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The Chronic Fatigue Syndrome: A Comprehensive Approach To Its Definition And Study

K. Fukuda, S. Straus, I. Hickie, M. Sharpe, J. Dobbins, A. Komaroff
Published 1994 · Medicine

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We have developed a conceptual framework and a set of research guidelines for use in studies of the chronic fatigue syndrome. The guidelines cover the clinical and laboratory evaluation of persons with unexplained fatigue; the identification of underlying conditions that may explain the presence of chronic fatigue; revised criteria for defining cases of the chronic fatigue syndrome; and a strategy for dividing the chronic fatigue syndrome and other unexplained cases of chronic fatigue into subgroups. Background The chronic fatigue syndrome is a clinically defined condition [1-4] characterized by severe disabling fatigue and a combination of symptoms that prominently features self-reported impairments in concentration and short-term memory, sleep disturbances, and musculoskeletal pain. Diagnosis of the chronic fatigue syndrome can be made only after alternative medical and psychiatric causes of chronic fatiguing illness have been excluded. No pathognomonic signs or diagnostic tests for this condition have been validated in scientific studies [5-7]; moreover, no definitive treatments for it exist [8]. Recent longitudinal studies suggest that some persons affected by the chronic fatigue syndrome improve with time but that most remain functionally impaired for several years [9, 10]. Issues in Chronic Fatigue Syndrome Research The central issue in chronic fatigue syndrome research is whether the chronic fatigue syndrome or any subset of it is a pathologically discrete entity, as opposed to a debilitating but nonspecific condition shared by many different entities. Resolution of this issue depends on whether clinical, epidemiologic, and pathophysiologic features convincingly distinguish the chronic fatigue syndrome from other illnesses. Clarification of the relation between the chronic fatigue syndrome and the neuropsychiatric syndromes is particularly important. The latter disorders are potentially the most important source of confounding in studies of chronic fatigue syndrome. Somatoform disorders, anxiety disorders, major depression, and other symptomatically defined syndromes can manifest severe fatigue and several somatic and psychological symptoms and are diagnosed more frequently in populations affected by chronic fatigue [11-13] and the chronic fatigue syndrome [14, 15] than in the general population. The extent to which the features of the chronic fatigue syndrome are generic features of chronic fatigue and deconditioning due to physical inactivity common to a diverse group of illnesses [16, 17] must also be established. A Conceptual Framework for Studying the Chronic Fatigue Syndrome In the United States, 24% of the general adult population has had fatigue lasting 2 weeks or longer; 59% to 64% of these persons report that their fatigue has no medical cause [18, 19]. In one study, 24% of patients in primary care clinics reported having had prolonged fatigue ( 1 month) [20]. In many persons with prolonged fatigue, fatigue persists beyond 6 months (defined as chronic fatigue) [21, 22]. We propose a conceptual framework Figure 1 to guide the development of studies relevant to the chronic fatigue syndrome. In this framework, in which the chronic fatigue syndrome is considered a subset of prolonged fatigue ( 1 month), epidemiologic studies of populations defined by prolonged or chronic fatigue can be used to search for illness patterns consistent with the chronic fatigue syndrome. Such studies, which differ from casecontrol and cohort studies based on predetermined criteria for the chronic fatigue syndrome, will also produce much-needed clinical and laboratory background information. Figure 1. A conceptual framework of abnormally fatigued populations, including those with the chronic fatigue syndrome (CFS) and overlapping disorders. This framework also clarifies the need to compare populations defined by the chronic fatigue syndrome with several other populations in casecontrol and cohort studies. The most important comparison populations are those defined by overlapping disorders, by prolonged fatigue, and by forms of chronic fatigue that do not meet criteria for the chronic fatigue syndrome. Controls drawn exclusively from healthy populations are inadequate to confirm the specificity of chronic fatigue syndrome-associated abnormalities. Need for Revised Criteria To Define the Chronic Fatigue Syndrome The possibility that chronic fatigue syndrome study populations have been selected or defined in substantially different ways has made it difficult to interpret conflicting laboratory findings related to the chronic fatigue syndrome [23]. For example, the North American chronic fatigue syndrome working case definition [1] has been inconsistently applied by researchers [24]. This case definition is frequently modified in practice because some of the criteria are difficult to interpret or to comply with [25] and because opinions differ about the classification of chronic fatigue cases preceded by a history of psychiatric illnesses [26, 27]. Current criteria for the chronic fatigue syndrome also do not appear to define a distinct group of cases (28; Reyes M, et al. Unpublished data). For example, participants in the Centers for Disease Control and Prevention (CDC) chronic fatigue syndrome surveillance system [29] who met the chronic fatigue syndrome case definition did not substantially differ by demographic characteristics, symptoms, and other illness features from those who did not meet the definition (except by criteria used to place patients into one of our predetermined surveillance classification categories [Reyes M, et al. Unpublished data]). These findings indicate that additional subgrouping or stratification of study cases into more homogeneous groups is necessary for comparative studies. Need for Clinical Evaluation Standards Our experience suggests that fatigued persons often receive either inadequate or excessive medical evaluations. In the CDC chronic fatigue syndrome surveillance system, all participants were clinically evaluated by a primary physician before enrollment. Subsequently, 18% were found to have a preexisting medical condition that plausibly accounted for their chronic fatiguing illness (Reyes M, et al. Unpublished data). These medical conditions were identified either from a single battery of routine laboratory tests done on blood specimens obtained at enrollment or from review of available medical records. We believe that inappropriate tests are often used to diagnose the chronic fatigue syndrome in chronically fatigued persons. This practice should be discouraged. Need for a Comprehensive and Integrated Approach The complexities of the chronic fatigue syndrome and the existence of several obstacles to our understanding of it make a comprehensive and integrated approach to the study of the chronic fatigue syndrome and similar illnesses desirable. The purpose of the following proposed guidelines Figure 2 is to facilitate such an approach. Figure 2. Evaluation and classification of unexplained chronic fatigue. Guidelines for the Clinical Evaluation and Study of the Chronic Fatigue Syndrome and Other Illnesses Associated with Unexplained Chronic Fatigue Definition and Clinical Evaluation of Prolonged Fatigue and Chronic Fatigue Prolonged fatigue is defined as self-reported, persistent fatigue lasting 1 month or longer. Chronic fatigue is defined as self-reported persistent or relapsing fatigue lasting 6 or more consecutive months. The presence of prolonged or chronic fatigue requires clinical evaluation to identify underlying or contributing conditions that require treatment. Further diagnosis or classification of chronic fatigue cases cannot be made without such an evaluation. The following items should be included in the clinical evaluation. 1. A thorough history that covers medical and psychosocial circumstances at the onset of fatigue; depression or other psychiatric disorders; episodes of medically unexplained symptoms; alcohol or other substance abuse; and current use of prescription and over-the-counter medications and food supplements. 2. A mental status examination to identify abnormalities in mood, intellectual function, memory, and personality. Particular attention should be directed toward current symptoms of depression or anxiety, self-destructive thoughts, and observable signs such as psychomotor retardation. Evidence of a psychiatric or neurologic disorder requires that an appropriate psychiatric, psychological, or neurologic evaluation be done. 3. A thorough physical examination. 4. A minimum battery of laboratory screening tests including complete blood count with leukocyte differential; erythrocyte sedimentation rate; serum levels of alanine aminotransferase, total protein, albumin, globulin, alkaline phosphatase, calcium, phosphorus, glucose, blood urea nitrogen, electrolytes, and creatinine; determination of thyroid-stimulating hormone; and urinalysis. Routinely doing other screening tests for all patients has no known value [20, 30]. However, further tests may be indicated on an individual basis to confirm or exclude another diagnosis, such as multiple sclerosis. In these cases, additional tests or procedures should be done according to accepted clinical standards. The use of tests to diagnose the chronic fatigue syndrome (rather than to exclude other diagnostic possibilities) should be done only in the setting of protocol-based research. The fact that such tests are investigational and do not aid in diagnosis or management should be explained to the patient. In clinical practice, no additional tests, including laboratory tests and neuroimaging studies, can be recommended for the specific purpose of diagnosing the chronic fatigue syndrome. Tests should be directed toward confirming or excluding other etiologic possibilities. Examples of specific tests that do not confirm or exclude the diagnosis of the chronic fatigue syndrome include serologic tests for Epstein-Barr vi
This paper references
Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases
Requests For Reprints: Keiji (1600)
Current Author Addresses: Drs. Fukuda and Dobbins: Mailstop A15, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases
(1600)
10.1001/ARCHPSYC.1981.01780290015001
National Institute of Mental Health Diagnostic Interview Schedule. Its history, characteristics, and validity.
L. Robins (1981)
10.1097/00005650-198108000-00001
The Sickness Impact Profile: Development and Final Revision of a Health Status Measure
M. Bergner (1981)
10.1001/JAMA.1988.03410070057028
Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome.
K. Kroenke (1988)
10.1001/ARCHPSYC.1988.01800360017003
The Composite International Diagnostic Interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures.
L. Robins (1988)
10.1016/S0140-6736(88)92107-1
WHAT IS MYALGIC ENCEPHALOMYELITIS?
A. Lloyd (1988)
10.7326/0003-4819-108-3-387
Chronic fatigue syndrome: a working case definition.
G. Holmes (1988)
10.1056/NEJM198812293192608
The chronic fatigue syndrome--one entity or many?
M. N. Swartz (1988)
10.7326/0003-4819-109-6-511
Definition of the chronic fatigue syndrome.
D. Matthews (1988)
10.1001/ARCHINTE.1988.00380100077017
The mental health of patients with a chief complaint of chronic fatigue. A prospective evaluation and follow-up.
P. Manu (1988)
What is myalgic encephalomyelitis? [Letter]
Ar Lloyd (1988)
10.1136/jnnp.52.8.940
Fatigue syndromes: a comparison of chronic "postviral" fatigue with neuromuscular and affective disorders.
S. Wessely (1989)
Psychiatric diagnoses in patients who have chronic fatigue syndrome.
M. Kruesi (1989)
10.1007/978-1-349-13397-0_25
The Development of an Instrument to Measure the Subjective Dimension of Fatigue
Barbara F. Piper (1989)
10.1001/ARCHNEUR.1989.00520460115022
The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.
L. Krupp (1989)
10.1016/S0033-3182(89)72244-1
Somatization disorder in patients with chronic fatigue.
P. Manu (1989)
Chronic fatigue: frequency, causes, evaluation, and management.
K. Kroenke (1989)
10.1097/00000441-199005000-00005
The low yield of physical examinations and laboratory investigations of patients with chronic fatigue.
T. Lane (1990)
10.5694/j.1326-5377.1990.tb126191.x
Prevalence of chronic fatigue syndrome in an Australian population
Andrew R Lloyd (1990)
10.1093/CLINIDS/13.SUPPLEMENT_1.S94
Definition and measurement of fatigue.
I. Barofsky (1991)
10.1097/00007611-199104000-00010
Panic Disorder Among Patients With Chronic Fatigue
P. Manu (1991)
10.1177/014107689108400224
A Report–Chronic Fatigue Syndrome: Guidelines for Research
M. Sharpe (1991)
Chronic fatigue syndrome in Minnesota.
P. Peterson (1991)
Definition and measurement of fatigue. Rev Infect Dis. 1991;13(Suppl l):S94-7
I Barofsky (1991)
10.7326/0003-4819-117-4-325
NIH conference. Chronic fatigue syndrome research. Definition and medical outcome assessment.
A. Schluederberg (1992)
10.1093/ajcn/55.2.495s
Prevalence of overweight and weight gain in the United States.
R. Kuczmarski (1992)
10.1001/ARCHPSYC.1992.01820080032005
The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description.
R. Spitzer (1992)
THE MOS 36- ITEM SHORT FORM HEALTH SURVEY (SF- 36) CONCEPTUAL FRAMEWORK AND ITEM SELECTION
Ware J.E.Jr. (1992)
10.1001/ARCHINTE.1992.00400200042008
Chronic fatigue syndrome criteria. A critique of the requirement for multiple physical complaints.
W. Katon (1992)
Estimating the prevalence of chronic fatigue syndrome and associated symptoms in the community.
R. K. Price (1992)
10.1136/bmj.305.6846.147
Follow up of patients presenting with fatigue to an infectious diseases clinic.
M. Sharpe (1992)
10.1136/jech.46.2.92
The epidemiology of fatigue: more questions than answers.
G. Lewis (1992)
Defining the chronic fatigue syndrome [Editorial]
Se Straus (1992)
10.1016/0022-3999(93)90104-N
The measurement of fatigue: a new instrument.
J. Schwartz (1993)
10.1001/ARCHINTE.1993.00410240067007
Prevalence of fatigue and chronic fatigue syndrome in a primary care practice.
D. Bates (1993)
10.1002/9780470514382.CH6
Epidemiology of chronic fatigue syndrome: the Centers for Disease Control Study.
W. Gunn (1993)
10.1016/0022-3999(93)90081-P
Development of a fatigue scale.
T. Chalder (1993)
Is chronic fatigue syndrome an infectious disease?
A. Mawle (1993)
10.1016/0002-9343(94)90095-7
The treatment of chronic fatigue syndrome: science and speculation.
A. Wilson (1994)
10.1016/0022-3999(94)90099-X
Dimensional assessment of chronic fatigue syndrome.
J. Vercoulen (1994)
10.1136/bmj.308.6931.756
Longitudinal study of outcome of chronic fatigue syndrome
A. Wilson (1994)
10.1136/bmj.308.6931.763
Population based study of fatigue and psychological distress
T. Pawlikowska (1994)
Is chronic fatigue syndrome an infectious disease? Infect Agents Dis
Ac Mawle (1994)
10.1017/S0033291700037417
Can the chronic fatigue syndrome be defined by distinct clinical features?
I. Hickie (1995)
The development of an instrument to measure the subjective dimension of fatigue Fatigue and Nausea
Bf Piper
King's College School of Medicine and Dentistry, London, United Kingdom: Simon Wessely, MRCP, MRC Psych; Polyclinic Medical Center and Pennsylvania State College of Medicine
Andrew R Lloyd
Karolinska Institute at Huddinge University Hospital Centers for Disease Control and Prevention
Md Peterson
Hickie: School of Psychiatry and Department of Infectious Diseases and Immunology
Dr
et 958 15 December @BULLET Annals of Internal Medicine @BULLET Volume 121 @BULLET Number
Ln Robins



This paper is referenced by
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10.3390/healthcare9020106
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10.1080/21641846.2021.1915131
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L. Jason (2021)
10.1186/s12967-021-02742-4
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Rebekah Maksoud (2021)
10.1038/s41598-021-83660-9
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Paula I. Metselaar (2021)
10.1016/j.jpsychores.2021.110417
An exploratory study of discrepancies between objective and subjective measurement of the physical activity level in female patients with chronic fatigue syndrome.
Kuni Vergauwen (2021)
10.3389/fmed.2021.656692
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Ji-Sook Lee (2021)
10.3390/jcm10143105
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I. Baklund (2021)
10.28951/RBB.V39I1.533
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10.3389/fpsyt.2021.684556
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Teri W. Hoenemeyer (2021)
10.3389/fpsyt.2021.580924
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M. Gotaas (2021)
10.1007/s11910-021-01130-1
The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 infection
N. Moghimi (2021)
10.1016/j.lfs.2021.119636
Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC): A collaborative research infrastructure for intervention and implementation.
Amanpreet K. Cheema (2021)
10.1002/brb3.2040
Open‐label study with the monoamine stabilizer (‐)‐OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome
S. Haghighi (2021)
10.3390/nu13082658
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J. Castro-Marrero (2021)
10.1101/2021.03.23.21254175
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J. Malato (2021)
10.1016/j.clinph.2020.11.043
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E. Klaver-Król (2021)
10.1101/2021.02.06.21249256
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10.1177/2049463719875164
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10.1016/j.jpsychores.2021.110533
Adverse outcomes in trials of graded exercise therapy for adult patients with chronic fatigue syndrome.
P. White (2021)
10.7861/clinmed.2020-0743
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10.1007/s11136-021-02919-w
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