic fatigue syndrome: guidelines for research. Journal of the Royal Society of Medicine, 84(2):118–21.

• Ellen M Goudsmit 2015 Feb 14 4:49 p.m.

  I had contact with the main author to alert her to certain misconceptions published earlier. Sadly, I found I had wasted my time.

  For example, we can not tell how many, if any, patients in the PACE trial met the London criteria. Having read that the researchers planned to select individuals with ME and had listed the criteria in the protocol, I checked that Prof. White would use the original version which had not been published. I had been the Chair of the Research Working Group at AFME when they were being tested and still had a copy. They came with a questionnaire as well as a physician to establish their reliability. Prof. White was unwilling to confirm that he would use the original so in light of the uncertainty, I requested that he did not cite me as a co-author. I did not work on the lay version published in the Westcare report which I felt was deeply flawed. I was right to be cautious. The trial manual indicates that the researchers adapted the lay version and I could tell from the results that the London criteria were not used as they exclude individuals with psychological disorders so the percentage for that variable should have been nil. It wasn’t.

  A second point. The review does not pay the required attention to the lack of actigraphy, an objective measure to confirm fidelity to the protocol. This has been included in most studies conducted in the USA and the Netherlands. The results from actigraphy indicate that, except for 7 individuals, there were no significant increases in activity after GET and similar therapies. According to Friedberg who assessed the phenomenon, patients on exercise trials tend to reprioritise their activities, choosing those that result in less stress etc. In short, they learn to pace themselves (Goudsmit et al 2012). That is why they feel better and less fatigued, but it’s not possible to attribute improvement to an increase in activity (or fitness).

  Pacing was not defined and adaptive pacing therapy (APT) refers to a programme consisting of several components including stress management, advice on sleeping etc. There are no data for pacing alone in the PACE trial, so to conclude that GET is superior to pacing therapies is premature. There is only one pacing therapy. Pacing is not a therapy. It’s a simple strategy. Research by Jason suggests that people who pace themselves feel better, irrespective of the protocol they are on.

  Finally, we know that many patients have adverse reactions to activity. It’s a criterion for diagnosis. To dismiss them (“no evidence that exercise therapy worsens outcomes”) is hard to comprehend. Every survey in every country to date has revealed that GET does have marked adverse reactions and can result in relapse. See also Sisto et al and Black and McCully, cited in Goudsmit et al 2012.

  To summarise: lack of a definition of pacing resulting in confusion, repetition of incorrect information, failure to consider the findings from objective measures suggesting patients did not adhere to the protocol and ignoring consistent reports from surveys that undermine one’s conclusions. I expect more objectivity and attention to detail from the Cochrane Library.

  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. Online 19th December. doi: 10.3109/09638288.2011.635746.

• This article was mentioned in a comment by Tom Kindlon 2015 Oct 06 4:36 p.m.

  See: Randomised controlled trial of cognitive behaviour therapy delivered in groups of patients with chronic fatigue syndrome. [Psychother Psychosom. 2015.]