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Clinical features and diagnosis of chronic fatigue syndrome (systemic exertion intolerance disease)

Stephen J Gluckman, MD
Section Editor
Mark D Aronson, MD
Deputy Editor
Howard Libman, MD, FACP


Chronic fatigue syndrome (CFS), also known as systemic exertion intolerance disease (SEID), has received considerable attention but remains a complicated and controversial disease [1]. Much of this is due to the lack of objective findings. Nonetheless, patients with CFS/SEID have real symptoms and are not malingerers. The prevalence of this syndrome is unclear in part due to difficulties in proving the diagnosis.

The condition has long been recognized and many different terms have been used to describe it (eg, DaCosta's syndrome, effort syndrome, soldier's heart, neurasthenia, myalgic encephalitis/encephalomyelitis, Iceland disease, Akureyri disease, and Royal Free disease, chronic fatigue and immune dysfunction syndrome) [2,3].

The clinical manifestations and diagnosis of CFS/SEID are reviewed here. The general approach to a patient with fatigue and the treatment of CFS/SEID are discussed separately. (See "Approach to the adult patient with fatigue" and "Treatment of chronic fatigue syndrome (systemic exertion intolerance disease)".)


There are multiple case definitions for CFS/SEID, and these have changed over time [4-9]. In 2015, the Institute of Medicine (IOM) redefined the diagnostic criteria for CFS/SEID (table 1) and suggested the name change to systemic exertion intolerance disease [9]. The IOM diagnostic criteria focus on the most specific features of the disease. As with previous definitions, symptoms should be present for at least six months and have moderate, substantial, or severe intensity at least one-half of the time. Other criteria include: postexertional malaise, sleep problems, cognitive impairment, and orthostatic-related symptoms.

These clinical case definitions are standard epidemiologic tools that are employed when there is no diagnostic test for a specific disorder. They are "intentionally restrictive, to maximize the chances that research studies will detect significant associations if such associations truly exist" [7]. Though a clinical case definition is a well-established instrument, its strict application may not always be appropriate in the evaluation of a specific patient.

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Literature review current through: Sep 2017. | This topic last updated: Sep 05, 2017.
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  1. Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet 2006; 367:346.
  2. Aronowitz RA. From myalgic encephalitis to yuppie flu: A history of chronic fatigue syndromes. In: Framing Disease, Rosenberg CE, Golden J (Eds), Rutgers University Press, New Brunswick, NJ 1992.
  3. Kim E. A brief history of chronic fatigue syndrome. JAMA 1994; 272:1070.
  4. Smith MEB, Nelson HD, Haney E, Pappas M, Daeges M, Wasson N, McDonagh M. Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Evidence Report/Technology Assessment No. 219. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-I.) AHRQ Publication No. 15-E001-EF. Rockville, MD: Agency for Healthcare Research and Quality; December 2014. www.effectivehealthcare.ahrq.gov/reports/final/cfm.
  5. Haney E, Smith ME, McDonagh M, et al. Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 2015; 162:834.
  6. Green CR, Cowan P, Elk R, et al. National Institutes of Health Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Ann Intern Med 2015; 162:860.
  7. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108:387.
  8. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994; 121:953.
  9. IOM (Institute of Medicine). Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015 http://www.iom.edu/mecfs (Accessed on February 12, 2015).
  10. Bates DW, Schmitt W, Buchwald D, et al. Prevalence of fatigue and chronic fatigue syndrome in a primary care practice. Arch Intern Med 1993; 153:2759.
  11. Kroenke K, Wood DR, Mangelsdorff AD, et al. Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome. JAMA 1988; 260:929.
  12. Wessely S, Chalder T, Hirsch S, et al. The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. Am J Public Health 1997; 87:1449.
  13. Patel V, Kirkwood BR, Weiss H, et al. Chronic fatigue in developing countries: population based survey of women in India. BMJ 2005; 330:1190.
  14. Buchwald D, Umali P, Umali J, et al. Chronic fatigue and the chronic fatigue syndrome: prevalence in a Pacific Northwest health care system. Ann Intern Med 1995; 123:81.
  15. Reyes M, Nisenbaum R, Hoaglin DC, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med 2003; 163:1530.
  16. Jones JF, Ray CG, Minnich LL, et al. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med 1985; 102:1.
  17. Straus SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 1985; 102:7.
  18. Straus SE. The chronic mononucleosis syndrome. J Infect Dis 1988; 157:405.
  19. Gilliam AG. Epidemiologic study of an epidemic diagnosed as poliomyelitis, occurring among personnel of Los Angeles County General Hospital during the summer of 1934: Bull no 240. Institute of Health; US Public Health Service, Division of Infectious Diseases, Washington, DC 1938.
  20. ACHESON ED. The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neuromyasthenia. Am J Med 1959; 26:569.
  21. HENDERSON DA, SHELOKOV A. Epidemic neuromyasthenia; clinical syndrome. N Engl J Med 1959; 260:757.
  22. AN OUTBREAK of encephalomyelitis in the Royal Free Hospital Group, London, in 1955. Br Med J 1957; 2:895.
  23. Levine PH, Dale JK, Benson-Grigg E, et al. A cluster of cases of chronic fatigue and chronic fatigue syndrome: clinical and immunologic studies. Clin Infect Dis 1996; 23:408.
  24. Holmes GP, Kaplan JE, Stewart JA, et al. A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr virus the cause? JAMA 1987; 257:2297.
  25. Working Group of the Royal Australasian College of Physicians. Chronic fatigue syndrome. Clinical practice guidelines--2002. Med J Aust 2002; 176 Suppl:S23.
  26. Ablashi DV, Josephs SF, Buchbinder A, et al. Human B-lymphotropic virus (human herpesvirus-6). J Virol Methods 1988; 21:29.
  27. Archard LC, Bowles NE, Behan PO, et al. Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatine kinase. J R Soc Med 1988; 81:326.
  28. DeFreitas E, Hilliard B, Cheney PR, et al. Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci U S A 1991; 88:2922.
  29. Khan AS, Heneine WM, Chapman LE, et al. Assessment of a retrovirus sequence and other possible risk factors for the chronic fatigue syndrome in adults. Ann Intern Med 1993; 118:241.
  30. Mawle AC, Nisenbaum R, Dobbins JG, et al. Seroepidemiology of chronic fatigue syndrome: a case-control study. Clin Infect Dis 1995; 21:1386.
  31. Gow JW, Simpson K, Behan PO, et al. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. Clin Infect Dis 2001; 33:2080.
  32. Oakes B, Hoagland-Henefield M, Komaroff AL, et al. Human endogenous retrovirus-K18 superantigen expression and human herpesvirus-6 and human herpesvirus-7 viral loads in chronic fatigue patients. Clin Infect Dis 2013; 56:1394.
  33. 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; 326:585.
  34. Lo SC, Pripuzova N, Li B, 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; 107:15874.
  35. Henrich TJ, Li JZ, Felsenstein D, et al. Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions. J Infect Dis 2010; 202:1478.
  36. Erlwein O, Kaye S, McClure MO, et al. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One 2010; 5:e8519.
  37. van Kuppeveld FJ, de Jong AS, Lanke KH, et al. Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. BMJ 2010; 340:c1018.
  38. Groom HC, Boucherit VC, Makinson K, et al. Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 2010; 7:10.
  39. Alter HJ, Mikovits JA, Switzer WM, et al. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus. MBio 2012; 3.
  40. Knox K, Carrigan D, Simmons G, et al. No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science 2011; 333:94.
  41. Simmons G, Glynn SA, Komaroff AL, et al. Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study. Science 2011; 334:814.
  42. Silverman RH, Das Gupta J, Lombardi VC, et al. Partial retraction. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2011; 334:176.
  43. http://www.sciencemag.org/content/334/6063/1636.1.full (Accessed on December 22, 2011).
  44. Lo SC, Pripuzova N, Li B, et al. Retraction for Lo 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 2012; 109:346.
  45. Hué S, Gray ER, Gall A, et al. Disease-associated XMRV sequences are consistent with laboratory contamination. Retrovirology 2010; 7:111.
  46. Oakes B, Tai AK, Cingöz O, et al. Contamination of human DNA samples with mouse DNA can lead to false detection of XMRV-like sequences. Retrovirology 2010; 7:109.
  47. Smith RA. Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retroviruses. Retrovirology 2010; 7:112.
  48. Hurlburt WB. Linitis plastica in a 16-year-old. Alaska Med 1975; 17:77.
  49. Gupta GS, Bawa SR. Radiation effects on rat testes. V. Studies on lysosomal enzymes (acid phosphatase and acid DNAse) and their physiological significance following partial body gamma-irradiation. J Reprod Fertil 1975; 44:223.
  50. Paprotka T, Delviks-Frankenberry KA, Cingöz O, et al. Recombinant origin of the retrovirus XMRV. Science 2011; 333:97.
  51. Katzourakis A, Hué S, Kellam P, Towers GJ. Phylogenetic analysis of murine leukemia virus sequences from longitudinally sampled chronic fatigue syndrome patients suggests PCR contamination rather than viral evolution. J Virol 2011; 85:10909.
  52. Landay AL, Jessop C, Lennette ET, Levy JA. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet 1991; 338:707.
  53. Klonoff DC. Chronic fatigue syndrome. Clin Infect Dis 1992; 15:812.
  54. Buchwald D, Cheney PR, Peterson DL, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med 1992; 116:103.
  55. Nishikai M, Tomomatsu S, Hankins RW, et al. Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology (Oxford) 2001; 40:806.
  56. Vernon SD, Reeves WC. Evaluation of autoantibodies to common and neuronal cell antigens in Chronic Fatigue Syndrome. J Autoimmune Dis 2005; 2:5.
  57. Montoya JG, Holmes TH, Anderson JN, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A 2017; 114:E7150.
  58. Mawle AC, Nisenbaum R, Dobbins JG, et al. Immune responses associated with chronic fatigue syndrome: a case-control study. J Infect Dis 1997; 175:136.
  59. Natelson BH, LaManca JJ, Denny TN, et al. Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis. Am J Med 1998; 105:43S.
  60. Vollmer-Conna U, Cameron B, Hadzi-Pavlovic D, et al. Postinfective fatigue syndrome is not associated with altered cytokine production. Clin Infect Dis 2007; 45:732.
  61. Bouquet J, Gardy JL, Brown S, et al. RNA-Seq Analysis of Gene Expression, Viral Pathogen, and B-Cell/T-Cell Receptor Signatures in Complex Chronic Disease. Clin Infect Dis 2017; 64:476.
  62. Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991; 73:1224.
  63. Sharpe M, Hawton K, Clements A, Cowen PJ. Increased brain serotonin function in men with chronic fatigue syndrome. BMJ 1997; 315:164.
  64. Bennett AL, Mayes DM, Fagioli LR, et al. Somatomedin C (insulin-like growth factor I) levels in patients with chronic fatigue syndrome. J Psychiatr Res 1997; 31:91.
  65. Crofford LJ, Pillemer SR, Kalogeras KT, et al. Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum 1994; 37:1583.
  66. Joseph-Vanderpool JR, Rosenthal NE, Chrousos GP, et al. Abnormal pituitary-adrenal responses to corticotropin-releasing hormone in patients with seasonal affective disorder: clinical and pathophysiological implications. J Clin Endocrinol Metab 1991; 72:1382.
  67. Leese G, Chattington P, Fraser W, et al. Short-term night-shift working mimics the pituitary-adrenocortical dysfunction in chronic fatigue syndrome. J Clin Endocrinol Metab 1996; 81:1867.
  68. Young AH, Sharpe M, Clements A, et al. Basal activity of the hypothalamic-pituitary-adrenal axis in patients with the chronic fatigue syndrome (neurasthenia). Biol Psychiatry 1998; 43:236.
  69. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995; 274:961.
  70. Rowe PC, Calkins H. Neurally mediated hypotension and chronic fatigue syndrome. Am J Med 1998; 105:15S.
  71. Naschitz JE, Rosner I, Rozenbaum M, et al. The head-up tilt test with haemodynamic instability score in diagnosing chronic fatigue syndrome. QJM 2003; 96:133.
  72. Poole J, Herrell R, Ashton S, et al. Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome. Arch Intern Med 2000; 160:3461.
  73. Peterson PK, Pheley A, Schroeppel J, et al. A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Arch Intern Med 1998; 158:908.
  74. Taerk GS, Toner BB, Salit IE, et al. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med 1987; 17:49.
  75. Kruesi MJ, Dale J, Straus SE. Psychiatric diagnoses in patients who have chronic fatigue syndrome. J Clin Psychiatry 1989; 50:53.
  76. Manu P, Lane TJ, Matthews DA. The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 1988; 109:554.
  77. White PD, Thomas JM, Kangro HO, et al. Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet 2001; 358:1946.
  78. Cope H, David A, Pelosi A, Mann A. Predictors of chronic "postviral" fatigue. Lancet 1994; 344:864.
  79. Togo F, Natelson BH, Cherniack NS, et al. Sleep structure and sleepiness in chronic fatigue syndrome with or without coexisting fibromyalgia. Arthritis Res Ther 2008; 10:R56.
  80. Smith AK, White PD, Aslakson E, et al. Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue. Pharmacogenomics 2006; 7:387.
  81. Goertzel BN, Pennachin C, de Souza Coelho L, et al. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics 2006; 7:475.
  82. Katon WJ, Buchwald DS, Simon GE, et al. Psychiatric illness in patients with chronic fatigue and those with rheumatoid arthritis. J Gen Intern Med 1991; 6:277.
  83. Lane TJ, Manu P, Matthews DA. Depression and somatization in the chronic fatigue syndrome. Am J Med 1991; 91:335.
  84. Goldenberg DL, Simms RW, Geiger A, Komaroff AL. High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice. Arthritis Rheum 1990; 33:381.
  85. Buchwald D, Garrity D. Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Arch Intern Med 1994; 154:2049.
  86. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 2000; 160:221.
  87. Schacterle RS, Komaroff AL. A comparison of pregnancies that occur before and after the onset of chronic fatigue syndrome. Arch Intern Med 2004; 164:401.
  88. Schwartz RB, Garada BM, Komaroff AL, et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. AJR Am J Roentgenol 1994; 162:935.