 
National Institute of Allergy and Infectious Diseases
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National Institutes of Health
U.S. Public Health Service
 
 
                                CHRONIC FATIGUE
 
                                   SYNDROME
 
 
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National Institute of Allergy an infectious Diseases
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-------------------------------- Backgrounder --------------------------------
 
                           CHRONIC FATIGUE SYNDROME
 
        We all get tired; most of us, at times, have felt depressed.  But the
enigma known as chronic fatigue syndrome (CFS) is not the ups and downs we
experience in everyday life, or even the temporary persistence of such
feelings in response to exceptional physical or emotional stress.  The
hallmark of the illness is fatigue--a fatigue that comes on suddenly and is
relentless or relapsing, causing debilitating tiredness or easy fatigability
in someone who has no apparent reason for feeling this way.  Unlike the mind
fog of a serious hangover, to which CFS has been compared, the profound
weakness of CFS does not go away with a few good nights of sleep but instead
slyly steals a person's vigor over months and years.
 
Onset
 
        People diagnosed with CFS often describe its onset as sudden but not
alarming because many of its symptoms--headache, sore throat, low-grade fever,
fatigue and weakness, tender lymph glands, muscle and joint aches, and
inability to concentrate--mimic those of the flu.  But whereas flu symptoms
usually go away in a few weeks, CFS symptoms persist or recur frequently for
more that 6 months.  ("Syndrome" means a group of symptoms that occur together
but that can result from different causes.)
 
Prevalence
 
        Contrary to the popular image, CFS is not a new "yuppie plague."  This
stereotype arose because those who sought help for and renewed scientific
interest in CFS in the early 1980s (the illness is thought to be much older)
were mainly well-educated and reasonably affluent women in their thirties and
forties.  Since then, physicians have seen the syndrome in people of all ages,
races, and socioeconomic classes from several countries around the world.
 
        Still, young caucasian women continue to be the major group seeking
medical care for CFS.  Several factors may figure into this: (1) this group
may more aggressively seek medical care for such symptoms; (2) like lupus and
multiple sclerosis, for example, CFS may in fact turn out to affect more women
than men; and (3) certain sectors of the medical community and general
population are unaware or skeptical that this syndrome exists.  As the medical
community becomes more familiar with CFS, an increasingly diverse population
with this syndrome will probably emerge.
 
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        It is not known how many people have CFS.  Until recently, no standard
clinical description of the syndrome existed.  CFS's symptoms overlap with
those of many other diseases, making it likely that the illness has been
overdiagnosed.  Even now, diagnosing CFS relies heavily on first excluding
similar diseases such as fibromyalgia (painful muscles), multiple sclerosis,
depression, and lupus, some of which take years to become clearly manifest.
 
        However, after rigorously excluding people who have other diseases, a
sizeable group of people with debilitating chronic fatigue remains, and these
people may be considered to have the chronic fatigue syndrome.
 
Historical Perspective
 
        Clinical portraits of diseases similar to CFS have appeared under
different guises in the medical literature for more than a century.  In the
1860s, Dr. George Beard named the syndrome neurasthenia, believing it to be a
neurosis characterized by weakness and fatigue.  Succeeding generations have
favored but not proved different explanations--iron poor blood (anemia), low
blood sugar (hypoglycemia), environmental allergy, or a bodywide yeast
infections (candidiasis)--for this baffling malaise.
 
        Most recently, scientists have considered Epstein-Barr virus (EBV) as
a possible cause of CFS.  Some researchers believe that EBV may cause CFS in
people who never recovered from mononucleosis, or in whom the virus has
somehow been reactivated.  Newer evidence indicates that EBV cannot, however,
explain the entire spectrum of the illness.
 
A New Definition
 
        Still, in the mid-1980s the illness became popularly tagged "chronic
EBV."  To create an official name and definition of the illness that reflects
its broader nature, the Centers for Disease Control (CDC) recently convened a
group of CFS experts.  The group agreed on the name "chronic fatigue syndrome"
and has now published in the medical literature strict symptoms and physical
criteria that researchers can use to select patients for studies of this
illness.  (See the Annals of Internal Medicine, March 1988.)
 
        With these more uniform guidelines, CDC has begun studying how
widespread the illness is.  The National Institute of Allergy and Infectious
Diseases (NIAID) is also funding a similar epidemiological study.  In
addition, several multifaceted studies around the country, some supported by
NIAID, are now under way to characterize the viral, immunologic, physiologic,
and psychologic aspects of CFS.
 
Clinical Findings in CFS
 
        Neuropsychiatric Findings
 
        Physicians sometimes misdiagnose CFS as depression, and vice versa,
because the two illnesses share many symptoms:  fatigue, malaise, sleep
disorders, low-grade fever, and memory and concentration problems, for
example.  Yet other CFS symptoms--including persistent sore throat, tender
 
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lymph glands, muscle and joint aches, and feelings of feverishness--do not fit
the typical clinical picture of depression.
 
        Is the overlap in symptoms between CFS and depression merely a
coincidence, or might it indicate that these illnesses are linked in more
significant ways?
 
        NIAID-supported researchers have teamed up with neuropsychologists to
explore this question; similar projects are ongoing at other research
institutions.  These projects encompass psychiatric evaluations, physical
tests of nerve and muscle functions, explorations of brain hormone
functioning, as well as visualization of the brain by sophisticated imaging
techniques.
 
        Using a standard psychiatric interview, a psychiatrist at the National
Institutes of Health (NIH) evaluated a small group of people with CFS to
determine the incidence of a history of depression, anxiety, phobia, or other
psychiatric disorder.  A large percentage of these people had a past or
present history of psychiatric disorder.  The study was not designed to
determine if CFS or the psychiatric illness came first.  But based on the
patients' responses, it appears that some psychiatric illnesses, particularly
depression, may in part be a reaction to having CFS.  Similar findings
regarding psychiatric problems in patients with CFS have bee reported from
other centers as well.
 
        Other NIH researchers have administered standard psychological tests
to CFS patients to validate subjective reports of depression, anxiety, and
problems with thinking, memory, and judgment.  They found that objective test
results correlate well with how severe the illness is perceived to be by the
people with CFS and their doctors.  A wide range of functional impairment in
these areas is typically seen among people with CFS, however.
 
        These same researchers have now begun examining how people with CFS
perform on tests that specifically measure nerve and muscle functions.  Their
objective is to pinpoint the source of CFS fatigue--that is, does it originate
in the muscles or in the central nervous system?
 
        Other NIH scientists are probing the more subtle molecular
interactions between the brain and the immune system.  Some scientists
theorize that the symptoms shared by CFS and depression could be caused by the
dysregulation of one or more homones, such as the stress hormone cortisol,
that act in the brain.  Indirect evidence suggests that viral infections may
upset a delicately balanced feedback loop regulating hormone production among
the major hormone-secreting glands.
 
        Brain scans can also help locate possible areas of brain dysfunction.
People with neurologic diseases such as multiple sclerosis show charcteristic
brain scan abnormalities.  The results of magnetic resonance imaging (MRI)
studies of the brains of CFS patients, however, are inconclusive: some
researchers have found no apparent abnormalities, but others have seen
findings they say appear unusual.  If further research verifies these
abnormalities, the next step will be to determine whether viral activity is
directly of indirectly causing them.
 
        All these studies represent scientists' increasing understanding that
brain and immune system functions are intricately intertwined.
 
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        Immunologic Findings
 
        Scientists at the NIAID and elsewhere have observed several immune
system abnormalities in people with CFS.  Many patients have relatively high
antibody levels to virtually any virus measured, for example, cytomegalovirus,
herpes simplex 1, or measles.  (Antibodies are infection-fighting proteins.)
About one-third of CFS patients studied have shown relatively high levels of
immune complexes, large molecules formed when antigen (a virus or other
foreign molecule) and antibody bind together.  Some people with CFS also have
abnormal production of interferon (an infection-fighting chemical) or
abnormalities in the activity of a particular enzyme, 2'5'-oligoadenylate
synthetase, induced by interferon during acute viral infections.
 
        A few years ago, a group of scientists found that some people with CFS
lack antibodies to certain protein components of EBV, including one called
EBNA-1 (Epstein-Barr nuclear antigen 1).  They are now investigating whether
the immune recognition of EBNA-1, and hence the ability to make antibodies to
it, is important for controlling EBV infection.
 
        Several research groups have seen abnormal "natural killer" (NK) cell
function in many patients with CFS.  Unlike antibodies, which are targeted to
specific antigens, NK cells nonspecifically seek and destroy abnormal cells.
NK cells thus act as the first line of defense against viral infections,
particularly against herpesviruses.  Whether the NK dysfunction in CFS is a
cause or effect of the main illness is uncertain, but researchers continue to
study this problem.
 
        Overall, however, the immunologic findings in people with CFS are
inconsistent and not highly reproducible.  With improved immunologic tests and
the more rigorous selection of patients in studies that have recently begun,
scientists expect to obtain less equivocal data.
 
Treatment
 
        Currently, no proven effective treatment for CFS exists.  Through the
current studies to characterize CFS, scientists hope to identify markers for
the illness that will allow researchers to target treatments to specific
abnomalities as well as to objectively follow the course of the illness.  By
measuring changes in those markers in treated patients, the effectiveness of
different therapies can be evaluated.
 
        Physicians have anecdotally reported successes in small numbers of
patients with a wide range of treatments including antiviral, antidepressant,
and immunomodulating (boosting the immune system) drugs.  Few drugs, however,
have undergone rigorous clinical testing.  In a double-blind, placebo-
controlled study of the drug acyclovir, NIAID researchers found that as many
patients reported feeling better during placebo treatment as during acyclovir
treatment.  This outcome diminishes claims of a therapeutic role for acyclovir
in CFS.  More recent carefully controlled studies revealed conflicting data
regarding the value of high dose intravenous immunoglobulin: one study
reported no benefit, the other reported some benefit.
 
        The lack of any proven effective treatment is frustrating to both
patients and their physicians.  Experts recommend that people with CFS try to
maintain a healthy lifestyle by eating a balanced diet and getting adequate
rest.  Physical conditioning should be preserved by exercising regularly as
much
 
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as can be tolerated short of causing more fatigue.  It is important that
people with CFS learn to pace themselves--physically, emotionally, and
intellectually--since too much stress can exacerbate the symptoms.
 
        CFS is not a progressive disease, that is, it does not appear to
worsen over time.  For most people, symptoms plateau early in the course of
the illness and thereafter wax and wane.  A healthy person experiencing CFS-
like complaints following a normal illness usually recovers in a few weeks or
months; likewise, even some people with CFS have been known to spontaneously
recover.  Counseling may help some people cope with the uncertain prognosis
and ups and downs of the illness.
 
        Finding treatments for CFS will probably be most helped by advances in
basic immunology and molecular biology--understanding how the body normally
responds to virus infections, what chemicals are liberated during infection,
and why an infection makes us feel the way it does.
 
Possible Causes of CFS
 
        CFS probably is not caused by any single agent.  Whether several
viruses can cause the same syndrome, whether the syndrome results from the
synergistic effect of viruses, or whether the syndrome results from an immune
or neuroimmune dysregulation is still uncertain, however.
 
        Epstein-Barr Virus
 
        Scientists have recently focused on EBV, a member of the herpesvirus
family, as a possible cause of chronic fatigue.  This theory arose in the
early 1980s after scientists at NIAID and elsewhere independently found high
levels of antibodies to EBV in patients with symptoms of chronic fatigue.
(Most people have been exposed to EBV by age 30.  Because EBV can cause
asymptomatic infection, many people are unaware that they carry the virus.
Carrying the virus chronically is probably medically unimportant.)
 
        In some of these patients, the fatigue began after they had had EBV
mononucleosis.  The idea that EBV could cause chronic fatigue seemed plausible
because the virus establishes lifelong infection; after an acute infection,
EBV retreats to salivary glands and B cells (an immune system cell), from
where it can later be reactivated.
 
        More recent information casts doubt on the theory that EBV could be
the sole agent causing CFS.  Elevated levels, or titers, of EBV antibodies
have now been found in some healthy people, too.  Likewise, some people who
lack EBV antibodies, and who thus have never been infected with the virus, can
display CFS symptoms.  Furthermore, for reasons unknown, people with other
illnesses such as depression sometimes have elevated antibody titers to
Epstein-Barr and other viruses.
 
        Human Herpesvirus 6 (HHV6)
 
        Another virus receiving much attention as a possible cause of CFS is a
newly identified herpesvirus, human herpesvirus 6 (HHV6) (formerly known as
human B lymphotropic virus, or HBLV).  Like EBV, HHV6 is a latent virus: once
it finds its way into the body, it resides in certain cells for life.
 
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        Researchers at the National Cancer Institute (NCI) discovered HHV6 in
1986.  Since then, they have screened several thousand blood samples from
around the world to determine the prevalence of antibodies to HHV6 in people
with CFS.  Preliminary results of their work show that antibodies to the virus
appear in most people with CFS and in a smaller but still considerable
percentage of healthy people.
 
        But the researchers caution not to overinterpret their findings.
First, while the sensitivity of their antibody test is good, they continue to
make needed improvements.  Second, latent viruses can be a barometer
indicating the health of the immune system: the ability of a virus like EBV or
HHV6 to reactivate, as reflected by levels of antibodies to the virus, varies
inversely with the integrity of the immune system.  Having high antibody
titers to certain latent viruses could be just a warning sign that an immune
system abnormality exists.  Third, herpesviruses are prevalent worldwide and
thus are easily transmitted but also well tolerated.  Once the initial
infection has resolved, those who carry these viruses, even people with high
antibody titers, are generally healthy.
 
        Scientists expect that HHV6, like other herpesviruses, will eventually
be implicated in more than one disease.  Based on their preliminary evidence,
however, the NCI researchers think it unlikely that HHV6 plays a
straightforward role in causing CFS.
 
        Immune System Dysfunction
 
        Equally as important as the study of individual viruses is the
understanding of what is unique about the immune systems of people with CFS.
One theory is that these people may share an abnormal response to viruses in
general.
 
        A curious finding that supports this theory is that a large number of
people with CFS, 50 to 80 percent, have allergies that predate the onset of
their CFS.  The incidence of allergies in the U.S. population is only 17
percent.  Perhaps, scientists theorize, the immune system that overreacts to
allergens may also be one more likely to overrespond to other challenges, such
as an infection.
 
        On the other hand, the data gathered so far indicate that the immune
system in CFS is not simply overactive.  Some immune functions are overactive
but others appear normal or underactive.
 
        One scientist has compared the immune system to a sophisticated turbo
engine.  Such an engine has numerous settings on it to adjust fuel flow, air
flow, and other variables.  Turning one setting up will shut the engine down,
but turning up a different setting will rev the engine up.  Like a turbo
engine, the immune system is highly complex and its proper regulation requires
the increased activation of some systems and the decreased activation of other
systems.
 
        Another possibility is that CFS results from a dysfunction in whatever
signals the immune system to relax after an infection is over.  Scientists do
not know what the "return to normal" signal (or signals) is.  However, some
work indicates that a person's psychiatric state may influence the reset
message.  Studies of influenza, chronic brucellosis, and infectious
mononucleosis have found that people with certain psychiatric profiles have
longer periods of convalescence than others, suggesting that a person's
neuropsychological state during an infection may subtly influence when the
immune system stops fighting infection.
 
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        Cyokines
 
        Another theory is that an immune system component normally active in
fighting infections may be involved in CFS.  Cytokines, chemicals that
regulate the immune response and are released by cells during infection, have
been identified as possible key players in the etiology of this illness.
 
        Some infections, the flu-like illnesses, seem more likely to trigger
the production of certain cytokines.  Infections such as rubella and the
common cold don't involve flu-like symptoms, may not involve the same
cytokines as CFS, and haven't been observed to precede CFS.  Prehaps,
scientists theorize, a dysfunction in the immune systems of people with CFS
allows the release of cytokines during flu-like illnesses to continue
unchecked.
 
        Recently, the importance of cytokines in disease processes has become
a focus of increased scientific research.  One cytokine, interleukin-1 (IL-1),
produces fever symptoms.  Studies published last year provide evidence that
similar chemicals may cause the fatigue, muscle aches, and malaise also
associated with flu-like illnesses.
 
        Similarly, a recent study of cancer patients receiving high doses of
interleukin-2 (IL-2, another cytokine) as an experimental treatment found
notable neuropsychiatric side effects, including severe lethargy, muscle
aches, and memory problems.  All these symptoms disappeared after treatment
was stopped.
 
        Researchers have also administered interferon to monkeys and found
that their brain-wave patterns looked very similar to those of people with
depression.
 
        Scientists thus suspect that an overproduction of IL-1, IL-2, the
interferons, and other cytokines may play a role in CFS, and they are closely
examining this possibility.
 
NIAID-Supported Basic Research
 
        Much NIAID-supported research for the past 30 years has focused on
viruses, the immune system, and the interactions between the two.  Basic areas
of investigation include identifying the infectious agents that cause disease,
determining how they stay in the body, and understanding the nature of the
immune response mounted against such agents.
 
        Specifically, NIAID has supported research into herpesviruses since
they were first discovered nearly 30 years ago.  Of particular interest to the
Institute is how these viruses establish and maintain their footholds in the
body.  What keeps the dormant herpesviruses in check, and, conversely, what
brings them back to life?
 
        In 1985, NIAID-supported researchers reported discovering a gene whose
protein product triggers latent EBV to replicate.  Currently, these
researchers are examining how this gene is controlled and whether differences
in control of expression of this gene could be causing some symptoms of CFS.
 
        Similarly, NIAID researchers recently reported discovering a novel
genetic signal that may keep herpes simplex virus 1 dormant.
 
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        If latent viruses are implicated in causing CFS, the search for
molecular switches that turn viruses on and off could help efforts to develop
therapies for this illness.  The studies cited illustrate how basic research
can contribute to our understanding of possible molecular mechanisms
underlying chronic fatigue.
 
Conclusion
 
        Several different routes to chronic fatigue syndrome may exist.  In
some people, a persistent viral infection may provoke CFS symptoms, and
virologists continue to explore this possibility.  Vulnerability to CFS may be
associated with a subtle immune system defect.  It also appears likely,
however, that CFS involves interactions between the immune and central nervous
systems, interactions about which relatively little is now known.  Scientists'
concerted efforts to penetrate the complex neuroimmunologic events in CFS has
created a challenging new concept of the pathology of this and other
illnesses.
 
 
 
 
 
Prepared by:
Office of Communications
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892
 
January 1989
(revised December 1990)
 
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                           CHRONIC FATIGUE SYNDROME
 
SUPPORT GROUPS & RESOURCES
 
NATIONAL ORGANIZATIONS
Chronic Fatigue Immune Dysfunction Syndrome Society
(formerly National CEBV Syndrome Association)
Post Office Box 230108
Portland, OR 97223
(503) 684-5261
 
Chronic Fatigue and Immune Dysfunction Syndrome Association
P.O. Box 220398
Charlotte, NC 28222
(704) 362-CFID
 
National Chronic Fatigue Syndrome Association
3521 Broadway, Suite 222
Kansas City, MO 64111
(816) 931-4777
 
WASHINGTON, D.C. AREA GROUPS
 
Woodrow Wilson Regional Library           The Central Fairfax CFS/CFIDS
6101 Knollwood Drive                        Support Group and Forum
Falls Church, VA 22041                    712 Upham Place, NW
(703) 590-9404                            Vienna, VA 22180-4130
                                          Contact: Pamela J. Lindsay
Baltimore Hotline:                        (703) 242-3630 or (703) 517-9216
Contact: Esther Rodman (301) 358-1203
 
NOTE: The above groups are listed solely for your information because of their
interest in chronic fatigue syndrome.  This list does not constitute an
endorsement of the organizations or any of their referrals, products, or
services.
 
FINDING A DOCTOR
 
University-affiliated medical schools may help in locating physicians who can
evaluate symptoms or who can provide an appropriate referral.
 
U.S. PUBLIC HEALTH SERVICE
 
The Centers for Disease Control offers a background article and provides
information about CDC research, including: 1) surveillance of community health
departments to determine the incidence of CFS, and 2) studies of blood samples
from CFS patients to detect evidence of viral infection.
 
        Centers for Disease Control, Division of Viral Diseases
        Bldg. 6, Rm. 120, Atlanta, GA 30333 Phone: (404) 639-1388
 
NIAID Clinical Study Update:  NIAID is no longer accruing new patients for its
CFS studies.  At present, NIAID's research involves extensive clinical and
laboratory evaluations of the CFS study patients--by identifying the clinical
characteristics of the disease, the researchers hope to find the cause.
 
National Institute of Allergy and Infectious Diseases, NIH
March 1991
 
END
 
