By Anthony L. Komaroff, MD
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 Definition
"Perfect Diagnostic Test" below) for any illness. When a test gets
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). Low levels of circulating
cortisol, identified in several CFS research studies2,3, 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
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 mononucleosis5,6 (a viral infection), Lyme disease7-9
(a bacterial infection) and Q fever10 (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.
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.
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 fibro-myalgia.27
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:
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 100,000.38 This makes CFS more common than well-known illnesses such as
multiple sclerosis41 and systemic lupus erythematosus42, which, like CFS, predominantly
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.
- Komaroff AL. The biology of chronic fatigue syndrome. Am J Med. 2000;108:169-71.
- Demitrack MA, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal
axis in patients with chronic fatigue syndrome. J Clin Endo Metab. 1991;73(6):1224-1234.
- Scott LV, Dinan T. Urinary free cortisol excretion in depression, in chronic fatigue
syndrome and in health. J Affect Disord. 1998; 47:49-54.
- Zivin JA, Choi DW. Stroke therapy. Scientific American. July 1991;265:56-63.
- 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;102(1):1-7.
- Straus SE et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr
virus infection. Ann Intern Med. 1985;2(1):7-16.
- Sigal LH. Summary of the first 100 patients seen at a Lyme disease referral center. Am
- Steere AC et al. The overdiagnosis of Lyme disease. JAMA. 1993; 269:1812-16.
- Coyle PK et al. Borrelia burgdorferi reactivity in patients with severe persistent fatigue
who are from a region where Lyme disease is endemic. Clin Infect Dis. 1994;18:S24-7.
- Marmion BP et al. Protracted debility and fatigue after acute Q fever. Lancet.
- Buchwald D et al. A chronic illness characterized by fatigue, neurologic and immunologic
disorders and active human herpesvirus type-6 infection. Ann Intern Med. 1992;116:106-13.
- Yalcin S et al. Prevalence of human herpesvirus 6 variants A and B in patients with chronic
fatigue syndrome. Microbiol Immunol. 1994;38:587-90.
- Zorzenon M et al. Active HHV-6 infection in chronic fatigue syndrome patients from Italy:
new data. J CFS. 1996;2(1):3-12.
- Patnaik M et al. Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38)
in patients with chronic fatigue syndrome. J of Infect Dis. 1995;172:1364-1367.
- Lloyd et al. Immunological abnormalities in the chronic fatigue syndrome. Med J Austral.
- Landay AL et al. Chronic fatigue syndrome: clinical condition associated with immune
activation. Lancet.1991;338: 707-12.
- Klimas NG et al. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol.
- Caligiuri M et al. Phenotypic and functional deficiency of natural killer cells in patients
with chronic fatigue syndrome. J Immunol. 1987;139:3306-13.
- Gupta S, Vayuvegula B. A compre-hensive immunological analysis in chronic fatigue syndrome.
Scand J Immunol. 1991; 33:319-27.
- Whiteside TL, Friberg D. Natural killer cells and natural killer cell activity in chronic
fatigue syndrome. Am J Med. 1998;105(3A) :27S-34S.
- Eby N et al. Natural killer cell activity in the chronic fatigue immune
Ades EW, Lopes C, eds. Natural Killer Cells and Host Defense. 1988;141-45.
- Bates DW et al. Clinical laboratory test findings in patients with chronic fatigue syndrome.
Arch Intern Med. 1995;155;97-103.
- Suhadolnik RJ et al. Biochemical evidence for a novel low molecular weight 2-5A-dependent
RNase L in chronic fatigue syndrome. J Interferon Cytokine Res.1997;17(7): 377-85.
- Suhadolnik RJ et al. Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled
clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome. In Vivo. 1994; 8(4): 599-604.
- Suhadolnik RJ et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated
with chronic fatigue syndrome. Clin Infect Dis. 1994;18(1):S96-104.
- DeMeirleir K et al. A 37 kDa 2-5A binding protein as potential bio-marker for chronic
fatigue syndrome. Am J Med. 2000;108: 99-105.
- Natelson BH et al. A controlled study of brain magnetic resonance imaging in patients
with the chronic fatigue syndrome. J Neurol Sci. 1993;120(2):213-7.
- Lange G et al. Brain MRI abnormalities exist in a subset of patients with chronic fatigue
syndrome. J Neurol Sci. 1999;171(1):37.
- 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.1994;
- Ichise M et al. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic
fatigue syndrome. Nucl Med Commun. 1992;13(10): 767-72.
- Rowe PC et al. Is neurally mediated hypotension an unrecognized cause
of chronic fatigue?
- Bou-Houlaigah I et al. The relationship between neurally mediated hypotension and the
chronic fatigue syndrome. JAMA. 1995;274:961-67.
- Schondorf R et al. Orthostatic intolerance in the chronic fatigue syndrome. J Auton
Ner Syst.1999; 75:192-201.
- Freeman R, Komaroff AL. Does the chronic fatigue syndrome in-volve the autonomic nervous
system? Am J Med. 1997;104:957-64.
- De Lorenzo F et al. Pathogenesis and management of delayed orthostatic
patients with chronic fatigue syndrome. Clin Auton Res. 1997;7:185-90.
- Streeten DHP, Anderson GH Jr. The role of delayed orthostatic hypotension in the pathogenesis
of chronic fatigue. Clin Autonom Res.1998;8:11924.
- 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 England J Med in press.
- Jason LA et al. A community-based study of chronic fatigue syndrome. Arch Int Med.
- Centers for Disease Control and Prevention: Chronic Fatigue Syndrome Program Review;
Objective 1: Surveillance. November 1999.
- National Institute of Neuro-logical Diseases and Stroke (NINDS): Multiple Sclerosis:
Hope Through Research. National Institutes of Health, 1999 http://www.ninds.nih.gov/patients/Disorder/MS/MSTEXT1.htm
- National Institute of Allergy and Infectious Diseases (NIAID): Lupus Erythematosus.
National Institutes of Health, 1999: http://www.nih.gov/niams/healthinfo/lupusguide/chp1.htm
Dr. Komaroff is Professor of Medicine, Harvard Medical
School, and Editor-in-Chief,
Harvard Health Publications, Boston, Mass.
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.