terça-feira, 11 de julho de 2017

UPDATE: Chronic Fatigue Syndrome (CFS)

Chronic fatigue syndrome (CFS) is a disorder characterized by a state of chronic fatigue that persists for more than 6 months, has no clear cause, and is accompanied by cognitive difficulties.
CFS was initially termed encephalomyalgia (or 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).
More recently, the US Institute of Medicine (IOM) proposed that the condition be renamed “systemic exertion intolerance disease” (SEID) to better reflect the condition's hallmark defining symptom, postexertional malaise. [1]
Various unrelated infectious diseases (eg, pneumoniaEpstein-Barr virus [EBV] infection, diarrhea, upper respiratory tract infections) appear to lead to a state of prolonged fatigue in some persons. Generally, if this condition is accompanied by cognitive difficulties, it is referred to as CFS.
The cause of CFS is unknown, but the disorder is probably an infectious disease with immunologic manifestations. EBV has been excluded as a cause of CFS, even though EBV infection is one of the many causes that may lead to a state of chronic fatigue. CFS is not synonymous with chronic EBV infection or chronic infectious mononucleosis.
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). The absence of cognitive dysfunction should exclude CFS as a potential diagnosis.
Because no cause of CFS has been determined, no effective therapy exists for CFS.
For patient education resources, see the Back, Ribs, Neck, and Head Center, as well as Chronic Fatigue SyndromeFibromyalgia, and Fatigue.
Diagnostic criteria
According to the Centers for Disease Control and Prevention (CDC), [2in order to receive a diagnosis of CFS, a patient must (1) have severe chronic fatigue of at least 6 months’ duration, with other known medical conditions excluded by clinical diagnosis, and (2) concurrently have 4 or more of the following symptoms:
  • Substantial impairment in short-term memory or concentration
  • Sore throat
  • Tender lymph nodes
  • Muscle pain
  • Multijoint pain without swelling or redness
  • Headaches of a new type, pattern or severity
  • Unrefreshing sleep
  • Postexertional malaise lasting more than 24 hours
The symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.
The CDC case definition also states that any unexplained abnormality detected on examination or other testing that strongly suggests an exclusionary condition must be resolved before further classification is attempted. Conditions that do not exclude CFS include the following:
  • Any condition defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests, including fibromyalgia, anxiety disorders, somatoform disorders, nonpsychotic or melancholic 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, including 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 symptoms
  • 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, including 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
In children, CFS is poorly defined. Most studies of CFS in the pediatric age range have followed the CDC criteria. However, whether the adult CDC case definition can be applied to children and adolescents is debatable.
Children have typically been referred to specialty clinics after extensive screening by their primary care physician has yielded negative or nonspecific test results. Therefore, common short-lived causes of fatigue are effectively excluded. The length of fatigue (6 months) also effectively excludes many common illnesses and probably should be retained in any forthcoming pediatric case definition.
In 2015, the IOM proposed new diagnostic criteria for both adults and children, as follows: [1]
  • Ongoing (>6 months) substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest
  • Postexertional malaise (often described by patients as a "crash" or "collapse" after even minor physical or mental exertion)
  • Unrefreshing sleep
Cognitive impairment and/or orthostatic intolerance


Because the immune system is upregulated 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 elevated levels of immunoglobulin G (IgG) viral capsid antigen (VCA) EBV, this determination should be considered as an incidental finding in CFS. Most patients with CFS demonstrate elevated IgG, coxsackievirus B, human herpesvirus 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 abnormalities.


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 relation has been determined. A role for xenotropic murine leukemia virus–related virus (XMRV) and other murine retroviruses was posited, [34but XMRV has been ruled out as a cause of CFS. [5678]
Patients with CFS are often referred to an infectious disease specialist because of elevated levels of immunoglobulin G (IgG) to the viral capsid antigen (VCA) of 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.
Some have suggested that the infectious agent responsible for CFS is Chlamydia pneumoniae, which may become activated after contact with another infectious agent. 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. [910]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.


CFS is common in the United States, but the data are difficult to interpret because the various studies define CFS in different ways. Outside the United States, CFS appears to be less common, but it probably exists worldwide. Overall, CFS is more common in females than in males. [11It occurs most commonly in young to middle-aged adults.


As suggested by the term chronic, the clinical course of CFS is punctuated by remissions and relapses, often triggered by intercurrent infection, stress, exercise, or lack of sleep. The course in adolescents is similar to that in adults.
Most cases improve to some degree over time.


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 Epstein-Barr virus (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.
From a personality standpoint, patients with CFS are usually cardiac type A intensive people. They are not malingerers, and they do not seek secondary gain. As a group, they typically want a fully functioning life to be restored to them, 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 with long-term memory. They may also report verbal dyslexia that is manifested 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, feeling excessively tired after doing relatively normal tasks that they did for years before 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 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 who experience 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 Examination

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 exclude a diagnosis of CFS. Signs of adrenal or thyroid disorders should also exclude a diagnosis of CFS, in that the fatigue is explained by endocrinologic factors. Similarly, HIV infection and AIDS may also cause chronic fatigue.
The physical examination often reveals no abnormalities, but left axillary node involvement or crimson crescents are the most consistent findings on physical examination.
Many patients with or without CFS have small, moveable, painless lymph nodes that most commonly involve the neck, axillary region, or inguinal region. 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.
In the oropharynx, purple or crimson discoloration of both anterior tonsillar pillars 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.
Trigger points, which suggest fibromyalgia, are absent in patients with CFS. CFS and fibromyalgia rarely coexist in the same patient.

Diagnostic Considerations

Chronic fatigue syndrome (CFS) is, in large measure, a diagnosis of exclusion. The key diagnostic task is to differentiate it from other disorders that also have a fatigue component. CFS may be distinguished from other causes of fatigue on the basis of the presence of cognitive dysfunction, which is absent in almost all other fatigue-producing disorders. Once a specific cause of fatigue has been diagnosed, CFS is excluded by definition.
Careful perusal of the Centers for Disease Control and Prevention (CDC) criteria indicates that essentially any chronic illness that produces extensive disability in a setting of persistent fatigue may be included in the differential diagnosis. Conditions that can cause fatigue include the following:
  • Chronic heart disease
  • Psychiatric illnesses
  • Thyroid disease
  • Connective tissue diseases
  • Chronic anemia
  • Neoplastic disease
  • Chronic infections (eg, AIDS)
  • Endocrine diseases (eg, Addison disease)
  • Inflammatory bowel disease
  • Drug abuse
  • Liver disease
  • Renal disease
Patients with psychosomatic disorders may have elevated titers of immunoglobulin G (IgG) to Epstein-Barr virus (EBV) viral capsid antigen (VCA), which may be incorrectly interpreted as evidence for CFS. EBV infection may precede CFS, but it does not cause CFS. Such patients do not present with the physical findings or abnormal laboratory findings that characterize CFS. Such patients also lack the cognitive dysfunction characteristic of CFS.
CFS is readily differentiated from Lyme disease. Patients from areas with endemic Lyme disease may have elevated IgG Lyme titers. Few have neuroborreliosis, which is diagnosed by simultaneously measuring cerebrospinal fluid and serum IgM and IgG Lyme titers. CSF IgM titers that are higher than serum IgM titers indicate neuroborreliosis (if the patient has not been treated with antibiotics). Acute Lyme disease usually has a neurologic component.
Because fibromyalgia does not cause cognitive defects, it is readily differentiated from CFS. Furthermore, patients with CFS do not have the trigger points that are characteristic of fibromyalgia.
It is especially important to rule out systemic disorders, particularly lymphoreticular malignancies, in patients who present with fatigue. Other diseases may be ruled out on the basis of the history, physical examination, or laboratory findings. These other potential causes of fatigue sometimes must be reinvestigated several times.

Differential Diagnoses

Laboratory Studies

Laboratory tests have 2 functions in chronic fatigue syndrome (CFS). First, they may be used to assess the possibility that another condition is causing the fatigue; second, they may be used to help diagnose CFS. CFS laboratory abnormalities are not specific, but, taken together, they can make up a pattern consistent with CFS in patients who have a cognitive dysfunction in whom other diseases have been excluded as a cause for their fatigue.
The Centers for Disease Control and Prevention (CDC) has recommended a “basic battery” that includes the following:
  • Complete blood count (CBC)
  • Liver function tests
  • Thyroid function tests
  • Erythrocyte sedimentation rate (ESR)
  • Serum electrolyte level measurement
Some clinicians also include antinuclear antibody and morning cortisol measurements. Adrenal function tests are useful for the purposes of exclusion.
The most consistent laboratory abnormality in patients with CFS is an extremely low ESR, typically in the range of 0-3 mm/h. An normal ESR or one that is in the upper reference range suggests another diagnosis.
Most patients with CFS usually have 2 or 3 of the following nonspecific abnormalities:
  • Elevated immunoglobulin M (IgM)/immunoglobulin G (IgG) coxsackievirus B titer
  • Elevated IgM/IgG human herpesvirus 6 (HHV-6) titer
  • Elevated IgM/IgG C pneumoniae titer
  • Decrease in natural killer (NK) cells (either percentage or activity)
The WBC count in patients with CFS is normal. Leukopenia, leukocytosis, or an abnormal cell differential count indicates a diagnosis other than CFS, and another cause should be pursued to explain these findings.Results of liver function tests are within the reference range in patients with CFS. Increased levels of serum transaminases, alkaline phosphatase, or lactic dehydrogenase should prompt a search for another explanation because these values are typically normal CFS.
Serum protein electrophoresis is normal in patients with CFS but may be used to rule out other diseases that cause fatigue, including lymphoma and myeloma.
Urinalysis findings are unremarkable in CFS.

Other Tests

CT, MRI, and PET

Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain is useful for ruling out central nervous system (CNS) disorders in patients with otherwise unexplained CNS symptoms. Results of CT scans and MRI may be normal in patients with CFS. Findings of CNS imaging studies are not specific for CFS and are thus used to rule out alternative explanations rather than to diagnose CFS.
Positron emission tomography (PET) shows hypoperfusion in the frontoparietal/temporal region.

Approach Considerations

Because most cases of chronic fatigue syndrome (CFS) may be due to a viral infection, no uniformly effective therapy exists for CFS. Trials of antiviral agents have been ineffective in relieving the symptoms of CFS. In patients with elevated C pneumoniae levels, particularly those with increased immunoglobulin M (IgM) titers, antichlamydial therapy may be effective. No special diet or vitamin supplements are effective.
Otherwise, treatment is largely supportive and responsive to symptoms.

Exercise Therapy

In a 2017 Cochrane review, exercise therapy for patients with CFS was evaluated. The study found that patients felt less fatigued following exercise therapy and felt improved in respect to sleep, physical function, and general health. However, the authors could not conclude that exercise therapy improved the outcomes of pain, quality of life, anxiety, and/or depression. [12]

Medication Summary

Trials of antiviral agents have been ineffective in relieving the symptoms of chronic fatigue syndrome (CFS). Various medications have been shown to be ineffective, including steroids, liver extract, chelating agents, intravenous (IV) vitamins, vitamin B-12, and IV or oral vitamin or mineral supplements. Antidepressants have no major role to play in the treatment of CFS.

Antibiotics, Tetracyclines

Class Summary

Antibiotics are used in patients with elevated immunoglobulin M (IgM) Chlamydia pneumoniae titers.

Doxycycline (Vibramycin, Doryx, Oracea, Oraxyl, Adoxa)

Doxycycline is a second-generation tetracycline. Compared with tetracycline, it is much more active against many pathogens and has a different adverse-effect profile and pharmacokinetic characteristics. Doxycycline inhibits bacterial growth, possibly blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

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