Highly Anticipated Study Is Second to Link Chronic Fatigue Syndrome and Retrovirus

Kathleen Louden

August 25, 2010

August 25, 2010 — The authors of a new study that found a strong association between chronic fatigue syndrome (CFS) and a group of mouse retroviruses closely related to XMRV, or xenotropic murine leukemia virus–related virus, offered possible explanations for the varying results among different research laboratories in Europe and the United States.

Published online August 23 in the Proceedings of the National Academy of Sciences, the study is the first to confirm the results of Lombardi and colleagues from last October (Science. 2009;326:585-589). That group reported finding XMRV in peripheral blood mononuclear cells from 67% of 101 patients with CFS compared with 3.7% of 218 healthy control patients. Four subsequent studies failed to find evidence of XMRV or related viruses in patients with CFS, including a study from the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, published online July 1 (Retrovirology. 2010;7:57).

The current study, conducted by researchers at the National Institutes of Health (NIH) and the US Food and Drug Administration (FDA), found a high rate of infection in CFS-affected patients with what the authors called murine leukemia virus (MLV)–related viruses; 86.5% of 37 patients with CFS had MLV-like virus gene sequences in their peripheral blood mononuclear cells vs 6.8% of 44 healthy blood donors, the researchers reported.

Although the scientists did not find XMRV in their patient samples, XMRV is a type of MLV, according to study coauthor Harvey Alter, MD, chief of clinical studies for the NIH Department of Transfusion Medicine.

Their data, Dr. Alter said August 23 during a media briefing held by the NIH in Bethesda, Maryland, "are highly confirmatory" of the findings of the Science study, led by researchers at the Whittemore Peterson Institute in Reno, Nevada, and 2 other institutions.

Results Contrast With Other Studies

"A dilemma is how to reconcile why some labs find this association and others do not," Dr. Alter said.

Differences in test methods do not appear to explain the disparities between the results from the new study and those of the recent CDC study, Dr. Alter said in an interview with Medscape Medical News.

"We tested some of their [blood] samples and also found them negative," he said.

In addition, an NIH institute "determined both laboratories had equivalent sensitivities in their assays," the lead author of the other study, CDC microbiologist William Switzer, MPH, told Medscape Medical News.

The best method of collecting and testing blood samples for this class of retroviruses is not yet established, according to Dr. Alter. The NIH will convene a panel of experts September 7 to 8 to discuss this issue and others related to XMRV at the 1st International Workshop on XMRV. Some researchers also have linked XMRV to prostate cancer.

Dr. Alter said the most likely reason for the discrepancy in results is patient selection. Diagnosis of CFS is based on a symptom complex, not a specific disease marker. All patients in the NIH-FDA study met the accepted diagnostic criteria for the syndrome, and most blood samples were from the patient population of a single coauthor, who is a CFS expert, he said.

"There may be a geographic difference," Dr. Alter told Medscape Medical News. "In the Northeast, CFS may be due to MLV, and in the West, it may be due to XMRV."

However, he cautioned against interpreting their results as proving causation of CFS. "We haven't answered that question yet," Dr. Alter said, adding that the cause could be multifactorial.

It is also possible that the high frequency of MLV-related infections in their cohort with CFS indicates "an increased susceptibility to viral infections" because of immune dysfunction, rather than a causal role, the authors speculated in their article.

The research team did prove that MLV infection persists. As a follow-up to using frozen blood samples obtained from patients with CFS nearly 15 years ago, the investigators obtained fresh blood samples from 8 of the 32 MLV-positive patients, and 7 again tested positive for the retrovirus. "It was the same virus, but it had mutated, as a retrovirus does," Dr. Alter said.

Virus sequences seen in their patient samples were polytropic, not xenotropic, and were more diverse than those reported by the Nevada group, according to Dr. Alter. This variability is characteristic of a retrovirus and boosted the authors' confidence that laboratory contamination was not responsible for their findings, he said during the media briefing.

Indeed, the researchers were "very thorough" in showing there was no mice contamination, said a coauthor of an accompanying commentary in the Proceedings, Andrew Mason, MBBS, associate professor of medicine at the University of Alberta in Canada. "Taken together [with the research by Lombardi et al], these are 2 important studies that should not be ignored," Dr. Mason told Medscape Medical News.

Publication Delayed

Dr. Alter said his team went to extra lengths to rule out the possibility of laboratory contamination, even asking the journal editor to delay publication of their article after it was accepted so they could do more testing. The lay media reported in July that this action drew criticism from the CFS community, who feared suppression of the findings.

The decision came from the US Department of Health and Human Services, Steve Monroe, PhD, of the CDC, told Medscape Medical News. Officials wanted to find out why results of the 2 federal studies differed.

"I appreciate the frustration of the advocate community, but our goal was to ensure we were providing the best and most accurate data. Sending out an incorrect message would be detrimental," said Dr. Monroe, director of the CDC Division of High-Consequence Pathogens and Pathology.

Switzer said he and his coauthors also temporarily held up publication of their paper but ended up changing nothing.

"We felt it was the very best science we could do," he said.

They were unable to test patients' blood samples from Dr. Alter's group, Switzer said, because those scientists did not have sufficient stored specimens left.

Although the 2 teams could not explain their conflicting results, Dr. Alter said he and his coworkers also feel confident about their data. "We were able to add information that, I think, made the paper much stronger," he said regarding their efforts to retest some patients and to address concerns about potential laboratory contamination.

Dr. Alter said, "I thought all along: It's more important to be right than to be fast."

Dr. Alter, Dr. Mason, Dr. Monroe, and Mr. Switzer have disclosed no relevant financial relationships.

Proc Natl Acad Sci USA. Published online August 23, 2010.

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