Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Chronic Fatigue Syndrome

  • Author: Burke A Cunha, MD; Chief Editor: Michael Stuart Bronze, MD  more...
 
Updated: Feb 16, 2016
 

Background

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, pneumonia, Epstein-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 Syndrome, Fibromyalgia, and Fatigue.

Diagnostic criteria

According to the Centers for Disease Control and Prevention (CDC),[2] in 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

Next

Pathophysiology

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.

Previous
Next

Etiology

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,[3, 4] but XMRV has been ruled out as a cause of CFS.[5, 6, 7, 8]

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.[9, 10]

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.

Previous
Next

Epidemiology

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.[11] It occurs most commonly in young to middle-aged adults.

Previous
Next

Prognosis

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.

Previous
 
 
Contributor Information and Disclosures
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

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, Infectious Diseases Society of America

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

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, Oklahoma State Medical Association, Southern Society for Clinical Investigation, Association of Professors of Medicine, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

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.

References
  1. Clayton EW. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An IOM Report on Redefining an Illness. JAMA. 2015 Feb 10. [Medline].

  2. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994 Dec 15. 121(12):953-9. [Medline].

  3. Lombardi VC, Ruscetti FW, Das Gupta J, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009 Oct 23. 326(5952):585-9. [Medline].

  4. Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R, et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci U S A. 2010 Sep 7. 107(36):15874-9. [Medline]. [Full Text].

  5. Shin CH, Bateman L, Schlaberg R, et al. Absence of XMRV retrovirus and other murine leukemia virus-related viruses in patients with chronic fatigue syndrome. J Virol. 2011 Jul. 85(14):7195-202. [Medline]. [Full Text].

  6. Schutzer SE, Rounds MA, Natelson BH, Ecker DJ, Eshoo MW. Analysis of cerebrospinal fluid from chronic fatigue syndrome patients for multiple human ubiquitous viruses and xenotropic murine leukemia-related virus. Ann Neurol. 2011 Apr. 69(4):735-8. [Medline].

  7. Maggi F, Focosi D, Lanini L, et al. Xenotropic murine leukaemia virus-related virus is not found in peripheral blood cells from treatment-naive human immunodeficiency virus-positive patients. Clin Microbiol Infect. 2012 Feb. 18(2):184-8. [Medline].

  8. Knox K, Carrigan D, Simmons G, et al. No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science. 2011 Jul 1. 333(6038):94-7. [Medline].

  9. Nicolson GL, Gan R, Haier J. Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS. 2003 May. 111(5):557-66. [Medline].

  10. Komaroff AL, Wang SP, Lee J, Grayston JT. No association of chronic Chlamydia pneumoniae infection with chronic fatigue syndrome. J Infect Dis. 1992 Jan. 165(1):184. [Medline].

  11. Capelli E, Zola R, Lorusso L, Venturini L, Sardi F, Ricevuti G. Chronic fatigue syndrome/myalgic encephalomyelitis: an update. Int J Immunopathol Pharmacol. 2010 Oct-Dec. 23(4):981-9. [Medline].

  12. Brurberg KG, Fønhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open. 2014 Feb 7. 4(2):e003973. [Medline]. [Full Text].

  13. Katz BZ, Jason LA. Chronic fatigue syndrome following infections in adolescents. Curr Opin Pediatr. 2013 Feb. 25(1):95-102. [Medline].

  14. Morris G, Maes M. Case definitions and diagnostic criteria for Myalgic Encephalomyelitis and Chronic fatigue Syndrome: from clinical-consensus to evidence-based case definitions. Neuro Endocrinol Lett. 2013. 34(3):185-99. [Medline].

  15. Moss-Morris R, Deary V, Castell B. Chronic fatigue syndrome. Handb Clin Neurol. 2013. 110:303-14. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.