Wednesday, February 9, 2011

XMRV-An Emerging Infection Case Study

In the early 1980’s, physicians in San Francisco and New York were puzzled by a growing number of aggressive cases of a rare malignancy known as Kaposi’s sarcoma, as well as a rare lung infection, Pneumocystis carinii (now "jirovecii") pneumonia. These illnesses were discovered initially in homosexual men, but were later seen in a growing number of patients suffering from hemophilia.

We know now, of course, that the illness in question was Acquired Immune Deficiency Syndrome (AIDS), and that the causative agent, Human Immunodeficiency Virus (HIV), had been unknowingly transmitted to a number of hemophilia patients through blood products from infected donors. In the decades that have passed since that disastrous time, numerous blood donor policies have been established and decisions made (both appropriate and inappropriate) based largely on the blood banking industry’s desperate fear of repeating the HIV experience. The Xenotropic Murine Leukemia virus-related Virus (XMRV) crashed headlong into that backdrop recently, and the full effect of its appearance is still unclear.

XMRV is not, by strict definition, a “new” virus. It was actually discovered in 2006, in association with a rare, hereditary form of prostate cancer. In what will become a recurring theme in this discussion, however, many subsequent studies showed a much less definitive link between the virus and prostate cancer. Despite this, the virus’ characteristics were well studied soon after its identification. XMRV is related to a group of similar-appearing viruses that cause leukemia in mice and also infect other species (Murine Leukemia Viruses, or MLV; thus the last part of the name “Murine Leukemia Virus-RELATED virus”). The fact that XMRV infects humans makes it “xenotropic” (definition: originating in one species and causing disease in another). Like HIV, XMRV is a retrovirus, but it is a different type of human retrovirus than HIV (so-called “gamma retroviruses”). Like all retroviruses, XMRV infects cells by translating its RNA into DNA, which then integrates into the host cell genetic material and causes manufacture of new virus particles. It should be noted that XMRV, despite its name and status as a retrovirus, has no association with either leukemia or AIDS-like immune defects in humans.

XMRV became much more widely known because of a 2009 report of a potential association with Chronic Fatigue Syndrome (also known as “myalgic encephalomyelitis” and abbreviated as “CFS-ME” or just “CFS”). CFS is an illness that is more severe than its rather benign-sounding name. CFS patients are not just “tired”; they are nearly debilitated by extreme fatigue, in association with sleep disturbances, cognitive impairment, flu-like symptoms, and muscle pain (“myalgia”), all lasting at least six months. Millions of people (mostly women) around the world are believed to suffer its effects. Some researchers and clinicians have suggested over the years that CFS may be caused by an infectious agent, but until 2009, concrete evidence of such an association was lacking. Dr. Judy Mikovits and her colleagues at the Whittemore Peterson Institute (Reno, NV), National Cancer Institute, and Cleveland Clinic published a paper in Science in October 2009, noting that 67% of the 101 patients with CFS they tested had detectable XMRV genetic material (vs. 3.7% in controls). This finding led the group to suggest that “XMRV may be a contributing factor in the pathogenesis of CFS.”

Throughout the early portion of 2010, several international research groups unsuccessfully attempted to confirm the results reported by Dr. Mikovits and colleagues. However, in August 2010, a study sponsored by the U.S. Centers for Disease Control (CDC) led by Drs. Lo and Alter, performed in labs at the FDA and the U.S. National Institutes of Health (NIH), showed similar but even more impressive XMRV-CFS associations than the previous paper. The CDC study reported XMRV sequences in almost 90% of CFS patients, seemingly confirming the earlier study’s result. More recently, however, to complicate matters, four separate studies published in Retrovirology in December 2010 cast doubt on the whole XMRV-CFS association by reporting data suggesting that XMRV sequences could be simply contaminants rather than true pathogens (this claim was strongly denied by Dr. Mikovits, among others). Working groups from the U.S. Department of Health and Human Services and AABB are actively trying to sort through all the conflicting data and test methods at this writing.

Those of us in the worldwide blood industry responded to these revelations with varying speed. Most had immediate concern that XMRV could be transmitted through transfusion (a fear that is currently unproven). As a result, throughout 2010, many countries (including the United Kingdom, Australia, Canada, and New Zealand) moved to prevent donors who volunteered that they have or had CFS from donating blood. In the U.S., AABB likewise recommended a voluntary self-deferral of donors diagnosed with CFS (so-called “active discouragement”) in June 2010 (click for more details on AABB's position); that policy is still the most active form of CFS screening in the U.S. at this writing. Donors are not asked a specific question about having CFS on the standard donor questionnaire at this time. Many in the lay press and several patient advocate and blood safety groups have sharply criticized the U.S. Food and Drug Administration (FDA) and the blood industry for not acting specifically and definitively to permanently defer all donors with CFS from blood donation.

So where do we stand with XMRV? The answer is really quite simple, but unsatisfying: We just don’t know for sure yet! The data, as outlined above, is conflicting, but the pressure on the blood industry to “do something” (partially external and partially self-imposed) seems to be mounting. In December 2010, the Blood Products Advisory Committee (BPAC) of the U.S. FDA heard presentations from the AABB task force mentioned above, as well as from representatives of the infectious disease testing industry and an advocate for patients with CFS. BPAC rejected the task force recommendations that voluntary self-deferral was adequate, and voted to recommend that FDA require a specific question about a history of CFS on the donor questionnaire by a vote of 9 to 4. FDA has not formally mandated such a question at this time, however. The reality is that we don’t even have a good way to test for the virus at this point, nor is there conclusive evidence that we need to do anything beyond what is already being done to discourage individuals with CFS from donating blood.

The XMRV-CFS association and its subsequent effect on the blood banking industry is a great example of how difficult decisions can be in the HIV-influenced world we now inhabit. The “what do we do and when do we do it?” questions are challenging both ethically and scientifically, especially when the evidence is developing and sometimes conflicting and the answers are unclear. It seems that many in the public arena and in the blood industry, following the HIV calamity of the early 1980’s, have embraced the so-called “precautionary principle” when considering the possible effect of a new infectious agent. This principle, as stated in 1998, is: “When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically”. However, in the current environment of limited resources and a seemingly endless flood of emerging and novel infectious agents, those of us in this industry are put in the difficult position of trying to make wise choices based on limited information and evidence, making our best efforts to balance incomplete information and unease about the unknown with the desire to protect our recipients and donors as best we can.

Updated on 2/10/11 to correct laboratories for Lo and Alter study.
Updated on 2/21/11 to correct Pneumocystis name.