Erratum: Still No Answers for Chronic Fatigue Syndrome



This article corrects:

    This Message From The Editor originally published in 69#4. The title and introductory quotation attribution were inadvertently deleted during the production process. The message should read as follows.

    Chronic fatigue syndrome (CFS) (Table) has probably been with us for at least 3 centuries, traveling under various names including the vapors, neurasthenia, effort syndrome, hyperventilation syndrome, chronic brucellosis, epidemic neuromyasthenia, myalgic encephalomyelitis, hypoglycemia, multiple chemical sensitivity syndrome, chronic candidiasis, chronic mononucleosis, chronic Epstein-Barr virus infection, and post-viral fatigue syndrome.1 Related conditions with overlapping symptoms include chronic Lyme infection and also Gulf War Illness, a problem affecting approximately 30% of veterans of the first Gulf War in 1990-1991, and perhaps equal numbers of soldiers in the current Middle East conflict.2 Many others who suffer from chronic, medically unexplained symptoms not satisfying full criteria for CFS may be labeled as having nonspecific chronic fatigue, chronic musculoskeletal pain, fibromyalgia, or other ailments.

    Table  . CDC Criteria for Diagnosis of Chronic Fatigue Syndrome
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    The cause of CFS is unknown. Because persistent fatigue can follow some viral infections, and is associated with various inflammatory (especially autoimmune) conditions, the focus of research into CFS has been to investigate possible viral or immune causes. Numerous reports of viruses (most prominently HTLV-II3) or immune biomarkers have been advanced over the years, yet none have withstood the test of replication. In October 2009, a new virus claim appeared: xenotropic murine leukemia virus-related virus or XMRV.4 This retrovirus, a relative of the murine leukemia virus (MLV) family, had first been identified in a small number of human prostate cancers. In the journal Science, Lombardi and colleagues reported successful PCR amplification of XMRV gag sequences from peripheral blood mononuclear cells in 68/101 CFS patients and only 8/218 controls. Furthermore, in some positive cases anti-XMRV antibodies could be detected in the serum, and cell-cell transfer of XMRV could also be demonstrated by co-culture. In September 2010, a second report by Lo and colleagues that appeared in the Proceedings of the National Academy of Sciences USA provided support for a role for a retrovirus by identifying MRV-like gag sequences in 32/37 CFS patients and only 3/44 controls.5 However, the identical XMRV-specific gag primers used by Lombardi tested negative in CFS in the study of Lo, thus on closer inspection this by no means could be considered a replication.

    In addition to the high prestige of the journals in which these reports were published, the authors themselves included well known scientists from the Food and Drug Administration, Harvard Medical School, and National Institutes of Health. This all served to add gravitas to the claim. For many sufferers of CFS, the concept that a new retrovirus was the culprit was extremely attractive. It offered a simple, clear and reasonable explanation for their symptoms; provided reassurance that they had a true illness and not a psychological condition; and generated new hope that effective therapy could be quickly found. Indeed, anecdotal reports of success with antiretrovirals have recently appeared in such places as the Wall Street Journal.6

    In this issue of the Annals of Neurology, Schutzer and colleagues searched for evidence of XMRV in the cerebrospinal fluid of 43 patients with CFS, based on the reasonable hypothesis that, if a retrovirus is responsible for CNS infection, it might be revealed more easily in cerebrospinal fluid than in peripheral blood.7 The study was well-performed, employing the identical primers used by Lombardi and also co-culture, but results were dramatically negative. As this issue of the Annals goes to press, at least seven other reports - from various regions in the US, Europe, and Asia - have now been unable to find any evidence for XMRV or MLV involvement in CFS (summarized by Satterfield, et al.).8 Perhaps not surprisingly, these negative reports attracted less attention in the lay media than did the earlier positive claims. Although it is possible that subtle technical differences in the protocols permitted detection of pathogenic retroviruses by a few groups but not by many others, or that CFS is caused by a retrovirus only in a few isolated locations, a far more likely explanation is that the original positive findings represented false-positives, perhaps due to laboratory contamination.9

    The confluence of the Internet, the hope for a simple and correctible answer to a common, mysterious and untreatable problem, and well-organized patient advocacy groups, can create a “perfect storm” in which preliminary or uncertain claims are rapidly disseminated and acquire momentum well beyond that justified by the strength of evidence. A similar situation, discussed earlier in these pages, followed preliminary reports that potentially correctible venous abnormalities (chronic cerebro-spinal venous insufficiency or CCSVI) might underlie multiple sclerosis (MS). Sadly, repeated failures to replicate these original claims using carefully designed methodologies have not yet reduced the considerable attention and public interest in CCSVI, nor eliminated unsound and dangerous attempts to “repair” abnormal veins in MS patients (outrageously called “the liberation procedure”).10–12

    A few simple steps can go a long way towards reducing the number of scientific claims that are not ultimately validated. Replications should be carried out prior to publication.13 Reports of failures to replicate should be published expeditiously, and when possible by the same journal that published the original claim. Scientists should not introduce new results to the press before the underlying data can be reviewed in adequate detail by their peers, either in peer-reviewed publications or at platform presentations at meetings. The lay media also needs to be equally cautious, and strive not to disseminate false hope that ultimately frustrates vulnerable people searching for answers to terrible problems.14 It is not possible, or even desirable, to police scientific ideas and theories, but as journal editors we have a responsibility to do everything possible to insure that data appearing in our pages will stand the test of time.