Chronic Fatigue Syndrome (CFS) & Xenotropic Murine Leukaemia Related Virus (XMRV)
The New York Times (7/14, Tuller) reported, "Researchers at the National Institutes of Health and the Food and Drug Administration, citing a need to re-evaluate their data, have delayed publication of a new study believed to provide evidence of a link between chronic fatigue syndrome and" XMRV. The decision to not run the paper in the Proceedings of the National Academy of Sciences "has sparked an outcry on blogs and social networking sites among chronic fatigue patients, who...fear that important scientific data are being suppressed." But "federal officials said publication was delayed because the findings contradicted those of the Centers for Disease Control and Prevention," which "found no connection." Although that paper "was initially also held up for reassessment because of the discrepancies," it "was eventually published on July 1 in the journal Retrovirology."
Delay in Release of Study on Chronic Fatigue Syndrome Prompts an Outcry
http://www.nytimes.com/2010/07/14/health/14fatigue.html?ref=health
July 14, 2010
By DAVID TULLER
Researchers at the National Institutes of Health and the Food and Drug Administration, citing a need to re-evaluate their data, have delayed publication of a new study believed to provide evidence of a link between chronic fatigue syndrome and a little-known retrovirus.
The study, already peer-reviewed, was supposed to appear in the prestigious Proceedings of the National Academy of Sciences. The delay has sparked an outcry on blogs and social networking sites among chronic fatigue patients, who are desperate for answers about their debilitating illness and fear that important scientific data are being suppressed.
“A cabal of top government administrators” with a habit of “heavy-handed, anti-science manipulation of peer-reviewed science” ordered the delay, Hillary Johnson, author of a book about the history of chronic fatigue syndrome, alleged on her Web site, OslersWeb.
Federal officials said publication was delayed because the findings contradicted those of the Centers for Disease Control and Prevention, which conducted its own study on chronic fatigue and the retrovirus, known as XMRV. The C.D.C. study, which found no connection, was initially also held up for reassessment because of the discrepancies, but was eventually published on July 1 in the journal Retrovirology.
A spokeswoman for the National Institutes of Health declined to comment in detail, but provided a statement from Dr. Harvey Alter, an author of the still-unpublished study and an N.I.H. infectious-disease expert. He said, “My colleagues and I are conducting additional experiments to ensure that the data are accurate and complete,” adding, “Our goal is not speed, but scientific accuracy.”
Word of the findings from the N.I.H. study spread rapidly last month when a Dutch magazine quoted Dr. Alter as saying that his research team had found a high rate of XMRV infection among patients with chronic fatigue syndrome. Dr. Alter reportedly made the statements at a blood safety meeting in Zagreb, Croatia.
Dr. Randy Schekman, editor in chief of the Proceedings of the National Academy of Sciences, said last week that he expected the matter to be resolved within weeks, although he would not discuss specifics of the study or the journal’s review of it. The journal, he added, had been “inundated by e-mails from people with chronic fatigue syndrome begging us to release this paper.”
The debate over XMRV began last fall, when the journal Science published a study reporting that two-thirds of blood samples from 101 chronic fatigue patients showed evidence of infection with the retrovirus, compared with less than 4 percent of 218 healthy controls.
According to the C.D.C., at least one million Americans are believed to have chronic fatigue syndrome, marked by disordered sleep, cognitive problems, headaches, joint pain and profound exhaustion. The illness has no known cause and has frequently been dismissed by doctors, researchers and the general public as psychosomatic or psychiatric in nature.
Retroviruses, like H.I.V. and XMRV, store their genetic material as RNA but convert it to DNA to replicate within host cells. Since XMRV was first identified four years ago, several studies have linked it to prostate cancer, although other research has failed to find a link. Whether the retrovirus plays a causal role in this or any disease remains unknown.
The emerging research has caught the attention of the blood bank industry. Canada recently began barring people with chronic fatigue syndrome from donating blood because of concerns about possible XMRV transmission. The AABB, formerly known as the American Association of Blood Banks, issued a similar recommendation last month.
A confirmed link between chronic fatigue syndrome and XMRV could spur thousands of patients to demand treatment with antiretroviral medications. Although some drugs used to treat the human immunodeficiency virus have demonstrated XMRV-fighting properties in the lab, they have not been clinically tested for this use.
Nonetheless, Dr. Jamie Deckoff-Jones, a physician in Santa Fe, N.M., has been blogging to an eager audience about the improvements she and her daughter, both given a diagnosis of chronic fatigue syndrome, have experienced while following a regimen of H.I.V. medications.
“I’m taking antiretrovirals in an attempt to save my life,” she explained in an e-mail message. “I don’t have five years to wait around while the scientists and politicians try to figure it out.”
Since the report last year in Science, however, three other published studies, like the new C.D.C. paper, have raised doubts by failing to replicate the findings. The contradictory findings have been attributed to factors like how chronic fatigue cases have been selected and the difficulty in identifying XMRV infection because of a lack of standardized testing protocols.
The Science study was conducted by the Whittemore Peterson Institute for Neuro-Immune Disease, a research center at the University of Nevada, Reno, along with the National Cancer Instituteand the Cleveland Clinic. Annette Whittemore, founder and president of the institute, faulted C.D.C. researchers for historically focusing on stress and other psychological factors as major causes of chronic fatigue syndrome, rather than possible infection.
“They’ve been working on chronic fatigue syndrome since the mid-80s, and yet we still don’t have any answers from the C.D.C.,” said Ms. Whittemore, whose daughter has the illness.
Stephan Monroe, director of the C.D.C.’s division of high-consequence pathogens and pathology, said the agency believed that infectious agents could be one of many possible triggers for the disease but that no pathogen had yet emerged as a “primary cause.”
He said he was not surprised by the current uproar among patients. “This is a very well-informed and highly connected patient and advocacy population, and whenever there’s any new information, it’s circulated widely,” he said.
Groom H, Boucherit V, Makinson K, et al.
Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology;7(1):10.
BACKGROUND: Detection of a retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), has recently been reported in 67% of patients with chronic fatigue syndrome. We have studied a total of 170 samples from chronic fatigue syndrome patients from two UK cohorts and 395 controls for evidence of XMRV infection by looking either for the presence of viral nucleic acids using quantitative PCR (limit of detection <16 viral copies) or for the presence of serological responses using a virus neutralisation assay.
RESULTS: We have not identified XMRV DNA in any samples by PCR (0/299). Some serum samples showed XMRV neutralising activity (26/565) but only one of these positive sera came from a CFS patient. Most of the positive sera were also able to neutralise MLV particles pseudotyped with envelope proteins from other viruses, including vesicular stomatitis virus, indicating significant cross-reactivity in serological responses. Four positive samples were specific for XMRV.
CONCLUSIONS: No association between XMRV infection and CFS was observed in the samples tested, either by PCR or serological methodologies. The non-specific neutralisation observed in multiple serum samples suggests that it is unlikely that these responses were elicited by XMRV and highlights the danger of over-estimating XMRV frequency based on serological assays. In spite of this, we believe that the detection of neutralising activity that did not inhibit VSV-G pseudotyped MLV in at least four human serum samples indicates that XMRV infection may occur in the general population, although with currently uncertain outcomes.
Switzer W, Jia H, Hohn O, et al.
Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States. Retrovirology;7(1):57.
BACKGROUND: XMRV, a xenotropic murine leukemia virus (MuLV)-related virus, was recently identified by PCR testing in 67% of persons with chronic fatigue syndrome (CFS) and in 3.7% of healthy persons from the United States. To investigate the association of XMRV with CFS we tested blood specimens from 51 persons with CFS and 56 healthy persons from the US for evidence of XMRV infection by using serologic and molecular assays. Blinded PCR and serologic testing were performed at the US Centers for Disease Control and Prevention (CDC) and at two additional laboratories.
RESULTS: Archived blood specimens were tested from persons with CFS defined by the revised 1994 CDC case definition and matched healthy controls from Wichita, Kansas and metropolitan, urban, and rural Georgia populations. Serologic testing at CDC utilized a Western blot (WB) assay that showed excellent sensitivity to MuLV and XMRV polyclonal or monoclonal antibodies, and no reactivity on sera from 121 US blood donors or 26 HTLV-and HIV-infected sera. Plasma from 51 CFS cases and plasma from 53 controls were all WB negative. Additional blinded screening of the 51 cases and 53 controls at the Robert Koch Institute using an ELISA employing recombinant Gag and Env XMRV proteins identified weak seroreactivity in one CFS case and a healthy control, which was not confirmed by immunofluorescence. PCR testing at CDC employed a gag and a pol nested PCR assay with a detection threshold of 10 copies in 1 ug of human DNA. DNA specimens from 50 CFS patients and 56 controls and 41 US blood donors were all PCR-negative. Blinded testing by a second nested gag PCR assay at the Blood Systems Research Institute was also negative for DNA specimens from the 50 CFS cases and 56 controls.
CONCLUSIONS: We did not find any evidence of infection with XMRV in our U.S. study population of CFS patients or healthy controls by using multiple molecular and serologic assays. These data do not support an association of XMRV with CFS.
