CHRONIC FATIGUE SYNDROME AMONG PHYSICIANS: A POTENTIAL RESULT OF OCCUPATIONAL EXPOSURE TO STEALTH VIRUSES W. John Martin, M.D., Ph.D. Center for Complex Infectious Diseases Rosemead, CA 91770 Subtitle: CFS In Physicians Address for Correspondence: CCID 3328 Stevens Avenue Rosemead, CA 91770 Phone: 626-572-7288 Fax: 626-572-9288 E-mail: ccidlab@hotmail.com Abstract 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 travelling 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. References 1. Goldstein JA. Chronic Fatigue Syndromes: The Limbic Hypothesis. New York. Haworth; 1993 2. Barsky AJ, Borus JF. Functional somatic syndromes. Ann Int Med. 1999;130:910-21 3. Shefer A, Dobbins JG, Fukuda K, et al. Fatiguing illness among employees in three large state office buildings, California, 1993: was there an outbreak? J Psychiatr Res 1997;31:31-43 4. Martin WJ, Zeng LC, Ahmed K, Roy M. Cytomegalovirus-related sequences in an atypical cytopathic virus repeatedly isolated from a patient with the chronic fatigue syndrome. Am J Path. 1994;145:441-452. 5. Martin WJ. Severe stealth virus encephalopathy following chronic fatigue syndrome-like illness: Clinical and histopathological features. Pathobiology 1996;64:1-8. 6. Martin WJ. Stealth adaptation of an African green monkey simian cytomegalovirus. Exp Mol Path. 1999;66:3-7. 7. Martin WJ. Detection of RNA sequences in cultures of a stealth virus isolated from the cerebrospinal fluid of a health care worker with chronic fatigue syndrome. Pathobiology 1997;65:57-60. 8. Bowers L. Community psychiatric nurse caseloads and the 'worried well': misspent time vital work? J Adv Nurs. 1997 26:930-6. 9. Martin WJ. Cellular sequences in stealth viruses. Pathobiology 1998;66:53-58. 10. Martin WJ. Bacteria related sequences in a simian cytomegalovirus-derived stealth virus