Link Between Chronic Fatigue Syndrome and Viruses Disproved

September 19, 2012 — Xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV) are not linked to chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), according to an article published online September 18 in mBio. The new study confirms recent evidence that the associations, initially reported in 2009 (for XMRV) and in 2010 (for pMLV), were erroneous and a result of laboratory contamination.

The idea that viruses are causal agents in CFS/ME gained popularity because many patients report symptoms of viral infection shortly before the onset of profound fatigue, and a viral cause would provide a treatable target. Hypothesized pathogens have included enteroviruses, Epstein-Barr virus, Borna disease virus, human herpesvirus 6, Borrelia burgdorferi, Candida albicans, Coxiella burnetii, Mycoplasma pneumoniae, and retroviruses.

After the putative retroviral link emerged in 2009, some physicians and clinics began prescribing antiretroviral drugs off-label. However, several groups of investigators could not replicate the findings linking the 2 retroviruses to CFS/ME. In 2011, genome sequencing of XMRV revealed that it was an artifact created accidentally when 2 proviruses recombined in mice.

In the current investigation, Harvey J. Alter, MD, chief of the Infectious Disease Section at the Clinical Center of the National Institutes of Health, and colleagues further challenge the retroviral link by expanding the sample size and taking strict measures to avoid contamination.

Some of the researchers from the current study were involved in the earlier studies that reported the association with the retroviruses.

Dr. Alter and colleagues analyzed blinded blood samples from 147 patients with CFS/ME and 146 highly matched healthy control participants. Patients came from 6 clinical centers. Mean age when CFS/ME began was 35.5 ± 10.1 years, and mean duration of illness was 15.9 ± 8.5 years.

The patients did not have neural or psychiatric comorbidities, had symptoms of viral infection before CFS/ME began, were between the ages of 18 and 70 years, and were not pregnant, lactating, or in the postpartum period. Control patients were matched for age (within 5 years), sex, race/ethnicity, season during blood sampling, and geographic location. The investigators ruled out infectious, metabolic, or endocrine causes of fatigue.

Genetic, culture, and serological tests were used on the blood samples to detect the retroviruses. Positive and negative controls ensured the accuracy of the detection protocols.

The researchers identified antibodies against either retrovirus in 9 (6.1%) of the 147 patients and 9 (6.1%) of the 146 control patients. The protocols detected no genetic material from either virus. The antibodies in the 18 patients could have been the result of nonspecific binding, according to the investigators.

"Our results definitively indicate that there is no relationship between CFS/ME and infection with either XMRV or pMLV," the investigators conclude. They caution that sensitive genetic detection methods may amplify contaminants, necessitating "an expensive and complex pathogen dediscovery process.... It is imperative, therefore, to establish standardized strategies for rigorously testing the validity of molecular discoveries."

"The paper is a definitive and final refutation of the idea that XMRV and pMLV are causative agents for CFS, although it had been pretty clear for many months now that XMRV was not linked to this syndrome," John Moore, PhD, professor of microbiology and immunology at Weill Cornell Medical College in New York City, told Medscape Medical News.

This study was funded by National Institutes of Health. The authors and the commentator have disclosed no relevant financial relationships.

mBio. Published online September 18, 2012. Full text