A Conceptual Framework for Studying the Chronic Fatigue Syndrome
In the United States, 24% of the general adult population has
experienced fatigue lasting 2 weeks or longer, with 59% to 64% of these people
reporting no medical cause (18,19). In one study, 24% of primary care clinic
patients reported having had prolonged fatigue ( 1 month) (20). In many persons
with prolonged fatigue, fatigue persists beyond 6 months (defined as chronic
We propose a conceptual framework (Figure 1 below) 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 (one 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
case-control and cohort studies based on predetermined criteria for the chronic
fatigue syndrome, will also produce much-needed clinical and laboratory
background information. This framework also clarifies the need to compare
populations defined by the chronic fatigue syndrome with several other
populations in case-control 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
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 with regard to 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 Unpublished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
Need for Clinical Evaluation Standards
Our experience suggests that fatigued persons often receive 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 proposed guidelines in Figure 2 below is to
facilitate such an approach.
Definition and Clinical Evaluation of Prolonged Fatigue and Chronic Fatigue
Prolonged fatigue is defined as self-reported, persistent
fatigue of 1 month or longer. Chronic fatigue is defined as self-reported
persistent or relapsing fatigue of 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 areas should be included in
the clinical evaluation.
- 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.
- A mental status examination to identify abnormalities in
mood, intellectual function, memory, and personality. Particular attention
should be directed toward current symptoms of depressive 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.
- A thorough physical examination.
- 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 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 obtained according to accepted
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
In clinical practice, no additional tests, including
laboratory tests or 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 virus, retroviruses,
human herpesvirus 6, enteroviruses, and Candida albicans; tests of immunologic
function, including cell population and function studies; and imaging studies,
including magnetic resonance imaging scans and radionuclide scans (such as
single-photon emission computed tomography and positron emission tomography) of
Conditions That Explain Chronic Fatigue
The following conditions exclude a patient from the diagnosis of unexplained chronic fatigue.
- Any active medical condition that may explain the presence
of chronic fatigue (31), such as untreated hypothyroidism, sleep apnea and
narcolepsy, and iatrogenic conditions such as side effects of
- Any previously diagnosed medical condition whose resolution
has not been documented beyond reasonable clinical doubt and whose continued
activity may explain the chronic fatiguing illness. Such conditions may include
previously treated malignancies and unresolved cases of hepatitis B or C virus
- Any past or current diagnosis of a major depressive disorder
with psychotic or melancholic features; bipolar affective disorders;
schizophrenia of any subtype; delusional disorders of any subtype; dementias of
any subtype; anorexia nervosa; or bulimia nervosa.
- Alcohol or other substance abuse within 2 years prior to the
onset of the chronic fatigue and any time afterward.
- Severe obesity (32,33) as defined by a body mass index [body
mass index = weight in kilograms/(height in meters)2] equal to or greater than
Any unexplained physical examination finding or laboratory or
imaging test abnormality that strongly suggests the presence of an exclusionary
condition must be resolved before further classification.
Conditions That Do Not Adequately Explain Chronic Fatigue
The following conditions do not exclude a patient
from the diagnosis of unexplained chronic fatigue.
- Any condition defined primarily by symptoms that cannot be
confirmed by diagnostic laboratory tests, including fibromyalgia, anxiety
disorders, somatoform disorders, nonpsychotic or nonmelancholic 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. Such conditions include 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 symptomatic
- 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. Such conditions include an
elevated antinuclear antibody titer that is inadequate to strongly support a
diagnosis of a discrete connective tissue disorder without other laboratory or
Major Classification Categories: Chronic Fatigue Syndrome and Idiopathic Chronic Fatigue
Clinically evaluated, unexplained chronic fatigue cases can be
separated into either the chronic fatigue syndrome or idiopathic chronic fatigue
on the basis of the following criteria.
A case of the chronic fatigue syndrome is defined by the
presence of the following: 1) clinically evaluated, unexplained persistent or
relapsing chronic fatigue that is of new or definite onset (has not been
lifelong); is not the result of ongoing exertion; is not substantially
alleviated by rest; and results in substantial reduction in previous levels of
occupational, educational, social, or personal activities; and 2) the concurrent
occurrence of four or more of the following symptoms, all of which must have
persisted or recurred during six or more consecutive months of illness and must
not have predated the fatigue: self-reported impairment in short-term memory or
concentration severe enough to cause substantial reduction in previous levels of
occupational, educational, social, or personal activities; sore throat; tender
cervical or axillary lymph nodes; muscle pain; multijoint pain without joint
swelling or redness; headaches of a new type, pattern, or severity; unrefreshing
sleep; and postexertional malaise lasting more than 24 hours.
The method used (for example, a predetermined checklist
developed by the investigator or spontaneous reporting by the study participant)
to establish the presence of these and any other symptoms should be specified.
A case of idiopathic chronic fatigue is defined as clinically
evaluated, unexplained chronic fatigue that fails to meet criteria for the
chronic fatigue syndrome. The reasons for failing to meet the criteria should be
Subgrouping and Stratification of Major Classification Categories
In formal studies, cases of the chronic fatigue syndrome and
idiopathic chronic fatigue should be subgrouped before analysis or stratified
during analysis by the presence or absence of essential variables, which should
be routinely established in all studies. Further subgrouping by optional
parameters can be performed according to specific research interests.
Essential Subgrouping Variables
- Any clinically important coexisting medical or
neuropsychiatric condition that does not explain the chronic fatigue. The
presence or absence, classification, and timing of onset of neuropsychiatric
conditions should be established using published or freely available
instruments, such as the Composite International Diagnostic Instrument (34), the
National Institute of Mental Health Diagnostic Interview Schedule (35), and the
Structured Clinical Interview for DSM-III(R) (36).
- Current level of fatigue, including subjective or
performance aspects. These levels should be measured using published or widely
available instruments. Examples include instruments by Schwartz and colleagues
(37), Piper and colleagues (38), Krupp and colleagues (39), Chalder and
colleagues (40), and Vercoulen and colleagues (41).
- Total duration of fatigue. Current level of overall
functional performance as measured by published or widely available instruments,
such as the Medical Outcomes Study Short Form 36 (42) and the Sickness Impact
Optional Subgrouping Variables
Examples of optional variables include:
- Epidemiologic or laboratory features of specific interest to
researchers. Examples include laboratory documentation (or self-reported
history) of an infectious illness at the onset of fatiguing illness, a history
of rapid onset of illness, or the presence or level of a particular immunologic
- Measurements of physical function quantified by means such
as treadmill testing or motion-sensing devices.
Several general points must be appreciated if these guidelines
are to be used as intended. First, the overall purpose of the proposed
conceptual framework and guidelines is to foster a more systematic and
comprehensive approach toward the collection of data about the chronic fatigue
syndrome and similar illnesses. As such, these tools are intended for use as
standard references. However, none of the components, including the revised case
definition of the chronic fatigue syndrome, can be considered definitive. These
research tools will evolve as new knowledge is gained. Second, none of the
provisions in these guidelines, especially the definition of idiopathic chronic
fatigue and subgroups of the chronic fatigue syndrome, establish new clinical
entities. Rather, these definitions were designed to facilitate comparative
studies. Finally, general reference to these guidelines should not be
substituted for clear and detailed methodologic descriptions when reporting
studies. The lack of detailed information about the sources, selection, and
evaluation of study participants (including controls), case definitions, and
measurement techniques in reports of chronic fatigue syndrome research has
contributed substantially to our current difficulties in interpreting research
Several specific points about the clinical evaluation are
worth emphasizing. The primary purpose of clinically evaluating a person with
unexplained fatigue is to identify and treat any underlying and contributing
factors. Such an evaluation should begin, whenever possible, before 6 months has
elapsed. Because the particulars of any clinical evaluation will vary from
patient to patient, our recommendations have been limited to those aspects of
clinical evaluation that can be universally applied to all patients. With regard
to the clinical psychiatric evaluation of fatigued persons, we consider a mental
status examination to be the minimal acceptable level of assessment. Although a
structured psychiatric evaluation of all patients with fatigue is highly
desirable, we recognize the practical difficulties of implementing such a
recommendation. The diagnosis of the chronic fatigue syndrome should not impede
the treatment of coexisting disorders, notably depression.
Many conditions that are primary causes of chronic fatigue
preclude the diagnosis of the chronic fatigue syndrome or idiopathic chronic
fatigue. We presented principles for identifying such exclusionary conditions
rather than listing them because of the range and complexity of human illnesses.
In some instances, however, we identified specific exclusionary conditions. The
presence of severe obesity makes the diagnosis of unexplained symptoms, such as
fatigue or joint pains, extremely difficult.
We distinguished between psychiatric conditions for pragmatic
reasons. It is difficult to interpret symptoms typical of the chronic fatigue
syndrome in the setting of illnesses such as major psychotic depression or
schizophrenia. More importantly, the care of these persons should focus on their
chronic psychiatric disorder. On the other hand, we did not use other
psychiatric disorders, such as anxiety disorders and less severe forms of
depression, as a basis for exclusions. Such psychiatric conditions are highly
prevalent in persons with chronic fatigue and the chronic fatigue syndrome, and
the exclusion of persons with these conditions would substantially hinder
efforts to clarify the role that psychiatric disorders have in fatiguing
illnesses. This is a particularly important issue to resolve. These parts of the
guidelines concur with the recommendation by a 1991 National Institutes of
Health workshop (24) that chronic fatigue cases preceded by some, but not all,
psychiatric syndromes can be classified as the chronic fatigue syndrome.
The revised case definition for the chronic fatigue syndrome
is modeled on the 1988 chronic fatigue syndrome working case definition (1). The
purpose of the revision was to address some of the criticisms (25) of that case
definition and to facilitate a more systematic collection of data
internationally. We dropped all physical signs as inclusion criteria because all
of us agreed that their presence had been unreliably documented in past studies.
The required number of symptoms was decreased from 8 to 4 and the list of
symptoms was decreased from 11 to 8 because we agreed that multiple symptom
criteria had increased the restrictiveness of the 1988 chronic fatigue syndrome
working case definition without increasing the homogeneity of cases (Reyes M, et
al. Unpublished data).
Whether to retain any symptom criteria other than chronic
fatigue generated the most disagreement among the authors. Disagreement occurred
between those who favored a more restrictive approach (using several symptom
criteria), as was done in the 1988 chronic fatigue syndrome working case
definition, and those who favored a broader definition of chronic fatigue
syndrome (using fewer symptom criteria) as was done in the Australian (3) and
British (4) chronic fatigue syndrome case definitions. Those favoring multiple
symptoms argued that use of multiple symptoms best reflected the empiric
clinical sense of the chronic fatigue syndrome as a distinct entity. Others
argued that no symptoms have been shown to be specific for the chronic fatigue
syndrome (28) and that some studies suggest that a requirement for multiple
symptoms biases the selection of cases toward those with psychiatric disorders
(28, 44). Disagreement over this particular issue underscores the need to
establish specific features of the chronic fatigue syndrome and the validity of
any chronic fatigue syndrome case definition.
Developing an operational definition of fatigue was a problem
because the concept of fatigue itself is unclear (45,46). In our conception of
the chronic fatigue syndrome, the symptom of fatigue refers to severe mental and
physical exhaustion, which differs from somnolence or lack of motivation and
which is not attributable to exertion or diagnosable disease. We retained the
requirement of 6 months' duration of fatigue to facilitate comparison with
earlier cases of the chronic fatigue syndrome. The requirement for an "average
daily activity below 50%" was eliminated because this level of impairment is
difficult to verify.
We defined the condition of "idiopathic chronic fatigue" to
focus attention on the need to clarify how other forms of unexplained chronic
fatigue are related to the chronic fatigue syndrome.
Our strategy for subgrouping major classification categories
depends upon the data made available from standardized evaluations of patients
with chronic fatigue. Subgrouping by essential variables will encourage the
collection of a body of core data. Additional subgrouping by optional variables
will allow researchers considerable individual flexibility in defining specific
subgroups to answer specific research questions.
The name "chronic fatigue syndrome" is the final issue that we
wish to address. We sympathize with those who are concerned that this name may
trivialize this illness. The impairments associated with chronic fatigue
syndrome are not trivial. However, we believe that changing the name without
adequate scientific justification will lead to confusion and will substantially
undermine the progress that has been made in focusing public, clinical, and
research attention on this illness. We support changing the name when more is
known about the underlying pathophysiologic process or processes associated with
the chronic fatigue syndrome and chronic fatigue.
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