A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus

19 Dec

There was much discussion of the possible imprtance of the xenotropic murine leukemia virus-related virus (XMRV) in conditions such as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME), prostate cancer and autism. To be clear, the possibility of an autism association was made in the press, not in the research literature. For XMRV in general, there was much discussion in the press, in journals and online as it became clear over time that there were possible problems with the analyses that led to the main papers on the topic. The present study includes work by a multi-site team including the principle author of the original study linking XMRV with CFS/ME.

If one can boil a large, multi-site study result into one line, it would be this:

Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects

I.e. there is no link between XMRV and CFS/ME.

Here is the abstract, and the full paper is online as well:

The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. IMPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen dediscovery that may be helpful to others working in this field.

There was a lot of hope in the CFS/ME community that this was a breakthrough that could lead to a treatment. Unfortunately, the answers they seek are elsewhere.

As this is an autism-focused site, allow me to bring this back to autism. Unlike CFS/ME, there were no papers claiming an association between autism and XMRV. Instead there were public comments by the researcher involved and inflammatory journalism. In a search for XMRV autism the first article I get is: Is Autism Associated with A Viral Infection?, by David Kirby published at the Huffington Post. Mr. Kirby’s article was probably the first that pushed the (now failed) XMRV/autism hypothesis strongly into the public’s eye. Mr. Kirby was well known for some time previous for his work promoting the idea that vaccines cause autism. In specific, he was a major proponent of the idea that thimerosal in vaccines caused autism, having published a book Evidence of Harm: Mercury in Vaccines and the Autism Epidemic. For his Huffington Post article on XMRV, Mr. Kirby had some rather irresponsbile speculations from XMRV researcher Judy Mikovits and the founder of her reseach institute Annette Whittemore. From those quotes, Mr. Kirby proceeded to present the XMRV news story in his own way, as a series of speculative questions to create an impression built like a house of cards. The impression he left the reader with was that the XMRV story helped to explain a possible link between autism and vaccines. Following a quoted statement by Mikovits, Mr. Kirby wrote

So there you have it – a possible explanation of regressive autism in a significant number of cases associated with immune system deregulation triggered by vaccination.

Of course, much more work is needed to nail down the exact significance of such an association. For example, is the virus implicated in the cause of autism, or do children harbor the virus as a result of autism?

Notice that he doesn’t say, “much more work is needed to show that this is a real association“. No, rather than stress again that the hypothesis was poorly supported, he jumps to assuming the association and asking what significance it has. Classic David Kirby.

To be fair, the comments by Mikovits and the founder of the research center where she worked (Annette Whittemore) fed directly into his story. To say it again, those statements by Mikovits and Whittemore were irresponsible given the early stage this work was in. But even with those statements, Mr. Kirby had no justification to go into this speculative paragraph:

The discovery raises more questions than it answers. What, exactly, is it about immunization that might switch on XMRV viral expression? Could the effect of heavy metals upon cytokine balances be at play? Where did this retrovirus come from, and how did it apparently become so prevalent in children with autism? Did these children inherit the virus from a parent, or was there some other unexplained route of transmission? Why has the NIH said nothing about XMRV in association with autism, and did Dr. Insel know about these findings without sharing them with the IACC

Again, we see the series-of-questions approach that is Mr. Kirby’s style. He isn’t saying immunization switches on XMRV viral expression (whatever he meant by “XMRV viral expression”. It sounds technical though). He’s posing it as a question. Notice how he brought in his mercury hypothesis, but as “heavy metals”. “Could the effect of heavy metals upon cytokine balances be at play?”. This is a great example of a sciency-sounding sentence that has no substance. Whoever was his editor at the Huffington Post should have shot that back with “do you even know what your talking about here?” But if the editor at the Huffington Post was doing his/her job, this article (and many more by Mr. Kirby) wouldn’t have been published there anyway. It is worth noting that by the time this article was written, the evidence was overwhelmingly against the idea that mercury in vaccines raised autism risk, but this was Mr. Kirby’s way of loosely tying his failed hypothesis to his then current speculation.

To pull the last sentence out of Mr. Kirby’s paragraph: “And why had the NIH said nothing about XMRV?”. Perhaps because they were more responsible than Mr. Kirby.

As a point of fact, XMRV is not prevalent in autistics (Lack of infection with XMRV or other MLV-related viruses in blood, post-mortem brains and paternal gametes of autistic individuals and PCR and serology find no association between xenotropic murine leukemia virus-related virus (XMRV) and autism.) In fact, as will be discussed below, it appears to not infect humans. Unfortunately, Mr. Kirby has not seen fit to post corrections. To the XMRV story or others.

The impression Mr. Kirby created with his story was strong. For example, he gathered 298 comments to his article, largely focused on vaccines. Here’s the last one, prominently at the top of the list:

David: As big as this autism story is, it is only one toe of the elephant. Here is another: There are no protections in place to prevent more XMRV from entering the nation’s blood supply. There is as of yet no XMRV screening test for donated blood. And — I just called my local Red Cross – there is as of yet nothing to prevent people diagnosed with CFS from donating blood. We are all at risk.

The elephant: How did our government let this potentially deadly retrovirus spread unchecked for twenty-five years? XMRV has, so far, now has been found to occur in people with autism, lymphoma, a severe form of prostate cancer, atypical MS, ME/CFS, and fibromyalgia. Twenty-three years ago the CDC was first informed of an outbreak of what we now know to be an XMRV-associated local epidemic. Eighteen years ago a study showed a retrovirus was associated with ME/CFS.

The band played on.

Yes, let’s spread fear about the blood supply, based on news reports, speculation and bad science.

Some of the authors of this present XMRV and CFS/ME study were also involved in a separate major multisite study on MMR and autism. I am referring to a study intended to replicate the key findings of some of Andrew Wakefield’s research. That study, by Mady Hornig, W. Ian Lipkin and others, Lack of association between measles virus vaccine and autism with enteropathy: a case-control study been re-interpreted by some as supporting Mr. Wakefield’s work. Some have gone so far as to claim that Mr. Lipkin’s team is signalling support for Mr. Wakefield’s work by citing it in other studies. It’s a stretch, a mind boggling stretch, and it’s wrong.

From the CFS/ME paper:

Sensitive molecular methods for microbial discovery and surveillance have enabled unique insights into biology and medicine. However, increased sensitivity for bona fide signal increases the risk that low-level contaminants may also be amplified. This can lead to spurious findings that pose challenges for public health and require an expensive and complex pathogen dediscovery process. Examples wherein authors of this paper have been engaged in this process include refutation of associations between enterovirus 71 and amyotrophic lateral sclerosis (24) and MMR vaccine and autism (25).

Lipkin and Hornig consider their work to be a “refutation” of the association between MMR and autism. But don’t take that one sentence from the paper as the only proof. Here’s an interveiw with Prof. Lipkin at Nature.

Had we done this when Andrew Wakefield [the former medical researcher who proposed that autism was caused by vaccines] came out with the initial report about the measles, mumps and rubella (MMR) vaccine and autism, and had something this definitive, there are many more children who would have been vaccinated against measles during the ten years it took us to finally complete the MMR–autism work. So I think it’s crucial that we don’t do things in a half-baked fashion, so we can test hypotheses and move on to new ones.

The interviewer even includes the MMR refutation as part of a question: “You have disproved the autism–MMR connection and other controversial disease links.”

In general, what can one say about XMRV? Aside from the drama involved in the story (which I did not discuss in detail in this article), and the questions about CFS/ME, autism, prostate cancer and more, what can we say? Prof. Lipkin says it very clearly in the interview:

We did not find any genetic sequences [of XMRV or related viruses] in the people with CFS or the controls. As far as we know, there is no human being that is infected with XMRV.

But there were papers (some now retracted) claiming some links between XMRV and human disease? What about those? Another quote pulled from the interview:

I think the explanation is that there was contamination. I don’t see any reason to invoke anything beyond that.

For this you have to give Judy Mikovits some credit. She worked with the team that was attempting to replicate her results. Contrast this with, say, Andrew Wakefield. A man whose hospital offered him the opportunity to replicate his own results, and he quit rather than accept that offer. A man who has repeatedly denied the science which has been clearly against his hypothesis. A man who denies the fact that he acted unethically in many ways in conducting his research. Judy Mikovits made some mistakes, both scientific and socially, but she seems to be part of the solution.

But that’s a bit of a sideshow. The main conclusion is that XMRV is not involved with autism. Or, apparently, any human disease.

With apologies for revisiting David Kirby and Andrew Wakefield.

By Matt Carey

4 Responses to “A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus”

  1. Science Mom December 19, 2012 at 19:18 #

    If the anti-vaxx illuminati ever recinded their erroneous statements and/or apologised for their wrongness then Kirby and Wakefield would barely have to be mentioned. And I don’t think they would like that. This will just be waved away and the next vaccinesdidit candidate will be broadcast as fact. Lather. Rinse. Repeat.

  2. Visitor December 21, 2012 at 11:15 #

    Don’t apologise for mentioning either of them. David Kirby has years of life left in him, as he seeks to weasel around the fact that his Great Book has turned out to be a pile of shit about a bunch of cranks who never had any proper call on the public’s attention.

    I don’t know whether Mr Kirby goes to dinner parties, but I can imagine the contortions he will be forced into as he seeks to explain away the American Academy of Pediatrics and the World Health Organization demanding the retention of thimerosal.

    Since anybody would know that, from a commercial point of view, the drug industry would be as happy to go over to single-dose theimerosal-free vials as pediatricians would be happy to separate combined vaccines into single shots, Mr Kirby has a real job on his hands.

    His “award winning” tome will join such masterworks as “The HIV Myth” in the dustbin of lazy opportunism.

    • Sullivan (Matt Carey) December 21, 2012 at 20:21 #

      I apologize for bringing up people who are no longer relevant. I spent more time on Kirby than the actual paper. Of course part of that is because the paper had a negative result. Not much to talk about as to the implications of XMRV *not* having anything to do with human disease. Not that that should stop Mr. Kirby from publishing a follow on article.


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    […] A multicenter blinded analysis indicates no association between chronic …Left Brain Right BrainIn specific, he was a major proponent of the idea that thimerosal in vaccines caused autism, having published a book Evidence of Harm: Mercury in Vaccines and the Autism Epidemic. For his Huffington Post article on XMRV, Mr. Kirby had some … […]

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