'Final Nail' for XMRV in Chronic Fatigue Syndrome?

Emma Hitt, PhD

July 01, 2011

July 1, 2011 — Results outlined in a new commentary challenge the findings of a 2009 study suggesting that xenotropic murine leukemia virus (MLV)–related virus (XMRV) is associated with chronic fatigue syndrome (CFS). In fact, XMRV may not be a genuine human pathogen, and its presence in that study may have resulted from contamination of laboratory reagents, the commentary authors conclude.

The article by Vincent C. Lombardi, PhD, with the Whittemore Peterson Institute, in Reno, Nevada, and colleagues, in the October 23, 2009, issue of Science, described the presence of XMRV, a gammaretrovirus, in the white blood cells in 67% of patients with CFS vs only 3.7% of healthy controls.

But in a new commentary published online first June 21 in The Lancet, Dr. Frank J. M. van Kuppeveld and Professor Jos W. M. van der Meer, with the Radboud University Nijmegen Medical Centre in the Netherlands, review 3 new independent studies that have questioned the validity of these findings.

"In these studies, no XMRV was detected in patients with CFS and healthy controls," the editorialists write, and these "three new publications seem to provide the final nail in the coffin of the XMRV-CFS story."

Dr. van Kuppeveld and Dr. van der Meer add, "We have to conclude that the world has witnessed another false claim that gave new hope to patients with CFS, who are desperately seeking a cause for their suffering."

Nails in the Coffin

The first nail was an article by Clifford Shin and colleagues at the University of Utah in Salt Lake City, published online May 4 and appearing in the current July issue of the Journal of Virology. These researchers concluded that their findings "do not support an association between CFS and MLV-related viruses, including XMRV, and the off-label use of antiretrovirals for the treatment of CFS does not seem justified at present."

The other 2 article were both published online in Science — one by Konstance Knox, from the Wisconsin Virus Research Group in Milwaukee, and colleagues and the other by Tobias Paprotka, from the Viral Mutation Section of the National Cancer Institute's HIV Drug Resistance Program in Frederick, Maryland, and colleagues. Both studies found no link to XMRV, and the authors of both reports speculated that the previous association likely resulted from laboratory contamination. The study by Knox and colleagues actually included patients who were examined in the original study by Lombardi and colleagues.

The negative outcome of the Knox study was one reason that Science subsequently asked for a retraction of the article by Lombardi and colleagues. However, lead investigator of that paper, Judy A. Mikovits, PhD, director of research at the University of Nevada's Whittemore Peterson Institute for Neuro-Immune Disease in Reno, has refused.

Science editor-in-chief Bruce Alberts, PhD, went so far as to publish an Editorial Expression of Concern about those findings online May 31, along with the articles by Knox and Paprotka and colleagues. Since that first publication, Dr. Alberts writes, "at least 10 studies conducted by other investigators and published elsewhere have reported a failure to detect XMRV in independent populations of CFS patients."

He added that the study by Lombardi and colleagues "attracted considerable attention, and its publication in Science has had a far-reaching impact on the community of CFS patients and beyond.

"The US National Institutes of Health is sponsoring additional carefully designed studies to ascertain whether the association between XMRV and CFS can be confirmed," Dr. Alberts concluded. "Science eagerly awaits the outcome of these further studies and will take appropriate action when their results are known."

Responding to the Science papers and editorial, Dr. Mikovits contended that Knox and colleagues failed to replicate data from the study by Lombardi and colleagues because the researchers used different, less sensitive methods.

She told Medscape Medical News at that time, "There are no data in Knox et al to support the authors' conclusions or those expressed in the Editorial Expression of Concern. In fact, a close look at Western blots shows seropositive patients. They did not use our assays for infectious virus."

The 4 'P's'

According to Dr. van der Meer, the current thinking of the etiology of CFS can be described by the 4 "P's."

Patients have predisposing factors, which are to some extent genetic. There may also be precipitating factors, such as an infection and such as mononucleosis, as well as perpetuating factors, which probably are located in the brain, although it remains unclear which neurotransmitters are involved. Psychological factors also play a role, and this explains the success of cognitive behavioral therapy for CFS, he told Medscape Medical News.

"We do not have any effective drug for CFS," said Dr. van der Meer. "Essential in the approach of the patient is empathy and the avoidance of quarrel about the illness," he said. "We should acknowledge that we do not understand the full picture and we are open to new developments."

Jay Levy, MD, with the University of California, San Francisco, senior investigator on the article by Knox and colleagues that found no association, noted that although there are many theories about the etiology of CFS, the one that he prefers is a "disorder of the immune system in response to an infectious agent, an allergen, or some pollutant.

"The immune system gets activated but does not quiet down as normally occurs," Dr. Levy told Medscape Medical News. "Patients with CFS should recognize that they have a definite illness and that more research and attention must be given to this syndrome so that a solution can be obtained," he said.

The editorialists have disclosed no relevant financial relationships.

Lancet. Published online June 20, 2011. Abstract

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