Attempts to define the chronic fatigue syndrome (CFS) as a clinical diagnostic entity1 have met with difficulties mainly because of a lack of clear separation of what could be considered normal variation in human functional capacity, and what should be considered a medical illness. Patients with debilitating fatigue are inappropriately grouped along with individuals with only minimal impairment in their daily activities. Some severely affected CFS patients eventually meet criteria for neurological, psychiatric and/or immunological disease classifications. The possible connection between CFS and these other diseases is unfortunately obscured by present day terminology.

The thesis of our studies is that severe CFS is but one of many manifestations of a persistent, systemic viral infection that causes brain damage.2 Involvement of the brain in CFS is implied by the historical use of terms such as neurasthenia, myalgic encephalomyelitis, and limbic encephalopathy.3 Some investigators have argued that the disturbed brain function is a secondary phenomenon resulting, for example, from the overproduction of neuromodulatory cytokines.4 Immune dysregulation is also proposed to explain reactivation of normally tolerated ubiquitous microorganisms, such as Epstein-Barr virus, human herpesvirus-6, Candida albicans, Mycoplasma fermentans, Chlamydia pneumoniae, etc.5 Recent attention has also been given to possible brain damage from exposure to environmental neurotoxins, including gut derived bacterial products.6

Minimizing the potential infectious etiology of CFS has occurred in spite of past and recent epidemic outbreaks of CFS-like illnesses.7,8 Reasons for this bias include the inability of most investigators to isolate pathogenic viruses from CFS patients, and the lack of any correlation of disease with conventional anti-viral serology.9 Published studies using the polymerase chain reaction (PCR) to test for evidence of retroviruses,10 enteroviruses,11 conventional herpesviruses 12 and mycoplasma 13 infections, were also flawed by erroneous assumptions concerning the specificity of the PCR assays when performed under low stringency conditions.

These earlier studies can now be reconciled by the finding that most severely ill CFS patients are infected with atypically structured cytopathic viruses.14-16 The viruses have been termed "stealth" since they apparently lack crucial antigenic determinants that would act as effective targets for cell mediated anti-viral immunity. The viruses can be grown in a wide range of cells of both human and animal origins, inducing a foamy, vacuolating cytopathic effect (CPE). A similar CPE can be seen in brain biopsies obtained from severely ill stealth virus infected humans 16-18 and from experimentally inoculated animals.19 The cellular changes occur in the absence of an inflammatory reaction and are easily overlooked if not specifically sought.

Although many of the patients' symptoms are referable to the brain, virus infection is widespread and can involve multiple organs. The term multi-system stealth virus infection with encephalopathy (MSVIE) more accurately conveys the complexities of the illnesses seen in infected CFS patients. This term also helps to restore the extensive overlaps between CFS and other stealth virus associated illnesses, including aberrant behavioral and learning problems in children, fibromyalgia, Gulf War syndrome and psychiatric illnesses in adults, and progressive movement disorders and dementia in the elderly. The systemic nature of the infection can explain the varied endocrine, cardiovascular, gastrointestinal, immunological and other disease manifestations seen in many of these patients.

Stealth adaptation can presumably occur with any type of cytopathic virus. I have primarily focussed on a stealth adapted African green monkey simian cytomegalovirus (SCMV). Extensive sequencing studies on this virus have confirmed the lack of critical antigens utilized by anti-cytomegalovirus cytotoxic T lymphocytes.20 The virus has managed to capture, amplify and mutate various non-viral genes, including cellular genes and genes of bacterial origin.21-23 The term viteria has been introduced to describe viruses infectious for humans and animals that have acquired bacterial genetic sequences.23 The presence of bacterial sequences can help explain the unusual serological and PCR based assay results seen in some CFS patients. They may also contribute to the allergic manifestations occasionally observed in these patients.

Rational therapy for severely ill stealth virus infected patients can reasonably include empirical trials with anti-viral agents. Significant improvement has been reported in some patients using valcyclovir and in a larger group of patients using ganciclovir.24,25 Antibiotics may have a role if viteria infected bacteria can be demonstrated. Additional therapy needs to be individualized according to the patient's symptoms and the extent of multi-organ damage. There is a role for neurally active medications, nutritional supplements and possibly probiotics. The vexed question of how to help minimize transmission of infection within both the workplace and the family also needs to be addressed. Additional information relating to stealth viruses and copies of key publications can be found at the web site www.ccid.org

W. John Martin, M.D., Ph.D.
Center for Complex Infectious Diseases
Rosemead CA 91770

References

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Martin WJ: Cellular sequences in stealth viruses. Pathobiology 1998;66:53-58
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22.  Martin WJ. Bacteria related sequences in a simian cytomegalovirus-derived stealth virus culture. Exp Mol Path 1999;66:8-14.
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