Summary
Evidence Report/Technology Assessment: Number 42
Please Note: The evidence report this summary was derived from has not been updated within the past 5 years and is therefore no longer considered current. It is maintained for archival purposes only.
Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of the Full Report
Overview
This evidence report is a systematic review
that summarizes scientific literature about the
following aspects of chronic fatigue syndrome
(CFS) in adults:
- Case definitions.
- Prevalence
and natural history.
- Treatment.
In an
effort to organize and clarify this body of
research knowledge, the Agency for
Healthcare Research and Quality (AHRQ)
contracted for this evidence-based review
with the San Antonio Evidence-based
Practice Center (EPC). The National
Institute of Allergy and Infectious Diseases
nominated the topic for an evidence-based
review.
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Reporting the Evidence
Initially, a broad-ranging list of more than
20 questions was considered for the evidence
report. Seventeen technical experts from the
United States, Canada, Australia, and the
United Kingdom used a Delphi consensus
process to prioritize questions that the
evidence report could realistically address,
given the enormity of the data, and the limits
on time and resources. The scope of the
report was narrowed to the following high
priority questions:
- What are the existing case definitions of
CFS in adults?
- Which case definitions, if any, have been
substantiated and/or validated with reliably
discriminating constellations of symptoms
in adults?
- What are the prevalence and natural
history of CFS in adults?
- Do controlled studies in adults show that
particular therapies improve clinical
symptoms of CFS when compared to
placebo, no therapy, or each other?
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Methodology
Sources and Search Methods
English and non-English citations
addressing research in humans were identified
from the following electronic bibliographic
databases: MEDLINE, The Cochrane
Library, PsycINFO (all from 1980 to July
2000), and EMBASE (1988-93, 1998-2000).
Other sources included the Journal of Chronic
Fatigue Syndrome (1996-2000); Internet sites
addressing CFS; bibliographical references
from pertinent articles and reviews;
textbooks; and experts (through January
2001). An updated electronic bibliographic
search through October 1, 2000 was
conducted using PubMed.
The electronic
databases were searched using the following
terms: chronic fatigue syndrome,
neurasthenia, chronic fatigue disorders,
chronic fatigue immune dysfunction
syndrome, myalgic encephalomyelitis,
postviral fatigue, infectious mononucleosis
like, whiplash syndrome, royal free disease,
chronic epstein-barr, yuppie flu, and yuppy
flu.
Selection Criteria
Based on input from technical experts and
feasibility constraints, the following criteria
were used to select published and
unpublished articles for review:
- Literature addressing case definitions—written in English and addressing
definitions developed specifically for adults
with CFS.
- Literature addressing the substantiation and/or validation
of case definitions—written in English involving at least
30 adults with CFS; and examining whether individual or
clusters of manifestations listed in the commonly used
case definitions occurred more frequently in persons with
CFS than in other populations. Literature addressing
biologic markers for CFS was not reviewed.
- Literature addressing the prevalence of CFS—written in
English involving at least 100 adults with CFS; using at
least one of the four common case definitions for CFS;
and conducted in a community or primary care setting.
Literature addressing the natural history of CFS—written
in English involving at least 30 adults with CFS; using at
least one of the four common case definitions for CFS;
and a prospective study with a followup period of at least
1 year.
- English or non-English literature addressing therapy for
CFS—a controlled trial or a case-control study that
involved at least 10 adults who met one of the commonly
used case definitions for CFS.
Data Collection and Analysis
Two reviewers (a physician, psychometrician, research
methodologist, and/or nurse) independently abstracted data
from the selected studies. Data were synthesized
descriptively, emphasizing the quality and methodologic
design of studies. Items that were addressed included sources
and characteristics of study populations, sample sizes, case
definitions, assignment and followup protocols, response
and dropout rates, outcome assessments, and analytic
procedures. Relationships between clinical outcomes,
participant characteristics, and methodological characteristics
of studies were examined in evidence tables. Outcomes were
categorized using established schema for CFS symptoms.
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Findings
- There are four well-recognized case definitions of CFS.
The Centers for Disease Control and Prevention (CDC)
is currently spearheading the development of a fifth
definition. Definitions have been developed primarily by
expert knowledge and consensus processes, and have
evolved over time. A few comparative research studies
support the concept of a condition, characterized by
prolonged fatigue and impaired ability to function, which
is captured by the case definitions. The superiority of one
case definition over another is not well established. The
validity of any definition is difficult to establish because
there are no clear biologic markers for CFS and no
effective treatments that are specific only to CFS have
been identified.
- Findings from surveys that have involved at least 100
adult participants suggest the prevalence of CFS in
community populations is less than 1 percent. Prevalence
rates reported in surveys conducted in primary care
settings range from approximately 0.04 percent to 2.6
percent. Ability to interpret the reliability of these
estimates is limited by the following factors: use of
different case definitions, variability in assessment and
reporting methods, and poor response rates in some
studies.
- Prospective natural history studies have varied findings.
Precise estimates of recovery, improvement, and/or relapse
are not possible because there are few natural history
studies and those that are available have involved selected
referral populations or have used varying case definitions
and followup methods. Rates of self-reported global
improvement in symptoms at 12 to 18 months range
from 11 percent to 64 percent. Rates of self-reported
worsening of symptoms at 12 to 18 months range from
15 percent to 20 percent. Investigators from one study
estimate that the cumulative probability of recovery from
CFS at 5 years is approximately 30 percent.
- Thirty-eight controlled trials evaluated a heterogeneous
mix of interventions and had mixed results.
Immunologic therapy: Nine placebo-controlled trials,
one trial with a no-treatment control group, and one
four-arm trial that assessed immunologic therapy with
and without cognitive behavioral therapy were reviewed.
These 11 trials involved a total of 515 adult patients.
None had more than 100 participants. Followup duration
ranged from 2 months to 7 months; dropout rates ranged
from 2 percent to 13 percent. Immunologic therapies that
were assessed included agents such as immunoglobulin,
Ampligen, Acyclovir, interferon, and transfer factor.
The three randomized placebo-controlled trials that evaluated
immunoglobulin showed mixed results: one found general
improvement with immunoglobulin, another found
worse social functioning with immunoglobulin, and
another found no differences between immunoglobulin
and placebo. A single randomized placebo-controlled trial
found twice weekly infusions of intravenous Ampligen, an
agent with immunomodulatory and antiviral effects,
improved physical functioning, activity level, and
cognitive functioning and did not affect depression or
anxiety. This high quality double-blind trial included 92
severely debilitated patients who met the 1988 CDC
definition for CFS. It had a 6-month followup period and
a 9 percent dropout rate.
Participants given Ampligen had
more complaints of dry skin, and participants given
placebo had more complaints of insomnia. A single
randomized trial found Acyclovir, an antiviral agent,
increased depression, anxiety, and confusion compared to
placebo. A single randomized four-arm trial found
improved quality of life when transfer factor was
combined with cognitive behavioral therapy (CBT)
compared to either therapy alone. Placebo-controlled
trials that evaluated other immunologic therapies (e.g.,
interferon) were inconclusive. In sum, evidence from trials
involving immunologic therapies was relatively scant and
insufficient to conclude whether these treatments were
effective or ineffective. Ampligen, an investigational drug
that is not approved by the Food and Drug
Administration, given intravenously to severely debilitated
patients yielded the most promising results.
Corticosteroids: Two short-term (less than 3 months)
double-blind placebo-controlled randomized trials
involving 125 adults showed no benefit of
mineralocorticoids (fludrocortisone) in improving general
and/or functional outcomes. One of these two trials was
restricted to CFS patients with neurally mediated
hypotension. Two short-term (less than 3 months)
double-blind placebo-controlled randomized trials
involving 105 adults found low-dose glucocorticoids
(hydrocortisone) may improve fatigue and functioning,
but at the expense of potentially dangerous suppression of
adrenal function. Dropout rates in these trials ranged
from 9 percent to 20 percent. In sum, evidence from these trials was scant and insufficient to conclude whether
corticosteroids were effective or ineffective for CFS, but
there is some evidence of harm from glucocorticoid
therapy.
Antidepressants: There were five placebo-controlled
trials, involving 382 participants, that evaluated effects of
antidepressants in adults with CFS. Four were
randomized trials. Followup duration ranged from 6
weeks to 6 months; dropout rates ranged from 10 percent
to 29 percent. Two of the five studies excluded
participants with depression, while three involved mixed
populations, including participants with depression. One
of the randomized trials was a four-arm trial that
compared effects of an antidepressant with and without
graded exercise therapy. Compared to placebo,
antidepressants alone and antidepressants plus exercise
showed no consistent patterns of improvement, though
occasional improvements were found in some symptoms,
such as increased vigor and less anxiety.
Behavioral interventions: There were six controlled trials
involving 597 adults that evaluated some form of CBT.
Five were randomized trials. One of the randomized trials
was a four-arm trial that evaluated effects of CBT with
and without immunological therapy (transfer factor). In
the five randomized controlled trials, CBT was compared
to an attention placebo, relaxation, guided support,
counseling, and standard medical care. Trained therapists
delivered CBT. Numbers of CBT sessions ranged from 6
to 16 over periods of 6 weeks to 8 months. Dropout rates
at end of treatment periods ranged from 0 percent to 18
percent. Followup observations after completion of
treatment sessions ranged from 1 month to 5 years.
Content of CBT sessions emphasized increasing activity
and exercise, examination of psychosocial issues, and
explanations of illness. Of note, although the investigators
in the non-randomized trial labeled their intervention
CBT, this intervention focused on coping skills and
making lifestyle changes consistent with activity
limitations imposed by CFS. The comparison group in
the nonrandomized trial received no therapy. The
randomized trial that compared CBT with counseling
and the nonrandomized trial that compared CBT with no
treatment found no differences in outcomes between
groups. Randomized trials that compared CBT with
standard care, relaxation, and guided support found CBT
decreased fatigue and improved functional status or
quality of life.
There were three randomized trials that evaluated an
intervention other than formal CBT. These trials,
involving 350 adults, exercise focused on increasing
activity and exercise. In one, 12 weekly sessions of graded
therapy delivered by an exercise physiologist was
compared to flexibility and relaxation therapy. The
dropout rate was 29 percent. Participants assigned to
exercise therapy had greater overall improvement,
decreased fatigue symptoms and increased physical
functioning compared to participants given flexibility and
relaxation therapy.
In the second trial, effects of graded
exercise therapy delivered by a physiotherapist (8 sessions
over 6 months) with and without antidepressants were
evaluated. The dropout rate at the end of treatment was
29 percent. No differences between groups in outcomes
were found. The third randomized trial was a four-arm
trial that compared three different intensities of education
aimed at encouraging graded home exercise programs
with standard care. The interventions in this trial lasted
for 3 to 4 months and included instructions for
participants to examine predisposing and perpetuating
psychosocial factors and causal explanations of illness.
These interventions were described as briefer than formal
CBT and were not delivered by trained CBT therapists.
The dropout rate was 14 percent. Participants assigned to
any of the educational interventions had greater overall
improvement, decreased fatigue symptoms and increased
physical functioning compared to standard care. No
differences between the three intervention groups were
found. In sum, behavioral therapies that emphasize increasing
activity and physical exercise generally result in decreased
symptoms of fatigue and improvements in functional
status and quality of life. Whether formal and
comprehensive CBT delivered by experienced therapists is
superior to graded exercise programs alone is not clear.
Also, it is unlikely that the beneficial effects of such
general treatments are specific or limited only to patients
with CFS. In other words, although these therapies may
help some people with CFS, their effectiveness does not
help establish an underlying etiology or cause of CFS.
Other pharmacological agents or supplements: One
small randomized, double-blind placebo-controlled trial
involving 32 magnesium-deficient adults found
intramuscular magnesium sulfate given weekly for 6
weeks improved overall wellness and energy and reduced
pain and distress. One small double-blind placebo-controlled
trial in 35 adults found oral nicotinamide
adenine dinucleotide given daily for 4 weeks improved
general well-being. Small short-term trials evaluating
galanthamine, growth hormone, essential fatty acids, and
liver extract provided insufficient evidence to conclude
whether these therapies were or were not effective in
improving symptoms or functional outcomes.
Complementary therapies: One small, placebo-controlled
randomized trial of homeopathy in 64 adults
was inconclusive. One small, randomized trial in 20
adults found massage therapy led to improvements in
fatigue, sleep, myalgia, depression, and anxiety compared
to sham transcutaneous electrical nerve stimulation. One
non-randomized trial in 80 adults found osteopathic
therapy improved general health compared to normal
care.
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Future Research
There is no shortage of questions for future CFS research.
Our technical experts and peer reviewers identified the
following questions as high priority:
Case Definition, Etiology
- How should CFS be defined such that the definition is
reliable, valid, discriminatory from related conditions, and
acceptable to both the lay and scientific community?
- What is the pathogenesis of CFS? Does it result from
single or multiple etiologies? Can CFS be predicted in
people exposed to particular physical and/or psychological
challenges?
- What disorders frequently mimic CFS and what is the
most efficient approach to identify these disorders?
Natural History
- Are the psychiatric and neurologic conditions frequently
reported in CFS a result of CFS or are they an
underlying, predisposing factor to developing CFS?
- What is the spectrum of the severity of functional
impairment and disability associated with CFS?
- What is the long-term natural history of CFS, as
determined by large, longitudinal cohort studies that
include people representative of the entire spectrum of
CFS? Does natural history vary by gender, age, or other
coexisting medical conditions?
Treatment
- What are effective treatments for CFS, as determined by
replicable randomized controlled trials with adequate
numbers of participants and measurement of appropriate
outcomes and adequate followup? Are therapies borrowed
from related fields (e.g., sleep medicine, autonomic
nervous system abnormalities, endocrinology,
gastrointestinal illness, neurocognitive therapy) applicable
to treatment of CFS? Does response to treatment vary by
duration of illness?
- What is the comparative efficacy of cognitive behavioral
therapy versus exercise therapy for people with CFS?
What predicts response to either one of these therapies?
Outcomes
- Can reliable, standardized outcome measures that assess
degree of severity and a comprehensive range of
symptoms, and that are sensitive to changes in illness
status be developed?
- Can standardized definitions of outcomes such as
recovery and improvement be developed?
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Availability of the Full Report
The full evidence report from which this summary was
taken was prepared for AHRQ by the San Antonio
Evidence-based Practice Center at The University of Texas
Health Science Center at San Antonio under contract
number 290-97-0012. Printed copies may be obtained
free of charge from the AHRQ Publications Clearinghouse
by calling 1-800-358-9295. Requesters should ask for
Evidence Report/Technology Assessment No. 42, Defining
and Managing Chronic Fatigue Syndrome. (AHRQ Publication No. 01-E061).
The Evidence Report is available online on the National Library of Medicine Bookshelf.
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AHRQ Publication Number 01-E061
Current as of September 2001
Internet Citation:
Defining and Managing Chronic Fatigue Syndrome. Summary, Evidence Report/Technology Assessment: Number 42. AHRQ Publication No. 01-E061, September 2001. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/cfssum.htm