Epidemiology

Idiopathic chronic fatigue is very common (5%–10% of patients in general medical practice), but very few (≤1%) can be diagnosed with CFS using the 1994 criteria. The US national prevalence of CFS was estimated by the CDC through a network of physicians in four American cities. The prevalence ranged from 3 to 11 per 100 000 population, and the gender and age distribution were similar in all four sites. Most patients were female (7:1) in the fourth and fifth decades of life. Estimates from clinic-based studies in Australia and the United Kingdom yield similar results. However, a population-based survey in San Francisco and other community-based studies elsewhere suggest a prevalence of about 0.2%, with a larger proportion of males, ethnic minorities, and those of lower socioeconomic classes. The discrepancy between community- and clinic-based studies is attributable to the greater utilization of clinical services by middle- and upper-class women. It belies the notion of a “yuppie flu,” a pejorative term applied to this disorder in the past.

Illnesses consistent with CFS also occasionally occur in epidemic fashion. In some instances, the outbreaks may be associated with an infectious event; however, in others, the distribution of illness among the populations at risk clearly does not resemble the spread of an infection. Examples of the latter type include the large hospital-based outbreaks in Los Angeles, California, and London, UK, that affected the hospital professional staff but not the hospitalized patients or nonprofessional staff.

Pathophysiology

Research on the pathophysiology of CFS has been complicated by the definitional problems described above; most importantly by the problem of selecting a homogenous group of subjects for study who have symptoms that are attributable to the same cause or causes. Many patients have an acute onset of the syndrome. A small proportion can be traced to a diagnosed infectious disease; more often this is presumed based on the history but cannot be confirmed. CFS may also follow other physically and psychologically stressful events, such as surgeries, accidents, deaths, and divorces. Many patients have an insidious onset with no definite precipitating event. Regardless of the onset, the majority of patients have past or current psychiatric disorders, but a large minority has no active or past psychiatric symptoms.

Numerous infections have been associated with CFS, but evidence that the syndrome is not associated with any specific infectious agent is of three main types. First, there is no single infectious agent that is detectable in all cases of CFS; the disorder may occur even in the absence of the most common agents, such as EBV. Second, the development of the same syndrome occurs during convalescence after infections with nonoverlapping geographic distribution (e.g., Ross River virus, Q fever, or Lyme disease). Third, attempts to treat CFS with anti-infectives have been uniformly disappointing. It may be true that only a specific type of infection with prolonged duration or severity is necessary to precipitate CFS. Indeed, patients seen in general practice for common, simple infections do not have an increased frequency of prolonged fatigue relative to patients seen for other medical problems. However, postinfectious cases and those with no apparent precipitant are clinically indistinguishable with respect to symptoms and psychosocial features once the defining criteria are met. These observations lead to the conclusion that the syndrome is a nonspecific sequel to a variety of infections or other precipitants. Whether patients who have CFS will reactivate latent viruses more frequently than well individuals is an unsettled issue, but no correlation between viral reactivation (e.g., EBV) and the expression of symptoms has been demonstrated.

From time to time, sensational reports appear linking a persistent infectious agent with the syndrome, as in 1985 with EBV. The latest of these events occurred in late 2010 when an article appeared in Science reporting the presence of a xenotropic murine retrovirus (XMRV) in two-thirds of a panel of CFS patients and only ~4% of controls. The putative presence of this virus was later shown to be due to contamination of samples with mouse DNA, and the original article supporting the claim was subsequently retracted. Clinicians should maintain skepticism about claims of this kind, since the attribution of CFS to a single transmissible agent is not easy to reconcile with the clinical and epidemiologic features described above.

Apart from infections, disruptions in various biologic systems associated with CFS have been proposed as inciting or perpetuating factors. These include subtle alterations in immunologic, neuroendocrine, and neuropsychological function. Attempts to correlate cytokine levels with the presence or severity of CFS have been inconsistent. However, interferons are known to activate expression of the enzyme 2′,5′-oligoadenylate synthetase. This enzyme generates 2′,5′-adenylate oligonucleotides that bind to and activate RNAse L, leading to the cytoplasmic degradation of viral and other RNAs. CFS is associated with increased levels of 2′,5′A oligonucleotides, RNAse L activity, and the expression of a low-molecular-weight RNAse L molecule. The pathophysiologic significance of this phenomenon is uncertain, but measurement of this pathway has been suggested as a potential biologic marker for CFS.

The hypothesis that the central nervous system is the principle site of the pathophysiology in CFS has gained support in recent years. This hypothesis is bolstered by the presence of neuropsychological symptoms in the active syndrome, the observation of prior or pre-existing psychiatric disorders in a large proportion of patients, and subtle alterations of hormones regulated at the hypothalamic level. Previous or concurrent depression is frequently present in CFS. When patients in general practice are evaluated for “viral” illnesses, the psychiatric morbidity and the patient’s belief structure concerning the illness are better predictors of subsequent chronic fatigue than the severity of symptoms at the time of presentation. More objective evidence of central nervous system involvement includes the observed disruption of the hypothalamic–pituitary–adrenal (HPA) axis. As a group, patients with CFS appear to have lower HPA axis activity than age- and gender-matched controls. Most evidence points to the hypothalamus as the affected element of the axis; however, it is not known whether this defect is primary or secondary to inactivity, sleep disruption, or continuing stress accompanying CFS. Nevertheless, the decreased HPA activity in CFS contrasts with the increased activity of the HPA axis observed in patients with major depressive disorder. It is more consistent with findings in post-traumatic stress disorder (PTSD), suggesting that CFS may represent a dysfunctional capacity to respond to both physical and psychological stress, either acquired or genetic or both.

Some evidence for a genetic predisposition to CFS has been generated by twin studies. Studies in the United States, Australia, and Great Britain have shown an increased concordance in monozygotic, rather than dizygotic, twins. However, a microarray analysis of the transcriptome of monozygotic twins who are discordant for CFS failed to show any significant differences. These observations and the other findings mentioned above support a pathophysiologic theory of CFS that depends on a predisposition involving genetic or environmental factors or both. In the presence of an acute provocation, such as an infection, the stress response system fails and results in both the production and perpetuation of subjective symptoms (i.e., fatigue, pain, disrupted sleep, poor cognition) and detectable immune alterations.

Diagnosis

CFS is a clinical diagnosis that depends almost entirely on the history and the patient’s report of symptoms. There are no characteristic clinical signs. There are no laboratory tests that can be used with any reliability to rule in or rule out the diagnosis. The purpose of the physical examination and basic laboratory testing is to confirm that there is not another medically definable condition that may be causing the symptoms. In the absence of any confounding medical conditions, the diagnosis of CFS may be guided by the published consensus criteria. For reasons explained above, the clinician need not apply these criteria stringently for individual patients.

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