Report's Purpose and Scope

Several thousand references to chronic fatigue syndrome (CFS) appear in MEDLINE and other medical, bibliographic research databases. 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 of the CFS medical literature with the San Antonio Evidence-based Practice Center (EPC). The National Institute of Allergy and Infectious Diseases nominated the topic and partnered with the San Antonio EPC to utilize the report in their research agendas.

Initially, a broad-ranging list of more than 20 questions was suggested for the evidence report. Seventeen technical experts from the U.S., Canada, and the U.K 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. They narrowed the initial scope of the report to the following high priority questions:

1. What are the existing case definitions for CFS in adults?
2. Which case definitions, if any, have been substantiated and/or validated with reliably 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?

Defining Chronic Fatigue and Chronic Fatigue Syndrome

The symptom of fatigue may be defined by a pervasive sense of tiredness or lack of energy that is not related exclusively to exertion.¹ This type of fatigue is not alleviated by rest and must be distinguished from weakness, malaise, and temporary tiredness that occur as a direct result of excessive physical or mental exertion. In order to qualify fatigue as pathological, researchers have described the symptom as a continuum, much like blood pressure or obesity.² Although no obvious cutoff exists between normal and abnormal fatigue, assessment of fatigue using unique qualifiers, such as duration and degree of functional impairment, may help distinguish between the transient, mild states and more severe, prolonged disorders.

Researchers and clinicians distinguish prolonged fatigue from both chronic fatigue and CFS.³ Prolonged fatigue is defined as disabling fatigue that lasts at least one month. If this degree of fatigue lasts at least six months, it is called chronic. If the fatigue syndrome is disabling, lasts at least six months, is unexplained by other medical or psychological conditions, and is associated with a requisite number of other symptoms, it is considered CFS. Scientists have proposed other more specific definitions of CFS. These are discussed in the Results Section of the report entitled, “What are the existing case definitions for chronic fatigue syndrome?”

Burden of Disease

Fatigue is commonly reported by people in community settings and by patients attending primary care practices. For example, as many as 9% to 13% of people in community settings, and as many as 10% to 25% of people visiting general practitioners complain of prolonged and disabling fatigue.^4,56,7 Most such people do not have CFS. They do not have accompanying symptoms (e.g., sore throat, impaired memory or concentration, tender lymph nodes, myalgia, arthralgia, headaches, sleep disturbance, fever, muscle weakness) that are required for current definitions of CFS, and they may have medical or psychiatric conditions that explain their prolonged fatigue. The actual prevalence of prolonged fatigue states that meet CFS definitions is described later in this report under the Results section entitled, “What is the prevalence and natural history of CFS?”

People with CFS have described their burden of illness in various manners.^8-10 For example, some people describe CFS as a state of illness that is experienced as “an integrated whole encompassing body, mind, and spirit.”^9,10 They may experience fatigue as a flu-like illness or a sensation of heaviness or being weighted down or of being drained, groggy, foggy-minded, or drugged.^8,10 Others describe a lack of energy or stamina, or multiple cognitive problems such as an inability to complete short, routine tasks or difficulty concentrating.^8,10 Some people describe fluctuating courses of illness characterized by sudden and unexpected changes in symptoms.^8,9 They may feel marginalized, socially isolated, embarrassed, or stigmatized.^8,9 Some people find CFS extremely debilitating, such that they lose their social and occupational functioning.

History and Terms Used to Describe Chronic Fatigue Syndromes

Disorders characterized by severe chronic fatigue have been reported in the literature as early as the 18^th Century.¹¹ In 1750, Manningham described a syndrome of severe fatigue with symptoms of low-grade fever, weariness throughout the body, and pains.¹² In 1869, George Beard, a New York physician, used the term neurasthenia to describe a chronic fatigue syndrome.² The diagnosis of neurasthenia was given to patients with general nervousness, hysteria, or minor depression, as well as to patients with fatigue. Neurasthenia is still listed in the World Health Organization's International Classification of Diseases as a syndrome of mental and physical fatigue of at least three months' duration.

In the early 1900s, the concept that chronic fatigue followed infections, such as influenza and typhoid, was established and widely accepted.² For example, myalgic encephalomyelitis, also known as Royal Free Disease, was originally thought to represent a post-viral fatigue syndrome. In 1955, an epidemic of fatigue with myalgia, and sensory motor symptoms occurred at several Royal Free Hospital branches in London. An infectious viral etiology that affected the brain and muscle was initially considered.²

In the mid-1980s, associations between Epstein-Barr virus and chronic fatigue were reported.^13-17 The proposed Epstein-Barr etiology received enormous media and medical attention and led to a consensus conference organized in 1985 by the National Institute of Allergic and Infectious Diseases. Numerous CFS groups were developed and began lobbying for answers to their questions about the condition. Publications addressing chronic mononucleosis, and another U.S. epidemic in the Lake Tahoe, Nevada area convinced researchers that methods to study the nosology and causality of CFS were needed.^16,18,19

In the last two decades, several case definitions for CFS have been proposed, and there have been multiple studies aimed at describing particular manifestations of patients with chronic fatigue syndrome. Investigators have conducted surveys aimed at describing the prevalence of CFS in community and clinical settings, as well as longitudinal studies describing the natural history of CFS. Several trials have evaluated whether various therapies improve symptoms and outcomes. Finally, hundreds of studies examining potential etiologies and diagnostic markers for CFS have been conducted. The purpose of this evidence report is: a) to organize and categorize research related to CFS; b) describe existing case definitions of CFS and how they are substantiated; c) assess the prevalence and natural history of CFS in adults; and d) summarize trials of therapies for adults with CFS.