“Is it me? Or is it XMRV?” – the Chronic Fatigue blame game continues

Several million perpetually tired people heaved a weary sigh of relief last year when a research group “raised the possibility” that Chronic Fatigue Syndrome, a much-debated (and sometimes-mocked) condition, was caused by a retrovirus. Well, okay, the researchers didn’t outright declare that this virus, XMRV, caused CFS. What they coyly said in their paper was, “XMRV may be a contributing factor in the pathogenesis of CFS.”

Not so, said a clutch of papers that appeared within six months of this study. But none of these papers made as much noise as the one published a couple of weeks ago in a journal called Retrovirology by a group from the Centers for Disease Control (CDC), a US public health behemoth. Like the batch that came before, this paper also presents data that “do not support an association of XMRV with CFS.” Not only that, the scientists at the CDC as well as a lab in Berlin and one in San Francisco didn’t detect XMRV in any of the samples, suggesting that the negative result isn’t just a reflection of statistical analysis.

Credit: Priscilla Gilman, http://www.heaveninmyfoot.com

This sort of IS/IS NOT disagreement obviously isn’t uncommon in science. But what seems to have made this particular paper controversial isn’t so much the science as the misrepresentation and politicization of it by a few CFS patient groups and their (extremely energetic) advocates.

A couple of days before this latest “negative results” paper came out, it emerged that a “positive results” study (i.e., one showing a link between XMRV and CFS) by researchers at two other public health institutions, the FDA and the NIH, was being withheld from publication at another journal.

A quick check on Google indicates that the FDA/NIH scientists themselves initiated the hold in order to run some additional experiments. But anxious (and understandably cranky) patients and their surprisingly energetic advocacy groups are crying “foul!” and the CFS advocacy blogosphere is alight with “outrage” and charges of a government conspiracy to “suppress” the paper, which if published, will allegedly show a positive link between XMRV and CFS.

I was a sophomore in college when I first heard of CFS. A classmate tried to use it as an excuse to bail out on her part of an organic chemistry group project. Assuming that she was kidding, I wisecracked that her problem wasn’t so much CFS as LSS – Lazy Sophomore Syndrome – a pretty weak joke. I know better now: for millions of people, CFS is a real and complex medical issue that comes in a depressing package of symptoms that add up to various levels of physical and mental fatigue, which can last for up to 6 months at a time.

Although there are somewhat standardized diagnostic criteria for CFS now, there’s no treatment chiefly because no one’s sure of what actually causes it. Various viruses and bacteria have been linked to it, but none of these studies have stood up to scrutiny and all suspects have thus far been acquitted. Most of these studies suggest that the link between viruses and CFS might be one of reverse causality – CFS patients have such weak immune systems that their bodies have pretty much thrown out a welcome mat for certain viruses (such as XMRV) to come set up residence.

Still, at first glance, last year’s XMRV study seemed to be a cut above those that came before it for two broad reasons: first, the study was in Science, the journal with the reputation for the most stringent peer-review/editorial process. And second, the numbers—based on the inclusion of 101 CFS cases and 218 healthy controls—were pretty convincing: the virus had been found in more than 65% of people with CFS but only in 3% of healthy people in the study.

The CFS patient community whole-heartedly embraced the results, for here at last was a solution: if CFS was caused by a virus, then perhaps all they needed to do to get better was to pop an anti-viral pill (I’ve heard of a few misguided CFS souls out there who are dosing themselves with AZT, the anti-HIV drug that comes with some pretty horrendous side-effects).

But much of the CFS research community wasn’t having any of it. In the next 6 months, three other studies from the UK and the Netherlands (totaling 388 CFS patients and 438 controls) reported not finding any links between CFS and XRMV. And three other research groups came forth to hang the “XMRV-causes-CFS” Science study on some pretty strong technical arguments summed up as follows:

“However, (the Science) report has few features of a well-conducted case-control study, making their findings potentially misleading.”

The Science study got slammed because:

  • The CFS samples used were a little sketchy to start with: they didn’t represent a broad geographic or demographic spread (a must in virology/epidemiology-type studies). Rather, they’re from a rather infamous “outbreak” of CFS that occurred in Nevada in the 1980s. These “outbreak” patients are, immunologically speaking, quite different from most people who get CFS. So the proper thing to do would have been to include a few non-outbreak-related CFS patients in the study, which the researchers didn’t do.
  • The study was thin on clinical data such as medical histories, etc. of those included, as well as on the details of sample collection, processing and storage, all of which are factors that can influence the outcome of the tests.
  • The tests themselves, which used a method called PCR to detect viral RNA in the samples, posed an even bigger question mark, with critics making the case for sample contamination and detection of false positives.

The studies that came after and showed no link between XMRV and CFS are better designed in that they include a broader cohort of CFS patients, among other things. And these studies use tests that not only assay for the presence of XMRV virus particles directly via PCR, but also indirectly via serology tests – looking for antibodies that are formed against XMRV.

Here’s how the scientists of the Retrovirology paper try to account for the contradictory findings between their’s and the Science study:

“Several possibilities could explain these discordant results, including technical differences in assays used for the testing in each study.  However, the inability of four independent laboratories to replicate the high XMRV prevalence in CFS cases reported by Lombardi et al. (the Science paper) cannot be explained by minor differences in assays used in each study.”

In other words, even if the Science study was poorly designed, how to explain the fact that it found XMRV in so many CFS patients when other studies didn’t find it in any patients despite using multiple methods? Assuming there were no technical flaws in the Science study (something that can be settled if the other groups are allowed to test this group’s samples themselves), one possibility is that XMRV might be associated with only some cases or types of CFS. To me, the fact that none of the other groups found XMRV in any of the samples is a bigger mystery.

I can’t wait to see what the NIH/FDA re-testing will turn up. But either way, what’s certain is that XMRV-CFS research is going to remain a touchy, confusing topic as long as patients and their advocates spend less time on educating themselves on the science than on using contradictory reports as an excuse to dismiss the science or to pressure scientists into reshaping it to suit what they want to hear.

Switzer, W., Jia, H., Hohn, O., Zheng, H., Tang, S., Shankar, A., Bannert, N., Simmons, G., Hendry, R., Falkenberg, V., Reeves, W., & Heneine, W. (2010). 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) DOI: 10.1186/1742-4690-7-57

Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, & Mikovits JA (2009). Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science (New York, N.Y.), 326 (5952), 585-9 PMID: 19815723

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