The Physical Basis of CFS

by Anthony L. Komaroff, M.D.
Harvard Medical School

Often, when people hear that there is no known test or cause for chronic fatigue syndrome (CFS), they mistakenly understand that to mean that the illness is not real. This is incorrect.

Over the past 15 years, scientists have identified numerous biological abnormalities that provide evidence for the reality and seriousness of CFS, even though the cause of CFS and diagnostic tests for it are still unknown. (1) These biological abnormalities have given researchers clues to the cause of the illness. In particular, they have provided evidence that the illness involves both the brain and the immune system.

There are no diagnostic tests yet for CFS because none of the biological abnormalities clearly distinguishes patients with CFS from other individuals. In reality, there are no perfect biological tests (see sidebar at end) for any illness. When a test gets close enough to perfect, clinicians use it to help confirm or refute their clinical judgment. Testing in CFS has primarily been used to rule out other illnesses that also can cause chronic fatigue.

What is the cause of CFS?

The leading model of CFS pathogenesis is rooted in scientifically identified abnormalities in the brain (central nervous system) and the immune system, which influence and alter the function of the other in a reciprocal cycle (see Fig. 1).Figure 1 Low levels of circulating cortisol, identified in several CFS research studies (2,3) can increase immune activation, which is also a key feature of CFS.

This immune system activation could theoretically result in brain dysfunction: when the immune system is activated, it makes chemical messages. Brain cells as well as other immune system cells can receive these messages. This could lead to fatigue, cognitive dysfunction, enhanced sense of pain, hormonal dysregulation and other features of CFS. (4)

Post-viral onset

Many cases of CFS cases begin with symptoms suggesting an infection, like a common viral illness. Doctors do not usually perform tests to confirm common viral infections, since they typically quickly resolve. For that reason, there is no documentation of the infection that seems to start CFS in many patients.

However, some of the most interesting research in recent years involves studies that did document an infection at the start of the illness. For example, CFS has been reported following acute mononucleosis (5,6) (a viral infection), Lyme disease (7-9) (a bacterial infection) and Q fever (10) (an infection with a different kind of infectious agent). These studies prove that CFS can indeed follow in the wake of a well-documented infection.

This research indicates that no single infectious agent is likely to be the cause of CFS. Instead, CFS is likely to be caused by some abnormality in the body’s response to any of several different infectious agents. The studies of infectious agents in CFS are complicated.

One reason is that the symptoms of CFS almost surely arise from the brain, yet it is very hard for scientists to study infectious agents in the human brain: that requires taking brain tissue (biopsies), a potentially dangerous test.

Another reason is that some infectious agents permanently live in a dormant state inside our bodies. There is evidence that some of these infections, like infection with the virus HHV-6, (11-14) get reawakened in patients with CFS. The unanswered question is whether the reawakened virus is the cause of the bodily damage, and resulting symptoms, or whether it is result of the illness.

Immune system abnormalities

Several immune system patterns are seen more often in patients with CFS. The identified abnormalities mimic the immune pattern of a body fighting a virus, even though no virus has been identified as the cause of CFS. Specific findings include:

  • Increased numbers of CD8+ activated “cytotoxic” T cells (cells commonly increased when the body is fighting viral infections). (11,15-17)

  • Low natural killer cell function. (18-21)

  • Elevated immune complexes. (22)

The most intriguing recent immunological finding in CFS is the discovery of a novel, low molecular weight protein in an antiviral pathway called the RNase-L pathway. (24-27) This novel protein is found much more often in CFS patients than in healthy people, or people with two other conditions that can cause fatigue: depression or fibromyalgia.(27)

Neurological findings

There is considerable evidence that the brain and central nervous system are involved in CFS. “Soft” evidence includes patient-reported symptoms such as: cognitive dysfunction; sensitivities to stimuli such as bright lights, noise and odors; numbness and tingling in the extremities; and disordered and fragmented sleep. “Hard” evidence includes:

  • Hyperintense signals on MRI scans.(11,28,29)

  • Reduction in cerebral blood flow on SPECT scans—an abnormality that changes over time, and is not an indication of any permanent brain damage. (30,31)

  • Autonomic dysfunction, primarily orthostatic intolerance and neurally mediated hypotension seen on tilt table tests. (32-37) The control centers for maintenance of blood pressure lie in the brain’s limbic system.


Recent epidemiological data has helped to establish the relevance and importance of CFS as a serious public health issue. Data from private investigators and from the Centers for Disease Control and Prevention (CDC) indicate that more than 200 of every 100,000 Americans have CFS. (38-40)

Depending on demographic factors—such as age, sex and ethnicity—the prevalence can range from 200 to 800 cases per l00,000. (38) This makes CFS more common than well-known illnesses such as multiple sclerosis (41) and systemic lupus erythematosus (42), which, like CFS, predominantly affect females.

CFS is real

Taken together, these and other findings provide important evidence that CFS is not “all in the head” or an imagined illness. While there is not yet a test, scientists are moving closer to developing tools to assist clinicians in the diagnosis of CFS. In the interim, scientists have provided clues to the biology of CFS and have given clinicians, scientists and patients critical data that shows that CFS is a real and serious illness.

Definition of the "Perfect Diagnostic Test"

  • Abnormal in every patient with the disease

  • Normal in every healthy person

  • Normal in patients with other diseases that cause similar symptoms

  • Reliably performed by many laboratories (not just research labs); and

  • Has an acceptable cost.


I. Komaroff AL. The biology of chronic fatigue syndrome. Am J Med. 2000;108:169-71.

2. Demitrack MA, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J din Endo Metab. 199173(6): 1224-1234.

3. Scott LV, Dinan T. Urinary free cortisol excretion in depression, in chronic fatigue syndrome and in health. JAffect Disord. 1998; 47:49-54. 4. Zivin JA, Choi DW. Stroke therapy. Scient,jic American. July 1991 ;265:56-63.

5. Jones JF et al. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med. 1985; l02( 1): 1-7.

6. Straus SE et al Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med. 1985;2(l):7-l6.

7. Sigal LH. Summary of the first 100 patients seen at a Lyme disease referral center. Am J Med. 1990;88:577-81.

8. Steere AC et al The overdiagnosis of Lyme disease. JAMA. 1993; 269:1812-16.

9. Coyle PK et al. Borrelia burgdorferi reactivity in patients with severe persistent fatigue who are from a region where Lyme disease is endemic. Cl/n Infect Din. l994;18:S24-7.

10. Marmion BP et al. Protracted debil. ity and fatigue after acute Q fever. Lancet. t996;347:977-8.

11. Buchwald D et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders and active human herpesvims type.6 infection. Ann Intern Med. 1992;ll6:106-13.

12. Yalcin S et al Prevalence of human herpesvirus 6 variants A and B in patients with chronic fatigue syndrome. Microbiol Insmunol. 1 994;38:587-90.

13. Zorzenon Metal. Active HHV-6 infection in chronic fatigue syndrome patients from Italy: new data. J CFS. 1996;2(l):3-l2.

14. Patnaik M et al. Prevalence of 1gM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome. J of Infect Dis. 1995;l72:1364-1367.

15. Lloyd et al. Immunological abnormalities in the chronic fatigue syndrome. Med J Austral. 1989; 15 1: 122-4.

16. LandayALetal. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet.199l;338: 707-12.

17. Klimas NG et al Immunologic abnormalities in chronic fatigue syndrome. J C/in Microbiol. 1990;28:1403-l0.

18. Caligiuri M et al Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol. 1987;139:3306-l3.

19. Gupta S, Vayuvegula B. A comprehensive immunological analysis in chronic fatigue syndrome. Scand J Immunol. 1991; 33:319-27.

20. Whiteside TL, Friberg D. Natural killer cells and natural killer cell activity in chronic fatigue syndrome. AmJMed. 1998;105(3A) :27S-34S.

21. Eby Net al. Natural killer cell activity in the chronic fatigue immune dysfunction syndrome.ln: Ades EW, Lopes C, eds. Natural Killer Cells and Host Defense. 1988; 14 1-45.

22. Bates DW et al. Clinical laboratory test findings in patients with chronic fatigue syndrome. Arch Intern Med. 1995;155;97-103.

23. Suhadolnik RJ et al Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome. J Interfernn Cytokine Res. 1997;17(7): 377-85.

24. Suhadolnik RJ et al. Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)poly(CI2U) in chronic fatigue syndrome. In Vivo. 1994; 8(4): 599-604.

25. Suhadolnik RJ et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Di,s. t994;l8(l):S96-I04.

26. DeMeirleir K et al. A 37 kDa 2-5A binding protein as potential biomarker for chronic fatigue syndrome. AmJMed. 2000;108: 99-105.

27. Natelson BH Ct al. A controlled study of brain magnetic resonance imaging in patients with the chronic fatigue syndrome. J Neurol Sci. l993;120(2):21 3-7.

28. Lange G et al. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. JNeurol Sci. 1999;I71(l):37.

29. Schwartz RB et al. SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression. Am J Roentgenol.l994; l62(4):943-51.

30. Ichise Metal. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. NucI Med Commun. 1992;13(l0): 767-72.

31. Rowe PC et al. Is neurally mediated hypotension an unrecognized cause of chronic fatigue? Lancet. 1995;345:623-4.

32. Bou-Houlaigah I et al The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274:96l-67.

33. Schondorf R et al. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Ner Syst. 1999; 75: 192-201.

34. Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med. 1997;104:957-64.

35. Dc Lorenzo F et at. Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clin Auton Res. 1997;7:185-90.

36. Streeten DHP, Anderson OH Jr. The role of delayed orthostatic hypotension in the pathogenesis of chronic fatigue. Clin Autonom Res. l998;8: 11924.

37. Reyes M et al. Wichita population-based study of a fatiguing illness. Presented at the American Association for Chronic Fatigue Syndrome Fourth International Research Conference. Cambridge, Mass., October 12, 1998. New Englandf Med in press.

38. Jason LA et al. A community-based study of chronic fatigue syndrome. Arch Int Med. l999;159:2l29-37.

39. Centers for Disease Control and Prevention: Chronic Fatigue Syndrome Program Review; Objective I: Surveillance. November 1999.

40. National Institute of Neurological Diseases and Stroke (NINDS): Multiple Sclerosis: Hope Through Research. National Institutes of Health, I 999

41. National Institute of Allergy and Infectious Diseases (NIAID): Lupus Erythemafosus. National Institutes of Health, 1999:

Dr. Komaroff is Professor of Medicine, Harvard Medical School, and Editor-in-Chief Harvard Health Publications, Boston, Mass.

This article appeared in the CFS Research Review, Spring 2000, Vol. 1 Issue 2, a quarterly newletter of the CFIDS Association of America, PO Box 220398, Charlotte, NC 28210. (704) 365-2343, and is Copyright © 2000 by the CFIDS Association of America.

The CFIDS Association of America does not endorse products or services, and the ideas expressed belong strictly to the authors, not the Association or The CFS Research Review. The Association and The CFS Research Review assume no liability for any medical treatment or other activity undertaken by readers.

We subscribe to the HONcode principles
of the Health On the Net Foundation

Go to
Home Page || About Co-Cure || Articles and Posts || Reading Room || Additional Resources || Let's Work Together || Co-Cure-HMC || Guestbook || Issue Boards || Search this site

Copyright © 2000 Co-Cure
Last Revision: August 6, 2000
Please report any problems with this page to the Webmaster