Chronic Fatigue Syndrome

Etiology of CFS is unknown. No infectious, hormonal, immunologic, or psychological cause has been established. Among the many proposed infectious causes, Epstein-Barr virus, Lyme disease, candidiasis, and cytomegalovirus have been proven not to cause CFS. Similarly, there are no allergic markers and no immunosuppression. People with CFS are not at increased risk for opportunistic infections.

Some people who have recovered from COVID-19 infection have become "long-haulers" with persistent symptoms. Some of these symptoms result from organ damage from the infection and/or treatment, and others may be from posttraumatic stress disorder (PTSD). In addition, in some patients, COVID-19 seems to trigger typical CFS. This association is being actively studied.

Various minor immunologic abnormalities have been reported. These abnormalities include low levels of IgG, abnormal IgG, decreased lymphocytic proliferation, low interferon-gamma levels in response to mitogens, poor cytotoxicity of natural killer cells, circulating autoantibodies and immune complexes, and many other immunologic findings. However, none provide adequate sensitivity and specificity for defining CFS. They do, however, underscore the physiologic legitimacy of CFS.

Relatives of patients with CFS have an increased risk of developing the syndrome, suggesting a genetic component or common environmental exposure. Recent studies have identified some genetic markers that might predispose to CFS. Some researchers believe the etiology will eventually be shown to be multifactorial, including a genetic predisposition and exposure to microbes, toxins, and other physical and/or emotional trauma.

Before onset of CFS, most patients are highly functioning and successful.

Onset is usually abrupt, often following a psychologically or medically stressful event. Many patients report an initial viral-like illness with swollen lymph nodes, extreme fatigue, fever, and upper respiratory symptoms. The initial syndrome resolves but seems to trigger protracted severe fatigue, which interferes with daily activities and typically worsens with exertion but is alleviated poorly or not at all by rest. Patients often also have disturbances of sleep and cognition, such as memory problems, "foggy thinking," hypersomnolence, and a feeling of having had unrefreshing sleep. Generalized pain is also a common complaint.

The physical examination is normal, with no objective signs of muscle weakness, arthritis, neuropathy, or organomegaly. However, some patients have low-grade fever, nonexudative pharyngitis, and/or palpable or tender (but not enlarged) lymph nodes.

Because patients typically appear healthy, friends, family, and even health care professionals sometimes express skepticism about their condition, which can worsen the frustration and/or depression patients often feel about their poorly understood disorder.

• Clinical criteria

• Laboratory evaluation to exclude non-CFS disorders

The diagnosis of CFS is made by the characteristic history combined with a normal physical examination and normal laboratory test results. Any abnormal physical findings or laboratory results must be evaluated and alternative diagnoses that cause those findings and/or the patient's symptoms excluded before the diagnosis of CFS can be made. The case definition is often useful but should be considered an epidemiologic and research tool and in some circumstances should not be strictly applied to individual patients.

Testing is directed at any non-CFS causes suspected based on objective clinical findings. If no cause is evident or suspected, a reasonable laboratory assessment includes complete blood count and measurement of electrolytes, blood urea nitrogen, creatinine, erythrocyte sedimentation rate, and thyroid-stimulating hormone. If indicated by clinical findings, further testing in selected patients may include chest x-ray, sleep studies, and testing for adrenal insufficiency. Serologic testing for infections, antinuclear antibodies, and neuroimaging are not indicated without objective evidence of disease on examination (ie, not just subjective complaints) or on basic testing; in such situations, pretest probability is low and so the risk of false-positive results is high. This can result in incorrect diagnoses, additional unnecessary testing, and inappropriate treatments.

In February 2015, the Institute of Medicine (now the Health and Medicine Division of The National Academies of Science, Engineering, and Medicine ["the National Academies"]) published an extensive review of this disease called Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. In this review, they proposed a new name, systemic exertion intolerance disease (SEID), and new diagnostic criteria that simplified the diagnosis and emphasized the most consistent features (see table Diagnostic Criteria for Chronic Fatigue Syndrome). In addition, the review clearly emphasized the validity of this debilitating disease. Referring the patient and family members to this document can help improve their understanding and emphasize the validity of their often disabling disease.

• Acknowledgment of patient's symptoms

• Sometimes cognitive-behavioral therapy

• Sometimes graded exercise, limited to avoid a setback

• Medications for depression, sleep, or pain if indicated

To provide effective care to patients with CFS, physicians must acknowledge and accept the validity of patients' symptoms. Whatever the underlying cause, these patients are not malingerers but are suffering and strongly desire a return to their previous state of health. For successful management patients need to accept and accommodate their disability, focusing on what they can still do instead of lamenting what they cannot do.

Cognitive-behavioral therapy and a graded exercise program have been helpful in some studies but not in others (1, 2). They should be considered for patients who are willing to try them and have access to the appropriate services. Depression is common and expected in any patient with a disability. This should be treated with antidepressants and/or psychiatric referral. Sleep disturbances should be aggressively managed with relaxation techniques and improved sleep hygiene (see table Approach to Patient, Sleep Hygiene).

If these measures are ineffective, hypnotic medications and/or referral to a sleep specialist may be necessary. Patients with pain (usually due to a component of fibromyalgiaorthostatic hypotension may also be helpful.

Unproven or disproven treatments, such as antivirals, immunosuppressants, elimination diets, and amalgam extractions, should be avoided.

Most patients with CFS improve over time though often not back to their pre-illness state. That time is typically years and improvement is often only partial. Some evidence indicates that earlier diagnosis and intervention improve the prognosis.

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

1. Centers for Disease Control and Prevention: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: General information about CFS symptoms and treatment and ongoing CFS research

2. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); 2015 Feb 10.