Open Access Highly Accessed Research article

Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study

William C Reeves1*, Dieter Wagner1, Rosane Nisenbaum12, James F Jones1, Brian Gurbaxani1, Laura Solomon13, Dimitris A Papanicolaou45, Elizabeth R Unger1, Suzanne D Vernon1 and Christine Heim6

Author Affiliations

1 Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA

2 University of Toronto, Toronto, Canada

3 Current Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA

4 Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

5 Merck & Co., Inc., Rahway, NJ, USA

6 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

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BMC Medicine 2005, 3:19  doi:10.1186/1741-7015-3-19

Published: 15 December 2005



The lack of standardized criteria for defining chronic fatigue syndrome (CFS) has constrained research. The objective of this study was to apply the 1994 CFS criteria by standardized reproducible criteria.


This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28). Participants were admitted to a hospital for two days and underwent medical history and physical examination, the Diagnostic Interview Schedule, and laboratory testing to identify medical and psychiatric conditions exclusionary for CFS. Illness classification at the time of the clinical study utilized two algorithms: (1) the same criteria as in the surveillance study; (2) a standardized clinically empirical algorithm based on quantitative assessment of the major domains of CFS (impairment, fatigue, and accompanying symptoms).


One hundred and sixty-four participants had no exclusionary conditions at the time of this study. Clinically empirical classification identified 43 subjects as CFS, 57 as ISF, and 64 as not ill. There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF, who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm.


The empirical definition includes all aspects of CFS specified in the 1994 case definition and identifies persons with CFS in a precise manner that can be readily reproduced by both investigators and clinicians.