Chronic Fatigue Syndrome (CFS)



Chronic fatigue syndrome (CFS) is a disorder characterized by unexplained profound fatigue that is worsened by exertion. The fatigue is accompanied by cognitive dysfunction and impairment of daily functioning that persists for more than 6 months.

CFS was originally termed myalgic encephalomyelitis (ME) because British clinicians noted a skeletal muscle component manifesting as chronic fatigue and an encephalitic component manifesting as cognitive difficulties. However, this term is inappropriate because of a lack of encephalomyelitis in laboratory and imaging studies, and myalgia is not a core symptom of the disease.[1]

In 2015, the 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.[2]

​The cause of CFS is unknown, and there are no direct tests to diagnose CFS. If the source of the fatigue can be explained, the patient probably does not have CFS. The diagnosis is one of exclusion that meets the clinical criteria below.

Diagnostic criteria

A diagnosis of CFS requires the following three symptoms:[1]

At least one of the following must also be present:


CFS is a biological illness, not a psychologic disorder. The exact pathogenesis is unknown. Numerous mechanisms and molecules have been implicated that lead to abnormalities in immune dysfunction, hormonal regulation, metabolism and response to oxidative stress to include impaired natural killer cell function and/or T-cell function, elevated cytokines, and autoantibodies (rheumatic factor, antithyroid antibodies, antigliadin, anti–smooth muscle antibodies, and cold agglutinins).[3, 4] Infections have been suspected; however, no causal role has been established.


Many viruses have been studied as potential causes of CFS; however, no definitive causal relation has been determined. Historically, human herpesvirus type 6, enterovirus, rubella virus, Candida albicans, bornavirus, Mycoplasma, Chlamydia pneumoniae, retroviruses, coxsackie B virus, cytomegalovirus, and xenotropic murine leukemia virus-related virus have been studied and have not been found to cause CFS.[5, 6, 7, 8, 9, 10, 11, 12] Some people infected with Epstein-Barr virus, Ross River virus, Coxiella burnetii, or Giardia have developed criteria for CFS, but not all individuals with CFS have had these infections.[3]

Environmental factors have also been suspected as a trigger for CFS; however, no specific factors have been identified.


CFS affects 836,000 to 2.5 million Americans.[1] An estimated 84%-91% of individuals with the condition have not been diagnosed; therefore, the true prevalence is unknown. Overall, CFS is more common in females than in males and occurs most commonly in young to middle-aged adults.[13] The average age of onset is 33 years, although cases have been reported in patients younger than 10 years and older than 70 years. Patients with CFS experience loss of productivity and high medical costs that contribute to a total economic burden of $17-24 billion annually.[1]


CFS has no cure, its symptoms can persist for years, and its clinical course is punctuated by remissions and relapses. One prospective study suggests that approximately 50% of patients with CFS can return to part-time or full-time work.[14] Longer duration of illness, severe fatigue, comorbid depression, and anxiety are factors associated with a poorer prognosis.[15] Good outcomes are associated with less fatigue severity at baseline, a sense of control over symptoms, and no attribution of the illness to a physical cause.[16] Despite the considerable burden of morbidity associated with CFS, there is no evidence of an increased risk of mortality.

Patient Education

For patient education resources, see the Back, Ribs, Neck, and Head Center, as well as Chronic Fatigue Syndrome, Fibromyalgia, and Fatigue.


Patients with CFS typically report experiencing postexertional fatigue and feeling excessively tired after relatively normal tasks that they did for years before CFS without any particular problem. Patients also report fatigue even after prolonged periods of rest or sleep. At least one quarter of patients with CFS are bed- or house-bound at some point in their illness. Patients with CFS often report a history of antecedent flulike infection that precipitated the prolonged state of fatigue and followed the initial illness.

Patients with CFS typically report problems with short-term memory but not with 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.

The five main symptoms of CFS are summarized as follows:[1]

Physical Examination

Physical examination often reveals no abnormalities. Some patients may have positive orthostatic vital signs.

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 crescent 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 unknown, but they are common in patients with CFS. Nonetheless, crimson crescents are not specific for CFS.

Trigger points, which suggest fibromyalgia, are absent in patients with CFS. Fibromyalgia and CFS rarely coexist in the same patient.

Laboratory Studies

Laboratory findings are normal in CFS. Tests are used to assess for other underlying causes of fatigue, as follows:

Other Tests

Other tests may include the following:

Imaging Studies

Brain Imaging

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 scanning 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.

Approach Considerations

CFS has no cure. Treatment is largely supportive and focuses on symptom relief. Large randomized controlled trials such as the pacing, graded activity, and cognitive behavior therapy: a randomized evaluation (PACE) trial and Cochrane reviews have recommended cognitive behavioral therapy (CBT) as an effective method for treating CFS in adults.[17, 18] However, the surveillance report in 2017 from the National Institute for Health and Care Excellence (NICE) evidence reviews recommend against CBT.[19] The Centers for Disease Control and Prevention (CDC) and the Agency for Healthcare Research and Quality (AHRQ) both have removed CBT as a recommended treatment for CFS because of insufficient evidence.[20]


No restrictive or elimination diets have been proven to be beneficial.

Exercise Therapy

Exercise is not a cure for CFS. A 2017 Cochrane review evaluated exercise therapy for patients with CFS. The study found that patients felt less fatigued following exercise therapy and felt improved in terms of 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.[21]

The PACE trial found that graded exercise therapy (GET) effectively improved measures of fatigue and physical functioning.[17] However, updates from the NICE guideline surveillance report in 2017 recommend against GET. The CDC and AHRQ both have removed GET as a recommended treatment.[20]

Medication Summary

No drugs have been FDA-approved for CFS treatment. Clinical trials have found that antiviral agents are ineffective in relieving the symptoms of CFS.[22] Various medications have been shown to be ineffective, including antibiotics, glucocorticoids, liver extract, chelating agents, intravenous (IV) vitamins, vitamin B-12, and IV or oral vitamin or mineral supplements. Antidepressants have no major role in the treatment of CFS.

A randomized placebo-controlled double-blind trial to evaluate the effect of cytokine inhibition with anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, was conducted and did not show any improvement in fatigue severity both in the short term (4 weeks) or the long term (6 months).[23] Future studies may evaluate inhibition of other cytokines such as IL-6, tumor necrosis factor, and/or interferons.

To date, no evidence-based interventions are available for the treatment of CFS.

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Jefferson R Roberts, MD, Chief of Rheumatology Service, Tripler Army Medical Center; Assistant Clinical Professor of Medicine, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.


Mary L Lan, MD, MPH, Resident Physician, Department of Medicine, Tripler Army Medical Center

Disclosure: Nothing to disclose.

Michael W Price, MD, Chief, Medical Specialty Clinic #1, Tripler Army Medical Center; Instructor in Medicine, Uniformed Services University of the Health Sciences, F Edward Herbert School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

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

Disclosure: Nothing to disclose.


Bryan D Carter, PhD Professor of Child Psychology in Psychiatry and Behavioral Sciences, Chief Psychologist in Division of Child and Adolescent Psychiatry, Director of Predoctoral Internship in Clinical Child/Pediatric Psychology, Director of Postdoctoral Fellowship Program in Pediatric Psychology, Director of Pediatric Consultation-Liaison Service to Kosair Children's Hospital, University of Louisville School of Medicine

Bryan D Carter, PhD is a member of the following medical societies: American Psychological Association

Disclosure: Nothing to disclose.

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech Carilion School of Medicine

Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Leonard R Krilov, MD Chief of Pediatric Infectious Diseases and International Adoption, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital

Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Medimmune Grant/research funds Cliinical trials; Medimmune Honoraria Speaking and teaching; Medimmune Consulting fee Consulting

Mark R Schleiss, MD American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School

Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Julian M Stewart, MD, PhD Associate Chairman of Pediatrics, Director, Center for Hypotension, Westchester Medical Center; Professor of Pediatrics and Physiology, New York Medical College

Julian M Stewart, MD, PhD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Robert W Tolan Jr, MD Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine

Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility

Disclosure: Novartis Honoraria Speaking and teaching

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.


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