Evidence Report/Technology Assessment

Number 42

Prepared for:
Agency for Healthcare Research and Quality
U. S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852

http://www.ahrq.gov

Contract No: 290-97-0012

Prepared by:
San Antonio Evidence-based Practice Center at
The University of Texas Health Science Center at San Antonio
Cynthia D. Mulrow, MD, MSc
Program Director
Gilbert Ramirez, DrPH
Project Director

John E. Cornell, PhD
Karen Allsup, BS
Investigators

AHRQ Publication No. 02-E001

October 2001

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and Research (AHCPR) was reauthorized and renamed the Agency for Healthcare Research and Quality (AHRQ). The law authorizes AHRQ to continue its research on the cost, quality, and outcomes of health care and expands its role to improve patient safety and address medical errors.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers -- patients and clinicians, health system leaders, and policymakers -- make more informed decisions and improve the quality of health care services.

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Acting Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

Objectives of this evidence report are to summarize research evidence regarding the case definitions, prevalence, natural history and therapy of chronic fatigue syndrome (CFS).

English and non-English citations were identified through July 2000 from four electronic bibliographic databases (MEDLINE, The Cochrane Library, PsycINFO, EMBASE), CFS Internet sites, the Journal of Chronic Fatigue Syndrome, references of pertinent articles, textbooks, and experts. The electronic search was updated through October 2000 using PubMed; experts identified relevant citations up to January 2001.

Published and unpublished studies that were conducted after 1980 and that involved adults with CFS were reviewed.

Two reviewers (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. Meta-analyses were not done because of marked heterogeneity of study designs.

• There are four well-recognized case definitions of CFS, and the Centers for Disease Control and Prevention (CDC) is spearheading the development of a fifth. Definitions, developed primarily by expert knowledge and consensus, 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 specific only to CFS have been identified.
• Findings from surveys show that the prevalence of CFS in community populations is probably less than 1% and in primary care populations less than 3%. The reliability of these estimates is limited, because surveys used different case definitions and varied assessment and reporting methods, and sometimes had poor response rates.
• Precise estimates of recovery, improvement, and/or relapse from CFS 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.
• Thirty-eight controlled trials evaluating multiple treatment interventions show the following mixed results:

Evidence from 11 trials is scant and insufficient to conclude whether immunological therapies, such as immunoglobulin, Ampligen, Acyclovir, interferon, and transfer factor, are effective or ineffective.

Evidence from four trials suggests that there are no consistent benefits from mineralocorticoids (fludrocortisone), but that there are some improvements in fatigue and functional status with glucocorticoids (hydrocortisone). However, glucocorticoid therapy may severely suppress adrenal function.

Evidence from five trials show that there is no consistent pattern of benefit from antidepressant therapy, though some participants in these trials experienced improved vigor and less anxiety.

Evidence from nine trials generally show that behavioral interventions that emphasize increased activity levels result in improvements in fatigue, overall well-being, quality of life and functional status.

Evidence from trials is scant and insufficient to conclude whether complementary therapies, such as homeopathy, massage therapy and osteopathy are effective or ineffective. Evidence from trials is scant and insufficient to conclude whether multiple other therapies, such as nicotinamide adenine dinucleotide (NADH), galanthamine, growth hormone, essential fatty acids, and liver extract therapies, are effective or ineffective. Findings from one small trial suggest that magnesium therapy may improve energy, overall well-being, pain and distress in patients with CFS and magnesium deficiency.

Existing case definitions for CFS appear to characterize a group of people with prolonged fatigue and impaired ability to function. The validity and superiority of any particular case definition are not well established. Surveys suggest that the prevalence of CFS in community populations is less than 1%. Precise estimates of rates of recovery, improvement and/or relapse from CFS are not available. Although several therapies have been studied, potential benefits as well as harms of most therapies are not well established. Behavioral interventions that emphasize increasing activity levels may improve quality of life and function in some people with CFS.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Mulrow CD, Ramirez G, Cornell JE, et al. Defining and Managing Chronic Fatigue Syndrome. Evidence Report/Technology Assessment No. 42 (Prepared by San Antonio Evidence-based Practice Center at The University of Texas Health Science Center at San Antonio under Contract No. 290-97-0012). AHRQ Publication No. 02-E001. Rockville (MD): Agency for Healthcare Research and Quality; October 2001.

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, and 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.

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:

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.

Based on input from technical experts and feasibility constraints, the following criteria were used to select published and unpublished articles for review:

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.

• There are four well-recognized case definitions of CFS exist. 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.

Nine placebo-controlled trials, one trial with a no-treatment control group, and one 4 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 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 4-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.

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.

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.

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 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 focused on increasing activity and exercise. In one, 12 weekly sessions of graded exercise 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.

One small randomized, double-blind placebo-controlled trial involving 32 magnesium-deficient adults, found intramuscular magnesium sulfate given weekly for six 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.

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.

There is no shortage of questions for future CFS research. Our technical experts and peer reviewers identified the following questions as high priority.

• 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?

• 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?

• 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?

• 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?