EXCHANGE OF CORRESPONDENCE BETWEEN THE ME ASSOCIATION AND THE CHIEF MEDICAL OFFICER: PROFESSOR DAME SALLY DAVIES
Resulting in the introduction of a new blood donation policy re ME/CFS as from 1 November 2010
August 16 2010
Dear Dame Sally Davies
ME/CFS and blood donation
I wrote to Sir Liam Donaldson on 27 October 2009 following publication of the paper in Science which contained the results of a research study that had found evidence of XMRV infection in people with ME/CFS.
In this letter I referred to The MEA website statement on XMRV, which called for the current UK ban on people with ME/CFS donating blood while being symptomatic to be extended to include anyone who had suffered from the illness in the past but now appeared to be in remission or had recovered. We felt this was necessary given the uncertainty over prevalence, transmission and possible pathogenicity of this infection.
Dr David Harper (Director General of Health Improvement and Protection) replied on 9 November 2009 by stating that this correspondence had been brought to the attention of the Director of the UK Blood Services Joint Professional Advisory Committee and that the situation was to be reviewed by the Standing Advisory Committee on Transfusion Transmitted Infections (SACTTI), who would be producing a risk assessment for the UK Blood Services and the Health Protection Agency. Dr Harper also stated that The MEA concerns had been brought to the attention of the Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) and the National Expert Panel on New and Emerging Infections (NEPNEI).
Relevant part of the 2009 MEA website statement >>
BLOOD DONATION AND XMRV
In relation to blood donation in the UK, current advice is that people with ME/CFS who have symptoms, or are receiving treatment, should not donate blood. It would seem sensible in the short term, until we know more about transmission and pathogenicity of XMRV, to consider extending this restriction to people who have recovered from ME/CFS. It seems strange that many overseas countries have not followed the UK lead on blood donation and ME/CFS.
The MEA has written to Sir Liam Donaldson, Chief Medical Officer at the Department of Health, regarding the possibility of XMRV being transmitted via human blood products and the implications that this has for blood donation.
The CFIDS Association of America has been issued with guidance from the National Cancer Institute regarding blood donation in the US. The guidance can be read on the CFIDS website.
We now understand, through a letter that is circulating on the internet, that a decision to extend the ban has been made.
Letter in circulation >>
Dear Ms xxxx,
Thank you for your email of 19 July to Andrew Lansley about the xenotropic murine leukemia virus-related virus (XMRV) and chronic fatigue syndrome/myalgic encephalomyelitis (CFS / ME). I have been asked to reply on his behalf.
The issue of XMRV was not specifically raised during the meeting on 20 July with campaigners from Tainted Blood. The National Expert Panel on New and Emerging Infections (NEPNEI) undertook a thorough assessment of the scientific data in June 2010 and concluded that although XMRV can infect humans, there is currently no evidence that it causes disease in humans. NEPNEI’s view is that development of a robust diagnostic tool to detect infection accurately is a priority for further investigation of this infection. Further work is required to investigate which human tissues are susceptible to infection, the epidemiology of infection and whether this infection is of any public health significance.
Both NEPNEI and the Advisory Committee on the Safety of Blood, Tissues and Organs have considered the current evidence and have recommended that no public health action is required at this time. However, the situation will be monitored closely.
In the absence of any infectious cause of CFS, people with this relapsing syndrome are currently excluded from donating blood while they feel unwell, in order to protect their own health. The UK Blood Services will shortly be amending its criteria to exclude such people from blood donation on a lifetime basis, bringing them in line with the practice of not accepting donations from people with other relapsing conditions. Whilst the purpose of this is to protect the donor’s health from any possible harmful effects from donating blood, it will also minimise the likelihood that donations from people who have ever suffered from CFS could enter the blood supply.
I hope this reply is helpful.
Customer Service Centre
Department of Health 13 August 2010
We would therefore appreciate some further clarification on this important point and the date when the UK Blood Services will be bringing this extension into effect.
Could I also point out in relation to the opening sentence in the final paragraph of the above letter from Mary Heaton, that whilst it is true that the role for persisting infection in ME/CFS remains uncertain there is very sound evidence, as is referred to in Sir Liam Donaldson’s report into ME/CFS, to show that a variety of infections, predominantly viral, can precipitate this illness. There is also evidence of reactivation of latent viral infection (eg EBV and HHV-6) in some of these patients.
Finally, you may not be aware that a number of other countries have followed the UK lead in banning blood donations from people with ME/CFS. These countries include Australia, Canada and New Zealand.
However, I find it surprising that no such precautionary action has been announced, at present, by those responsible for blood safety in America.
Dr Charles Shepherd
Hon Medical Adviser, ME Association
Member: CMO Working Group on ME/CFS (2002)
Member: MRC Expert Group on ME/CFS Research
7 Apollo Office Court
Bucks MK18 4DF
Thank you for your further letter to Professor Dame Sally Davies, Chief Medical Officer (CMO) for the Department of Health, about myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and blood donation. I am responding on her behalf.
As of 1st November 2010, blood donors who report that they have had ME/CFS will be permanently excluded from giving blood in the UK. This change is being made on the grounds of donor safety, as ME/CFS is a relapsing
condition. It brings practice for ME/CFS into line with other relapsing conditions or neurological conditions of unknown origin.
The change to donor selection criteria is being made following a recommendation by the UK Blood Services Standing Advisory Committee on the Care and Selection of Donors, and Joint Professional Advisory Committee (JPAC).
Director of Health Protection
Department of Health
Wellington House, 133-155 Waterloo Road, London SE1 8UG
Murine leukaemia viruses (MLV) are retroviruses known to cause cancer in certain mice. In 2006, investigators found that a type of MLV, called xenotropic murine leukaemia virus-related virus (XMRV), could potentially infect humans after finding it in tissue samples from men with prostate cancer. XMRV is one of a number of MLVs that appear to be transmitted to humans.
In October 2009, Lombardi et al published the results of study in Science which contained evidence that XMRV was present in a high percentage (67%) of people with ME/CFS and in a small percentage of healthy controls.
Since then there has been a great deal of interest from researchers in a number of countries where ME/CFS is recognised. A number of research groups have attempted (or are still attempting) to repeat these positive XMRV findings.
Confirming or refuting new findings is a vital part of the scientific evaluation process and involves other independent research groups trying to either replicate or validate the results.
In relation to XMRV, a true replication study should involve exactly the same laboratory methods and same type of patients that were used in the original Science study. A validation study gives scientists a degree of flexibility. In particular, it provides the opportunity for other research groups to try and repeat the findings using what they feel are the most sensitive and accurate laboratory methods they have access to for testing for XMRV.
In the case of XMRV almost all of the first wave of research has involved validation studies. Firstly, because there is no international agreement about the most accurate and sensitive way of detecting XMRV in blood samples. Secondly, because these research groups all wanted to move quickly, and the easiest way to do so was to use stored blood samples from people who had been diagnosed with CFS in the past according to Fukuda research criteria. Stored blood samples from people who met both Fukuda and Canadian criteria (which were used in the original study) are not readily available.
Results from four emphatically negative validation studies of varying quality – three carried out in Europe and one carried out by the CDC in America – have now been published in scientific journals. Results from a further (so far unpublished) study, carried out by Professor Brigette Huber, were presented at the Invest in ME conference in May 2010 (report available on MEA website and in the August 2010 of ME Essential).
None of these five research groups – which in the case of the UK included Professor John Gow, Dr Kate Bishop, Dr Jonathan Kerr and Dr Jonathan Stoye and used patient samples supplied by physicians and neurologists including Dr Abhijit Chaudhuri and Professor Peter Behan – have been able to find evidence of XMRV in blood samples from ME/CFS patients, or in the healthy controls.
Although some very valid criticisms have been made about all of the XMRV negative studies, in particular the most recently reported one from America, a number of distinguished virologists who work with retroviruses and XMRV have been involved – so these XMRV negative results have to be taken seriously as well.
THE LO et al STUDY
On 23 August 2010 the results from the first follow up study to firmly support a link between a retroviral infection and ME/CFS were published.
This study is clearly an important contribution to the XMRV debate in that it fully supports a link between ME/CFS and retroviral infection. In this respect it also supports the findings in the Lombardi paper.
However, it is not a true replication study, and in the words of the authors they have not attempted to fully replicate the Lombardi et al findings.
Lo et al have used different laboratory methods and different patient criteria and their findings relate to what are called MLV-related viruses.
The research group have found segments of genetic material (not whole virus) from what they term a genetically diverse group of MLV-related viruses. These sequences are more closely related to those of polytropic mouse endogenous (=arising within or derived from the body) retroviruses than to those of XMRVs – hence the use of the term MLV (murine = mouse leukaemia virus) in the title. But they all belong to a closely related family of retroviruses.
In contrast to the Lombardi et al study, which involved patients who met both Fukuda research criteria and Canadian Clinical Criteria for CFS, this research used stored blood samples from ME/CFS patients who had been diagnosed using either the 1988 Holmes research criteria or the 1994 Fukuda research criteria. The patients were diagnosed with CFS from the mid 1990s onwards and most of the frozen blood samples were supplied by Professor Tony Komaroff at Harvard Medical School, Boston. Professor Tony Komaroff is a well respected physician with a longstanding interest in ME/CFS. In addition, 12 patient samples came from other US physicians whose diagnostic criteria for ME/CFS is not stated.
The numbers involved were surprisingly small for a study of this nature: 37 patients with CFS and 44 healthy controls.
The healthy control samples came from Washington DC blood donors recruited between 2003 and 2006.
So these results apply to a rather broader group of ME/CFS patients than was used in the Lombardi et al study and the patient sample is probably very similar to at least one of the other validation studies that produced negative findings in relation to XMRV. As with some of the other validation studies, it is highly likely that a significant number of people who also meet Canadian Clinical Criteria will have been included in this study.
MLV-like virus gag gene sequences (in simple terms segments of viral genetic material) were found in 32 out of 37 (86.5%) of the ME/CFS patients compared to only 3 out of 44 (6.8%) of the (blood donor) healthy controls.
Follow-up samples were collected from 8 of the CFS patients in 2010, and 7 of these again tested positive for MLV-like gene sequences.
As already pointed out, the evidence in this paper relates to a genetically diverse group of MLV- related viruses with gene sequences that are more closely related to those of polytropic mouse endogenous retroviruses (mERVs) than to those of XMRV. XMRV is a genetic variant of MLV-like viruses – so this is a subtle but relevant distinction.
The authors point out that they have taken exhaustive steps to try and ensure that they have not produced false positive results as a result of mouse DNA contamination, or any of the other potential laboratory problems that come when working with retroviral infections.
CORRELATION, INFECTION AND POSSIBLE CAUSATION
The authors point out (p5) that the finding of XMRV or MLV genetic sequences in people with ME/CFS, or any other disease, does not constitute definite proof of viral infection.
They then go on to make it clear that further research will be required before any definite conclusion can be drawn as to whether MLV-related viruses play a role in the causation of ME/CFS. This is a process that is going to take time and further research.
They also state (p6), as has been pointed out in previous MEA summaries on XMRV, that a high frequency of MLV-related viruses (or XMRV) in ME/CFS patients could reflect an increased susceptibility to viral infections due to the underlying immune dysfunction found in ME/CFS rather than a primary disease causing role in the pathogenesis of ME/CFS. In other words the retrovirus could just be there as a ‘harmless passenger’.
COMMERCIAL TESTING FOR MCVs and XMRV
The MEA continues to believe that there is no point in spending very large sums of money on arranging blood tests, which may not have been properly validated, for XMRV (or MCVs) outside the UK. Having a positive result is not, in our present state of knowledge, a diagnostic marker for ME/CFS. Equally, having a negative result does not mean that you do not have ME/CFS. Having a positive result will not affect ME/CFS management at present and if this information is inserted into medical records it could in due course cause problems with other health matters such as applications for insurance policies or travel abroad.
The way in which these viruses might be transmitted from person to person also remains uncertain and sexual transmission is one possibility – as in the case of HIV. However, if this is a disease causing virus like HIV, sexual transmission appears very unlikely given the fact that ME/CFS appears to be very rare in sexual partners of people with ME/CFS, even after long periods of time.
The MEA continues to believe that the current uncertainty over transmission of these viruses/viral segments means that people with a current or past history of ME/CFS should not be donating blood and we have recently written to the acting Chief Medical Officer at the Department of Health to seek clarification on what appears to be a recent decision to extend the UK ban to people who have recovered from ME/CFS. Copy of this correspondence [here]
We find it surprising that the American authorities responsible for blood safety have not followed the UK lead here.
The authors of this paper make no comment or recommendations regarding the use of antiviral drugs. However, others (including the authors of the accompanying commentary) are now suggesting that it is time to assess the use of antiretroviral therapy (ART) in ME/CFS in some clinical trials. It is well accepted that one way of examining the possible cause of a disease is to assess the response to specific forms of treatment.
The MEA has already pointed out on several occasions that this type of clinical trial would have to proceed with great care given the fact that ARTs can have serious side-effects. In the case of AZT, this drug can cause mitochondrial damage – which is obviously very relevant in ME/CFS. But there are other ARTs becoming available that appear to be active against XMRV and may be much safer to use (eg reverse-transcriptase inhibitors such as tenofovir and emtracitabine).
We have also pointed out that ARTs appear to have very limited effect in reducing fatigue in HIV/AIDS, and that this may be due to the immune system activation that is occurring in this situation rather than any direct effect on reducing the viral load of the HIV infection. So drugs that dampen down immune activity (eg a tumour necrosis factor inhibitor such as etanercept) may be a more appropriate route to follow. More information [here]
In the UK doctors are very unlikely to be willing to prescribe any type of antiviral treatment on an individual (ie non research) basis. This is because the 2007 NICE guideline on ME/CFS specifically recommends that antiviral drugs should not be used to treat ME/CFS. And if anything goes wrong through the use of a potentially toxic antiviral drug, that is in effect banned by NICE, and has not been assessed in a proper clinical trial, the doctor responsible could face legal action even though the patient accepted the risk.
FURTHER RESEARCH AND THE ROLE OF MEA RAMSAY RESEARCH FUND
Investigators at FDA, NIH, CDC and other scientific institutions are in the process of conducting studies to verify the capabilities of the tests used by the different laboratories for the detection of XMRV or MLV-related viruses in blood. These studies are intended to develop and standardise a highly sensitive and specific XMRV test to better study its association with disease, as well as the possibility that XMRV can be transmitted to blood or tissue recipients.
The UK Medical Research Council’s Expert Group on ME/CFS research (of which CS is a member) has identified all aspects of viral infection in ME/CFS (including carefully targeted use of antiviral agents) as a priority item for further UK research and we expect that this recommendation will now be translated into action.
The MEA is again making it clear to UK research groups with expertise in retrovirology, and access to reliable patient samples, that we would very much welcome good quality research applications relating to any aspect of XMRV or MLVs. The MEA is also willing to consider co-funding research applications in this area.
We are in contact with most of the key UK researchers working on XMRV and we are also assisting with a small UK study that is intending to retest people who already have a positive XMRV result as a result of having this test done in America.
We also need to find out how common these new retroviruses are in people with other chronic disabling conditions, especially those that involve immune system dysfunction.
In America, the paper has been quite widely reported with most of the coverage being supportive. In the UK there has been very little interest in the press release – apart from the Daily Mail (which carried an on-line story) and the New Scientist:
which includes quotes from Professor Myra McClure, one of the UK virologists involved in a negative validation study.
Lack of coverage in the UK is partly because selected health journalists, who might have reported the story, like to have access to a new research paper well before the information enters the public domain – so they have a day or two to chase around and obtain informed comment on the story. Health reporters have finished writing their copy for the next days paper well before 8pm in the evening – so unless there is a real breakthrough news item they are not at their desks in the evening. The US press conference at 8pm UK time did not fit in with their working arrangements for printing something on Tuesday and the findings would be ‘old news’ by Wednesday. In addition, they also had a good headline health scare story for Tuesday morning relating to people being refused an anti-cancer drug due to a NICE ruling.
Unfortunately, there are health correspondents that I speak to on the more influential papers and journals who are now very cautious about covering ME/CFS stories.
In very simple terms the clinical and scientific community regards published papers rather like goals (of varying quality) in a football match. So the current score is XMRV and MLV positive 2 (with a spectacular first goal!): XMRV negative 4 (of varying quality) with plenty of time left before the final score.
The comments so far that I have read, or been given, by experts in this area of virology indicate that everything has been done correctly in this study and that this is a sound piece of laboratory research. However, with differing results from differing well respected retroviral laboratories, the clinical and scientific community is likely remain uncertain or sceptical about the link between retroviral infection and ME/CFS.
Another analogy is fitting pieces into a jigsaw puzzle with a lot of blue sky. We now have six pieces (ie published papers of varying quality) in place and some strong opinions on either side. But a lot of pieces have still to be fitted into the picture.
Overall, there is no sign of any real scientific consensus emerging as to whether XMRV and/or MLVs are playing a significant role in ME/CFS and many key questions regarding prevalence, transmission and pathogenesis remain unanswered. Things may become a bit clearer as a result on the international meeting on XMRV in September, which will include a session on ME/CFS. Proposals for further research may also emerge after this meeting.
This uncertainty and scientific disagreement seems likely to continue until well into 2011 and the current findings are unlikely to have any significant influence on the forthcoming review of the NICE guideline or the increasingly difficult position faced by people with ME/CFS in relation to sickness and disability benefits. [Our most recent correspondence on 24 August from NICE indicates that they have still to decide on the date at which the review will take place, whether it will be a full review – which could take up to a year, or whether they might delay the review to await the results of further research from clinical trials.
More top quality research is clearly needed here in the UK and the MEA is very willing to consider funding it.
Answers to the final three questions, which are of importance to US readers:
9. Does FDA agree with the AABB recommendation to discourage donation by people with history of CFS?
FDA does not object to the AABB recommendation. The AABB recommendation is consistent with a long-standing position of the Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) Association of America that individuals with CFS voluntarily should not donate blood.
10. How are the differences between the CDC and FDA study results being evaluated?
Differences in the results could reflect differences in the patient populations that provided the samples. Alternatively, undefined differences in the method of sample preparation could be contributing to the discordant test results. All of the scientists involved are working collaboratively to design experiments to quickly answer this scientifically puzzling question. An independent investigator at the National Heart, Lung, and Blood Institute (NHLBI) set up a test set of 36 samples, including known positives and presumed negatives. Both the FDA/NIH and CDC labs participated in this test, and the results showed that both labs were able to detect XMRV present at low levels in blinded samples. Additionally, the CDC laboratory provided 82 samples from their published negative study to FDA, who tested the samples blindly. Initial analysis shows that the FDA test results are generally consistent with CDC, with no XMRV-positive results in the CFS samples CDC provided (34 samples were tested, 31 were negative, 3 were indeterminate).
11. What do these findings mean to CFS patients and clinicians who treat them?
Although this study found MLV-like viral gene sequences in a high percentage of CFS patients, this does not prove that these retroviruses are the cause of CFS or of any other disease. Moreover, other studies have not found evidence of such retroviruses in patients with CFS. Further studies are necessary to determine if XMRV or other MLV-like viruses are reproducibly associated with CFS, and if so whether the virus is a causative agent or a harmless co-traveler. The different findings from various studies reinforce the need for more research–including careful analysis of other cohorts of CFS patients from different geographic regions, studies of larger populations of healthy people, and testing of transmissibility of the agents through blood transfusions in animal models. FDA, NIH, and CDC have and will continue to collaborate with other agencies and groups involved in this research.
Summary prepared by Dr Charles Shepherd
Hon Medical Adviser, MEA
M.E.charity calls on MRC to put its money where its mouth is, following new research from States
Action for M.E., the UK’s leading charity for people with M.E., is calling on the Medical Research Council to prioritise research into the link between viral infections and M.E., following the latest findings from the United States.
Scientists at the American Food and Drug Administration, National Institutes of Health and Harvard Medical School have found murine leukemia virus-related viruses (MLVs) in 32 out of a sample of 37 (86.5%) people with chronic fatigue syndrome, compared to 3 out of 44 (6.8%) healthy blood donors.
Chronic fatigue syndrome is also known as M.E. or M.E./CFS.
The findings, published in the Proceedings of the National Academy of Sciences (PNAS) support research from the Whittemore Peterson Institute in Reno, last October, which identified genetic material (DNA) from a mouse virus – murine leukaemia virus-related virus (XMRV) – in 68 out of 101 CFS patients (67%) compared to 8 out of 218 (3.7%) of healthy people.
Action for M.E.’s Chief Executive, Sir Peter Spencer, welcomed the latest news saying, “It is extremely encouraging to see positive results linking different strains of viruses and CFS, after disappointing results from other studies earlier this year.
“However, we cannot afford to leave this to the Americans. M.E. affects 250,000 men women and children in the UK, from toddlers aged two to people in their eighties. Many become so severely affected that they are bedbound or housebound.
“In June, the MRC’s expert group on M.E./CFS identified viral infection as a priority. We now call on the MRC to take this forward in real terms, as a matter of urgency, by allocating a significant level of funding to research in this area.
“There are still many questions to be answered, not least the variations in findings. Large-scale studies involving many more patients are also required.”
Chronic fatigue syndrome ‘may be caused by mouse-related virus’
Chronic fatigue syndrome may be caused by a rare mouse-related virus, new research suggests.
Scientists found evidence of murine leukaemia virus – known to cause cancer in mice – in 86 per cent of chronic fatigue patients.
However, traces from this family of bugs were only found in seven per cent of samples from healthy blood donors. It adds to the growing body of evidence that an infection could play a role in the complicated illness.
“…The data do seem solid, admits Steve Monroe, who co-authored the conflicting CDC paper. “It’s simply a good paper,” adds Reinhard Kurth, the former director of the Robert Koch Institute in Germany, who helped test some of CDC’s samples and did not find the virus either. Alter—a widely respected virologist and winner of the Albert Lasker Award for Clinical Medical Research—”clearly knows what he is doing. They did everything correctly,” says Kurth, who nonetheless says he remains skeptical.
So too does virologist Robin Weiss of Imperial College London (ICL), who says he’s seen too many instances of proposed new human retroviruses that fell apart on closer inspection, including one he reported in arthritis and lupus patients in 1999 that turned out to be an innocuous rabbit virus. (In a 40-page review that he co-authored in 2008, Weiss called such mishaps “human rumor viruses.”) “You can have a very good reputation and be very careful and still get it wrong,” Weiss says.
Part of the problem, skeptics say, is that the researchers didn’t exactly replicate the Science paper. XMRV is a so-called xenotropic murine virus, which means it can no longer enter mouse cells but can infect cells of other species. (Murine means “from mice.”) The researchers in the PNAS paper say the viral sequences they find are more diverse than that and resemble more closely the so-called polytropic viruses, which is why they adopted the term MLV-related virus, for murine leukemia virus. “Let’s be clear: This is another virus. They did not confirm [Mikovits’s] results,” says retrovirologist Myra McClure of ICL, a co-author of one of the four negative studies…”
WSJ’s blog on health and the business of health.
By Amy Dockser Marcus
August 24, 2010, 1:55 PM ET.
PNAS Paper on Virus-Chronic Fatigue Syndrome Link Has Its Own Story
The much-awaited PNAS paper published yesterday (and reported in today’s WSJ) about the discovery of a family of retroviruses in patients with chronic fatigue syndrome came with a backstory — its own editorial explaining the publication process.
Here’s why that was necessary. Earlier in the summer, the WSJ reported that the completed paper, by a team of researchers from the NIH, FDA and Harvard Medical School, contradicted findings of a similar study done by CDC researchers and was being held until the discrepancy could be sussed out.
The just-released study detects variants of the retrovirus XMRV in most CFS patients. In addition, nearly 7 percent of the healthy U.S. controls—all of whom are blood donors—test positive, signaling the contamination of the U.S. blood supply…
…the authors state that their conclusions “clearly support” the October 2009 Science paper linking a retrovirus to the neuroimmune disease Chronic Fatigue Syndrome (CFS), which afflicts 17 million people worldwide…
…Most surprising is that the PNAS study didn’t find XMRV, which stands for Xenotropic Murine Leukemia Virus-Related Virus, in any patients or controls. Instead, the researchers—from the National Institutes of Health (NIH), the FDA and Harvard Medical School—detected novel close cousins to XMRV called MLVs—which stands for Murine Leukemia Viruses—in 86.5 percent of 37 patients and nearly 7 percent of 44 controls.
Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors
1. Shyh-Ching Lo a , 1 ,
2. Natalia Pripuzova a ,
3. Bingjie Li a ,
4. Anthony L. Komaroff b ,
5. Guo-Chiuan Hung a ,
6. Richard Wang c , and
7. Harvey J. Alter c , 1
+ Author Affiliations
aTissue Microbiology Laboratory, Division of Cellular and Gene Therapies and Division of Human Tissues, Office of Cellular, Tissue and Gene Therapy, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892;
bDepartment of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and
cDepartment of Transfusion Medicine, The Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892
Contributed by Harvey J. Alter, May 25, 2010 (sent for review March 23, 2010)
Chronic fatigue syndrome (CFS) is a serious systemic illness of unknown cause. A recent study identified DNA from a xenotropic murine leukemia virus-related virus (XMRV) in peripheral blood mononuclear cells (PBMCs) from 68 of 101 patients (67%) by nested PCR, as compared with 8 of 218 (3.7%) healthy controls. However, four subsequent reports failed to detect any murine leukemia virus (MLV)-related virus gene sequences in blood of CFS patients. We examined 41 PBMC-derived DNA samples from 37 patients meeting accepted diagnostic criteria for CFS and found MLV-like virus gag gene sequences in 32 of 37 (86.5%) compared with only 3 of 44 (6.8%) healthy volunteer blood donors. No evidence of mouse DNA contamination was detected in the PCR assay system or the clinical samples. Seven of 8 gag-positive patients tested again positive in a sample obtained nearly 15 y later. In contrast to the reported findings of near-genetic identity of all XMRVs, we identified a genetically diverse group of MLV-related viruses. The gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs and were even less closely related to those of ecotropic MLVs. Further studies are needed to determine whether the same strong association with MLV-related viruses is found in other groups of patients with CFS, whether these viruses play a causative role in the development of CFS, and whether they represent a threat to the blood supply.
Author contributions: S.-C.L., N.P., and B.L. designed research; G.-C.H. designed mouse-specific mitochondria PCR assay; N.P. and B.L. performed research; B.L. and R.W. contributed new reagents/analytic tools; S.-C.L., N.P., G.-C.H., and R.W. analyzed data; and S.-C.L., N.P., A.L.K., and H.J.A. wrote the paper.
Study: Presence of Murine Leukemia Virus Related Gene Sequences Found in CFS Patients
Download image SILVER SPRING, Md., Aug. 23 /PRNewswire-USNewswire/ — Researchers have found murine leukemia viruses (MLV) related gene sequences in blood samples collected from patients diagnosed with chronic fatigue syndrome (CFS) and some healthy blood donors, according to a study published online today by the scientific journal Proceedings of the National Academy of Sciences (PNAS).
Investigators from the U.S. Food and Drug Administration’s Center for Biologics Evaluation and Research and the National Institutes of Health Clinical Center, in collaboration with a physician scientist at Harvard Medical School, examined blood samples from 37 patients diagnosed with CFS and from 44 healthy blood donors.
MLV is a type of retrovirus known to cause cancer in mice. Several different MLV gene sequences were identified in samples from 32 of the 37 patients with CFS (87 percent) and 3 of the 44 (7 percent) healthy blood donors. Investigators performed DNA sequencing on all positively amplified samples to confirm MLV like gene sequences.
This study supports a previous investigation [Lombardi et al. Science October 23, 2009 326: 585] that showed XMRV, a genetic variant of MLV-like viruses, to be present in the blood of people with CFS. The study demonstrates a strong association between a diagnosis of CFS and the presence of MLV-like virus gene sequences in the blood. The study also showed that MLV-like viral gene sequences were detected in a small fraction of healthy blood donors. Although the statistical association with CFS is strong, this study does NOT prove that these retroviruses are the cause of CFS. Further studies are necessary to determine if XMRV or other MLV-related viruses can cause CFS.
A previous study, published in 2009, reported finding XMRV infections in a high percentage of CFS patients and a small percentage of healthy blood donors. However, several other studies from the United States (including a recent report from the Centers for Disease Control and Prevention), the United Kingdom, and the Netherlands have found no evidence of XMRV or other MLV-like viruses in the blood of people with CFS.
Scientists to discuss research on XMRV in blood, chronic fatigue syndrome
Telebriefing by experts from the Food and Drug Administration, the National Institutes of Health and the Centers for Disease Control and Prevention to respond to questions about this study. The paper is currently under embargo until Monday, August 23 at 3:00 p.m., by the Proceedings of the National Academy of Sciences.
Harvey Alter, M.D., Chief, Clinical Studies and Associate Director for Research, Department of Transfusion Medicine, NIH Clinical Center
Shyh-Ching Lo, M.D., Ph.D., Director, Tissue Safety Laboratory Program, Division of Cellular and Gene Therapies and Division of Human Tissues, Office of Cellular, Tissue and Gene Therapies, Food and Drug Administration Food and Drug Administration
Celia Witten, M.D., Ph.D., Director, Office of Cellular, Tissue and Gene Therapies, Food and Drug Administration
Hira Nakhasi, Ph.D., Director, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Food and Drug Administration
Steve Monroe, Ph.D., Director, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention
Monday, August 23, 3:01 p.m. EDT
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XMRV: Whittemore Peterson Institute (WPI) Opens on campus of University of Nevada (Parts 1 and 2)
Sam Shad for Nevada Newsmakers
Update: This transcript was revised on 20 August and supersedes previous versions.
May be reposted if posted in full, unedited and a link to source is given.
Dorset CFS/ME Society
Annual Medical Lecture
27th March 2010
The Future of Research in CFS/ME
It’s a great pleasure to be here, everybody, and I’m really glad actually that my talk actually fits in very nicely with what William’s just said – Phew!
I’m going to be talking a lot about the collaborative research and the first half of my talk actually was given to the MRC Working Group at the end of last year. So you’ll actually see what we were talking about where the MRC gathered lots and lots of researchers together to discuss a way forward with chronic fatigue [sic] and I did the talk on Epidemiology.
I couldn’t resist talking about XMRV. I think we have to know about what’s actually happened and I will discuss that as well and what the implications are.
[Rest of intro and presentation skipped.]
Approx 27 mins in from start of presentation:
XMRV. OK, so in the next, last, remaining bit of the talk I want to summarise what’s happened about the XMRV story for you. I think it’s really important that we’re all informed about it.
Many of you will have woken up and read this story, in fact I knew about it 24 hours before it was about to break – “Has science found the cause of chronic fatigue syndrome?” – we’re all very excited and hopeful this might give us something we can treat. Great.
Don’t you think this is the most beautiful picture? That’s the XMRV virus. I don’t know how they get those colours on them – very beautiful.
Now this is the Centre that reported it. Do any of you notice anything about that picture? XXXX you’re not allowed to say.
Member of the audience: Sunshiny?
EC: Sunshiny, yeah. It’s in Reno, yeah, yeah. Anything else? It’s a bit far away.
Has anyone looked at the website? Isn’t that interesting? That doesn’t exist. That’s a fake picture – it’s what they would like to exist, when you donate money, when you go on the website. I thought everybody knew that! Yeah, sorry? This is Dorset.
OK. The Centre isn’t built. That’s their picture of what they would like to build and when you go on the website it has “Please donate.”
OK. What do the Lombardi group originally show?
OK. This is a complicated slide. I’m just going to take you through bit by bit because it’s really important when we look at all the research evidence.
OK. The gag sequences – the DNA that’s associated with these particular type of viruses – so they use PCR. PCR is basically when you get a tiny bit of DNA and you multiply and multiply and multiply and then you run it on a gel and see if it’s there. And what they found, and you’ll all remember these figures, I’m sure, is that they found it in 68 out of 100 [Ed: 101 on slide] chronic fatigue [sic] patients and 8 out of 218 controls.
They then looked in the cells and they found the protein in the cells and then they looked at whether it’s infectious. Now I have to say, this bit made me slightly worried – so they looked to see whether this virus could infect other cells within the lab and they showed that it’s infectious and they also looked at what happened if you put the virus with other cells in terms of did it develop an immune response?
And these are some of the pictures they showed. So when you multiply out the DNA, you then run it on a gel and you tag it with a thing that shines – I did my PhD doing this, I can tell you all sorts of awful stories of gels breaking and all sorts of other things going wrong. But these are the chronic fatigue [sic] patients – you see all these lines, here? That’s that gag sequence – here and here – that’s the end of the line and these are the controls.
Then they looked at the expression in cells and you could see it. And then they looked at the infection and this is the infection happening here.
Now this paper went out for review by virologists – not by clinicians and that’s a very important point and it was passed and it was published.
And this is what they said on their website and I think this is kind of interesting: “
“We have detected the retroviral infection XMRV is greater than 95%…”
Where did the 95% come from? Did anybody notice the 95%? Can anybody remember the percentage they found it in? Yeah, 66% [sic], slightly less.
OK. Says on the website “…95%…The current [working] hypothesis is that [XMRV]…” infects these cells…and I found this absolutely terrifying…viral chronic fatigue syndrome “causes the chronic inflammation and immune deficiency resulting in an inability to mount an effective immune response to opportunistic infections”.
OK. Have they shown any of that? Have they shown increased risk of opportunist infections? Have they shown a defect in the immune system that’s actually going to affect someone rather than just in a cell lab plate?
No. But that’s what’s on their website. That’s what they say they’ve found. So what happens? The research community runs to replicate the work.
OK. And you’ll all remember when this first paper came out “Failure to replicate…” – this is an English paper [Ed: the McClure PLoS ONE paper]. Well obviously this is wrong because they didn’t use the same techniques and it wasn’t the same patient group.
So in this particular experiment, they actually characterised the patients.
Now on the original paper, they say that the chronic fatigue [sic] patients were well-characterised but they do not describe them at all. We don’t know how many were girls – we don’t know how many…girls! – I’m such a paediatrician – we don’t know how many were female. We don’t know how long they had had the illness for. We don’t know who diagnosed them and we don’t know whether they had any blood tests to exclude other illnesses.
In this one, [Ed: the McClure paper], they actually had all the exclusion stuff excluded, they then used the DNA sequence. They had positive and negative controls. Why do you need positive and negative controls? Yes, so you’re worried that maybe when you do PCR it’ll pick up…you’ve all seen crime scenes, right? So PCR will pick up one bit of DNA, so if you’ve got a bit of DNA in your solution or something like that, you must have negative controls because you need to be certain that the DNA has come from the samples – not from your lab solutions.
Yes. OK. And you must have positive controls to make sure your experiments work.
They used a virus free laboratory. So they did it in a laboratory that had not had the virus in the past and they blinded the person doing the PCR. Does everyone know about “blinding”? So what they did, was that the person that was reading the gels didn’t know whether they were patients or not, because it’s really easy on those gels to over-interpret what you see.
OK and their results, you might all remember, they didn’t find any out of 186 patients – none of them had chronic fatigue [Ed: corrects herself] – XMRV.
And then a few days later, this one came out. This one had several people from England – Jonathan Kerr and so on. And they’re very open – they said, John Gow – these are all people that we’re collaborating with – they said we wanted to find chronic fatigue syndrome – we wanted to find the XMRV virus. We wanted to – we looked hard.
Now the criticism of the previous paper was that they hadn’t used the same techniques, so in this one they used the same techniques. They had 170 patients, 395 controls. You can already see the sample size is much bigger and they did both PCR and looked at the serology.
They found none in 299 samples of patients – had chronic fatigue [Ed: corrects herself] – had XMRV. And although they found what’s called “neutralising activity” they looked at this further and suggested that the immune response was actually related to other viruses and not to the XMRV.
And then this was published a couple of weeks later [Ed: BMJ paper] – from the Dutch group. Again, a very well described Dutch cohort – smaller, 76 patients 69 controls. And what they did, they actually went completely overboard with trying to find it. They used very, very sensitive techniques that should have detected – if any was there at all, they should have detected it – much more sensitive than the original paper and they looked at a variety of DNA and they tried several times to improve the sensitivity – all samples were negative for XMRV.
So what do you think’s going on?
Member of the audience: Publicity.
….I have actually given a clue.
Member of the audience: Money?
EC: Sorry. Money…money…money…
Member of the audience: XXXX wants to tell us.
EC: OK, go on, XXXX…
EC’s young son (in front row): Did they all do it from one place?
EC: Ye…es! The first group – actually, the question is, was the first group chronic fatigue syndrome? And eventually, when they were asked, they told the research community that, this is in Lisbon, at the end of last year, that all the samples came from an outbreak of chronic fatigue syndrome in one village in Lake Tahoe.
And when you actually go and have a look at all the research data around that outbreak, everybody at that time thought it was a viral infection. And nobody could find the virus.
So most of us think that that was probably the issue – it was probably a viral outbreak that has certainly caused chronic fatigue syndrome but is not necessarily going to be relevant for us here in the UK.
It’s not clear about the PCR operator, the person that looks – it’s not clear from the paper, whether they were blinded. There might be issues about whether you work in a virus free lab, remember they showed that this was infectious.
And there’s a big question here [Ed: indicates on slide] – this XMRV virus was initially described with prostate cancer and the prostate research community has shown this in prostate cancer in two studies in the USA. These are different labs in different studies but no association in Europe.
So maybe this is a virus that’s important in America but not important in this country – it’s not clear.
And I think this is of interest. Within a week of their paper being published they produced a test for the XMRV virus at $650 a test. [Ed: Slide reads, at point 4: Conflict of interest?].
And if I was developing a test, I would declare that as a conflict of interest on the paper – “I’m developing a test for this.” Then people can make up their mind about whether it has affected the results. We don’t know, it wasn’t declared they’d produced a test.
Why are patients so upset?
OK, well I don’t know and you’ll probably be able to tell me more than I can tell. But I think when they first publicised this they went on everything, lots and lots of American television.
[Reads from slide]
“Vindication” they said, “This “[new] report has intrigued scientists, been seen as vindication by some parents [Ed: corrects herself] – patients and inspired hope for treatment.”
Well you know, the history of this condition is that patients have not been listened to, they’ve been dismissed, they’ve had a terrible time and if a virus comes along as a cause, that is going to be seen as a vindication – I can understand that.
And it’s very disappointing, isn’t it, the negative replications?
But I do think that there’s been other stuff that’s been going on that I have particular difficulties with. When I prepared this talk for an infectious diseases conference, I went through and I just got some quotes off the web from the research team.
Look at this:
[Reads from slide]
“Here you’ve got your immune system working well and the virus and the immune system are coexisting just fine and then some other bug, whether it be Lyme, a flu, anything gets you…and then you’ve just tipped the scale to where your immune system can’t handle [XMRV] or anything, and every day you’re seeing new infections.”
And then at one point, rumour has it (and I couldn’t find any evidence for this) that they started to suggest that patients with chronic fatigue syndrome should have anti-retrovirals, ie HIV drugs.
They’ve taken that back, and this is all I could find:
[Reads from slide quoting Dr Judy Mikovits; the “she says” refers to Dr Mikovits]:
“While it’s not advisable to take highly toxic anti-retrovirals [without tests confirming effectiveness], she says some available therapies may help, including: immune modulators; anti-inflammatories, because inflammation activates XMRV, things that improve natural killer cell function; medications that help [level progesterone levels, because progesterone up-regulates XMRV in lab tests]; avoiding stress.”
It appears – and this really upset me, OK. All of their studies are in adults. OK, all in adults. And then they say:
[Reads from slide]
“Early infection in children can lead to more severe disease later on.”
Oh, that’ll be that test that they produced for $605 [sic] a pop.
[Reads from slide]
“and intervention important to keep viral loads from getting high.”
I find that really frightening. If I had a child with chronic fatigue syndrome and I read that on the web, the first thing I’d do, I’d go and buy the test, and the second thing I’d be doing would be phoning an infectious disease doctor which is what’s happened and ask about anti-retrovirals for my child, having read that.
So I do feel as researchers, we do take some responsibility for saying “This is a first paper! Let’s wait and see what happens.”
You know, I think it’s really interesting, it look likes they did find something in a group of patients and we haven’t found it here. That’s really interesting and is deserving of more research. But let’s just say, it’s interesting at the moment, rather than all of this speculation, which I think can be very harmful for patients.
The future for infection
OK, I gather that this may well already have happened, not been published, the way forward in these things is to replicate the studies in both labs and try and look at why there are differences.
I think it may be important for a subtype of chronic fatigue syndrome.
I very much doubt it effects all of them, as they claim.
It doesn’t appear to be important in this country.
And there’s actually very beautiful research which we need to understand more, looking at the relationship between genetics, infection and other things like mood.
OK. After a whistle-stop tour of most research on chronic fatigue syndrome, this is now my summary slide – this is what I’ve talked about.
There are two arms for research in chronic fatigue syndrome and I don’t believe that one replaces the other. The funding for both arms is different in this country and they both need to be done together and both influence the other.
The first is important for providing services and treatment:
We need to know more about how common this is.
We need to understand who it affects.
And we need to know about the different types of chronic fatigue syndrome.
We need to understand how the different types influence treatment.
We need to know much, much more about the impact of this devastating condition on patients and carers.
The second one is that we need to know more about the aetiology, about the causes of this condition and in my view, the fastest way forward is to use the large, very large sample sizes that we have available in this country to conduct rigorous genome-wide association studies and I’m not so certain about the role of infection but I do think there is an interesting story with XMRV that we need to get to the bottom of.
And it just remains for me to thank my funders – I’m funded by the National Institute of Health Research and my Clinician Scientists Fellowship, the Linbury Trust, Action for M.E. and I’m the Medical Adviser for AYME.
And this is where I work.
Thank you very much.
There was a Q and A session which included questions about the RNHRD NHS FT/University of Bristol Lightning Process pilot.
On 4 February, it was widely reported around the internet that the Molecular Diagnostics Unit, Imperial College, London, is now offering XMRV Detection Testing. All the available information on this £200 test, as it currently stands on Imperial College website, is published in this posting:
In January, a study published by PLoSOne, and led by Prof Myra McClure of Imperial College, had reported that its authors found no evidence that XMRV is associated with CFS in the UK.
The study concluded:
“Based on our molecular data, we do not share the conviction that XMRV may be a contributory factor in the pathogenesis of CFS, at least in the U.K.”
“XMRV or MLV sequences were not amplified from DNA originating from CFS patients in the UK. Although we found no evidence that XMRV is associated with CFS in the UK, this may be a result of population differences between North America and Europe regarding the general prevalence of XMRV infection, and might also explain the fact that two US groups found XMRV in prostate cancer tissue, while two European studies did not.”
On 5 February, a member of the ME community, Fiona Verity, contacted Professor Simon Wessely, one of the co- authors of the paper: Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A. (2010) Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One. 2010; 5: e8519. Full paper
Prof Wessely is acknowledged in the paper as having been responsible for “providing samples and associated data from a well characterised and valuable cohort of subjects.”
[Cohort = 186 patients (62% female, age range 19-70, mean 39.6±11.3 years) from consecutive referrals to the CFS clinic at King’s College Hospital, London.]
On 5 February, the ME Association issued this position statement:
Imperial College, the research centre in the UK that has found no evidence of XMRV infection in any of the blood samples from people with ME/CFS that they have looked at, has announced that their Molecular Diagnostics Unit is now offering their method for XMRV testing to the public: Imperial College announcement
MEA POSITION STATEMENT
Until we have the results from more replication studies the link between XMRV and ME/CFS remains speculative and unproven. We do not therefore believe that there is any point in spending money on an expensive blood test which is not, at present, going to act as either a diagnostic marker or an aid to management. And any laboratory offering this test to the public has an ethical duty to make these points clear.
We would, however, be interested to hear from anyone in the UK who does decide to have an XMRV test.
“Late last night The ME Association was informed that this announcement about XMRV testing does not apply to people with ME/CFS, or suspected ME/CFS. It only relates to the availability of the Imperial College XMRV test to referring doctors who are dealing with cases of prostate cancer. A full clarification will appear on the Imperial College website on Monday. It will appear here once we have it.”
The ME Association does not specify the provenance of this information.
When Imperial College does publish a clarification I will post an update at the top of this posting.
There has been much confusion about the purpose of this test and the patient population(s) that might be referred for it.
Questions have also been raised around the specific testing methods being used in relation to XMRV and its possible association with prostate cancer or suspected prostate cancer. Other laboratories have found XMRV in prostate tumour and tumour-associated tissues only, not in whole blood samples as specified by Imperial College. (References ,  and , Imperial College website text.)
Ms Verity has very kindly given permission to publish in full the email exchange between herself and Professor Wessely.
From: Fiona Verity Sent: 05 February 2010 16:57 To: Zielona, Olga Subject: F.A.O Prof Wessley please forward
Dear Professor Wessley,
I am aware that the XMRV test is to be made available for purchase. I am concerned about this and would be grateful if you would read the following email that I have sent to ME agenda (below). I hope you will understand that there are many very vulnerable people aware of the research into an illness that is crippling their lives. Whilst you and your colleagues I am sure have their best interests at heart I fail to see why you are now offering this test to CF/ME sufferers and furthermore they will be charged.
Your own research failed to detect the XMRV virus yet you are going to sell this test for £200 to the very people that your research results concluded will not have this virus. I feel I must have misunderstood the thread of all this somewhere and I hope you will take the time to reply; my main question at this point is, do you expect the XMRV virus to now be detected in these tests perhaps through a different approach, if so what will you be doing with the findings and if not is there a benefit to be had by those paying and having the test?
Your advice is keenly awaited.
Fiona Verity MSc
5th February 2010
To Whom It May Concern,
As I understand it the research for the connection between CF and XMRV virus tests according to Kings College were inconclusive. Furthermore, it appears questionable that this UK study can be compared with the major research and findings carried out in the US, as the exact conditions were not replicated and therefore one would expect different outcome measures. From what I understand it the very approach offered by Kings College for the process/testing of XMRV is flawed in-as-much as their controls do not replicate the procedures and protocols applied in the US therefore suggesting that King’s College research would fail to detect the XMRV virus.
Needless-to-say I am concerned that you are now making this same XMRV test available to ME/CF patients because it appears that this will be wasting their money – unless of course the testing approach has been altered to replicate US study and test? Secondly if the test is the same as that used in Kings College’s initial research then these results from the new tests paid for by CF/ME sufferers will go further to ‘falsely’ supporting inconclusive outcome result of Kings College’s own research.
I urge you therefore to look further into the matter so as not to afford a disservice to those you wish to assist i.e. ME/CF sufferers not to mention the devastating consequences of supporting research that could indeed be harmful to further much needed research in the field.
However, if I have misunderstood any element of this I look forward to an explanation at your earliest convenience.
F. Verity MSc
From: Wessely, Simon Date: 5 February 2010 18:26 Subject: RE: F.A.O Prof Wessley please forward To: Fiona Verity
Thank you for your inquiry re the announcement from Imperial College that they are offering a diagnostic test for XMRV
I understand that this is not intended for people who know they have CFS or are concerned they might have CFS
I can see that this is not clear from the announcement though, but it seems this was an oversight which is going to be speedily corrected
I hope this clarifies matters
Professor Simon Wessely
Vice Dean, Institute of Psychiatry,
Head, Department of Psychological Medicine,
Director, King’s Centre for Military Health Research,
King’s College London
Imperial College website content as it stood at 6 February 10
Having published, last month, in PloS One, that a study led by Prof Myra McClure (Imperial College London) and Prof Simon Wessely (King’s College London) found no evidence that XMRV is associated with CFS in the UK, Imperial College London is now offering a £200 XMRV test.
Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome
Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome
Otto Erlwein¹, Steve Kaye¹, Myra O. McClure¹*, Jonathan Weber¹, Gillian Wills¹, David Collier², Simon Wessely³, Anthony Cleare³
1 Jefferiss Research Trust Laboratories, Section of Infectious Diseases, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, St Mary’s Campus, Norfolk Place, London, United Kingdom, 2 Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry (King’s College London) De Crespigny Park, Denmark Hill, London, United Kingdom, 3 Department of Psychological Medicine, Institute of Psychiatry, King’s College London, Camberwell, London, United Kingdom
Infection with the newly discovered retrovirus xenotropic murine leukaemia virus-related virus (XMRV) has been associated with prostate cancer [1, 2] and chronic fatigue syndrome (CFS) . No causal link between infection and any human disease has been proven and the association between XMRV and prostate cancer or CFS remains controversial [4-6]. Indeed, in a study in our own laboratory of 186 patients with well-defined CFS we failed to detect the virus in any sample .
The test uses the polymerase chain reaction (PCR) to detect XMRV provirus (the DNA form of the viral genome) in peripheral blood mononuclear cells. The limit of detection of the method is one XMRV proviral DNA copy in 105 cells. The test includes controls for non-specific inhibition of PCR to avoid false negative results. The method is a fully validated in-house method. A summary of the validation is available from the Unit Manager.
The results will be reported as “XMRV detected” or “XMRV not detected”, the test is not quantitative at present.
We aim to issue reports within two weeks of receiving a sample. Details of samples and sample shipment are given on the user instruction page [weblink]. Please note we can only accept test requests and samples from medical practitioners (GPs or hospital doctors) we will not accept test requests directly from patients.
The current charge for testing is £200/sample.
If you are unhappy with the service provided by MDU or if you wish to make suggestions on how our service can be improved, please contact the Unit Manager.
1.Urisman A, Molinaro RJ, Fischer N Plummer SJ, Casey G et al. (2006) Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNaseL variant. PLoS Pathog. 2: 211- 225.
2.Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR (2009) XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumours. Proc Natl Acad Sci U S A. 106: 16351-6
3.Lombardi V, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS et al. (2009) Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 326: 585-589.
4.Fischer N, Hellwinkel O, Schulz C, Chun FK, Huland H et al. (2008) Prevalence of human gamma retrovirus XMRV in sporadic prostate cancer. J Clin Virol. 43: 277-283.
5.D’Arcy FR, Foley A, Perry L, Marignol L, Lawler M et al. (2008) No evidence of XMRV in Irish prostate cancer patients with the R462Q mutations. European Urology 7 Suppl: 271
6.Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde N et al. (2009) Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology 6:92.
7.Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A. (2010) Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One. 2010; 5: e8519.
Dr Tim Harrison PhD, DSc, FRCPath. is a Trustee of the CFS Research Foundation and member of the CFSRF Research Committee.
Professor Stephen T. Holgate FMedSci, MRC Clinical Professor of Immunopharmacology, University of Southampton is a member of the CFS Research Foundation’s Research Committee.
Professor Holgate chairs the MRC’s “CFS/ME Expert Panel”.
Dr Jonathon Kerr is a member of the MRC’s “CFS/ME Expert Panel”.
Dr Paul Kellam BSc PhD, Department of Infection, University College London is also a member of the CFS Research Foundation’s Research Committee and one of the project supervisors for the UCL PhD Project: Project title:
A role for XMRV in human disease Division of Infection & Immunity, University College London: Project Supervisors: Prof G Towers; Dr P Kellam
It is likely that you will have heard or read about the interesting work being carried out by Dr Judy Mikovits and her team at the Whitmore Peterson Institute in Reno, Nevada to see if the retrovirus XMRV (exenotrophic murine leukaemia virus-related virus) might be associated with CFS/ME.
This research has been given tremendous coverage by the media throughout the world and while anyone suffering from CFS/ME must feel a degree of excitement we must caution restraint. A good deal more work needs to be done before too many claims can be made as to the relevance of this virus in CFS/ME.
Recently the retrovirus XMRV was found in the tumour tissue of a subset of prostate cancer patients. Both XMRV positive cancer and CFS/ME have been linked to alterations in a certain antiviral enzyme. The team in Nevada decided to carry out a study to see if this retrovirus might be associated with CFS/ME.
When the team analysed blood taken from 101 CFS/ME patients 68 (67%) tested positive to XMRV genes compared with only 8 (3.7%)out of 218 healthy controls. They stated that their results are consistent with the hypothesis that CFS/ME patients mount a specific immune response to XMRV. The have discovered a highly significant association between XMRV and CFS/ME.
The research associating XMRV with CFS/ME leaves many questions to be answered. First, it will be necessary for the study to be repeated. Over the years there have been claims for other retroviruses in other illnesses which have come to nought so it is essential that this research is found to have been concluded correctly and for the conclusions reached to be confirmed in independent studies around the world.
We have to ask the question is XMRV a cause or factor in the pathogenesis of CFS/ME oe a passenger virus in the immunosuppressed CFS patient population. Several other viruses have been linked to CFS/ME, for instance the Epstein-Barr virus, enteroviruses or herpes viruses, so we must ask what is their relationship to XMRV and the presence or absence off theses viruses.
Another question must be to ask if the virus XMRV causes CFS/ME or is it just more common in people with the illness.
In the USA the National Institutes of Health (NIH) have taken this research very seriously. They have called meetings of different departments to discuss the implications of these findings, and they and various groups throughout the world are currently setting out to determine whether this association can be confined for CFS/ME patients in Europe and other countries. They have also made a grant of $2 million to take the research further.
Dr Jonathan Kerr and Dr Judy Mikovits have been awarded $2 million from the NIH to study the disease mechanisms in CFS/ME. $1 million has been awarded to the research team in Nevada, the other $1 million has been awarded to Dr Jonathan Kerr at St George’s University of London, the scientist well known to all the supporters of the CFS Research Foundation who carried out the research which discovered 88 genes which were abnormal in CFS/ME patients but remained normal in healthy people. Dr Kerr will study CFS/ME patients to identify important genes which are turned on and off, proteins in the immune system (cytokines) and mutations in the DNA. Some of these American patients have developed Mantle Cell Lymphoma (MCL) after many years of having CFS/ME; these patients will also be included.
The CFS Research Foundation tackles some of the questions.
In spite of the large grant which Dr Jonathon Kerr has received from the NIH the Research Committee has decided that it is imperative that we know if UK and USA patients are infected with XMRV. So the Foundation is to fund a study to establish whether there is a relationship between XMRV and CFS/ME by testing samples from the UK and the USA. Dr Jonathan Kerr and Dr Kate Bishop, who is working at the national Institute for Medical Research in London, are planning to examine patients with CFS/ME and match comparison groups. They will test for the virus itself as well as for the immune responses to this virus. It is of course, vitally important to confirm or refute the finding recently published in the USA.
The Gene Work Continues
While this work is causing such excitement the work of gene expression continues. Of the 88 genes which are abnormal in the CFS/ME group but normal in the control group, Dr Kerr found that these genes could be divided into 7 subtypes. What was so interesting was that theses subtypes were associated with distinct differences in their clinical patterns and severity. Each of these subtypes had a different list of genes which were abnormal.
In a further study Dr Kerr tackled a problem which always causes great concern to CFS/ME sufferers and their families and friends. For years there has been dissension among doctors and scientists as to whether CFS/ME patients were suffering from endogenous depression. Many sufferers felt that this was holding up scientific research. Dr Kerr tested the genes of people with endogenous depression and compared them with the genes of 29 healthy blood donors. Gene levels in the endogenous depressed patients were similar to those in normal controls, but, importantly they are different from the CFS/ME patients.
Dr Kerr and his team are currently extending the previous findings by including a larger number of well-defined patients. These investigations are being conducted on a blinded basis in order to ensure that there has not been any potential bias on the technical aspects of the study. The samples have recently been collected by Dr Tim Harrison, a Reader in Molecular Virology at University College London Medical School, who visited St George’s Hospital to prepare the blinding. The samples were placed in tubes, each one coded, and then frozen. Dr Harrison will keep the code, and no one else will know it until the time set for unblinding.
You will see that this team will have made sure that their findings are accurate. This contrasts with some previous attempts carried out by other groups on a purely empirical treatment methods that have no firm scientific basis. The research being conducted at the present time by Dr Kerr and his team may well result in not only a reliable diagnostic test but also the initial steps for appropriate therapy based on firm scientific data.
The outlook for CFS/ME research has never been brighter. Increasingly, doctors and scientists are believing that this is an organic disease which need organic research. The paper from Nevada suggesting that the retrovirus XMRV might be associated with CFS/ME has caused great interest and scientists throughout the world have been attempting to repeat this study. Whether or not it is confirmed we already know that virus infection is important in CFS/ME.
We have some encouraging news from the Medical Research Council (MRC). For years people with CFS/ME, their relations, friends and some research scientists have been frustrated by the MRC’s concentration on psychiatrists when conducting research into this illness. This has now changed. The Chief Executive of the MRC, Sir Lezek Borysiewicz is anxious that CFS/ME research should go ahead in a wide field. This must be the best possible news.
The Foundation is seeking new studies of a high standard. We shall have to re-double our efforts to produce these studies and we hope we can receive some part funding from the MRC. We see the possibility of our research expanding and producing even more radical results as it has in the past. The speed at which we can go forward is up to all of us. We can now look to the future with even greater hope.
XMRV is Not the retrovirus identified by De Freitas et al.
the publication and patent submitted by De Freitas et all clear describe the molecular characteristics of a retrovirus that is not a gamma (type C) retrovirus. The patent submitted for the retroviruses states
“Chronic Fatigue Immunodeficiency Syndrome associated virus, hereafter referred to by the name CAV may be morphologically characterized as a retrovirus, particularly a non-C retrovirus which is capable of infecting humans. Electron microscopy of viral particles formed in infected human cell cultures suggests that CAV is a non-C type retrovirus because of its diameter, morphology, formation and location of intracellular virions. The Electon micrographs of XMRV shown in Lombardi et al clearly depict a budding type C retrovirus of 90-100microns The DeFritas patent goes on to say “More specifically, CAV-infected cells could be characterized by electron-dense circular virions, some with electron-luscent cores and others with electron-dense cores, associated with the rough endoplasmic reticulum and inside large abnormally distended mitochondria in the cells. All particles are the same shape and size, 46-50 nm. No extracellular virus is observed. No forms budding from the cytoplasmic membranes are observed.
Thus, CAV-infected cells could also be charcterized by the presence of intracytoplasmic particles”Gamma (type C) retroviruses are 90 1100uM as shown in Lombardi et al and all are shown to consist of electron dense cores and specifically to bud extra-cellularly not intracellularly.
The data describes in the Defreitas patent can be found at:
Paul Rowen: To ask the Minister of State, Department for Business, Innovation and Skills what biomedical research into myalgic encephalomyelitis and xenotropic murine leukaemia virus-related virus is being undertaken. 
Mr. Lammy: The Medical Research Council (MRC) is one of the main agencies through which the Government support medical and clinical research. The MRC is an independent body which receives its grant in aid from the Department for Business, Innovation and Skills.
In 2008-09 the MRC’s total expenditure for research relating to Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) amounted to £728,000. This supported four projects including a £164,000 research programme led by Dr. C Clark at Queen Mary College, London on the general and specific risk markers and preventive factors for chronic fatigue and irritable bowel syndromes. CFS/ME continues to be a strategic priority area for funding and the MRC remains committed to supporting scientific research into all aspects of CFS/ME including evaluations of treatments and studies into the biological basis of the condition.
The MRC recently held a CFS/ME research workshop where the recent xenotropic murine leukaemia virus-related virus (XMRV) findings were among the items discussed. A note of the discussions will be published on the MRC website in due course.
The MRC’s National Institute for Medical Research are leading a programme on infection and replication of retroviruses (including XMRV). One study within the programme is looking at how XMRV reproduces in the cell, its interaction with host cell factors and how it subverts the host immune systems.
Response from Dr Charles Shepherd to concerns from member of the ME community:
Neil [Riley, Chair MEA Board of Trustees] has asked if I could respond to your email to the MEA about patient selection in XMRV research that might be funded by the RRF.
This is a complex issue and I’ve tried to explain the situation in rather more detail in version 4 of the MEA position statement, which is now up on the MEA website: http://www.meassociation.org.uk
Very simply, we are looking at a two stage research situation that will hopefully clarify the situation regarding XMRV prevalence in the ME/CFS population at some point in 2010, and (depending on the results) then move on to looking at viral pathogenicity in more detail (ie is this a disease causing virus?) and antiviral treatment. Incidentally, the results of a new research study looking at the use of AZT as a possible treatment for XMRV will be up on the MEA website later today: www.meassociation.org.uk .
As you know, the WPI study used patients who met both Fukuda research criteria and Canadian clinical criteria – partly because scientific journals don’t accept the validity of the CCC as a valid research tool..
Not surprisingly, the first stage of the attempt to replicate these results has resulted in various international groups almost entering a race to see who could replicate or refute the WPI results first. And this has meant they have gone for an easy and immediate source of patient material >> stored blood samples. I am not aware of any stored blood samples here in the UK that are from patients who meet Fukuda plus Canadian criteria and I doubt if there are any. So there was no point in the MEA insisting that research funding in stage one could only be used in studies involving Canadian criteria patients, or CC + Fukuda.. I therefore suggested that these ‘first off the mark’ studies should only involve Fukuda criteria patients as here in the UK there is a real worry that retrovirologists, who have very little general knowledge of ME/CFS, might be using samples from patients from NHS sources that meet either Oxford research or even NICE clinical criteria – the latter being used by the NHS clinics. It would have been helpful if the paper itself had carefuly specified the selection criteria because I know that there are researchers taking this forward on the basis that CFS in the paper = CFS Fukuda.
As far as the second stage is concerned, we would certainly be looking at funding a study that would use Fukuda plus Canadian criteria but there are still going to be major problems and we cannot be dogmatic here. This is because the NHS services do not use Canadian criteria in their clinical assessments and most of us who work in the UK private sector don’t have sufficient numbers of new patients coming through to quickly build up a decent number (ie 100 cases) meeting both criteria, and we don’t tend to be dogmatic about the use of criteria in patients already diagnosed.
And this may be why MERUK has decided to fund a study in Sweden rather than here in the UK. The MEA would prefer to fund UK XMRV studies but we are willing to look at overseas proposals – as has already happened.
As you will have seen I have spent a great deal of time over the past few weeks talking to virtually all the virologists and retrovirologists here in the UK that are interested in taking this work forward, and the MEA is very keen to help in whatever way we can. I hope the researchers are now well aware of the issues surrounding careful patient selection (some of them were definitely not) and not just the science behind XMRV.
I hope you find this helpful.
I would be happy to discuss in more detail if you would like to call me on my home number when convenient.
Dr Charles Shepherd
Hon Medical Adviser, MEA
(This information may be forwarded if you wish to do so)
Version 4 of the MEA position statement on XMRV clarifies some of the points and queries raised in the previous three summaries. Version 4 also updates the situation on XMRV research in the UK, testing for XMRV, and refers to our correspondence with the Chief Medical Officer regarding blood supplies and blood donation.
This summary is intended to be a balanced account of the current situation. It therefore not only raises questions but is also very cautious when it comes to drawing any firm conclusions about the role of XMRV in ME/CFS as either a diagnostic marker, causative agent, or abnormality that requires active treatment with antiviral medication.
ROLE OF ME RESEARCH UK (MERUK) and IRISH ME TRUST
MERUK and The Irish ME Trust have just announced that they are providing joint funding for a replication study that will be carried out in Sweden. This work will be carried out by Professor Blomberg, Head of the Research Group of Clinical Virology, University of Uppsala and Professor Gottfries, from the Sahgrenska University Hospital, Molndal. The researchers will retrospectively test previously stored samples from 3 groups of patients (20 Fukuda defined ME/CFS; 20 fibromyalgia; 20 irritable bowel) and 20 controls. In addition, they will prospectively test samples from 120 ME/CFS patients defined by Fukuda 1994 and Canadian 2003 clinical criteria. Results are expected in Spring/Summer 2010. More information on this study can be found on the MERUK website.
There is clearly an immediate need for international agreement and co-operation on the research criteria being used to select well-characterised ME/CFS patients for further research into XMRV. Otherwise, we could end up in spring/summer 2010 with a collection of conflicting results on prevalence because different international research groups have been using different patient selection criteria.
In the present situation, many research groups are reluctant or unwilling to use Canadian criteria. This is because these are essentially clinical criteria and in the eyes of many researchers they have not been validated for use in research studies as stand alone criteria. There is also the problem in that most research groups do not having ready access to stored blood samples from ME/CFS patients that meet Canadian criteria.
So the best way forward may be for everyone to agree to use either Fukuda-defined CFS – which would obviously help to define which sub-groups of patients are XMRV positive under this CFS umbrella – or, if possible, to use patients that meet both Fukuda CFS and Canadian clinical criteria. It is worth noting that a significant proportion of people with Ramsay-described ME will not meet Fukuda criteria for CFS – so they are likely to be excluded from research currently taking place.
We do not believe that it is sensible to extend the entry criteria into research studies by using the 2005 ’empirical’ definition of CFS for patient selection purposes as this will bring in an even more diverse group of patients who have chronic fatigue. This point has also been made by Dr Nancy Klimas when she addressed the CFSAC meeting in Washington in October.
Provided there is careful selection of ME/CFS patients, healthy controls and disease controls, we may then be able to draw some meaningful conclusions about which people who come under the wide clinical spectrum of CFS clinical presentation have XMRV and which do not.
Besides using stored blood samples, research needs to involve fresh clinical cases, as well as other disease groups (particularly inflammatory conditions with immune activation) and properly matched healthy controls.
Professor Tony Pinching, Action for M.E.’s Principal Medical Adviser, sets out his views on XMRV in this article from InterAction 70, published this week:
InterAction 70 Christmas 2009
Potential virus breakthrough
We thought all our Christmases had come early in October, when researchers at the Whittemore Peterson Institute in Reno, USA announced that they had identified genetic material (DNA) from a mouse virus – murine leukaemia virus related virus or XMRV- in 68 out of 101 CFS patients (67%) compared to 8 out of 218 (3.7%) of healthy people.
Further blood tests showed that more than 95% of CFS patients have antibodies to XMRV, indicating they had been infected with the virus, which may then have lain dormant in their DNA.
Dr Judy Mikovits, research director, Whittemore Peterson Institute, is testing a further 500 blood samples collated from patients diagnosed with CFS in London.
In our press statement, quoted in part by the BBC, Sir Peter Spencer said:
“It is still early days so we are trying not to get too excited but this news is bound to raise high hopes among a large patient group that has been ignored for far too long.
“If the researchers can go on to prove a definitive cause and effect between this retrovirus and M.E., it will make an enormous difference to 250,000 men, women and children who have M.E. in this country.
“Action for M.E. has long been calling on the UK Government to invest more in research into the causes of this horrible illness. Once we know the cause, researchers can start working on more effective treatments, preventive measures and ultimately a cure for M.E.”
What does this research signify?
Professor Tony Pinching, Action for M.E.’s Principal Medical Adviser says the study needs to be confirmed by independent research and it would be very premature to think about clinical tests or treatments based on these early findings (see below). His caution is echoed in statements by Professor Andrew Lloyd, Director, Centre for Infection and Inflammation Research, University of New South Wales (see www.me-cfs.org.au/node/448 ), NCI director Dr John Niederhuber (www.cfids.org/temp/xmrv-guidelines-nci.asp ) and Dr Charles Shepherd, ME Association www.meassociation.org.uk (under ‘quick links’ on their home page). Professor Pinching comments:
“A new research report about CFS in a major science journal is obviously reason for some excitement. Many of you will have heard the news reports – some will have been hopeful, others sceptical, and many others unsure what to think. And that’s about the size of it too for the informed observer of the scientific data.
“In essence, a US study has shown apparent evidence of a virus (XMRV) in the blood cells of people with CFS, taken from a repository of samples from ‘well-characterised cohorts of patients.’
“XMRV is related to a class of mouse leukaemia viruses that have not been previously firmly associated with any human disease, although recently seen in some patients with prostate cancer. Although these viruses have been much studied in cancer biology, they can also be contaminants, although circumstantial evidence is against this here.
“67% of CFS patients compared with 4% of controls showed evidence of the DNA of this virus. Other evidence shows that the virus is actively expressed in patient cells, is capable of passing from cell to cell, and generates a detectable immune response in patients.
“The brief report lacks information about patient characteristics, and the comparability of patient and control samples, but the data seem plausible and internally consistent.
“However, much more work is needed to determine what these early findings signify. The first and most crucial test would be independent verification, through studies on large numbers of carefully characterised patients at other sites, preferably on fresh, not stored, samples.
“We also need studies on large numbers of both healthy people and people with other conditions. This is to clarify how specific the association is, and the extent to which XMRV occurs in other chronic immunological or neurological conditions.
“Biologically, there is no obvious mechanism that would link this sort of virus (very different from familiar viruses) to this sort of condition, although various plausible hypotheses could be devised. Most importantly, the virus could as easily be an effect of the illness, as it could be a cause or disease mechanism. An altered state of immune cells – from which the virus was derived – could activate an innocent passenger virus, for example.
“For the usual reasons, very preliminary research results have led to much speculation, inevitably raising hopes of people with CFS/ME. Loose talk of clinical tests and therapies based on these findings may reflect a genuine need for such things, but not any clear justification from the published science to date.
“So my thoughts so far are:
. this is interesting, but it first needs independent and substantive confirmation
. we don’t know whether XMRV is cause, effect, or just a passenger
. it would be very premature to think about clinical tests or treatments based on these early findings
. perhaps the most important thing is that this work will foster more high quality research on the biology of this clinically important but scientifically enigmatic condition.”
Professor Tony Pinching, for Action for M.E. InterAction 70 Christmas 2009