By Kim McCleary
President & CEO of the Solve ME/CFS Initiative from 1991-2013
and Suzanne Vernon, PhD, Scientific Director
In mid-March, researchers, clinicians, patients, caregivers and advocates from around the world gathered in Reno, Nevada, to share information, critique the latest research and network in the hallways and over meals. The 9th research and clinical conference sponsored by the International Association for CFS/ME (IACFS/ME) drew about 220 participants for the four-day event held at the Peppermill Resort & Casino.
Marking the 25th year since CFS was first brought to national attention, pioneering clinician and researcher Dr. Daniel Peterson had the honor to be the local host as well as to open and close the conference sessions. Dr. Peterson is well-known for having been among the first, with his then-partner Dr. Paul Cheney, to recognize CFS among a cluster of ill patients in his internal medicine practice in Incline Village, Nevada, just over Mount Rose from Reno. Dr. Peterson has stuck with CFS and by his patients with CFS, so it seemed a fitting tribute to hold the meeting in his backyard. Philanthropists Annette and Harvey Whittemore, whose adult daughter Andrea has CFS, have founded a center for research and clinical care, the Whittemore Peterson Institute, that will open mid-2010 on the campus of University of Nevada Reno. Several conference attendees drove past the construction site at McCarran & Virginia streets while they were in Reno.
IACFS/ME conference organizers established the first day as a patient-oriented conference designed to provide an overview of current research and management, with longer presentations delivered by current and past members of the IACFS/ME Board of Directors. Dr. Peterson delivered the opening talk, followed by Dr. Anthony Komaroff of Harvard Medical School. Both gave summaries of some of the most promising and durable research findings about abnormalities in many body systems of CFS patients. Two presentations on coping were then given by Dr. Fred Friedberg of Stony Brook University and Dr. Leonard Jason of DePaul University. Both spoke to the need for pacing and energy management to avoid the “push-crash” cycle of overactivity followed by a relapse that can be so destructive over time.
Dr. Hirohiko Kuratsune of Osaka City University in Japan reviewed his group’s experience with research and treatment over the past 19 years since he saw his first CFS patient in 1990. The Japanese group has taken a holistic approach to therapy, incorporating everything from medications to anti-fatigue foods to laughter to healthy housing. Dr. Ken Friedman of University of Medicine and Dentistry of New Jersey (UMDNJ) highlighted central nervous system abnormalities and problems with the body’s energy-producing cells in CFS. Dr. Gudrun Lange, also of UMDNJ, gave a detailed tour of brain anatomy and function and then provided several coping tips to compensate for the attention and processing deficits that can be so problematic for CFS patients.
Dr. Nancy Klimas, concluding a four-year term as president of the IACFS/ME, provided an overview of pharmacologic therapy for CFS, emphasizing that people with CFS often cannot tolerate the usual doses of medications used to treat sleep, pain and depression, and that starting low and very gradually increasing dose can be the key to deriving a benefit from a particular drug. She also talked about the importance of gentle exercise, made easier by doing things like swimming, recumbent biking and pilates in a horizontal position to get around the orthostatic problems with upright posture that many patients experience. A panel of all the day’s speakers concluded the formal program; they took questions that people in the audience submitted on written cards.
During the day, researchers and clinicians had the opportunity to attend four three-hour workshops, two of which were offered concurrently in the morning followed by two other sessions in the afternoon. CFIDS Association scientific director Suzanne Vernon, PhD, led one of the workshops. Dr. Vernon’s session attracted approximately 40 people who spent the afternoon in dialogue about research design and how genomics can inform clinical practice of CFS.
That evening, an unreleased documentary, “Invisible,” produced by Rik Carlson and Michael Thu was shown. Although it focuses on CFS patients living in Vermont, its themes were recognized by all present. A patient reception sponsored by Sierra Internal Medicine enabled participants to socialize and network. Annette Whittemore recognized the local volunteers who helped make the meeting a success.
Research and Clinical Conference
The sessions on Friday, Saturday and Sunday were dedicated to short (11-minute) data presentations by researchers on specific study results that bridged somewhat overlapping topics of treatment, epidemiology, immunology, assessment, pediatric CFS, genomics, genetics, brain functioning and the integrative approach being utilized by the Japanese to study CFS. Dr. Komaroff closed Sunday’s session with a brilliant overview of the 115 presentations delivered from the podium and via two poster sessions displayed in the exhibit hall.
Taking a step back from the order of the presentations, several themes emerge, although there is overlap among them, too. We’ve organized our summary this way to draw attention to some of the most interesting studies reported at the conference.
The brain: Two studies used different techniques to document brain abnormalities in CFS patients. Dr. Frank Duffy, a Harvard neurologist, studied a large group of patients using spectral coherence EEG and was able to discriminate, with nearly 90% accuracy, patients with rigorously defined CFS from healthy control subjects and from subjects with major depression. He stopped short of calling this pattern diagnostic, but stated that it did define CFS as an organic brain-based condition. The study was large, with a total of 632 subjects; however, the CFS patients referred by community-based physicians did not demonstrate the same frequency of EEG patterns, suggesting that the label of CFS may be misapplied in some settings. Leighton Barnden, PhD, of the University of Adelaide in Australia, analyzed brain magnetic resonance (MR) images from 25 CFS patients and 25 healthy control subjects. Comparing volume differences in specific areas of the brain, Dr. Barden reported that changes in CFS subjects were consistent with the symptoms and symptom severity they reported. For example, changes in the medulla and insula are consistent with the autonomic dysfunction reported in CFS. He was unable to determine based on this study alone whether the changes represent the cause of the symptoms or the effect of CFS.
Triggering agents/factors for CFS: While early studies of CFS sought to identify a single agent that caused the illness, most researchers now appear to agree that CFS can be “triggered” by a number of different insults including microorganisms (bacteria, viruses, etc.), environmental exposures and severe injuries (such as closed head trauma). At this conference, researchers reported data on a number of agents that set off a CFS-like illness. Here is a list of the agents explored by researchers who gave presentations:
- Giardia lambia (Eva Stormorken, RN, University of Oslo, Norway)
- Coxiella burnetii (Andrew Lloyd, MD, University of New South Wales, Australia)
- Parvovirus B19 (Jonathan Kerr, MD, PhD, St. George’s University of London, England)
- Parvovirus B19 and herpesviruses (Kenny DeMeirleir, MD, PhD, University of Brussels, Belgium)
- Mammalian viruses (Judy Mikovits, PhD, Whittemore Peterson Institute, USA)
- HHV-6 and -7 (Modra Murovska, MD, PHD, Riga Stradins University, Latvia)
- Epstein-Barr virus (EBV), CMV and HHV-6 (Barbara Cameron, PhD, University of New South Wales, Australia)
- Enteroviruses, EBV, Chlamydia pneumoniae, coxiella burnetii and parvovirus B19 (Lihan Zhang, St. George’s University of London, England)
The main debate about these various triggers seemed to be whether different subgroups of illness were defined by the specific trigger (B19 vs. EBV), or whether the resulting illness was the same regardless of the triggering event/agent. More research will be required to sort this out. It is worth noting that none of the agents studied were found in all the CFS patients studied and that none of the researchers suggested that the agent alone caused the CFS.
Other triggers explored were repetitive strain injury (Eliana Lacerda, MD, PhD, London School of Hygiene and Tropical Medicine) and disruption of normal diurnal rhythms in children (Teruhisa Miike, MD, Kobe, Japan).
Subgrouping by biologic abnormalities: Another sign of the maturing of the CFS research field is the broad agreement that the definition for CFS results in a rather heterogeneous patient group and that studies should seek to define subgroups of patients using one or more biologic measures. Several research groups reported evidence of immune system and neuroendocrine abnormalities, building on some of the earliest CFS reports in the biomedical literature. One of the most impressive presentations was delivered by Alan Light, PhD of University of Utah. His group reported differences between CFS patients, healthy controls and a smaller group of MS patients on adrenergic and sensory receptor peripheral blood cell gene expression after a modest exercise challenge. The Solve ME/CFS Initiative is providing support to expand the study that was begun with a grant from the National Institutes of Health.
The CFS group at the University of Miami (UM) and collaborators presented several immune system abnormalities in Gulf War Illness/CFS patients following a graded exercise test, including elevated levels of neuropeptide Y (NPY) (Mary Ann Fletcher, PhD, UM) and a plasma cytokine shift from Th1 (antiviral defense) to Th2-type (proinflammatory activation) immune response (Nancy Klimas, MD, UM). These observations were confirmed by Gordon Broderick, PhD, at University of Alberta who found distinct patterns of coordinated change in NPY, cytokine and cortisol concentrations at rest and under challenge using data collected from the UM subjects.
Researchers working with the Whittemore Peterson Institute studied a group of CFS patients who were found to have clonal T-cell rearrangements, predictive of non-Hodgkin’s lymphoma. These patients demonstrated chronic inflammatory stimulation and differential expression of human endogenous retroviruses (Judy Mikovits, PhD). Vincent Lombardi, PhD, showed that a distinctive pattern of serum cytokines and chemokines could distinguish between CFS patients who did and did not have the clonal t-cell receptor gene rearrangement.
Andrea Suarez Segade, MD of the University of Barcelona, reported that there were significant differences in the values of growth hormone, prolactin and cortisol in women with CFS compared to healthy women after an exercise challenge. A small study at Bond University in Australia reported by Ekua Brenu, HBSc, found that CFS patients demonstrated significant decreases in respiratory burst, while the number of T cells, monocytes and B cells were comparable to healthy controls.
Most of these investigators expressed hope that these findings, perhaps combined with other measures of symptom expression or severity or other biological measures, would yield characteristic “fingerprints” for subtypes of CFS that would aid in diagnosis and therapy.
Several of these studies (Light, University of Miami, Segade) have used exercise challenge to identify biologic differences that seem to be subtle at rest, but are more pronounced after exertion. One important study that found no meaningful difference between CFS cases and controls, was presented by Christopher Snell, PhD, of University of Pacific. His group tested for a low-molecular weight RNaseL (37 kDa) and elastase activity as biomarkers for CFS, as had been reported previously by other groups to be abnormal in CFS. 22 CFS patients and 21 matched controls underwent serial exercise tests and samples were taken at various time points and then processed by a commercial lab. Results were variable and did not correlate with symptoms, illness status or pre- and post-exercise. Dr. Snell concluded that neither “RNase L ratio nor elastase levels have any efficacy as biomarkers for CFS.”
Metabolic/mitochondrial dysfunction: Three researchers suggested that CFS stems from a problem producing energy at the cellular level in the mitochondria. Dr. Norman Booth of University of Oxford presented results obtained from 71 CFS patients using an ATP profile test combined with the Bell Ability Scale as a measure of functional capacity. The two collaborating physicians found a correlation between the degree of mitochondrial dysfunction and the severity of illness, suggesting that the fatigue in CFS is due to cellular respiration dysfunction. Mark Van Ness, PhD, of the University of Pacific reported that half of the women with CFS displayed metabolic dysfunction as assessed through a test-retest graded exercise protocol; 56% of a group of patients with high EBV/HHV-6 viral levels also showed quantifiable metabolic dysfunction. Finally, Alan Light’s data (described above) indicate a problem in metabolism that prolongs the sensation of muscle fatigue and pain after exercise, even when the muscles are not active.
Therapy/treatment: Although two sessions were dedicated to pharmacologic and non-pharmacologic treatment advances, unfortunately there was little new presented. Cognitive behavioral therapy (CBT) was addressed by two speakers, Greeta Moorkens, MD, PhD, of Antwerp University Hospital, and Elke van Hoof, PhD, of Vrije Universiteit Brussel. Dr. Moorkens reported that the majority of 180 patients treated with 10 sessions of CBT over six months reported some improvement but did not show statistically significant improvement on fatigue or physical functioning scores. Dr. van Hoof confirmed earlier studies that show a high percentage (30%) of drop-outs due to deterioration during CBT trials. She indicated that differing expectations between the provider and the patient for treatment can affect satisfaction and that communication is essential; yet her studies do not support large scale application of CBT. Michael Antoni, PhD, of University of Miami, discussed a telephone-based program of Cognitive Behavioral Stress Management that allowed patients to receive information, relaxation training and support without leaving home. Preliminary data suggests that the program was well-accepted and that patients showed improved quality of life and some reduction in symptoms. Dr. van Hoof also presented a study on Eye Movement Desensitization and Reprocessing (EMDR) to decrease hypervigilance seen among CFS patients. Preliminary data analysis was also showing some benefits with physical functioning. Patricia Fennell, MSW, identified several types of trauma induced by CFS and other chronic conditions.
Nicole Porter, PhD, of DePaul University presented a review of trials of alternative therapies and concluded that several have some potential for future clinical research, but that no firm conclusions can be drawn because of the limited number of subjects and somewhat suspect methods used. Among those with the most promise are acupuncture, meditative practice and magnesium, L-carnitine and S-adenoslymethionine (SAMe) supplements. Hirohiko Kuratsune, MD, of Osaka City University reported that supplementing the diet with essential fatty acids (EFAs), zinc, copper, manganese and vitamins B6 and B12 had demonstrated some effectiveness in his patients. Dr. Yasuyoshi Watanabe, proposed using functional foods, coenzyme Q10, applephenon, imidazole dipeptide and crocetin to combat fatigue, based on his studies at Osaka City University and RIKEN (of Japan).
The studies of three pharmacological treatments were presented: Ampligen, isopinosine and sodium oxybate. David Strayer, MD, of manufacturer Hemispherx, reported that Ampligen improved the physical function of CFS patients as measured by exercise treatment duration. He indicated that the drug, now under review by the Food and Drug Administration (FDA) for marketing approval, was well-tolerated and that its use allowed patients to reduce their dependence on other drugs. A decision is expected from FDA in May 2009. Isoprinosine is sold in Ireland and Costa Rica under the trade name Immunovir. Maria Araceli Vera, MD, of University of Miami, presented a chart review of 61 patients who took isoprinosine for six months. Using data from their charts to assess both clinical status and immune status, Dr. Vera concluded that there was highly significant improvement in both clinical and immunological status, stating that a large, randomized clinical trial would be appropriate based on this review. Natalie Hone, MD, of University of Miami, also presented results of a chart review of 27 CFS patients with documented alpha-wave intrusion in slow-wave sleep who had taken sodium oxybate (Xyrem) to treat this condition. 20 of these patients reported improvement in their sleep after treatment. Like her colleague, Dr. Hone concluded that further studies are indicated.
Pediatric/childhood CFS: Several presentations throughout the conference focused attention on kids who get CFS. Leonard Jason, PhD, of DePaul University reported that the pediatric ME/CFS criteria published in 2006 were more effective than the 1994 Fukuda (adult) criteria as a diagnostic tool for children and adolescents. Ritchie Shoemaker, MD, of the Center for Biotoxin Associated Illnesses, conducted a retrospective chart review of 163 patients ages 10-17 years to identify biomarkers that would separate cases of CFS from non-cases. He found an association of increased autoimmune abnormalities and elevated levels of a regulatory cytokine, TGF beta-1, that merit additional evaluation. Greta Moorkens, MD, PhD, reviewed the clinical charts of 81 patients ages 14-21 years who were referred to a hospital clinic. Headache, muscle ache, concentration or memory disorder and joint pain were the symptoms most often reported. She reported that vitamin D deficiency was common, especially among the housebound patients, and that there were three suicide attempts among the patient group. 13 of 22 patients tested for sleep problems were found to have them and 11 of 19 patients referred to a psychiatrist were found to have a depressive disorder as well. She underscored the importance of thorough sleep and psychiatric evaluations in this population.
Dr. Esther Crawley of University of Bristol (United Kingdom) presented two studies of children with CFS. First, she followed 46 children with CFS who were housebound for one year at three different assessment points. She compared them with children with CFS who were able to attend clinic. The housebound patients had higher scores on the symptom inventories and had more co-morbid conditions. 30% of the more severely ill patients either recovered completely or had improved sufficiently to attend some school by the time of follow-up. Dr. Crawley’s second study focused on grouping 333 children with CFS/ME by symptom assessment to determine if clusters would emerge that might represent different underlying disease processes. Factor analysis suggested three groups of patients, while cluster analysis produced five groups.
Laura Younis of Deakin University in Victoria, Australia, studied cognitive function in a group of 27 adolescents and young adults with CFS and 27 healthy matched controls. She found that the CFS patients missed 8.28 days of school per month, compared to the 1 day per month for the healthy students. While the CFS patients were unwell and reported high levels of distress and disability, their objective performance on the cognitive tests performed in a laboratory setting was comparable to that of their healthy peers. Dr. Younis suggested this reflected the motivation of the CFS patients to do well in the study and that it may not be indicative of performance in classroom or home settings where there are other influences and distractions.
The final group of childhood CFS (CCFS) studies came from the group in Japan. Sanae Fukuda, PhD attempted to identify common characteristics of children with CFS as risk factors for developing the illness. She found that school problems were a better predictor for boys who went on to develop CFS, while family problems were more common among the girls. They found that the “sleep score” was a predictor for both groups. Kei Mizuno, PhD, found that selective and divided attention processing was impaired in the 414 children with CFS studied, compared to 190 healthy children tested. He indicated that they are now using functional MRI testing to clarify the neural substrates associated with different subtypes of attention processing deficits. Teruhisa Miike, MD, PhD, showed that over 20 years during which CCFS has been studied in Japan, they have linked it to disruptions in the normal biological clock that is evident in contemporary Japanese culture. Long-term sleep deprivation, coupled with excessive bright light exposure during nighttime hours (from TV, video games, cell phones, etc.) upset the normal diurnal rhythms and developed into CFS. He also noted that 30% of the CCFS cases have tested positive for HHV-6A. He urged the importance of preventing CCFS by maintaining normal activity and sleep schedules.
Genetics and genomics studies: There were several presentations describing genetic contributions to CFS. Marc Fremont, PhD, of Protea Biopharma (Belgium), reported on differences in toll-like receptor genes that are important for modulating bacteria-induced immune activation that were more frequent in CFS. Also, these investigators found genetic differences in genes important in TH17 protein function. TH17 cells fight off bacterial infections and abnormal function has been implicated in intestinal diseases of autoimmunity. Mangalathu Rajeevan, PhD, of the U.S. Centers for Disease Control and Prevention, presented results from the first CFS genome-wide association study. He reported that variants in GRIK2, a gene involved in glutamate transmission, and NPAS2, a gene important in brain function, were associated with CFS. Further, CFS subjects with these gene differences also showed correlation with gene expression providing further evidence of neuroendocrine and immune dysfunction in CFS. In a targeted genetic analysis, Judy Mikovits, PhD of the Whittemore Peterson Institute, found that variations in HLA and KIR genes – genes important in a proper immune response – might increase the risk for CFS. Andrew Lloyd, MD, PhD, of the University of New South Wales presented exciting findings on changes in the functional polymorphisms for two cytokines in particular, IL-10 and interferon-gamma. Subjects with a “low-risk” combination of sequences were ill for an average of 34 days, whereas those with the “high-risk” combination remained unwell for 80 days on average. Therefore, he posited, the intensity of the inflammatory response may determines the severity of the acute infection and duration of the illness that follows.
On Thursday evening, to welcome colleagues from Japan and return the hospitality extended to us last year when we visited Osaka City and Kobe, we hosted a small dinner for Dr. Watanabe’s team and three of our funded investigators, Dr. Dikoma Shungu and Drs. Kathy and Alan Light. While this took us away from the patient reception at the hotel that evening, it was a good opportunity to catch up on the recent approaches being taken and advances being made on both sides of the Pacific.
The Keynote Address was delivered on Friday, March 13, by the Honorable John Kitzhaber, former governor of the state of Oregon. Dr. Kitzhaber spoke about the need for sweeping health care reform. As founder of the Archimedes Movement, he is challenging the federal government to replace the current outdated framework with a totally new approach to providing health care services and covering costs. His talk was not specific to CFS, but was informative to providers and patients alike.
On Friday evening, about 75 people gathered at the Nevada Museum of Art for a reception in support of the IACFS/ME sponsored by Annette and Harvey Whittemore of the Whittemore Peterson Institute. There was no formal program, but Annette Whittemore welcomed the Honorable John Kitzhaber and several guests representing the Nevada state legislature and University of Nevada Reno who were pivotal in helping establish the Whittemore Peterson Institute. The museum’s exhibits were open to attendees and the event offered an opportunity for informal socializing and networking.
On Saturday afternoon, the IACFS/ME held its biennial business meeting for members and others to hear organizational plans and to vote on nominees to the Board of Directors.
Installed as president was Fred Friedberg, PhD and four newly elected directors joined five others continuing for another term on the Board. Suzanne Vernon, the Solve ME/CFS Initiative’s scientific director, is one of the four individuals who joined the IACFS/ME Board.
It has become a tradition at these conferences to hold an awards banquet on the night of the last full day of the schedule. On Saturday, March 14, the awards ceremony followed a large buffet dinner, emceed by new IACFS/ME president Fred Friedberg. The following individuals were honored:
Benjamin Natelson, MD
Governor Rudy Perpich Memorial Award
Charles Lapp, MD
Nelson Gantz Clinican Award
Nicole Porter, PhD
Junior Investigator Award
Special Service Award
Michael Antoni, PhD
Nancy Klimas Research Excellence Award
John Chia, MD
Nancy Klimas Research Excellence Award
Suzanne D. Vernon, PhD
OFFER Research Excellence Award
Molly Brown, MA
OFFER Research Excellence Award
In summary, at this truly international meeting, represented by 17 countries where CFS is being studied, there was much enthusiasm for the varied approaches being taken and the new technologies being employed to investigate CFS. There was some disappointment with the small and preliminary nature of many of the studies, but this was largely seen as a function of the meager funding streams available in the U.S. and most other countries. Hopefully when IACFS/ME convenes its next conference in two years, some of these investigations will have matured and there will be more standardization of studies through enhanced communication, established networks (like the one being formed by the Solve ME/CFS Initiative’s funded investigators) and expanded funding opportunities.
March 30, 2009