Chronic Fatigue Syndrome 

Chronic fatigue syndrome (CFS) is a disorder characterized by a state of chronic fatigue that persists for more than 6 months, has no clear cause, and is accompanied by cognitive difficulties. It was initially termed encephalomyalgia (or myalgic encephalomyelitis) because British clinicians noted that the essential clinical features of CFS included both an encephalitic component (manifesting as cognitive difficulties) and a skeletal muscle component (manifesting as chronic fatigue).

Various unrelated infectious diseases (eg, pneumonia, Epstein-Barr virus [EBV] infection, diarrhea, upper respiratory tract infections) appear to lead to a state of prolonged fatigue in some persons. Generally, if this condition is accompanied by cognitive difficulties, it is referred to as CFS.

The cause of CFS is unknown, but the disorder is probably an infectious disease with immunologic manifestations. EBV has been excluded as a cause of CFS, even though EBV infection may lead to a state of chronic fatigue. CFS is not synonymous with chronic EBV infection or chronic infectious mononucleosis.

Because no direct tests aid in the diagnosis of CFS, the diagnosis is one of exclusion but that meets certain clinical criteria, which are further supported by certain nonspecific tests. The diagnosis of CFS also rests on historical criteria (ie, otherwise unexplained fatigue for more than 6 months accompanied by cognitive dysfunction). The absence of cognitive dysfunction should exclude CFS as a potential diagnosis.

Because most cases of CFS may be based on a viral infection, no uniformly effective therapy exists for CFS.

For patient education resources, see the Mental Health and Behavior Center, Muscle Disorders Center, and Back, Ribs, Neck, and Head Center, as well as Chronic Fatigue Syndrome, Fibromyalgia, and Fatigue.

Diagnostic criteria

According to the Centers for Disease Control and Prevention (CDC),^[1] in order to receive a diagnosis of CFS, a patient must (1) have severe chronic fatigue of at least 6 months’ duration, with other known medical conditions excluded by clinical diagnosis, and (2) concurrently have 4 or more of the following symptoms:

• Substantial impairment in short-term memory or concentration
• Sore throat
• Tender lymph nodes
• Muscle pain
• Multijoint pain without swelling or redness
• Headaches of a new type, pattern or severity
• Unrefreshing sleep
• Postexertional malaise lasting more than 24 hours

The symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.

The CDC case definition also states that any unexplained abnormality detected on examination or other testing that strongly suggests an exclusionary condition must be resolved before further classification is attempted. Conditions that do not exclude CFS include the following:

• Any condition defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests, including fibromyalgia, anxiety disorders, somatoform disorders, nonpsychotic or melancholic depression, neurasthenia, and multiple chemical sensitivity disorder
• Any condition under specific treatment sufficient to alleviate all symptoms related to that condition and for which the adequacy of treatment has been documented, including hypothyroidism for which the adequacy of replacement hormone has been verified by normal thyroid-stimulating hormone levels, or asthma in which the adequacy of treatment has been determined by pulmonary function and other testing
• Any condition, such as Lyme disease or syphilis, that was treated with definitive therapy before development of chronic symptoms
• Any isolated and unexplained physical examination finding, or laboratory or imaging test abnormality that is insufficient to strongly suggest the existence of an exclusionary condition, including an elevated antinuclear antibody titer that is inadequate, without additional laboratory or clinical evidence, to strongly support a diagnosis of a discrete connective tissue disorder

In children, CFS is poorly defined. Most studies of CFS in the pediatric age range have followed the CDC criteria. However, whether the adult CDC case definition can be applied to children and adolescents is debatable.

To date, the CDC has declined to modify the CFS case definition for the pediatric age group, even when common pediatric findings (eg, frequent sore throat and swollen glands) are included in the criteria; these findings fail to distinguish patients from their otherwise healthy contemporaries. Moreover, the CDC has indicated that CFS is unlikely to occur in patients younger than 10 years. However, establishing the existence of a self-reported illness in younger age groups is difficult, and the truth concerning juvenile CFS remains unclear.

Children have typically been referred to specialty clinics after extensive screening by their primary care physician has yielded negative or nonspecific test results. Therefore, common short-lived causes of fatigue are effectively excluded. The length of fatigue (6 months) also effectively excludes many common illnesses and probably should be retained in any forthcoming pediatric case definition.

Currently, no single model fully explains the pathogenesis of CFS. A simple linear medical model, wherein a single infectious agent causes a specific series of detrimental biologic effects, has not been supported.

In more complex models, the final common pathway may be the result of various insults, including viral infection and stress. The consequence of these insults may be immune system activation and dysregulation. The resulting cytokine release and epiphenomena, such as reactivation of latent viruses, contribute to fatigue and associated symptoms.

Because the immune system is upregulated in CFS, the levels of antibodies to various previously encountered antigens are increased. Although increased titers do not indicate a causal relationship in CFS, the titers are nonetheless useful as laboratory clues, which, when taken together, are common in patients with CFS.

Because so many patients with a possible diagnosis of CFS are found to have high levels of immunoglobulin G (IgG) viral capsid antigen (VCA) EBV, this determination should be considered consistent with but not diagnostic of CFS. Most patients with CFS demonstrate elevated IgG, coxsackievirus B, human herpesvirus 6 (HHV-6), and/or C pneumoniae titers. Patients with CFS also commonly have a decreased percentage of natural killer (NK) cells. Most patients with CFS have 2 of the 3 above-mentioned immunological perturbations.

There is also no convincing support for a simple psychological model, which posits that fatigue is the expression of a primary psychopathologic condition. A more dynamic biopsychosocial model proposes that an acute infectious or immunologic event, associated with a physiologic state of fatigue, initiates a cycle in which avoidant behaviors that diminish symptom severity may become associated with various attributional and cognitive factors. Thus, symptoms are attributed to an external agent (eg, virus).

The finding that both children and adults with CFS maintain strong convictions that their fatigue is purely physiologic, rejecting psychological explanations, lends some support to this attributional model. A prospective study of patients experiencing a viral illness found that the presence of an attributional style characterized by belief in vulnerability to illness, along with physician indecisiveness in making a diagnosis, predicted which patients developed CFS better than viral illness factors did.

Therefore, there may be some psychological factors inherent in patients with CFS, which clinicians have yet to understand. These factors result in a differential prolonged response to the initial physical insult and interact with the response to treatment approaches in such a way that outcome is highly variable despite the potential validity of the physical explanatory model (eg, use of antihypotensive medications for neurally mediated hypotension).

Synergism between psychological factors and physiologic factors at the level of the CNS appears likely. Support for this notion is derived from other areas of orthostatic and autonomic study; for example, fluoxetine has been used as highly effective therapy for persons with refractory vasovagal faint, migraine, and panic disorder. Although the pathogenesis of CFS remains unclear, a synthesis of psychology with physiology is attractive.

Many viruses have been studied as potential causal agents, including EBV, HHV-6, coxsackievirus B, spumaviruses, and even human T-cell leukemia virus strains; however, no definitive causal relation has been determined. A role for xenotropic murine leukemia virus–related virus (XMRV) and other murine retroviruses was posited,^{[2, 3]} but XMRV has been ruled out as a cause of CFS.^{[4, 5, 6, 7]}

Patients with CFS are often referred to an infectious disease specialist because of elevated levels of immunoglobulin G (IgG) to the viral capsid antigen (VCA) of EBV. Increased IgG titers to the VCA of EBV are common in the general population, regardless of whether the patient is fatigued. An increased IgG VCA EBV titer indicates past exposure to EBV but does not indicate acute disease or explain the patient’s chronic fatigue state. EBV infection is often the precipitating event that has triggered the patient’s chronic fatigue state.

Some have suggested that the infectious agent responsible for CFSis Chlamydia pneumoniae, which may become activated after contact with another infectious agent. In hospitals or commercial laboratories, immunoglobulin M (IgM) tests and IgG enzyme-linked immunosorbent assay (ELISA) are used to test for C pneumoniae. As with elevated EBV IgG VCA titers, many individuals in the healthy population have elevated IgG titers to C pneumoniae.

Some patients with CFS are found to have elevated IgM C pneumoniae titers, indicating a recent C pneumoniae infection, and these patients are the most likely to respond to antichlamydial therapy. However, definitive proof supporting causality is lacking.^{[8, 9]}

Some investigators studying the potential role of C pneumoniae in CFS believe that serum tests are insensitive and that a more sensitive test (eg, polymerase chain reaction [PCR]) should be used for evaluation. PCR for C pneumoniae is a very sensitive technique but, unfortunately, is available only in research centers.

Candida albicans and other yeast infections do not cause CFS.

Genetic factors

A familial predisposition (eg, for CFS or related fibromyalgia) has been reported; studies aimed at accurate assessment of genetic factors are under way. Preliminary data suggest that the illness is different in boys and girls. An allergic history is common. Milk intolerance is often reported.

CFS is common in the United States, but the data are difficult to interpret because the various studies define CFS in different ways. Outside the United States, CFS appears to be less common, but it probably exists worldwide. Overall, CFS is more common in females than in males.^[10] It occurs most commonly in young to middle-aged adults.

For pediatric CFS, estimates of prevalence vary widely and have yet to be accurately determined. In many studies, a prevalence range of 2 to nearly 300 cases per 100,000 children has been proposed, and some reports cite figures as high as several percent. These surveys used various polling techniques and were conducted in different parts of the United States, as well as in other countries. Regional differences in CFS incidence and prevalence may be observed.

The clinical profile of a pediatric patient with CFS is of a high-achieving student or athlete who is usually female (80%), white, and in the middle-class or upper–middle-class socioeconomic level. This may reflect referral bias but appears consistent throughout most studies.

As suggested by the term chronic, the clinical course of CFS is punctuated by remissions and relapses, often triggered by intercurrent infection, stress, exercise, or lack of sleep. The course in adolescents is similar to that in adults.

Most cases improve to some degree over time. Compelling evidence presented by Rowe and Bell at the American Association of Chronic Fatigue Syndrome meeting in January 2001 demonstrated that most children with CFS improve and that improvement is independent of short-term therapy with various agents. Nevertheless, a substantial minority of children have long-term symptoms and morbidity.

Follow-up data from the Lyndonville outbreak indicated successful resolution in most cases as determined by self-assessment measures. However, improvement was often a matter of interpretation on the part of the patients. When questioned further, many had persistence of symptoms but had tailored their lifestyles to the persistent disability.