New Data Spark Retraction Request for Chronic Fatigue Virus Study

You cannot un-ring a bell, but you can retract a scientific study. Then again, as a raging debate over a Science paper that linked a mouse retrovirus to chronic fatigue syndrome (CFS) makes clear, retractions can be a tall order, too.

In conjunction with their decision to publish two additional papers that strongly question the link between the virus, known as XMRV, and CFS, editors at Science last week privately requested the retraction of the study that 2 years ago first made this connection. Replying on behalf of the original paper's authors, Judy Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease in Reno, Nevada, yesterday declined the request in a letter to Science, calling the action "premature." Today, after The Wall Street Journal published leaked details of the exchange, Science released online the two new papers along with an Editorial Expression of Concern about the 2009 paper written by Editor-in-Chief Bruce Alberts.

On 26 May, Alberts and Executive Editor Monica Bradford wrote Mikovits and noted they were "extremely concerned" about the validity of the original paper given "the growing number of research papers from independent investigators who have either failed to replicate your original finding that XMRV is associated with chronic fatigue syndrome and/or who have provided evidence that laboratory reagents are widely contaminated with the virus." They asked Mikovits and her co-authors to voluntarily retract their paper, known as Lombardi et al., writing that "it would be in the best interest of the scientific community." CFS patients, who have no treatment for their baffling condition, have paid intense attention to the XMRV findings with some already taking antiretroviral drugs marketed to combat HIV.

Mikovits, who supplied the Science letter and her subsequent responses to ScienceNOW, says the retraction request "came out of nowhere" late on Thursday afternoon before a holiday weekend and did not include the new papers Science planned to publish. "We were all just pretty well stunned," she says, noting that all but one of the co-authors of the original paper joined a conference call Friday morning and agreed not to retract. In her 30 May letter to Alberts and Bradford, Mikovits wrote that she and her co-authors shared the "deep concern" over the number of studies that have not been able to replicate their findings. But she warned that publishing the expression of concern would have a "disastrous impact on the future of this field of science" and maintained that their original report that found evidence of the virus in 67% of CFS patients and only 3.7% of controls was accurate.

The two new papers published online by Science today both point to contamination as the most likely explanation for the results from Mikovits's 2009 paper and from one other high-profile report that found a link between CFS and XMRV-related mouse retroviruses. One study, led John Coffin of Tufts University in Boston and Vinay Pathak of the U.S National Cancer Institute in Frederick, Maryland, describes how laboratories in the 1990s accidentally created XMRV while working with mice and a human prostate tumor to make an immortalized cell line to study prostate cancer. The first reports of XMRV came in 2006 from labs studying prostate cancer. The links to that disease are now in question, too. (ScienceNOW reported on Pathak's presentation of his origin findings at a meeting in March.)

Retrovirologist Jay Levy of the University of California, San Francisco, headed the group behind the second paper released today, which failed to find XMRV in 61 patients who had confirmed diagnoses of CFS. Although other studies have not found XMRV in CFS patients, this one included 43 people who were notified earlier by Mikovits's group that they were infected with the virus. The researchers further showed that mouse retroviruses routinely contaminate many commonly used lab reagents. "The net is really closing around" the 2009 paper, says Jos van der Meer of Radboud University in the Netherlands, who pointed out several shortcomings in the study in a 2010 comment in Science and whose own study of 32 Dutch CFS patients failed to find any trace of XMRV.

Mikovits says neither of the new studies undermines her group's original report. Anyone who reads the new papers, she asserts, will conclude that they "have nothing to do with Lombardi et al." The origin study only speaks to labs that have used a specific prostate cancer cell line or its derivatives, she contends. As her letter to Alberts and Bradford explains in detail, the human cell lines in her group's lab repeatedly tested negative for XMRV, and they have no mouse lines. As for the Levy study, Mikovits insists that her team carefully controlled for contamination of reagents. She also claims the work fails to faithfully replicate their methods. "They didn't do one thing we did," she says. Levy disagrees, saying, "We did it exactly the way they did it."

Jonathan Stoye, a retrovirologist at the MRC National Institute for Medical Research in London who co-authored a perspective in Science supportive of the original work when it first appeared, now believes that contamination explains those results. He says Mikovits and her team have offered "an endless succession" of criticisms about the way other labs have conducted studies. "This isn't a conspiracy against them: Tens of labs have tried to reproduce their findings without success," Stoye says. "There are some very smart people in this, and they would not have got this wrong. It's an insult to us all. My lab will not do any more XMRV research."

Stoye may be abandoning the topic, but two multilab studies organized by the U.S. National Institutes of Health are now evaluating blinded blood samples from CFS patients and controls to determine whether XMRV indeed has links to the disease. Mikovits's team is participating, and results are expected by the end of the year. "Science eagerly awaits the outcome of these further studies and will take appropriate action when their results are known," concludes Alberts's expression of concern.

Thanks. I haven't yet but I will read your link after posting this.

The post I made initially was a paraphrase of a comment made by another doctor at a recent journal group discussion on the difficulty in dealing with patients whose presentation treads a thin line between organic and psychologic. That comment, BTW, elicited in that context, laughter. It implied rather preposterously a return to the old days where chronic fatigue and fybromyalgia were clear cut cases of somatasizing.

Although things have changed considerably (as you point out) some things remain the same:

Most patients with either of these complaints go to their family doctor first. Then if they are persistent they make the rounds to specialists and eventually to mental health; Usually they are found to have psychopathology.

Immunology opens another insight, as you say, including Psychoimmunology and other brain-body interactions.

Did Descartes have it pegged: "Cogito ergo suum," or what?

“Most patients with either of these complaints go to their family doctor first. Then if they are persistent they make the rounds to specialists and eventually to mental health; Usually they are found to have psychopathology.”

Your medical opinion is no laughing matter to people with ME/CFS, as opposed to general complaints of fatigue.

People with ME/CFS, diagnosed under the either the flawed Fukuda criteria or the much better Canadian Consensus Criteria (CCC) absolutely do not have psychopathology other than as secondary to ME/CFS IMO and my personal experience. The CCC is increasingly being used for ME/CFS research including XMRV research.

Here is the link to the Canadian Consensus Criteria:

http://www.cfids-cab.org/MESA/ccpccd.pdf

INTRODUCTION

“Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe systemic, acquired illness that can be debilitating. It manifests symptoms predominantly based on neurological, immunological and endocrinological dysfunction. While the pathogenesis is suggested to
be multi-factorial, the hypothesis of initiation by a viral infection has been prominent. A wide range of viruses and other infectious agents, such as Epstein-Barr Virus (1,2,3,4,5), Human Herpesvirus-6 and 7 (6,7,8,9,10), Entrovirus (11,12), Cytomegalovirus (13,14,15), Lentivirus
(16), Chlamydia (17), and Mycoplasma (18,19), have been investigated but findings are mixed and there is no conclusive support for any one pathogen. As antibody titers in standard laboratory tests usually employ a whole viral preparation or a single viral polypeptide, an incomplete or
mutated pathogen replication could go undetected. It is unclear whether the pathogens play a direct causal role, accompany an underlying infection, trigger reactivation/replication of latent pathogens, represent reactivated latent pathogens, activate a neural response or modulate the immune system to induce ME/CFS (20). Possibly a new microbe will be identified. Viral involvement is supported by an infectious initiating trigger in at least half of the patients (21), and by confirmed findings of
biochemical dysregulation of the 2-5A synthetase/ribonuclease L (RNase L) antiviral defense pathway in monocytes (22,23,24,25,26), a pathway
which is activated in viral disorders (27).”

In my own case I have severe “post-exertional malaise” (PEM) and “chronic orthostatic intolerance” (COI) as my two most debilitating symptoms. PEM is one of the CCC diagnostic criteria and COI is associated with ME/CFS.

PEM is a cytokine inflammatory response unique to ME/CFS which occurs a day or two after a physical exertion.

See the “Light Study”

http://www.ncbi.nlm.nih.gov/pubmed/20230500

Abstract

“Chronic fatigue syndrome (CFS) patients often report symptom flare (SF) for >24 h after moderate exercise (post-ex). We hypothesized that SF is linked to increases in circulating cytokines and CD40 Ligand (CD40L). In 19 CFS patients and 17 controls, mental and physical fatigue and pain symptom ratings were obtained together with serum for 11 cytokines and CD40L before and at 0.5, 8, 24, and 48 h post-ex. Before exercise, CFS had lower CD40L (p<.05) but similar cytokines versus controls. In subgroups based on SF at 48 h, high SF patients (n=11) increased in IL-1beta, IL-12, IL-6, IL-8, IL-10, and IL-13 (p<.05) 8 h post-ex. Low SF patients (n=8) showed post-ex decreases in IL-10, IL-13, and CD40L, and controls decreased in IL-10, CD40L, and TNFalpha (p<.05). Thus, in CFS, cytokine activity may vary directly with SF, which may explain prior inconsistent findings.”

My Chronic Orthostatic Intolerance (COI) has become progressively worse and matches the autonomic dysregulation described at this link except that my variant during HUTT (tilt-table testing) results in orthostatic hypertension (increased blood pressure) followed by neurocardiogenic feinting as opposed to POTS which involves orthstatic hypotension followed by feinting:

http://www.nymc.edu/fhp/centers/syncope/chronic_orthostatic_intolerance.htm

“Indeed, the only effective treatment for CFS in adults and children seems to target orthostatic intolerance. The cardiovascular form taken by OI in these syndromes is distinct in producing low blood pressure without overt fainting but with severe, often disabling postural symptoms associated with tachycardia. Data suggest a post-inflammatory mechanism involving abnormality in venous blood flow returning to the heart and resulting in a hypovolemic state (low blood volume) not unlike hemorrhage.”

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