Monday, June 14, 2010


The Chronic Fatigue Syndrome XMRV controversy heats up with the second British XMRV study, the Dutch study and the unpublished CDC study 

This is Part 2 of an article on the newly discovered retrovirus XMRV in patients with Chronic Fatigue Syndrome (CFS).  Part 1 can be read here.

Last fall, a group of American researchers published a study in Science that offered hope to the 17 million Chronic Fatigue Syndrome (CFS) sufferers worldwide, most of whom are women.  Identifying what may turn out to be an important clue to the illness, the researchers found that 67 percent of 101 CFS patients were infected with the retrovirus XMRV.  More sophisticated testing later showed that 98 percent of patients were infected.

But in January, British XMRV researchers published a study that didn’t find the retrovirus in even one of 186 CFS patients.  Each XMRV camp blamed the other for flaws in methodology, and the exchanges between principal investigator Dr. Judy Mikovits of the U.S. cohort and Dr. Myra McClure of the British cohort quickly became testy.  Many patients were incensed that another of the British study authors, psychiatrist Simon Wessely, has been a 20-year proponent of the disease as a psychological malady.

British study #2
Just when the transatlantic bickering was beginning to abate, a second British CFS study published in Retrovirology on February 15th didn’t find any firm evidence of XMRV either, sending some patients into a tailspin.  Blogged one:  “If anyone can put a positive spin on this then please post now.  I sense defeat (in myself).  And another 13 yrs (to life) in the wilderness.”

From a group of 170 patients and 395 controls, these British researchers found that 26 exhibited antibodies to XMRV.  The surprise came when the scientists unblinded the study and discovered that 25 of the 26 were controls.  “I was quite shocked,” divulges principal investigator Dr. Kate Bishop, who expected that most of the 25 would be patients.  However, Bishop isn’t convinced that the antibodies were caused by XMRV.  That’s because the antibodies of all but three controls and one patient weren't specific for XMRV and neutralized other viruses as well as XMRV.

While the media has categorized the two British studies as replications, both McClure and Bishop acknowledge that they’re not. 

Bishop's group and the U.S. group have remained civil.  One reason beyond the obvious—that scientists don’t usually insult one another, at least publicly—may be that Mikovits and Dr. Jonathan Kerr—a Retrovirology author who has published papers linking CFS to genetic mutations—share a $1.6 million five-year NIH grant to decipher the cause of CFS.  While the media has categorized the two British studies as replications, both McClure and Bishop acknowledge that they’re not.  For her part, Bishop says one of the reasons her cohort didn’t adhere to the U.S. protocol is that she believes it’s tougher to get a paper published when the experiment is conducted in exactly the same way as the original study.

As for McClure, her study “was never designed to replicate [the U.S.] study or to say, ‘Look how clever we are, and they’re wrong,’ she says.  “It was simply an investigation to see if we in this country could detect this virus in our CFS patients that were homegrown here.”

Critics caution, however, that it’s essential to follow the identical protocol of the original study to validate or disprove it, and if the researchers don’t, they’re in essence comparing apples to oranges.  Interestingly, one of the authors of the second British study was an investigator on a study that failed to replicate the retroviral CFS research of Dr. Elaine DeFreitas at University of Pennsylvania’s Wistar Institute 20 years ago.   Back then, that scientist didn’t follow DeFreitas’s protocol either, and the media mislabeled the study a replication as well.  Given that back story, some patients and long-time researchers have categorized the current crop of British studies as déjà vu all over again.  Others call it a coda to And The Band Played On.

The negative findings in the British studies don’t faze Judy Mikovits, who says other studies due out in the next six months will confirm her study.  She believes that neither group of British researchers could confirm the U.S. findings because neither followed her protocol.

The Aha moment?
But perhaps there is another reason. A week after Bishop’s study came out, researchers at Emory University’s primate lab who injected XMRV into macaques reported that even when the virus was undetectable in the blood, it thrived in the reproductive organs as well as the spleen, gut, bladder, lung, liver and lymph nodes.  It’s possible the British studies couldn’t find XMRV in the blood because it’s not where the retrovirus likes to hang out. In addition, a German study published June 16 found XMRV in the respiratory tracts of 2 to 3 percent of 168 healthy controls and 10 percent of 161 patients with compromised immune systems, lending credence to the hypothesis that the retrovirus flourishes in areas other than the blood.

One government source says that the yet-unpublished XMRV study by the CDC didn't find the virus—though another government agency has.

More studies in the works
Retrovirologists at the University of Utah, Tufts, Stanford, Cornell and Columbia universities, and in Canada, Sweden, Russia, Spain, Australia and China are at work on XMRV studies.  The German researchers who found no association with XMRV and prostate cancer are now repeating their study using the methods of the U.S. cohort, which did.

The CDC also completed and is due to publish an XMRV study shortly.  One highly placed government source says that the CDC’s study didn’t find the virus—though, the source says, another unnamed government agency has.  In the fall, the CDC and NIH predicted it would take six months for the government to complete its studies, but there have been delays.  At the Chronic Fatigue Syndrome Advisory Committee meeting held at the CDC on May 10, Dr. Jerry Holmberg of the Department of Health and Human Services’s Office of Public Health and Safety apparently tipped his hand when he remarked that part of the holdup was determining the patient-notification policy on the positive XMRV patients from the 25 Whittemore-Peterson CFS samples.

Patients, meanwhile, have been fretting over the CDC’s XMRV study for months because of the agency’s longstanding position that CFS is largely a psychiatric problem.  More than a decade ago, the government agency began watering down the already trifling name of Chronic Fatigue Syndrome to “chronic fatigue,” “fatigue” and “unwellness,” largely due to the philosophy of its longstanding principal investigator, Dr. William Reeves. 

In recent months, the agency seems to be sending out mixed signals about its stance toward CFS.  On the one hand, Reeves was reassigned to a new CDC post in Mental Health Surveillance on February 14.  Some observers read this as a possible shift in the agency’s philosophy.

On the other hand, Dr. Steve Monroe, Reeves’s old boss and the agency’s director of the division of viral and rickettsial disease, where, oddly, most of the CFS psychological research has been carried out, applauds the British research.  “I respect the scientific credentials of the people who did the testing,” says Monroe, a careful speaker with a fondness for qualifiers.  He reasons that since the initial U.S. study found the virus in 67 percent and the first British study didn’t find it at all, “XMRV is not universally present in the majority of CFS patients.  Based on the U.K. results, it’s not universally true that XMRV is associated with the majority—more than half—of CFS patients.  Of course, there could be regional differences.” 

The tipping point
Everyone with a stake in Chronic Fatigue Syndrome has a point of view and something to prove, and it may take a year or more before science yields a verdict on XMRV’s place in the disease.  XMRV may turn out to be the tipping point that changes the game and the players in CFS.  Or it may turn out to be an inconsequential finding or collateral damage from a weakened immune system.  One argument against causality is that HIV and HTLV—the two other known human retroviruses—are transmitted solely through blood or sexual contact, which may be difficult to reconcile with the occurrence of several cluster outbreaks of CFS in the U.S. and England, including an outbreak among schoolchildren in Lyndonville, New York, in the 1980s.

Eminent Tufts University retrovirologist Dr. John Coffin, who’s working on an XMRV replication study, put the uncertainty into perspective at a retrovirology conference in February, reminding scientists of the confusion back in 1983 in the early days of HIV and affirming, “There’s no question that the virus is real and that the virus is infecting some number of people.”  An earthy, measured optimist, which makes him a big hit at conferences, Coffin remarked that it takes a long time to “grind the sausage” and come to a consensus about a big finding like XMRV, and that “although it’s annoying and confusing, it’s really very exciting at the same time.” 

Then again, a February 25 editorial in the British Medical Journal by Drs. Simon Wessely and Myra McClure categorized the research community as “underwhelmed” by the XMRV link to CFS.  The editorial accompanied a small Dutch study that didn’t find XMRV in any of its 32 patient blood samples frozen in 1991 and 1992.  Two of the study’s scientists are psychiatric CFS proponents and have co-authored more than 50 papers on the disease, including the 2008 “Guided self-instructions for people with Chronic Fatigue Syndrome,” which combined cognitive therapy with “email contact.”

Until the dust settles, the uncertainty and media frenzy over whom to believe is bound to continue, prompting Science’s Sam Kean to comment that the search for the cause of CFS, which “seemed to be gaining traction, now seems likely to descend into the same confusion and acrimony that characterized it for years, as a supposed viral link to CFS published just last autumn might be unraveling.”

Longtime patient Pat Fero, who tested positive for XMRV and whose son, Casey, came down with CFS at the age of 9, hopes it does not unravel.  She lived through the fallout from Dr. Elaine DeFreitas’s study 20 years ago and now hopes that the XMRV discovery leads to new treatments, “so that those young adults with CFS can look forward to a better life and experience a childhood they never had.”  Casey died in his sleep from the disease in 2005 at the age of 23.  His autopsy revealed viral myocarditisan infection of the heartand old scarring, but doctors never took his health complaints seriously.  “I’m hopeful,” she says wistfully, “that many sick children may soon wake up.”

This article, “Blood Feud,” Part 2 is copyright © CFS Central 2010.  All rights reserved.   You may quote up to two paragraphs from this article as long as you indicate in the body of your post (as opposed to a footnote or an endnote) that the excerpt is by from CFS Central.  

Coming up:  CFS patients do hard time in mental wards and foster care.


  1. "The editorial accompanied a small Dutch study that didn’t find XMRV in any of its 32 patient blood samples frozen in 1991 and 1992."

    Might be worth checking the diagnostic criteria used for that group of patients. IIRC, they ruled out patients who showed any clinical signs of infection. Hardly a good start to subsequently finding infectious agents, nearly 2 decades later.

  2. I knew I couldn't be the only one experiencing deja vu. The researchers who attempted to replicate De Freitas' retroviral findings didn't use the right media, used frozen blood samples, failed in every way to actually reproduce her methods---and then their shoddy work was used to call her years of careful study into question.

    The difference this time? The communication tools we patients have at our disposal, for one thing. Such an excellent blog should serve as notice to the scientific community that they are not hidden in ivory towers. Thanks for great research, organization and writing!

  3. Someone who hasn't done the background reading might still be left with the idea that "CFS" (myalgic encepthalomylitis) could be a psychological illness. This lecture by Anthony L. Komaroff, M.D. of the Harvard Medical School makes it abundantly clear that the illness is viral in origin:
    Unfortunately he mistakenly claims that people don't die from the illness - sadly there is a growing list of deaths, including a 39-year old woman in England who recently dropped dead at home; the pathologist was unable to find the cause of death (he clearly didn't know what to look for), and called it "sudden adult death syndrome".
    Clearly things need to change.

  4. Thank you all for your comments from the June 10 post and today’s. It's gratifying to read them and to know that this blog is helpful to the ME/CFS community.

    I'd like to respond to each comment, but, alas, this is a one-woman operation, and I'm at work on my next article.

    Please know that I read all the comments and suggestions for future articles.

    Mindy Kitei

  5. Hey Mindy,
    Great work, congratulations and keep on going!

  6. Agree strongly with Nicky's comment above - important to highlight - in your articles - that the debate (re psychological versus biological cause of ME/CFS) should be over - there is now overwhelming scientific evidence to support a viral illness (as highlighted in Anthony L. Komaroff, M.D.’s lecture). While we in the CFS/ME community know this - many others in the general community don’t. Thanks so much Mindy for your research and contribution!

  7. Thank you sincerely for your interest in and coverage of ME/CFS!
    It would be interesting to directly ask Dr Coffin if he believes that 'Science is outrunning hope' as has been reported widely in the media over recent days. Last quote that I am aware of from Coffin was February 2010. It would be wonderful to get something more recent considering the (now) 5 studies refuting the Science article.

  8. Excellent. Thank you for starting this blog. We do need this.

    I would add mention of the use of patently invalid definitions- Oxford and Reeves used by the charlatans to muddy the science. eg the patients studied in the dutch study were Oxford "CFS" ie NOT ME/CFIDS, but idiopathic chronic fatigue thus rendering the study totally invalid. and van der meer has the balls to attack WPI?

    Please do some treatment on the bogus defintions! If studies were put out on tired people and they purported to be about Leukemia or MS patients, the authors would be run out of medicine, not published in BMJ! This is how they say 'well they're depressed and the findings are not clear' so they can continue to persecute us. This is the emperor parading around with no clothes and very few or none in power calling him on it.

  9. Great work! Already "salivating" for more =).

    As for the series, I hope you can get it published in a major newspaper or news magazine. It is definitely written from a thoughtful and well-researched perspective.

    One thing you might want to mention is that the "acrimony" of the psychological vs. medical causation models was in many ways precipitated by Straus at the NIH in the late 80s and early 90s. Due to his position as "Senior Investigator" he held enormous political power, the power to deny funding for research, the power to publicly disparage the illness while being considered by the medical community at large as one of its foremost experts.

    He had at first published on the illness being "Chronic EBV" but once that concept was shown to be outdated Straus apparently decided if patients didn't have his biomedical model they wouldn't get to have any biomedical model at all.

    As I'm sure you know despite being the "designated researcher" on this subject in NIH he never went to any CFS Conferences and when he went to other medical conferences, he was always ready to disparage sufferers as "Mercedes driving nut-jobs" (my paraphrase.).

    Great Work!

  10. Love your cutting edge research and the connections you make. Wish you were a CFS scientist, because we need people who can connect things together like you do in the CFS historo-political world. Fascinating insights.

  11. I've read and come back and reread this post. It makes me feel gobsmacked! "For her part, Bishop says one of the reasons her cohort didn’t adhere to the U.S. protocol is that she believes it’s tougher to get a paper published when the experiment is conducted in exactly the same way as the original study."

    If researchers won't follow the scientific method because they can't get published we are in bigger trouble than I thought. And I have known for years we are in trouble.


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