XMRV and ME/CFS – Third negative study reported in the British Medical Journal

February 26, 2010


A third European XMRV study, which has attempted to find the human retrovirus XMRV in people with ME/CFS, has failed to do so.  Results from the case-control study by Kuppeveld et al is reported today in the British Medical Journal:along with an accompanying editorial from Professors Myra McClure and Simon Wessely.

This latest XMRV study was carried out by a research group based in the Netherlands.
The virologists examined peripheral blood mononuclear cells in blood samples that were taken from a cohort of Dutch ME/CFS patients whose diagnosis met with (the very broad) Oxford research criteria for CFS.  They also tested blood samples from some neighbourhood controls.  Blood samples were taken between December 1991 and April 1992 and were cryopreserved.
The virologists used a polymerase chain reaction (PCR) assay to target the XMRV integrase gene and/or a nested PCR assay targeting the XMRV gag gene. PCR is a way of detecting viral genetic material in the blood samples.  PCR testing was carried out on 32 patient samples and 43 control samples – which are low numbers for this type of scientific study. The authors state that their PCR technique is sensitive enough to detect low virus copy numbers.
No XMRV sequences were detected in any of the patient or control samples in any of the assays.
The authors conclude that their data casts doubt on the claim that XMRV is associated with chronic fatigue syndrome in the majority of patients.
The first and so far only study to positively link XMRV to ME/CFS was reported in October 2009 in Science by Lombardi et al.
Since then this is the third XMRV follow up study to be reported in the medical literature.  All three follow up studies have emphatically failed to confirm the presence of XMRV in people with ME/CFS.  The previous two studies involved much larger CFS patient cohorts (meeting Fukuda research criteria) numbering 186 (Erlwein et al) and 170 (Groom et al).
This latest study, along with the other two negative studies from the UK, will again be criticised for not being a true replication study because (a) the patient cohort did not meet the same strict entry criteria as was used in the American study (ie Fukuda CFS as well as Canadian clinical criteria) and (b) differing laboratory protocols were used to try and identify the presence of XMRV.  These are perfectly valid criticisms regarding the interpretation of what constitutes a replication study – an essential part of the scientific evaluation of new findings and theories.
However, it should be noted that under the umbrella of either Oxford or Fukuda CFS research criteria there are going to be a significant number of people who will also meet Canadian clinical criteria if the patient cohorts from all three negative studies are added together.  In addition, Kuppeveld et al appear to be unaware of the use of the Canadian criteria in the US study – probably because this was not mentioned in the paper that appeared in Science. It also has to be accepted that the various laboratory investigations for finding XMRV have been carried out in very reputable microbiological research centres and involved retrovirologists of international repute.  So the scientific testing procedures and results for XMRV must be taken seriously.
Overall, these three negative studies now place a very serious question mark over the proposition that XMRV is present in a significant proportion of the ME/CFS population and that the infection plays a significant role in most cases of sporadic ME/CFS.
Various explanations are being put forward to explain the stark differences between the US and European findings – including geographical variation in the prevalence of XMRV and the possibility that the US patient cohort came from geographical clusters of XMRV that are not representative of the wider and sporadic ME/CFS population.  But it seems more likely that the explanation lies with the differing ways of testing for XMRV in the lab.
The MEA believes that it is vital to quickly resolve why these stark differences are occurring.  One small but important step we are discussing with both researchers and people with ME/CFS is whether people in the UK who have sent their blood to the US and tested positive would be willing to have it retested by a UK research group.  We also believe it would be helpful if a fresh cohort of ME/CFS patients could be agreed by all and their blood tested for XMRV in the different laboratories involved in these four studies.  If the explanation does appear to be with laboratory testing methods for XMRV we hope that the international retrovirology experts will step in and help to achieve an agreed position. 
In the meantime we eagerly await the results of further XMRV studies and once again point out that the MEA Ramsay Research Fund is very willing to consider funding high quality research proposals relating to XMRV, especially any proposal that would include the use of a fresh cohort of patients that would meet Fukuda CFS research criteria and Canadian clinical criteria.
The MEA has a very comprehensive XMRV website summary (>> Quick Links) covering the publication of the Science study and events that followed publication. 
Summaries covering the two follow up studies from the UK can be found in the MEA website news archives for January and February 2010.
Our position on individual XMRV testing remains exactly the same.  We do not see any point in spending a large sum of money on a test that cannot, at present, be used as a diagnostic marker or for the purpose of management.
Dr Charles Shepherd
Hon Medical Adviser, ME Association
26 February 2010


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