Infections in CFIDS
Joseph F. John,
Jr., MD and Kenneth Friedman, PhD
Many people with chronic fatigue and
dysfunction syndrome (CFIDS) suffer from fever, sore throat and lymph node
swelling and tenderness. These symptoms often accompany diseases caused by
microorganisms such as viruses and bacteria. It seems logical, therefore, that
microbial infections could be linked to the development or perpetuation of
Yet the role of infections in CFIDS
unclear and, in many cases, controversial. Good data suggest that one, or
possibly many, microorganisms can trigger the onset of CFIDS or worsen its
symptoms. But much work remains to identify these microbes and discover how they
may function in CFIDS.
It is clear that at least 50 percent
people with CFIDS (PWCs) have an infectious episode prior to the development of
CFIDS.1 In some cases the inciting event is a mononucleosis-like illness,
occasionally a standard Epstein-Barr virus (EBV)-associated mononucleosis. More
often, it is a non-specific upper respiratory infection, a sinusitis or
bronchitis or occasionally an influenza-like illness, the latter characterized
by severe muscle pain, high fever and extreme malaise.
Some PWCs may actually describe vividly
event at a specific date and time of day when they became ill, relating that
after that event they never felt healthy again. Paradoxically, the initial
symptoms may blur over time for many patients with CFIDS, making them difficult
to recapture in the medical history obtained years later.
Looking for a link
agents seem capable of inciting CFIDS, but few good studies have linked the
illness to specific agents. One early study depicted an outbreak of disease
probably associated with human herpes virus 6 (HHV-6) at Incline Village,
Nevada. In this outbreak there was evidence of depletion of B-cell lymphocytes,
a specific type of immune cell that makes antibodies, and development of
symptoms consistent with CFIDS.1,2
Older observations from Europe suggested
that an illness called myalgic encephalomyelitis had occurred in clusters that
suggested an infectious/contagious basis for the outbreak.3 Although it is
tempting to attribute CFIDS to an unresolved infection secondary to viral
infection like mononucleosis or influenza, it is difficult to attribute the
constellation of symptoms and signs that currently define CFIDS as due to a
single infectious agent.
There is some evidence, however, that
CFIDS may be
associated with unresolved or persistent infectious agents. For example, most
patients with CFIDS have persistently and, at times, markedly elevated
antibodies to portions of the EBV, suggesting that their latent infection with
EBV has in some way been re-activated. This indicates that they have been
exposed to EBV at least once and possibly on an ongoing basis. The same can be
said, albeit less assuredly, for HHV-6. Belgian and French co-workers also have
reported recently that certain types of bacteria known as Mycoplasma are
associated with precipitating or perpetuating the illness.1 One species of
special interest is Mycoplasma fermentans.
Other evidence for an infectious basis
CFIDS hinges on the recent observations that one of the major antiviral pathways
in the immune systems of PWCs is dysfunctional. Over the last decade it has
become clear that PWCs generate abnormal concentrations of an intracellular
enzyme called RNase L.1,4,5 Activated RNase L serves as one final arm in a more
general antiviral pathway, triggered initially outside the cell by a group of
compounds called interferons. Interferons are produced in response to foreign
double-stranded DNA (usually a virus), and, in turn, stimulate the activation of
a substance called 2-5 adenylate inside the cell. This substance activates RNase
L, an enzyme capable of degrading single-stranded viral RNA or perhaps other
messenger RNA and halting the virus from producing further damage.4,5
In a sense, this system works as a
nonspecific defense mechanism before specific humoral (antibody) and other
specific cellular responses take over. Patients with CFIDS tend to fragment the
functional, large molecular weight RNase L (80 Kda) and produce instead a
dysfunctional, low molecular weight RNase L (37 Kda). So the symptoms suggestive
of recurrent viral infections in PWCs may be due to such an alteration in this
Weighing the evidence
infectious diseases cause the number and diversity of symptoms seen in patients
with CFIDS. The disease that most resembles CFIDS is acute and subacute EBV
infection. But patients with mononucleosis tend to be younger and do not suffer
from the other primary symptoms of CFIDS such as cognitive dysfunction, sleeping
disorders and allodynia.
Nevertheless, EBV was initially thought
be the cause of CFIDS. When blood was tested for antibodies against two EBV
replicating enzymes, abnormal titers of antibodies were found twice as often in
PWCs than in controls (34.1% vs. 17.1%). While this may indicate a more frequent
occurrence of EBV in patients with CFIDS (or perhaps that EBV may precipitate
CFIDS in a subset of PWCs), EBV is not the universal cause or precipitant of
Buchwald et al tested 548 chronically
fatigued patients, including patients with CFIDS, for prevalence of antibodies
to 13 viruses. No consistent differences were found in PWCs compared to control
subjects. An earlier study by Mawle et al at the U.S. Centers for Disease
Control and Prevention (CDC) could not find elevated antibody titers to any
herpes virus, including EBV.7 Recently, workers at CDC examined 26 patients
52 controls for the presence of HHV-6 and HHV-7 and found no differences
between patients and controls.8
The recent report of an “outbreak”
in Japan9 which may be affecting as much as one-third of the Japanese workforce
may rekindle efforts to identify an infectious agent as the cause of CFIDS. A
preliminary report suggests that this is a post-hepatitis B vaccination outbreak
and may be due to a contaminating organism.
The failure to find a single virus
patients with CFIDS has led to the assertion by some that CFIDS is not caused by
a viral agent. However, the failure to identify a causative viral agent does not
preclude the possibility that CFIDS is caused by a yet-to-be-identified virus or
co-infection with two or more viral agents or an unknown infective agent.
An intriguing, unifying hypothesis
forward by Lerner et al is that CFIDS symptoms are caused by a viral infection
of the heart.10 These investigators have described electrocardiographic changes
that can be explained by changes in membranes of some heart cells.11 They
believe that such changes may be caused by the presence of a virus and claim
success with long-term therapy with antiviral medication.
Other non-CFIDS literature documents
ability of viral infection to alter the way that a cell moves substances across
its membrane through specific “channels.” Human immunodeficiency virus type 1
(HIV-1) has been shown to inhibit a potassium channel in some brain and human
spinal cord cells,12 while herpes simplex virus has been shown to inhibit sodium
channel activity in some nerve cells of adult guinea pigs.13 Virus-induced
alteration of cell membrane function, therefore, is a possible, but unproven,
mechanism of CFIDS pathophysiology.
There is other indirect immunologic
evidence for persistent viral infection. Patients with CFIDS often have lower
numbers of immune system cells called lymphocytes, in particular CD4+ and CD8+
lymphocytes. This type of depletion should not be confused with the CD4+
depletion seen with HIV infection. In HIV disease the CD4+ to CD8+ ratio is
Bacteria, viruses and
parasites have been linked to fatiguing syndromes including brucella, bartonella
and cyclospora.14 Not widely known, it has been
reported that the cat scratch disease due to Bartonella henselae
may be present as chronically fatiguing
illness.11 In considering bartonella infection as a cause of fatigue, a good
history of cat exposure including being licked by or sleeping with the cat and
cat scratch disease serology, coupled with newer techniques to amplify
bartonella DNA in blood, should help eliminate that diagnosis.
Some patients complain of recurrent
oral or vaginal
candidiasis. Some may insist that they are chronically infected with yeast, a
holdover from the pseudoepidemic promul-gated by some health care providers
claiming that many patients with undefined disease had deep-seated, unresolved
mycotic infection due to Candida albicans
, thus the term “the yeast
connection.”15 Nevertheless, in some patients
C. albicans can be cultured at
times from the oral cavities and genital tracts. Some patients in fact report
improvement of fatigue when oral azoles are used to treat the mucosal
In patients with Lyme disease, exhausting
bone and body pain and cognitive dysfunction are unusual. Nevertheless, in areas
of the country where Lyme disease caused by Borrelia borgdorferi is
endemic, patients with CFIDS and physicians will fixate on Lyme disease as a
cause. To confound the clinical picture, Lyme disease does have a chronic form,
and blood serology showing increased antibodies to Borrelia borgdorferi
that was positive early in the disease may persist for years. Ehrlichiosis
caused by agents related to the rickettsia is an emerging disease endemic in the
same geographic regions as Lyme disease. The capacity for E. canis to produce a chronic disease
like CFIDS has not been
As mentioned, workers in Belgium have
reported in abstract
form an association of circulating peripheral blood cell-associated
Mycoplasma fermentans with CFIDS. This bacterium awaits more
definitive studies to define its role in CFIDS.
In this age of emerging infectious
including those of bioterrorism, other new microbial agents will surely arise as
causes of chronic fatigue.
initiate the workup
of PWCs after a thorough history and physical examination, primary care
physicians can obtain blood tests for EBV, HHV-6, cytomegalovirus (CMV),
toxoplasmosis and HIV. The next level of testing could include other serologies,
tests for HHV-6 viremia, RNase L determinations, Mycoplasma, ricksettial or
chlamydia DNA amplification by PCR. These advanced tests may be difficult to
obtain because of lack of insurance coverage. PWCs often have to secure and pay
for this testing themselves by finding the most appropriate laboratory to
perform the testing and arranging third-party payment — a very frustrating
Regional specialty labs may be helpful
patients arranging specialized diagnostic testing. An infectious diseases
physician specializing in CFIDS can assist the primary care physician in
choosing tests that may support the diagnosis of CFIDS or other infectious
diseases. The chart above outlines the diagnostic tests involving some
infectious agents that may be considered for the patients with CFIDS.
no studies that
support the routine use of anti-infective medications in the therapy of CFIDS.16
Nevertheless, since CFIDS is devastating to individuals and their families, and
since there is evidence that CFIDS may be associated with persistent infectious
agents, it is reasonable to expect careful trials of antivirals, antibacterials
and, in certain instances, antifungal agents.
PWCs with early CFIDS and high titers
antibody to DNA viruses may benefit from a one-to-two month trial of antivirals,
usually starting with an agent like valcyclovir at doses of 500 mg two or three
times a day. If there is no response at two months, therapy should be
Ampligen is a 50-base-pair compound
consisting of double-stranded RNA that several studies have shown improve the
Karnofsky score, a measure of well-being.17 Ampligen is a proprietary compound
manufactured by Hemispherx Biopharma. Preliminary evidence has also been
presented to show that Ampligen can decrease the level of low molecular weight
RNase L. A current clinical trial now underway with Ampligen compared to placebo
will determine if the product will be approved by the federal Food and Drug
Some PWCs will give a history of a
response to an incidental antibacterial they had taken in the past. While there
are no studies to substantiate empiric use of agents like the macrolides or
quinolones, when patients are debilitated it seems reasonable to attempt one- or
two-month trials in selected patients who have had such beneficial responses
historically. New studies are underway to determine the efficacy of
antimicrobials in those patients with evidence of active Mycoplasma infection.
Since cytokine regulation may play a role in CFIDS, agents to modulate cytokine
pathways like isoprinosine, infliximab or thalidomide will serve as yet another
potentially exciting area for clinical trials.18-20
Dr. Joseph John Jr. is chief of
services at the Ralph H. Johnson Department of Veterans Affairs Medical Center
and Professor of Medicine, Immunology and Microbiology at the Medical University
of South Carolina in Charleston. Besides, CFIDS, Dr. John’s diverse research
interests include bacterial resistance, staphylococcal infections and infections
in hospital settings.
Kenneth J. Friedman, PhD, is associate
pharmacology and physiology at the University of Medicine & Dentistry of New
Jersey, New Jersey Medical School, in Newark.
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This article was
adapted and reprinted with permission from A Consensus Manual for the
Primary Care and Management of Chronic Fatigue Syndrome, published in 2001
by The Academy of Medicine of New Jersey, the University of Medicine and
Dentistry of New Jersey and The New Jersey Dept. of Health and Senior Services.
For more information on the manual, please see Research
News in this edition.