Diagnosis: Viruses

Because some cases of chronic fatigue syndrome (CFS) begin with a flu-like infection, several viruses have been studied as possible causes of CFS.¹ None has yet been found to be the cause of CFS; many are relatively common in the general population and researchers have been unable to link any of them to all cases of CFS.

In 2009 the search for a viral cause of CFS heated up with research that showed an association between 67% of 101 cases of CFS with a novel retrovirus called Xenotropic Murine Leukemia Virus-related virus, or XMRV.² There is still much debate in scientific circles over whether any infectious agent will emerge as the only cause of CFS. Current thinking is that there may ultimately be found several triggers for the illness in genetically, environmentally or otherwise susceptible individuals.³

Epstein-Barr Virus
In the mid-1980s, several researchers reported slightly higher levels of antibodies to Epstein-Barr virus (EBV) in patients with CFS-like symptoms compared with healthy individuals.^4,5 Most of these patients had experienced an episode of infectious mononucleosis a few years before the onset of chronically fatiguing symptoms. As a result, the illness became known as "chronic Epstein-Barr syndrome."

In subsequent investigations, it became clear that elevated EBV antibody titers are not diagnostic for CFS⁶; some healthy people have high titers of EBV, and some people with CFS do not. More than 90 percent of adults in developed countries have been exposed to EBV by age 30, and moderately elevated antibody titers have not been associated with any EBV-related disease. The medical community eventually decided that chronic EBV is an inappropriate label for this illness.

Human Herpesvirus (HHV)-6 and -7
Some viruses, like HHV-6  and -7, can live in a dormant state inside the human body. There is evidence that HHV-6 and -7 get "reawakened" in patients with CFS.^7,8 These viruses have also been linked to multiple sclerosis (MS), an illness that shares many clinical features with CFS.⁹ But not all researchers have found a connection. Scientists at the U.S. Centers for Disease Control and Prevention, for example, have found no evidence that active or latent infection with HHV-6 or -7 is associated with CFS.¹⁰

The role of human herpesviruses in CFS, MS and other illnesses remains controversial, and it is difficult to compare studies due to the different methodologies used to detect the viruses. The question still remains whether the reawakened virus, if present, is the cause of the physical damage and resulting symptoms or the result of the illness.

Retroviruses
Retroviruses are known to cause uncommon neurological disorders that have a relapsing and remitting pattern similar to CFS. In 1991, a team of researchers led by Dr. Elaine DeFreitas published evidence suggesting that a human T lymphocytic virus type II (HTVL-II)-like retrovirus was present in the lymphocytes of CFS patients and might be the cause of their symptoms.¹¹ Other preliminary evidence of possible retroviral involvement in CFS has been published. Dr. W. John Martin of California reported an association of CFS with a "stealth virus." ¹² Dr. Sidney Grossberg of Wisconsin discovered a new virus, called the "JHK" virus, in a CFS patient. Subsequent study by other laboratories failed to reproduce any of these results.^{13, 14, 15}

XMRV, a retrovirus in the gammaretrovirus family that has been associated with prostate cancer, was first linked to CFS by researchers at the Whittemore Peterson Institute, Cleveland Clinic and National Cancer Institute. Another positive study from researchers at the Food and Drug Administration, National Institutes of Health and Harvard Medical School, found evidence of polytropic murine leukemia virus-related (MLV) sequences in 87% of 37 CFS patients.¹⁶ XMRV and MLV's are part of the same family of retroviruses. However, seven other groups have not been able to detect XMRV or MLV sequences using polymerase chain reaction. More studies are underway and other methods for testing for viruses are being employed.

Enteroviruses
Researchers in the United Kingdom have focused on enteroviruses, which include polio and Coxsackie virus, as a possible cause of CFS. So far, there has been no conclusive genetic evidence for the presence of enterovirus in CFS patients.^{17, 18} More recently, Dr. John Chia has published studies that indicate the presence of enteroviruses in gastrointestinal tract.¹⁹ The results of muscle biopsies do not rule out enterovirus as a causative agent, but suggest that CFS is not dependent on a persistent enterovirus infection.¹

Cardiac Infection
Dr. Martin Lerner, an infectious disease specialist and clinical professor at Wayne State University School of Medicine, has suggested a possible connection between CFS and continuing or reactivated cardiac infection by EBV or cytomegalovirus.²⁰ Dr. Lerner presented data to back up his theory at an international medical meeting in October 2000. He reported that in two small studies, 95 percent of CFS patients tested by holter monitoring had subnormal electrocardiograms indicating heart damage.²¹ It is important to keep in mind that these studies involved a small number of patients and have not been peer reviewed or published in mainstream medical literature. In addition, the cardiac abnormalities are described as mild and showed up in a high percentage of controls.

Mycoplasmas
In addition to viruses, other microorganisms such as mycoplasmas have been studied as possible causal agents for CFS. Mycoplasma are primitive forms of bacteria that have been identified in the blood of some CFS patients and veterans with Gulf War Illnesses, which present with many of the same symptoms.

A few laboratories claim that they find a high rate of mycoplasmal blood infections in CFS, fibromyalgia and Gulf War illness patients,²² but those findings have not been published in scientific literature. Mycoplasmas are difficult to detect in patients' blood, requiring very sensitive tests and careful handling of samples, making research difficult.

Role of viral testing in diagnosis
Because research has documented no clear association between a virus and CFS, testing patients for viral infection has limited use unless clinical signs indicate that an active viral infection may be present and requiring treatment. The results are also difficult to interpret, because the immune system in CFS may be up-regulated and latent viruses may not be fully suppressed.

Tests to determine elevated antibody titers for EBV and other viruses are not considered diagnostic for CFS by most physicians, and are usually performed only when a specific viral infection is suspected as a cause of the patient's symptoms. Commercial tests for XMRV and MLV's have not been validated or approved by FDA.

Articles with more Information

• XMRV Resource Page
• MLV Resource Page
• "CFS and the Viral Connection" webinar by Anthony L. Komaroff, MD
• Cardiac Involvement in CFS Studied
• HHV-6 

References

1. Gow JW and Behan PO. Viruses and chronic fatigue syndrome. J CFS. 1996; 2: 67-83.
2. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Lombardi VC, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Science 8 October 2009. 1179052.
3. Komaroff AL. The biology of chronic fatigue syndrome. Am J Med. 2000; 108: 169-71.
4. Straus SE at al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med. 1985; 102: 7-16.
5. Hotchin NA et al. Active Epstein-Barr virus infection in postviral fatigue syndrome. J Infect. 1989; 18: 143-50.
6. Bell DS. Chronic fatigue syndrome update: findings now point to CNS involvement. Postgrad Med. 1994; 96: 73-81.
7. Levine PH and Komaroff AL. Human herpesvirus type 6 and chronic fatigue syndrome. Arch Intern Med. 1993; 153: 661.
8. Deluca J et al. HHV-6 and HHV-7 in CFS. J Clin Microbiol. 1995; 33: 1660-61.
9. Ablashi DV et al. Frequent HHV-6 reactivation in multiple sclerosis and chronic fatigue syndrome patients. J Clin Virol. 2000; 16: 179-91.
10. Reeves et al. Human herpesviruses 6 and 7 in chronic fatigue syndrome: a case-control study. Clin Infect Dis. 2000; 31: 48-52.
11. De Freitas E et al. Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci USA. 1991; 88: 2922-26.
12. Martin WJ et al. Cytomegalovirus-related sequence in an atypical cytopathic virus repeatedly isolated from a patient with chronic fatigue syndrome. American J Pathol. 1994; 145: 440-51.
13. Kahn AS et al. Assessment of a retrovirus sequence and other possible risk factors for the chronic fatigue syndrome in adults. Ann Intern Med. 1993; 118: 241-45.
14. Heineine W et al. Lack of evidence for infection with known human and animal retroviruses in patients with chronic fatigue syndrome. Clin Infect Dis. 1994; 18: 121-25.
15. Honda M et al. Japanese patients with chronic fatigue syndrome are negative for known retrovirus infections. Microb Immunol. 1993; 37: 779-84.
16. Lo S-C, Pripuzova N, Li B, Komaroff AL, Hung G-C, Wang R, Alter H. (2010) Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proceedings of the National Academy of Sciences. 10.1073/pnas.1006901107
17. Gow JW et al. Studies on enterovirus in patients with chronic fatigue syndrome. Clin Infect Dis. 1994; 18: S126-29.
18. Swanink CMA et al. Enteroviruses and the chronic fatigue syndrome. Clin Infect Dis. 1994; 19: 860-64.
19. Chia JK, Chia AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. Journal of Clinical Pathology. 2008; Jan;61(1):43-8.
20. Lerner M et al. A unified theory of the cause of chronic fatigue syndrome. Infect Dis Clin Pract. 1997; 6: 239-43.
21. Presentation by Dr. Martin Lerner at American Society for Microbiology conference, Toronto, Canada, September 18, 2000.
22. Nicolson G. The role of microorganism infections in chronic illness: support for antibiotic regimens. The CFIDS Chronicle. September/October 1999; 19-21.

Page updated January 3, 2011