Situacion actual de la investigacion del XMRV (Medscape)

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From Medscape Medical News
[t]Controversy Continues on Whether XMRV Retrovirus Contributes to Chronic Fatigue Syndrome[/t]
Kathleen Louden

June 17, 2010 — Concern that a new human gamma-retrovirus may be transmissible through blood has led one infectious diseases specialist to recommend new steps to protect the US blood supply against possible infection with the virus.

The transfusion medicine organization AABB has formed a task force to study the transmission potential of xenotropic murine leukemia virus–related virus (XMRV), which has been linked to familial prostate cancer and, more recently, to chronic fatigue syndrome (CFS).

"I think the task force is very close to a recommendation that we provide donors with information about CFS and XMRV and ask CFS-affected donors to defer themselves," said Louis Katz, MD, executive vice president of medical affairs for Mississippi Valley Regional Blood Center in Davenport, Iowa, and a member of the task force.

Speaking at an American Society for Clinical Pathology teleconference June 11, Dr. Katz said he spoke for himself, and not on behalf of the AABB or its task force.

Transmission Risk Unclear

Concerns about the potential for XMRV to be passed through blood arose after publication in the October 23, 2009, issue of Science of an article by Lombardi et al (Science 2009;326:585-589). That study found XMRV in peripheral blood mononuclear cells from 67% of 101 patients with CFS compared with 3.7% of 218 healthy controls. The authors reported that they could secondarily transmit the virus from the blood cells and plasma of infected patients with CFS, raising the possibility of blood-borne transmission.

The new virus is a retrovirus similar to HIV, but with apparent differences, including fewer cycles of virus replication. However, no transmission event of XMRV through blood transfusion or transplantation has been identified, according to a February 18 fact sheet from the Centers for Disease Control and Prevention, Atlanta, Georgia.

Furthermore, several subsequent studies from Europe, which reportedly attempted to replicate the findings of Lombardi and coworkers, failed to find XMRV in patients with CFS (including a UK study published in the January issue of PLoS Pathogens). Finally, although XMRV was initially discovered in tumor tissue of a subset of patients with prostate cancer (according to results published in March 2006 in PLoS Pathogens), other studies have had varied results in finding the virus in prostate tumors.

The mixed results leave the significance of XMRV unclear, experts say. Retrovirologist John Coffin, PhD, a research professor at Tufts University in Boston, Massachusetts, told Medscape Infectious Diseases, "The take-home message is we don't know yet whether there is a causal role of XMRV for any human disease."

Dr. Katz agreed, but said, "Doing nothing while we sort out the science is not going to be an option."

His blood center, Dr. Katz told Medscape Infectious Diseases, is developing a policy to give informational materials to all prospective donors at registration that asks them to not donate blood if they have or ever had a diagnosis of CFS. He said the center will retain the donors' contact information in the event that the possibility of XMRV transmission through blood is ruled out.

Given that many symptomatic individuals with CFS are very ill and unlikely to donate blood, Dr. Katz said, "I think the impact on the donor base will be quite small."

The Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) Association of America, based in Charlotte, North Carolina, has long recommended that individuals with CFS voluntarily not donate blood or organs. Reasons include affected individuals' frequent low blood volume, orthostatic intolerance, and rate of infections. Three countries currently ask people with CFS to not donate blood: Canada, Australia, and New Zealand.

Lucinda Bateman, MD, a CFS specialist in Salt Lake City, Utah, said she would discourage her patients with the syndrome from donating blood, and not just because of their illness. "Why donate blood when there's a question whether XMRV is a problem?" she commented to Medscape Infectious Diseases.

Research Tries to Validate XMRV–CFS Link

Dr. Bateman's research team is among a number of groups conducting studies to look for XMRV in samples of patients with CFS, but they do not yet have results.

"Retrovirologists are feverishly working on this," she said.

Dr. Bateman is not surprised that various research groups in Europe have been unable to find XMRV in blood samples from people with CFS. The difficulties in obtaining consistent results are numerous, she said. They include differences in patient populations and testing methods used between laboratories, as well as the small quantities of virus found in blood cells of infected patients so far, which make it difficult to measure. For that reason, researchers are not sure whether to measure the virus in blood cells or tissues, according to Dr. Coffin.

Even the diagnosis of CFS is not standardized. The 1994 Centers for Disease Control and Prevention case definition of CFS (called the Fukuda criteria) is nonspecific and may capture in the diagnosis some non-CFS conditions such as fibromyalgia, Dr. Bateman said.

"The biggest stumbling block is we don't have a good [diagnostic] assay for XMRV," she said. "I'm telling my patients the test isn't ready."

Detection Tests Need Standardization

Although several XMRV assays have been developed, "at present, there is no standardized, validated assay for the virus," said Simone Glynn, MD, director of the Blood Resources Program of the National Heart, Lung and Blood Institute (NHLBI) and cochair of an NHLBI scientific research working group formed to evaluate whether XMRV poses a threat to blood safety.

The NHLBI is leading a study that compares the sensitivity and specificity of the available tests for the virus, a first step in standardizing the assays. Results of the NHLBI Retrovirus Epidemiology Donor Study–II are expected within the next few weeks, Dr. Glynn told Medscape Infectious Diseases.

Once an assay is standardized, researchers can use it "to mount proper epidemiological studies in very large groups of patients," Dr. Coffin said.

Among the XMRV assays that have been developed is one by the Whittemore Peterson Institute for Neuro-Immune Disease in Reno, Nevada. Researchers at the institute coauthored the Science article last fall, along with scientists at the National Cancer Institute in Bethesda, Maryland, and Ohio's Cleveland Clinic. The institute's assay is expected to be commercially available by the end of June, according to a statement from Reno-based Viral Immune Pathways Diagnostic, the lab that has a nonexclusive license to administer the test in the United States.

Although benefits to patients of XMRV testing are unclear to some researchers at this time, Annette Whittemore, president and founder of the Whittemore Peterson Institute, told Medscape Infectious Diseases that there are many reasons to continue to test for the virus. One is that retroviruses cause lifelong infection. Also, she said, more detailed testing has found that 99% of the original patient samples are positive for XMRV — far above the 67% the researchers reported.

"No other single pathogen has been found associated with this disease at this rate," she said.

Testing for XMRV also will allow researchers to study whether they can connect CFS symptoms to XMRV infection and to test for other disease associations, Whittemore said.

Countering the Criticism

The lack of a standardized test has not kept research teams from trying to find XMRV in their own patients with CFS. However, the studies published this year that failed to do so did not use all 4 of the virus detection methods used by Lombardi and colleagues, so Dr. Coffin said it is not clear that they are "true" replication studies.

He also dispelled the criticism of some researchers that the blood samples in the Science-published study could have been contaminated, pointing to the authors' comment that the patients had an immune response to XMRV. "The presence of antibodies is an important confirmation that patients were infected and that contamination was not an issue," he said.

Some researchers also wrote that the patient population from which Lombardi and colleagues obtained blood samples was not representative of typical patients with CFS, partly because all the patients had severe disability, and some had immunologic perturbations. Others objected on the basis of a statement in the online supporting materials: "Samples were selected from several regions of the United States where outbreaks of CFS had been documented."

Although some construed this to mean the patients were from clusters of CFS, such as occurred in Incline Village, Nevada, in the 1980s, Whittemore said that was not the case."Only 25 of the 101 patients became ill around the same time and location. Seventy-five percent of the other patients did not become ill in an identified cluster," she said on behalf of the institute's researchers, who were unavailable for comment.

To encourage replication studies, the institute has sent reagents and patient samples to independent research groups around the world, she said.

Unanswered Questions

Still, even if other institutions find an association between XMRV and CFS, it does not prove that the virus causes CFS or that it is the only cause, Dr. Coffin said.

Whittemore said their researchers do not believe that XMRV is the sole cause of what she calls ME (myalgic encephalomyelitis)/CFS. "It may, however, be the underlying cause of ME/CFS and other neuroimmune diseases," she said.

In the meantime, the millions of patients with CFS and the physicians who treat them must wait for answers. However, some patients with CFS reportedly are using antiretroviral drugs intended to treat HIV infection, according to a June 8 article in the Chicago Tribune.

"I think it's premature to put patients with CFS on antiretroviral drugs, which are quite toxic," Dr. Bateman said. "There are so many unanswered questions."

Dr. Katz, Dr. Coffin, Dr. Bateman, and Dr. Glynn have disclosed no relevant financial relationships. Whittemore disclosed that the Whittemore Peterson Institute will acquire Viral Immune Pathways Diagnostic and will earn royalties on each XMRV test conducted; she and her family put their financial interest in Viral Immune Pathways Diagnostic into a trust to benefit the institute.