Clinical Rheumatology

, Volume 37, Issue 5, pp 1161–1170 | Cite as

On chronic fatigue syndrome and nosological categories

  • Kassem Sharif
  • Abdulla Watad
  • Nicola Luigi Bragazzi
  • Michael Lichtbroun
  • Mariano Martini
  • Carlo Perricone
  • Howard Amital
  • Yehuda ShoenfeldEmail author
Review Article


Chronic fatigue syndrome (CFS) is a heterogeneous disease which presents with pronounced disabling fatigue, sleep disturbances, and cognitive impairment that negatively affects patients’ functional capability. CFS remains a poorly defined entity and its etiology is still in question. CFS is neither a novel diagnosis nor a new medical condition. From as early as the eighteenth century, a constellation of perplexing symptoms was observed that resembled symptoms of CFS. Commencing with “febricula” and ending with CFS, many names for the disease were proposed including neurocirculatory asthenia, atypical poliomyelitis, Royal Free disease, effort syndrome, Akureyri disease, Tapanui disease, chronic Epstein-Barr virus syndrome, and myalgic encephalitis. To date, it remains unclear whether CFS has an autoimmune component or is a condition that precedes a full-blown autoimmune disease. Research suggests that CFS may overlap with other diseases including postural orthostatic tachycardia syndrome (POTS), autoimmune syndrome induced by adjuvants (ASIA), and Sjögren’s syndrome. Additionally, it has been postulated that the earliest manifestations of some autoimmune diseases can present with vague non-specific symptoms similar to CFS. Sometimes only when exposed to a secondary stimulus (e.g., antigen) which could accelerate the natural course of the disease would an individual develop the classic autoimmune disease. Due to the similarity of symptoms, it has been postulated that CFS could simply be an early manifestation of an autoimmune disease. This paper will provide a historical background review of this disease and a discussion of CFS as an entity overlapping with multiple other conditions.


Autoimmune syndrome induced by adjuvants Chronic fatigue syndrome Myalgic encephalomyelitis Postural orthostatic tachycardia syndrome 


Compliance with ethical standards

The manuscript does not contain clinical studies or patient data.




  1. 1.
    Reyes M, Gary HE Jr, Dobbins JG, Randall B, Steele L, Fukuda K, Holmes GP, Connell DG, Mawle AC, Schmid DS, Stewart JA, Schonberger LB, Gunn WJ, Reeves WC (1997) Surveillance for chronic fatigue syndrome—four U.S. cities, September 1989 through August 1993. MMWR CDC Surveill Summ: Morb Mortal Wkly Rep CDC Surveill Summ 46(2):1–13Google Scholar
  2. 2.
    Maquet D, Demoulin C, Crielaard JM (2006) Chronic fatigue syndrome: a systematic review. Ann Readapt Med Phys: revue scientifique de la Societe francaise de reeducation fonctionnelle de readaptation et de medecine physique 49(6):337–347, 418-327. CrossRefGoogle Scholar
  3. 3.
    Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S (1999) A community-based study of chronic fatigue syndrome. Arch Intern Med 159(18):2129–2137. CrossRefPubMedGoogle Scholar
  4. 4.
    Lawrie SM, Manders DN, Geddes JR, Pelosi AJ (1997) A population-based incidence study of chronic fatigue. Psychol Med 27(2):343–353. CrossRefPubMedGoogle Scholar
  5. 5.
    Jason LA, Taylor R, Wagner L, Holden J, Ferrari JR, Plioplys AV, Plioplys S, Lipkin D, Papernik M (1995) Estimating rates of chronic fatigue syndrome from a community-based sample: a pilot study. Am J Community Psychol 23(4):557–568. CrossRefPubMedGoogle Scholar
  6. 6.
    Griffith JP, Zarrouf FA (2008) A systematic review of chronic fatigue syndrome: don’t assume it’s depression. Prim Care Companion J Clin Psychiatry 10(2):120–128. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lee S, Yu H, Wing Y, Chan C, Lee AM, Lee DT, Chen C, Lin K, Weiss MG (2000) Psychiatric morbidity and illness experience of primary care patients with chronic fatigue in Hong Kong. Am J Psychiatry 157(3):380–384. CrossRefPubMedGoogle Scholar
  8. 8.
    Mahagna H, Mahroum N, Amital H (2015) Infections, vaccinations, and chronic fatigue syndrome. In: Vaccines and Autoimmunity John Wiley & Sons, Inc, pp 345–348. doi:
  9. 9.
    Ablashi DV, Eastman HB, Owen CB, Roman MM, Friedman J, Zabriskie JB, Peterson DL, Pearson GR, Whitman JE (2000) Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol: Offi Publ Pan Am Soc Clin Virol 16(3):179–191. CrossRefGoogle Scholar
  10. 10.
    Kerr JR, Mattey DL (2008) Preexisting psychological stress predicts acute and chronic fatigue and arthritis following symptomatic parvovirus B19 infection. Clin Infect Dis: Off Publ Infect Dis Soc Am 46(9):e83–e87. CrossRefGoogle Scholar
  11. 11.
    Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT (2004) IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome. In Vivo (Athens, Greece) 18(2):101–106Google Scholar
  12. 12.
    Wheatland R (2005) Chronic ACTH autoantibodies are a significant pathological factor in the disruption of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome, anorexia nervosa and major depression. Med Hypotheses 65(2):287–295. CrossRefPubMedGoogle Scholar
  13. 13.
    Kuratsune H, Yamaguti K, Sawada M, Kodate S, Machii T, Kanakura Y, Kitani T (1998) Dehydroepiandrosterone sulfate deficiency in chronic fatigue syndrome. Int J Mol Med 1(1):143–146PubMedGoogle Scholar
  14. 14.
    Byrne E (1991) The chronic fatigue syndrome: a reappraisal and unifying hypothesis. Clin Exp Neurol 28:128–138PubMedGoogle Scholar
  15. 15.
    Klimas NG, Salvato FR, Morgan R, Fletcher MA (1990) Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 28(6):1403–1410PubMedPubMedCentralGoogle Scholar
  16. 16.
    Maxmen A (2018) A reboot for chronic fatigue syndrome research. Nature 553(7686):14–17. CrossRefPubMedGoogle Scholar
  17. 17.
    Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ (1991) A report—chronic fatigue syndrome: guidelines for research. J R Soc Med 84(2):118–121CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 121(12):953–959. CrossRefPubMedGoogle Scholar
  19. 19.
    Manningham R (1760) The symptoms, nature, causes, and cure of the febricula, or, little fever: commonly called the nervous or hysteric fever; the fever on the spirits; vapours, hypo, or spleen. By Sir Richard Manningham, Knt. M. D. F. R. S. and of the College of Physicians, London. The fourth edition. edn. printed for G. Kearsly, at the Golden-Lion in Ludgate-Street, LondonGoogle Scholar
  20. 20.
    Harvey SB, Wessely S, Kuh D, Hotopf M (2009) The relationship between fatigue and psychiatric disorders: evidence for the concept of neurasthenia. J Psychosom Res 66(5):445–454. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Oppenheimer BS (1942) Neurocirculatory asthenia and related problems in military medicine. Bull N Y Acad Med 18(6):367–382PubMedPubMedCentralGoogle Scholar
  22. 22.
    Da Costa JM (1951) On irritable heart. Am J Med 11(5):559–567. CrossRefGoogle Scholar
  23. 23.
    Paul O (1987) Da Costa’s syndrome or neurocirculatory asthenia. Br Heart J 58(4):306–315. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Shoenfeld Y, Shapiro Y, Drory Y, Glasevsky V, Sohar E, Kellerman JJ (1978) Rehabilitation of patients with NCA (neurocirculatory asthenia) through a short term training program. Am J Phys Med 57(1):1–8PubMedGoogle Scholar
  25. 25.
    Patarca-Montero R (2004) Medical etiology, assessment, and treatment of chronic fatigue and malaise. Haworth Press 6–7Google Scholar
  26. 26.
    Shorter E (1993) Chronic fatigue in historical perspective. CIBA Found Symp 173:6–16 discussion 16-22PubMedGoogle Scholar
  27. 27.
    Sigurdsson B, SigurjÓnsson J, JHJ S, Thorkelsson J, Gudmundsson KR (1950) A disease epidemic in Iceland simulating poliomyelitis. Am J Epidemiol 52(2):222–238. CrossRefGoogle Scholar
  28. 28.
    Ramsay AM, Dowsett EG, Dadswell JV, Lyle WH, Parish JG (1977) Icelandic disease (benign myalgic encephalomyelitis or Royal Free disease). Br Med J 1(6072):1350–1350. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Dawson J (1987) Royal Free disease: perplexity continues. Br Med J (Clin Res Ed) 294(6568):327–328. CrossRefGoogle Scholar
  30. 30.
    Ali N (2015) Understanding chronic fatigue syndrome. Rowman & LittlefieldGoogle Scholar
  31. 31.
    Ramsay AM (1965) Hysteria and “Royal Free disease.”. Br Med J 2(5469):1062. CrossRefPubMedCentralGoogle Scholar
  32. 32.
    Poore M, Snow P, Paul C (1984) An unexplained illness in West Otago. N Z Med J 97(757):351–354PubMedGoogle Scholar
  33. 33.
    Levine PH, Snow PG, Ranum BA, Paul C, Holmes MJ (1997) Epidemic neuromyasthenia and chronic fatigue syndrome in West Otago, New Zealand: a 10-year follow-up. Arch Intern Med 157(7):750–754. CrossRefPubMedGoogle Scholar
  34. 34.
    Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO (1985) Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med 102(1):1–7. CrossRefPubMedGoogle Scholar
  35. 35.
    Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, Schonberger LB (1987) A cluster of patients with a chronic mononucleosis-like syndrome: is Epstein-Barr virus the cause? JAMA 257(17):2297–2302. CrossRefPubMedGoogle Scholar
  36. 36.
    Buchwald D, Sullivan JL, Komaroff AL (1987) Frequency of chronic active Epstein-Barr virus infection in a general medical practice. JAMA 257(17):2303–2307. CrossRefPubMedGoogle Scholar
  37. 37.
    Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, Dubois RE, Cunningham-Rundles C, Pahwa S et al (1988) Chronic fatigue syndrome: a working case definition. Ann Intern Med 108(3):387–389. CrossRefPubMedGoogle Scholar
  38. 38.
    Manu P, Lane TJ, Matthews DA (1988) The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 109(7):554–556. CrossRefPubMedGoogle Scholar
  39. 39.
    David AS, Wessely S, Pelosi AJ (1988) Postviral fatigue syndrome: time for a new approach. Br Med J (Clin Res Ed) 296(6623):696–699CrossRefGoogle Scholar
  40. 40.
    Jason LA, Torres-Harding SR, Taylor RR, Carrico AW (2001) A comparison of the 1988 and 1994 diagnostic criteria for chronic fatigue syndrome. J Clin Psychol Med Settings 8(4):337–343. CrossRefGoogle Scholar
  41. 41.
    Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI (2003) Myalgic encephalomyelitis/chronic fatigue syndrome. J Chron Fatigue Syndr 11(1):7–115. CrossRefGoogle Scholar
  42. 42.
    Meeus M, Ickmans K, Struyf F, Kos D, Lambrecht L, Willekens B, Cras P, Nijs J (2016) What is in a name? Comparing diagnostic criteria for chronic fatigue syndrome with or without fibromyalgia. Clin Rheumatol 35(1):191–203. CrossRefPubMedGoogle Scholar
  43. 43.
    Unger ER, Lin JS, Tian H, Natelson BH, Lange G, Vu D, Blate M, Klimas NG, Balbin EG, Bateman L, Allen A, Lapp CW, Springs W, Kogelnik AM, Phan CC, Danver J, Podell RN, Fitzpatrick T, Peterson DL, Gottschalk CG, Rajeevan MS (2017) Multi-site clinical assessment of myalgic encephalomyelitis/chronic fatigue syndrome (MCAM): design and implementation of a prospective/retrospective rolling cohort study. Am J Epidemiol 185(8):617–626. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Clayton EW (2015) Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. JAMA 313(11):1101–1102. CrossRefPubMedGoogle Scholar
  45. 45.
    Jason LA, Sunnquist M, Kot B, Brown A (2015) Unintended consequences of not specifying exclusionary illnesses for systemic exertion intolerance disease. Diagnostics 5(2):272–286. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Fleming KC, Volcheck MM (2015) Central sensitization syndrome and the initial evaluation of a patient with fibromyalgia: a review. Rambam Maimonides Med J 6(2):e0020. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Castro-Marrero J, Faro M, Aliste L, Sáez-Francàs N, Calvo N, Martínez-Martínez A, de Sevilla TF, Alegre J Comorbidity in chronic fatigue syndrome/myalgic encephalomyelitis: a nationwide population-based cohort study. Psychosomatics 58(5):533–543.
  48. 48.
    Mckay PG, Duffy T, Martin CR (2009) Are chronic fatigue syndrome and fibromyalgia the same? Implications for the provision of appropriate mental health intervention. J Psychiatr Ment Health Nurs 16(10):884–894. CrossRefPubMedGoogle Scholar
  49. 49.
    Abbi B, Natelson BH (2013) Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the ‘single syndrome’ hypothesis. Int J Med 106(1):3–9. Google Scholar
  50. 50.
    Aaron LA, Buchwald D (2001) A review of the evidence for overlap among unexplained clinical conditions. Ann Intern Med 134(9 Pt 2):868–881. CrossRefPubMedGoogle Scholar
  51. 51.
    Grubb BP, Kanjwal Y, Kosinski DJ (2006) The postural tachycardia syndrome: a concise guide to diagnosis and management. J Cardiovasc Electrophysiol 17(1):108–112. PubMedGoogle Scholar
  52. 52.
    Schondorf R, Benoit J, Wein T, Phaneuf D (1999) Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst 75(2–3):192–201. CrossRefPubMedGoogle Scholar
  53. 53.
    Okamoto LE, Raj SR, Peltier A, Gamboa A, Shibao C, Diedrich A, Black BK, Robertson D, Biaggioni I (2012) Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes. Clin Sci (Lond, Engl: 1979) 122(4):183–192. CrossRefGoogle Scholar
  54. 54.
    Shoenfeld Y, Agmon-Levin N (2011) ‘ASIA’—autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 36(1):4–8. CrossRefPubMedGoogle Scholar
  55. 55.
    Agmon-Levin N, Zafrir Y, Kivity S, Balofsky A, Amital H, Shoenfeld Y (2014) Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ (ASIA). Immunol Res 60(2–3):376–383. CrossRefPubMedGoogle Scholar
  56. 56.
    Tsai CK CH, Cheng CA (2011) Novel H1N1 influenza vaccine the cause of postural orthostatic tachycardia syndrome followed by cerebral hypoperfusion. J Med Sci 31:91–93Google Scholar
  57. 57.
    Poser CM, Behan PO (1982) Late onset of Guillain-Barre syndrome. J Neuroimmunol 3(1):27–41. CrossRefPubMedGoogle Scholar
  58. 58.
    Calabrese LH, Davis ME, Wilke WS (1994) Chronic fatigue syndrome and a disorder resembling Sjogren’s syndrome: preliminary report. Clin Infect Dis: Off Publ Infect Dis Soc Am 18(Suppl 1):S28–S31. CrossRefGoogle Scholar
  59. 59.
    Nishikai M, Akiya K, Tojo T, Onoda N, Tani M, Shimizu K (1996) ‘Seronegative’ Sjogren’s syndrome manifested as a subset of chronic fatigue syndrome. Br J Rheumatol 35(5):471–474. CrossRefPubMedGoogle Scholar
  60. 60.
    Mosca M, Tani C, Neri C, Baldini C, Bombardieri S (2006) Undifferentiated connective tissue diseases (UCTD). Autoimmun Rev 6(1):1–4. CrossRefPubMedGoogle Scholar
  61. 61.
    Watad A, Quaresma M, Bragazzi NL, Cervera R, Tervaert JWC, Amital H, Shoenfeld Y (2018) The autoimmune/inflammatory syndrome induced by adjuvants (ASIA)/Shoenfeld's syndrome: descriptive analysis of 300 patients from the international ASIA syndrome registry. Clin Rheumatol 37(2):483–493. CrossRefPubMedGoogle Scholar
  62. 62.
    Scanzi F, Andreoli L, Martinelli M, Taraborelli M, Cavazzana I, Carabellese N, Ottaviani R, Allegri F, Franceschini F, Agmon-Levin N, Shoenfeld Y, Tincani A (2017) Are the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and the undifferentiated connective tissue disease (UCTD) related to each other? A case-control study of environmental exposures. Immunol Res 65(1):150–156. CrossRefPubMedGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Zabludowicz Center for Autoimmune DiseasesSheba Medical CenterTel-HashomerIsrael
  2. 2.Sackler Faculty of MedicineTel-Aviv UniversityTel-AvivIsrael
  3. 3.School of Public Health, Department of Health Sciences (DISSAL)University of GenoaGenoaItaly
  4. 4.Department of Health Sciences, Section of History of Medicine and EthicsUniversity of GenoaGenoaItaly
  5. 5.Reumatologia, Dipartimento di Medicina Interna e Specialità MedicheSapienza Università di RomaRomeItaly

Personalised recommendations