Thursday, January 14, 2010

An Indefatigable Debate Over Chronic Fatigue Syndrome

thanks to Kim500 at the PhoenixRising forums for the full text of the article
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Science 15 January 2010:
Vol. 327. no. 5963, pp. 254 - 255
DOI: 10.1126/science.327.5963.254

News of the Week
Virology:

An Indefatigable Debate Over Chronic Fatigue Syndrome
Sam Kean

Here we go again. The search for the cause of chronic fatigue
syndrome, which just months ago 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.

Many patients with CFS—long-term fatigue and other ailments that have
no known biological cause—report that their symptoms began after an
acute viral infection, and scientists have tried many times, but never
successfully, to pin CFS to viruses such as Epstein-Barr. Patients
have faced skepticism for years over whether CFS is a "real" disease;
a viral trigger could vindicate them and explain their nebulous
symptoms.

That's why a paper published online 8 October 2009 in Science
(http://www.sciencemag.org/cgi/content/abstract/1179052) caused such a
stir. A U.S. team reported finding DNA traces of a virus, XMRV, in the
blood cells of two-thirds of 101 patients with CFS, compared with 4%
of 218 healthy controls. Strangely, XMRV, a rodent retrovirus, had
previously been implicated in an aggressive prostate cancer. No one
knows how XMRV might contribute to either or both diseases, but the
authors argued that the link made some sense: XMRV ravishes natural
killer blood cells, which attack both tumors and cells infected by
viruses.

Other scientists thought the link dubious, criticizing the team, led
by Vincent Lombardi and Judy Mikovits at the Whittemore Peterson
Institute for Neuro-Immune Disease in Reno, Nevada, for not explaining
enough about the demographics of their patients or the procedures to
prevent contamination (Science, 9 October 2009, p. 215). Several
virologists around the world practically sprinted to their labs to
redo the experiments, and the discovery that a clinic associated with
some people at Whittemore was selling, among other CFS services, a
$650 diagnostic test for XMRV made the issue more pressing. A U.K.
team already exploring the XMRV–prostate cancer link won the race,
submitting a paper to PLoS ONE challenging the claim on 1 December
2009. It was accepted for publication after 3 days of review.

The British team, led by retrovirologist Myra McClure of Imperial
College London, examined DNA from the blood of 186 CFS patients
ranging in age from 19 to 70, with an average age of 40. Most were
markedly unwell. McClure's team used a PCR machine—which copies and
amplifies scraps of DNA—to search for two viral sequences, one from
XMRV and the other from a closely related virus. They discovered
nothing. At a press conference discussing the results, published
online 6 January in PLoS ONE, McClure was blunt and confident: "If
there was one copy of the virus in those samples, we would have
detected it."

This null result prompts the question of what—if anything—was wrong
with the original paper. The PLoS ONE authors seem to suggest that
contamination was at fault, stating that they were careful to work in
labs that had never handled XMRV and use PCR machines that analyze no
mouse tissues. But McClure says her group merely wanted to make that
explicit, not accuse anyone.

The U.S. team followed the same procedures, retorts Lombardi, a
biochemist. He also expressed bewilderment that the McClure group
didn't search its CFS samples for the same DNA sequence as his team
had, raising the possibility that they had different results because
they searched for different things. The McClure team, however, looked
for not only an XMRV sequence but also a sequence in a closely related
virus, MLV. That MLV sequence, highly conserved among viruses of its
class, would presumably have been found if XMRV was present, they
said.

One distinct possibility, says John Coffin, a microbiologist at Tufts
University in Boston who studies retroviruses and wrote a separate
analysis for Science when the original paper was published
(http://www.sciencemag.org/cgi/content/short/1181349), is that both
papers are right. He called the PLoS ONE paper too "preliminary" to
settle the debate and said XMRV could show more genetic variety, and
thus be harder to detect, than anyone assumed. It's also possible that
distinct strains of XMRV appear in different parts of the world, as do
the retroviruses HIV and HTLV (a leukemia virus). Intriguingly,
although research teams in the United States have linked XMRV to
prostate cancer, multiple teams in Germany and Ireland have failed to
find a connection.

Coffin says one more possibility, raised by many scientists, is that
CFS is actually a suite of diseases that present the same symptoms and
so might have many causes. Lombardi agrees. "It's naïve to think that
everyone with chronic fatigue has the same etiology. There's probably
going to be a subset of people with CFS that have XMRV, and it will
probably end up being classified as XMRV-related CFS."

All of this leaves doctors and patients in a muddle. There's no doubt
they're hungry for information. Out of curiosity, Lombardi did a
Google search on "XMRV" the day before the Science paper hit and found
about 22,500 hits. Three months later, there are 400,000.

But some scientists, including Coffin and McClure, fear that the Viral
Immune Pathology Diagnostics clinic (VIP Dx) took advantage of that
hunger by offering the $650 diagnostic test for XMRV, 300 of which
have been administered so far and which already has a 4 to 6 week
backlog. "Leaving aside the issue of who's right and who's wrong,"
says Coffin, "the original paper did not establish the virus [caused
CFS] and didn't establish it as a viable marker." So it's not clear
what a patient or physician could do with a positive result. Steve
Kaye, a colleague of McClure's at Imperial College London and a
co-author of the PLoS ONE paper, noted with some alarm that the
authors of the Science paper had speculated about treating XMRV with
antiretroviral drugs, which can have harsh side effects.

However, VIP Dx developed its XMRV test only after a different company
began offering one; VIP Dx officials saw their test as a more expert
alternative. What's more, Lombardi—an unpaid consultant for VIP Dx who
helped set up and manage the testing program—argues that the test is
useful. Patients could in theory avoid infecting other people with
XMRV and can have their diagnoses validated, if nothing else. His test
results also bolster the science in the original paper; he says 36% of
tests have detected XMRV, including a few from the United Kingdom.
(Test proceeds roll back into research and development at Whittemore,
which licenses the test to VIP Dx. VIP Dx has also received financial
support from the Whittemore family in the past.)

To resolve the dispute, both sides say they are willing to work with
the other and possibly test each other's samples. In the meantime,
more papers exploring the link are slated to appear in the next few
months, and each side says it knows of work supporting its results.
All that suggests that the field will continue to churn. As McClure
told Science, "we take no pleasure in finding colleagues wrong or
dashing the hopes of patients, but it's imperative the truth gets
out."
 
 
 
 
 

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