What is chronic fatigue syndrome?

Causes and Symptoms

Chronic fatigue
syndrome is a heterogeneous disease state that has been difficult to define, diagnose, and treat because of poorly understood cause-and-effect relationships. The disease can be best described in terms of long-lasting and debilitating fatigue, the etiology of which has been linked to such external factors as microbial agents, stress, and lifestyle as well as such internal factors as genetic makeup and the body’s immune response. The physical disease also has psychological components, which has caused confusion in the medical community as to the exact cause of the syndrome.

Among the many names that have been used for the disease, two that demonstrate the many factors that contribute to chronic fatigue syndrome are chronic Epstein-Barr virus syndrome and chronic fatigue immune dysfunction syndrome. Because of the marked immunological aspects of the disease and the fact that different viruses have been found in patients with chronic fatigue, the disease is often referred to as chronic fatigue immune dysfunction syndrome. The US Centers for Disease Control and Prevention (CDC) continues to refer to it as chronic fatigue syndrome (CFS).

Although the disease is not specific by race, gender, or age group, it affects significantly more women than men. It is estimated by the CDC that between 20 and 40 of every 10,000 people in the United States have CFS.

CFS can manifest itself in acute and chronic phases, although some patients do not remember an acute phase presentation. Acute phase symptoms are general and flulike, with a low-grade fever, sore throat, headache, muscle pain, painful lymph nodes, and overall fatigue. Unlike with a bout of influenza, the symptoms do not subside with time, instead intensifying into a chronic phase. The fatigue can become disabling, with severe muscle and joint pain, swollen and painful lymph nodes, and the inability to develop proper sleep patterns. The similarity of CFS to fibromyalgia, diffuse muscular pain throughout the body, has resulted in cross diagnosis by many physicians of the two syndromes. Some researchers blame psychological and emotional stress, with a viral infection having triggered the initial acute phase. Although the psychological description does not fit all cases, problems of concentration, attention, and depression have been implicated to the point that researchers recognize both psychological and physical components. The working definition from both a research and a clinical perspective requires that the fatigue cause at least 50 percent incapacitation and last at least six months. The ineffectiveness of treatment, compounded by the inability to provide a concrete diagnosis, further complicates the psychological aspects of the disease for the patient.

Although the environment provides an array of agents that could trigger the physical condition of CFS, the hypothesis for a viral cause is supported by the flulike symptoms, occasional clustering of cases, and presence of antiviral antibodies in the patient’s serum. The involvement of the Epstein-Barr virus in some forms of CFS seems likely because of its role as the etiological agent of
mononucleosis and Burkitt’s lymphoma, which are similar diseases. In both of these diseases, the Epstein-Barr virus has a unique and harmful effect on the immune system because it directly invades B lymphocytes, the antibody-producing cells of the body, using them to grow new virus particles while disrupting the proper functioning of the immune system. Like CFS, mononucleosis is characterized by flulike symptoms and fatigue, but the disease is self-limiting and the patient eventually recovers.

Despite this seeming difference in outcome, the Epstein-Barr virus can cause a chronic condition. The viruses that infect humans can become dormant within the cells that they infect. The nucleic acid of a virus can become incorporated into the deoxyribonucleic acid (DNA) of its host cell, and the body no longer shows physical signs of its presence. A virus can become active at times of physical or emotional stress and can once again trigger the physical symptoms of disease. For example,
herpes simplex virus 1 remains dormant in its host cell but periodically, in response to environmental factors, causes a cold sore lesion.

Immunological dysfunction has been observed in CFS patients because they demonstrate increased allergic sensitivity to skin tests when compared to individuals without CFS. Cells and cellular chemicals directly involved with protective immunity and the regulation of the immune response have been found in these patients in abnormal concentrations. For example, they have abnormal numbers of the natural killer cells and suppressor T cells that are essential to cell-mediated immunity. A variety of cytokines, such as gamma interferon, and various interleukins that regulate the activities of the cells in the cell-mediated and humoral immune responses are seen in abnormal concentrations in some CFS patients. Some of these cytokines are already known to mediate the immune response to viral infections. Infectious agents such as bacteria, viruses, yeast, intracellular parasites, and even cancer cells are eliminated from the body when humoral and cell-mediated immune systems are operating properly. The presence of abnormally high concentrations of these cytokines may contribute to inflammatory processes sometimes found in patients with CFS. When the immune system is not working properly, however, not only is the body more susceptible to a variety of infectious agents, but the immune system can begin to damage or destroy normal tissues as well. Such disease states are referred to as autoimmune diseases. Inflammation and allergic reactions are other examples of uncontrolled immune responses.

The psychological and emotional aspects of CFS are also in question. Some studies indicate that the brain is physically affected by inflammation and hormonal changes. Other studies demonstrate that some of the known viral infective agents can have neurological effects. Psychiatric studies give ample evidence that depression, memory loss, and concentration are significant problems for some CFS patients. The extent to which stress is a factor in the disease is unknown.

Treatment and Therapy

Defining and treating chronic fatigue syndrome has been difficult because it manifests itself as a systemic disease with confusing cause-and-effect relationships involving external factors such as infectious viruses, internal factors such as the immune response, and a psychological component that is difficult to assess. The symptoms, provided by patient histories, physical examinations, and laboratory findings, involve neuromuscular, psychoneurological, and immunological changes that vary between patients. The variety of factors to consider has caused difficulty in establishing diagnostic criteria for primary care in a clinical setting or further definition of the disease and treatments in a research setting.

In 1988, the CDC established diagnostic criteria that are divided into two major criteria, eleven minor symptom criteria, and three minor physical criteria. The first major criterion defines chronic fatigue as lasting at least six months and causing debilitation to 50 percent of the patient’s normal activity. The second major criterion requires that all other disease conditions that could fit the patient history, physical examination, and appropriate laboratory tests be ruled out. The categories of disease that might be similar to CFS are cancers, chronic degenerative disease, autoimmune disorders, microbial and parasitic disease, and chronic psychiatric disease. Combinations of some minor criteria that would fit a general flulike condition must be demonstrated.

In 1993, a meeting at the CDC attempted to evaluate what had been learned over the previous five-year period and to make recommendations regarding a case definition. It was suggested that the case definition format involve inclusion and exclusion criteria that would increase the number and range of cases being studied because of the heterogeneous nature of the disease. The cases should also be subcategorized to provide a homogeneity that would allow for subgroup identification and comparison. The inclusion evidence should be simple, with a descriptive interpretation of the fatigue being essential and having objective criteria to define a 50 percent reduction of physical activity. Symptoms that are specific to unexplained fatigue should be used, while the physical exam information should not be included. It was also suggested that exclusion of any cases should involve an in-depth history (both medical and psychiatric), a physical examination, and standardized testing that would involve medical, laboratory, and psychiatric information.

Because it appears that CFS overlaps with many other medical and psychiatric conditions that can be identified and treated, there is debate as to how to interpret CFS as it relates to patient care and research. Some believe that an in-depth history is fundamental to the understanding of CFS and that CFS could be caused by a variety of biological and psychosocial factors.

The minor criteria used to define CFS involve both symptom and physical criteria that have not been proved adequate to validate or define the condition. In fact, the conflicting data have only served to emphasize further the clinical heterogeneity of the disease and suggest a heterogeneity of cause. Suggestions have been made to drop the concept of minor criteria, use symptoms that are specific to the unexplained fatigue, and drop all physical examination criteria. The argument for eliminating physical criteria is that more specific criteria exist for a case definition. Because physical symptoms are inconsistent or periodic, it is believed that a documented patient history would provide more case-specific information.

Although symptom criteria have widespread support in the case definition of CFS, symptoms with the greatest sensitivity and specificity are also being debated. Night sweats, cough, gastrointestinal problems, and new and worsening allergies are not presently considered and are believed by some to be more specific than fever or chills and sore throat. Others have proposed that symptoms should be reduced to chills and fever, sore throat, neck or axilla adenopathy, and sudden onset of a main symptom complex. The most prevalent symptoms are believed to be muscle weakness and pain, problems in concentration, and sleep disturbance.

The importance of the psychiatric component in CFS continues to be a problem in case definition. Some believe that the neurological component is a major criterion in case definition and that behavioral symptoms, including stress and psychiatric illness, must be emphasized in clinical diagnosis as well as in treatment. It has been recommended that objective neuropsychological testing be used to determine cognitive dysfunction and depression. There is a general agreement that CFS patients have impaired concentration and attention, but forgetfulness and memory problems are questioned. There is also evidence that the duration and severity of myalgia are closely associated with psychological distress and that psychotherapy improves physical symptoms. Finally, it has been argued that the psychiatric component of the case definition is essential because there is evidence that the disease directly affects the brain and that CFS can cause both isolation and limitation of the patient’s normal lifestyle.

Proper patient care necessitates extensive evaluation in order to identify the biological or psychological reasons for the problem. Proper CFS patient care demands the elimination of other serious disease possibilities that may appear superficially similar. Primary care physicians may find it difficult to make a diagnosis without a team of specialists in the areas of hematology, immunology, and psychiatry. Numerous laboratory tests must be made available. Although there are no specific recommended tests, those that must be performed should be tailored to specific patients.

The possibility of infectious disease, either as part of CFS (as in the case of certain viral agents) or as an autonomous infection having no relation to CFS, requires a variety of antibody tests to detect such viruses as Epstein-Barr or HIV. Skin tests such as the purified protein derivative (PPD) test for tuberculosis are used. Polymerase chain reaction and tissue culture for cytopathic effects have been developed to detect certain retroviruses for use in diagnosis.

The immune system is so intimately interactive with the entire body that most disease conditions are affected by and affect its function. Carefully monitoring the components of the immune system can provide clues to the identity of the disease that is operating because they indicate whether normal protection activity or immune dysfunction (or a combination) is occurring in the patient.

The components of the immune system can be measured in numerous ways, from methodologies used in standard clinical laboratory procedures to research protocols used to study immune function and disease treatment. Tests are available that can measure total antibody concentration and the various subgroups IgG, IgM, IgA, IgE, and IgD; cytokines such as interleukin-2 and gamma interferon; cellular components such as T cells and their subtypes (such as suppressor T cells and natural killer cells); and B cells.

Autoimmune diseases and allergies are immune dysfunction diseases in their own right. Because there is an immune dysfunction component to CFS, tests for these conditions are important considerations. An antinuclear antibody (ANA) test determines the presence of antibodies that attack the tissues of the patient, as in systemic lupus erythematosus. The type and extent of allergic reactions can be measured using the radioimmunosorbent (RIST) tests for total IgE concentration and radioallergosorbent (RAST) tests for IgE concentration for particular antigens.

Systemic disease states, including CFS, often involve generalized inflammation that is considered part of the body’s protective response. While inflammation is important to the elimination of various infective agents, it is also involved in neurological and muscle tissue damage. C-reactive protein (CRP) and the erythrocyte
sedimentation rate (ESR) tests measure the intensity of the inflammatory response. A variety of other tests provide information that indicates the extent of muscle, liver, thyroid, and other vital organ damage.

Although a diagnosis can be made for CFS, there is no standard treatment. Clinical treatment essentially takes the form of alleviating the symptoms. Antidepressants such as doxepin (Sinequan) are useful in the treatment of depression and are also used to control muscle pain, lethargy, and sleeping problems. Nonsteroidal anti-inflammatory drugs (NSAIDs) provide relief for headache and muscle pain. Two drugs that have demonstrated antiviral activities are acyclovir and ampligen; ampligen can also modulate the immune response. Psychological counseling is also recommended for CFS patients in order to help them identify alternatives to work around some of the limitations that CFS creates. Physical therapy and graded exercise have also been shown to ease some of the symptoms of CFS, although patients should be careful not to overexert themselves, which could lead to a worsening of symptoms.

Because of the systemic nature of the disease, including its psychoneurological component, consideration must be given to holistic medical treatment. Any treatment protocol must be able to address the interactive factors of CFS that are still being defined in terms of cause and effect. Some researchers believe that therapeutic treatment should comprise diet, exercise, vitamins, and homeopathic medicine.

Perspective and Prospects

The vague, often “flulike” symptoms used to define chronic fatigue syndrome have historically been associated with numerous infectious agents, such as Brucella (brucellosis), Coxsiella, Epstein-Barr virus infections (infectious mononucleosis), and other chronic viral diseases. In most cases, a specific etiological agent was discovered. Association with a specific agent allowed for treatment in many cases, or at the least a means to define the illness.

Continued technological advances and research into both the immune system and the nature of viral infection will provide new insights into more effective treatment protocols for CFS, including the role played by immune responses to the triggering agent. The neuropsychological components of the disease, as well as evidence demonstrating ties between these components and the immune system, require an active approach by the patient to achieve a healthy state. CFS provides a challenge to the patient to adapt a personal lifestyle that is conducive to a healthy mind and body.

Medical treatment and diagnostic testing can be costly as well as useless, particularly as the health care community continues to refine its understanding of the condition. Patients must remain vigilant regarding phony or trendy treatments that have no correlation to acceptable research findings; such treatments not only can be expensive but also could lead to deteriorating health.

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