Chronic Fatigue Syndrome
- Author: Burke A Cunha, MD; Chief Editor: Michael Stuart Bronze, MD more...
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.
CFS 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).
More recently, the US Institute of Medicine (IOM) proposed that the condition be renamed “systemic exertion intolerance disease” (SEID) to better reflect the condition's hallmark defining symptom, postexertional malaise.
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 is one of the many causes that 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 no cause of CFS has been determined, no effective therapy exists for CFS.
According to the Centers for Disease Control and Prevention (CDC), 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
Tender lymph nodes
Multijoint pain without swelling or redness
Headaches of a new type, pattern or severity
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.
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.
In 2015, the IOM proposed new diagnostic criteria for both adults and children, as follows:
Ongoing (>6 months) substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest
Postexertional malaise (often described by patients as a "crash" or "collapse" after even minor physical or mental exertion)
Cognitive impairment and/or orthostatic intolerance
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 elevated levels of immunoglobulin G (IgG) viral capsid antigen (VCA) EBV, this determination should be considered as an incidental finding in 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 abnormalities.
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,[3, 4] but XMRV has been ruled out as a cause of CFS.[5, 6, 7, 8]
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.
Some have suggested that the infectious agent responsible for CFS is 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.[9, 10]
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.
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. It occurs most commonly in young to middle-aged adults.
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.
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