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Evidence Report/Technology Assessment: Number 42

Defining and Managing Chronic Fatigue Syndrome


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


This evidence report is a systematic review that summarizes scientific literature about the following aspects of chronic fatigue syndrome (CFS) in adults:

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:

  1. What are the existing case definitions of CFS in adults?
  2. Which case definitions, if any, have been substantiated and/or validated with reliably discriminating constellations of symptoms in adults?
  3. What are the prevalence and natural history of CFS in adults?
  4. 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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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:

  1. Literature addressing case definitions—written in English and addressing definitions developed specifically for adults with CFS.
  2. 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.
  3. 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.
  4. 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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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

Natural History



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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. It can also be downloaded as a zipped file.

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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.

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