1. Aetna considers the following as medically necessary exclusionary tests to be used for the evaluation of members suspected of having chronic fatigue syndrome (CFS) as recommended by the National Institutes of Health. The selection of studies depends on the specific characteristics of a given case:

   1. Complete blood count (CBC) with differential cell count
   2. Urinalysis
   3. Blood and serum chemistries (serum electrolytes, blood urea nitrogen, glucose, creatinine, calcium)
   4. Liver function tests (chemistries)
   5. Thyroid function tests (thyroid hormone [T3 or T4] uptake or thyroid hormone binding ratio [THBR], TSH)
   6. Erythrocyte sedimentation rate (ESR)
   7. Anti-nuclear antibodies (ANA)
   8. Serum cortisol*
   9. Immunoglobulin levels (in patients with documented recurrent bacterial infections)*
   10. Rheumatoid factor (RF)*
   11. TB skin test*
   12. HIV serology*
   13. Lyme serology* (when endemic)
   14. MRI of head* (to rule out multiple sclerosis)
   15. Polysomnography* (to rule out sleep disorder).

   * Optional tests to be used when clinically indicated.

2. Aetna considers the following laboratory tests experimental and investigational for the diagnosis or management of members with CFS. The peer reviewed medical literature does not support their value in making a diagnosis or influencing the course of treatment of individuals with CFS:

   1. Quantification of natural killer (NK) cells
   2. Quantification of B and T cell subsets
   3. Functional elevation of NK cells
   4. T cell response to mitogenic stimulation
   5. Measurements of delayed hypersensitivity
   6. Production and response to cytokines
   7. ELISA/ACT testing
   8. Serological tests for Candida albicans
   9. RNAse L enzymatic activity assay or RNase L protein quantification
   10. Gene expression profiling

   11. Viral serologies including but not limited to:

       1. Herpes virus serologies (e.g., Epstein Barr virus, cytomegalovirus, human herpes virus-6)
       2. Coxsackie virus serology
       3. Enterovirus serology

       4. Retrovirus serologies (except HIV).

3. Aetna considers tilt table testing experimental and investigational for identifying members with CFS or for evaluating treatment effectiveness of this condition (see CPB 299 - Tilt Table Testing).

4. Aetna considers measurements of muscle blood flow (e.g., by Doppler ultrasound), muscle metabolism (e.g., by magnetic resonance spectroscopy) and muscle oxygen saturation and blood volume (e.g., by near-infrared spectroscopy) experimental and investigational for identifying members with CFS because their clinical values have not been established.

5. Aetna considers the following imaging studies experimental and investigational for CFS because they do not confirm or exclude the diagnosis of CFS and, according to available literature, should not be routinely performed for this indication:

   1. Radionuclide scans (such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET)).

   2. Magnetic resonance imaging (MRI) scans (except MRI of the head where signs and symptoms suggest multiple sclerosis).

Note: Based on the position of the Centers for Disease Control and Prevention (CDC), the following guidelines should be used for the evaluation and study of CFS.

A thorough medical history, physical examination, mental status examination, and laboratory tests must be conducted to identify underlying or contributing conditions that require treatment. Diagnosis or classification cannot be made without such an evaluation. Clinically evaluated, unexplained chronic fatigue cases can be classified as CFS if the member meets both of the following criteria:

1. Clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (i.e., not 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: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain, multi-joint pain without swelling or redness; headaches of a new type, pattern, or severity; non-refreshing sleep; and post-exertional malaise lasting more than 24 hours. These symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.

Conditions that exclude a diagnosis of CFS:

1. Any active medical condition that may explain the presence of chronic fatigue, such as untreated hypothyroidism, sleep apnea and narcolepsy, and iatrogenic conditions such as side effects of medication.

2. Some diagnosable illnesses may relapse or may not have completely resolved during treatment. If the persistence of such a condition could explain the presence of chronic fatigue, and if it cannot be clearly established that the original condition has completely resolved with treatment, then such members should not be classified as having CFS. Examples of illnesses that can present such a picture include some types of malignancies and chronic cases of hepatitis B or C virus infection.

3. 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; dementia of any subtype; anorexia nervosa; or bulimia nervosa.

4. Alcohol or other substance abuse, occurring within 2 years of the onset of chronic fatigue and any time afterwards. Severe obesity as defined by a body mass index [body mass index = weight in kilograms divided by (height in meters)2] equal to or greater than 45. [Note: body mass index values vary considerably among different age groups and populations. No “normal” or “average” range of values can be suggested in a fashion that is meaningful. The range of 45 or greater was selected because it clearly falls within the range of severe obesity.]

Any unexplained abnormality detected on examination or other testing that strongly suggests an exclusionary condition must be resolved before attempting further classification.

Conditions that do not exclude a diagnosis of CFS:

1. Any condition defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests, including fibromyalgia, anxiety disorders, somatoform disorders, non-psychotic or melancholic depression, neurasthenia, and multiple chemical sensitivity disorder.

2. 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 as been determined by pulmonary function and other testing.

3. Any condition, such as Lyme disease or syphilis that was treated with definitive therapy before development of chronic symptoms.

4. 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, without additional laboratory or clinical evidence, to strongly support a diagnosis of a discrete connective tissue disorder.

A note on the use of laboratory tests in the diagnosis of CFS:

According to the Centers for Disease Control and Prevention, a minimum battery of laboratory screening tests should be performed. Routinely performing other screening tests for all individuals has no known value. 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 should be done according to accepted clinical standards.

The use of test to diagnose CFS (as opposed to excluding 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 individual.

In clinical practice, no tests can be recommended for the specific purpose of diagnosing chronic fatigue syndrome. Tests should be directed toward confirming or excluding other possible clinical conditions. Examples of specific tests that do not confirm or exclude the diagnosis of chronic fatigue syndrome include serologic tests for Epstein-Barr virus, enteroviruses, retroviruses, human herpes virus 6, and Candida albicans; tests of immunologic function, including cell population and function studies; and imaging studies, including magnetic resonance imaging scans and radionuclide (such as single-photon emission computed tomography and positron emission tomography).

Chronic fatigue syndrome, also known as myalgic encephalomyelitis,  is a clinically defined condition characterized by severe, persistent, disabling fatigue and a combination of symptoms that prominently feature self-reported impairments in concentration and short-term memory, sleep disturbances, and musculoskeletal pain. Diagnosis of chronic fatigue syndrome can be made only after alternative medical and psychiatric causes of chronic fatiguing illnesses have been excluded. No definitive diagnostic tests for this condition have been validated in scientific studies. Because chronic fatigue syndrome is clinically nonspecific and lacks an identifiable cause or diagnostic test, it remains a diagnosis of exclusion.

In the revised definition, a consensus viewpoint from many of the leading CFS researchers and clinicians (including input from patient group representatives), chronic fatigue syndrome is treated as a subset of chronic fatigue, a broader category defined as unexplained fatigue of greater than or equal to six month's duration. Chronic fatigue in turn, is treated as a subset of prolonged fatigue, which is defined as fatigue lasting one or more months. The expectation is that scientists will devise epidemiologic studies of populations with prolonged fatigue and chronic fatigue, and search within those populations for illness patterns consistent with CFS.

In addition to a thorough history and physical examination, recommended procedures for evaluating patients suspected of having chronic fatigue syndrome include a mental status examination to identify abnormalities in mood, intellectual function, memory and personality. Evidence of psychiatric, neurologic or cognitive disorder requires that an appropriate psychiatric, psychological, or neurological evaluation be done.

Laboratory tests include a complete blood count with differential cell count, an erythrocyte sedimentation rate, a chemistry profile including liver function tests, thyroid function test (either a thyroid panel or thyroid stimulating hormone), antinuclear antibodies, and urinalysis. Additional tests, if indicated, include rheumatoid factor, immune globulin levels, tuberculin skin test, Lyme disease serology (if patient lives in an endemic area), HIV serology, MRI of the head (if indicated to rule out multiple sclerosis), and polysomnography (if indicated to rule out a sleep disorder).

The following tests do not confirm or exclude the diagnosis of chronic fatigue syndrome: serologic tests for Epstein-Barr virus, retroviruses (except HIV), human herpes virus 6, enteroviruses and Candida albicans; and tests of immunologic function, including cell population and function studies.

Immunologic abnormalities in patients with suspected chronic fatigue syndrome (CFS) is an active area of research into the pathogenesis of CFS. However, the published literature is inadequate to determine the sensitivity, specificity, and positive and negative predictive values of these tests. Most of the research has compared the immunologic function of patients with CFS with healthy normal controls, so that it is impossible to know whether the subtle immunologic abnormalities seen are specific to CFS or could be seen in other patients with a wide variety of illnesses with overlapping symptoms.

Although it was originally thought that CFS was related to a viral etiology, more recent studies have failed to find any predictable association between CFS and any particular virus.

A NIH consensus conference recommended a list of exclusionary laboratory tests that were considered appropriate for the work-up of a patient with suspected CFS. Since that time, there have been investigations into the immune function of patients with CFS, such as quantitative studies of natural killer cells, B and T cell subsets, and the production of cytokines, such as interferons and interleukin-2. Assessments of these immunologic parameters have produced conflicting results, in part related to varying methodologies used, the heterogeneity of patients who are tested at different points in their disease, and the dynamic nature of the immune system which makes assessment of single tests difficult. While assessments of levels of IgG subsets have shown a decrease in IgG1 and IgG3, the studies were performed on small numbers of patients with undefined control groups or only healthy controls. Therefore, it is not unexpected that the published data fail to indicate the sensitivity, specificity, positive and negative predictive value of the above immunologic tests. While immune function may provide a fertile path for research, its use in the clinical diagnosis and management of CFS is still investigational.

McCully et al (2004) examined if CFS is associated with reduced blood flow and muscle oxidative metabolism. Muscle blood flow was measured in the femoral artery with Doppler ultrasound after exercise. Muscle metabolism was measured in the medial gastrocnemius muscle with (31)P-magnetic resonance spectroscopy. Muscle oxygen saturation and blood volume were measured using near-infrared spectroscopy. The authors concluded that CFS patients showed evidence of reduced hyperemic flow and reduced oxygen delivery but no evidence that this impaired muscle metabolism. Thus, CFS patients might have altered control of blood flow, but this is unlikely to influence muscle metabolism. In addition, abnormalities in muscle metabolism do not appear to be responsible for the CFS symptoms.

Ribonuclease L (RNase L) is a protein induced by interferon that may affect certain anti-viral and anti-tumor effects observed when interferon is induced. Once activated, RNase L is thought to cleave viral DNA and triggering removal of the infected cell by inducing apoptosis. It has been posited that, in the immune cells of CFS patients, RNase L is cleaved by proteases; the resultant RNase L fragments have been posited to increase RNase L enzymatic activity and cleave cellular RNA at an accelerated rate, and also bind to and disrupt normal cellular ion flow. In this way, the RNase L fragments are thought to account for some of the physiological symptoms of CFS. Tests have been developed to quantify RNase L protein fragments (RNase L protein assay (RNAP), R.E.D. Laboratories, Reno, NV)) and to measure abnormal RNase L activity (RNase L activity assay (RNAA)). Although there is evidence that RNase L fragments are increased in a subset of patients with CFS, it has not been demonstrated that measurement of RNase L fragments or enzymatic activity is useful for either the diagnosis or management of persons with CFS.

Kawai and Rokutan (2007) noted that CFS is a complex disease and has no laboratory biomarkers, which makes diagnosis of CFS difficult. Several research groups challenged to identify genes specific for CFS; however, there are no overlaps between studies. The U.S. Centers for Disease Control and Prevention reported remarkable gene expression profiles of a large scale cohort study (n = 227). Reported genes were mostly different from the previously reported genes, again featuring the complexity of CFS. Separately, these investigators identified 9 genes that were significantly and differentially expressed between CFS patients and healthy subjects using an original microarray.

Fostel and colleagues (2006) stated that CFS is a complex syndrome that can not simply be associated with changes in individual laboratory tests or expression levels of individual genes. No clear association with gene expression and individual symptom domains was found. However, analysis of such multi-faceted datasets is likely to be an important means to elucidate the pathogenesis of CFS.