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Beth Smith ME, Nelson HD, Haney E, et al. Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 Dec. (Evidence Reports/Technology Assessments, No. 219.)

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Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

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July 2016 Addendum

Introduction

The AHRQ evidence report on the Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome was published in December, 2014 and provided a literature review for the National Institutes of Health Pathways to Prevention Workshop on Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.1, 2 The review found eight case definitions for either chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), or ME/CFS, and since its publication, an additional case definition was published by the Institute of Medicine along with the recommendation of a new name, Systemic Exertional Intolerance Disease.3 The Oxford (Sharpe, 1991) case definition is the least specific of the definitions and less generalizable to the broader population of patients with ME/CFS. It could identify individuals who have had 6 months of unexplained fatigue with physical and mental impairment, but no other specific features of ME/CFS such as post-exertional malaise which is considered by many to be a hallmark symptom of the disease.3 As a result, using the Oxford case definition results in a high risk of including patients who may have an alternate fatiguing illness or whose illness resolves spontaneously with time. In light of this, we recommended in our report that future intervention studies use a single agreed upon case definition, other than the Oxford (Sharpe, 1991) case definition. If a single definition could not be agreed upon, future research should retire the use of the Oxford (Sharpe, 1991) case definition. The National Institute of Health (NIH) panel assembled to review evidence presented at the NIH Pathways to Prevention Workshop agreed with our recommendation, stating that the continued use of the Oxford (Sharpe, 1991) case definition “may impair progress and cause harm.”2 In light of this, we have received public comment requesting a separation of results based on case definition to appraise the impact of Oxford based trials on conclusions of the report. Additionally, the public has requested that we separate cognitive behavioral therapy (CBT) from other counseling and behavioral interventions given that CBT is a specific therapeutic approach.

The purpose of this addendum to our original report is to assess the impact of studies using the Oxford (Sharpe, 1991) case definition on conclusions and to assess the impact of separating studies of cognitive behavioral therapy from other counseling and behavioral interventions.

Results

What are the (a) benefits and (b) harms of therapeutic interventions for patients with ME/CFS, and how do they vary by patient subgroups?

All intervention trials used a case definition for CFS as eligibility for trial inclusion. The results may not be applicable to individuals fulfilling criteria for ME or ME/CFS. Harms are generally poorly reported and conclusions surrounding harms are not impacted by this further analysis.

Medications

Of the nine studies that met inclusion criteria for medical treatment of ME/CFS, eight studies used a CDC (Holmes or Fukuda) case definition for CFS4-11 and one study used the Oxford (Sharpe, 1991) case definition for CFS.12 This latter study was the only trial comparing a selective serotonin reuptake inhibitor (fluoxetine) with a placebo or graded exercise therapy and found no significant differences on measures of fatigue or function with fluoxetine although there were greater withdrawals in the fluoxetine group (13% [9/68] vs. 3% [2/68]). We previously found the evidence on fluoxetine's effect on function or fatigue to be insufficient, such that consideration of the impact of the Oxford (Sharpe, 1991) case definition does not change this conclusion. Because the Oxford (Sharpe, 1991) case definition was not used in other medication trials, there remains low strength of evidence that Rintatolimod improves work capacity compared with placebo based on two randomized controlled trials10, 11 and insufficient evidence on the effectiveness of all other medications reviewed.

Complementary and Alternative Medicine Therapies

Of the seven trials that met inclusion criteria for the use of a complementary and alternative medicine (CAM) approach in treating ME/CFS, five studies used the CDC (Fukuda, 1994) case definition13-17 and two studies used the Oxford (Sharpe, 1991) case definition.18, 19 The latter two studies included a trial by Weatherly-Jones et al., that compared homeopathy with placebo and a trial by Williams et al., that compared melatonin with phototherapy or placebo. These trials as well as all of the other CAM trials were small, single studies, and there remains insufficient evidence on the effectiveness of diets, supplements, or phototherapy.

Counseling and Behavior Therapies

Of the 14 counseling and/or behavioral therapy trials included, several with multiple publications, eight compared CBT with another intervention or wait list control20-30 while six studies used a different counseling or behavioral technique.31-39 One of the CBT trials that used the CDC (Fukuda, 1994) case definition compared telephone CBT with face-to-face CBT and does not contribute to the addendum.2

Cognitive Behavioral Therapy

Two of seven remaining CBT studies used the Oxford case definition for eligibility (n=841)29, 30 (Table 1), while five studies used case definitions that ultimately fulfilled the CDC (Fukuda, 1994) case definition (n=800) (Table 2). Of note, one of these studies fulfilled both the Oxford (Sharpe, 1991) and the CDC (Fukuda, 1994) case definition.22, 23 Any differences in findings between the studies using the Oxford (Sharpe, 1991) and the CDC (Fukuda, 1994) case definitions are discussed by outcome below.

Table 1. Cognitive behavioral therapy trials using Oxford case definition for inclusion.

Table 1

Cognitive behavioral therapy trials using Oxford case definition for inclusion.

Table 2. Cognitive behavioral therapy trials using non-Oxford case definitions for inclusion.

Table 2

Cognitive behavioral therapy trials using non-Oxford case definitions for inclusion.

Function

Function was evaluated in six trials (n=932). Statistically significant between group improvement in measures of function were found with CBT in both trials using the Oxford (Sharpe, 1991) case definition (n=540)29, 30 and in two of the four other trials. (n=174).22-26 Of the two trials that found no improvement, one trial found worsening function in the usual care group with stable function in the CBT group (F=9.12, p=0.004),20 and one trial found no difference, n=153.28 We performed a meta-analysis of four trials that considered the 36-item Short Form (SF-36) physical function subscale (range 0-100) as an outcome (including one trial that used the Oxford [Sharpe, 1991] case definition) and found a trend toward improvement but no statistically significant difference (weighted mean difference [WMD] 10.46, 95% confidence interval [CI], -7.47 to 27.77, Figure 1). We repeated the meta-analysis excluding the single Oxford based trial and found similar results (WMD 9.16, 95% CI, -10.28 to 28.6). We also repeated the meta-analysis excluding one trial that was an outlier and this found benefit from CBT with a more precise point estimate (WMD 6.02, 95% CI, 1.05 to 10.99). Two trials, one based on Oxford and one on CDC (Fukuda, 1994) case definitions, used alternative measures of function. The Oxford based trial found benefit as measured by the Karnofsky Performance Scale (n=60),29 while the CDC based trial found worsening function in the control group using the Sickness Impact Profile 8-items (n=60).20

Figure 1 is a forest plot of 4 studies reporting the weighted mean differences in changes on the SF-36 physical functioning subscale for cognitive behavioral therapy versus controls. Data for Figure 1 are presented in Tables 1 and 2. This figure is described further on pages 3 and 4 as follows: “We performed a meta-analysis of four trials that considered the 36-item Short Form (SF-36) physical function subscale (range 0-100) as an outcome and found a trend toward improvement but no statistically significant difference (weighted mean difference [WMD] 10.46, 95% confidence interval [CI], -7.47 to 27.77, Figure 1). We repeated the meta-analysis excluding the single Oxford based trial and found similar results (WMD 9.16, 95% CI, -10.28 to 28.6). We also repeated the meta-analysis excluding one trial that was an outlier and this found benefit from cognitive behavioral therapy with a more precise point estimate (WMD 6.02, 95% CI, 1.05 to 10.99).”

Figure 1

Effects of cognitive behavioral therapies on physical function. Abbreviations: CI = confidence interval; N = sample size; SD = standard deviation.

Based on these results, the overall analyses of function outcomes, including the studies using Oxford (Sharpe, 1991) case definition inclusion criteria, provided low strength of evidence that CBT improves function. In removing the two Oxford case definition based studies, we are left with four fair-quality studies, two finding benefit (n=174), one finding no benefit (n=153), and one finding stable function in the CBT group but worsening function in the usual care group (n=65). Unlike the positive results of the Oxford based trials, the results of the trials fulfilling the CDC criteria are mixed and would provide insufficient evidence to determine the effectiveness of CBT on the outcome of function due to study limitations, inconsistency and imprecision of results.

Fatigue

Fatigue outcomes were evaluated in six trials (n=930), one of which used the Oxford (Sharpe, 1991) case definition for inclusion.30 Decreased fatigue was found in four (n=807), including the Oxford based trial30and three fair quality CDC based trials.22, 23, 28, 34 The overall analyses of fatigue outcomes, including the single study using Oxford case definition inclusion criteria, provided low strength of evidence that CBT improves fatigue. In removing the Oxford case definition based study, we are left with four fair-quality studies, three finding benefit (n=327) and one finding no benefit (n=65), and one poor-quality study finding no benefit (n=58). The results are generally consistent with the overall conclusion and would provide low strength of evidence that CBT improves fatigue.

Quality of Life

Three trials assessed quality of life (n=325) and all fulfilled the CDC (Fukuda, 1994) case definition.24-28 Two of three trials assessing quality of life did not find a benefit with CBT. The one trial that found an improvement with CBT was a small (n=58) poor-quality study,27 which leads to a low strength of evidence that quality of life is not impacted by CBT.

Employment

Four trials, one with Oxford inclusion criteria (n=932) evaluated employment outcomes based on the work and social adjustment scale.20, 22-26, 30 Two trials (n=540), one Oxford based (n=480) and one CDC based (n=60),22, 23, 30 found significant improvement for CBT compared with controls while two CDC based trials (n=179), found no benefit. Based on these results, there is insufficient evidence to determine the effect of CBT on the outcome of work impairment whether the study using the Oxford definition is included or excluded. There is inconsistency between the mixed results of the three CDC based trials and the positive results of the one Oxford based trial.

Global Improvement

Two trials (n=540), one with Oxford inclusion criteria, evaluated global improvement and found benefit with CBT providing low strength of evidence that CBT benefits global improvement22, 23, 30 By excluding the study that used the Oxford case definition, there would be insufficient evidence to determine the effectiveness of CBT on the outcome of global improvement although the results of the single CDC based trial are consistent with the Oxford based trial.

Counseling and Other Behavioral Therapies

Two of the seven trials comparing counseling and other behavioral therapies with another intervention or a control used the Oxford (Sharpe, 1991) case definition (Table 3),31, 38-40 while the others used criteria that ultimately fulfilled the CDC (Fukuda, 1994) case definition (Table 4.24-26, 32-37

Table 3. Counseling and other behavioral therapy trials using Oxford case definition for inclusion.

Table 3

Counseling and other behavioral therapy trials using Oxford case definition for inclusion.

Table 4. Counseling and other behavioral therapy trials using non-Oxford case definition for inclusion.

Table 4

Counseling and other behavioral therapy trials using non-Oxford case definition for inclusion.

Function

Of the six trials evaluating measures of function (n=725), two used the Oxford (Sharpe, 1991) case definition for inclusion and both did not find improvement in function, n=301.31, 38-40 Of the four trials fulfilling the CDC (Fukuda, 1994) case definition, two found benefit (n=283),24-26,33,35 and two found no benefit (n=141).32,36 Four of the trials considered the SF-36 physical function subscale as the outcome measure (Figure 2). Of these, none found statistically significant benefit. Two of the other trials (n=183), one comparing self-instruction with wait list control and one comparing cognitive therapy with anaerobic activity therapy or relaxation, found improvement in measures of function.24-26, 33, 35 Overall, the analyses including the trials based on the Oxford (Sharpe, 1991) case definition provides low strength of evidence that counseling and other behavioral therapies do not improve function compared with controls. By excluding the Oxford case definition based trials, we are left with two trials finding benefit (n=283) and two trials, including one poor-quality trial, finding no benefit (n=141), which would provide insufficient evidence to determine the effectiveness of counseling and other behavioral therapies on the outcome of function. The CDC based results are mixed and thus inconsistent with the Oxford based studies, which found no improvement.

Figure 2 is a forest plot of 4 studies reporting weighted mean differences in chages on the SF-36 physical functioning subscale for counsling vs. behavioral therapies. Data for Figure 2 are presented in Tables 3 and 4. This figure is described further on pages 7 and 8 as follows: “Four of the trials considered the SF-36 physical function subscale as the outcome measure. Of these, none found statistically significant benefit. Two of the other trials (n=183), one comparing self-instruction with wait list control and one comparing cognitive therapy with anaerobic activity therapy or relaxation, found improvement in measures of function.”

Figure 2

Effects of counseling therapies on physical function subscale of SF-36. * Therapy intended to change behavioral and belief factors that may trigger and maintain symptoms. † vs. all controls from study combined.

Fatigue

Of the six trials evaluating outcomes of fatigue (n=725), two trials used the Oxford case definition for inclusion with one poor-quality trial (n=44) finding benefit31 and one good-quality trial finding short but not long term benefit (n=257).38-40 Fatigue was improved in three of the other trials of which one was of poor-quality (n=30),32 one was of fair-quality (n=114)33, 35 and one was of good-quality (n=111).36 Overall, this provides low strength of evidence that measures of fatigue improve with counseling and other behavioral therapies compared with control groups. Considering only the four trials that used the CDC based criteria for inclusion, three trials found benefit (n=310), and one trial found no benefit (n=114), which would provide low strength of evidence that counseling and other behavioral interventions improve the outcome of fatigue. The CDC based results are consistent with the Oxford based results demonstrating improvement in fatigue up to 6 months.

Quality of Life

Quality of life was evaluated in two trials using criteria that fulfilled the CDC (Fukuda, 1994) case definition for inclusion. One found no improvement with cognitive therapy (n=114) and one found improvement with counseling compared with a wait list control (n=47).34 This provides insufficient evidence that counseling and other behavioral therapies improves quality of life.

Employment and Global Improvement

Measure of employment was evaluated in one CDC based trial (n=114) with no improvement found when comparing cognitive therapy with anaerobic therapy or relaxation.24-26 No study evaluated the outcome of global improvement. There is insufficient evidence to determine the effectiveness of counseling or other behavioral therapies on the outcomes of employment or global improvement.

Summary

The body of evidence on counseling and behavioral therapy is evenly split in number of subjects from studies that used the Oxford (Sharpe, 1991) case definition (n=841) and studies that used the CDC (Fukuda, 1994) case definition (n=843).

In the CBT evidence, more subjects were enrolled in Oxford based studies then CDC based studies (n=983 vs. n=722). In considering the overall results including our meta-analysis of studies using SF-36 physical function outcomes in combination with the two other studies that assessed function using alternative measures of function, we are left with a low strength of evidence that CBT improves function. When we remove both studies that used the Oxford (Sharpe, 1991) case definition for inclusion, we are left with four trials with mixed results (n=392) which would provide insufficient evidence of the effect of CBT on the outcome of function. There is inconsistency between results from the CDC based trials and the Oxford based trials. For the outcome of fatigue, the overall results included a greater number of participants enrolled in the four trials that found benefit (n=807, including the Oxford based trial) compared with the two trials that found no benefit (n=123) providing a low strength of evidence for benefit with CBT. By removing the single Oxford based study, we found consistent results with three fair-quality trials finding benefit (n=327), one fair-quality trial finding no benefit (n=65), and one poor-quality trial finding no benefit (n=58) which would provide a low strength of evidence that CBT improves outcomes of fatigue. The conclusions for effect on quality of life has changed from a low strength of evidence of benefit when considering all counseling and behavioral interventions to low strength of evidence that CBT provides no benefit in quality of life based solely on studies that fulfilled a CDC (Fukuda, 1994) case definition for inclusion. There would be insufficient evidence on the effect of CBT on employment outcomes when considering all trials as well as when excluding the single study that used the Oxford (Sharpe, 1991) case definition for inclusion criteria. The CDC based trials had mixed results whereas the Oxford based trial had positive results. The strength of evidence on global improvement is downgraded from moderate to low when considering CBT separately from other counseling and behavioral interventions based on two trials, one Oxford based and one CDC based, both finding benefit. It would be further downgraded to insufficient when considering only the one small study that fulfilled CDC based criteria for inclusion (1trial, n=60).

When considering counseling and behavioral interventions other than CBT, two studies were Oxford based (n=301) and five were CDC based (n=471). Although there is enough variability amongst the other techniques that a meta-analysis might be inappropriate, all involve supportive guidance aimed at improving coping strategies and reducing impact of one's disease state on overall well-being justifying the decision to consider these together as a group. Although CBT is a unique approach with disputable underlying rationale regarding the fear avoidance theory contributing to the perpetuation of symptoms in ME/CFS, it has similar aims of improving coping strategies and improving overall well-being. We considered this as justification for our original approach of combining all interventions when determining the overall strength of evidence of this body of literature. By separating these interventions from CBT, and considering the overall results, there is low strength of evidence that counseling and other behavioral therapies excluding CBT provide improvement in fatigue, low strength of evidence for no improvement in outcomes of function, and insufficient strength of evidence for all other outcomes (Table 5). By removing the Oxford based studies, there would be a low strength of evidence that counseling and other behavioral therapies excluding CBT reduce fatigue (4 trials, n=424) with the mixed results being consistent with the results of the Oxford based trials. There would be insufficient evidence for all other outcomes. On the outcome of function there is inconsistency between the mixed results of the CDC based and the negative results of the Oxford based trials.

Table 5. CBT and other behavioral therapies strength of evidence.

Table 5

CBT and other behavioral therapies strength of evidence.

Exercise Therapies

Six trials compared different forms of exercise therapy with control groups. Three trials used the Oxford (Sharpe, 1991) case definition for inclusion, all of which evaluated the effectiveness of graded exercise therapy (GET).12, 30, 41 Of the three trials using the CDC (Fukuda,1994) case definition, one trial evaluated the effectiveness of GET.42 The other two trials evaluated other exercise interventions and do not impact this addendum.43-45

Graded Exercise Therapy

Four trials evaluated the effectiveness of GET compared with a control group (n=656) (Table 6, Figures 3 and 4). Of these, three used the Oxford (Sharpe, 1991) case definition (n=607)12, 30, 41 while one small trial used the CDC (Fukuda, 1994) case definition (n=49).42 The results are consistent across trials with improvement in function, fatigue, and global improvement and provided moderate strength of evidence for improved function (4 trials, n=607) and global improvement (3 trials, n=539), low strength of evidence for reduced fatigue (4 trials, n=607) and decreased work impairment (1 trial, n=480), and insufficient evidence for improved quality of life (no trials) (Table 7). By excluding the three trials using the Oxford (Sharpe, 1991) case definition for inclusion, there would be insufficient evidence of the effectiveness of GET on any outcome (1 trial, n=49).

Table 6. Graded exercise therapy trials.

Table 6

Graded exercise therapy trials.

Figure 3 is a forest plot of 3 studies reporting the weighted mean differences in changes on the SF-36 physical functioning subscale for exercise versus controls. Data for Figure 3 are presented in Table 5. This figure is described further on page10 as follows: “The results are consistent across trials with improvement in function, fatigue, and global improvement.”

Figure 3

Graded exercise therapy effect on function. Abbreviations: CI = confidence interval; N = sample size; SD = standard deviation; SF-36 = 36-item Short Form Survey.

Figure 4 is a forest plot of 3 studies reporting improvement on the CGI for exercise versus controls. Data for Figure 4 are presented in Table 6. This figure is described further on page 10 as follows: “The results are consistent across trials with improvement in function, fatigue, and global improvement.”

Figure 4

Graded exercise therapy effect on global improvement. Abbreviations: CI = confidence interval; N = sample size.

Table 7. Graded exercise therapy strength of evidence.

Table 7

Graded exercise therapy strength of evidence.

Conclusions

Although future studies should refrain from using the Oxford (Sharpe, 1991) case definition as eligibility requirements, this early work provided a foundation on which future work can expand. This addendum has delineated differences in treatment effectiveness and harms according to case definitions, highlighting studies that used the Oxford (Sharpe, 1991) case definition and how these studies impacted our conclusions. Additionally, results of studies evaluating CBT have been considered independently from other counseling and behavioral therapies. Our sensitivity analysis would result in a downgrading of our strength of evidence on several outcomes which can be attributed to the decrease in power, dominance of one large trial, or lack of trials using criteria other than the Oxford (Sharpe, 1991) case definition for inclusion. Blatantly missing from this body of literature are trials evaluating effectiveness of interventions in the treatment of individuals meeting case definitions for ME or ME/CFS.

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