Editorials

Chronic fatigue syndrome and human retrovirus XMRV

BMJ 2010; 340 doi: http://dx.doi.org/10.1136/bmj.c1099 (Published 26 February 2010) Cite this as: BMJ 2010;340:c1099
  1. Myra McClure, professor of retrovirology and honorary consultant in genitourinary medicine1,
  2. Simon Wessely, professor of psychological medicine2
  1. 1Jefferiss Research Trust Laboratories, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, London W2 1PG
  2. 2Institute of Psychiatry, King’s College London, London SE5 8AF
  1. m.mcclure{at}imperial.ac.uk

    Three studies now refute the original study reporting the link

    In the linked case-control study (doi:10.1136/bmj.c1018), van Kuppeveld and colleagues describe their failure to find evidence of a new human retrovirus in Dutch patients with chronic fatigue syndrome.1 The study is the latest contribution to a controversy that has surrounded two conflicting publications on the retroviral aetiology of this syndrome.2 3

    The saga started, not with chronic fatigue syndrome or a virus, but with an enzyme (RNaseL) that plays a pivotal role in antiviral defences when activated by the interferon released in response to infection. Variants of the gene encoding this enzyme have been linked to an increased susceptibility to prostate cancer, and this led to the identification of a new virus in prostate tissue that was related to, but different from, known xenotropic murine leukaemia viruses4; hence the designation xenotropic murine leukaemia virus-related virus (XMRV). Sequence analyses showed that it is not an endogenous human virus, and the fact that eight clones derived from eight different patients are slightly different from one another confirms it as a new virus that has found its way into a human population.

    Abnormalities in the RNaseL gene of patients with chronic fatigue syndrome had been reported in some studies,5 but not in others.6 Nevertheless, this prompted the search for evidence of XMRV in patients with chronic fatigue syndrome. The resulting study claimed that 67% of patients with chronic fatigue syndrome were XMRV carriers, compared with 3.7% of healthy controls.2

    The news was received philosophically by most retrovirologists, who are used to claims of associations between retroviruses and diseases that fail to withstand the test of time. Most researchers into chronic fatigue syndrome were also sceptical, mindful of the problems of defining the syndrome, its imprecise boundaries, and almost certain heterogeneity. It was not that they doubted a viral cause in some patients because this had already been shown,7 8 but the possibility that any single agent or risk factor could account for more than two thirds of cases seemed implausible on the basis of what has already been established.9

    But if the research community was underwhelmed, people with the syndrome were not. If true, these findings would have transformed the understanding of the illness and opened up new avenues of treatment. Some saw this as a definitive response not only to those few professionals who, they claim, continue to doubt the reality of the syndrome, but also to the larger number of professionals who believe that, irrespective of causation, rehabilitative treatments can reduce symptoms and disability. It is depressing that the first, untenable, view is too often confused with the second, a perspective that offers hope to patients and is backed by evidence.

    First and foremost, however, as with any discovery, the data must be unequivocal, and the finding has to be confirmed by others. In January 2010, our own group found no evidence of XMRV in a well characterised cohort of 186 patients with chronic fatigue syndrome in the United Kingdom.3 Van Kuppeveld and colleagues’ study adds to this negative evidence. Although the study is small, the patients are well defined and matched in age, sex, and geographical location. The polymerase chain reaction used to amplify XMRV gene sequences has been well controlled and its sensitivity is sufficient to detect low virus copy numbers. XMRV was not detected in this Dutch cohort, a result that comes in the wake of a third study published this month,10 which also failed to identify XMRV in 170 patients with chronic fatigue syndrome.

    There has been much talk of different protocols being used in the four studies. These technical differences are irrelevant provided amplification is controlled by inclusion of a “housekeeping gene”—to show that a known human gene can be amplified under the conditions used—and the sensitivity of the assay is known, as was the case in all three European studies.

    Meanwhile, a different strategy is also being considered to reconcile these different findings: that new blood samples should be taken from patients with diagnosed chronic fatigue syndrome and sent to laboratories capable of carrying out the analysis. This is unlikely to be soon.

    Three studies have now generated data that are in stark contrast to those of the original study. However, at least two explanations for this are still possible. The first, and more unlikely, explanation is that XMRV infection is geographically confined to the United States. The second is that the virus is infecting an atypical cohort. This may well be so. Although the patients were not well described in the original study, van Kuppeveld and colleagues provide the additional information reported at a conference last year that the patients in question came from an outbreak of chronic fatigue syndrome at Incline village on the northern border of Lake Tahoe in the mid-1980s. Whether or not this was a genuine cluster was never established,11 but an association with viruses, such as Epstein-Barr virus and human herpesvirus 6, has already been suggested.12 It is possible that XMRV is implicated in the Lake Tahoe episode but does not play a substantial role in most cases of chronic fatigue syndrome elsewhere.

    The results from other US laboratories investigating XMRV and chronic fatigue syndrome are eagerly awaited. If the link fails to hold up, it will be another bitter disappointment to affected patients. Nonetheless, the current debate will still bring critical attention to the causes of chronic fatigue syndrome, and XMRV may turn out to be important in the pathogenesis of other diseases.

    Notes

    Cite this as: BMJ 2010;340:c1099

    References