Chronic fatigue syndrome (CFS) is marked by severe and persistent fatigue with a cluster of other symptoms. Fatiguing syndromes were chronicled 100 years ago and have long been the focus of considerable controversy in the medical establishment (Straus 1991; Wessely 1998). The study of unexplained fatiguing illnesses was greatly facilitated and legitimized in the last decade with the development of a case definition sponsored by the Centers for Disease Control and Prevention (CDC). That case definition has helped clinicians and scientists to recognize and classify CFS (Table 5.10). CDC’s case definition, first published in 1988 and revised in 1994 (see below), requires fatigue and related impairment in function, and the occurrence of four of eight other defining symptoms over at least 6 months (Fukuda et al. 1994; Holmes et al. 1988). Of the eight symptoms, the most commonly reported are headaches, post-exertional malaise, impaired cognition, and muscle pain (Buchwald and Garrity 1994).

The etiology of CFS is unknown, and no widely accepted laboratory tests or pathologic physical signs are widely accepted (Epstein 1995). Several biologic correlates of the syndrome have emerged, including dysregulation of the hypothalamic-pituitary-adrenal axis, immune activation, and other measures (Goshorn 1998), but they might be present in only a minority of patients; and those findings are not specific to CFS. Although infectious agents may trigger some cases of CFS, a complex, multifactorial etiology that incorporates biologic, psychologic, and social factors is likely (Wessely 1998). The degree of disability associated with CFS is striking, with high rates of unemployment (Bombardier and Buchwald 1996; Buchwald et al. 1996) and poor quality of life related to health (Hardt et al. 2001; Komaroff et al. 1996).

Before defining a primary and secondary study, it should be noted that CFS is a diagnosis of exclusion. The CDC criteria require that three elements be completed as part of a comprehensive evaluation. The first element, determining whether the symptom criteria for CFS are present, requires that a person be queried specifically about length and severity of fatigue and about eight ancillary symptoms. The second element, determining whether other medical conditions are present, mandates a complete physical examination, a battery of specified laboratory tests, and a medical history. The third element, assessing exclusionary psychiatric conditions, requires an interview by a trained professional to obtain diagnostic information.

Thus, in this report, a primary study for CFS is one in which CFS has been diagnosed. A secondary study is one in which a CFS-like condition has been documented. Both primary and secondary studies needed to include a suitable control group so that findings could be interpreted. Other studies that estimated the prevalence of symptoms of “chronic fatigue” (Gray et al. 1999a; Unwin et al. 1999), or multisymptom illness (Fukuda et al. 1998), are not considered further in this section. Likewise, studies that used scalar measures of disability and poor quality of life related to health (Reid et al. 2001) as surrogates for the CDC criteria are not included. Finally, self-reports of CFS (Unwin et al. 1999) and self-reports of a physician diagnosis of CFS (Gray et al. 2002) were not included among the secondary studies, because diagnostic data obtained that way are highly inaccurate. For example, in the Eisen et al. (2005) study, which the committee considered to be the only primary study, only two or three of 38 deployed and eight nondeployed veterans who self-reported CFS received a formal diagnosis after a comprehensive examination. Others, using a method of classifying a case of CFS based on cutoff scores on a fatigue scale and a functional status instrument, found that only 11% of veterans reporting a diagnosis of CFS met operational CFS study criteria.

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