I think this was actually written at the end of October 2011 but I might be wrong. Still... Spring 2012 edition: http://www.mentalhealthglobal.com/pdf/SONspring 2012_final.pdf#page=3 Playing lost and found with the cause of chronic fatigue syndrome Alex J. Mitchell University of Leicester, UK How often are truly ground-breaking discoveries made in medicine? The kind of discoveries that immediately convert a misunderstood psychiatric condition into an undeniable medical one? This may well have applied to chronic fatigue syndrome in 2009. Chronic fatigue syndrome is a condition with unclear definition, unclear cause, unclear treatment and unclear lines of medical responsibility, despite up-to-date National Institute for Health and Clinical Excellence (NICE) guidance (www.nice.org.uk/CG053). Chronic fatigue syndrome is characterised by 6 months or more of fatigue, sometimes with diffuse symptoms such as insomnia, difficulty with concentration and physical symptoms such as muscle weakness, sore throat and lymphadenopathy. There is no doubt it is a common and problematic condition, with currently no single clear-cut cause. However, this all looked to change in 2009. In 2009, US researchers from the Whittemore Peterson Institute (Nevada), Cleveland Clinic (Ohio), and National Cancer Institute-Frederic (Maryland) reported that a gammaretrovirus may explain the majority of chronic fatigue syndrome cases. The virus in question was xenotropic murine leukemia virus-related virus (XMRV), itself only described in 2006. In a paper in Science, the authors reported that XMRV DNA was present in 67% of 101 people with chronic fatigue syndrome but in only 3.7% of healthy controls.1 This was really an incredible finding as most experts had considered chronic fatigue syndrome to be a syndrome with many possible underlying causes.2,3 The positive tests in the small but significant number of healthy controls also led to fears that XMRV could be present in the blood donor supply in many countries. This appears to have led the American Association of Blood Banks to immediately discourage patients with chronic fatigue syndrome from blood donation.4 A lesser known paper from an independent group examined 41 peripheral blood mononuclear cell-derived DNA samples from 37 patients with chronic fatigue syndrome and found murine leukemia viruses-like virus (the parent family of XMRV) gene sequences in 32 of 37 patients (86.5%) compared with only 3 of 44 (6.8%) healthy volunteer blood donors.5 Two conclusive results from two independent groups. Using the fail-safe meta-analysis number of three, only one more similar result was needed and the landscape of chronic fatigue syndrome would be changed forever. In the past year, about ten independent laboratories have looked but failed to replicate these findings, all finding no XMRV in patient groups with chronic fatigue syndrome (or control populations) using blood or cerebrospinal fluid. Even those using the same laboratory conditions (identical polymerase chain reaction primers) used in the first investigation failed.6 But if these replication failures were to be believed, where had the XMRV results come from? One possibility is a faulty test lacking specificity, but this seems unlikely as like-for-like replication failed. One group found that XMRV was probably created in laboratory experiments with mice that made an immortalised cell line to study prostate cancer.7 To resolve this confusion, the US Department of Health and Human Services organised a nine-laboratory Blood Working Group (which included the original laboratory), and although their aim was to assess whether the donor blood supply was at risk from XMRV or related mouse retroviruses, it would also in effect illuminate the situation of chronic fatigue syndrome. Collectively, the Blood Working Group found that no one could reliably detect the virus, even in previously positive samples from patients. This caused a house of cards effect. In June 2011, Science published an expression of concern, then in September Science issued a partial retraction, followed by a full retraction in December. The PNAS article5 was also retracted. The authors of the Science paper apparently fell out with each other over what they had and had not originally found. But in an unfortunate turn of events, study author Dr Mikovits was dismissed for insubordination and misappropriating laboratory equipment leading to her arrest. However, in an equally remarkable recovery of fortunes, Dr Mikovits is now working again and is a co-author on a US$2.3 million multi-laboratory grant that will look for XMRV and related viruses in many more patients with chronic fatigue syndrome than were analysed in the Blood Working Group study. As we go to press, the American Red Cross has just analysed blood samples from over 17,249 donors and recipients across the USA. Three donors but no recipients tested weakly positive for one out of three possible antibodies, leading to the conclusion of no evidence of XMRV or related retroviruses in their blood banks.8 The story is not yet concluded as some of the original authors clearly feel their findings are real and meaningful. They state in a new publication that this work clearly rules out any possibility of gross contamination and additionally, represents the first identification and isolation of naturally occurring infectious XMRV.9 There are some important lessons for everyone here. Exciting new findings, particularly revolutionary ones, should be viewed with caution until replicated with sufficient scale and rigour. In my view, journals should be asking for scrutiny of the original data by peer reviewers and also asking for permission to publish these data online. Peer reviewers must be accountable for both unfair rejections and premature acceptance of articles and this will only happen if their identities are disclosed. Unfortunately, there may be a more immediate and negative connotation. I suspect that many patients with chronic fatigue syndrome will be even more likely to reject psychological help after reading how the medical profession nearly found the cause of chronic fatigue syndrome, only to lose it again. Author Alex J. Mitchell, Consultant in Liaison Psychiatry and Psycho-oncology, University of Leicester, UK. Email: firstname.lastname@example.org References 1. Lombardi VC, Ruscetti FW, Das Gupta J, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009; 326: 5859. 2. Hickie I, Davenport T, Vernon SD, et al. Are chronic fatigue and chronic fatigue syndrome valid clinical entities across countries and health-care settings? Aust N Z J Psychiatry 2009; 43: 2535. 3. Kerr JR, Petty R, Burke B, et al. Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Infect Dis 2008; 197: 117184. 4. American Red Cross. American Red Cross statement on XMRV and chronic fatigue syndrome. December 3, 2010. 5. Lo SC, Pripuzova N, Li B, et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci U S A 2010; 107: 158749. 6. Groom HCT, Boucherit VC, Makinson K, et al. Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 2010; 7: 10. 7. Paprotka T, Delviks-Frankenberry KA, Cingz O, et al. Recombinant origin of the retrovirus XMRV. Science 2011; 333: 97101. 8. Dockser Marcus A. Scientists say XMRV poses no risk to blood supply. The Wall Street Journal 2011; October 24 (http://blogs.wsj.com/health/2011/10/24/scientists-say-xmrvposes-no-risk-to-blood-supply/). 9. Lombardi VC, Hagen KS, Hunter KW, et al. Xenotropic murine leukemia virus-related virus-associated chronic fatigue syndrome reveals a distinct inflammatory signature. In Vivo 2011; 25: 30714.