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A paper in the October 23rd, 2009 issue of Science, “Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome,” renewed hope that a single, treatable cause might be responsible for chronic fatigue syndrome. The work by Judy Mikovits and colleagues at the Whittemore Peterson Institute in Reno, NV and collaborators at the National Cancer Institute and the Cleveland Clinic met with immediate controversy among scientists. The key finding was that DNA from xenotropic murine leukemia virus (XMRV) could be detected in the blood of 68 of 101 chronic fatigue syndrome (CFS) patients (67%) and 8 of 218 healthy individuals (3.7%). Since many patients with syndromes which include chronic fatigue as a symptom have evidence of immune activation (high levels of antibody production, for example), the high-profile appearance of the work in Science led to excitement in the patient community that a long-sought infectious cause for chronic fatigue syndrome could be hand. Based on the paper, some patients sought and obtained treatment with potentially toxic anti-retroviral drugs typically reserved for the treatment of HIV.

This week, the Science website published two accepted manuscripts that show how the XMRV virus was produced as a lab artifact and that evidence for XMRV infection in CFS patients could not be reproduced. The first paper by Vinay Pathak and colleagues at the NCI shows that the XMRV virus was created as a lab artifact in the 1990s when a human prostate cancer tumor graft was implanted in mice. A prostate cell line derived from this experiment contained XMRV due to a chance event – a shuffling of DNA called recombination – that put two mouse viral sequences together. The authors estimate that the likelihood of a virus existing other than through the recombination event is on the order of 10-12, so not so likely. The second study by Jay Levy and colleagues at UCSF shows that evidence of XMRV infection could not be found in 61 patients with CFS, importantly 43 of these patients were found to have had XMRV in the initial study. The two studies provide very strong evidence that the detection of XMRV in human blood is a laboratory artifact and that this virus does not appear to be able to cause natural infection in humans. The papers were accompanied by an “editorial expression of concern” by Bruce Alberts, editor of Science. The authors of the original paper do not feel that a retraction is warranted.

More likely than not, the latest science will only fuel the often emotional debate on chronic fatigue. Patients who suffer from “constitutional” (doctor talk for symptoms not specific to a diagnosis) symptoms including fatigue, joint and muscle pain, sleep disturbance, abdominal pain and cognitive problems have long felt marginalized by their doctors. One can only imagine how frustrating and humiliating it would be to experience real and frighteningly debilitating symptoms and to be told repeatedly by doctors that the symptoms were “all in your head” or non-existent. As an example of the impact of the internet on health care, the estimated 17 million chronic fatigue patients are now organized and are demanding answers and better treatment.

My pediatric rheumatology division at Children’s Hospital Boston discussed the original Science paper the week that it was published in the fall of ’09. We met the study with a great deal of skepticism, particularly our senior mentors who have seen a lot of causal theories on chronic fatigue syndrome come and go over the years. Why was this paper of such interest to us? It turns out that conditions such as chronic fatigue, post-viral syndromes, fibromyalgia, and reflex sympathetic dystrophy happen not infrequently in children. Pediatric rheumatologists typically refer to this group of disorders, where some inciting trigger, in some cases known and in other cases surmised, leads to persistent constitutional symptoms as “pain amplification syndromes.” The inciting trigger very often is a physical condition such as a known infection or an injury. What is clear and dramatic in these cases is that the pain, fatigue, and debilitation in these cases is significantly out of proportion to the event that kicks off the process. As a result, the amplified pain syndrome takes on a life of its own and requires its own treatment. Although amplified pain syndromes can be treated successfully, unfortunately, there is no easy answer that would fit on one prescription slip. The philosophy of treatment is to re-train the patient to no longer perceive normal sensations and physical stimuli as potential danger signals that trigger the body’s pain perception. The treatment protocol includes a combination of physical therapy and massage, aerobic exercise, which in itself appears to be able to re-set the body’s pain perception pathways, treatment for sleep disturbance if present, and in some cases, medication to decrease the perception of neuropathic pain. In some cases, psychological and psychiatric care may be integral to recovery. Our colleague David Sherry at Children’s Hospital of Philadelphia has a special interest in this condition and maintains this useful website for patients. The challenge to successful treatment is that it is so effort dependent. If patients and families question the diagnosis and are skeptical about the treatment plan, the possibility for a successful outcome is placed in jeopardy.

Many doctors and even specialists like pediatric rheumatologists dread working with “pain patients.” These patients are viewed by many practitioners as high-maintenance and demanding. Some will question the patients’ desire to improve and suspect malingering to obtain some secondary benefit for maintaining the sick role. My experiences with children with pain syndromes have been some of my most satisfying. Often times, patients with pain syndromes and their families are grasping at straws to try to find a “medical” diagnosis to explain the symptoms. As is so often the case in medicine, one diagnostic test leads to several others. Patients often have accumulated a huge chart filled with an exhaustive and expensive medical work-up and have seen multiple consulting specialists when they finally are referred to the rheumatologist. Experience allows one to step back from the details and recognize the big-picture pattern: no single unifying diagnosis can explain all of the symptoms and findings other than pain amplification. Being able to help patients like a skilled practitioner of traditional Indian dance and a Division I caliber Nordic skier return to academic and athletic achievement and break the cycle of endless diagnostic tests and specialty referrals are highlights of my experience as a pediatric rheumatology fellow. By the way, as we have discussed in other posts, our medical system is happy to reimburse more sophisticated testing but not the kind of diagnostic thought and discussion with patients that can cost-effectively solve these medical mysteries.

The bigger issue regarding the controversy over XMRV and CFS is that the goal of most pain syndrome research is misguided. The field is saddled by a “one exotic infection, one disease” mentality that clearly does not fit the features and epidemiology of pain syndromes. Investigators continue to search for a single infectious cause that can account for the great diversity of clinical presentations. Abnormal immune system responses to common viral infections certainly do appear to be a potential trigger of pain syndromes in many patients. The important point is that these infections can serve as a trigger and that the symptoms they produce persist despite the fact that the body’s immune system has controlled or eradicated the infection. Giving drugs to treat an infection that used to exist but is now gone is unlikely to do much to improve the situation. The focus on exotic viruses has distracted the field from the fundamental, and really interesting, questions. What is different about some individual’s immune response to routine triggers that results in an exaggerated syndrome? Many of our pediatric pain patients have family members who also have problems with chronic fatigue or fibromyalgia. Genetic studies should be a promising way to open the door to a more mechanistic understanding of these conditions. Work should be done to provide better care for a population of patients who have long been dismissed by medicine. That being said, better answers will not be forthcoming until the right questions are being asked.