Vandemere -> Van der Meer
Rabojt -> Radboud Ziekenhuis (the last word means "hospital", and probably was there)
Nemakin -> Nijmegen
BMJ Podcast Part 2
DJ: We briefly mentioned XMRV there. In October of last year, the Lombardi team, based in the US, published a paper in the journal Science in which they suggested that a novel virus, this XMRV, could cause the syndrome. The papers garnered some controversy and one scientist whos looked at it in closer detail is Cathy Sudland. Cathys a senior clinical lecturer and honorary consultant neurologist at the University of Edinburgh. Shes actually written a response to this paper which is due to be published in Science soon. And, shes also written up her experience of that in the BMJ this week.
So Cathy, for a start, could you describe the Lombardi study for us?
Cathy Sudland: It was a study looking to see whether a particular newly discovered virus, called XMRV - which is a new retrovirus, which has been found in prostate cancer patients - they wanted to see if it was associated with Chronic Fatigue Syndrome. So, they did whats called a Case Control Study. Uhm, they had samples from patients with Chronic Fatigue Syndrome and samples from patients without Chronic Fatigue Syndrome, healthy controls, and they used a variety of viral detection methods to compare the cases with the controls and they found an excess of the virus, a very large excess of the virus, in the samples from the cases as compared to the controls.
DJ: Ok, so they thought that this might have something to do with CFS, then - a causative agent.
CS: Uhm, yes.
DJ: Now, for people who are listening who might not pay much attention to basic science journals, Science is a prestigious one, isnt it?
CS: Yes. I mean, its not a journal I read an enormous amount because its often has articles that have a lot of laboratory science and thats not something that I do a great deal of myself. And, it covers the whole spectrum of scientific discovery, really, from climate change to things that a relevant to everyday medicine. And, so, when there is an article that relevant to everyday clinical practice, and I hear about it, then I would take an interest but that doesnt happen very often.
DJ: But, you did take an interest in this particular paper and you looked a little further into the methodology of their study, didnt you?
CS: Because the paper seemed to be suggesting that there was a very big excess of the presence of the virus in samples from patients with Chronic Fatigue Syndrome - and, Im not an expert in Chronic Fatigue Syndrome - but I knew from my own clinical work as a neurologist and from talking to colleagues who know a great deal about the field, that thered been an interest in viruses as a potential causative factors, or triggers. And, I think youve heard from Simon Wessely, a causal link for some cases has never been identified. But theres never been suggestion that theres one virus thats predominant. And, theres always been, I think, a number of other factors contributing to the syndrome. So, I thought it would be interesting to find out a little bit more about what this paper was claiming, so I read it in quite a lot of detail.
DJ: And, what did you find?
CS: Well, Im an epidemiologist so Im very interested in the methods that people used to make comparisons between cases and controls and what I found, mainly, was a description of the laboratory methods but what I couldnt find in there was very much information about how the cases with disease, with this condition, had been selected - exactly where theyd come from. And, in particular, how the controls had been selected to make sure that they were an unbiased comparison group. And, to me, that seemed to be one of the most important potential uhm missing bits of information from this paper which might help us to assess whether the finding was accurate, reliable, repeatable and generalizable to other patients with this condition.
DJ: Since the paper was published, there have been a few more studies that have tried to replicate these results. What have they found?
CS: The original study in Science, its clear from the paper that the patients were recruited from the United States and they described that theyd been recruited from areas of outbreaks of Chronic Fatigue Syndrome. So, some case of chronic fatigue seem to occur in clusters, others seem to occur more sporadically and they may have different causes.
Uhm, but whatever, these patients came from the United States. And, subsequently thereve been three studies, that Im aware of, that have been published that have looked for the virus in patients with Chronic Fatigue Syndrome and theyve looked at samples from the UK in two cases and, in one case, samples from the Netherlands.
DJ: So, the paper just mentioned from the Netherlands was just published in the BMJ last week and so is available online, for free, from BMJ.com.
Im now joined, on the phone from Cathy in Holland [sic] by one of the researchers of that paper Jos Van der Meer is a professor of Internal Medicine at Radboud University in Nijmegen.
Hes been studying infectious diseases, and the host response to them, and particularly Chronic Fatigue Syndrome.
Jos, we heard from Cathy there that the patients in the Lombardi study were all from a cluster of Chronic Fatigue Syndrome that appeared in the states. How did you recruit the patients in your study?
Jos Vandemere: The patients we studied were all sporadic cases that came to our out-patient clinic. We wanted to be fast so we needed material which we had frozen away so we - and, we needed lymphocytes - so we had to go to a cohort we did, a cohort of patients, ahhh, which were very well defined and, actually, which we had used for other viral studies. And, in [this is unclear but is most likely:] methodological studies with matching controls.
DJ: You looked for the presence of this XMRV virus
JV: Yes.
DJ: And, can you take us through your results?
JV: Yeah, so, in none of the patients, and none of the controls, we got any signal that there was, really, the genomic material of this virus present. And, we really scrutinized that with high sensitivity and high specificity PCRs. And we used the same PCRs as the Lombardi group did...
DJ: Uhm...
JV: and we really challenged our own results: redid it and redid it, really to find and think, actually we put in... All our positive controls, we had the virus just by luck, by sheer luck, in our urology department because of the prostatic cancer connection. They were, they were... urologists were into the virus. So, we had the virus and we had this, kind of a, head start and we could do, beautifully, the positive controls. Which were all doing what they should do. Whereas the patients really was negative.
DJ: Ok, so does...
JV: Of course, were not alone in that. There are now at least two other cohorts that are found negative and I have heard rumours from the US that other people cant, ahh, also cant confirm the Lombardi data.
DJ: Ok, so does that... do you think youve really refuted the role of XMRV in Chronic Fatigue Syndrome?
JV: I think Im done, Im done with this. If the two British groups dont find the virus, we dont find it, and there is, according to the rumours at least, one American group with a good virology score [?] who couldnt find anything, I think this is the wrong track. And, probably there is some kind of contamination in the Lombardi lab.
DJ: OK...
JV: Or, it is peculiar for this [unclear: score?]. They looked at ... But for us, it is a closed book now. I would say I dont have too much urge to go deeper into this matter.
DJ: Ok, so if youre closing the book on this virus particularly, are you doing any other research thats looking into this?
JV: Were very much open to, say, other viralogical triggers. Right now were more on the track to say its not so important whether you get Epstein Barre virus, or a flu, or Q fever, or any other causative organism.
The interesting part, to my mind, at the neurobiology of this. Whats happening to the brain at that point in time? How is the neuro___ ____ [unclear] system, at a level of the brain, being deranged and why does that give rise to fatigue these people sense and how is this maintained. For me, those are the major questions right now.
DJ: So, XMRV doesnt appear to be the single cause of Chronic Fatigue Syndrome. But, even if it were, it wouldnt effect the outcome for the patient. The syndrome would still be treated pragmatically with the aim of mitigating its symptoms.
Ill leave you with a final word from Simon Wessely about the future of the research into this disease.
SW: And, Im... but I do think about this particular episode, you know, the XMRV story. I dont want people to go around thinking that science isnt making progress in this area, cause it is. Im not so involved now as I used to be but Im still watching out whats going on. And, we know so much more than we did twenty years ago as a result of careful, painstaking research by a large number of people.
I dont think were going to get that sudden eureka Archimedes moment before which everything was dark, after which everything is light. I think it will be a gradual, steady series of small steps forward.
And, I really do hope that, you know, doctors and medical scientists in all sorts of disciplines get more involved in this area because we certainly need it - its an under-researched area - particularly to bring in people from right across the board of medicine, and to get involved in this area. And, uhm, because I can just tell you that its... youd be surprised to learn that its actually very enjoyable and very rewarding. And, we want people to engage in this area and help move it forward in a steady fashion.
Berta: And thats all for this week...