.“Removing the doubt is part of the cure” (RedLabs)
Two months ago I wrote about two contradictory studies on the presence of the novel XMRV retrovirus in blood of patients with Chronic Fatigue Syndrome (CFS).
The first study, published in autumn last year by investigators of the Whittemore Peterson Institute (WPI) in the USA [1], claimed to find XMRV virus in peripheral blood mononuclear cells (PBMC) of patients with CFS. They used PCR and several other techniques.
A second study, performed in the UK [2] failed to show any XMRV-virus in peripheral blood of CFS patients.
Now there are two other negative studies, one from the UK [3] and one from the Netherlands [4].
Does this mean that XMRV is NOT present in CFS patients?
No, different results may still be due do to different experimental conditions and patient characteristics.
The discrepancies between the studies discussed in the previous post remain, but there are new insights, that I would like to share.*
1. Conflict of Interest, bias
Most CFS patients seem “to go for” WPI, because WPI, established by the family of a chronic fatigue patient, has a commitment to CFS. CFS patients feel that many psychiatrists, including authors of the negative papers [2-4] dismiss CFS as something “between the ears”. This explains the negative attitude against these “psych-healers” on ME-forums (i.e. the Belgium forum MECVS.net and http://www.forums.aboutmecfs.org/). MECVS even has a section “faulty/wrong” papers, i.e. about the “failure” of psychiatrists to demonstrate XMRV!
Since a viral (biological) cause would not fit in the philosophy of these psychiatrists, they might just not do their best to find the virus. Or even worse…
Dr. Mikovits, co-author of the first paper [1] and Director of Research at WPI, even responded to the first UK study as follows (ERV and Prohealth):
“You can’t claim to replicate a study if you don’t do a single thing that we did in our study,” …
“They skewed their experimental design in order to not find XMRV in the blood.” (emphasis mine)
Mikovits also suggested that insurance companies in the UK are behind attempts to sully their findings (ERV).
These kind of personal attacks are “not done” in Science. And certainly not via this route.
Furthermore, WPI has its own bias.
For one thing WPI is dependent on CFS and other neuro-immune patients for its existence.
WPI has generated numerous press releases and doesn’t seem to use the normal scientific channels. Mikovits presented a 1 hr Q&A session about XMRV and CFS (in a stage where nothing has been proven yet). She will also present data about XMRV at an autism meeting. There is a lot of PR going on.
Furthermore there is an intimate link between WPI and VIP Dx, both housed in Reno. Vip DX is licensed by WPI to provide the XMRV-test. Vipdx.com links to the same site as redlabsusa.com, for Vip Dx is the new name of the former RedLabs.
Interestingly Lombardi (the first author of the paper) co-founded Redlabs USA Inc. and served as the Director of Operations at Redlabs, Harvey Whittemore owns 100% of VIP Dx, and was the company President until this year and Mikovits is the Vice President of VIP Dx. (ME-forum). They didn’t disclose this in the Science paper.
TEST_RQN_Feb_2010
Vip/Dx offers a plethora of tests, and is the only RedLab -branch that performs the WPI-PCR test, now replaced by the “sensitive” culture test (see below). At this stage of controversy, the test is sold as “a reliable diagnostic tool“(according to prohealth). Surely their motto “Removing the doubt is part of the cure” appeals to patients. But how can doubt be removed if the association of XMRV with CFS has not been confirmed, the diagnostic tests offered have yet not been truly validated (see below), as long as a causal relationship between XMRV and CFS has not been proven and/or when XMRV does not seem that specific for CFS: it has also been found in people with prostate cancer, autism, atypical multiple sclerosis, fibromyalgia, lymphoma)(WSJ).
Meanwhile CFS/ME websites are abuzz with queries about how to obtain tests -also in Europe- …and antiretroviral drugs. Sites like Prohealth seem to advocate for WPI. There is even a commercial XMRV site (who runs it is unclear)
Project leader Mikovits, and the WPI as a whole, seem to have many contacts with CSF patients, also by mail. In one such mail she says (emphasis and [exclamations] mine):
“First of all the current diagnostic testing will define with essentially 100% accuracy! XMRV infected patients”. [Bligh me!]….
We are testing the hypothesis that XMRV is to CFS as HIV is to AIDS. There are many people with HIV who don’t have AIDS (because they are getting treatment). But by definition if you have ME you must have XMRV. [doh?]
[….] There is so much that we don’t know about the virus. Recall that the first isolation of HIV was from a single AIDS patient published in late 1982 and it was not until 2 years later that it was associated with AIDS with the kind of evidence that we put into that first paper. Only a few short years later there were effective therapies. […]. Please don’t hesitate to email me directly if you or anyone in the group has questions/concerns. To be clear..I do think even if you tested negative now that you are likely still infected with XMRV or its closest cousin..Kind regards, Judy
These tests costs patients money, because even Medicare will only reimburse 15% of the PCR-test till now. VIP Dx does donate anything above costs to XMRV research, but isn’t this an indirect way to support the WPI-research? Why do patients have to pay for tests that have not proven to be diagnostic? The test is only in the experimental phase.
I ask you: would such an attitude be tolerated from a regular pharmaceutical company?
Patients
Another discrepancy between the WPI and the other studies is that only the WPI use the Fukuda and Canadian criteria to diagnose CFS patients. The Canadian criteria are much more rigid than those used in the European studies. This could explain why WPI has more positives than the other studies, but it can’t fully explain that WPI shows 96% positives (their recent claim) against 0% in the other studies. For at least some of the European patients should fulfill the more rigid criteria.
Regional Differences
Patients of the positive and negative studies also differ with respect to the region they come from (US and Europe). Indeed, XMRV has previously been detected in prostate cancer cells from American patients, but not from German and Irish patients.
However, the latter two reasons may not be crucial if the statement in the open letter* from Annette Whittemore, director of the WPI, to Dr McClure**, the virologist of the second paper [2], is true:
We would also like to report that WPI researchers have previously detected XMRV in patient samples from both Dr. Kerr’s and Dr. van Kuppeveld’s cohorts prior to the completion of their own studies, as they requested. We have email communication that confirms both doctors were aware of these findings before publishing their negative papers.(……)
One might begin to suspect that the discrepancy between our findings of XMRV in our patient population and patients outside of the United States, from several separate laboratories, are in part due to technical aspects of the testing procedures.
Assuming that this is true we will now concentrate on the differences in the PCR -procedures and results.
PCR
All publications have used PCR to test the presence of XMRV in blood: XMRV is present in such low amounts that you can’t detect the RNA without amplifying it first.
PCR allows the detection of a single or few copies of target DNA/RNA per milligram DNA input, theoretically 1 target DNA copy in 105 to 106 cells. (RNA is first reverse transcribed to DNA). If the target is not frequent, the amplified DNA is only visible after Southern blotting (a radioactive probe “with a perfect fit to” the amplified sequence) or after a second PCR round (so called nested PCR). In this second round a set of primers is used internal to the first set of primers. So a weak signal is converted in a strong and visible one.
All groups have applied nested PCR. The last two studies have also used a sensitive real time PCR, which is more of a quantitative assay and less prone to contamination.
Twenty years ago, I had similar experiences as the WPI. I saw very vague PCR bands that had all characteristics of a tumor-specific sequence in normal individuals, which was contrary to prevailing beliefs and hard to prove. This had all to do with a target frequency near to the detection limit and with the high chance of contamination with positive controls. I had to enrich tonsils and purified B cells to get a signal and sequence the found PCR products to prove we had no contamination. Data were soon confirmed by others. By the way our finding of a tumor specific sequence in normal individuals didn’t mean that everyone develops lymphoma (oh analogy)
Now if you want to proof you’re right when you discovered something new you better do it good.
Whether a PCR assay at or near the detection limit of PCR is successful depends on:
- the sensitivity of the PCR
- Every scientific paper should show the detection limit of the PCR: what can the PCR detect? Is 1 virus particle enough or need there be 100 copies of the virus before it is detected? Preferably the positive control should be diluted in negative cells. This is called spiking. Testing a positive control diluted in water doesn’t reflect the true sensitivity. It is much easier for primers to find one single small piece of target DNA in water than to find that piece of DNA swimming in a pool of DNA from 105 cells.
- the specificity of the PCR.
- You can get aspecific bands if the primers recognize other than the intended sequences. Suppose you have one target sequence competing with a lot of similar sequences, then even a less perfect match in the normal genome has every chance to get amplified. Therefore you should have a negative control of cells not containing the virus (i.e. placental DNA), not only water. This resembles the PCR conditions of your test samples.
- You can get aspecific bands if the primers recognize other than the intended sequences. Suppose you have one target sequence competing with a lot of similar sequences, then even a less perfect match in the normal genome has every chance to get amplified. Therefore you should have a negative control of cells not containing the virus (i.e. placental DNA), not only water. This resembles the PCR conditions of your test samples.
- Contamination
- this should be prevented by rigorous spatial separation of sample preparation, PCR reaction assembly, PCR execution, and post-PCR analysis. There should be many negative controls. Control samples should be processed the same way as the experimental samples and should preferably be handled blinded.
- The quality and properties of your sample.
- If XMRV is mainly present in PBMC, separation of PBMC by Ficoll separation (from other cells and serum) could make the difference between a positive and a negative signal. Furthermore, whole blood and other body fluids often contain inhibitors, that may lead to a much lower sensitivity. Purification steps are recommended and presence of inhibitors should be checked by spiking and amplification of control sequences.
Below the results per article. I have also made an overview of the results in a Google spreadsheet.
WPI
The PCR conditions are badly reported in the WPI paper, published in Science[1]. As a matter of fact I wonder how it ever came trough the review.
- Unlike XMRV-positive prostate cancer cells, XMRV infection status did not not correlate with the RNASEL genotype.
- The sensitivity of the PCR is not shown (nor discussed).
- No positive control is mentioned. The negative controls were just vials without added DNA.
- Although the PCR is near the detection limit, only first round products are shown (without confirmation of the identity of the product). The positive bands are really strong, whereas you expect them to be weak (near the detection limit after two rounds). This is suggestive of contamination.
- PBMC have been used as a source and that is fine, but one of WPI’s open letters/news items (Feb 18), in response to the first UK study, says the following:
- point 7. Perhaps the most important issue to focus on is the low level of XMRV in the blood. XMRV is present in such a small percentage of white blood cells that it is highly unlikely that either UK study’s PCR method could detect it using the methods described. Careful reading of the Science paper shows that increasing the amount of the virus by growing the white blood cells is usually required rather than using white blood cells directly purified from the body. When using PCR alone, the Science authors found that four samples needed to be taken at different times from the same patient in order for XMRV to be detected by PCR in freshly isolated white blood cells.(emphasis mine)
- point 7. Perhaps the most important issue to focus on is the low level of XMRV in the blood. XMRV is present in such a small percentage of white blood cells that it is highly unlikely that either UK study’s PCR method could detect it using the methods described. Careful reading of the Science paper shows that increasing the amount of the virus by growing the white blood cells is usually required rather than using white blood cells directly purified from the body. When using PCR alone, the Science authors found that four samples needed to be taken at different times from the same patient in order for XMRV to be detected by PCR in freshly isolated white blood cells.(emphasis mine)
- But carefully reading the methods, mentioned in the “supporting material” I only read:
- The PBMC (approximately 2 x 107 cells) were centrifuged at 500x g for 7 min and either stored as unactivated cells in 90% FBS and 10% DMSO at -80 ºC for further culture and analysis or resuspended in TRIzol (…) and stored at -80 ºC for DNA and RNA extraction and analysis. (emphasis mine)
Either …. or. Seems clear to me that the PBMC were not cultured for PCR, at least not in the experiments described in the science paper.
How can one accuse other scientists of not “duplicating” the results if the methods are so poorly described and the authors don’t adhere to it themselves??
- Strikingly only those PCR-reactions are shown, performed by the Cleveland Clinic (using one round), not the actual PCR-data performed by WPI. That is really odd.
- It is also not clear whether the results obtained by the various tests were consistent.
Suzanne D. Vernon, PhD, Scientific Director of the CFIDS Association of America (charitable organization dedicated to CFS) has digged deeper into the topic. This is what she wrote [9]:
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, four of the 12 CFS subjects (WPI 1118, 1150, 1199 and 1125) included in the Science paper were also reported to have cancer – either lymphoma, mantle cell lymphoma or myelodysplasia. The presentation reported that 17 WPI repository CFS subjects with cancer had tested positive for XMRV. So how well are these CFS cases characterized, really?
The Erlwein study was published within 3 months after the first article. It is simpler in design and was reviewed in less then 3 days. They used whole blood instead of PBMC and performed nested PCR using another set of primers. This doesn’t matter a lot, if the PCR is sensitive. However, the sensitivity of the assay is not shown and the PCR bands of the positive control look very weak, even after the second round (think they mad a mistake in the legend as well: lane 9 is not a positive control but a base pair ladder, I presume). It also looked like they used a “molecular plasmid control in water”, but in the comments on the PLoS ONE paper, one of the authors states that the positive control WAS spiked into patient DNA.(Qetzel commenting to Pipeline Corante) Using this PCR none of the 186 CSF samples was positive.
Groom and van Kuppeveld studies
The two other studies use an excellent PCR approach[3,4]. Both used PBMC, van Kuppeveld used older cryoperserved PBMC. They first tried the primers of Lombardi using a similar nested PCR, but since the sensitivity was low they changed to a real time PCR with other optimized primers. They determined the sensitivity of the PCR by serially diluting a plasmid into PBMC DNA from a healthy donor. The limit of sensitivity equates to 16 and 10 XMRV-gene copies in the UK and the Dutch study respectively. They have appropriate negative controls and controls for the integrity of the material (GAPDH, spiking normal control cDNAs in negative DNA to exclude sample mediated PCR inhibition[1], phocine distemper virus[2]), therefore also excluding that cryopreserved PBMC were not suitable for amplification.
The results look excellent, but none of the PCR-samples were positive using these sensitive techniques. A limitation of the Dutch study is the that numbers of patients and controls were small (32 CSF, 43 controls)
Summary and Conclusion
In a recent publication in Science, Lombardi and co-authors from the WPI reported the detection of XMRV-related, a novel retrovirus that was first identified in prostate cancer samples.
Their main finding, presence of XMRV in peripheral blood cells could not be replicated by 3 other studies, even under sensitive PCR conditions.
The original Science study has severe flaws, discussed above. For one thing WPI doesn’t seem to adhere to the PCR to test XMRV any longer.
It is still possible that XMRV is present in amounts at or near the detection limit. But it is equally possible that the finding is an artifact (the paper being so inaccurate and incomplete). And even if XMRV was reproducible present in CFS patients, causality is still not proven and it is way too far to offer patients “diagnostic tests” and retroviral treatment.
Perhaps the most worrisome part of it all is the non-scientific attitude of WPI-employees towards colleague-scientists, their continuous communication via press releases. And the way they try to directly reach patients, who -i can’t blame them-, are fed up with people not taking them serious and who are longing for a better diagnosis and most of all a better treatment. But this is not the way.
Credits
*Many thanks to Tate (CSF-patient) for alerting me to the last Dutch publication, Q&A’s of WPI and the findings of Mrs Vernon.
– Ficoll blood separation. Photo [CC] http://www.flickr.com/photos/42299655@N00/3013136882/
– Nested PCR: ivpresearch.org
References
- 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
- Erlwein, O., Kaye, S., McClure, M., Weber, J., Wills, G., Collier, D., Wessely, S., & Cleare, A. (2010). Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008519
- Groom, H., Boucherit, V., Makinson, K., Randal, E., Baptista, S., Hagan, S., Gow, J., Mattes, F., Breuer, J., Kerr, J., Stoye, J., & Bishop, K. (2010). Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome Retrovirology, 7 (1) DOI: 10.1186/1742-4690-7-10
- van Kuppeveld, F., Jong, A., Lanke, K., Verhaegh, G., Melchers, W., Swanink, C., Bleijenberg, G., Netea, M., Galama, J., & van der Meer, J. (2010). 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 BMJ, 340 (feb25 1) DOI: 10.1136/bmj.c1018
- McClure, M., & Wessely, S. (2010). Chronic fatigue syndrome and human retrovirus XMRV BMJ, 340 (feb25 1) DOI: 10.1136/bmj.c1099
- http://scienceblogs.com/erv/2010/01/xmrv_and_chronic_fatigue_syndr_5.php
- http://scienceblogs.com/erv/2010/01/xmrv_and_chronic_fatigue_syndr_6.php
- http://scienceblogs.com/erv/2010/03/xmrv_and_chronic_fatigue_syndr_11.php
- http://www.cfids.org/xmrv/022510study.asp
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Laika's MedLibLog 
Social comments and analytics for this post…
This post was mentioned on Twitter by laikas: Blogging: Three Studies Now Refute the Presence of XMRV in Chronic Fatigue Syndrome (CFS) http://bit.ly/az7oVZ (ping didn’t work)…
[…] Attempts to reproduce this study have failed, and from my limited understanding of the science, this looks like a bust for the XMRV theory. Ah well. Maybe someday they’ll figure out what the hell is causing this stuff, and finally be able to fix it (or at least treat it properly). The current treatments are all pretty hit and miss (in my case, pretty much miss), and it would be nice to get them aimed in the right direction. […]
[…] This post was mentioned on Twitter by Laika (Jacqueline), Laika (Jacqueline), ResearchBlogging.org, Aitor Guitarte, Lurino and others. Lurino said: RT @ResearchBlogs: Three Studies Now Refute the Presence of XMRV in Chronic Fatigue Syndrome (CFS) http://goo.gl/fb/xVOsJ […]
Firstly, it’s great to find NEW, innovative perspective on the XMRV. Thanks for your work on the XMRV lab science. I’d like to add however that there are additional perspectives that one might consider before deeming the XMRV/ME/CFS linkage a bust! 3:1 is a simplistic approach that doesn’t factor in the quality of the studies – and specifically whether they were studying the same patients. Here are some other considerations to factor in:
THE CANCER LINK IN ME/CFS
In October 2009 we heard that a disproportionately high percentage of patients who have had ME/CFS for 20-30 years were presenting with clonal T-Cell receptor gamma rearrangements (a danger signal for cancer) , and were coming down with deadly lymphomas. As Stewart LeGrice, head of the Center of Excellence in HIV/AIDS and cancer virology at the US National Cancer Institute (NCI) said in the Wall Street Journal, “NCI is responding like it did in the early days of HIV”. (http://online.wsj.com/article/SB125501227713473525.html ).
PROSTATE CANCER RESEARCHERS JUMPING INTO CFS/XMRV RESEARCH
What is perhaps most compelling about the XMRV/CFS linkage is that renowned prostate cancer researchers are crossing over to the “dark side”: namely ME/CFS research. It appears that some (not all) patients with the most malignant prostate cancer Gleason Grades (and XMRV infection) share a genetic defect that is also found in many XMRV-positive ME/CFS patients: namely a defect in the RNase-L antiviral pathway. If you remember high-school chemistry, the suffix “ase” describes an enzyme, or a chemical that breaks down things. RNase breaks down RNA – and (you guessed it), XMRV, and indeed all retroviruses are made up of RNA. In short, some prostate cancer and ME/CFS patients share a genetic susceptibility to viral infection, and it is believed that a state of chronic inflammation potentially caused by XMRV may lead to cancers.
Dr Robert Silverman, prostate cancer expert, was in fact one of the authors of the Science paper on XMRV and ME/CFS. His organization, the renowned Cleveland Clinic has drawn an interesting line in the sand. Just recently, the Cleveland Clinic very publicly announced an award to Dr Silverman and his colleague Dr Klein for discovering the linkage between XMRV, prostate cancer, ME/CFS, and RNase-L (See 2-minute video @ the Cleveland Clinic’s YouTube site: http://www.youtube.com/watch?v=RWOWvdiXiSE ). Drs Silverman and Klein are being compared to the likes of Dr Sones, who pioneered the use of injectable dye imaging in cardiac surgery.
Similarly, Dr Ila Singh, another eminent prostate cancer researcher, has been forging full-speed ahead in XMRV research on prostate cancer AND ME/CFS. She has wasted no time, testing 45 compounds and 28 drugs on XMRV “in vitro” (or in the test tube)- and being reported widely in media such as USA Today and Scientific American. Not the behavior one would expect from someone who thinks XMRV is benign. Dr Singh clearly “gets” the plausability of the potential link with ME/CFS. As her team commented in their source article: http://www.plosone.org/article/fetchArticle.action?annotationId=info%3Adoi%2F10.1371%2Fannotation%2F5217bc5f-fac3-4cca-bb52-a6914754608c&articleURI=info%3Adoi%2F10.1371%2Fjournal.pone.0009948
“… the notion that a retrovirus might be involved in both cancer and a neuroimmune illness in humans is not without precedence. Human T-cell lymphotrophic virus, type 1 (HTLV-1), another retrovirus, causes both T-cell lymphoma/ leukemia as well as tropical spastic paraparesis, a myelopathy due to immune defects resulting from the viral infection.”
Dr Singh is also conducting research on XMRV and ME/CFS with Dr Bateman and Drs Light at ARUP, a cutting-edge national US reference laboratory. The Lights are noted for capturing a spectacular chemical signature of Post-Exertional Malaise in ME/CFS patients that was featured on the cover of the Journal of Pain. (See slides 26 & 27 at http://www.cfids.org/webinar/xmrv-slides-jan2010.pdf). ARUP is using sophisticated blood draw techniques, literally using stopwatches to ensure that collected blood is preserved before any XMRV might degrade.
ABOUT THOSE FAILED XMRV/CFS STUDIES:
Also consider those failed XMRV/CFS studies. An analysis of the British Medical Journal’s science on XMRV, presented as the “trump card” in negative XMRV/CFS research, reveals that their 20 year old blood samples were not from Chronic Fatigue Syndrome (ME/CFS) patients, and not remotely comparable to the Science CFS cohort. The BMJ (Nijmegen team) represented their (Vercoulen et al) cohort as CFS, when in fact they were studying the blood of largely tired, depressed patients. Here’s the evidence:
Some shocking quotes from the study where the BMJ and Nijmegen’s 20 year old blood came from:
• “Information on physical abnormalities and treatment relied on self-report”.
• “Using a score of 16 or more, 36% of patients could be considered as having a clinical depression.”
• “To test generalizability, the present study sample was compared with a recently tested group of 68 patients with Unexplained Fatigue” (not CFS).
• And the clincher: the source of the blood came from a study where they, “Minimalized the risk of including patients with delayed convalescence of a viral infection”.
For a detailed analysis of the BMJ article’s flaws, complete with meticulous references, see: http://www.forums.aboutmecfs.org/showthread.php?3860-Scandal-in-BMJ-s-XMRV-CFS-Research the 5-part article Scandal in BMJ’s XMRV/CFS Research, posts #1,2,4,6,7. The BMJ stated their XMRV research was on a “well-defined cohort” of CFS patients, when it was on a group of depressed patients with Unexplained Fatigue – which had been explicitly screened to remove patients with “delayed convalescence of a viral infection”. Not much chance of finding XMRV in that cohort. How strong are the BMJ’s conclusions that XMRV isn’t in the UK – and that it isn’t associated with CFS!
PROBLEMS WITH VAN KUPPEVELD’S REPRESENTATION OF THE SCIENCE COHORT
Van Kuppeveld’s team also rashly criticized the cohort of the Science paper as coming from an “outbreak”. Unfortunately, their facts were incorrect. From a letter published last week from the Whittemore Peterson Institute: http://www.wpinstitute.org/news/docs/DearDrMcClureaw4.pdf
“…van Kuppeveld and colleagues provide the additional information reported at a conference last year that the patients in question came from an outbreak of chronic fatigue syndrome at Incline Village on the northern border of Lake Tahoe in the mid-1980s. This statement about the origin of the 101 patient samples is untrue. The patients in the Science study were well defined in the paper as having CFS by the Fukuda and Canadian consensus definitions of ME/CFS. More importantly the patient samples did not come from the “Lake Tahoe outbreak” as you assert, but rather from patients who had become ill while living in various parts of the United States.”
GLAXO SMITH KLINE FOLLOWING THE SCIENCE TEAM’S METHODOLOGY
Pharma giant Glaxo Smith Kline just announced their own study into XMRV and ME/CFS and are so confident in the Science results that they are using positive XMRV samples from patients studied by the Science researchers (See: http://www.forums.aboutmecfs.org/showthread.php?4066-New-XMRV-study-to-be-undertaken ). In other words, GSK “gets” the difference between research on cohorts of depressed, tired patients; versus patients with rigorously defined Canadian/Fukuda criteria ME/CFS, reproducible immune abnormalities, and severe, disabling fatigue. Further, by using positive samples from actual CFS patients with XMRV in the Science study, GSK is in effect saying:
1) We believe that XMRV exists; and
2) We believe that you found XMRV in CFS patients.
3) Further, we believe that it is necessary to look for XMRV in rigorously defined cohorts of ME/CFS patients, particularly those with a viral onset – rather than 20-year old samples of tired, depressed patients. Now, can we please use your samples as a positive control?
THE PSYCHIATRY ANGLE
And now for the psychiatry angle: psychiatrists studying this viral neuro-immune disease have been stating for years that the most rigorous Canadian Criteria (2003) for ME/CFS (Summary here: http://www.cfids-cab.org/MESA/me_overview.pdf ) are just too difficult to apply in research. They have also advantageously expanded their market for exercise and feel-good clinics, by including out-of-shape patients, depressed patients, patients with Unexplained Fatigue, together with patients with classical Canadian-Criteria ME/CFS. In fact in the UK, patients with a diagnosis of ME/CFS are routinely denied biological diagnostics, such as lab-work or immunological workups. This creates a self-fulfilling prophesy, a delusion on the part of psychiatrists that ME/CFS has no physicial findings. Eschewing the rigorous Canadian Criteria is a little like saying one should abandon speed limits because no one likes to follow them. Or lumping together appendicitis patients with diffuse stomach ache patients to “simplify” research. Like appendicitis, which has right-sided abdominal pain as a cardinal sign, ME/CFS’s hallmark is Post-Exertional Malaise – something the 3 failed XMRV studies have not fastidiously observed. A helpful primer on the importance of CFS criteria has just been made available last week by noted CFS psychologist, Dr Leonard Jason. His slides on how CFS cohort selection can bias research outcomes, can be seen at: http://www.cfids.org/webinar/jason-slides041410.pdf
A WELCOME BAN ON ME/CFS BLOOD DONATIONS
So the news that the Canadian, New Zealand, and now Australian Blood Services are barring anyone who has had Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from donating blood is welcome and necessary. Here’s why:
• ME/CFS is horrendously under-diagnosed. Many patients go for years without knowing what is causing their bizarre, multisystem symptoms.
• Mild or early stages of ME/CFS are readily ignored: mistaken for “aging” or (you guessed it) anhedonia, or depression, because patients don’t physically enjoy the things they used to enjoy. The more they do, the worse they feel. Particularly given the complex, multi-system nature of the symptoms, misdiagnosis is rampant, and the easy cop-out is a diagnosis of “hypochondria”. (Remember MS used to be called “Hysterical Paralysis”; Epilepsy used to be believed to be associated with demons or witchcraft)
• ME/CFS is like MS in its relapsing/remitting nature. Many patients have had spectacular remissions, returning back to full activity (and blood donations) for months or years – only to relapse again later.
So YES to international Blood Services organizations, and indeed potential XMRV researchers: please take this retrovirus seriously. The science demands it.
ABOUT THE “MOTIVATIONS” OF THE WHITTEMORES
A final note – I have a hard time taking seriously the aspersions cast on the WPI’s motivations for developing diagnostic tests for XMRV. Yes, VIPDx profits are sunk right into the WPI – a not-for-profit… which then funds additional research for patients with neuro-immune conditions. And the problem is….?
Keep in mind that the Whittemore family if anything has “lost” millions through their direct investment to start up the WPI. If they were doing it for the money, they’d stick to their knitting – real estate, which I might add put them in the lucrative position to be so philanthropic. That a wealthy mother would be faulted for putting her money where her mouth is – and attempting to find a cure for her seriously ill daughter – is a wonderful example of Obama’s “Yes, we can” mantra. We need MORE business-savvy people like the Whittemores who can help drive desperately needed innovation in medicine!
WHO HAS THE MOST TO LOSE IF THE ME/CFS/XMRV LINK IS PROVEN?
These are fascinating times, as retrovirologists and politically-motivated psychiatrists jockey for position. After all, psychiatrists have built their reputations – and an entire industry of exercise and “positive attitude” clinics – on the backs of patients who are known in the biomedical literature to have persistent opportunistic infections – and who may also have a cancer-causing retrovirus: XMRV. And the psychs won’t give up their fiefdoms without a fight. But it is nothing short of earth-shaking that the BMJ’s XMRV research team committed such an enormous research blunder – while the “big boys” in immunology, molecular biology, retrovirology and oncology take over the exploration of what may indeed be the next AIDS. If you don’t trust XMRV research in ME/CFS, just follow what the prostate cancer researchers are doing – and they’re jumping to the “dark side”!
And yes, I’m a patient with ME/CFS, AND the RNase-L antiviral deficiency. No, I don’t get any pension – I had and lost my own company to this disease.
Dear Science_Based
Thanks for the long and detailed comment. That’s real good background information on the topic. To find a cause for CFS/ME is important, but challenging.
It was not my intention to give a complete review on XMRV, nor to discuss why XMRV could play a key role in CFS, nor to show which highly renowned scientist or pharmaceutic company believes in XMRV or not, nor to describe the consequences for blood donations, nor to deem the XMRV/ME/CFS linkage a bust (at least that was not my basic assumption)!
All I did -for this is a researchblogging post- is to try to figure out what it means that 3 studies don’t show that XMRV are present against one study that doesn’t. Note my avoidance of the word FAIL here.
You’re right. Three against one doesn’t mean much. The three studies could still be “wrong”. As a matter of fact you can’t prove that something is not there, so in a way finding something is ‘more convincing’ than finding nothing. Furthermore the WPI studies did more tests (besides PCR) than the other three.
The aim of this post was to compare the differences between the four studies. So to look merely at the scientific findings as far as reported in the published papers. I made a (short) overview of the results in a Google spreadsheet.
From this (and the text, plus the issues discussed in a previous post) it is clear that the 3 negative studies also have their flaws: the diagnostic criteria and the co-authoring by psychiatrists (who don’t believe in a biological cause) being one of them. The PCR-performance the use of whole blood makes the Erlwein study less convincing.
I did not feel too strongly about the the choice of the van Kuppeveld inclusion criteria, not because they are good (see spreadsheet), but for the simple fact that WPI states in a open letter that they did find positives PCR products in the Groom and van Kuppeveld series (I thought 3 or 4 out of 10). So if patients are not CSF patients but ‘merely’ depressed patients what do such positives mean? Probably that XMRV is not specific for CFS.
Next I merely concentrated on PCR, because if the WPI is right about positives in this sample, than the difference can only be attributed to differences in PCR-procedures. The PCR procedures were excellent in the last two ‘negative’ studies, (also good control for the quality of the older cryopreserved samples), but were very poor and sometimes strange (no controls, no sensitivity demonstrated, too strong positives after first round, only results shown by Cleveland, not their own, inconsistencies in results) in the WPI study. I’m not going to repeat this in detail. It is all in the above post.
Then WPI suggests that the “failure” of the others is due to the fact that they don’t adhere to the WPI-protocol. However, the PCR-protocol -as described in the Science paper- was used by the last two research group, but later replaced by a more sensitive PCR-test. It is more important that you have a sensitive PCR with appropriate controls than to adhere to conditions that are not optimal. For it is the sensitivity/specificity that counts.
Next WPI states that you should culture the XMRV-infected PBMC in order to get a signal, because they did so in the Science paper. But here it can’t be found. On the contrary.
These inconsistencies are worrying. So i digged deeper in what WPI says and does. And I didn’t like what I saw.
Their attitude against other scientists is very unprofessional, but what I liked least of all is that they try to “sell” patients that they have validated tests, which they didn’t. Plus their claim that they can “diagnose” CFS a 100% is not founded on hard data.
Apparently the patients just swallow it all. They are so uncritical against WPI.
Mind me, that XMRV may play a role in CFS, may still be the case. XMRV may even play a causal role. But we must await the results of other studies. They working hard on it, so it shouldn’t take too long.
The WPI findings as published in Science (alone) are not convincing, and WPI’s attitude reprehensible.
That is all I had to say.
“Apparently the patients just swallow it all. They are so uncritical against WPI.”
I think you did a good job here in your analysis.
I’ve been reading around a bit and noticing a frustration of academics, skeptics, and other science minded people toward patients. As a skeptical patient this is quite exasperating.
Please remember that patients of any illness, unless they have relevant education or training, do not have intimate knowledge of how research works. People with CFS know their experience as patients. Many have been suffering for over a decade and live in situations that most people would find devastating. Research for CFS is underfunded and a nonpriority; in the past federal health agencies have misappropriated millions of dollars assigned to CFS research into other programs. To have any researchers actually interested in studying them is like shining a light in a dark little room. Please don’t judge them.
I too am dismayed by the lack of professionalism by the WPI; the handful of patients posting comments on blogs or message boards are not indicative of the entire patient group as a whole. Thankfully the XMRV research is in more objective hands.
Bravo for the “Science-Based” response! It should be obvious that the National Cancer Institute/ Cleveland Clinic/ and Whittimore Peterson Institute have the preponderance of evidence on their side – and making snide remarks about their presumed motivations are irrelevant. Thank you for your detailed response. A fellow person with CFIDS/CFS/ME.
Mark Elliott
[…] Three Studies Now Refute thе Presence οf XMRV іn Chronic Fatigue Syndrome (CFS) &laqu… […]
I wanted to make just one correction, as Science Based addressed all other issues quite well.
You quote Dr. Suzanne Vernon of the CFIDS Association of America and state the following:
” The presentation reported that 17 WPI repository CFS subjects with cancer had tested positive for XMRV. So how well are these CFS cases characterized, really?”
The presentation she is referring to was one that described findings after the Science paper; it did not refer to the Science study samples. In a Q & A by the WPI on March 29, 2010, they state the following:
“Did any of the samples used in the original study come from patients who ultimately developed cancer?
Yes, one. ”
I thought you may also find interest in the following 2 recent studies:
http://www.ncbi. nlm.nih.gov/ pubmed/20425007
PubMed
Curr Allergy Asthma Rep. 2010 Apr 7.
Quote from study:
“The six strains of XMRV that have been sequenced have greater than 99% identity, indicating a new human infection rather than laboratory contamination.”
And
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010255
Plos One
“Therefore, the recent evidence of authentic infections of humans by XMRV and the association of XMRV infection with prostate cancer and chronic fatigue syndrome [1], [6], [7] are alarming and warrant further investigations to determine the causal relationship and pathogenic mechanisms.”
[…] More @ Laika’s MedLibLog […]
What about Myra McClure Saying she was 1000 % sure XMRV did not cause cfs. The UK press have touted the negative studies as absolute proof that WPI is wrong and that there is no xmrv in the UK at least.
The result is that WPI cannot get funding to continue the research. Had WPI said nothing that might have been the end of all funding etc.
The UK psycho-babbble crowd moved quickly to shut down all research into XMRV and CFS. McClure made statements to the UK press that she must have known to be false. One of the worlds formost retrovirologists of more than 40 years “Dr John Coffin” has praised the work methods of Mikovits and WPI. He believes the possibility of contamination implied by McClure is very very remote to impossible. Mc Clure was implying her results were 1000 % right and further -ve psyche studies appearing to confirm this means there are no government research grants to look further. WPI are now in financial strife with no money to keep things going at a good pace or quality. I don’t blame WPI for speaking. McClure has back tracked a little since the web response has shown her to be a deceptive Hag.
Lets not forget that without Mikovits this study would not have been done at all. The major reason for the lack of progress in this disease has been that the majority of the patients happen to be women. So to some bloke patients slagging off Mikovits and WPI. You should be damned grateful for the work she and Annette have done for you. Perfect or not. I am always suspicious of people being misquoted. I.E. In rape cases here in NZ deliberate lies are fed to the media about trials and complainents. This happened in one high profile case where men were feeding complete lies to our media which they published as truth without question. The womens stories completely distorted on purpose. Luckily she had the guts to take it and perseverred with the truth finally being undeniable.
God bless Judy Mikovits. No matter who completes her work and claims credit for it, or even if her discovery proves to be wrong I am so grateful that she has tirelessly worked towards finding the cause of and illness which as ruined my entire life. No one else gives a toss.
Judy Mikovits, Annette Whittemore and Dan Peterson are my hero’s and real scientists because they do not go along with all the rubbish science from respected circles who have willingly denegrated and destroyed us.
[…] I am about to notify both Jason and the authors of the article and send them the famous PLoS ONE t-shirts as prizes. This month’s runners-up are Jeremy of Voltage Gate, Razib from Gene Expression and Jacqueline of the Laika’s MedLibLog. […]
UPDATE FROM PRAGUE
I have an interesting update from the latest retrovirology conference in Prague from today, and some more info that might interest your readers.
THE IMPORTANCE OF CONTEXT IN SCIENCE
Firstly, I wanted to acknowledge: yes, this is a researchblogging site. But medical science doesn’t happen in a vacuum, and I would argue that a holistic perspective – particularly in this controversial arena – is essential. I learned a great deal from the prior discussion on lab science, and genuinely appreciate your openness to acknowledge different perspectives. However the context – particularly the political and economic drivers around ME/CFS MUST be considered in order to make an informed and judicious pronouncement on the science. And that includes assessing the thorny cohort issue, and the mind-bending reality that psychiatrists have such a stranglehold on ME/CFS science that they deem physical tests to rule out infection or immune abnormalities etc. “feeding into” the patient’s delusions. ME/CFS is the mainstay of Medically Unexplained Disorders – contributing a huge number of patients to a juggernaut psychiatric industry. What we have is a situation where medical progress on Medically Unexplained Disorders has screeched to a grinding halt in many countries – and beleaguered physicians have allowed this to happen. In the UK, patients with a diagnosis of ME/CFS, are routinely -and as a matter of policy – denied lab diagnostics. There is abundant evidence that psychiatrists inflate the ME/CFS cohort to include psychiatric diagnoses – and that overwhelmed physicians inappropriately punt their complex multisystem disorder patients to the psych profession. It’s a massive cop-out. Just look at the latest submissions to the DSM under Somatoform Disorders. A personal example: my first family physician would only allow me to talk about one symptom per visit. This ensured that she never saw that this was a complex, multisystem disease. At the end of the day, we’re on the same team: patients are simply focused on ensuring that science on our disease is robust and unfettered by economic and ego bias.
IS XMRV SPECIFIC TO ME/CFS?
To address your question: will the practice of “padding” ME/CFS cohorts with psych patients bring the finding of XMRV to zero, even in these lousy Vercoulen/van Kuppeveld studies? No – after all preliminary indications are that from 1.7 (Japanese) to 3.7% (American) of healthy controls have XMRV – AND it is entirely feasible that patients with early, mild, or remitting ME/CFS might be in those cohorts. After all, I wasn’t diagnosed until year 9, and during remissions I was willing to try just about any therapy.
A SAMPLE SIZE OF 10
As a patient with ME/CFS and with everything at stake, I would also add that basing your statement about XMRV in CFS, on a sample size of 7 or 10 patients is statistically rather thin: “So if patients are not CSF patients but ‘merely’ depressed patients what do such positives mean? Probably that XMRV is not specific for CFS.” Come on – with a sample that small, any such conclusion about epidemiology is conjecture at best. What IS really interesting is that WPI (using techniques validated in the Cleveland Clinic, National Cancer Institute and WPI) could find XMRV when van Kuppeveld couldn’t.
FOUR METHODS USED BY THE SCIENCE TEAM, NOT JUST PCR
Also, you did a very detailed analysis of the PCR. But the Science team used four methods, and they have been very open and transparent about this – in fact generating flak for sharing this information:
– PCR (67%)
– Antibodies in plasma (19/33)
– Transmissible virus in plasma (10/33)
– Protein expression i Decitibine (5Aza2DC) treated PBMC’s (10/33)
Thus 99/101 patients in Science paper ultimately showed evidence of XMRV infection. I would also add that there exist abundant examples on the net of open and documented invitations by Dr Silverman at the Cleveland Clinic, and Dr Mikovits at WPI to collaborate. And they have indeed followed up with many labs who have openly asked – and received – assistance in their lab protocol. THOSE are the results that I’m really interested in – the ones who care enough to TRY to replicate the Science team’s work.
A couple of updates that might add more to the discussion:
1) POSITIVE XMRV STUDY A MATTER OF TIME ( Published today at Orthomolecular Magazine: http://www.voedingenpsyche.nl/nieuwsitem.php?item=86 and translated from Dutch) Of particular note – the translated comments by world-renowned retrovirologists John Coffin, and also Francis Ruscetti:
“U.S. researchers presented last October in Science, a breakthrough around the chronic fatigue syndrome (CFS). In the blood of CFS patients, they found traces of the retrovirus XMRV. Thereafter, three groups of researchers, including one from Nijmegen, these findings do not confirm. The first positive “replication study” seems only a matter of time, as demonstrated during the “Centennial Retrovirus Meeting in Prague.
In the June issue of the journal expanded Ortho will focus on the multi-day conference in Prague today her last day for you. Especially in the corridors was the youngest retrovirus the talk of the day. Insiders agree that the negative XMRV studies have been published so far, replication studies were not pure. For this week addressing the various research too heavily on that of U.S. researchers. This objection also applies to a still unpublished German study, which was not XMRV found in blood samples from CFS patients.
Recently visited the American investigator Dr. Judy Mikovits different European research groups to instruct them in proper laboratory technique. It is now clear that these visits are starting to pay off. During the Prague Congress Mikovits explained the complex methodology of the Whittemore-Peterson Institute (WPI), the National Cancer Institute (NCI) and the Cleveland Clinic to further extend. This method, in which the virus is grown, is needed because XMRV only in extremely low concentrations present in the peripheral blood.
Francis Ruscetti of the renowned NCI – a U.S. government agency – Ortho spoke against hope that the controversy in 2011 the world will be. He especially surprised about the fact that the investigators of the UMC St. Radboud in their publication that concealed the Americans in the same blood samples from Dutch patients found traces of XMRV. “I do not know how ethical they think they get away,” said Ruscetti. “I do not think this is good science.”
Ruscetti pointed out again that the WPI, the NCI and the Cleveland Clinic four procedures applied in their research. “In the negative studies only tried a (one) procedure.” Ruscetti well ventilated his annoyance over what he calls the “whisper campaign” about contamination. For according to the Nijmegen Dutch researchers, the Americans have blood samples contaminated or polluted.
Ruscetti may include the support of Prof. Dr. John Coffin, both linked to the NCI as at Tufts University in Boston. He is considered one of the most prominent retrovirologen world. “People have raised the issue of contamination,” said Coffin. “But nothing is known about at the moment. There is no proof. Much of the research is done at the NCI, in the laboratory of Francis and Sandra Ruscetti. They have a long experience with these viruses and are very cautious. ”
Coffin emphasized again that doing a replication study implies that the exact same manner. “None of the negative studies have been published so far, the virus is grown,” said Coffin. “Only in the Science study has been done, and that is a very strong point.” The researchers from Nijmegen missing at this leading conference.”
2) THE REBUTTAL LETTER about not disclosing positive WPI results: by Frank van Kuppeveld (http://www.umcn.nl/Research/Departments/kcv/Documents/F%20v%20Kuppeveld%20brief%20naar%20Whittemore.pdf) In this open letter to the WPI, Dr van Kuppeveld confirms that samples of his cohort were sent to the WPI and did test positive – but his team intentionally withheld this information: “Given the robustness of our paper, we considered it scientifically premature to report this finding before having settled the reason for the discrepancy.” Interestingly, van Kuppeveld also notes that the paper was rejected by the Lancet.
Yet the BMJ published this work? Did or did not the BMJ know about this withholding of information? And isn’t that what the Discussion section of research papers is for? Since when is it OK to not publish conflicting results, and to assume that you know the reason for the discrepancy?
Now let’s revisit Coffin and Ruscetti’s comments from the Prague Retrovirus Conference:
FRANCIS RUSCETTI “I do not know how ethical they think they get away,” said Ruscetti…”In the negative studies only tried a (one) procedure (qPCR).” Ruscetti well ventilated his annoyance over what he calls the “whisper campaign” about contamination.
JOHN COFFIN: “People have raised the issue of contamination,” said Coffin. “But nothing is known about at the moment. There is no proof. Much of the research is done at the NCI, in the laboratory of Francis and Sandra Ruscetti. They have a long experience with these viruses and are very cautious.”Coffin emphasized again that doing a replication study implies that the exact same manner. “None of the negative studies have been published so far, the virus is grown (have grown the virus),” said Coffin. “Only in the Science study has been done, and that is a very strong point.”
———————————————————————-
I’m hanging my hat with Coffin, Ruscetti et al. – not a bunch of psychiatrists and their cabal, who stand to lose their reputations, fiefdoms, contracts with insurance and pharma companies, and more. And yes, the esteemed NCI researchers may prove that XMRV isn’t “it” in ME/CFS. But at least they will have done so thoroughly and fastidiously: that’s all we patients ask for. In the interim however, apparently many researchers just swallow what they read. They are so uncritical against the BMJ and entrenched interests. And their noses are definitely out of joint at an upstart, and innovative grassroots enterprise that is supremely motivated to find a cure – albeit on a learning curve when it comes to PR.
All this to say – keep an open mind on the emerging XMRV/ME/CFS science, and for those of you also digging into analysis, DO also consider whether we are comparing apples with oranges – and why. Sometimes it’s also helpful to hear the perspective from a patient who has lost “only” 11 years – in the prime of life – when other ME/CFS patients have lost 2,3, and more decades. Put yourself in our shoes. If you saw garbage research coming out – when there was the potential for treatment on the horizon – if not a cure – would you fight to see that science proceeded credibly? Or would you sit back, content to wait another decade? On the flip side, we don’t want false assurances that XMRV is “it” if it isn’t. Bottom line, we want effective treatment! And that will only come from credible and open-minded science that is willing to overturn entrenched paradigms. Time is ticking, and many of us have little of that left.
Pesky though patients can be, we are after all, your bread and butter. And the raison d’etre of docs and researchbloggers – or am I wrong? It is only natural for us to contribute to the integrity of the discussion – particularly when it is at risk of derailing a promising search for a cure. Just count how many times your title: “Three studies now refute the presence of XMRV in CFS” was tweeted.
Here’s where the rubber hits the road: the Whittemore-Peterson Institute, which spearheaded the XMRV/CFS discovery, has yet to receive government funding. And this is the spirit of scientific innovation? Why fund the laggards, when the upstart is already in sprint mode, with their first publication in Science? Oh right, many of the committee members who dole out government funding for ME/CFS are psychiatrists. Catch 22.
It’s time to put aside grievances over an entrepreneurial spirit in medicine, and to see the forest for the trees. WPI and their team of the Cleveland Clinic and NCI literally blew ME/CFS scientific conventions out of the water. Don’t hate WPI because they’re beautiful!
Excellent post and some thoughtful well thought out replies.
For those interested in following the web 2.0 virological end of XMRV drop in on the award winning blog http://www.virology.ws/ where Columbia University microbiology professor Dr. Vincent Racaniello helps make virology understandable. It’s nice to hear from someone who is just interested in the scientific process regardless of the outcome and sticks to the peer-reviewed research.
(Like many, Dr. Racaniello accepts ME/CFS as a devastating organic disease as does the World Health Organization. The ICD-10 exclusively lists myalgic encephalomyelitis under the brain disease nomenclature G93.3. Both post-viral syndrome and the chronic fatigue syndrome (CFS) are also listed under G93.3 in the alphabetical index pg. 528. Phew. Say that ten times fast.
And, as an aside to this debate, it should be noted that modern scientists know that one disease can be caused by many different pathogens and that many different diseases can be caused by one pathogen. So scientists are looking at not only the role of XMRV in disease, but the possibility of other pathogens and toxins as well as synergy between multiple toxins and pathogens in diseases including ME/CFS. One pathogen = one disease is so 19th century.
Scientists are also researching the possibility that a virus or toxin, in and of themselves non pathogenic, can trigger a cascade of multi-system signs, symptoms and even diseases (possibly related) in genetically or immunologically vulnerable individuals. For example, retroviruses are known to trigger the kind of viral persistence and reactivation of the many viruses researchers have found in subgroups of CFS patients.
As noted by virologist Dr. Dharam V. Ablashi, co-discoverer of HHV-6 A&B, in U.S. DHHS testimony, “While infection may not trigger the illness in all cases, I have long believed that the evidence indicates
infectious agents are involved in many cases. Indeed, the literature documents clearly that CFS can follow in the wake of infection with Epstein‐Barr virus, human herpesvirus‐6, Ross River virus, B.
burgdorferi (the cause of Lyme disease), C. burnetii (the cause of Q fever), parvovirus B19, the enteroviruses and possibly mycoplasma organisms…”
“…Even if XMRV is found in the majority of CFS patients, we expect that there are at least 8‐12 other pathogens that act as co‐factors to cause pathology. Unless you are looking for subsets, infections such as parvovirus B‐19 or Q fever (which might represent a small fraction of the cases) will be completely overlooked as unimportant. Statistically, none of the subsets may be statistically significant, but when added together, these subsets could be very important.”
Dr. Ablashi went on to note, “Given the known tropism of retroviruses, XMRV is an entirely plausible candidate to be producing the well‐documented abnormalities of the central and autonomic nervous system, of the immune system, and of energy metabolism. Moreover, it is entirely plausible that XMRV may reactivate latent infectious agents—particularly the herpesviruses and endogenous retroviruses—which then contribute to producing pathology.”
Another question may be whether such viral subsets account for the variety of signs and symptoms in various subgroups of CFS patients based on the tropism of the viruses activated.
So why are the scientific results uneven, what might it mean and how might additional studies – negative or positive – build on this knowledge?
Dr. Ablashi states, “It is imperative that the CDC study biopsy samples from the gut, and brain as well as heart tissues, and that they look at spinal fluid.
Most of the studies done … have been on serum. However, many pathogens cannot be found in the serum because they do not circulate in the peripheral blood after the initial infection.
For example, Dr. Steven Jacobson’s team at NIH has found a high viral load of HHV‐6 in the brain tissue biopsies from mesial temporal lobe in epilepsy patients, even though serum and spinal fluid were negative for the virus. They also found that HHV‐6 is barely detectable in the spinal fluid, even after full‐blown HHV‐6 encephalitis. A virus such as HHV‐6 can persist in the brain tissue in spite of completely normal antibody levels in the peripheral blood.
Of course it is far more convenient to look for virus in the serum.”
That and patients sometimes object to researchers slicing open their head to rummage around for tissue samples.
Seriously though, this obviously begs the question of viral reservoirs in disease as well as the disease stage of the patient studied.
Regarding PCR methods, as retrovirus expert Dr. Stephen Goff, who believes more data is needed to say one way or the other regarding pathogenicity, points out in a recent podcast,“… there might be PCR primers that people are using that don’t work for some strains of virus. One base pair is all you need in the primer to cause you to miss that…”
Although the focus right now is unfortunately on a relatively few contentious scientists on both sides and knee jerk reactions by uninformed people there is good science being promoted and done as well as thoughtful discussion in this area.
In any other disease educating patients and clinicians would probably not be seen as a nefarious scheme – many physicians and organizations do so regarding a multitude of diseases – even those with multiple points of view. For example, regarding CFS, check out the wide variety of scientific webinars hosted by the CFIDS Association for example or check the information given by the WPI using original sources in PubMed.
Nor are the researchers and clinicians at the WPI or the professors of in two of the European studies and their reactions representative of everyone in their various professions or the field. For example, check the website of the highly professional International Association of CFS/ME (www.iacfs.org) which is the largest body of ME/CFS biomedical and behavioral researchers, educators and clinicians in the world.
Although there is far more money thrown at the yet unproven psychosomatic hypothesis that CFS and other diseases such as GWS and fibromyalgia are in truth psychosomatic in nature – as pointed out by Laika – it’s hard to prove a negative.
As well, it could be it is much easier to focus on unhappy patients rather than to actually read the research. It may even be an attempt to deflect attention away from legitimate biomedical and behavioral researchers who disagree with the psychosomatic theory, their published findings as well as published evidence of pathological processes and abnormalities in subgroups of ME/CFS patients.
Disagreement with the medical evidence and explanations, or being unfamiliar with such evidence, is not necessarily the same thing as the signs and symptoms of ME/CFS, or other diseases, being “medically unexplained.”
Which circles back around to the question, “Are they even studying the same groups?”
Many researchers believe CFS has become an umbrella term. One which may well include people who are merely tired or depressed as well as patients with this severe neuro-immune disease. Or even patients with diseases that may have some core symptoms in common. It’s as simple as that whole apples and oranges thing.
The 1994 Fukada CFS definition, used by three out of the four studies referred to on this blog, is essentially a cafeteria diagnosis. Patients need only have four out of eight symptoms to meet that particular criteria for CFS and have experienced “fatigue” for six months or longer.
You don’t need to be a statistician to see that patients studied under this loose of a definition may have little in common when you get down to the nitty gritty.
Unlike the Fukada definition, ME/CFS patients diagnosed under the 2003 Consensus Criteria – which only Lombardi et al used – are required to be more than tired. They must have the pathogenic symptom of post exertional exhaustion upon very little exertion lasting more than 24 hours to be considered an ME/CFS patient.
It could be said that vague and undifferentiated terms often contribute to poor science, confusion and misinformation as does the failure to control for variables.
Many of the upcoming studies on XMRV in CFS such as the Glaxo Kline Smith study, are also now requiring this more rigorous and selective criteria. After all a differential diagnosis isn’t based on disability or function alone – it requires severity as well as frequency. And homogeneity in patient groups is as critical to replicative work as methodology.
Additional funding of well-defined CFS studies in proteomics, molecular diagnostics and metagenomics will most likely render the debate moot at some point.
Multiple sclerosis was originally termed “faker’s” disease or “hysterical paralysis.” The invention of the MRI and demyelination studies settled that debate. As did the discovery that a bacteria known as h. pylori was found to be the main cause of ulcers rather than stress.
The search for somatic biomarkers in any disease is unlikely to be an attempt by anyone to “get rid of the psychiatrists” as claimed by psychiatrist Dr. Wessely (2009), one of the psychosomatic professors involved in Erlwein et al. (As an aside it should also perhaps be noted that this is the same Dr. Wessely who controls which CFS studies are entered into the Cochrane database which mainly consist of his own and that of his colleagues so maybe the WPI isn’t the only one with motives.)
As psychologists will tell you, psychosocial overlays can be found in all organic diseases, but that doesn’t automatically mean they are present or that they are not a normal response to being severely ill. And scientific, and for that matter human, knowledge is never complete, but such lack isn’t automatic proof diseases are psychosomatic disorders in and of themselves or that infectious elements don’t have a role.
The scientific process will work itself out and responsible blogging such as Laika’s will do much to make sure that process happens.
** Factual notation regarding the role of insurance companies in CFS: in the early part of the decade the attorney general’s in New York, California and Tennessee sued the disability conglomerate UnumProvident for denying legitimate claims. Google it. Both Dateline and 20/20 did pieces on it as did other journalists. Among those included in the class action suits were patients with fibromyalgia, ME/CFS and GWS.
The basis of the lawsuits was essentially this – payouts on disability insurance claims are divided into lifetime benefits for patients diagnosed with organic diseases and maximum payouts of two years for patients who have so-called “stress-related” diseases or mental illness. Claiming patients have a psychiatric disorder saves them possible millions or billions. And that is what UnumProvident was proven to be doing. Who says Big Pharma is the only health care business proven to play dirty pool to boost their profit margin?
And this is where Dr. Mikovat’s reference may have come from – Unum Provident, which among others used UK psychosomatic medicine professors and other consultants, to declare disabled patients were “mentally ill” – despite medical evidence to the contrary. UnumProvident “lost” and paid out millions of dollars to patients.
The connection between disability and insurers and psychosomatic practitioners is easily verified – go to the APA site and check the formally declared conflict of interest statements of some of the members of the American Psychiatrists Association DSM-V psychosomatic working group – in particular that of UK psychiatrist Dr. Michael Sharpe – and you will find disability insurance companies.
Another small world note – Dr. Sharpe was the lead author of the 1991 Oxford criteria used by the small, controversial Dutch study looking at XMRV in CFS. Original source – check PubMed.
An excellent post. My view is that the controversy will only be resolved when the WPI, and one or more of the groups who’ve shown negative findings, analyze the same blood samples.
Say the WPI could send in 50 “positive” ones, someone else (i.e. from Europe) sends in 50 “negative” ones, the 100 samples are then somehow mixed up and anonymized, and both “sides” analyze them.
This should show once and for all whether there is some difference in method and if so, which samples are affected. If the WPI are able to correctly find XMRV in the ones they originally declared “positive” and find none in the European blood, that strongly suggests that the WPI are right that there is XMRV, but only in America.
I’ve heard rumours that the WPI have analysed some European samples but I don’t think they’ve published it yet.
Two new developments adding fuel to the XMRV quest:
WPI AND CERUS CONFIRM INACTIVATION OF XMRV BY THE INTERCEPT BLOOD SYSTEM
From: http://www.marketwatch.com/story/whi…k=MW_news_stmp
CONCORD, Calif. & RENO, Nev., May 18, 2010 (BUSINESS WIRE) — The Whittemore Peterson Institute for Neuro-Immune Disease (WPI) and Cerus Corporation announced positive results from a study demonstrating the efficacy of the INTERCEPT Blood System to inactivate XMRV, a human retrovirus, in donated platelet components. After sample platelet components were inoculated with XMRV, the infected blood components were treated with INTERCEPT, a system that inactivates pathogens in donated blood. Following treatment, no evidence of infectious XMRV was detected in blood samples. The study results have been submitted for presentation at the AABB Annual Meeting in October.
Further information available at: http://finance.yahoo.com/news/Whittemore-Peterson-Institute-bw-988313878.html?x=0&.v=1 and http://www.wpinstitute.org/news/docs/WPI_pressrel_051810.pdf
GERMAN STUDY POSTED ON CDC WEBSITE CONFIRMS FINDINGS OF XMRV IN CONTROLS; INCREASED IN IMMUNOCOMPROMISED PATIENTS
This German study was posted yesterday on the U.S. Centres for Disease Control website at: http://www.cdc.gov/eid/content/16/6/pdfs/10-0066.pdf Interesting, because the results are from several centers in Germany, and because they are interestingly in line with the finding of XMRV in controls (1.7% Japanese; 3.7% US), with heightened prevalence in immunosuppressed patients. Additionally, one of the centers is the Robert Koch Institute – the same institute where Bannert and his colleagues were not able to find XMRV in their prostate cancer cohort. Now what we need is for the Koch scientists to put their heads together and retest those prostate cancer samples. Excerpts from this latest article:
“Xenotropic murine leukemia virus–related gammaretrovirus (XMRV) has been recently associated with prostate cancer and chronic fatigue syndrome. To identify nucleic acid sequences, we examined respiratory secretions by using PCR. XMRV-specific sequences were detected in 2%–3% of samples from 168 immunocompetent carriers and ≈10% of samples from 161 immunocompromised patients.
The observed increase in prevalence among immunosuppressed patients with RTI suggests that XMRV might be reactivated in absence of an efficient antiviral defense. Together with earlier observations on increased XMRV replication in RNase L–deficient cells (1,12), this finding implies that the immune system plays a role in controlling XMRV replication (Note: I’ve tested positive for this deficiency). It remains unknown whether immunosuppression predisposes a patient to secrete infectious XMRV from the respiratory tract or whether presence of virus might be meaningless for epidemiology in a way similar to HIV-1 (15). Future studies should address whether the respiratory tract might serve as a source of XMRV infection or whether immunosuppression might cause an increased risk for primary infection.”
The investigators compared three groups of patients:
• Group 1 comprised patients who had traveled from Asia to Germany; location of their permanent residency was unknown.
• Groups 2 and 3 and the control group comprised only persons from northern Germany.
• Group 3 comprised patients with severe respiratory tract infections and immunosuppression as a result of solid organ or bone marrow transplantation.
If the original Science prevalence is confirmed (~67-95% XMRV in ME/CFS patients), and causality established, this raises one interesting possibility that ME/CFS patients might be even more vulnerable to XMRV than organ/marrow transplantation patients…. Very interesting stuff.
After reading the post and all the comments I understand that XMRV though associated with Chronic Fatigue Syndrome, may not be a causative factor for it.
NATIONAL INSTITUTES OF HEALTH AND FEDERAL DRUG ADMINISTRATION IN US CONFIRM SCIENCE FINDINGS OF XMRV IN CFS
Readers might be interested that the web has been buzzing with news that the NIH and FDA have confirmed the Science findings of XMRV in Chronic Fatigue Syndrome patients. The unofficial report is from here: http://www.mmdnewswire.com/xmrv-9040.html (attached), and it refers to a presentation given by Dr. Harvey Alter of the U.S. National Institutes of Health, in Zagreb, Croatia, this May.
Dr Alter is renowned for discovering the Hepatitis C virus – and is head of the Infectious Diseases section, Department of Transfusion Medicine, at the National Institutes of Health.
From Dr Alter’s Zagreb presentation here: http://www.sanquin.nl/ipfa/ipfa.nsf/Web%20Body?OpenFrameSet&Frame=Body&Src=%2Fipfa%2Fipfa.nsf%2Fv-HomePage%2F%24first!OpenDocument%26AutoFramed . From slide # 10:
“Comments on the Agent Du Jour -XMRV
•The data in the Lombardi, et al Science manuscript are extremely strong and likely true, despite the controversy. Not only have they detected gag and envelope XMRV sequences, but they have infected prostate cell lines and recovered gamma retrovirus particles and have transmitted XMRV to rhesus macaques by the IV route and demonstrated infectivity
•Although blood transmission to humans has not been proved, it is probable
•The association with CFS is very strong, but causality not proved (MY note: “Yet”)
•XMRV and related MLVs are in the donor supply with an early prevalence estimate of 3%‐7%.
•We (FDA & NIH) have independently confirmed the Lombardi group findings”
How’s that for a barn-burner? I do recognize that causality has not yet been proven, and of course it will also remain for research to show a link with associated conditions and causes of early mortality such as lymphomas and viral cardiomyopathy. But this news should give the skeptics an opportunity to pause. If patients have been forthright all along about the debilitating symptoms of fatigue, perhaps the medical community should actually lean forward, to listen more carefully to the myriad and complex multisystem complications of ME/CFS, including Atypical Angina … which is reported to be fatal in so many of us. After all, the FDA/NIH have one-upped the WPI, noting that XMRV and related MLVs are in the donor supply with not just 3.7% prevalence (as per the initial Science study for XMRV); but 3-7%. If the 7% figure holds true, that’s 21.6 Million people in the US alone that might be infected. What are the triggers that prompt pathology? These kinds of important questions will no doubt be addressed in feverish research. And we thought SARS was bad…
This is however a very positive step in unraveling this mystery – that has devastated so many of our lives. The word on the street is that the formal NIH/FDA studies will be formally released shortly. And if you are thinking what a drain ME/CFS patients will be on the system, just consider all the decades that many of us have not been able to contribute income tax. Please, help get us healthy, so we can go back to work!
Kelly, thanks for your excellent post on the economics and the politics behind the ME/CFIDS denialists negative posturing on WPI, Mikovits, Lombardi and the whole XMRV field.
I find it amazing that people can get so upset over Mikovits mentioning UnumProvident’s involvement in trying to derail research into the biomedical causes of ME/CFIDS, but don’t display the same intensity of outrage at the FACT of what this and other disability insurance companies have been doing for decades. Unum also advises the UK government on how to deny disability to those with ME/CFS there. They give a Vulture Award to the employee who can deny the most claims. The psyche lobby is intimately involved in denying disabled and seriously ill people the medical care they are entitled to by law and by medical ethics. Where’s the outrage at that?
Bill Reeves at CDC tried to do the same thing in the US and only narrowly failed at it. But much of his misinformation is still on the CDC website and shows up in their philosophy and “research” goals. They’re still trying to “prove” this disease is caused by stress and the “inappropriate response” to stress. It’s a slightly updated form of thinking that illness is caused by witchcraft!
Anyone blogging on this topic who doesn’t know the history and the politics behind it really does science and the sufferers of ME/CFS a big disservice. Anyone who has been paying attention to this, as I have for 28 years of this illness, would know that a paper that has Wessely’s name on it is going to be anti-science spin. People in UK have died of ME because of this man and his cronies. Treating him as if he were on the same level as Lombardi, Mikovits, Silverman, the Ruscetti’s…it’s just plain misinformation, at best. The Dutch paper also came from the psyche lobby.
Dr Myhill in UK is being persecuted for treating ME sufferers as if they had a real illness instead of forcing them into exercise “therapy” and talk “therapy” according to government guidelines.
Recently two doctors in Belgium have been “convicted” of treating ME sufferers as if they had a physical illness instead of a mental one. They’ve lost their license to practice and are being fined and forced to repay the State for the medications they prescribed for their patients. This is no trivial matter. The power struggle and the economic battle are very real and have extreme repercussions.
Thank you, too, Science_Based. I’m sure you’ve heard by now that the FDA and the NIH have recently confirmed, in a yet to be published paper, that XMRV is even more prevalent in ME/CFIDS than the original WPI paper in Science disclosed.
It’s really way past time for those who would sustain the status quo to get out of the way and let the “racehorses” of XMRV do what they do so well. That term, “racehorse”, is how Annette Whittemore described Judy Mikovits, adding that everyone else is just a plough horse. A truly apt metaphor. So, all you plough horses, time to get out of the way.
From someone who has been suffering the exact symptoms of CFS for the last 3 years after a risky sexual incident and being infected with CMV I have been researching trying to find out the root cause of my fatigue, vitamin loss, IBS, and being blamed for imagining all of this came to a dead end. So much info out there with the best doctors stating I am imagining all of this.
My question could CMV cause all this what is happening to me?
HOw do we test for XMRV? Do we begin anti virals?
Two doctors in america called Dr Lerner and Dr cheney seem to have done ground breaking work on CFS. Anyone else have any experience with them or heard about them?
If anyone replies I can then go onto to tell you guys exactly the myriad of symptoms I am facing. I hope together we can find an answer to the troubles afflicting us.
Shamus, in response to your enquiry re: CMV and XMRV… there are a few helpful forums where you can hear often up-to-the-minute discussions on the latest XMRV and ME/CFS developments. A few suggestions – check out:
XMRV Global Action on Facebook: http://www.facebook.com/pages/XMRV-Global-Action/216740433250?v=app_2373072738#!/pages/XMRV-Global-Action/216740433250?v=wall
The Good Science Forum: http://www.mecfsforums.com/index.php
Phoenix Rising forum at: http://www.forums.aboutmecfs.org/forum.php
Like anything on the internet, use your judgement in digesting info at these sites.
The short answer to your Cytomegalovirus question – yes, several opportunistic viruses (eg. CMV, EBV, HHV-6, Parvovirus B19) are variously associated with ME/CFS. The question seems to be not necessarily, “which virus do you have”, rather, “why can’t patients with ME/CFS fight off common viruses that are largely insignificant to the general population?” The possibility of a retrovirus (eg. XMRV) underlying all these infections, causing immune deficiency is entirely plausible. There has been discussion of a “two-hit” hypothesis, where patients might have XMRV which then gets activated by exposure to a second pathogen; toxic exposures; vaccine adjuvants; or hormonal fluctuations (eg. cortisol, testosterone). In other words, your persistent CMV infection may be a symptom of an underlying retroviral infection. You can learn more about testing also at the forums identified above.
Best of luck…
Shamus, I hesitate to answer such questions, because I’m not a doctor and I think I should refrain from any sort of ‘medical advice’. I can discuss scientific background though, although my specialism isn’t virology. With regard to CFS, no cause has been found yet. Associations with CMV, EBV and many other viruses, likely don’t mean a lot, because many people (up to 80%) are exposed to these viruses, i.e. they are not specific for CFS. However, some conditions including retroviruses, might reactivate such viruses (ie. CMV retinitis in AIDS). Therefore, I agree with science_based when he/she says: The question seems to be not necessarily, “which virus do you have”, rather, “why can’t patients with ME/CFS fight off common viruses that are largely insignificant to the general population?.
We now little about XMRV, and we know even less of its association with CFS. The data look interesting, but -as you can read in this post- are not very strong yet (the original Science paper has its flaws). And if there is an association with XMRV -even WPI admits- it might still not be causal. So in my opinion it is too early for taking/advising anti-retroviral drugs. They are no candies…, so you should know whether they are really required.
And about those doctors. A search on the Internet shows the opinions are divided.
One thing is sure: you’re are not imagining things. So try to find a doctor who knows how to diagnose CFS and who takes you seriously. Contact with other patients may help too. The forums science-based suggested may be a good start. (although many patients are so eager to find a cure -I don’t blame them- that they blindly follow some ideas.) There are very strong beliefs (pro and contra) in the CSF-world.
But with you I hope it will not take long before more definite answers to the cause of CFS are found.
All the best, Jacqueline
ask dr. garth nicolson about the 45% of the hiv aids virus envelope he already found by pcr in cfs and gulf war vets blood samples! now you all now know why patients claim to be responding to a.c.t. or other aids drugs! what are these meds working against? XMRV? OR THE 45% OF THE HIV AIDS VIRUS MADE IN A U.S. LABRATORY!! $25 million grant many years ago went to creating two diseases and they were, HIV-AIDS AND CFS/GWI… DO NOT BELIEVE IN JUDY AS SHE IS PART OF THE AMERICAN BIOLOGICAL WARFARE UNIT!! SINCERELY AIDAN WALSH SOUTHAMPTON, UNITED KINGDOM…P.S. GOD BLESS ALL OF YOU WHO ARE SUFFERING AND BEST WISHES TO YOUR LOVED ONES WHO HAVE STUCK BY YOUR SIDES AND THE ONES WHO DID NOT!! YOU ARE BETTER OFF WITHOUT THEM!! X X BE WELL…BE WISE AND SEEK NOTHING BUT THE HONEST TO GOD’S TRUTH ALWAYS AND FILE THOSE LAWSUITS AND BE HEARD IN A COURT OF LAW!!
it was to bad to learn of those two doctors in belgium who are being prosecuted for treating cfs patients! they have nothing to worry about as they are in a great position now for a serious multi-million dollar settlement! anyone who knows these doctors in question have them get in touch with me as i have some very serious documents in a safety deposit box that will prove a biological cover-up and the truth about these cronies and their cover-ups! i even have proof of their off-shore bank accounts where they all profited and were greesed by the insurance companies! in the mean time they are already under criminal investigations and my reliable sources say fbi is already involved! won’t be long now before warrants are served!!
You better contact the FBI then.
[…] CFS-population, had used old and/or too few samples (discussed in two previous posts here and here). In a way, negative studies, failing to reproduce a finding, are less convincing […]
[…] aberrations, using very sensitive molecular diagnostic tools, like polymerase chain reaction PCR (i.e. see this post) . The first attempts were directed at detecting the Y chromosome of male babies in the blood of […]
Your blog points out Mikovits as exploiting people for her own ends you fail to point out THE medical psychiatric camp being funded in the UK by the tax payers were most negative studies originate. They would lose that funding and there reputations if XMRV was found to be the cause of ME CFS. You fail to mention that psychiatry needs ME CFS to be psychological illness beliefs and mainly psychological as a reason for there existence .Without something they can pin there dubious psychiatric theory’s onto as they did with hysteria for multiple sclerosis and epidemic hysteria for HIV and stress for stomach ulcers they will have little power or credibility.
@Oldtimer
Emphasis in my XMRV post is on whether the XMRV findings in ME/CFS are “real”, both in terms of quality of the PCR, reliability of the findings, and the plausibility of a causal relationship. There are several (technical) flaws in the Mikovits paper, there is a clear bias, and there is no demonstration of a causal relationship whatsoever. Therefore I do not think it is justified to “sell” a test to patients guaranteeing 100% accuracy and advising people tested positive to consult their doctors about getting antiretroviral drugs normally prescribed to those with HIV (see recent article in Nature: http://www.nature.com/news/2011/110314/full/471282a.html) As a matter of fact I find this unethical.
With respect to the UK psychiatrists, I agree they have their bias too, and I have mentioned it both in this and the previous post.
Quotes from this post: CFS patients feel that many psychiatrists, including authors of the negative papers [2-4] dismiss CFS as something “between the ears”. ….
Since a viral (biological) cause would not fit in the philosophy of these psychiatrists, they might just not do their best to find the virus. Or even worse…
I can understand and symphetize with CFS/ME patients who feel that their disease is not taken seriously by many UK-psychiatrists, but find it far-fetched that virologists collaborating with these psychiatrists would sabotage molecular research. I have no means to check this, but the PCR-results as such (from this UK-group) were very weak and didn’t convince me that there was proof of absence (of XMRV). The Dutch groups’ PCR experiments looked very good, but (as mentioned before) their patient groups was small and perhaps not appropriate.
In the meantime the doubts as to the meaning of the findings of the WPI are only growing. It is no longer WPI versus psychiatrists only.
[…] I repeat my concerns expressed in earlier posts [13 and 14]. (please read these posts first, if you are unfamiliar with […]
[…] a blood test for this putative debilitating virus (marketed by the commercial arm of the WPI, RedLabs, which became VIP/dx) and surrogates in the ME/CFS community promoted it there. The Whittemores were already […]