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

October 2005

Table of contents


Review Questions ..........................................................................................................5

Review methods.............................................................................................................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.

Review Questions

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

and carers?


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

electrodermal analysis.

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.


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

of life).166

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

severity, activity).

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

outcomes investigated.212

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

validity assessment.


Severely affected

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

scores (p=0.04).211

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.


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

carefully considered.

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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