The diagnosis, treatment and management of chronic fatigue
syndrome (CFS) / myalgic encephalomyelitis (ME) in adults and children
Work to support the NICE Guidelines
Carried out by: Anne-Marie Bagnall, Susanne Hempel, Duncan
Chambers, Vickie Orton and Carol Forbes
Centre for Reviews and Dissemination University of York
Table of contents
Review Questions ..........................................................................................................5
Evidence to answer Question 1, part 1: .......................................................................12
Evidence to answer Question 1, part 2: .......................................................................15
Evidence to answer Question 2:...................................................................................28
Evidence to answer Subquestion 2: .............................................................................34
Evidence to answer Question 3:...................................................................................36
Evidence to answer question 4:....................................................................................77
Evidence to answer question 5:....................................................................................80
CFS/ME is a relatively common illness that places substantial burden on
patients, carers and families, and society. It comprises a range of symptoms
including fatigue, which can be triggered by minimal activity, malaise,
headaches, sleep disturbances, difficulties with concentration and muscle pain.
Symptoms may fluctuate in intensity and severity. It raises especially complex
issues in severely affected children and adults.
The evidence suggests a population prevalence of at least 0.2-0.4%, which
means that a general practice of 10,000 patients is likely to have at least 20-
40 patients with CFS/ME, half of whom will need input from specialist
services.1 However, there is a lack of epidemiological data for the UK, which
means that population estimates are based on extrapolations from other countries.
CFS/ME, like other chronic illnesses with no certain disease process, poses
real problems for healthcare professionals. CFS/ME can cause profound,
prolonged illness and disability, which has a substantial impact on patients
and their families. Uncertainties about diagnosis and management, and lack
of clinical guidance for health professionals exacerbate this impact.
In 2002, the Independent Working Group convened by the Chief Medical
Officer reported their findings and the Medical Research Council made
research on CFS/ME a priority.1 Guidelines on the diagnosis and treatment of
CFS/ME have been published in Canada,2 USA3 and Australia4, and in the UK,
the Royal College of Paediatrics and Child Health published guidelines on the
management of CFS/ME in children and young people in December 2004.
Previous research into CFS/ME has focussed on possible causes, diagnostic
criteria and natural history of the illness, with research into the treatment or
management of the condition increasing only in recent years. A number of
studies are now available, which have assessed the effectiveness of
interventions used in the treatment or management of CFS/ME. A systematic
review has been conducted that focussed on defining and managing chronic
fatigue syndrome.5 A further systematic review that assessed the
effectiveness of all available interventions to treat or manage adults and
children with CFS/ME was carried out at the Centre for Reviews and
Dissemination.6 There is also a systematic review on the effectiveness of
cognitive behavioural therapy. 7
Systematic and scoping reviews of the literature were being carried out to
inform the NICE Guidelines on diagnosis and management of CFS/ME.
Where appropriate, previous reviews were updated.
The review was undertaken to provide evidence to support the NICE
Guideline on the diagnosis and the management/ treatment/ rehabilitation of
CFS/ME as well as the support and information needs of people diagnosed
with CFS/ME, their carers and health professionals.
The following questions were addressed:
Question 1: What are the existing case definitions for chronic fatigue
syndrome in adults and children and what evidence exists to substantiate or
validate these case definitions?
Question 2: Are there any substantiated or validated evaluations to support
the diagnosis of chronic fatigue syndrome in adults and children?
(Subquestion: In people presenting with early suspected CFS/ME (before 6
months) what are the risk factors/ prognostic flags that might be linked with
progression to CFS/ME?)
Question 3: Does the evidence show that any particular intervention or
combination of interventions is effective in treatment, management or
rehabilitation of adults and children with a diagnosis of CFS/ME?
(Subquestion: In people presenting with early suspected CFS/ME what
interventions might be effective in preventing progression to CFS/ME?)
Question 4: What are the information needs of healthcare professionals,
patients and carers?
Question 5: What are the support needs of healthcare professionals, patients
Evidence to answer Question 1, part 1:
What are the existing case definitions for chronic fatigue syndrome in
adults and children?
As of 8th July 2005, one new publication2 was included in the case definition
table, in addition to the six definitions included in the Mulrow et al (San
Antonio)5 and Bagnall et al6 systematic reviews.
Evidence to answer Question 1, part 2:
What evidence exists to substantiate or validate the existing case
definitions for CFS/ME in adults and/or children?
Research literature evidence
Thirty-six new studies14-49 were included in the section on validation of case
definitions, in addition to the thirty-eight studies8, 50-86 included in the review of Mulrow
et al.5. Evidence from the previous review is briefly reproduced here and is
incorporated into this summary paragraph.
The CDC 1994 case definition was most often investigated (41 studies), followed by
CDC 1988 (16 studies), Oxford (6 studies), Australian (3 studies) and the Dowsett
and Canadian criteria (1 study each). Studies compared CFS patients to healthy
controls (40 studies), depressed patients (8 studies), multiple sclerosis patients (7
studies) and fibromyalgia patients (4 studies). Twenty-four studies examined multiple
features of CFS/ME but the majority (51 studies) looked at isolated symptoms and
were therefore limited in their validity.
The review of Mulrow et al.5 concluded that the evidence to substantiate the existing
case definitions of CFS was severely limited: studies that compared findings in
patients with CFS with findings in healthy individuals or patients with other conditions
do not provide an adequate basis for validation of any particular case definitions. The
reason for this is that most have selected patients based on the case definition that
often includes symptoms or findings that are then compared. This would make most
studies level 2- or lower. Few studies involved large unselected populations or used
comprehensive assessment methods to evaluate whether a distinct group of findings
characterised and differentiated CFS from other conditions. One large community
study suggested that characteristics that might distinguish CFS are: post-exertional
fatigue not alleviated by rest plus a cluster of symptoms including chronic fatigue,
sore throat, lymph node pain, post-exertional malaise, memory or concentration
problems, and unrefreshing sleep. No studies were able to establish the superiority of
one existing case definition over another.
The new studies that looked to be most useful came to the following conclusions:
symptoms suggesting infection are less frequently reported and less severe in
patients meeting CDC 1994 criteria than in those meeting than CDC 1988 criteria (1
study); patients meeting CDC 1988 criteria had more symptoms and symptoms that
were worse in severity than patients meeting 1994 criteria (2 studies); patients
meeting CDC 1994 criteria were a more heterogeneous group than patients meeting
CDC 1988 criteria (1 study); individuals with high symptom frequency were more
severely affected (CDC 1994, 1 study). One community based study that compared
CFS 1994 to Dowsett (ME) criteria found that both sets of patients had worse
symptoms than patients with chronic fatigue explained by psychiatric reasons, but on
different features. The ME and CFS groups did not seem to differ significantly from
one another. Another community based study compared patients meeting CDC 1994
CFS criteria to those meeting the Canadian criteria and found that the Canadian
group differed from a group with chronic fatigue explained by psychiatric reasons on
more variables than the CDC 1994 group. One study that investigated the CDC
1988, CDC 1994 and Australian criteria concluded that criteria-based approaches to
diagnosis did not yield homogeneous groups of patients. One study that undertook
factor analysis concluded that three factors (musculoskeletal, infection, and
cognition/ mood/ sleep) were essentially defined by CFS symptoms.
Evidence to answer Question 2:
Are there any substantiated or validated evaluations to support the
diagnosis of CFS/ME in adults and children?
Research literature evidence
Twenty-seven studies2, 4, 92, 94-118 met inclusion criteria for question 2. All but six were
of a low level of evidence (level 3 or 4), being case-control studies or consensus
guidelines. Studies at this level of evidence are vulnerable to bias from various
sources. The case-control studies often differentiated healthy controls from CFS
patients; however it would be more useful to differentiate patients with related
illnesses, such as depression and fibromyalgia. Some studies (e.g. the Naschitz
publications) used very sophisticated methods to differentiate participants, but it is
unclear how sample dependent the results are, they ideally need confirmation in
larger samples containing patients with related illnesses (rather than healthy
Three of the six studies that were graded as level 2 reported that the tests evaluated
showed no difference between CFS patients and controls. The other three all
reported that the tests were able to distinguish CFS patients from controls. All three
of these latter studies were of the head-up tilt test, and were published by the same
group of authors. Three other level 3 studies published by the same authors also
indicated that the head up tilt test was able to discriminate CFS patients from healthy
controls. However, we did not find any evaluations of the head up tilt test that did not
find in its favour, or any evaluations by other authors, which may suggest the
possibility of publication bias (negative studies may exist but may not have been
Other diagnostic tests found to discriminate between CFS and non-CFS individuals in
level III evaluations were: a panel of five laboratory tests (fibrinogen, prothrombin
fragment 1+2, thrombin-anti-thrombin complexes, soluble fibrin monomer (SFM) and
platelet activation (CD62P, ADP)); a test for auditory brainstem responses; and
It is perhaps not surprising that no definitive diagnostic test has been described for
CFS/ME, given that CFS/ME is a syndrome, as such defined by symptoms rather
than cause. It is probably unlikely that a diagnostic marker would be found before a
cause or causes of the syndrome are identified.
Evidence to answer Subquestion 2:
In people presenting with early suspected CFS/ME (before 6
months) what are the risk factors / prognostic flags that might be
linked with progression to CFS/ME?
Research literature evidence
Seven studies120-126 met inclusion criteria for the sub-question about risk factors for
progression to CFS/ME. Most of the studies seemed to be cross-sectional studies
involving retrospective surveys of people with and without CFS/ME and as such are
vulnerable to recall bias and other forms of bias. None seemed to indicate definite
prognostic flags for CFS/ME that would be useful to a clinician, however, the
following factors were found to be significantly associated with development of
CFS/ME in individual studies: sick certification after viral illness, presence of fatigue
at time of viral illness, lower physical functioning, higher pain and fatigue scores at
baseline, older age (adults and children), exhaustion, being female, low educational
level, visits to the GP, longstanding limiting medical condition aged 10 years, higher
social class in childhood, fatigue and psychological distress prior to presentation,
presence of infectious mononucleosis, positive Monospot tests at time of onset, time
in bed at onset, exercise power, mood disorder. A study of ME/CFS in children
identified presence of an anxiety disorder as a risk factor for developing the illness.
A birth cohort study reported that higher levels of exercise in childhood were
associated with a reduced risk of developing CFS/ME.
Evidence to answer Question 3:
How effective and safe are interventions for the treatment and/or
management of CFS/ME in adults and children?
Research literature evidence
Sixty-nine trials are included in this section. Detailed data extraction and validity
assessment tables are presented in an appendix. Additionally, four ongoing trials that
have not yet been published were identified.127-130
Fifteen papers that were ordered as potentially meeting inclusion criteria for question
3 had not arrived at the time of writing this report.131-145 One paper in the Russian
language was identified as potentially meeting inclusion criteria but has not been
translated.146 The paper is about a yeast extract supplement but it is unclear whether
patients all had CFS.
No RCTs, controlled trials, or good quality cohort studies, case-control studies
before-and-after studies or interrupted time series were found for the following
treatments which the Guideline Development Group (GDG) had identified a prior as
being of interest: Expert Patient Programme; amitriptyline; gabapentin; baclofen;
vitamin B12 injections.
EVIDENCE RELATING TO ADULTS WITH CFS/ME
Main results of behavioural treatment trials (Table 1)
CBT with the aim to increase activity and reduce rest time in a systematic manner,
independent of symptoms given in weekly or biweekly sessions was evaluated in
adults in four RCTs.147-151 A controlled trial of "modified CBT" used a different form
of treatment without graded activity, which is normally considered an integral part of
CBT for CFS/ME. The intervention used in this study aimed to promote shared
coping through relaxation training and guided imagery, cognitive therapy techniques
and behavioural prescription involving activity limitations.152 Other types of modified
CBT, with occupational therapy/ rehabilitation aspects, were examined in another
RCT153 and two controlled trials.154, 155 All studies included people diagnosed with
CFS according to one of the recognised case definitions, except one which included
people with post viral fatigue syndrome.156 CBT was compared to routine medical
care in two RCTs,150, 153 and two controlled trials,154, 155 to relaxation in one RCT,147,
148 to natural course (control) in another RCT,151 and to guided support in one
controlled trial of "modified CBT".152 A further RCT compared CBT plus placebo
injections to CBT plus leukocyte extract, a control clinic plus leukocyte extract and to
a control clinic plus placebo injections.149
The RCT which investigated the effects of both leukocyte extract and CBT showed a
significantly greater effect on general health in the group receiving both leukocyte
extract and CBT compared to the other groups. No differences were found between
groups (including CBT alone) for the other outcomes investigated.149 The controlled
trial of modified CBT found no difference between intervention and control groups for
fatigue, depression or symptom scores.152 This study scored very poorly on the
validity assessment, scoring only 1 out of a possible 20.
The remaining three RCTs reported a beneficial effect of CBT when compared to
controls.147, 150, 151 All three RCTs found a significant short term improvement in
physical functioning, fatigue, and global improvement, but neither of the two studies
that assessed depression found any differences between groups.147, 150 One of these
RCTs also followed patients for five years after the intervention. At the five year
follow-up assessment global improvement was greater in the intervention group, as
was the proportion of participants who completely recovered,148 however, no
differences were reported between the groups in terms of physical functioning,
fatigue, general health, symptoms, relapses or the proportion of participants that no
longer met the UK criteria for CFS.
The three studies of modified CBT with rehabilitation153-155 found significant
differences between groups for symptoms (one RCT, one controlled trial), emotional
distress (one controlled trial) and global health/ quality of life (3 controlled trials).
In one RCT two participants dropped out of the CBT group as they felt a deterioration
in their symptoms was due to the intervention.150 A second RCT showed very high
drop out rates of between 20 and 40% in all three treatment groups.151 Drop out
rates were highest in the CBT group and lowest in the control group, reasons for
drop-outs were not stated and no adverse effects from treatment were reported.
The effects of graded exercise therapy (GET) were investigated in five fairly large
RCTs of patients with CFS, all of which found significant improvements in the
intervention compared to the control groups. Improvements in measures of fatigue
and physical function were found in all five RCTs.157-161 Two also showed
improvement in general health157, 159 and one in physiological measurements and
symptoms.158 When exercise was combined with fluoxetine there was no additional
effect.158 One RCT assessed different interventions to encourage graded exercise
and found benefits of GET compared to standardised medical care for all outcomes
investigated. However, there were no differences between the different intervention
groups for any of the outcomes investigated. 159, 162
In one of the RCTs evaluating GET, one participant dropped out from each group
due to worsening of symptoms.157 In another RCT of exercise (and exercise plus
fluoxetine), 11 participants dropped out due to side effects but it is unclear which
intervention group they were in.158
Main results of immunological/ antiviral treatment trials (Table 2)
Three RCTs of participants diagnosed with CFS investigated the effects of
immunoglobulin in adults; two found some positive effect, and the third found no
effect of treatment. One RCT found greater improvements in the intervention group
on symptom scores and functional capacity but not in depression, immune outcomes
or quality of life.164 A second smaller RCT found improved immune measurements
(physiological outcome) but not functional or symptom measures.165 A third RCT,
which was the largest in the immunoglobulin category, found no improvement in any
of the outcomes investigated (functional status, mood, immune outcomes and quality
Other immunomodulators were investigated in four RCTs, all of which included
participants with CFS. Two of these evaluated interferon, one of which suggested
some positive effect. In one very small RCT treatment led to increased physical
activity and recovery which remained after 8 months follow-up, however it is not
reported whether this was statistically significant.167 In the other RCT, alphainterferon
led to an improvement in immune measurements (one outcome) but not in
quality of life measurements.168 The effects of Ampligen were investigated in one
relatively large (n=92) RCT, which found an improvement in functional ability, activity,
exercise, cognitive function and work measures but not in depression scores.169 In
the same RCT, elective use of other medications by participants was reported to
have increased significantly in the placebo group compared to the intervention group.
One RCT assessed the combined effect of leukocyte extract and cognitive
behavioural therapy using a factorial design.149 A significant improvement in general
health was reported for the group which received both interventions, compared to the
other groups. No beneficial effects were reported for physical and functional capacity,
mood or immune outcomes for any of the groups in this study.
The effect of acyclovir, an antiviral, was investigated in one small RCT in those who
fulfilled criteria for CFS and additionally had prior infection with Epstein Barr virus
confirmed.170 A significant negative effect was reported for anxiety, depression and
confusion with the control group showing a greater improvement in symptoms than
the treatment group, but not for the other outcomes investigated (rest, anger, vigour,
fatigue, oral temperature and personal well-being). A very small trial of gancyclovir
(n=11) found no beneficial effects, and the trial had to be stopped early due to
bleeding during invasive investigations.171 A small trial of inosine pranobex (n=16)
found significant improvements in immune function in the treatment group, but no
differences between groups for other outcomes (symptoms, cognitive function, global
One RCT of patients with CFS evaluated the antihistamine terfenadine.172 This study
found no differences between the groups for any of the outcomes investigated
(functional status and symptoms).
The effects of vaccination with staphylococcus toxoid were investigated in one small
controlled trial of patients with CFS173 and one fairly large RCT.174 In the controlled
trial, no differences were reported in depression, pain or psychological outcomes
between the intervention and control group. However, a greater improvement in the
clinical global impression in the treatment group was found. In the RCT, the
treatment group had a significantly better outcome than the control group for global
impression and one item on the fibromyalgia impact questionnaire.
Some severe adverse effects were noted in participants in the immunological
intervention groups. Three people had to withdraw from acyclovir treatment due to
reversible renal failure170 and two people from immunoglobulin treatment due to
severe constitutional symptom reactions.166 One recipient of immunoglobulin therapy
also withdrew due to mild but transient liver failure164 and phlebitis has also been
noted with immunoglobulin infusions.164 Transient elevation of serum uric acid was
noted in the trial of inosine pranobex.175 In the RCT of staphylococcus toxoid, 13
patients in the treatment group and seven in the placebo group experienced side
effects. It should be noted that immunoglobulins and leukocyte extract are blood
products. There are known risks associated with the use of blood products such as
the possible transfer of infectious diseases.
Main results of pharmacological treatment trials (Table 3)
Very few of the RCTs evaluating pharmacological interventions showed a beneficial
effect. No benefit was found in patients with CFS from treatment with anticholinergic
agents,177-179 antidepressants (either in treating symptoms of depression or any of
the other outcome measures reported)158, 180, 181 or growth hormone.182 However
some studies reported a positive effect on individual outcomes.
Oral NADH led to a greater improvement in symptoms (the only outcome investigated)
in the intervention group compared to the control group in one small RCT,183 but no
significant difference in symptoms in another low quality RCT.184 A trial of melatonin
versus phototherapy found significant improvements in sleep, vitality and mental
health, but worsening of bodily pain in the melatonin group.185
The effects of steroid treatment were investigated in six RCTs of participants with
CFS.186-191 Three of these RCTs evaluated hydrocortisone and all reported some
beneficial effect.186-188 One found an improvement in general health but not in
activity, depression, mood or symptom measures.186 The second smaller RCT found
improvements in clinical global impression, fatigue, symptoms and disability,
although the improvement in disability was not significant.187 The third found
improvement in fatigue and hormone levels.188 Two RCTs assessed fludrocortisone,
and did not find any association between treatment and the outcomes
investigated.189, 190 One RCT of fludrocortisone and hydrocortisone combined found
no significant benefit of treatment191 and a seventh RCT of topical nasal
corticosteroids also found no effect of treatment.192
One RCT and one controlled trial investigated the effect of monoamine oxidase
inhibitors in participants with CFS.193, 194 The RCT evaluated moclobemide, and
found no benefit of treatment.193 The small controlled trial of selegiline was
associated with greater improvement in tension, anxiety and vigour in the intervention
group compared to the control group, but not with functional capacity, fatigue, illness
severity or symptom measures.194
A trial of dexamphetamine found significant improvements in fatigue in the treated
group.195 Reduced food consumption was a side effect in this group.
One very small RCT (n=10) evaluated the effects of the antihypertensive drug
clonidine and found no significant effect on cognitive function.71
Adverse events serious enough to cause people to withdraw from the study occurred
with galanthamine hydrobromide,177, 178 phenelzine180, fludrocortisone190 and
Main results of alternative medicine treatment trials (Table 4)
Two RCTs assessed the effectiveness of homeopathy.196, 197 One study reported
‘greater improvement’ with treatment, however no measurements were presented
and so it is difficult to interpret the findings.196 The authors of the study state that
participants were suffering from ME, however the Oxford criteria for CFS were used
to make the diagnosis. This study also scored poorly on the validity assessment (6
out of 20). The other, high quality RCT reported significant improvements in fatigue
and on some physical dimensions of the functional limitations profile in the treatment
group.197 No adverse effects were reported in either group.
Massage therapy improved measures of fatigue, pain and sleep, depression and
cortisol levels in one small RCT in those diagnosed with chronic fatigue immune
deficiency syndrome (CFIDS).198 Osteopathy also reportedly improved measures of
fatigue, back pain and sleep, anxiety and cognitive function and general health in a
controlled trial of patients diagnosed with ME. However the quality of this study was
poor (score = 0 out of 20).199
Main results of supplement treatment trials (Table 5)
Two studies investigated the effect of essential fatty acid supplements. One RCT in
patients with CFS found some non-significant improvement as perceived by the
participants, as well as non-significant improvements in depression, but not in
general symptoms.200 A slightly larger controlled trial investigated the effect of
essential fatty acid supplements in those diagnosed with post viral fatigue syndrome
(PVFS).156 Improvement (as perceived by the participants) was reported in the
intervention group, along with an improvement in symptoms and a greater shift
towards normal levels of cell fatty acid concentration.
Magnesium supplements led to improvements in measures of energy and pain,
emotional reactions, general health and laboratory measures but not in sleep,
physical mobility or social isolation in one small RCT of patients with CFS.201 One
very small RCT assessed the effects of liver extract in patients with CFS but found no
difference in outcomes between the intervention and control groups.202
General supplements had no effect in two RCTs and one controlled trial of patients
with CFS.203-205 These studies also scored poorly on the validity assessment (6-10
out of 20).
RCTs of pollen extract206 and medicinal mushrooms207 reported no significant effects
of treatment. A controlled trial of acclydine and amino acids208 reported significantly
more improvement in IGF-1 levels in the intervention than control group, but no
significant difference in global improvement or symptoms. A RCT of acetyl-Lcarnitine
and propionyl-L-carnitine found significant improvements in fatigue and
cognitive function associated with treatment.209
Reasons for dropping out of the studies were not well described in the supplement
trials, however in the magnesium trial, two participants left the intervention group
after experiencing a generalised rash.201
Main results of other treatment trials (Table 6)
One controlled trial of combination treatment (including CBT) in patients with CFS was also
included.210 A greater number of participants returned to work in the intervention group (the
only outcome measured), however 49 of the 71 original participants were not followed up.
This study also scored very poorly on the validity assessment, receiving a score of two out of
a possible 20 and so these results should be interpreted with caution.
A controlled trial of ‘broad-based management’ (mainly information and advice) in people
diagnosed with post-infectious fatigue syndrome found significant improvements in the
intervention group in measurements of fatigue, somatic symptoms and self-efficacy.211 Again,
a low score on validity assessment (two points out of 20) indicates that these results should
be treated with caution.
A very small controlled trial of a buddy/mentor programme found significant improvements in
the treatment group compared to control for fatigue severity but not for any of the other six
A trial of ‘group therapy’, which was not well described, found no significant effects of
An unpublished trial of a low sugar, low yeast diet, compared to healthy eating, also found no
significant effect of treatment.214
A RCT of multiple symptom-based treatments (including supplements) found significant
improvements in favour of the treatment group in symptoms scores, overall response and
fibromyalgia-specific symptoms.215 This trial scored 19 points out of a possible 20 in the
One RCT assessed participants who had been ill for three years or more,
separately from participants who had been ill for less than three years. The
study reported no differences in response to fludrocortisone between the two
groups.190 A controlled trial of broad-based management also found no
differences in response between those who had been ill for shorter and longer
periods of time.211 In the same study, participants were also grouped
according to degree of initial functional impairment, emotional distress, and
fatigue. No differences in response were seen in those with a greater degree
of initial functional impairment and emotional distress, however those who
reported more initial fatigue showed greater improvements in self-efficacy
One study of rehabilitation treatment for inpatients found some benefits of
treatment.155 Patients with high fatigue and disability scores were included in
an RCT of a general supplement, but no significant treatment effects were
The inclusion criteria for the trial of pollen extract state that only relatively
serious cases were included.206
Very limited numbers of studies considered subgroups of patients. For
example, no studies were found that compared the effects of treatment in bed
and wheelchair bound patients with those who were less restricted by their
illness, or that assessed whether treatment had different effects in those
where the diagnosis had been made using criteria for CFS compared with
those where the diagnosis had been made using criteria for ME. It was
unclear in many trials how severely affected the participants were.
EVIDENCE RELATING TO CHILDREN
One RCT of immunoglobulin G included only children.216 A significant
improvement in functional score (based on attempts and attendance at school
or work and physical or social activities) was reported in the intervention
group compared to the control group. Significantly more children in the
intervention group had an improvement in score of 25% or more. A second
RCT of immunoglobulin included both adults and children according to
standard definitions, although no participants under the age of 16 were
included.166 Significant improvements were seen in symptom scores and in
functional capacity in the intervention group compared to the control group.
The findings from both of these studies have also been presented in the main
immunological section. The use of blood products such as immunoglobulin is
associated with known risks and so the use of this treatment should be
One controlled trial of rehabilitation/ CBT in children reported significant
improvements in the treatment group for measures of global wellness.217 One
RCT of CBT in children reported significant improvements in symptoms and
attendance at school.218 In both, the intervention was compared to routine
No evaluations of other interventions investigated in children were identified.
Validity of included studies
Most RCTs scored well on the objectivity and validity of outcomes, blinding of
investigators and participants, baseline comparability of groups, completeness
of follow-up and appropriate statistical analysis. RCTs generally scored
poorly on the concealment of treatment allocation and many failed to use an
intention to treat analysis. Controlled trials scored less well on the objectivity
and validity of outcomes and on all other validity criteria. Two of the eight
controlled trials in which groups were not comparable at baseline did adjust
for baseline differences or confounding factors. Only one of the controlled
trials used a sample size calculation.
No one intervention type scored more highly on the validity criteria than any
Summary of results
The results of each trial, ranked according to validity score, are presented in
Table 8. Trials were classified as having a positive, negative or no effect,
under the classifications of overall effect and any effect. Studies were judged
to show some effect of treatment if any of the outcomes measured showed a
statistically significant difference between the intervention and control groups.
Studies were classified as having an overall effect (positive or negative) if they
showed a statistically significant effect for more than one clinical (i.e. not a
physiological/ laboratory) outcome or, if only one clinical outcome was
measured, it was found to show a statistically significant effect. The effect was
considered to be positive if the intervention group showed a greater
improvement than the control group and negative if the control group showed
the greater improvement. Where no statistically significant differences
occurred, this was classified as showing no effect. Where studies presented
their findings as within group differences rather than as differences between
the intervention and control group, these results are presented but should be
treated with caution. The findings from each study should be considered
alongside the methodological quality.
Of the 69 included trials 34 (49%) showed some beneficial effect of the
intervention and 20 of these (29%) showed an overall beneficial effect, one
study reported a negative effect of the intervention. Overall, of those studies
that found some beneficial effect of the intervention, three studies (two of
immunological interventions and one of supplements) found a benefit for
physiological outcome measurements only. Some studies investigated a
large number of outcomes - the range across studies was from 1 to 15 -
making it possible that any statistically significant differences could have
arisen by chance. The results of those studies evaluating multiple outcomes
should therefore be treated with caution.
In the behavioural category, cognitive behavioural therapy showed positive
results. Four147, 150, 218, 219 of the five RCTs evaluating CBT found a positive
overall effect of the intervention and these studies also scored highly on
validity assessment. One RCT which also included immunologic therapy149
and one RCT163 and two controlled trials of modified CBT,152, 217 did not find
overall beneficial effects of CBT. These studies also scored lower on the
validity assessment, especially one of the controlled trials which scored 1 out
of a possible 20. Two studies (one RCT, one controlled trial) of rehabilitation,
including CBT, showed a positive overall effect153, 155 but scored less than
50% on validity assessment. An overall beneficial effect was also found in
two controlled trials of two different multi-treatment approaches, one of which
included CBT210 and one of which was based on providing information and
advice.211 However, the methodological quality of both these studies was very
poor. A controlled trial of a buddy/mentor programme found a beneficial effect
for one of the seven outcomes investigated; this study scored poorly on the
validity assessment and only included 12 participants.212
Graded exercise therapy (GET) also showed promising results: four of five
RCTs found an overall beneficial effect of the intervention compared to the
control groups. Two of these RCTs scored highly in the validity assessment,
(scoring 17 out of a possible 20).157, 159
In the immunological category two small RCTs evaluated interferon, one of
these found no beneficial effect167 and the other showed some positive effects
although this was in relation to physiological outcomes only.168 The
methodological quality of both these studies was fairly poor; scoring 6 and 11
respectively, out of a possible 20 on the validity assessment. Four RCTs
assessed the effects of immunoglobulin in patients with CFS, of these one
showed an overall beneficial effect,216 one showed some positive effects164,
and two found no effect.165, 166 All four of these RCTs scored reasonably well
on the validity assessment, achieving scores of between 13 and 16 out of 20.
Immunoglobulin is a blood product and so there is a risk of the possible
transfer of, for example, infectious diseases..
One immunological RCT of Ampligen found an overall beneficial effect,169 and
a positive effect was found in one small controlled trial of staphylococcus
toxoid173 and one larger RCT.174 A small RCT of the antihistamine oral
terfenadine reported no beneficial effects.176 These three studies score
between 9 and 12 on the validity assessment.
A small RCT of acyclovir, reported a greater improvement in anxiety,
depression and confusion in the control group compared to the treatment
group, however, no differences in treatment effect were found for the other six
outcomes investigated.170 This study scored 15 out of 20 on the validity
assessment. Small RCTs of gancyclovir171 and inosine pranobex220 showed
no effect of treatment.
In the pharmacological category two RCTs of fludrocortisone reported no
effect of treatment, these studies were of reasonable quality.189, 190 Also in the
pharmacological category, trials of anti-depressants179-181, 193 reported no
effects of treatment either on symptoms of depression or on any of the other
outcome measures reported. Some beneficial effects of hydrocortisone were
found in two RCTs.187, 188 One of these studies scored highly on the validity
assessment with a score of 18 out of 20, the other was of poor quality with a
validity score of 2.
One poor quality RCT showed an overall beneficial effect of oral NADH183 and
another of lower quality showed no effect.184One controlled trial of selegiline
reported some positive effects of treatment but found no overall effect.194
Alternative / complementary
Homeopathic therapies were evaluated in two RCTs, one of poor quality196
and one of good quality.197 Some positive effects of homeopathy were seen
in the better quality trial. One controlled trial of osteopathy found some nonsignificant
improvements in the intervention group, but the values were
estimated from graphs and so the results may not be entirely accurate.199
This study scored very poorly on the validity assessment, scoring 0. A poor
quality study of massage therapy also found some positive effects.198
In the supplements category one good quality RCT of essential fatty acids
reported no beneficial effects of the intervention200 and one found an overall
beneficial effect.156 Magnesium supplements were found to have an overall
beneficial effect in the one good quality RCT where these were evaluated.201
Three fairly poor quality RCTs evaluated general supplements, none found a
positive effect.203-205 Poor quality RCTs of liver extract,202 pollen extract206
and medicinal mushrooms207 reported no beneficial effects.
Poor quality RCTs of melatonin185 and of acetyl-L-carnitine209 reported overall
beneficial effects, and a poor quality trial of acclydine and amino acids
reported beneficial effects in physiological measures.208
Two controlled trials210, 211 and one high quality RCT of combined treatments
showed overall beneficial effects of treatment.215 A controlled trial of a buddy/
mentor programme showed some positive effects.212
It must be noted for most of the interventions the results are based on one or
two studies, which may limit the generalisability of the findings. Another factor
which may limit the applicability of the findings is the inclusion criteria
specified in some trials. For example, in some studies participants were only
eligible if they could physically get to the clinic, which implies a certain level of
fitness. Those people who were unable to walk or to get out of bed were
automatically excluded and so it is not possible to assess whether the
interventions investigated would be effective, ineffective or even hazardous for
a more severely disabled group of people. However, in many of the trials very
limited information was given about participants who were ineligible or indeed
about the baseline functioning on many of those who were included.
Therefore, it is difficult to extrapolate how the findings might transfer to other
people with CFS and/or ME.
Evidence to answer question 4:
What are the information needs of healthcare professionals,
patients and carers?
Research literature evidence (adults)
Twelve research reports considered the information needs of adult patients
with CFS/ME, their carers and healthcare professionals. In addition two
guideline documents also contained relevant statements.
All the identified studies used surveys to gather data. The majority were
surveys of members of support groups (7 studies) 221-227, in particular Action
for ME. A further four studies were in general groups of patients.228-231 One
survey of black and ethnic minority adults did not report where respondents
were recruited.231 All of the studies were in general agreement that
healthcare professionals often lack information regarding CFS/ME. This was
also the conclusion of one survey of doctors232 and the two guideline
documents.1, 233 The types of information required covered all aspects of
CFS in general, including diagnosis, treatment, management and support.
Survey respondents also expressed the need for further information in general
for patients and carers. Various types (verbal, written, electronic) and sources
of information (healthcare professional, support group, internet, leaflets/books,
telephone advice lines) were discussed and opinions varied as to which was
required. There were, however, no studies with a strong research design
evaluating the effectiveness of different types and sources of information.
Evidence to answer question 5:
What are the support needs of healthcare professionals,
patients and carers?
Research literature evidence (adults)
Fourteen studies provided evidence regarding the support needs of patients
with CFS/ME, carers and healthcare professionals. In addition two guideline
documents also refer to support needs.
All identified studies were surveys or interviews assessing support needs.
Eight studies surveyed the opinions of CFS/ME support group members221-227,
237 in particular Action for ME. A further three surveys used respondents
within the community or clinics. 228-230 One study focussed on Black and
ethnic minority adults with CFS/ME.231 Only one study examined the support
needs of doctors.232 Overall the studies agreed that patients, carers and
health professionals need more support. The one survey of health
professionals highlighted a need for support from medical colleagues and
other relevant professionals such as social workers. Guidelines also support
the need for collaborative working.233 Types of support for patients and carers
varied and included support from health and social services. In particular help
with claiming benefits, and obtaining housing and medical services were
reported. Guidelines also recommend that support services should extend to
patients family and carers.1 One report included also an evaluation of the
effectiveness of a support service using a suitable research design (a sparsely
documented before-and-after study of a nurse support service) it did however
not assess directly whether the support needs were met.228
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