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Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome


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Across different medical fields, authors have placed a greater emphasis on the reporting of efficacy measures than harms in randomised controlled trials (RCTs), particularly of nonpharmacologic interventions. To rectify this situation, the Consolidated Standards of Reporting Trials (CONSORT) group and other researchers have issued guidance to improve the reporting of harms. Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT) based on increasing activity levels are often recommended for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, exercise-related physiological abnormalities have been documented in recent studies and high rates of adverse reactions to exercise have been recorded in a number of patient surveys. Fifty-one percent of survey respondents (range 28-82%, n=4338, 8 surveys) reported that GET worsened their health while 20% of respondents (range 7-38%, n=1808, 5 surveys) reported similar results for CBT. Using the CONSORT guidelines as a starting point, this paper identifies problems with the reporting of harms in previous RCTs and suggests potential strategies for improvement in the future. Issues involving the heterogeneity of subjects and interventions, tracking of adverse events, trial participants’ compliance to therapies, and measurement of harms using patient-oriented and objective outcome measures are discussed. The recently published PACE (Pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation) trial which explicitly aimed to assess “safety”, as well as effectiveness, is also analysed in detail. Healthcare professionals, researchers and patients need high quality data on harms to appropriately assess the risks versus benefits of CBT and GET.
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Reporting of Harms Associated with Graded Exercise Therapy and Cognitive
Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Tom Kindlon
Information Officer (voluntary position)
Irish ME/CFS Association
PO Box 3075, Dublin 2, Rep. of Ireland
Tel: +353-1-2350965
E-mail: or
Across different medical fields, authors have placed a greater emphasis on the reporting of
efficacy measures than harms in randomised controlled trials (RCTs), particularly of
nonpharmacologic interventions. To rectify this situation, the Consolidated Standards of
Reporting Trials (CONSORT) group and other researchers have issued guidance to improve the
reporting of harms. Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT)
based on increasing activity levels are often recommended for Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, exercise-related
physiological abnormalities have been documented in recent studies and high rates of adverse
reactions to exercise have been recorded in a number of patient surveys. Fifty-one percent of
survey respondents (range 28-82%, n=4338, 8 surveys) reported that GET worsened their health
while 20% of respondents (range 7-38%, n=1808, 5 surveys) reported similar results for CBT.
Using the CONSORT guidelines as a starting point, this paper identifies problems with the
reporting of harms in previous RCTs and suggests potential strategies for improvement in the
future. Issues involving the heterogeneity of subjects and interventions, tracking of adverse
events, trial participants’ compliance to therapies, and measurement of harms using patient-
oriented and objective outcome measures are discussed. The recently published PACE (Pacing,
graded activity, and cognitive behaviour therapy: a randomised evaluation) trial which explicitly
aimed to assess “safety”, as well as effectiveness, is also analysed in detail. Healthcare
professionals, researchers and patients need high quality data on harms to appropriately assess
the risks versus benefits of CBT and GET.
Reporting of Harms Associated with Graded Exercise Therapy and Cognitive
Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
1. Introduction
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is increasingly recognised as
an important worldwide health problem (1,2). Community-based epidemiological studies have
shown it is more prevalent than previously thought and that it affects people of all races and
socioeconomic groups (3-7). Illness intrusiveness is high with patients having poor health-
related quality of life (8,9). Given that average onset is at an age when people should be at their
most productive, its economic impact is substantial with total direct and indirect costs in the
USA estimated at 18.7 to 24 billion dollars annually (10-13). There is a lack of consensus on
many issues, including what causes the illness, what it should be called, how it should be
defined, and whether it is one condition or many (14-31).
One of the most contentious views in the field of ME/CFS is the suggestion that gradual increase
of activity or exercise will substantially improve or even reverse the condition (32-34).
Proponents of Graded Exercise Therapy (GET), Graded Activity Therapy (GAT), and Cognitive
Behavioural Therapy (CBT) programs which involve graded exercise/activity for ME/CFS often
point to the efficacy that has been reported in the literature (35-41). Prior studies suggest that
approximately 40% of those who received CBT experienced lower fatigue levels post-
intervention in contrast to 26% in usual care, while those receiving GET experienced both lower
fatigue levels as well as improved self-rated physical functioning. Although a small number of
trials have shown some benefits over the long term, most of the efficacy data are from trials that
did not involve long-term follow-up (35,36,42-45). Other non-pharmacological interventions
have also been proposed, with some showing efficacy in trials (46-53).
Although RCTs of CBT and GET have generally shown average improvements on the measures
reported (which is not the same as meaning no individual deteriorated on these measures), one
recently published randomised controlled trial (RCT) of a “[m]ultidisciplinary treatment
combining CBT, GET, and pharmacological treatment” found that, at 12 months, there was a
statistically significant decline in physical function compared to baseline when measured by the
Medical Outcomes Study Short-Form questionnaire (SF-36) physical function subscale and that
pain was significantly worse when measured by both the SF-36 bodily pain and the pain subscale
of the Stanford Health Assessment Questionnaire (HAQ) (54). There was also a statistically
significant increase in the total number of the following co-morbidities: fibromyalgia, sicca
syndrome, endometriosis/dysmenorrhea, dysthymia, thyroid dysfunction, multiple chemical
sensitivity, and irritable bowel syndrome.
Many patients, as well as some clinicians and researchers, disagree that CBT and GET should be
routinely recommended at this time believing, amongst other reasons, that safety issues have not
been properly addressed (55). Using a generic definition of “harms”, the harms associated with
GET (or CBT) could be defined as the “totality of possible adverse consequences of GET (or
CBT)” (56). Breau and colleagues constructed a more detailed definition when looking at harms
in the urological literature (57) that could also be applied: “any undesirable event that occurred
during the trial that had a deleterious impact on morbidity, mortality, quality of life or increase in
the use of resources. Harm could be a primary or secondary outcome and could also be referred
to as adverse event, side effect, complication, toxicity or safety.” The purpose of this paper is to
explore issues of safety for ME/CFS patients in regards to GET and the form of CBT that
involves scheduling increasing activity and/or exercise.
2. Exercise and the measurement of the effects of exercise programs
It is well recognised that exercise can have beneficial effects for many in society. Exercise is
recommended not only as an important component of maintaining good health and preventing
disease but also suggested as an adjunct treatment for a host of chronic medical conditions.
However, exercise can also cause harm (58). As Cooper and colleagues note (58), “like
pharmaceutical therapies, prescribing exercise as therapy, an activity that is gaining in
acceptance throughout the medical community, must be predicated on understanding the risks
and benefits of exercise as thoroughly as possible.”
Given the limited understanding of exercise pathophysiology in ME/CFS, it is difficult to
formulate a definition of safe and effective exercise that confers the benefits of being active
without causing harm. The effects of exercise in ME/CFS, although not fully understood, have
been examined in several studies. A number of physiological abnormalities have been detected
with exercise in individuals with ME/CFS (59,60), including metabolic disturbances, modified
gene expression, decreased cognitive reaction times, impaired cellular ion channel functions, and
immune dysfunction. For example, the Pacific Fatigue Laboratory, using the commonly accepted
American Medical Association disability guidelines, found that 48% of 203 CFS subjects would
be classified as moderately to severely impaired based on peak oxygen uptake (VO2 max) during
cardiopulmonary exercise testing (CPET) (61). Furthermore, even among those participants who
were not impaired or mildly impaired during initial testing, repeated testing 24 hours later
yielded, on average, a 22% decline in VO2 max (62). This is unique and significantly different
from other chronic diseases where VO2 max initially can be low but is reproducible on repeated
CPET (61).
In another study, Light and colleagues compared the effect of moderate exercise on patients with
CFS and controls (63). These investigators found that after the exercise, CFS patients showed
enhanced gene expression for receptors detecting muscle metabolites and for both the
sympathetic nervous and immune systems; many of these changes correlated with symptoms of
physical fatigue, mental fatigue, and pain. Given the range of abnormalities that have been found
with exercise in ME/CFS subjects, it would not be unexpected if programs encouraging
increased physical activity resulted in adverse reactions for some patients.
Indeed, observational studies have shown that physical exertion of various intensities can
provoke a diverse array of symptoms in ME/CFS such as fatigue, light-headedness,
muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness,
trembling/instability, insomnia, and sore throat/glands (64,65). These symptoms are not
uncommon and can last days, if not weeks, for some individuals (65). In 2006, an audit of adult
specialty ME/CFS rehabilitation (CBT/GET) clinics in Belgium (clinics that had been set up
following a request from the Minister of Social Affairs (66)) found that, compared to before
treatment, about one-third of participants reported worsening of their pain, concentration, and
sleep after CBT/GET (67,68).
It should be noted that randomised controlled trials (RCTs) of GET and CBT have tended to
assess fatigue primarily, so it is unclear whether other symptoms have regularly been
exacerbated in such trials. Furthermore, the instruments used to measure fatigue often suffer
from ceiling/floor effects so it is not possible to ascertain whether some participants experienced
a worsening of their fatigue (69-71). Moreover, factor analysis has shown that fatigue in
ME/CFS is multidimensional and so other scales, such as the ME/CFS Fatigue Types
Questionnaire (MFTQ), may be required to capture the different fatigue-related sensations and
symptoms experienced by patients with the condition (72).
3. Direct reports of adverse reactions by patients
3.1. The value of patients’ self-reported data
Generally, in medicine, the documentation of adverse reactions to pharmacologic and non-
pharmacologic treatments has almost entirely been based on reports from researchers and
clinicians. However, Basch has contended that an accurate portrait of patients’ subjective
experiences cannot be obtained from clinicians’ and researchers’ documentation alone: “A
substantial body of evidence [shows that] clinicians systematically downgrade the severity of
patients' symptoms, that patients' self-reports frequently capture side effects that clinicians miss,
and that clinicians' failure to note these symptoms results in the occurrence of preventable
adverse events” (73). Given this information, a system for reporting adverse events to treatments
would ideally involve the collection of data from patients as well as health care professionals.
3.2. Qualitative and quantitative data about harms from GET and CBT
Currently, assessing the harms of non-pharmacologic treatment relies mainly on anecdotal data
Discourse within the ME/CFS patient community is replete with reports of adverse reactions
from those who undertook exercise programs. Some members of the Irish ME/CFS Association
have reported not just temporary increases in ME/CFS symptoms but also long-term decreased
levels of functioning. This was explicitly recorded in a United Kingdom 25% ME Group survey
where the authors noted that some participants had made clear that they had not been severely
affected before undertaking a GET program (75). This was echoed in a subsequent survey by the
same group (76):
- "I participated in Graded Exercise therapy via the <name of a ME/CFS specialist unit>.
This lead to a relapse, at home, and made me unable to sit upright for 1 year due to
pressure in my head, and chest pain. I then relapsed and ended up in my local NHS
Hospital in a cardiac care unit."
- "Graded Exercise Therapy worsened me dramatically and I have no doubt had been a
large factor in my being severely affected after 20 years.”
- "I worked with a physiotherapist, who also had no experience of M.E. I began to
seriously deteriorate, and 4 months in, suffered a major relapse. I had a kind of
undiagnosed 'stroke', collapsed, and became incapable of looking after myself. When I
went to the hospital I could walk 100 yd., feed, wash and dress myself. When I left I could
not weight bear at all, had no leg muscles to speak of, and needed two people to transfer
me on and off the toilet and in and out of bed. I had little use of my hands and was totally
bed bound. I could not tolerate sitting upright against the pillows, conversation was
beyond me, and I could barely manage to feed myself by picking up food in my hands --
cutlery was out of the question. Nine years later I have improved, but I'm still bed bound.
One recently published study found that there was a trend for both CBT (p=0.088) and GET
(p=0.02) (received before diagnosis) to be risk factors for severe illness at follow-up (77). In
addition, the risk for a related modality, physiotherapy (p=0.0009), was significant at an α-
threshold of 0.0036. It is important to point out that this was a self-report retrospective survey,
rather than a prospective longitudinal study, and thus has similar limitations to other surveys, as
itemised in section 3.3. Also, the sample sizes were relatively small. Of those reporting therapies
before diagnosis, there were 415 individuals with mild illness and 84 with severe illness (at
follow-up); 18 mild cases and 8 severe cases reported using CBT while 23/11 and 35/20,
respectively, reported receiving GET and physiotherapy.
High rates of adverse reactions following GA/GE programs have consistently been reported in
large patient surveys in various countries over the last two decades (see Table 1) (75, 77-85).
Participants in these surveys were asked about the effect of GET and a myriad of treatment and
management strategies on their health. The data has been pooled in Table 2, with the mean of
worsening for GET/GAT and CBT respectively amounting to 51.24% (range: 28.1-82%) and
19.91% (7.1-38%) of subjects. The percentages of subjects adversely affected in Table 2 are not
low; in comparison, an average of 2.58% (of 5894) subjects reported that “pacing” worsened
their health.
3.3. Limitations of survey data
Some researchers have been dismissive of the survey results, contrasting them with what they
see as the safety that has been proven in RCTs and suggesting the discrepancy might be due to
improper implementation of GET outside of RCTs. Even if safety had been shown in RCTs,
which is debatable given there appears to be scope for improvement in the reporting of harms
(see sections 4 and 5), it has been observed in other medical domains that outcomes from routine
practice may be more relevant than the “artificial” environment of a clinical trial (86, 87).
Moreover, a subgroup analysis of a GET survey performed by Action for M.E./AYME and
published in 2008 (82) found that there was no statistically significant difference in the rate of
people saying they were made worse from engaging in GET under a “NHS specialist” (31.27%,
111/355) compared to the rest of those reporting such an outcome from GET in another scenario
(33.02%, 70/212).
Secondly, in eight of the surveys, categories of harm have been collapsed into single categories
such as “harmful”, “made worse”, “disimproved with treatment” and “deterioration”. In two of
the surveys, two levels of severity of the harms were available to respondents: “somewhat
worse” and “a lot worse”. Although it is somewhat unsatisfactory to not have more details about
adverse events, participant-rated clinical global impression (CGI) change scores, which use
similar language, have been used as both primary and secondary outcome measures in RCTs of
non-pharmacologic interventions for ME/CFS (44, 49, 88-92). The current survey data and CGI
change scores can be subject to recall and other biases as they are dependent on the participant
having an accurate memory of how they were overall before the therapy and making an accurate
global comparison.
Thirdly, survey respondents may not be representative of all who undertake CBT and GET,
resulting in either an over- or under-estimate of harm. People who have been harmed by GET or
CBT may be more inclined to fill in treatment surveys or join patient groups. Members of
ME/CFS patient groups may also satisfy more restrictive definitions for ME/CFS (which may
correspond with less response to GET/CBT), have been sick for a longer period of time (79, 85),
or be more severely affected. On the other hand, some of the most disabled subset of patients
may not be able to respond to the survey. People who actively seek out support organizations or
fill in surveys may have higher levels of general education (93, 94). Compared to the general
ME/CFS population, these individuals might be less likely to be harmed by a therapy not only
because of cautions about exercise and CBT/GET issued by patient groups but also because they
have the confidence to challenge prevailing ideas about treatment that do not seem to be working
for them.
Fourthly, there may be differences in the content of the therapies received. For example, the first
Cochrane Review of CBT for CFS distinguished between two forms of CBT offered (95):
“The way in which modification of thoughts, beliefs, rest, and activity was attempted was used
to delineate two 'types' of CBT. ‘Type A' attempted to increase activity and reduce rest time in
a systematic manner, independent of symptoms, towards 'normal' levels. 'Type B' attempted to
tailor the patient's rest and activity towards levels which were compatible with the limitations
imposed by the disorder. Therefore, type B CBT did not explicitly attempt to increase the
patient's physical or psychological capacity beyond improving their ability to 'cope' with their
Even within ‘type A’ and ‘type B’ protocols, as well as within GET programs, there can be
heterogeneity in the components of the interventions (e.g., when activity levels should be
decreased, maintained, or increased and by how much; the intensity of the exercise; the
frequency per week, etc.). Consequently, harms-related data from one study may not be fully
applicable to another. In an editorial on the reporting of psychological interventions in general,
Marks highlights how there can be many differences between programs that appear superficially
to be similar (96). Practitioners themselves can alter the program they offer over time. In a
manual published in 2006, the influential team at Radboud University Nijmegen Medical Center
described how their CFS program had changed from the one assessed in an earlier RCT (32,97).
The newer approach involved dividing patients up into two groups, the so-called “relatively
active” and “relatively passive”, and giving different advice to each group. The new protocol for
“relatively passive” patients was quite intense (32): "So, for example, the first day the patient has
six 1-minute walks, the second day six 2-minute walks, the third day six 3-minute walks, and so
on. The aim is a total build-up of 5 minutes a week for each walk a day.” The therapy usually
offered in the UK does not divide patients in this way (41). Exactly what constituted GET or
CBT for each survey respondent was not made explicit. It would have been ideal if we had data
available on the activity/exercise performed by each survey participant; however, as discussed
later in Section 5.4, even data taken from RCTs has generally been of a poor quality in terms of
measuring the actual activity. These differences in focus, type, and execution of GET and CBT
might at least partly explain the wide range of means in Table 2.
Differences in the content of interventions may also explain the large difference in the rate of
harms reported between GET and CBT. So, for example, some therapists may employ the
aforementioned “type B” CBT which does not involve scheduling graded increases in activity.
Also, at least one set of authors have pointed out that many clinicians using CBT principles in
practice “add a host of interventions that are not specific for CBT” (98), for example measures
“target[ing] pain, sleep problems and emotional distress [...] stress management techniques,
experiential group discussions, family support and so on (see e.g. 99 [i.e. Pardaens et al.,
2006]).” Due to there being effectively more interventions involved in the CBT, participants may
focus less on exercise/activity between sessions.
Finally, there may be possible problems with pooling data in this way since there might be some
overlap among surveys (i.e. an individual filled in more than one survey) and since there was
inconsistent wording across surveys. However, looking at absolute figures, if one were to just
combine one of the UK surveys (80) with the Norwegian-language study from Norway that was
published 8 years later (84), there is likely to be very little, if any, overlap. Between the two
surveys, approximately 1100 respondents reported being made worse by a graded exercise
Despite these reservations, the consistently high rates and absolute numbers of adverse reactions
coupled with the potentially disabling effects of GET and CBT reported in these surveys are
concerning and need to be investigated more thoroughly.
4. Guidelines for the reporting of RCTs and application to ME/CFS RCTs
4.1. CONSORT randomized controlled trials statements
The CONSORT (Consolidated Standards of Reporting Trials) Group is an international
organization of experts in the methodology of clinical trials that was formed in 1993 due to
concerns regarding inadequate reporting of RCTs. The Group created a 25-item checklist (100)
of essential points that should be included in all publications of RCTs to “enabl[e] readers to
understand a trial's design, conduct, analysis and interpretation, and to assess the validity of its
results.” (101) Specific suggestions from the CONSORT statement include sufficiently detailed
interventions such that it is able to be replicated by other researchers, blinding of participants and
researchers as appropriate, and tracking participant withdrawals. CONSORT is endorsed by over
50% of the core medical journals listed in the Abridged Index Medicus on PubMed (102).
Since publication of the initial CONSORT guidelines, extensions for specific areas have been
prepared, e.g. for acupuncture interventions (103,104) and, more recently, for non-
pharmacologic treatment interventions (105). Reporting in general has been shown to improve
since the publication of CONSORT guidelines with some reviews demonstrating improvements
in particular areas such as weight loss intervention studies and acupuncture (106-109).
4.2. Poor reporting of harms in RCTs, particularly for non-pharmacological interventions
Evidence across various medical domains suggests the reporting of harms in clinical trials has
been especially inadequate and receives less attention than efficacy outcomes (110-113). As one
group of authors noted, “Reporting harms may cause more trouble and discredit than the fame
and glory associated with successful reporting of benefits” (114). Breau also observed that, in
general, “[t]rialists may not evaluate adverse outcomes because they believe the safety of the
intervention has already been established. However, this assumption is often invalid since the
adverse effects of an intervention may differ depending on the indication or population subjected
to treatment” (57).
To help remedy this, the CONSORT group issued a statement extension in 2004 focusing on
harms (56). This extension consisted of a 22-item checklist that researchers should consider in
the process of designing, carrying out, and publishing their studies. The checklist includes
“clarify[ing] how harms-related information was collected”, “list[ing] addressed adverse events
with definitions for each”, and “describ[ing] for each arm the participant withdrawals that are
due to harms and their experiences with the allocated treatment” (56).
Harms reporting for nonpharmacologic RCTs is generally inferior to that for pharmacologic
RCTs. A study focusing on the reporting of harm in RCTs of mental health interventions found
that no report of nonpharmacologic treatment trials adequately reported harms (115). Another
group of researchers compared the reporting of harm in pharmacologic (n=119) and non-
pharmacologic (n=74) RCTs of treatments for rheumatic disease (74). Pharmacologic treatment
reports included information related to harms more often than nonpharmacologic treatment
reports. This information consisted of collection methods, blinded assessment, reporting of
adverse events, causal relationship between the treatment and adverse events, withdrawals due to
the events, and severity of the events. A greater proportion of the space in the results section was
allocated to harms in pharmacologic than nonpharmacologic treatment reports. These differences
remained with adjustment for sample size, medical area, funding, and multicenter trials. Fewer
than half of the nonpharmacologic treatment trials assessed reported any harm-related data at all.
The authors commented (74):
“Presupposed lower toxicity profiles of nonpharmacologic treatment, such as exercise
therapy, complementary and alternative medicine, and behavioral interventions, could
explain a lower interest in the evaluation of adverse events. However, most therapy entails the
risk for adverse events, including serious events.”
The aforementioned CONSORT statements provide a framework against which to evaluate the
quality of RCTs. Reporting of harms from trials of nonpharmacologic trials should be as
systematic as the reporting recommended for pharmacologic trials.
4.3 Quality of reporting of harms in ME/CFS RCTs
RCTs of CBT and GET for CFS have been found lacking in their reporting of harms by the
Cochrane Collaboration, a multinational independent network of medical professionals,
researchers, and policymakers. For all five RCTs of GET that the Collaboration examined in
2004, no data for adverse effects was documented in any of the trials (36). However, the
CONSORT statement on harms (56) notes that “it is important to report participants who are
non-adherent or lost to follow-up because their actions may reflect their inability to tolerate the
intervention.” Perhaps this may partially explain the finding of a trend for a higher dropout rate
in GET as compared to the control group in the studies assessed in the Cochrane review
(Analysis 1.3). Thus the Cochrane reviewers concluded that (36) “studies of higher quality are
needed that involve different patient groups and settings, and that measure additional outcomes
such as adverse effects, quality of life and cost effectiveness over longer periods of time.”
The Collaboration similarly reviewed RCTs of CBT for CFS in 2000 (95) and performed an
update in 2008 (35). Out of 14 separate RCTs examined, only one had any data to assess patient
acceptability and none of the studies had good quality data related to adverse effects. In the
“Selective outcome reporting” subsection of “Risk of bias in included studies”, the Collaboration
authors wrote (35): “Whilst Lloyd 1993 collected data concerning the adverse effects of DLE
injection, data referring to adverse effects of psychological treatment was not systematically
presented by any study.” Drop-out rates averaged 16% across studies but definitions for what
constituted “drop-outs” varied and reasons for attrition were not detailed; a third of the studies
had drop-out rates over 20%. The authors finished by asserting that future studies should
incorporate data on adverse effects and acceptability among other outcome measures.
In 2006, a systematic review by Chambers and colleagues of the same set of GET trials and most
of the same CBT studies echoed similar concerns (38), “There is limited evidence about adverse
effects associated with behavioural interventions. Withdrawals from treatment in RCTs suggest
that there may be an issue but the evidence is often difficult to interpret because of poor
5. Considerations for future research
5.1 Recognize heterogeneity of patients with a diagnosis of ME/CFS
A complication in the ME/CFS field is the heterogeneity of patients who might have the
diagnosis of ME or CFS (22,31). Interventions such as GET and CBT may be associated with
lower rates of harms for some groups of patients but with much higher risks for others. Indeed,
the authors of one recent paper recommend that some patients should not participate in GET at
all: “the use of GET in the management of CFS is in serious doubt, and there stands a need to
develop a method of identifying which patients respond poorly to physical exercise and should
be advised to avoid GET” (116).
The various diagnostic criteria for ME and CFS may pick out groups of patients with different
symptomatology, functional impairment and psychiatric comorbidity (117-119). Some criteria
require post-exertional symptoms (23,24,29,30,31); others take a polythetic approach where such
symptoms are optional (25,26). At least one set of criteria do not mention them at all and could
be described as criteria for chronic fatigue (27). There are wide variations in the prevalence rates
for CFS depending on how it is defined. Population studies in the US using the Fukuda criteria
give estimates of 0.2-0.4% (6,7) while the figure for the empiric criteria is 2.5% (28,120). It is
clear from these figures that whether somebody is classified as having CFS largely depends on
the criteria used.
Given that fatigue, cognitive dysfunction and sleep problems can be part of depressive disorders
(121), some fear that some patients who satisfy criteria that do not specify post-exertional
symptoms may have primary depression (122-124). A model that is the basis for CBT trials was
found to adequately represent chronic fatigue secondary to psychiatric conditions but not CFS
(125,126). Moreover, it has been shown that satisfying the Fukuda CFS criteria (25) was the
most powerful predictor of poor response to either GET or CBT in those with fatigue (127).
Investigators may add specific criteria that may affect the generalisability of results. For
example, one study testing GET for CFS excluded those with “appreciable sleep disturbance”
problems (88) despite the fact that in the region of 90% of those with CFS have such symptoms
with sleep (128,129).
More severely affected patients have often been excluded from trials for ME/CFS. Indeed, a
review reported that "No severely affected patients were included in the studies of GET”, adding
that “the balance between effectiveness and adverse effects of interventions may be different in
more severely affected compared with less severely affected” (38). Some clinicians employ this
factor in their practice, giving different recommendations based on severity. Ho-Yen stated that
he does “not recommend an emphasis on greater activity until a patient feels 80% normal” (130)
while Lerner “prohibits” exercise (131,132) until CFS patients score 7 on his Energy Index Point
Score [meaning a person who does not need to nap during the day, is up from 7AM to 9PM, can
work a sedentary 40-hr/ week job, and do light house-keeping] saying “if you exercise before
that you're going to go backwards" (133).
Some researchers have examined whether certain biological markers might predict the efficacy
of CBT/ GET. Roberts and colleagues found that hypocortisolism predicted a poor response to a
CBT program designed to increase activity levels (134). These results are consistent with
findings reported by Jason and colleagues (135) who found, in a study of four non-
pharmacologic interventions (including CBT and an exercise program), that those with abnormal
baseline cortisol did not improve over time. In a follow-up paper (136), it was reported that
baseline measures including immune function, activity levels, sleep status and past psychiatric
diagnosis significantly differentiated those participants who demonstrated positive change over
time from those who did not. CFS subjects with a dominance of the Type 2 over the Type 1
immune response, as indicated by the patterns of lymphocyte subset distributions, did not
improve over time.
“At risk groups” may not be clearly defined by single variables so multivariate analyses may be
required. A recent exploratory study using latent class regression (LCR) explored the Chalder
Fatigue Questionnaire outcome data from 236 CFS patients as defined by the Oxford criteria (27)
who had received CBT at a specialist CFS clinic in the UK (137). It found that participants could
be divided into 4 classes with one class predicting a poor response to CBT outcomes. We were
not given data on all 38 possible predictors but this class was characterised by more frequent
weight fluctuation, physical shakiness and pain, and had higher anxiety and symptom focusing
scores compared to the other classes (137).
Given how frequently increased physical activity is recommended in healthcare settings, there
should be an added impetus to characterise those who might be at increased risk of harm from
following such recommendations.
5.2. Make detailed instructions of interventions easily accessible
The CONSORT statement on the reporting of RCTs (100) suggests that researchers describe "the
interventions for each group with sufficient details to allow replication, including how and when
they were actually administered." The CONSORT Extension for Trials Assessing
Nonpharmacologic Treatments re-emphasises this (105):
“authors [should] allow interested readers to access the materials they used to standardize
the interventions, either by including a Web appendix with their article or a link to a stable
Web site. Such materials include written manuals, specific guidelines, and materials used to
train care providers to uniformly deliver the intervention.”
Such materials have often not been available when RCTs have been published in the ME/CFS
field. Consequently the programs offered in clinical practice may not be the same as those
assessed in clinical trials and may have different rates of harms associated with them.
As alluded to in section 3.3, Marks has highlighted how there can be many differences between
psychological interventions that can appear superficially to be similar (96). Manuals can be long
and detailed so it can be useful if investigators can summarise the active components of
interventions and contrast them with other therapies being assessed. One example of this is
exemplified in Table 1 (“Shared and distinct activities among treatment groups”) of the Jason et
al. (2007) trial of four non-pharmacologic interventions for CFS (49).
If intervention details are not present, it can be difficult for readers and reviewers to classify
therapies correctly. In the PACE Trial, the GET intervention was guided by the principle that,
“[p]lanned physical activity and not symptoms are used to determine what the participant does”
(33); similarly “[i]t is their planned physical activity, and not their symptoms, that determine
what they are asked to do”(33). In contrast, in adaptive pacing therapy, “activity is planned and
then modified in the light of its effect on symptoms"(33). If one looks at the exercise
prescription used in the Wallman et al. (91,138) study from Australia, it appears perhaps more
like the latter program: “on days when symptoms are worse, patients should either shorten the
session to a time they consider manageable or, if feeling particularly unwell, abandon the session
altogether” (138). Given the low rate of harms reported in the survey data for pacing in contrast
to GET (Table 2), it may be that interventions that involve the principles of pacing may have
lower rates of harms associated with them and should be analysed separately in reviews.
5.3 Develop a system to track adverse effects
Some GET and CBT studies have included general statements, like “no adverse event
attributable to CBT was reported”, or have simply counted the number of subjects who did not
complete a study with scant details (35,38). CONSORT regards “using generic or vague
statements” as insufficient reporting so both they and others have suggested several strategies to
counter this practice (56, 74, 139).
Researchers should state in the study methods section why harms data were omitted if no data
was collected. For those studies where it will be collected, researchers should contemplate
setting up a system before study initiation to systematically track adverse effects as passive
surveillance of harms (i.e. spontaneous reporting) leads to fewer recorded adverse events than
active surveillance (140). Different methods of ascertainment can produce different reporting
incidences. For example, one study found that patient diaries yielded higher rates of Adverse
Drug Reactions (ADRs) than other forms of assessment (113). Open-ended questions may yield
different information, both quantitatively and qualitatively, than structured questionnaires (141).
If the latter are used, researchers should ideally be ready to make the questionnaire accessible
and to explain why it was selected or how it was constructed.
Pooling of data from various studies is often required to investigate signals of adverse events.
Abstracts should contain the existence of harms-related data (including no adverse events) to
help facilitate appropriate database indexing and information retrieval.
Investigators should also consider: defining adverse events; recording the
nature/frequency/severity of events (and the definition used to define severity); noting whether
an event led to subject withdrawal; stating whether harms appraisement was done blindly and its
timing; making explicit the rationale behind whether or not to attribute an event to an
intervention, and noting who did the attribution. Only if such detailed data collection is
attempted can a complete picture emerge of the benefits versus risks of proposed interventions.
5.4 Monitor intervention implementation and compliance using objective measures of activity
The CONSORT extension for RCTs of non-pharmacological interventions suggests that “details
of the experimental treatment and comparator as they were implemented” be reported. One
example given is of an exercise intervention where not only the mean sessions of exercise
attended by participants are noted but also the minutes exercised (105). The rationale behind this
suggestion is to demonstrate that the interventions are reproducible and were carried out as
intended, without contamination of treatment either by research staff treating participants
unequally and/or with different/ additional unintended protocols or by participants choosing to
treat themselves differently. Furthermore, it has long been recognised that adherence to
medication regimens can be poor; objective tools such as Medication Event Monitoring System
(MEMS) devices have shown that self-reported measures tend to inflate reports of compliance
(142-5). Without data on implementation and adherence, claims that an intervention is safe are
There are reasons to believe that compliance to interventions might be problematic. The
distinction between an exercise program and a Graded Exercise (GE)/ Graded Activity (GA)
program for CFS is that, for the latter, a participant is not supposed to decrease exercise (or
activity) levels based on his or her symptoms. As a GET expert described, "if [after increasing
the intensity or duration of exercise] there has been an increase in symptoms, or any other
adverse effects, they should stay at their current level of exercise for a further week or two, until
the symptoms are back to their previous levels" (146). One has to wonder how many patients
would dutifully comply with counterintuitive instructions to maintain a higher activity level for
7-14 days in the face of new or worsening symptoms. If participants did comply, their level of
activity on completion should increase substantially; however, a review of three studies using
objective measures found only a small increase in total activity levels at assessment subsequent
to treatment, and a similar level of increase was recorded in those who had undertaken no
intervention (147).
Another reason that some might feel measuring compliance is important is that some researchers
have hypothesised that personality factors such as higher “action proneness” (“the extent to
which one is oriented toward direct action and achievement”) might make people vulnerable to
ME/CFS (148,149). Theoretically, this might affect proper adherence to programs with high
“action prone” individuals potentially being more likely to increase activities or exercise
prematurely, leading to exertional symptoms. However, these personality studies were
retrospective, performed after subjects were ill, and thus are subject to recall bias. Additionally,
when the same team actually recorded “action-proneness” levels, using the "Vragenlijst voor
Habituele Actiebereidheid" (Questionnaire for Habitual Action-proneness) (HAB), they found a
score of 17.75 (SD6.21) and 20.23 (SD4.65) in CFS patients before and after a multidisciplinary
group treatment respectively (150). Both these sets of scores are lower than the Dutch norm of a
mean of 29.4 (SD6.5), derived from 316 industrial workers (148). It is thus unclear whether
people with CFS should be seen as having high “action-proneness” or not after they become ill.
It is also unclear whether being “action-prone” would lead to more or fewer adverse reactions
from activity programs: people who are “action prone” might in fact be more compliant with
treatment than the average subject if their interpretation of “action” or “achievement” is to
adhere to therapist recommendations. Nevertheless, for some, given possible concerns about the
theoretical effect of personality factors on compliance, this might be a sufficient reason to seek to
measure the activity that was actually performed.
In general, implementation of Graded Exercise (GE) or Graded Activity (GA) programs by
therapists and adherence to them by patients has not been rigorously assessed. No RCT of such a
therapy for ME/CFS, to my knowledge, has measured the intervention using objective measures
of activity. Some trials have employed participant self-report of activity but several studies have
found that activity questionnaires do not correspond well with objective measures (151-153). As
one set of researchers explained, "the subjective instruments do not measure actual behaviour.
Responses on these instruments appear to be an expression of the patients' views about activity
and may be biased by cognitions concerning illness and disability" (152). In fact, non-ME/CFS
exercise studies have shown that activity interventions can influence participants to overestimate
physical activity when compared to objective measures (154-7). This seems particularly relevant
in the context of GET and GET-based CBT which are designed to change patients’ attitudes
about activity.
Documenting the type of, intensity of, and frequency of exercise/activity sessions in GE/GA
programs is also needed. When assessing the safety of pharmaceuticals, dosage is important: a
drug may be safe at one dosage but quite dangerous at a higher dosage. There seems to be no
reason to view GE and GA differently. For example, a pilot study by Meyer et al. of high- and
low-intensity exercise for fibromyalgia, a condition that has considerable overlap in
symptomatology with ME/CFS (158,159), required participants to complete and post weekly
activity logs (160). An examination of the returns found very poor compliance with the assigned
exercise programs, leading the researchers to reassign participants to the high- and low- intensity
groups based on the actual activity levels recorded in their logs. Interestingly they found that
there was a difference (p<0.05) between the groups on the Fibromyalgia Impact Questionnaire,
with scores improving from baseline in the low-intensity exercise group but deteriorating in
those who had performed high intensity exercise.
Assessments of the effects of activity in ME/CFS as discussed in Section 2 may involve higher
levels of activity than the intensity of activity and exercise in some GET and CBT programs
(161-172). However, a gentle walking test, where participants with CFS covered on average
558m (0.35 miles) at a reported average speed of 0.9m/s (2 miles/hour), resulted in a statistically
significant worsening of fatigue, pain, sore throat, and general health perception (64). Moreover,
when Van Oosterwijck et al. (2010) assessed a short, self-paced and physiologically limited
exercise bout lasting just 5 minutes on average at a mean workload of only 46 Watts, there was a
worsening of the ME⁄CFS symptom complex post-exercise (173). Given the problems
individuals with ME/CFS have experienced with aerobic programs, one set of clinicians have
suggested exercise needs to be performed at below the anaerobic threshold (174). To be able to
satisfactorily assess any differences in adverse events or outcomes between various programs,
investigators need to collect good information on the activity or exercise performed.
Beyond merely showing compliance with interventions, objective measures can also test the
claims that CBT and GET have been shown to lead to recovery in CFS (175,176) indeed that
recovery should be seen as an achievable goal in months rather than years (177). However, since
we do not have data on patients attempting a normal level of activity in a ME/CFS trial, we do
not know the level of risk associated with patients attempting to achieve such a level of activity.
Given the ceiling of activity (178) that has been recorded in ME/CFS, higher levels of adverse
reactions seem possible at or close to this “dosage” of activity or exercise.
Good quality compliance data could help answer many questions. With non-pharmacologic
interventions such as GET and CBT, objective measures of activity, through use of devices such
as actometers or pedometers, should be utilized to confirm compliance and to assess any increase
that was achieved, e.g. the percentage increase in activity in comparison to baseline levels. There
should be careful documentation of sessions attended as well as type, duration, frequency, and
intensity of activity.
5.5 Evaluate for harms using objective measures
In pharmacologic trials, subjects are monitored for harm not only through interviews, patient
questionnaires, and clinical examinations but also with objective measures such as blood tests
assessing kidney function, liver metabolism, or any other anticipated adverse effects of the
medication. Non-pharmacologic interventions in contexts outside of ME/CFS are also monitored
similarly. During supervised exercise post-heart surgery, healthcare staff ask patients if they have
symptoms such as shortness of breath or chest pain (possible signs of the heart not receiving
adequate oxygen), take patients’ blood pressure/ heart rate regularly, and observe for abnormal
heart rhythms using portable monitors. If symptoms occur or abnormalities are seen, staff might
ask patients to stop exercising or decrease the intensity/ duration of exercise.
The effects of exercise on ME/CFS are not yet fully elucidated to the degree it is in coronary
heart disease but there are existing objective measures that that have been utilized to document
symptoms experienced by ME/CFS subjects with exercise. Aside from using repeated
cardiopulmonary exercise testing to measure fatigue/ energy metabolism as mentioned in section
2, standardized tests such as the CalCap reaction time component and the Stroop Word/Color
Test could be used to monitor for any deterioration in cognitive function (171,179).
Polysomnography could be used to examine changes in sleep patterns. Serum cytokine measures
are another possible avenue to monitor exercise effects: Light recently showed that post-exercise
symptoms (mental fatigue, physical fatigue, pain) in ME/CFS subjects were correlated with
persistently high levels of certain cytokines compared to healthy controls (60). Furthermore, in a
small subset of patients who developed CFS after documented infection with parvovirus B-19
and subsequently treated with intravenous immunoglobulin, Kerr and colleagues
demonstrated that recovery from CFS symptoms including post-exertional malaise correlated
strongly with normalization of cytokine levels (180).
Researchers should consider utilizing these or exploring other objective measures. If specific
objective measures correlating with exercise/ activity-associated symptoms are established, these
could be monitored to determine the intensity, frequency, type, or duration of activity that could
be safely tolerated by an individual with ME/CFS and customized treatment plans could be
5.6 Measure non-physical harms / patient-oriented outcomes pertaining to quality of life
Aside from any possible "direct" biological harm from increased activity/exercise, other
"indirect" harms, such as psychological, social, and economic harms (181), are also possible.
The magnitude of a harm can be judged by the effect it has on someone's ability to pursue life
goals and the duration of this interference (182). A distinction can be made between interfering
with minor (e.g. visit a museum, meet friends, vacation, etc.) and major (e.g. attend school,
work, have children, etc.) life goals. GET and GA-based CBT programs involve large
commitments of time and energy which might interfere with the pursuit of both minor and major
life goals by some participants. Given the post-exertional symptoms that are part of ME/CFS
(59,183), effects may not just be experienced during the activity sessions and since such
programs may not involve an increase in total activity levels, other activities are presumably
being substituted for (184). This could put a strain on individuals with ME/CFS in terms of their
ability to perform other roles, like employee, student, partner, and/or parent.
Even if eventually an increased total activity level was achieved, there is likely to be a transitory
period where a reduced amount of time and energy is available for other aspects of one’s life.
This could potentially lead to increased social isolation and, in particular, the break-down of
relationships (i.e. have a long-term, rather than just temporary, effect). Outside the ME/CFS
arena, it has been recognised that psychosocial treatments can have negative effects on family
functioning (185).
In terms of education, a student's academic performance could suffer due to the cognitive
problems which can occur post-exercise (171,179): they might underperform or fail exams, or
simply fall too far behind and drop out.
In the employment realm, an employee might lose their job because an employer was not
satisfied with their performance. In Belgium, an audit of five rehabilitation centres for CFS that
involved CBT and GET (66-68) found that the average hours working decreased at conclusion
and at follow-up six months later compared to the start. In addition, more people (10%)
decreased the number of hours they worked than increased (6%). In fact, when one notes that
only 27% were employed before the program, it means 37% (=10/27) of the participants
decreased how much they worked (which would have included stopping). A Dutch study of CBT
reported better results, with the number of hours worked increasing from a mean (median) of 9.4
(0) hours to 11.4 (0) hours (186). No data was available on the number of people whose hours
worked had decreased; however, the mean (median) number of contract hours (cf. hours actually
worked) decreased from 16.2 (10) hours to 14.9 (7) hours.
So, even if it were the case that there were no biological harms associated with GET and CBT,
individuals with ME/CFS or their physicians could believe that the potential for these secondary
or indirect harms might mean that the treatment is not suitable for a specific individual at a
particular time.
As is often the case when harms are being recorded, specific checklists may need to be
developed that assess some iatrogenic effects – in this case non-biological harms. Spontaneous
reporting of harms may not pick up some unintended consequences. Additionally, a greater use
could be made of patient-oriented outcome measures. Some might claim that the SF-36
questionnaire (187) would be suitable. However, criticisms have been made that it covers few
fields of functional limitation and that several questions cover the same field (two items on
“stairs” and three items on “walking”) (188). These five questions make up 50% of the physical
functioning subscale which is sometimes used on its own in ME/CFS trials. Given the nature of
GE/GA/CBT programs, this may not be a suitable tool to measure functional impairment when
assessing such interventions.
ME/CFS studies have found apparent improvements using this subscale without any actual
increase in total physical activity (184,189) or a difference with the control group on this
instrument was recorded despite no difference in actigraphy (147,190-192). A similar
phenomenon has been observed with fatigue scales where an improvement in (self-reported)
fatigue scores did not correspond with increased activity (147,184,189,192). Indeed, a recent
systematic review of patient-reported outcome measures (PROMs) confirmed that the quality
and acceptability of those that have been used in ME/CFS studies as “limited ... [as] [c]lear
discrepancies exist between what is measured in research and how patients define their
experience of CFS/ME. Future PROM development/evaluation must seek to involve patients
more collaboratively to measure outcomes of importance using relevant and credible methods of
5.7 Follow subjects for a longer period post-intervention
Only one study of CBT was recorded by the Cochrane Collaboration as having a follow-up of
over 1 year – it involved just 53 patients (35). Similarly, among GET trials reviewed by the same
group, the longest period of follow-up was 1 year post-intervention, leaving the authors to
comment that there is a need for more long-term follow-up data from GET studies (36).
As was pointed out in subsection 5.4., a ceiling of activity appears to exist for at least some
ME/CFS patients (178). During a trial, an individual may be able to increase the quantity or
intensity of exercise up to a certain level without experiencing significant adverse effects,
particularly if they are substituting this activity for other activities in their lives (184). However,
one cannot necessarily extrapolate from such data that patients can use the same program to
safely work their way up to a normal, or pre-ME/CFS, level of functioning, because of the
ceiling of activity nor that, post-study, they will be able to maintain gains. This point was
illustrated in a case study of a graded activity intervention (192):
"[T]his patient largely overcame his initially reported fear of triggering symptom
exacerbations. Yet his concern about exceeding the maximum prescribed weight lifting
levels appeared to be realistic because scheduled attempts to exceed these levels
consistently triggered symptom flare-ups. In addition, the work-related 4-week relapse
revealed an apparent upper limit on his ability to work. This suggests that eradication of a
fear-based activity avoidance will facilitate functional improvements up to a point, beyond
which a more biologically based mechanism of symptom generation may be involved."
With harms from some pharmaceutical treatments, some adverse reactions may only occur
following a certain number of “doses” of the treatment or take a relatively long period to
manifest. Similarly, given some of the mechanisms through which exercise might cause harm in
ME/CFS (59,194,195), adverse reactions may not become apparent with short-term treatment or
follow-up. Since the full recovery rate from ME/CFS, in general, is 5% over a decade (196),
many patients have been ill for longer than 5 years (79,85), and ME/CFS is known to be a
remitting-relapsing condition (197), it would behove researchers investigating this condition to
design studies with longer term follow-up (38).
5.8 Check for clustering/therapist effects
Therapist effects could be assessed to see whether certain types of results, whether positive or
negative, cluster with specific centres or therapists (198). If, for example, a particular
intervention were associated with a low rate of significant harms with all therapists except one
individual, that might suggest an intervention had less potential for harm than if the effect were
more uniform. Alternatively, if a significant rate of harms were recorded with most of the
therapists except a small number or those in a particular centre, interesting information might be
able to be gleaned from investigating how the treatments were executed differently. However,
the importance of the issue for GET and GA-based CBT for ME/CFS is uncertain. One recent
paper reviewed the results of 374 CFS patients who received CBT with 12 therapists (3 clinical
psychologists and 9 nurses with specialist CBT training) (199). The variance explained by
therapists, when demographic covariates were accounted for, was 0% for fatigue and under 2%
for disability. A review of therapist effects in general found that manualized therapies tend to
produce smaller therapist effects (200).
5.9 Interpret results of studies taking into account previous studies
Discussion sections should place trial results within the context of prior and current ongoing
research. CONSORT suggests that “[i]nterpretation [be] consistent with results, balancing
benefits and harms, and [that] other relevant evidence”, including that which does not support the
study the paper is based on, should be considered (100). Furthermore, researchers are
encouraged to “contrast the results on harm…with observational data from spontaneous
reporting, automated databases, case-control studies, and case reports” (56). The qualitative and
quantitative harms data presented in Section 3 of this paper have existed for several years yet has
rarely been mentioned in prior CBT or GET trials. RCTs play an important role in medical
research, but their results should not be overemphasized to the exclusion of basic research and
other clinical studies that may offer pertinent evidence to advance the field.
6. PACE Trial A model of excellence in harms reporting?
Within a week of receiving initial comments about this paper from reviewers, the Lancet
published the PACE Trial, a multi-centered randomised trial in the United Kingdom comparing
specialist medical care (SMC), GET+SMC (hereafter GET), CBT+SMC (hereafter CBT), and
SMC combined with a form of adaptive pacing therapy (APT) (hereafter APT) as treatment for
ME/CFS (90). The form of CBT evaluated in PACE aimed to “change the behavioural and
cognitive factors assumed to be responsible for perpetuation of the participant’s symptoms and
disability” based on the “fear avoidance theory of CFS”; this included “making collaboratively
planned gradual increases in both physical and mental activity” (90). The trial set out to not only
assess efficacy but also look at harms with outcome measures in the protocol paper designated as
“efficacy measures” or “adverse outcomes”.
The PACE Trial brought the reporting of harms in trials of non-pharmacologic interventions in
the field of ME/CFS to a new standard: compared to prior GET/ CBT studies, the PACE
researchers made available their interventions and protocols online and in published resources,
put forth some effort to establish a system of tracking adverse effects, and provided greater detail
about serious adverse events and reactions (SAEs and SARs). This transparency of PACE
researchers is to be praised and allows researchers to understand, evaluate, and replicate the trial
prudently. However, there remain some concerns about how harms data were collected,
interpreted, and reported and many of the considerations delineated in Section 5 could still be
applied to PACE and future trials; some of these are discussed below.
From online and published protocols, harms surveillance appears to have been active in the sense
that a harms detection system was set up but potential anticipated adverse events were not
specifically solicited by research staff and left open-ended (201,202).!!Therapists had the most
contact with participants but it is unclear what their role was in terms of reporting harm. The
manuals indicate that research nurses (RNs) were responsible for monitoring adverse events
(AEs) at 12, 24, and 52 weeks as well as when a participant dropped out of the trial. While some
examples were given to nursing staff regarding what was a SAE, RNs were still required to use
their clinical experience to decide what constituted a SAE and how severe of an impact a “non-
serious” adverse event could have. If an RN assessed the AE as an SAE, was unsure whether it
was a SAE or was concerned about the event generally, he/she was advised to seek the opinion
of other professionals.
Information conveyed to participants may influence whether certain symptoms were reported
and participants’ interpretation of them. Both GET and CBT models are based on a model of
inactivity/ deconditioning as the major driver in perpetuation of CFS symptoms (34). Thus,
patients were informed that a range of symptoms were due to inactivity. While some, such as
changes in muscle function or reduced tolerance to activity, are well-recognized consequences of
physical inactivity (although whether deconditioning could explain all muscle abnormalities in
ME/CFS is debatable [21,63,169,179,203-216]), other symptoms, such as visual/ hearing
changes, regulation of body temperature, and impairment of mental functioning, are more
questionable. Patients were also told to “consider increased symptoms as a natural response to
increased activity”, that “most people with CFS/ME felt either ‘much better’ or ‘very much
better’ with GET”, and that “the benefits of continuing with cognitive behaviour therapy makes
overcoming the difficulties worthwhile” (34).
Simultaneously, therapists were told that adverse effects of GET were “due to inappropriately
planned or progressed exercise programmes” without mention of what these effects were and
were instructed to encourage patients to focus on their symptoms less (33). This sort of priming
could easily lead to instances of symptoms not being reported. Previous research has
demonstrated that questionnaires, and especially interviews, addressing sensitive topics,
including physical activity, are susceptible to social desirability response bias (154-157,217).
Participants consciously or unconsciously (self-deception) present inaccurate information about
themselves to conform to what they believe the researcher expects. Participants may also worry
that their performance or demeanor during the trial might negatively influence their physician’s
treatment of them (the consent form included release of information to patients’ regular
healthcare providers) and receipt of disability benefits. Thus, given the way information was
conveyed to both patients and therapists, it is possible that there may be underreporting of
adverse effects.
SAEs and SARs were sub-divided into the following categories in the final report (218):
“a) Death; b) Life-threatening event; c) Hospitalisation (hospitalisation for elective
treatment of a pre-existing condition is not included), d) Increased severe and persistent
disability, defined as a significant deterioration in the participant’s ability to carry out
their important activities of daily living of at least four weeks continuous duration; e) Any
other important medical condition which may require medical or surgical intervention to
prevent one of the other categories listed; f) Any episode of deliberate self-harm.”
Details of all the SAEs were combined notation such as superscripts could have been used so
readers could identify which arm of the trial the participants had been in, as recommended by the
CONSORT guidelines. For SARs, these were divided up by intervention along with the
assessment of whether it was felt each individual SAR was associated with the intervention.
Given the large number of participants (n=640), the number of SARs was relatively small: APT
[2], CBT [4], GET [2] and SMC alone [2]. Apart from one SAR in the SMC arm (“Worse CFS
symptoms and function” (category d) which was rated as “probably related”), all the other SARs
were rated as “possibly related” [to the intervention]. The SARs listed for CBT were “Episode of
self harm” (category f), “Low mood and episode of self harm” (e & f), “Worsened mood and
CFS symptoms” (d) and “Threatened self harm” (e); for GET, the SARs were “Deterioration in
mobility and self-care” (d) and “Worse CFS symptoms and function” (d).
What adverse events are deemed to be serious or to be causally related to the interventions may
be debatable. For SAE/ SAR category (d), some researchers, clinicians, and patients might
argue that if a management program resulted in impairing a participant’s ability to function for a
lesser amount of time than 4 weeks continuously, that it should be still considered a serious
event. For example, many workplaces would not tolerate an employee who was out on sick leave
for a week or two at a time on a few occasions yet this would not be deemed a serious event due
to the lack of sensitivity of these criteria.
In contrast to the low number of SAEs and SARs, a large number of what were classed as “non-
serious adverse events” (APT: 949, CBT: 848, GET: 992 and SMC: 977) were recorded amongst
the 640 participants; virtually everyone had at least one adverse event (APT: 96%, CBT: 89%,
GET: 93% and SMC: 93%) but we are not given any information about what these events were,
whether certain events were a one-time occurrence or recurrences for a given participant, or
when the event occurred, important factors suggested by CONSORT (56). This meant that of the
3774 adverse events (AEs) recorded in the trial, we were given both the intervention and details
of the event for 0.26% (=10/3774) of them. Given that this was a trial of non-pharmacologic
therapies (cf. surgical and pharmacological interventions) on a group of individuals with an
average age of less than 40 throughout the trial, who could not have a range of medical and
psychiatric disorders and who were deemed capable of participating in an outpatient exercise
program, more information on adverse events would have been desirable, particularly if the
investigators want to claim, as they did in the Lancet paper, that the interventions were “safe”
The protocol stated that an “operationalised Likert scale of the nine CDC symptoms of CFS”
would be used as a secondary outcome measure (201,219). This potentially could have given
useful information on whether there were deteriorations in particular symptoms. Unfortunately,
in the final paper, we were only given information on the “chronic fatigue syndrome symptom
count” and the presence or absence (i.e. not the Likert scores) of two symptoms: “Poor
concentration or memory” and “Postexertional malaise.” Sleep scores were reported separately,
using the Jenkins sleep scale; however, no information on pain symptoms was presented despite
the importance of such symptoms in the condition (7,85,128,220-222) and existing findings of
increased pain following activity and exercise testing (60,63-65,173). It might also have been
useful to allow participants to rate the severity of adverse events outside those of the nine CDC
symptoms. It is also unclear how safety monitoring staff determined which events were causally
related to the interventions. If safety monitoring staff believe that GET or CBT is safe to begin
with, they might not be as vigilant about monitoring adverse events or attributing them to the
The researchers did not explain why they changed or did not report on pre-specified adverse
outcomes from the 2006 PACE Final Protocol. Originally, adverse outcomes were defined as a
“score of 5-7 on the self-rated Clinical Global Impression” (PCGI) or a drop of 20 points on the
SF-36 physical function score (187) from the prior measurement (201). By the time the Lancet
paper was published, “serious deterioration in health” is defined as (90):
“a short form-36 physical function score decrease of 20 or more between baseline and any
two consecutive assessment interviews;[ref] scores of much or very much worse on the
participant-rated clinical global impression change in overall health scale at two
consecutive assessment interviews;[ref] withdrawal from treatment after 8 weeks because
of a participant feeling worse; or a serious adverse reaction.” [bolding by author]
The Lancet paper does not include data on those participants with a PCGI score of 5 (“a little
worse”) and instead this rating is combined with “no change” and “a little better” to form the
category “minimum change”. We are also not given information about participants whose SF-36
PF score (187) dropped by 20 points from the previous measurement. Instead, a serious
deterioration now necessitates a change from the baseline score at two consecutive assessment
interviews. Given that there are 12 weeks between the first and second assessment and 26 weeks
between the second and third assessment and that the baseline scores for the four arms of the
trial all averaged below 40, a participant’s score would on average need to sustain a drop of
more than 50% of their function over a period of at least 12 weeks to qualify as a serious
deterioration in health. Another effect of this change is that any declines after 24 weeks would
not be counted as there is only one more assessment, at 52 weeks, after 24 weeks.
At the same time, the change required for a participant to be considered improved was modified
between the time that the final PACE protocol was published and publication of the trial and
sustainment of improvement was only needed between baseline and one other assessment (i.e.
52 weeks) to qualify as clinically significant.
“A clinically useful difference between the means of the primary outcomes was defined as
0.5 of the SD of these measures at baseline,[ref.] equating to 2 points for Chalder fatigue
questionnaire and 8 points for short form-36.
The justification for using the threshold of 0.5SD threshold comes from a 2002 paper by Guyatt
et al. but Guyatt also points out that the same threshold could be used for deteriorations (223);
unfortunately data on such deteriorations (e.g. participants who declined 8 points on the SF-36)
are not given. Likewise, if it was felt one could not be confident a deterioration had occurred
based on a measurement at one point in time, it suggests one should also probably not be
confident a participant has “improved” (the phrase in the paper) using one time point. In the
paper, Guyatt refers to another group of researchers who had used a similar definition in a trial
comparing temozolomide and procarbazine for recurrent glioblastoma multiforme (223); they
required that improvement in quality of life had to continue for two assessment points to be
considered clinically significant (224). As was discussed in section 5.6, PROMs need to be
further developed in the ME/CFS field (193): this would give better information on what should
be considered “important” changes. In the meantime, it would seem reasonable if there was
consistency in the reporting of improvements and deteriorations, with symmetrical clinically
useful differences scores and time periods unless there are clear rationales given to do otherwise.
Another major issue with PACE is the lack of detail about implementation of the interventions
and participant compliance. Participant compliance was considered to be adequate if a
participant attended 10 (out of a maximum of 15) therapist sessions but the contents of those
sessions are not described in the Lancet paper. Audio- and videotapes of participant-research
staff contact and rating of participant compliance by therapists were executed but these are
indirect measures. PACE CBT and GET manuals directed at therapists and participants give very
detailed instructions how to establish baselines and goals, how/ when to increase activity/
exercise, and how to manage setbacks; in addition, participants are to maintain an activity record.
For example, CBT participants are to set specific activity goals that incorporate the type of
activity, how long the activity will last, and how frequently they plan to perform the activity e.g.
“To walk for 15 minutes daily” or “To do gardening x 3 per week for half an hour.”
When they reach certain milestones, like achieving their targets 75% or more of the time, they
are advised to increase their activity. Likewise, GET participants are to start with gentle stretches
and light exercise that they can maintain for 5 days out of a week. Once they reach that level,
they are then to increase the duration of that activity up to 30 minutes a day at which point,
therapists can begin to increase the level of intensity as measured by heart rate. Ideally, objective
measure of correct implementation of the assigned intervention or good compliance via
actigraphy, heart rate monitors, etc. or direct observation of activity/ exercise by research staff
would be preferred but in absence of this, detailed reporting from participants’ activity logs
would have been helpful to assess compliance and confirm that participants did indeed receive
the intervention as intended. There is no mention in the paper of whether participants achieved
their target goals, exercised an increased amount via increased duration/ frequency/ or intensity,
or maintained/ increased activity despite symptoms.
A possible alternative to the use of motion sensors during treatment would have been their use as
an outcome measure: given the nature of the CBT and GET interventions being assessed, over
the course of 12 months, with good compliance one would expect reasonably large increases in
activity levels, particularly if an individual was coming from a low baseline. Unfortunately,
although the investigators initially planned to employ them on completion and indeed took a
week of measurements at baseline, they were dropped as an outcome measure in the final
protocol (225). The only objective outcome measure reported in the Lancet paper, the 6 minute
walking distance (6MWD), could conceivably be used for a similar purpose (90). Data was
available for only 72% of participants; for other outcomes, data was presented for 89%-94% of
participants. Reasons for this difference are not given. The CBT group only increased from an
average 6MWD of 333m to 354m, the same change as the SMC group; the GET cohort went
from 312m to 379m, or an (adjusted) increase of 35.3 metres compared to SMC. Both sets of
figures make one wonder what percentage of participants had a high rate of compliance,
especially when the final 6MWDs were still much lower than 644m, the predicted value for an
age- [39 years] and gender-matched [77% female] cohort of average height [176.5cm (male),
163.1cm (female)] (226,227). Decreases on such objective measures could also give useful
information on adverse events.
There is much to recommend in the PACE Trial with regard to its reporting of harms; however,
there are also important omissions which could be improved upon in future trials. White el al. do
mention that they “plan to report ... moderators and mediators, whether subgroups respond
differently, and long-term follow-up in future publications” (90). I look forward to reading these
papers and hope that they will consider reporting or sharing the data from their important trial
with other researchers to respond to the points raised by this paper.
7. Other issues
Due to the length of this paper, some other issues of relevance have not been broached: (i)
differences in regulatory requirements for pharmacologic and non-pharmacologic interventions
with no equivalent to post-marketing surveillance for interventions of the latter type; (ii) lack of
litigation concerning harms of GET or CBT leading to less focus on, or concerns about, harm;
(iii) conflicts of interest (COIs) and how they might affect harms reporting; and (iv) the
possibility that cognitive biases, beliefs, attitudes and behaviours of investigators and healthcare
professionals might influence the reporting of adverse events. Also, there has not been space to
cover some of the possible effects, such as coercion of patients to participate in GET or CBT,
that poor reporting might produce.
8. Conclusion
It is hoped that this paper will lead to a greater focus on the reporting of harms in ME/CFS, not
just those that might be associated with GET or CBT, but from any posited treatment.
Interventions should not be presumed to be harmless when there exists evidence of potential
harm and there have not been well-planned systematic methods to track and assess harms both
within and outside trials. Potential strategies to improve reporting of harms are summarized in
Table 3. ME/CFS research should at least conform to standards being recommended for the
majority of medical research while taking into account the unique features of the disease, such as
its relapsing-remitting nature. Moreover, in the ME/CFS field, comparisons are often not made
just within the classes of pharmacologic interventions and non-pharmacologic interventions but
also between pharmacologic and non-pharmacologic treatments (38). False conclusions could be
reached that a non-pharmacologic intervention is “safer” than a pharmacologic agent if harms-
related data was collected more rigorously for the latter (87).
Individuals with ME/CFS can face many challenges and have not always been treated as well as
they should have been by healthcare professionals (76,122,228-232). Many feel that their
symptoms have been downplayed and their negative experiences of some treatments ignored.
This can lead to a mistrust of the medical profession. Furthermore, healthcare professionals who
strive to help their patients cannot do so without assessing risks versus benefits for each
intervention they prescribe. To do this suitably, they need good data on harms. Greater vigilance
for harms could restore patient trust and assist clinicians in adhering to the maxim, "Primum non
nocere" (first, do no harm).
I would like to thank Lily Chu, MD, MSHS for her invaluable assistance. I would also like to
thank the reviewers and the many people who gave comments on earlier drafts of the paper. This
paper is dedicated to the memory of Amberlin Wu, who helped proofread the first draft.
Conflicts of Interest:
I am the Information Officer and Assistant Chairperson of the Irish ME/CFS Association. All my
work for the organisation is voluntary (i.e. unpaid).
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... We acknowledge that exercise is not always effective for people with chronic conditions in certain situations; clients with CFS reported a worsening of fatigue after receiving graded exercise training (GET), and GET was one of the risk factors for severe illness (p = 0.02). 89 One recommendation is that if symptoms get worse after increasing the intensity or duration of exercise, clients should stay at their current level of exercise until the symptoms stabilise. 89 This corresponds to the exercise programmes included in our review, which were inspired by self-management principles. ...
... 89 One recommendation is that if symptoms get worse after increasing the intensity or duration of exercise, clients should stay at their current level of exercise until the symptoms stabilise. 89 This corresponds to the exercise programmes included in our review, which were inspired by self-management principles. Continuous monitoring of fatigue levels and exercise progress and adjusting exercise intensity and duration accordingly may prevent people from exacerbating their symptoms. ...
Full-text available
Objective The aim of this study was to investigate the effectiveness of occupational therapist-/physiotherapist-guided fatigue self-management for individuals with chronic conditions. Methods Eight databases, including MEDLINE and EMBASE, were searched until September 2019 to identify relevant studies. Randomised controlled trials and quasi-experimental studies of self-management interventions specifically developed or delivered by occupational therapists/physiotherapists to improve fatigue symptoms of individuals with chronic conditions were included. A narrative synthesis and meta-analysis were conducted to determine the effectiveness of fatigue self-management. Results Thirty-eight studies were included, and fatigue self-management approaches led by occupational therapists/physiotherapists were divided into six categories based on the intervention focus: exercise, energy conservation, multimodal programmes, activity pacing, cognitive-behavioural therapy, and comprehensive fatigue management. While all exercise programmes reported significant improvement in fatigue, other categories showed both significant improvement and no improvement in fatigue. Meta-analysis yielded a standardised mean difference of the overall 13 studies: 0.42 (95% confidence interval:−0.62 to − 0.21); standardised mean difference of the seven exercise studies was −0.55 (95% confidence interval: −0.78 to −0.31). Discussion Physical exercises inspired by the self-management principles may have positive impacts on fatigue symptoms, quality of life, and other functional abilities.
... Patient surveys have highlighted the harmfulness of CBT, which contains an element of GET and GET for more than 20 years. Kindlon [77] and Geraghty et al. [78], who pooled patients' surveys (n = 1808, 5 surveys and n = 3251, 10 surveys in 2011 and 2017, respectively), found that 20 percent of respondents reported that CBT had worsened their health, and for GET, this was at least in 50% of cases. In a 2 to 5-year follow-up after treatment in NHS CFS clinics with CBT and GET, 13.5% were 'a little worse' and 17.1% were 'worse' or 'very much worse' [70]. ...
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The German Institute for Quality and Efficiency in Healthcare (IQWiG) recently published its draft report to the government about myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The IQWiG concluded that graded exercise therapy (GET) and cognitive behavioral therapy (CBT) should be recommended in the treatment for mild and moderate ME/CFS based on two CBT and two GET studies. In this article, we reviewed the evidence used by IQWiG to support their claims, because their conclusion is diametrically opposed to the conclusion by the British National Institute for Health and Care Excellence (NICE) in its recently updated ME/CFS guidelines. Our analysis shows that the trials IQWiG used in support suffered from serious flaws, which included badly designed control groups; relying on subjective primary outcomes in non-blinded studies; alliance and response shift bias, including patients in their trials who did not have the disease under investigation, selective reporting, making extensive endpoint changes and low to very low adherence of treatments. Our analysis also shows that the report itself used one CBT and one GET study that both examined a different treatment. The report also used a definition of CBT that does not reflect the way it is being used in ME/CFS or was tested in the studies. The report noted that one study used a wrong definition of post-exertional malaise (PEM), the main characteristic of the disease, according to the report. Yet, it ignored the consequence of this, that less than the required minimum percentage of patients had the disease under investigation in that study. It also ignored the absence of improvement on most of the subjective outcomes, as well as the fact that the IQWiG methods handbook states that one should use objective outcomes and not rely on subjective outcomes in non-blinded studies. The report concluded that both treatments did not lead to objective improvement in the six-minute walk test but then ignored that. The report did not analyze the other objective outcomes of the studies (step test and occupational and benefits status), which showed a null effect. Finally, the report states that the studies do not report on safety yet assumes that the treatments are safe based on a tendency towards small subjective improvements in fatigue and physical functioning, even though the adherence to the treatments was (very) low and the studies included many patients who did not have the disease under investigation and, consequently, did not suffer from exertion intolerance contrary to ME/CFS patients. At the same time, it ignored and downplayed all the evidence that both treatments are not safe, even when the evidence was produced by a British university. In conclusion, the studies used by the report do not provide any evidence that CBT and GET are safe and effective. Consequently, the report and the studies do not provide any support for the recommendation to use CBT and GET for ME/CFS or long COVID, which, in many cases, is the same or resembles ME/CFS, after an infection with SARS-CoV-2.
... Twisk and Maes concluded that treating PwME/CFS using CBT and GET is unethical. 28%-82%, n = 4338, eight surveys) reported that GET worsened their health, whereas 20 per cent of respondents (range = 7%-38%, n = 1808, five surveys) reported worsening with CBT [158]. In his review of the PACE trial data, Kindlon (2017) reported evidence that low-intensity exercise has the potential to exacerbate symptoms in CFS and he concluded that "the safety findings may not apply in other clinical contexts" (p. ...
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The psychosomatic approach to medically unexplained symptoms, myalgic encephalomyelitis and chronic fatigue syndrome (MUS/ME/CFS) is critically reviewed using scientific criteria. Based on the 'Biopsychosocial Model', the psychosomatic theory proposes that patients' dysfunctional beliefs, deconditioning and attentional biases cause or make illness worse, disrupt therapies, and lead to preventable deaths. The evidence reviewed suggests that none of these psychosomatic hypotheses is empirically supported. The lack of robust supportive evidence together with the use of fal-lacious causal assumptions, inappropriate and harmful therapies, broken scientific principles, repeated methodological flaws and an unwillingness to share data all give the appearance of cargo cult science. The psychosomatic approach needs to be replaced by a scientific, biologically grounded approach to MUS/ME/CFS that can be expected to provide patients with appropriate care and treatments. Patients with MUS/ME/CFS and their families have not been treated with the dignity, respect and care that is their human right. Patients with MUS/ME/CFS and their families could consider a class action legal case against the injuring parties.
... The PACE trial by White et al. [33] reported that CBT and GET are safe, but they assessed safety in the following manner: "Safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments," and "adverse events were considered serious when they involved death, hospital admission, increased severe and persistent disability, self-harm, were life-threatening, or required an intervention to prevent one of these". Patient surveys on the other hand, have shown over the last 20 years that both therapies often exacerbate ME/CFS symptoms, cause relapses, and lead to (severe) health deterioration [48][49][50]. In other words, patients do not complain about the things that were used by the PACE trial to assess the safety of CBT and GET. ...
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For the last few decades, medical guidelines have recommended treating patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with graded exercise therapy (GET) and cognitive behavioural therapy (CBT). Moreover, doctors have questioned the recovery behaviour of these patients and stimulated them to follow these treatments so that they would be able to go back to work. In this article, we reviewed trials of GET and CBT for ME/CFS that reported on work status before and after treatment to answer the question of whether doctors should continue to question the recovery behaviour of patients with ME/CFS. Our review shows that more patients are unable to work after treatment than before treatment with CBT and GET. It also highlights the fact that both treatments are unsafe for patients with ME/CFS. Therefore, questioning the recovery behaviour of patients with ME/CFS is pointless. This confirms the conclusion from the British National Institute for Health and Care Excellence (NICE), which has recently published its updated ME/CFS guideline and concluded that CBT and GET are not effective and do not lead to recovery. Studies on CBT and GET for long COVID have not yet been published. However, this review offers no support for their use in improving the recovery of patients with an ME/CFS-like illness after infection with COVID-19, nor does it lend any support to the practice of questioning the recovery behaviour of these patients.
... Similarly, a 2011 review of eight surveys found that 51% of survey respondents had reported that GET had made their health worse [51]. An analysis of primary and secondary surveys found that 54-74% of patients responded negatively to GET [52]. ...
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Background and Objectives: There is some evidence that knowledge and understanding of ME among doctors is limited. Consequently, an audit study was carried out on a group of hospital doctors attending a training event to establish how much they knew about ME and their attitudes towards it. Materials and Methods: Participants at the training event were asked to complete a questionnaire, enquiring about prior knowledge and experience of ME and their approaches to diagnosis and treatment. A total of 44 completed questionnaires were returned. Responses were tabulated, proportions selecting available options determined, 95% confidence limits calculated, and the significance of associations determined by Fisher’s exact test. Results: Few respondents had any formal teaching on ME, though most had some experience of it. Few knew how to diagnose it and most lacked confidence in managing it. None of the respondents who had had teaching or prior experience of ME considered it a purely physical illness. Overall, 91% of participants believed ME was at least in part psychological. Most participants responded correctly to a series of propositions about the general epidemiology and chronicity of ME. There was little knowledge of definitions of ME, diagnosis, or of clinical manifestations. Understanding about appropriate management was very deficient. Similarly, there was little appreciation of the impact of the disease on daily living or quality of life. Where some doctors expressed confidence diagnosing or managing ME, this was misplaced as they were incorrect on the nature of ME, its diagnostic criteria and its treatment. Conclusion: This audit demonstrates that most doctors lack training and clinical expertise in ME. Nevertheless, participants recognised a need for further training and indicated a wish to participate in this. It is strongly recommended that factually correct and up-to-date medical education on ME be made a priority at undergraduate and postgraduate levels. It is also recommended that this audit be repeated following a period of medical education
... 19 35 Some persons with illness may also develop considerable medical knowledge after intensively researching their condition, and the contributions of patients to medicine can be valuable in shaping critical conversations and debate. [36][37][38][39] Equally, clinicians may accrue deeper appreciation and insights about healthcare delivery by experiencing life as a patient. [40][41][42] In summation, as Blease et al argue, 'Injustice arises with respect to epistemic privilege when one group fails to recognise the unique expertise of another group, or when an individual fails to fully appreciate the epistemic contributions of another individual'. ...
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In many countries, including patients are legally entitled to request copies of their clinical notes. However, this process remains time-consuming and burdensome, and it remains unclear how much of the medical record must be made available. Online access to notes offers a way to overcome these challenges and in around 10 countries worldwide, via secure web-based portals, many patients are now able to read at least some of the narrative reports written by clinicians (‘open notes’). However, even in countries that have implemented the practice many clinicians have resisted the idea remaining doubtful of the value of opening notes, and anticipating patients will be confused or anxious by what they read. Against this scepticism, a growing body of qualitative and quantitative research reveals that patients derive multiple benefits from reading their notes. We address the contrasting perceptions of this practice innovation, and claim that the divergent views of patients and clinicians can be explained as a case of epistemic injustice. Using a range of evidence, we argue that patients are vulnerable to (oftentimes, non-intentional) epistemic injustice. Nonetheless, we conclude that the marginalisation of patients’ access to their health information exemplifies a form of epistemic exclusion, one with practical and ethical consequences including for patient safety.
Schmerz als Leitsymptom bei postviralen Syndromen ist häufig und eine adäquate Therapie komplex. Besonders wichtig beim schmerztherapeutischen Assessment von Menschen mit postviralen Syndromen ist es, eine mögliche post-exertionelle Malaise rechtzeitig zu erkennen: Denn Therapiemaßnahmen ohne Berücksichtigung einer solchen Belastungsintoleranz können zu einer bleibenden Zustandsverschlechterung führen. Das hat Auswirkungen auf die schmerzmedizinischen und -psychologischen Behandlungsverfahren.
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Despite evidence of physiological and cellular abnormalities in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), the dominant therapeutic approach has been cognitive behaviour therapy (CBT) and graded exercise therapy (GET). Patients report distress and dissatisfaction following healthcare encounters based on GET and CBT. A significant body of research suggests that CBT and GET are harmful for many patients with ME/CFS. These findings raise ethical concerns and suggest that more collaborative working between scientists, therapists and patients would be helpful in making scientific progress in this difficult field.
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Coronavirus disease 2019 (COVID-19) is a viral infection which can cause a variety of respiratory, gastrointestinal, and vascular symptoms. The acute illness phase generally lasts no more than 2–3 weeks. However, there is increasing evidence that a proportion of COVID-19 patients experience a prolonged convalescence and continue to have symptoms lasting several months after the initial infection. A variety of chronic symptoms have been reported including fatigue, dyspnea, myalgia, exercise intolerance, sleep disturbances, difficulty concentrating, anxiety, fever, headache, malaise, and vertigo. These symptoms are similar to those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic multi-system illness characterized by profound fatigue, sleep disturbances, neurocognitive changes, orthostatic intolerance, and post-exertional malaise. ME/CFS symptoms are exacerbated by exercise or stress and occur in the absence of any significant clinical or laboratory findings. The pathology of ME/CFS is not known: it is thought to be multifactorial, resulting from the dysregulation of multiple systems in response to a particular trigger. Although not exclusively considered a post-infectious entity, ME/CFS has been associated with several infectious agents including Epstein–Barr Virus, Q fever, influenza, and other coronaviruses. There are important similarities between post-acute COVID-19 symptoms and ME/CFS. However, there is currently insufficient evidence to establish COVID-19 as an infectious trigger for ME/CFS. Further research is required to determine the natural history of this condition, as well as to define risk factors, prevalence, and possible interventional strategies.
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The present study found adult rates of chronic fatigue syndrome (CFS) in Nigeria that were somewhat higher than rates from community-based CFS epidemiologic studies in the USA. The rates of chronic fatigue for both adults and children were also higher than in existing community-based studies. It is possible that the presence of several fatiguing illnesses such as malaria and typhoid, the lack of adequate healthcare resources and poverty in Nigeria, place individuals at greater risk for fatigue and its syndromes. There is a need for more epidemiologic studies on the prevalence and sociodemographic characteristics of CFS in developing countries.
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Background: The objectives of this study were to measure fatigue in patients with well-defined Myalgic Encephalomyelitis (ME) and to assess if there are any problems associated with the Chalder Fatigue Scale, which has been widely used to assess fatigue in patients with chronic fatigue syndrome (CFS). Methods: Twenty-six patients were recruited from a local support group. All had been diagnosed by physicians and met research criteria for ME. They completed the 11-item Chalder Fatigue Scale and were also asked to rate the severity of their illness. The fatigue scores were calculated using both the Likert method (0,1,2,3) and the bimodal method (0,0,1,1,). Results: The mean Likert score was 26.65 (SD 5.36) and the mean bimodal score was 9.81 (SD 2.04). Fifty per cent of the patients recorded the maximum score using the bimodal method and 77% recorded the two highest scores. Moreover, there was a marked overlap between those who rated themselves as moderately or severely ill. These findings are indications of a low ceiling. Conclusions: The findings from this study using the Chalder Fatigue Scale show that the low ceiling associated with the bimodal method means that this scoring system is not suitable for use in clinical trials. Researchers may wish to consider alternative instruments to obtain a more accurate measure of fatigue in patients with moderate to severe ME and similar conditions.
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Reduced functional capacity and post-exertional malaise following physical activity are hallmark symptoms of Chronic Fatigue Syndrome (CFS). That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing with CFS patients. The reproducibility of VO2 max in healthy subjects is well documented. This may not be the case with CFS due to delayed recovery symptoms. Purpose: To compare results from repeated exercise tests as indicators of post-exertional malaise in CFS. Methods: Peak oxygen consumption (VO2 peak), percentage of predicted peak heart rate (HR%), and VO2 at anaerobic threshold (AT), were compared between six CFS patients and six control subjects for two maximal exercise tests separated by 24 hours. Results: Multivariate analysis showed no significant differences between control and CFS, respectively, for test 1: VO2 peak (28.4 ± 7.2 ml/ kg/min; 26.2 ± 4.9 ml/kg/min), AT (17.5 ± 4.8 ml/kg/min; 15.0 ± 4.9 ml/ kg/min) or HR% (87.0 ± 25.4%; 94.8 ± 8.8%). However, for test 2 the CFS patients achieved significantly lower values for both VO2 peak (28.9 ± 8.0 ml/kg/min; 20.5 ± 1.8 ml/kg/min, p = 0.031) and AT (18.0 ± 5.2 ml/kg/min; 11.0 ± 3.4 ml/kg/min, p = 0.021). HR% was not significantly different (97.6 ± 27.2%; 87.8 ± 9.3%, p = 0.07). A follow-up classification analysis differentiated between CFS patients and controls with an overall accuracy of 92%. Conclusion: In the absence of a second exercise test, the lack of any significant differences for the first test would appear to suggest no functional impairment in CFS patients. However, the results from the second test indicate the presence of a CFS related post-exertional malaise. It might be concluded then that a single exercise test is insufficient to demonstrate functional impairment in CFS patients. A second test may be necessary to document the atypical recovery response and protracted malaise unique to CFS.
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PURPOSE: The etiology and pathophysiology of CFS remain unknown, but it is widely accepted that pain and fatigue are the two most common symptoms. However, only a few studies have investigated the treatment of chronic pain in CFS despite 94% of people diagnosed with CFS reporting muscle pain and 84% reporting joint pain (1). Treatment for pain in CFS relies heavily upon pharmacological intervention and many people have experienced serious side affects from taking medication. Therefore, the aim of this study was to evaluate the effectiveness of Myofascial Release to reduce musculoskeletal pain in people with CFS. METHODS: This study was of a repeated measure design. All participants met the Centre of Disease Control research criteria for CFS (2) and the Canadian Guidelines (3). Participants were randomised to either the treatment group (Myofascial Release, MFR) or the control group (Usual Care). MFR treatment was tailored to the needs of the patient and was provided once a week, for eight weeks. Assessments were conducted at baseline, week eight and at follow up (week 12). Outcome measures included the McGill Pain Questionnaire, Visual Analogue Scale, the Margolis Body Chart, the Pain Anxiety Symptoms Scale -20 and measures of physical activity. RESULTS: Eleven participants were recruited (treatment group n= 8, control group n=3). Participants who received MFR reported a significant reduction of pain severity and intensity compared to those people who received Usual Care (P
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Because the pathogenesis of Chronic Fatigue Syndrome (CFS) has yet to be determined, case definitions have relied on clinical observation in classifying signs and symptoms for diagnosis. The selec-tion of diagnostic signs and symptoms has major implications for which individuals are diagnosed with CFS and how seriously the illness is viewed by health care providers, disability insurers and rehabilitation planners, and patients and their families and friends. Diagnostic criteria also have implications for whether research based on varying definitions can be synthesized. The current investigation examined differences be-tween CFS as defined by Fukuda et al. (1994) and a set of criteria that has been proposed for a clinical Canadian Case definition. There were twenty-three participants who met the Canadian criteria, 12 in the CFS (Fukuda et al. (7) criteria) group and the 33 from the chronic fatigue (CF)-psychiatric group. Dependent measures included: work status, psychiatric comorbidity, symptoms, and functional impairment (measured by the Medical Outcomes Study). People meeting the Fukuda et al. and Canadian criteria were compared with people who had a chronically fatiguing illness explained by a psychiatric condition. Statistical tests used included binomial logistic regression and analysis of variance. The Canadian criteria group, in contrast to the Fukuda et al. criteria group, had more variables that statistically significantly differentiated them from the psychiatric comparison group. Overall, there were 17 symptom differences between the Canadian and CF-psychiatric group, but only 7 symptom differences between the CFS and CF-psychiatric group. The findings suggest that both the Canadian and Fukuda et al. case definitions select individuals who are statistically significantly different from psychiatric controls with chronic fatigue, with the Canadian criteria selecting cases with less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms.
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The purpose of this study was to evaluate predictors of change in physical function in individuals diagnosed with chronic fatigue syndrome (CFS) following participation in nurse delivered, non-pharmacologic interventions. Participants diagnosed with CFS were randomly assigned to one of four, 6-month interventions including cognitive behavior therapy, cognitive therapy, anaerobic exercise, or a relaxation control group. Baseline measures including immune function, actigraphy, time logs, sleep status, and past psychiatric diagnosis significantly differentiated those participants who demonstrated positive change over time from those who did not. Understanding how patient subgroups differentially respond to non-pharmacologic interventions might provide insights into the pathophysiology of this illness.
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The Centers for Disease Control and Prevention (CDC) recently developed an empirical case definition that specifies criteria and instruments to diagnose chronic fatigue syndrome (CFS) in order to bring more methodological rigor to the current CFS case definition. The present study investigated this new definition with 27 participants with a diagnosis of CFS and 37 participants with a diagnosis of a Major Depressive Disorder. Participants completed questionnaires measuring disability, fatigue, and symptoms. Findings indicated that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the new CDC definition. Given the CDC’s stature and respect in the scientific world, this new definition might be widely used by investigators and clinicians. This might result in the erroneous inclusion of people with primary psychiatric conditions in CFS samples, with detrimental consequences for the interpretation of epidemiologic, etiologic, and treatment efficacy findings for people with CFS.
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A 36-item short-form (SF-36) was constructed to survey health status in the Medical Outcomes Study. The SF-36 was designed for use in clinical practice and research, health policy evaluations, and general population surveys. The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The survey was constructed for self-administration by persons 14 years of age and older, and for administration by a trained interviewer in person or by telephone. The history of the development of the SF-36, the origin of specific items, and the logic underlying their selection are summarized. The content and features of the SF-36 are compared with the 20-item Medical Outcomes Study short-form.
Patiënten met het chronisch vermoeidheidssyndroom (ME/CVS) willen graag een richtlijn, waarin huisartsen, specialisten, psychologen en andere zorgverleners afspreken hoe ze omgaan met de aandoening. Veel van deze patiënten zeggen nu niet de medische zorg en ondersteuning te krijgen die ze nodig hebben, zo blijkt uit onderzoek onder de achterban van patiëntenorganisaties. Moeilijke diagnose De diagnose ME/CVS is moeilijk te stellen. Veel patiënten ervaren dat ze afhankelijk zijn van de persoonlijke opvattingen over ME/CVS van de zorgverlener die ze behandelt. Heeft deze wel voldoende kennis over de ziekte? Hoe wordt de diagnose gesteld? Welke behandelingen kunnen helpen? Patiënten voelen zich vaak niet serieus genomen en krijgen niet de medische zorg en ondersteuning die ze willen. De achterban van de ME/CVS-patiëntenorganisaties wil daarom graag een multidisciplinaire richtlijn voor ME/CVS. Huisartsen, specialisten en andere zorgverleners kunnen op basis van de beschikbare kennis in de richtlijn afspreken hoe ze omgaan met de aandoening. En bedrijfs- en verzekeringsartsen kunnen door zo’n richtlijn beter rekening houden met de beperkingen van ME/CVS-patiënten. Daarnaast verwachten patiënten dat de richtlijn helpt bij het toewijzen van de uitkeringen en voorzieningen die ze nodig hebben. Shoppen Het Kwaliteitsinstituut voor de gezondheidszorg CBO liet het NIVEL (Nederlands instituut voor onderzoek naar de gezondheidszorg) de ervaringen en meningen van patiënten met ME/CVS in kaart brengen. Het onderzoek werd gesubsidieerd vanuit het ZonMw-programma Chronisch Vermoeidheidssyndroom. De uitkomsten ervan worden gebruikt bij de ontwikkeling van een multidisciplinaire richtlijn ME/CVS door het CBO en het Trimbos-instituut. NIVEL-onderzoeker Anke de Veer: “Mensen met ME/CVS hebben ernstige klachten, maar artsen weten vaak niet waar ze de oorzaak moeten zoeken en zijn daardoor niet in staat de juiste hulp te bieden. Patiënten die hierdoor gaan ‘shoppen’ komen vaak met lege handen thuis. De richtlijn zou bijvoorbeeld moeten aangeven op grond van welke bevindingen de diagnose gesteld moet worden en welk onderzoek daarvoor nodig is. Patiënten kunnen dan beter worden voorgelicht over het diagnostisch proces en zullen minder snel het gevoel krijgen dat ze niet serieus worden genomen.” Onderzoek Het onderzoek is uitgevoerd in samenwerking met de ME/CVS-Stichting Nederland, de Steungroep ME en Arbeidsongeschiktheid en ME/CVS Vereniging, die de resultaten van het onderzoek inbrengen in het ontwikkeltraject van de richtlijn. Aan het onderzoek werkten 412 patiënten mee uit de achterban van de patiëntenorganisaties. De meesten (85,1%) beoordelen hun gezondheid als matig of slecht en kunnen niet meer dan vier uur per dag actief zijn.