XMRV Study No. 4

[Esther12]

Bless your heart, Esther. Don't ya just hate when that happens!

I'm back to playing it cool now!

 

[Gerwyn]

Perhaps I'm completely missing your point, but isn't the opposite true -- that (extrapolating from the Science study) more healthy people were found to have XMRV than people with CFS (or ME)?

Cheney mentioned 10 million healthy folks compared with 1 million PWC's in his talk with Mikovits...didn't he?

I don't get it. Seems like there must be other factors involved besides just XMRV...?

Respectfully,

67% had xmrv 4% controls . more people who are healthy will have xmrv because there are more of them but pwcs nhave much higher titres.A retrovirus can cause the symptoms of ME I dont know of anything else that can.I have had this conversation with court Oxford focuses on chronic fatigue in the absence of neurological signs.There is a quote from one of its creators above .it doesnt diagnose ME/CFS even the uk authorities state that.The fact that the dutch study didnt show xmrv even in "healthy" controls makes their results highly suspect considering that other researchers even groom did

Dan

67% had xmrv 4% controls . more people who are healthy will have xmrv because there are more of them but pwcs nhave much higher titres.A retrovirus can cause the symptoms of ME I dont know of anything else that can.I have had this conversation with court Oxford focuses on chronic fatigue in the absence of neurological signs.There is a quote from one of its creators above .it doesnt diagnose ME/CFS even the uk authorities state that.The fact that the dutch study didnt show xmrv even in "healthy" controls makes their results highly suspect considering that other researchers even groom

 

[PoetInSF]

Wake me up when someone finally does a decent replication study.

It could be another 25 years depending on what you mean by "decent". If the history is any indication, WPI will continue to find faults with any negative study.

One way to quickly end this controversy without wasting more resource is to take WPI's own samples, code them, and see if WPI can pick out the positives using their own method. I think they should resort to that if CDC also fails to confirm and controversy remains. It is utterly important for patients to get clean closure on this, so that they won't have to hang on to the viral theory and keep waiting. We don't want to repeat the history, after all.

 

[jspotila]

Here is Dr. Vernon's analysis of the Dutch study. The Association's website is experiencing problems at the moment, so the article has only been posted to Facebook so far. Once the website is back up, this article will be posted there and linked from our XMRV info page.

Playing A Weak Hand Well
Suzanne D. Vernon, PhD
Scientific Director, The CFIDS Association of America


XMRV was not detected in a third follow-up study from a well-characterized cohort of CFS subjects. In a paper published on February 25, 2010 in the British Medical Journal (BMJ) titled, Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort, Frank van Kuppeveld and an expert team of microbiologists and clinical investigators failed to find evidence of XMRV. (http://www.bmj.com/cgi/content/full/340/feb25_1/c1018) This team used a sensitive polymerase chain reaction (PCR) test that could detect as few as 10 copies of XMRV in 100,000 peripheral blood mononuclear cells (PBMCs) to test PBMCs from 32 CFS patients and 43 controls.

The CFS cases were enrolled from 1991 to 1992, satisfied Oxford Criteria (published in 1991), were severely ill with debilitating fatigue of at least one year, and reported duration of symptoms ranging from 2 to 45 years. The controls were neighbors selected by the CFS subjects, the same sex as and within two years of age of the CFS subject. This study used a well-characterized cohort, well-processed and preserved blood samples and a sensitive technique. Its weakness is the small sample size. Use of the less-restrictive Oxford criteria may be objectionable by current standards, but samples were collected before publication of either the Fukuda research criteria (1994) or the Canadian clinical definition (2003). So far all the XMRV studies have used banked CFS samples.

With the third negative study published in just 51 days, it is now harder to explain the negative results based on CFS patient characteristics and methods alone. The implication is that XMRV is likely to explain a subset of CFS rather than all cases defined as CFS (using any of the seven existing definitions). The PLoS ONE paper by Erlwein et al, the Retrovirology paper by Groom et al, and now the van Kuppeveld, et al, paper in BMJ all studied well-characterized patient cohorts that met accepted and widely used CFS case definition criteria. Importantly, many if not most of the CFS patients selected for these XMRV studies have been the subjects of other CFS studies by experienced investigators. While the CFS subjects from these three studies may be different from the CFS subjects in the Science paper, there certainly must have been some overlap between the cohorts chosen. Put another way, it is unlikely that case definition criteria alone accounts for the discrepant results ranging now from three negative studies to one study that found 67 percent of the CFS patients to be positive for XMRV.

The authors of the Dutch study go into a fair amount of detail to describe why they think their methods do not account for differences in the studys outcomes compared to the original XMRV study. Here is a brief, yet still pretty technical summary of their methods: they performed a real-time PCR test with the same primers as the original study. Positive and negative controls were included in each of the runs and they used a 22Rv1 XMRV-positive prostate cancer cell line to ensure that they could detect positives. They used a similar amount of nucleic acid as the original study to hunt for XMRV. The samples from all the CFS patients and controls tested negative for two different XMRV genes encoding integrase and gag proteins.

History has taught us the absolute importance of impeccable study design in looking for infectious agents as a possible cause of CFS. Back in 1991, Elaine DeFreitas, PhD, and colleagues published in the prestigious Proceedings of the National Academy of Sciences that they had detected retroviral sequences related to human T-lymphotropic virus type II (HTLV-II) in two-thirds of 31 CFS patients, compared with zero positive findings in 20 controls. This report was not confirmed by other investigators who found the same rate of these HTLV-II-like sequences in controls and CFS cases and the search for viral markers chilled for several years thereafter.

The study by Lombardi et al, published in Science showed that XMRV could be detected in samples from the WPI repository. Unlike the negative XMRV studies where results and characteristics of these CFS cohorts have been the subject of numerous earlier publications, little is known about the patient samples stored in this repository. The Science papers supplement refers to a variety of abnormalities without defining how they were measured or how uniformly they show up among the patients whose samples are stored there. The supplement makes reference to DeFreitass PNAS publication. Does this mean that WPI tested the same samples as DeFreitas, et al, or that they were obtained from the same cluster outbreaks mentioned in her paper? We do not know. We also know nothing about the controls reported in the Science paper from the published literature. Because the study design and the methods provided in the Science paper and supplemental material are lacking in detail, it makes it challenging for any investigator, no matter how expert, to replicate this study. It's not plausible to expect that researchers will piece together information about case selection or laboratory methods posted only to websites or delivered in presentations given to lay audiences to design the methods for serious replication or validation studies.

Since reliable, consistent information about the Science cohort has not been forthcoming, I have carefully analyzed data provided in the Science paper, its supplement and public presentations by two of the authors. The WPI investigators conducted a number of assays to detect XMRV DNA, protein, infectious virus and antibodies against XMRV. I used the patient ID numbers provided in the paper to track results. Of the 101 CFS subjects reported in the paper, results for the various assays are shown for only 32 CFS subjects. Of the 32 CFS subjects whose results for any of the tests are displayed, 12 CFS subjects were positive for XMRV on more than one assay. The other 20 CFS subjects were documented as positive by just one testing method. Using information from a public presentation at the federal CFS Advisory Committee, five of the 12 CFS subjects (WPI1169, 1118, 1150, 1199 and 1125) included in the Science paper were also reported to have cancer either lymphoma, mantle cell lymphoma or myelodysplasia. This once again raises questions about the lack of detailed clinical characteristics of the CFS subjects included in the Science paper, and the differing public reports about where the samples originated.

XMRV is a newly described virus that infects humans. There may be virus variability making it difficult to detect, and it may be more easily found in organ tissues rather than blood. There are going to be numerous technical, biologic and epidemiologic challenges associated with linking XMRV to CFS and other diseases including prostate cancer. Whether XMRV is in any way associated with CFS will be the subject of further investigation. But these investigations must be designed appropriately and impeccably. Investigators from several U.S. institutions reported outcomes from recent XMRV studies at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010), including infecting and establishing chronic XMRV infection in rhesus monkeys. Interestingly, XMRV was localized to the reproductive and lymphoid organs in these animals. (See http://www.facebook.com/CFIDSAssn#!/note.php?note_id=354510650538)

Time and precious resources are being consumed by studies in which the results are controversial ones. The CFIDS Association of America is working diligently to foster the type of well-designed studies of CFS and XMRV that will provide definitive grounds for moving forward on this hypothesis so that history does not repeat itself. True to our mission statement, we will continue to lead, support and conduct research with integrity, innovation and purpose in order to make CFS widely understood, diagnosable, curable and preventable.


Citations:
van Kuppeveld FJ, de Jong AS, Lanke KH, Verhaegh GW, Melchers WJG, Swanink CMA, Bleijenberg G, Netea MG, Galama JMD, van der Meer JWM. Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. British Medical Journal 2010 (Published 25 February 2010)

Groom HC, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, Gow JW, Mattes FM, Breuer J, Kerr JR, Stoye JP, Bishop KN. Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology. 2010 Feb 15;7(1):10.

Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One. 2010 Jan 6;5(1)

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. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009 Oct 23;326(5952):585-9.

Lombardi VC, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Supporting online material for Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 8 October 2009.

DeFreitas E, Hilliard B, Cheney PR, Bell DS, Kiggundu E, Sankey D, Wroblewska Z, Palladino M, Woodward JP, Koprowski H. Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proceedings of the National Academy of Sciences USA. 1991 Apr 1;88(7):2922-6.

Dr. Daniel Peterson, reporting at the DHHS CFS Advisory Committee meeting on Oct. 29, 2009. http://www.hhs.gov/advcomcfs/meetings/presentations/xmrv_cfs.html, accessed Feb. 26, 2010.

 

[anne]

Sometimes I get the feeling Dr. V wants more info on the cohort.

 

[sunnyslumber]

Sometimes I get the feeling Dr. V wants more info on the cohort.

Some Levity! Great Anne.

Yea, this response feels a lot like her earlier response-- hopefully she didn't just copy-paste-- JK =) . Apparently she thinks there were minor things wrong with the study but nothing that should prohibit them from finding XMRV at all. I'm getting the feeling she really doesn't have an idea why everything is turning out the way it is though. Even if there are variants they used the same primers WPI used (with WPI claiming to detect XMRV internationally with those primers). I'm wondering what Mikovit's response will be, hers might be more informative than Vernon's this time around.

 

[Lesley]

Something isn't right here. From Dr. Vernon's analysis above:

Using information from a public presentation at the federal CFS Advisory Committee, five of the 12 CFS subjects (WPI1169, 1118, 1150, 1199 and 1125) included in the Science paper were also reported to have cancer – either lymphoma, mantle cell lymphoma or myelodysplasia.

From the WPI website ():

Were any patients with lymphoma mentioned in the XMRV study?
Blood samples from the WPI repository were chosen at random and there were no patients chosen with lymphoma or mention of lymphoma in this study. Another preliminary study was done at a later date that had nothing to do with the XMRV Science publication.

ETA - The Science paper, Dr. Peterson's CFSAC cancer slide, and the WPI website are in conflict. This is something they need to explain.

 

[kurt]

67% had xmrv 4% controls . more people who are healthy will have xmrv because there are more of them but pwcs nhave much higher titres.A retrovirus can cause the symptoms of ME I dont know of anything else that can.I have had this conversation with court Oxford focuses on chronic fatigue in the absence of neurological signs.There is a quote from one of its creators above .it doesnt diagnose ME/CFS even the uk authorities state that.The fact that the dutch study didnt show xmrv even in "healthy" controls makes their results highly suspect considering that other researchers even groom

There are plenty of other conditions that can cause symptoms of ME and CFS. Including brain damage, chronic herpes infections, various bacterial infections, ciguatera type toxins (which may include toxins from mitochondria damage as their envelope is a ciguatoxin epitope), many different parasitic infections, particularly the protozoans, glutathione insufficiency from various causes, and organic mitochondria disease. Also add to that HPA damage or malfunction due to prolonged trauma or stress, post-polio type syndromes, and the list goes on. Of course combinations of these and other factors also can create ME/CFS type symptoms.

Also, the only reason the Dutch study used Oxford is that was all there was at that time. These were very sick patients evaluated in other CFS studies.

One way to quickly end this controversy without wasting more resource is to take WPI's own samples, code them, and see if WPI can pick out the positives using their own method. I think they should resort to that if CDC also fails to confirm and controversy remains. It is utterly important for patients to get clean closure on this, so that they won't have to hang on to the viral theory and keep waiting. We don't want to repeat the history, after all.

That is a great idea but I doubt WPI would go for that, they have too much at stake and any number of factors could cause that type of test to fail. But I agree patients need closure. We will get that eventually, when enough confirmation studies have been reported.

not to be mean, but do any of you ever get the urge to yell "CRUCIO!" at Wessely? ^_^ That guy has done more to slow down research. Who knows how many people are dead because of it, but it almost certainly is not 0.

I know that is how things look in the UK, but don't forget that things are not rosy in the US either. Our problem often is not the lack of treatment options but the lack of insurance coverage for those treatments. Then there is the small problem of effectiveness, people in the UK may be better off in some ways because the drug treatments used here can be dangerous. Yes, people in the UK have been killed with GET but people in the US have been killed by the supposedly 'better' biological therapies. A friend of mine with CFS died from effects of a drug given for CFS, and I nearly died from the same drug and have had other severe reactions to therapies doctors insisted were perfectly safe. That is one of the reasons I believe we have to be very careful about research claims and proposed drug therapies, we need a very competent scientific consensus process and serious debate and review of every CFS research finding.

 

[sunnyslumber]

I know that is how things look in the UK, but don't forget that things are not rosy in the US either. Our problem often is not the lack of treatment options but the lack of insurance coverage for those treatments. Then there is the small problem of effectiveness, people in the UK may be better off in some ways because the drug treatments used here can be dangerous. Yes, people in the UK have been killed with GET but people in the US have been killed by the supposedly 'better' biological therapies. A friend of mine with CFS died from effects of a drug given for CFS, and I nearly died from the same drug and have had other severe reactions to therapies doctors insisted were perfectly safe. That is one of the reasons I believe we have to be very careful about research claims and proposed drug therapies, we need a very competent scientific consensus process and serious debate and review of every CFS research finding.

I agree, it's happened at least once on one of the CFIDS groups I used... I'm talking more about the continual cranking out of subpar studies that divert attention from biomedical research and appear to have authority because they are repeated and there are so many of them.

 

[jspotila]

Something isn't right here. From Dr. Vernon's analysis above:

Using information from a public presentation at the federal CFS Advisory Committee, five of the 12 CFS subjects (WPI1169, 1118, 1150, 1199 and 1125) included in the Science paper were also reported to have cancer – either lymphoma, mantle cell lymphoma or myelodysplasia.
From the WPI website ():

Were any patients with lymphoma mentioned in the XMRV study?
Blood samples from the WPI repository were chosen at random and there were no patients chosen with lymphoma or mention of lymphoma in this study. Another preliminary study was done at a later date that had nothing to do with the XMRV Science publication.

I agree, Lesley. Dr Peterson's presentation to the CFSAC does not match the info on WPI's website. I don't know why the two do not match, and it won't serve any of us well to speculate. It would be appropriate for Dr. Peterson and/or Dr. Mikovits and/or WPI to clarify.

 

[Ecoclimber]

I don't know if this is getting of track but I ran across an article in the Journal of Virology Mar. 2010 p. 2556-2562. I have no idea what they are talking about or whether it is germane to CFIDS but I'll put it out there for anyone who can decipher the info.

Xenotropic Murine Leukemia Virus-Related Virus Establishes an Efficient Spreading Infection and Exhibits Enhanced Transcriptional Activity in Prostate Carcinoma Cells
Columbia University, Howard Huges Medical Institute Jason Rodriguez and Stephen Goff

http://jvi.asm.org/cgi/content/full/84/5/2556

Xenotropic murine leukemia virus-related virus (XMRV) is a novel human gammaretrovirus discovered in association with human prostate tumors. XMRV was first identified in prostate stromal cells surrounding the tumors of patients carrying a mutation in the HPC1 gene locus. To determine the tropism of XMRV in cell culture, we tested the ability of XMRV to spread and replicate in various prostate and nonprostate cell lines. We found that although the expression of XMRV viral proteins and the spread of infectious virus were minimal in a variety of cell lines, XMRV displayed robust expression and infection in LNCaP prostate tumor cells. The transcriptional activity of the XMRV long terminal repeat (LTR) was found to be higher than the Moloney murine leukemia virus LTRs in both LNCaP and WPMY-1 (simian virus 40-transformed prostate stromal cells). The U3 promoter of XMRV and a glucocorticoid response element (GRE) within the U3 were required for the transcriptional activity in LNCaP cells. Coexpression of the androgen receptor and stimulation with dihydrotestosterone stimulated XMRV-LTR-dependent transcription in 293T cells, and the GRE was required for this activity. These data suggest that XMRV may replicate more efficiently in LNCaP cells in part due to the transcriptional environment in LNCaP cells.

 

[Hope123]

There are plenty of other conditions that can cause symptoms of ME and CFS. Including brain damage, chronic herpes infections, various bacterial infections, ciguatera type toxins (which may include toxins from mitochondria damage as their envelope is a ciguatoxin epitope), many different parasitic infections, particularly the protozoans, glutathione insufficiency from various causes, and organic mitochondria disease. Also add to that HPA damage or malfunction due to prolonged trauma or stress, post-polio type syndromes, and the list goes on. Of course combinations of these and other factors also can create ME/CFS type symptoms..

These conditions can cause some of the symptoms of CFS but not all necessairily. Yes, you do have extreme cases which could cause all but the average case, I would have to disagree based on my experience. Although we've all been thrown for a loop with CFS, medicine isn't so primative and disease patterns so similar that we can't separate some of these from the others.

 

[dannybex]

There are plenty of other conditions that can cause symptoms of ME and CFS. Including brain damage, chronic herpes infections, various bacterial infections, ciguatera type toxins (which may include toxins from mitochondria damage as their envelope is a ciguatoxin epitope), many different parasitic infections, particularly the protozoans, glutathione insufficiency from various causes, and organic mitochondria disease. Also add to that HPA damage or malfunction due to prolonged trauma or stress, post-polio type syndromes, and the list goes on. Of course combinations of these and other factors also can create ME/CFS type symptoms.

Great list Kurt. I'm quite brain-fogged lately, but I would add pesticide and other chemical exposures (which are almost never tested for), hidden mold exposure (as was the case with Erik 'Mold Warrior' from the Tahoe outbreak), chronic fungal infections, chemicals in our food supply, heavy metals, methylation problems, etc..

And that (in my opinion) is why ME/CFS has been so difficult to treat, whether or not XMRV is involved. People have actually recovered, before XMRV was discovered, even though recovery is rare. Dr. Klimas will testify to that, and she's seen the worst of the worst.

I know that is how things look in the UK, but don't forget that things are not rosy in the US either. Our problem often is not the lack of treatment options but the lack of insurance coverage for those treatments. Then there is the small problem of effectiveness, people in the UK may be better off in some ways because the drug treatments used here can be dangerous. Yes, people in the UK have been killed with GET but people in the US have been killed by the supposedly 'better' biological therapies. A friend of mine with CFS died from effects of a drug given for CFS, and I nearly died from the same drug and have had other severe reactions to therapies doctors insisted were perfectly safe...

Insurance coverage...don't get me started. Just think...if they would pay for some of the tests that we know can direct treatment (try getting even a stool test for parasites), rather than deny, deny, deny, perhaps some of us could've returned to being productive citizens long ago. My heart breaks for patients in the UK and elsewhere, where the only option is CBT and GET. Just shameful...

Drug intolerance: That I think is one of the reasons why people just don't understand CFS. For the most part, we can't handle drugs...(with perhaps the exception of some antibiotics). We can't pop a pill and get back to work, despite all the ads on tv claming otherwise. People I've talked to during the last 12 years of this look at me googly-eyed when I tell them I can't tolerate drugs, even some mild over-the-counter drugs. Frust-rating.

okay...I'll shut up.

d.

 

[dannybex]

These conditions can cause some of the symptoms of CFS but not all necessairily. Yes, you do have extreme cases which could cause all but the average case, I would have to disagree based on my experience. Although we've all been thrown for a loop with CFS, medicine isn't so primative and disease patterns so similar that we can't separate some of these from the others.

I agree in part, if these causes or 'conditions' are taken separately...on their own...but if one has many, multiple 'triggers', they can or may certainly be the things that lead one to develop CFS. Just my two cents.

 

[Advocate]

Here is Dr. Vernon's analysis of the Dutch study..

The tone of the CAA press release is so critical of the Science study and so supportive of the other studies that it appears to be a biased and self-serving review. In the press release I received, there were direct links to the studies that failed to find XMRV, but no link to the Science study.

The following statement by Dr. Vernon, expressing phony concern for other people's resources, felt to me like an attack on the Whittemore-Peterson Institute.

Time and precious resources are being consumed by studies in which the results are controversial ones.

This press release does not serve patients well. The CAA missed a good opportunity to show that they are on our side.

 

[cfs since 1998]

I agree, Advocate. Vernon is soundling like a broken record. As if it's WPI's fault that this study used the Oxford criteria. It's really quite ridiculous.

 

[Angela Kennedy]

McClure says



This would be the Incline Village outbreak which lead to the CDC discovering the "new disease" CFS? If what she says is true it is only proof that people have diluted the original illness until it is meaningless.

I am getting tired of people saying that Mikovitz did not give any details of her patients or only released it at conferences. It is standard procedure at Science that that sort of detail is not put into the paper but is made available online. The weasels are just plain lying about it or they are very ignorant. I got to the supplementary materials by two mouse clicks from their references. They couldn't manage that!



It seems detailed enough to me.

The samples were unblinded at Christmas and she discovered that the patients came form outside the US as well. I believe they were unblinded because she said she would tell all the participants what their status was.

There follows as much detail about the testing procedure as is given in any of the other papers.

The exclusion of "proven organic brain disease" in the Oxford criteria means that anyone with a neurological sign on examination, such as the romberg, any abnormality on the usual neurological testing or any lesions in an MRI is excluded. Many people with ME have these signs so it is perfectly possible for a study to be done that does not contain a single person with ME.

It is difficult for those from the US to understand exactly what it is like here. Words are used almost like code so that ordinary people think it means one thing but it actually means another. Excluding organic illness is taken as the common sense thing that patients who turn out to have, say, coeliac disease won't be included as having CFS, but they mean it literally.

They have a second weapon. Typically, in this editorial they argue against a single virus being the cause because of the "heterogeniety" of the illness, yet they are the ones who insist on treating it as a single illness, somatisation with a shared cause and CBT and GET for everyone. They continually use something if it helps them and deny it if that helps them.

I am disgusted with Charles Shepherd. He should know better. I am not convinced that XMRV is the answer in ME, I feel that continuing enteroviral infection could account for all the symptoms but XMRV needs investigated, properly and scientifically not these travesties.

Mithriel

Here here Mithriel.

 

[Megan]

Professor Van der Meer is a professor of internal medicine at the University of Nijmegen, he has been involved in research into ME since at least the early nineties. He has always strongly opposed any bio-medical cause for ME. He doesn't believe ME exists, other than in our sick minds. Therefore he cooperated with Prof. VAn Bleijenberg, a psychologist from the same university. They set up a program for CBT and GET.

Thank you Bettine for the above information. It looks to me like this has highlighted some important information has been ignored in the general discussion of the cohorts. I agree with many others that there is an overlap between the Canadian Consensus Criteria and other definitions, so on the face of it you would expect something to show up in the other studies. However:

1) Forgetting the definitions they use, isn't there a problem with the clinics many of the European study patients have been selected from? Aren't they are coming from clinics or doctors basing their treatments on the use of GET and CBT (I dont know whether this is true of the Kerr study but sounds like it is in the other two)? I can't think of a better way to 'deselect' anyone with post exertional milaise than to offer a treatment such as GET! Speaking for myself I would not show up to one, or if I did stick around long enough become part of one of their studies. Surely this would be minimising the attendance of patients fitting Canadian criteria at these places. I have myself avoided going to a similar type clinic after seeing their philosophy on their website.

Likewise with CBT. While I can see that CBT may be helpful to us in managing with our illness, I can get this from any sympathetic psychologist, or read a book, without having to go to some specialist clinic that informs me that it is all in my head (this would be a source of added stress). On ths basis I would consiously not go to such a place.

I know many people may be mislead or sometimes have no choice in going to such places if they need to do so for benefits etc. I am in Australia so I do not fully understand the situation in Europe. But my observation here is that if the exercise is not helpful then people tend to avoid or get out of these places if they can. It is therefore imperative to me that, regardless of the definitions used, that any replication or validation study should be selecting patients from clinics that believe patients have an organic illness and do not push GET as these are where the highest concentration of true CFS patients are most likely to be.

2) Secondly much of the discussion has focussed on the level of overlap with the different CFS definitions. It seems to me that yes, there is overlap between Canadian criteria, the Fekuda and Oxford definitions. But maybe this doesn't tell you anything unless you also consider the prevalence of conditions in our community that can mimic CFS. If they are very prevalent, such as depression, then even a small percentage of such people getting accidentally diagnosed as CFS could mean that CFS studies get 'swamped' by such cases in studies. My understanding is that CFS makes up only as small percentage of our population (well below 1%). If you take a high prevalence illness such as depression and add number of other things mentioned on this thread that could also be misdiagnosed, then marry that to the more vague definitions, then it's easy to see how CFS patients could be left as a very tiny proportion of a sample selected for study. Add to this the 'self selection' bias that might be taking place on the part of patients with respect to different treatments/clinics (point one) and the cohort problem still seems alive and well to me.


Having said the above points, I still agree with many others that there must also be a difference in the testing between these studies and the WPI, as a finding of complete zero on all patients and controls (even the Kerr study said their antibody positive cases were due to cross reacting antibodies) is hard to believe if the WPI study got the 4% figure right on the healthy controls. As pointed out by someone earlier on this thread, the collective zero findings of the European CFS studies and their prostate ones seem to be challenging the very notion of XMRV itself! I think this is the more important observation at this point.



Megan.

 

[Michelle]

When the Kerr study came out, I remember that one observer noted:

"...discrepancies between labs are common, says David Griffiths, a virologist at Moredun Research Institute in Midlothian, United Kingdom, who has studied previous claims for retroviruses as the cause of chronic diseases. He also notes that he cannot find serious flaws with any of the published studies: 'All the people involved are doing things exactly as they should be.' For the time being, then, the XMRV results will remain frustratingly ambiguous. As Griffiths says, 'There must be an explanation for why disparate results are showing up, but it may not be an easy thing to turn up.'"

Given what we're hearing about how XMRV may work, both from the retrovirology conference last week, as well as Dr. Judy's comments about the slow replication rate and the difficulties with finding XMRV using PCR at the ProHealth talk, it sounds like XMRV may work quite differently than what everybody is used to. Thus I can see how it's possible that everybody really is doing everything "right" based on current virological knowledge but still coming up with contradictory results. The fact that the Kerr study and this new Dutch one didn't find XMRV in anybody shows that the problem here goes beyond just the connection to ME/CFS but to how much of a role XMRV plays in humans altogether, something neither study commented on because both were focusing so much on ME/CFS (one for good reason, one malicious).

Dr Vernon does mention the tissue depository issue, suggesting that she too has been reading about the findings at that retrovirology conference (as are people here in this forum) but isn't sure what to make of it yet. Indeed from the way the article summarizing the retrovirology conference ended, it sounds like everybody is still scratching their heads.

Detection in humans has proven challenging, but whether this reflects the virus's life cycle, a combination of viral properties and the length of time between infection and disease, or some other factor is unclear, Hackett said.(John Hackett of Abbot Diagnostics)

"Part of it is the ability to identify it to begin with," Hackett told MedPage Today. "You could argue we haven't been looking for it."

Or, I'd add, haven't been looking for it in the right place(s).

Clearly something big is going on with XMRV because there is so much money, so much excitement surrounding it at the moment -- more than anything I've ever seen connected with ME/CFS, even if it's more likely generating the money and excitement because of the cancer connection. The fact that someone like John Coffin, who has been studying retroviruses similar to XMRV for 35 years, is saying "there is no question I think that the virus is real and that the virus is infecting some numbers of people. And it’s VERY important to figure out where it is going as far as all of its disease associations are concerned…" outweighs these three speedy, fairly conventional studies in my mind. The IC and Dutch studies just seem like attempts -- if effective among the general public in the short term -- to shift momentum away from an XMRV-ME/CFS connection in the vain hope that will stop further study (i.e. "waste of valuable resources" B.S.). But as Robin pointed out in the thread about Coffin and Goff, these guys don't know really anything about ME/CFS and don't seem to have a bias about it one way or another. They just see a new human retrovirus to study and people who may well have it. And they seem to be really interested in really looking for it, as do a lot of their friends and competitors (Dr Mikovits said the guy who did the German prostate cancer XMRV study that was negative wants to try again with her techniques to see if then he can find it), especially if it takes them and the field of retrovirology into new places they've never been before. It looks like XMRV may just well be doing that.

Don't forget that it's only been 3 1/2 months since the Lombardi, et. al. paper. It took a few years for the scientific community to reach a consensus about HIV (the fact that so many of these retrovirologists are comparing it to the early days of HIV also feels very promising!). There's going to be a lot of back and forth for awhile.

But many of us are used to vertigo, right?

 

[Michelle]

Megan said:

If you take a high prevalence illness such as depression and add number of other things mentioned on this thread that could also be misdiagnosed, then marry that to the more vague definitions, then it's easy to see how CFS patients could be left as a very tiny proportion of a sample selected for study.

Isn't that sort of like what happened with the Witchita study where, at the end of it, they really only ended up including something like 6 CFS-Fukuda patients in a study of well over a 200?