Four physicians with complex chronic disabling illnesses
labeled as chronic fatigue syndrome (CFS) were shown by culture to be
stealth virus infected. The clinical histories indicate multi-system stealth
virus infection with encephalopathy (MSVIE). The exposure of physicians and
other health care providers to stealth viruses is a potential occupational
hazard.
Introduction
Complex arrays of symptoms typify a number of common, chronic, disabling
illnesses. To varying extents many patients report and/or demonstrate:
i) Impaired mental capacities, including loss of short
term memory, difficulties in verbal expression and/or
comprehension, attention deficit and lethargy;
ii) altered personality, including a reduced capacity to
relate emotionally to others;
iii) mood changes, including depression, anxiety and
anger;
iv) sleep disturbance; v) instability of autonomic
nervous system regulation of blood pressure, pulse rate
and/or bowel functions;
vi) headaches and; vii) generalized body aches and
pains. The medical community is split between those who
view these symptoms as an indication of an underlying
organic disease process, and those who consider the
symptoms merely as an extension of the normal stresses
and strains of everyday living (1,2).
Clinicians who advocate organic disease have used
various diagnostic terms such as chronic fatigue
syndrome (CFS), fibromyalgia, depression, Gulf war
syndrome, irritable bowel syndrome, attention deficit,
multiple chemical sensitivity, etc.; without clear-cut
distinguishing clinical or laboratory criteria. The use
of imprecise clinical labels has helped bolster those
who believe that none of the illnesses constitute
serious medicine.
Public
Health authorities have also been slow in pursuing a possible infectious
etiology of CFS and related conditions. Reports of community outbreaks of
CFS-like illnesses have typically been discredited as emotional
over-reactions of those affected, fueled by over-zealous, incompetent
physicians (3). With little support from established medicine, patients have
generally had to fend for themselves in explaining their illness to family,
friends and disability insurance carriers.
For
several years, I have been culturing atypical cytopathic viruses from CFS
patients (4-6). I coined the term "stealth" because the viruses were
apparently unseen by the cellular immune defenses responsible for triggering
an anti-viral inflammatory response. I postulated that stealth-adaptation
involved the deletion of critical viral genes that coded the major antigens
targeted by T lymphocytes (4). DNA sequencing data obtained on an African
green monkey simian cytomegalovirus (SCMV)-derived stealth virus support
this hypothesis (7).
During
the course of studies on stealth-adapted viruses, numerous physicians have
requested personal testing because of their own symptoms. Four particularly
severe cases have been selected to help underscore the apparent occupational
infectivity of stealth viruses.
Methods
Stealth Virus Cultures: Mononuclear cells were isolated from blood collected
in acid-citrate-dextrose (ACD), yellow-topped tubes, using ficoll-paque
(Pharmacia, NJ). The cells were added to MRC-5 fibroblasts and to rhesus
monkey kidney cells (BioWhittaker, MD).
The inoculated cultures were observed for the
development over one to several days, of rounded
vacuolated cells that form syncytia (4). The cytopathic
effect (CPE) was enhanced by regularly replacing the
medium (X-Vivo-15, BioWhittaker, MD). Confirmation of
the CPE can, if required, be generally obtained by
positive immunostaining of the culture with broadly
reactive polyclonal antisera raised against various
human herpesviruses.
Immunostaining will generally also occur with the
patient's own plasma and with many normal human sera
(4). The CPE is morphologically distinguishable from
that typically caused by human cytomegolovirus, human
herpesvirus-6, adenovirus and enteroviruses. Additional
distinctions from these conventional viruses can be made
by using highly specific monoclonal typing antibodies,
and by sequencing of polymerase chain reaction (PCR)
products generated using various primer sets under low
stringency conditions (4,6).
Case Histories
Case 1: An internist, who is now age 44, was well until 1987. At
that time a nurse accidentally struck her in the hand with the needle of a
syringe containing blood collected from an elderly patient. The patient had
developed a transient acute encephalitis-like illness shortly after
receiving a blood transfusion and subsequently became demented requiring
nursing home care.
The
physician began developing symptoms within several days
of the needle stick. These included vomiting, stiff
neck, vertigo, headache, left eye pain,
photosensitivity, somnolence and periodic fever to
100oC. CT and MRI scans were read as normal. The acute
symptoms peaked at approximately two weeks and gradually
improved. By two months, the patient had regained her
usual alertness and, in spite of continuing vertigo,
photophobia and headaches, she returned to work.
Gradually over the ensuing year, she became
progressively more clumsy and even occasionally fell
onto patients being examined. She had difficulty reading
because of down-beating nystagmus. A repeat MRI was
again negative. Routine viral cultures on a
cerebrospinal fluid (CSF) sample were negative. Detailed
auditory and vestibular testing were consistent with
endolymphatic hydrops with perilymphatic fistula, worse
on the left side, and benign paroxysmal positional
nystagmus, worse on the right side.
The
physician was unable to continue working. Her overall
clinical condition has further deteriorated over the
last ten years. Daily attacks of vertigo, ataxia,
headaches, photophobia; and week-long attacks of severe
fatigue; have prevented her from resuming any type of
work. Her short term memory also became impaired.
She
has experienced frequent upper respiratory tract
infections, which, based on positive serologies, have
been labeled as Legionnaire's disease, Mycoplasma
pneumoniae and Chlamydia pneumoniae. Among her many
illnesses, she has had recurrent bouts of nausea,
abdominal pain and diarrhea; one episode being
attributed to C. difficile infection.
Her
thyroid had periodically become swollen and painful,
with signs of de Quervain's thyroiditis with
thyrotoxicosis associated with thyroid stimulating
immunoglobulin. Resolution has required from 6 months to
2 years of prednisone therapy. She has had attacks of
pancreatitis, interstitial cystitis, and is allergic to
many foods and medications. The C5-C6 cervical disc has
herniated, as has the L4-L5 lumbar disc. She has a
reduced blood volume with orthostatic hypotension.
Additional laboratory testing has included positive PCR for chlanydia and
for mycoplasma, and positive serology for Borna virus. Her blood has shown
cryoglobulins and increased fibrinogen split products with signs of platelet
activation. Both CD4 and CD8 T lymphocyte levels have been reduced. Blood
2-5A' synthetase, RNase-L, alpha interferon and interleukin-10 levels were
raised. Urinary and stool porphyins were elevated. Her urine also showed
excess mercapturic acid, D-glucaric acid, B-alanine, and hydroxyproline. A
stealth virus culture was strongly positive.
Brain
imaging showed a 4mm herniation of the cerebellar tonsils, mild cerebral
atrophy and discernable subcortical encephalomalacia. Reduced perfusion and
metabolic activities involving the frontal, temporal and parietal lobes,
were shown using SPECT and PET scans, respectively.
Several years ago, the patient acquired a pet dog. The dog has had a
remarkable medical history, including partial complex seizures, elevated
liver enzymes, hypothyroidism, and recurrent prostate, urinary,
gastrointestinal and eye infections. The dog also tested positive for
stealth virus.
Case 2: At 43 years of age, a previously healthy ophthalmologist
experienced acute flu-like symptoms, which included sore throat, swollen
cervical lymph nodes, night sweats, muscle aches and fatigue.
The
symptoms were gradually resolving when he began to
develop burning parenthesia involving different regions
of his body. These were accompanied by marked muscle
weakness. Palpable nerves were tender. He had to
discontinue work for two months. When he returned, he
was still bothered by paresthesia, weakness, insomnia
and fatigue.
A
further exacerbation occurred eight months later with
several days of confusion and disorientation, followed
by apparent reduction in short-term memory, attention
span, and verbal expression and comprehension. Muscle
fasciculation was also noted. He again discontinued work
and has remained disabled for the last 11 years.
During this time he has periodically developed
superficial, mucus exudative lesions that involve areas
within the nostrils and on the lips. Cognitive
impairments were documented on neuropsychological
testing. Hypoperfusion was seen on SPECT scan and
hypometabolism was seen on PET scan.
Abnormal routine laboratory testing has included
slightly elevated liver function tests. Special tests
have shown marked elevations in alpha interferon and in
interleukin 1. Material collected from the exudative
lesions has shown herpesviral like-particles on electron
microscopy. Viruses were also seen in a semen
preparation and in an ultracentrifuge pellet from an
aceellular CSF sample. Multiple stealth virus cultures
from blood, CSF, lip lesion, and semen, have been
consistently positive on multiple occasions between 1992
and 1998.
Case 3: In 1983, a 38-year old medical oncologist was exposed to
hematemesis and bloody diarrhea from an elderly patient with persistent
thrombocytopenia, splenomegaly and progressive cirrhotic liver disease. The
patient showed elevated liver enzymes, but remarkably normal bilirubin until
shortly before her death. Among other investigations, the elderly patient
was negative for hepatitis A and B by serology, and strongly positive for
anti-EBV viral capsid antigen (VCA).
Within two months of this patient's death, the attending
physician began to experience irritable bowel symptoms
with abdominal discomfort and episodes of diarrhea. He
also tested strongly positive for EBV VCA, (titer
1:5,000). His symptoms gradually extended to include
diffuse myalgia and anthralgia, severe and progressive
lethargy, and reduced exercise tolerance.
Additionally, the physician began to experience
headaches accompanied by blurring of vision and
occasional diplopia, night sweats, periodic palpitations
and insomnia. He became intolerant of bright light,
which would trigger headaches, and was also intolerant
of cold night air that would trigger muscle aches and
anthralgia. He also had intermittent bouts of
pharyngitis.
The
illness continued to progress with increasing
generalized muscle weakness, chest pains, shortness of
breath, mild ataxia and tremor. He was seen by numerous
specialists whose aggregate diagnoses included the
following:
i)
Labile hypertension progressing to fixed hypertension
associated with left ventricular hypertrophy and EKG
signs of viral cardiomyopathy.
ii)
Hepato-splenomegaly with fluctuating elevated liver
enzymes and steatosis on liver biopsy, now progressing
to cirrhosis.
iii)
Progressive cerebral atrophy with hypoperfusion and
hypometabolism, manifesting as personality disorder,
impaired memory, depression and early dementia. He has
difficulty following conversations and is easily
confused.
iv)
Endolymphatic hydrops.
v)
Prolonged episodes of moderate thrombocytopenia with
ecchymosis, telangiectasia and splinter hemorrhages.
Plasmacytosis was seen on bone marrow biopsy with
ohgoclonal rearrangements within both B and T
lymphocytes. Megaloblastic anemia, refractory to folic
acid and vitamin B12 therapy.
vi)
Multiple chemical sensitivity and multiple food
allergies, which induce nausea and headaches.
vii)
Localized psoriasis and; viii) Recent onset of type II
diabetes. He has been on disability since 1984.
Abnormal laboratory tests include elevated levels of alpha interferon,
interleukin 1, tumor necrosis factor and C reactive protein. He has
auto-antibodies to nuclear, nucleolar and cytoplasmic antigens. 1gA and 1gG
levels are below normal, as are qualitative and quantitative NK cell assays.
CD4/CD8 T lymphocyte ratio is elevated. Plasma amino acid levels are
reduced, whereas plasma ammonia is increased. Stealth virus cultures have
been repeatedly positive since 1991.
Case 4: A 55 year old financially successful physician was alerted to a
possible illness when he noticed difficulties switching his concentration
from counting a patient's pulse to watching the clock. He also began to
forget telephone numbers. He had to carefully position himself before
getting up from a stool so as not to stagger and appear drunk.
He
stopped practicing medicine when he found himself
waiting for another motorist to come to a traffic light
so as to remind him on which color light he could
proceed. Neurological examinations were conducted, but
no abnormalities were found. His colleagues reassured
him that it was nothing other than stress. He became
despondent and overweight.
His
marriage failed and his adult children sided with their
mother in the disposition of various assets. For the
next 10 years, the physician lived alone, unable to
drive at night because of disorientation; unable to
socialize because of verbal and cognitive problems; and
unable to obtain relief in spite of literary having a
pharmacy within his apartment.
A
formal neurological examination was arranged in 1994, to
help document his disability for a Public health report.
It was essentially unremarkable except for a 4/5 mild
bilateral weakness in hand gripping. The examining
neurologist admitted that he was considering
schizophrenia when the patient began referring to
"multiple little men in my brain not listening to each
other."
The
disabled physician was provided a trip to Hawaii but
only on four occasions throughout a whole month did he
leave his hotel room. His traveling companion commented
on his relentless suffering and inability to take
delight from any of the days' happenings.
When
not sleeping, he would struggle with expressing his
ideas and would invariably return to the theme of his
illness. Upon his return to California, he answered a
mail-order bride advertisement from the Philippines,
where he now resides. Blood and an otherwise normal CSF
sample were strikingly positive in stealth viral
cultures.
Discussion
In
spite of the obvious differences, complexities and severity of the illnesses
experienced by these four physicians, they are all currently diagnosed as
having CFS. In current medical practice, this term embraces a broad range of
illnesses without defined boundaries at either the mild or severe extremes.
It
lumps seriously ill patients, such as those described in
this paper, with the so called "worried well" who are
accused of over utilizing medical services (8). For sick
patients, the CFS label is not infrequently applied to
individuals with variably recurring multi-system
illnesses with an overlay of neuropsychiatric
symptomatology.
A CFS
diagnosis will often limit the medical quest to
determine the actual causes of the many and varied
symptoms experienced by the patient. Being physicians,
the patients described in this paper, have had access to
more extensive laboratory and ancillary testing than do
most CFS patients. In particular, they sought and tested
positive for stealth viral infections.
Stealth viruses refer to a molecularly heterogeneous grouping of atypically
structured viruses that induce a vacuolating cytopathic effect (CPE) in
culture, yet seemingly are unable to evoke an anti-viral inflammatory
response in vivo (4-7).
Sequence studies on an African green monkey simian
cytomegalovirus-derived stealth virus are consistent
with the deletion of genes coding for the major targets
for anti-CMV cytotoxic T lymphocytes (CTL) mediated
immunity (6). More impressively, portions of this virus
have gained many additional sequences of both cellular
(9) and bacterial origins (10). The SCMV and captured
cellular and bacterial sequences have undergo
considerable mutations, yielding a diverse range of
molecular and antigenic components.
Stealth adaptation can presumably occur with other
cytopathic viruses of human and animal origin. The lack
of an accompanying inflammatory reaction and poor growth
in routine viral cultures have helped these viruses go
unnoticed by clinical investigators.
The
molecular and antigenic diversity of stealth viruses can help explain the
sometimes baffling results of PCR and serological based assays obtained in
CFS patients. In Case 1, for example, positive results were obtained in
tests for Borna virus, Legionella, chlamydia and mycoplasma.
Although it is conceivable that the patient had all of
these infections, it is more likely that the results
reflect molecular and antigenic cross-reactivity. The
presence of stealth viruses, especially their capacity
to assimilate genes of bacterial origins, poses a caveat
on the interpretation of many currently used PCR and
serological based tests.
While
the encephalopathic manifestations tend to dominate the clinical features of
most CFS patients, as is amply revealed in the case histories, many other
organ systems are affected. The detection of various abnormalities often
reflects the extent to which laboratory and ancillary diagnostic services
are employed.
The
sensitivity and specificity for CFS of many of the
various tests are not established. Given the vagueness
of the clinical diagnosis, it would not be surprising if
major discrepancies occurred. The diversity of
laboratory results is, however, quite consistent with an
overall diagnosis of multi-system stealth virus
infection with encephalopathy (MSVIE). This term can
embrace the widespread illnesses, including signs of
autoimmunity, allergy and metabolic failures, that were
especially apparent in cases 1 and 3.
The
four physicians have experienced many of the problems faced by CFS patients.
The social toil has included loss of income with considerable medical
expenses incurred in the performance of laboratory tests and ancillary
investigations. Two of the patients were divorced largely due to personality
changes and loss of empathy with their spouses.
One
physician lived apart from his wife for several years in
fear of transmitting his infection. Electron microscopy
and stealth virus testing of semen was a hopeful gesture
that they might still be able to conceive a healthy
child. The diagnosis of CFS was used in the denial of
the first physician's appeal for Worker's Compensation,
even though her initial illness clearly followed a
needle stick injury. Another physician felt pressured to
reach a settlement with his long term disability carrier
who had decided to terminate his benefits.
One of
the physicians visited NIH investigators, and met with CDC officials trying
to alert them to his illness without success. Patient 4 was formally
reported to a County Health Department in 1994, again with no response.
The
reluctance of Public Health authorities to deal with
chronic disabling illnesses may be partially explained
by an inadequacy of conventional epidemiological tools
when applied to complex and varied infectious diseases.
The sequence data on the prototype stealth virus may
also bear on Public Health concerns regarding the wisdom
of having used African green monkeys to produce live
poliovirus vaccine.
Although only four cases are presented, many more physicians have sought
stealth virus testing. Several other physicians have begun anti-viral
therapy with ganciclovir with self-reported benefit. Courageous clinicians
have continued to treat CFS patients, but with a greater respect for the
potential contagiousness of the illnesses they are encountering.
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