ME Association: Updates: Blood Donation, XMRV and ME/CFS Version 3

Two further statements around the XMRV study have been issued by the ME Association (UK) and are published, in full, below this preamble:

“There is 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 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, with many research groups reluctant or unwilling to use Canadian criteria, and not having stored samples from patients that meet Canadian criteria, the best way forward may be for everyone to agree to use Fukuda defined CFS. We may then be able to draw some conclusions about which people who come under the wide clinical spectrum of CFS clinical presentation have XMRV and which do not.”

Why is the MEA not recommending use of the more rigorous Canadian Criteria for replication studies?

Several years ago, the MEA held a formal postal ballot amongst its membership to vote for or against a proposal that the MEA should adopt the Canadian Criteria. Cases for and against adoption were published in the MEA’s magazine, ME Essential, with Dr Shepherd presenting the case against adoption. Of the very small percentage of the membership that returned a vote, the majority vote was in favour of adoption. The MEA announced the adoption “in principle” of the Canadian Criteria, then deftly kicked the Canadian Criteria under the carpet.

 “…Demonstrating a link between a retrovirus and ME/CFS does not, by itself, resolve the physical vs psychological debate. Research studies have demonstrated links between retroviruses and diseases as diverse as autoimmune disorders (which could be relevant to ME/CFS), immunodeficiency diseases, multiple sclerosis, tumours, anaemias and even schizophrenia.”

I am not a member of the MEA; I was barred from membership of the Association in 2005 by Chair’s Action. A subsequent application to become a member of the Association was voted against by the Board of Trustees. The Association has the power, within the framework of its constitution, its Memorandum and Articles of Association, to deny membership to anyone it decides not to admit to membership [Clause 4.1 (b)]. Were I a member, however, I would be demanding an explanation from Dr Shepherd of what he means by the first sentence of the statement above.

 

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1] XMRV and blood donation – update following letter to the Chief Medical Officer (02.11.09)

2] XMRV and ME/CFS:  WHAT DO WE KNOW SO FAR?  AND WHAT DON’T WE KNOW? (VERSION 3) (04.11.09)

 

1] XMRV and blood donation – update following letter to the Chief Medical Officer (04.11.09)

http://www.meassociation.org.uk/content/view/1067/161/

XMRV and blood donation – update following letter to the Chief Medical Officer

The ME Association wrote to Sir Liam Donaldson, Chief Medical Officer at the Department of Health, on Tuesday 27 October about XMRV research. In particular, we raised the situation regarding people with ME/CFS and blood donation.

Click  http://www.meassociation.org.uk/content/view/1059 

to read a copy of this letter.  An acknowledgement from the CMO has been received.

We are today writing to the CMO again to pass on the interim guidelines about blood donation and ME/CFS in America that have been issued by Dr John Niederhuber from the National Cancer Institute, US National Institutes of Health. This information was requested from the NCI by the CFIDS Association of America and has been published on their website:

http://www.cfids.org/temp/xmrv-guidelines-nci.asp

The MEA is very keen to build up an international database on the situation regarding blood donation and any information from people or support groups in other countries would be welcomed.

Following contact and discussions last week with a number of virologists and retrovirologists involved with XMRV research, the MEA will be updating our position statement on XMRV later in the week.

We shall also be repeating our offer to help fund good quality XMRV research here in the UK through the MEA Ramsay Research Fund:

http://www.meassociation.org.uk/content/view/30/205/

——————–

2] XMRV and ME/CFS:  WHAT DO WE KNOW SO FAR?  AND WHAT DON’T WE KNOW? (VERSION 3) (04.11.09)

http://www.meassociation.org.uk

Version 3 clarifies some of the points and queries raised in the previous two MEA statements and summarises the  various actions now being taken by the  ME Association.

It also updates the situation on XMRV research initiatives in the UK, testing for XMRV and refers to our letter to Sir Liam Donaldson, the Chief Medical Officer, regarding blood supplies and blood donation.

This summary is intended to be a balanced account which 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 at this very early stage in the research.

BACKGROUND

On Friday 9 October, the front page of the UK Independent newspaper carried a major news item under the heading ‘Has science found the cause of ME?’

This referred to new research findings from America which indicate that a recently discovered retrovirus, known as XMRV (xenotropic murine leukaemia virus-related virus), could be playing an important role in causing or maintaining ME/CFS. The news item was accompanied by a very supportive editorial about the need for recognition and research into ME/CFS. These two items can be read here:

http://www.meassociation.org.uk/content/view/1068/161/

The Independent story was soon followed up by the rest of the UK media, including the BBC. Most of the news reports gave a reasonably balanced and accurate account of the research. However, some reports incorrectly inferred that the cause of ME/CFS had now been conclusively discovered and that an effective antiviral treatment would soon be available. A selection of UK media reports can be found in the October news archive on the MEA website.

The actual research paper was published in the online edition of Science, along with a perspective written by John Coffin (Department of Molecular Microbiology, Tufts University, Boston, USA) and Jonathan Stoye (National Institute for Medical Research, London).

References:

Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Lombardi V et al. Science October 8 2009

http://www.sciencemag.org/cgi/content/abstract/1179052

Abstract

A new virus for old diseases? Coffin JM and Stoye JPScience October 8 2009 326; p215

http://www.sciencemag.org/cgi/content/abstract/1181349

These papers are also available on the WPI website http://www.wpinstitute.org

Additional online data from the study can be obtained if required.

XMRV AND PROSTATE CANCER

XMRV has also been found in an American study in men who have prostate cancer. This was partly why the ME/CFS study was carried out. However, the most recent study on XMRV in prostate cancer from Germany has queried any such a link and suggested that one possible reason could be a geographically restricted incidence of XMRV infections. An additional explanation involves the type of laboratory testing for XMRV used in the two studies. The precise role of XMRV in prostate cancer remains uncertain.

Reference:

Lack of evidence for xenotropic murine leukaemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology 2009, 6:92. Available on-line here:

http://www.retrovirology.com/content/6/1/92

MEA POSITION ON XMRV

These are potentially important research findings that could help with both the diagnosis and management of ME/CFS. We congratulate all those involved in deciding to do this research study.

However, a number of difficult questions have to be answered before anyone can conclude that this virus plays a significant role in either the cause, transmission, clinical assessment or management of ME/CFS.

The research has demonstrated a correlation between ME/CFS and XMRV – not that it is the causative infection.

Much more epidemiology and laboratory work now needs to be done to answer the essential points set out below:

o Carrying out further and larger studies using different populations of people in different countries with ME/CFS. This work should include people at different stages of the illness (to see if the virus is present in the same percentages in both early and late cases) and in all degrees of severity. Research in different countries is vital in view of the conflicting geographical findings relating to XMRV in prostate cancer.

o Using different international laboratories to test for evidence of the virus.

o Establishing a battery of properly validated tests for XMRV that can be consistently used in further research studies.

o Assessing what, if any, correlation there is between the presence of this virus and (a) severity of symptoms, (b) a clear infectious onset with a known infection, (c) immune system abnormalities, CD4 abnormalities in particular, and (d) various other factors involved in sub-grouping of people under the ME/CFS umbrella.

o Assessing to what extent this particular retrovirus virus is also present in other chronic conditions, especially those such as autism, multiple sclerosis and lymphoma where viral infections have been implicated as a causative factor.

o Assessing whether this virus is acting as a benign marker of disease or immune dysfunction, is a ‘passenger virus’, or whether it has a role in the actual disease process and development of symptoms.

o Investigating whether the presence of the virus in healthy people acts as a predisposing factor in the development of ME/CFS (possibly when another infective trigger appears) and/or prostate cancer – rather than being involved in the actual disease process.

o Investigating what effect, if any, the virus has in healthy people who carry it over a period of time.

o Assessing whether people with evidence of XMRV should be treated with antiretroviral medication, and if so developing a suitable antiviral drug or combination of antiviral drugs.

o Assessing whether animal model studies would help to increase our understanding of the way in which this virus may infect cells and possibly cause human disease.

TESTING FOR XMRV IN THE UK AND USA

Until these research findings have been properly replicated, and we have the answers to some of the above questions, there is no point in asking your doctor to be tested for XMRV. This is because the NHS does not currently have the facilities to do so and the testing procedures are only being used in a research capacity at present. But, if it does turn out that there is a consistent and strong association with ME/CFS, then testing for XMRV would almost certainly have to be made available on the NHS.

We are not aware of any private pathology laboratories here in the UK that are able to test for XMRV, or are intending to start offering to carry out testing.

Dr Vincent Lombardi, primary investigator and lead author of the Science paper is Director of Operations for XMRV testing at Viral Immune Pathology Diagnostics VIPDx – a commercial laboratory in America. This testing facility is not available to people living outside the US.

VIRAL TRANSMISSION

We know that some people with ME/CFS are now very concerned about the possibility of transmission of XMRV through what are termed body fluids (ie blood, saliva, semen). However, until we know more about what this virus does in the body it would be premature to start arriving at firm conclusions and recommending all kinds of restrictions to normal daily living.

Remember: we still do not know for certain whether this is a disease-causing virus in humans and whether it plays a role in causing or maintaining ME/CFS.

And if this virus was behaving as an ‘ME virus’ in the way that HIV, another retrovirus, causes and transmits HIV infection, often leading to AIDS, there would be a significant number of sexual partners of people with ME/CFS developing ME/CFS. But this is clearly not the case.

One simple way of obtaining some early clues about viral transmission of XMRV would be to test for the presence of the virus in healthy partners and offspring of people who have the infection and comparing the findings to a control group of people that have no such link.

PRESENCE OF XMRV IN THE HEALTHY POPULATION

If this virus is also present in up to 4% of the normal healthy population here in the UK (ie around 2.4 million, or ten times the number of people who have ME/CFS), as appears to be the case in America, and it does play a significant role in diseases such as ME/CFS and prostate cancer, there will be widespread and very serious implications for public health, blood donation etc. This could also include vaccination against the virus and treating people who are XMRV positive. These are complex decisions which can only be made in the light of further research studies.

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 now 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. A copy of this letter can be read here:

http://www.meassociation.org.uk/content/view/1059/

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:

http://www.cfids.org/temp/xmrv-guidelines-nci.asp

WHAT CAN WE LEARN ABOUT THE ROLE OF INFECTION FROM OUTBREAKS OF ME/CFS?

It should be noted that unlike the retroviral infection HIV, ME/CFS is an illness that occurs both sporadically and in highly localised acute geographical outbreaks, often involving closed communities such as schools and hospitals, where there is no obvious evidence of bodily fluid transmission. This fact would obviously question the role of XMRV as a precipitating infection in the onset of the illness.

In the pivotal Royal Free Hospital outbreak of ME back in 1955, far more than 4% of a previously healthy population of doctors and nurses contracted an unknown infection at roughly the same time (the hospital had to close due to lack of staff). This fact would question the role of XMRV as a key predisposing factor if it only occurs in 4% of the population.

TREATMENT OF XMRV: ANTIRETROVIRAL DRUGS AND VACCINE

Until we know more about the possible role of XMRV in ME/CFS there is no point in asking your doctor about antiviral drug treatment. If it turns out that the virus does play a role in causing or maintaining ME/CFS then antiviral drug treatment will need to be investigated. This will involve clinical trials to test possible drug treatments for both safety and efficacy – a process that normally takes a considerable amount of time and money.

The 2007 NICE Guideline on ME/CFS specifically states that doctors should not use antiviral medication to treat ME/CFS. This dogmatic position is unlikely to change without clear evidence of benefit in good quality randomised clinical trials. We understand that the NICE guideline will be reviewed in late 2010.

Vaccination against XMRV has also been raised as a possibility.

ROLE OF THE MEA RAMSAY RESEARCH FUND, VOLUNTEERING FOR RESEARCH and THE MEDICAL RESEARCH COUNCIL

The ME Association is keen to progress this research here in the UK through any way we can help. We have already made contact with virologists and retrovirologists who are interested in this virus here in the UK, and we are aware of at least four sound research groups who are keen to pursue this work. Funding from the Ramsay Research Fund (RRF) could be made available very quickly if we receive a good quality research proposal. However, our contacts and discussions with UK researchers so far indicate that short term funding is not an immediate problem and that initial plans can probably be covered from existing budgets.

More information on the work of the RRF can be found here:

http://www.meassociation.org.uk/content/view/30/205/

Since publication of these results it has become apparent that a number of international research groups outside the US and UK are also intending to try and confirm or refute the findings. The MEA has been contacted in relation to two such groups from overseas. This is obviously good news and should help to clear up some of the immediate uncertainties.

If volunteers are required for any research taking place in the UK we will place an announcement on the MEA website.

The Medical Research Council’s Expert Group on ME/CFS research (membership includes Dr Jonathan Kerr and Dr Charles Shepherd) will be holding a two day research workshop on 19 – 20 November where XMRV will obviously be one of the topics under discussion.

SELECTING PEOPLE FOR FURTHER RESEARCH STUDIES

There is 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 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, with many research groups reluctant or unwilling to use Canadian criteria, and not having stored samples from patients that meet Canadian criteria, the best way forward may be for everyone to agree to use Fukuda defined CFS. We may then be able to draw some 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.

KEY FACTS ABOUT THE XMRV RESEARCH

http://www.wpinstitute.org

o An American group from the Whittemore Peterson Institute, in collaboration with the National Cancer Institute and the Cleveland Clinic, have reported finding evidence of a human retrovirus known as XMRV in blood samples taken from people with ME/CFS.

o Using peripheral blood mononuclear cells, DNA (viral genetic material) from the virus was found in 67% of patients (68/101) compared to 3.7% in healthy controls (8/218).

o The XMRV virus was shown to grow in cell culture in the laboratory.

o Further studies have found that 95% of people with ME/CFS have antibodies to the virus – indicating an immune response to a recent or past infection.

o Blood samples were collected from people with what is referred to in the paper as CFS who live in different parts of the United States, as well as from healthy controls. More information on the patient and control cohorts can be found on the WPI website.

o A more detailed, but easy to understand, summary of the XMRV research has been prepared by Dr Suzanne Vernon for the CFIDS Association of America. This can be read at the CFIDS website. A press release summary produced by the National Cancer Institute is also worth reading:

http://www.cfids.org/cfidslink/2009/110402.asp

o The paper in Science does not provide any detailed information about the patient group (ie age, gender, illness characteristics) or control group. However, a report on the research published in The Wall Street Journal states that 20/101 people in the CFS group also had a lymphoma, a type of cancer affecting the lymph nodes. Questions have therefore been raised about the inclusion of these patients in the CFS group, as well as the makeup of the control group and how these patients were selected. See commentary from Professor Andrew Lloyd published on the website of the ME/CFS Society of NSW, Australia:

http://www.me-cfs.org.au/node/448

The WPI have now stated in a website response that none of the results in the Science paper relate to people with CFS plus lymphoma.

KEY FACTS ABOUT RETROVIRUSES

o Retroviruses infect a wide range of animal species.

o Human retroviruses consist of HIV (causing AIDS) , HTLV-1 (causing T-cell leukaemias and lymphomas) and HTLV-2 (often asymptomatic and not yet clearly linked to any specific disease).

o They were discovered in the 1980s when it became possible to culture T-cells in vitro.

o They infect CD4-bearing lymphocytes – a special type of immune system cell that is derived from the thymus gland.

o Endogenous retroviruses (ERVs) are also found in humans and usually cause no ill effects. Defective retroviruses which integrate into the host genome are passed down from generation to generation. And 2% of the human genome is made up of endogenous retroviral sequences.

o Retroviruses are enveloped viruses, with an RNA genome. The name retrovirus is derived from the fact that the virus particle contains an RNA-dependent DNA polymerase – reverse transcriptase. This enzyme converts the RNA genome into DNA, which then integrates into the host chromosomal DNA. The reverse transcriptase enzyme is highly error prone and rapid genetic variation is a feature of this group of viruses.

KEY FACTS ABOUT XMRV: Xenotropic murine leukaemia virus-related virus

o XMRV is a gammaretrovirus that was first described in 2006 in a group of men who had prostate cancer.

o It may also be linked to other medical conditions, including fibromyalgia.

o XMRV is closely related to a group of retroviruses that can infect mice.

o This type of virus is thought to be transmitted through body fluids such as blood, semen and breast milk. It is not thought to be transmitted through the air – like a flu virus. But the route of transmission remains uncertain.

o Testing for evidence of the XMRV virus in blood is currently only available at a few specialised laboratories here in the UK. Demonstrating a link between a retrovirus and ME/CFS does not, by itself, resolve the physical vs psychological debate. Research studies have demonstrated links between retroviruses and diseases as diverse as autoimmune disorders (which could be relevant to ME/CFS), immunodeficiency diseases, multiple sclerosis, tumours, anaemias and even schizophrenia.

CONCLUSIONS

The bottom line to this interesting research is that it currently raises more questions than answers.

o Does the presence of XMRV in healthy people make them more likely to develop ME/CFS when another infection appears?

o Does XMRV cause ME/CFS in some cases? Or does XMRV become active as a result of having ME/CFS?

o Or is it simply an innocent bystander with no role in the illness?

o Should XMRV be treated?

When we have accurate answers to at least some of these questions we can move forward, if necessary, with testing and treatment.

We will update this summary as further information becomes available.

If you want to comment on it please do so via the MEA Website.

Dr Charles Shepherd
Hon Medical Adviser, ME Association

Summary 3 dated 4 November 2009

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