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Chronic Fatigue Syndrome

Author: Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Contributor Information and Disclosures

Updated: Oct 19, 2009

Introduction

Background

Chronic fatigue syndrome (CFS) is a disorder of unknown etiology that probably has an infectious basis. CFS is characterized by a state of chronic fatigue that persists for more than 6 months, has no clear cause, and is accompanied by cognitive difficulties.

Various unrelated infectious diseases (eg, pneumonia, Epstein-Barr virus [EBV] infection, diarrhea, upper respiratory tract infections) appear to lead to a state of prolonged fatigue in some persons. If the condition is accompanied by cognitive difficulties, the disease is termed CFS.

While the cause of CFS is unknown, it is probably an infectious disease with immunological manifestations. CFS has been excluded as a cause of EBV, although EBV infection may lead to a state of chronic fatigue. CFS is not synonymous with chronic EBV infection or chronic infectious mononucleosis.

With the exception of EBV, numerous viruses have been implicated as the cause of CFS, but no causal relationship between any virus and CFS has been proven. Some have suggested that Chlamydia pneumoniae is the infectious agent responsible for CFS, which may become activated following contact with another infectious agent.

CFS was initially termed encephalomyalgia (also known as myalgic encephalomyelitis) because British clinicians noted that the essential clinical features of CFS included both an encephalitic component (manifesting as cognitive difficulties) and a skeletal muscle component (manifesting as chronic fatigue). The absence of cognitive dysfunction should exclude CFS as a potential diagnosis.

Because no direct tests aid in the diagnosis of CFS, the diagnosis is one of exclusion but that meets certain clinical criteria, which are further supported by certain nonspecific tests. The diagnosis of CFS also rests on historical criteria, ie, otherwise unexplained fatigue for more than 6 months accompanied by cognitive dysfunction.

Pathophysiology

Because the immune system is up-regulated in CFS, the levels of antibodies to various previously encountered antigens are increased. Although increased titers do not indicate a causal relationship in CFS, the titers are nonetheless useful as laboratory clues, which, when taken together, are common in patients with CFS.

Because so many patients with a possible diagnosis of CFS are found to have high levels of immunoglobulin G (IgG) viral capsid antigen (VCA) EBV, this determination should be considered consistent with but not diagnostic of CFS. Most patients with CFS demonstrate elevated IgG, coxsackievirus B, human herpes virus 6 (HHV-6), and/or C pneumoniae titers. Patients with CFS also commonly have a decreased percentage of natural killer (NK) cells. Most patients with CFS have 2 of the 3 above-mentioned immunological perturbations.

Frequency

United States

CFS is common, but data are difficult to interpret since the various studies define CFS differently.

International

CFS appears to be less common overseas but probably exists worldwide.

Sex

CFS is more common in females than in males.

Age

This condition occurs most commonly in young to middle-aged adults.

Clinical

History

• Patients with chronic fatigue syndrome (CFS) present with prolonged fatigue of an indeterminate cause. If the source of the fatigue can be explained, the patient probably does not have CFS.
• Patients with CFS often report a history of an antecedent infection that precipitated the prolonged state of fatigue and followed the initial illness. The patient may have a history of EBV infectious mononucleosis, cytomegalovirus (CMV) infectious mononucleosis, pneumonia, diarrhea, or upper respiratory tract infection. Patients with acute disease caused by these infections experience fatigue during the acute illness, but the fatigue resolves as the patient recovers. In patients with CFS, the fatigue continues for 6 months or more after they have recovered from the acute infectious event.
• Patients with CFS are usually cardiac "A" intensive people from a personality standpoint. These patients are not malingerers, and they do not seek secondary gain. As a group, they typically want a fully functioning life restored, and they become frustrated by their inability to perform their work and home tasks because of their prolonged fatigue and cognitive dysfunction.
• Patients with CFS may be depressed because of their inability to perform normal duties at home and at work, but they are not depressive individuals per se. Depressive individuals typically report longstanding depression (of several years’ duration), and they typically lack the cognitive dysfunction characteristic of individuals with CFS.
• Patients with CFS typically report problems with short-term memory but not long-term memory. They may also report verbal dyslexia that manifests as the inability to find or say a particular word during normal speech. This typically disturbs patients with CFS and may interfere with their occupation.
• Patients with CFS also typically report postexertional fatigue, being excessively tired after doing relatively normal tasks that they have done for years previous to their CFS without any particular problem. Patients also report fatigue even after prolonged periods of rest or sleep. Patients with CFS do not recharge or arise refreshed after sleeping and rarely rarely have sore throats or fevers.
• The diagnosis of CFS depends on eliminating other causes of chronic persistent fatigue. Many patients have lifestyles that would make anyone feel fatigue on a long-term basis. This may be related to job, family, or home stress. Patients with malignancy should be excluded because fatigue often accompanies neoplastic disease.
• Many patients with fatigue but not CFS have a supratentorial component to the illness, and psychosomatic illness often manifests as otherwise unexplained fatigue.
• If the above conditions can be excluded, then the diagnosis of CFS may be considered.

Physical

• Signs of adrenal or thyroid disorders should also exclude a diagnosis of CFS, as the fatigue is explained by endocrinologic factors.
• Similarly, HIV infection and AIDS may also cause chronic fatigue.
• CFS should be diagnosed only after other causes of fatigue are excluded and the fatigue has lasted for at least 6 months. An absence of cognitive difficulties should also exclude a diagnosis of CFS.
• The physical examination often reveals no abnormalities, but left axillary node involvement and/or crimson crescents are the most consistent findings during a physical examination.
• Patients with CFS have small, moveable, painless lymph nodes that most commonly involve the neck, axillary region, and/or inguinal region.
• In the oropharynx, purple/crimson discoloration of both anterior tonsillar pilars in the absence of pharyngitis is a frequent marker in patients with CFS. The cause of crimson crescents is not known, but they are common in patients with CFS. However, crimson crescents are not specific for CFS.
• A single lymph node that is very large, tender, or immobile suggests a diagnosis other than CFS. Similarly, generalized adenopathy suggests a diagnosis other than CFS.
• Trigger points, which suggest fibromyalgia, are absent in patients with CFS. CFS and fibromyalgia rarely coexist in the same patient.

Causes

• CFS may be caused by an infection due to a virus (except for EBV) or C pneumoniae.
• Many viruses have been studied as potential causal agents, including EBV, HHV-6, coxsackievirus B, spumaviruses, and even human T-cell leukemia virus strains; however, no definitive causal relationship has been determined.
• Patients with CFS are often referred to an infectious disease specialist because of elevated levels of IgG VCA EBV. Increased IgG titers to the VCA of EBV are common in the general population, regardless of whether the patient is fatigued. An increased IgG VCA EBV titer indicates past exposure to EBV but does not indicate acute disease or explain the patient's chronic fatigue state. EBV infection is often the precipitating event that has triggered the patient's chronic fatigue state.
• Some investigators have suggested that C pneumoniae is the cause of CFS. In hospitals or commercial laboratories, immunoglobulin M (IgM) tests and IgG enzyme-linked immunosorbent assay (ELISA) are used to test for C pneumoniae. As with elevated EBV IgG VCA titers, many individuals in the healthy population have elevated IgG titers to C pneumoniae.
• Some patients with CFS are found to have elevated IgM C pneumoniae titers, indicating a recent C pneumoniae infection, and these patients are the most likely to respond to antichlamydial therapy. However, definitive proof supporting causality is lacking.^1,2
• Some investigators studying the potential role of C pneumoniae in CFS believe that serum tests are insensitive and that a more sensitive test (eg, polymerase chain reaction [PCR]) should be used for evaluation. PCR for C pneumoniae is a very sensitive technique but, unfortunately, is available only in research centers.
• Candida albicans and other yeast infections do not cause CFS.

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