PHOENIX RISING

A Guide to CHronic Fatigue Syndrome (ME/CFS)

The Newsletter

NEWS

Repeat Canadian Exercise Capacity Study Needs Female Volunteers - These repeat exercise tests could revolutionize the medical establishment’s conception of ME/CFS. Single exercise tests have not been effective in differentiating ME/CFS patients but repeat exercise tests appear to be. Besides legitimizing ME/CFS these tests will also highlight a symptom – post-exertional fatigue - that may be critical in ME/CFS but is in danger of being ignored.

This study needs women with ME/CFS and significant post exertional malaise and even more importantly healthy, sedentary women in their 40’s and 50’s to act as a control group. This test won’t be fun but it will be important. As you lie there groaning afterwards you can know you may have helped usher in a new dawn in ME/CFS research. Please contact Dr. Stein at the University of Calgary at Elberta at (403) 287-9941 or via e-mail espc@shaw.ca

The Name Change Campaign Site is up. You can find the latest information on the status of the Name Change Campaign as well as a message board where you give input and ask questions, bio's on the Committee members, and a petition. Please sign the petition! Let's get this thing rolling.

The Whittemore-Peterson Neuro-Immune Institute Website is up! - This is not the full site but its a nice start and bodes well for things  to come The word is that we should be hearing some fascinating stuff from the research arm of the Institute before the year is out (and before the Institute is even open.)

Dr. Shoemaker has a new website and new on-line screening test for biotoxin involvement in the Fatiguing Illnesses. Plus it contains papers, new research, presentations, webcasts.

Grace Ziem's Chemical Injury Website has been extensively updated with new treatment protocols and more. She has an innovative new approach to treating MCS. This site looks like a must for anyone with this bewildering problem.

The Pall Chat Group. There is a website and a yahoo discussion group devoted to discussing Dr. Pall’s insights on ME/CFS. .  Dr. Ziem uses Dr. Pall’s ideas in her innovative approach to ME/CFS/FM and MCS.
Phoenix Rising has been upgrading its paltry treatment section. There are now sections on sleep (hygiene, prescription drugs, alternative therapies) and energy (prescription drugs, alternative therapies). The treatment section will be expanded greatly over the next year.

Congratulations to Dr. Kenneth Friedman and Dr. Ablashi for receiving the 2007 Achievement Award from the New Jersey CFS Association on October 6, 2007.  An interview with Dr. Friedman is forthcoming. Dr Friedman is an Associate Professor, Department of Pharmacology and Physiology, New Jersey Medical School and P.A.N.D.O.R.A. board member. Dr. Ablashi heads the HHV-6A Foundation and is the recipient of many awards over the his long and distinguished career.

RESEARCH


Dumbfounded in Dubbo!

ME/CFS researchers have been beset by two problems; a population that probably contains several different types of chronic fatigue syndrome and the fact that they generally examine ME/CFS after the fact – after the damage has occurred. The first problem is well known but the second is just as important. Unlike most diseases ME/chronic fatigue syndrome appears to be triggered by a range of mostly innocuous problems; colds, food poisoning, ‘stress’, etc. or at times nothing discernable at all. Figuring out how these mostly run of the mill problems translate into a long term chronic disease poses tremendous challenges to researchers.

Dr. Lloyd has taken an innovative approach to both these problems with his Dubbo studies. He’s examining only one subset of patients (post-infectious) and he’s following them as they come down with the disease. These studies have enormous potential to further our understanding of ME/CFS. In these two papers the Dubbo team is taking on two of the most important issues in ME/CFS research; the genes that are expressing themselves in  this disease and powerful immune agents called cytokines.

Cameron, B., Galbraith, S., Zhang, Y., Davenport, T., Vollmer-Conna, U. etc. and A. Lloyd. 2007. Gene expression correlates of postinfective fatigue syndrome after infectious mononucleosis. Journal of Infectious Disease 196, 56-66.

Gene Expression.  Gene expression studies indicate which genes are active at a particular point in time in the body. With their enormous range (30,000 genes) a complete gene expression study can give us an almost encyclopedic view of the body’s functioning. Thus far, though, they have only been generally helpful; although they’ve highlighted immune and neurological and other areas they haven’t displayed the specificity needed for ME/CFS researchers to really hone in on a specific area of dysfunction.

This study, which examined the changes in gene activity as people lapsed into ME/CFS after they came down with an infection, had the opportunity to (a) validate the use of gene expression technology in ME/CFS and (b) identify a valid subset. A successful study would prompt future researchers to concentrate on the post-infectious subset in ME/CFS and would provide new avenues for research. It would suggest that many of problems researchers have had getting consistent results might very well be due to an inadequate definition that didn’t separate out infectious and non-infectious patients. This would mark a turning point in our understanding of ME/CFS; it would invigorate research, break up the name, and allow researchers to hone in on one  type of CFS. It would certainly be a defining event in our history. An earlier study suggested we were on our way to such a breakthrough.

An Earlier Paper  - An earlier ‘preliminary’ paper (3,800 genes) highlighted three areas of interest in ME/CFS (viral infection, mitochrondrial functioning and cell suicide (apoptosis). It roughly coincided with the publication of a study by the MERGE group indicating abnormalities in cell suicide (apoptosis) in ME/CFS and if followed work by Dr. De Meirleir indicating the same. Because cell suicide is an important way the body clears itself of infected cells problems this study suggested ways ways an infection could either linger or at the very least take longer to be contained. The gene expression studies of the Dubbo group were off to an exciting start.

Preview – Their promise seemed to be fulfilled in what appeared to be a preview of the new study’s results at the 2007 IACFS/ME conference. There Dr Whistler in conjunction with two other CDC researchers (Dr. Vernon, Dr. Lonergan) reported in a presentation called ‘Alterations in Apoptosis Play a Role in Post-Infection Fatigue’, that they’d found evidence of a reduced innate (early) immune response, and reduced levels and unusual patterns of cell suicide (involving ceramide metabolism) in CFS patients. It appeared that the still-ill patients had trouble recognizing the pathogens and killing them. They concluded that ‘many of the symptoms (in post-infectious ME/CFS) may be immunologically mediated’.

Takeaway Points

● Mixed messages from different sets of Dubbo researchers? 
● Blood gene expression patterns in post viral fatigued patients are not significantly different than from healthy controls
● Blood gene expression patterns tell us nothing about fatigue or other symptoms
●The next step is the central nervous system                        

Dr. Whistler’s and Dr. Vernon’s interest cell suicide was apparently piqued enough for them to publish a new means of studying it. It seemed that we might be set for a full court press on the immune problems in the post-infectious subset of ME/CFS – exciting stuff, indeed! But by the time the full paper came out things had changed - dramatically.

Dumbfounded in Dubbo - Their successful preliminary study had prompted the Dubbo team to look at the full genome (30,000 genes) but instead of being more successful the larger effort turned out to be less successful.

Differentiating ME/CFS From the healthy controls. Right away there were problems. They had difficulty accomplishing the simplest aspect of a gene expression study; showing that the still ill participants had a different pattern of gene activity than the recovered participants. They did create two broad groups, one of which contained most of the ME/CFS patients but it also contained several of the healthy control group as well. After a year they could no longer even manage this degree of differentiation – the gene expression results of the still-ill subjects were no longer substantially different than those of who had recovered.

Uncovering the source of the fatigue, pain, etc. in ME/CFS. They did find 35 genes whose activity over time appeared to be associated with increased fatigue and pain. They expected these genes would be tied to neurochemical and neuro-immune processes but found that most were involved in very basic processes such as transporting iron, zinc, and copper ions in and out of the cell. They’d also hoped that they’d be able to tie these genes to specific tissues such as NK cells, or T-cells or neurons. This would allow them to zero in on a tissue in ME/CFS. But most of these genes were expressed in all the cells of the body.

This study was a disappointment on almost all levels. Instead of highlighting genes pin pointing the dysfunctions present in chronic fatigue syndrome they got genes involved in very basic processes that were occurring all over the body. Far from furthering their understanding of ME/CFS this study appears to have dealt a blow to the Dubbo teams hopes. Dr. Lloyd said that “None of them (the genes) are ones that I would have predicted, except for those relating to neurotransmitters”

Disarray in Dubbo? But what of the IACFS presentation in January, 2007? The three CDC researchers at the meeting came to the conclusion that there was clear evidence that altered immune processes did play a role in this subset of patients. The final study (which contained 7 more authors) did appear to highlight many of the genes the earlier presentation had focused on (apoptosis, the mitochondria, NK cells and ceramide metabolism) but no mention of them was made in the paper. Instead the final paper focused on a different and admittedly more abundant set of genes. What happened? Did the results change or did the interpretation of those results?

If there is a difference of opinion in the group it may not be the first one? An earlier gene expression study also highlighted immune genes and suggested they were linked to the slighter slower immune response seen in the ME/CFS group. But while they were doing that the full Dubbo group was pooh-poohing the significance of those results and their theory - stating that they believed the slightly slower immune response was essentially meaningless.

 Strike Two: Prominent Theory Axed

Ute Vollmer-Conna, Barbara Cameron, Dusan Hadzi-Pavlovic, Kristi Singletary, Tracey Davenport, Suzanne Vernon, William C. Reeves, Ian Hickie, Denis Wakefield, and Andrew R. Lloyd, 2007, Post-infective Fatigue Syndrome Is Not Associated with Altered Cytokine Production. Clinical Infectious Diseases 45, #6, pp 732-735.

Researchers have long had their eyes on powerful immune messengers called cytokines in ME/CFS. Cytokines are believed to be mostly responsible for the symptoms occurring early in infections that are so similar to those found in ME/CFS. Indeed, given the infectious trigger noted by so many ME/CFS patients and the close symptom fit it’s been hard to understand how cytokines could not be involved in ME/CFS.

The results of ME/CFS cytokine studies, however, have been mixed. Several theories have been offered why including poor laboratory procedures and the inclusion of non-infectious onset patients into the study. Since the Dubbo studies only contain infectious onset ME/CFS patients if any study would find increased cytokine levels one would think it would be this one.

The Study. As in all the Dubbo studies people who had an uneventful recovery from a major infection (infectious mononucleosis, Ross-River, Coxsackie burnetii) where compared with people who came down with ME/CFS after the same infection. They looked at a wide array of cytokines (IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-alpha, and IFN-gamma) from a number of different angles; basic levels over a year, additive levels over time and cytokine levels after being prompted by an immune stressor (LPS).

Study Findings: They found no significant cytokine differences between the two groups in any tests and concluded (once again) that while immune stressors such infections can trigger ME/CFS that the infection itself don’t seem to ‘drive it’.

Heading ‘Upwards’ - Finding nothing in the peripheral blood the Dubbo group is shifting it’s attention from the body to the central nervous system. They suggest that if cytokine levels are increased they’re probably increased not in the lower body but in the central nervous system. They proposed that increased cytokine production in nervous system cells called glial cells could be present. Alternately they propose that neural pathways could become sensitized to outside stimuli – something that appears to occur in FM.

Conclusions. Thus far the Dubbo studies have been better at telling us what’s NOT happening in ME/CFS than in what is happening. They have thus far dismissed the idea that a chronic infection or a chronically activated immune system is responsible. They do know that the patients who don’t recover from an infection appear to be sicker early in the disease and that they have a slightly slowed immune response but they’re not interested in the ‘periphery’ anymore – they’re heading for the brain. Their funding is precarious, however, with funding from the CDC over and the NIH turning its back on this project. Only time will tell if we will hear more from the Dubbo project.

Takeaway Points

● Immune activation is not the cause of the symptoms in infectious onset ME/CFS patients
● This is at odds with several theories proposing a chronic infection is at the heart of the disease
● Immune problems in the central nervous system may, however, play a role

False Impressions. Several people have suggested to me that the Dubbo studies are invalid because they're studying the wrong subset. They believe that the virus primarily under study, EBV, doesn't really cause ME/CFS or if it does it causes a mild version of it. They point to the low percentage of people who became ill (10%) who still met the disease criteria at the end of the year. This doesn't jive with the many people who have ME/CFS for many years.

The Dubbo studies focused on three types of serious infection; Ross-River Virus, Q fever and Infection Mononucleosis/glandular fever. After three months 27% of the patients had 'post-viral fatigue syndrome'; at six months 12% did and at a year 9%. Post-viral fatigue syndrome was characterized by increased levels of fatigue, pain, mood disturbance, cognitive problems and flu-like symptoms. At the end of the year, however, only about 1% of the original patients still meet the CDC criteria for CFS. They were still clearly quite ill  but most didn't meet the CDC criteria for CFS -  they fell  in that nether  world between CFS and still-ill that few know what to do with.

The confusion came because while the original study focused on all the patients the following laboratory studies only focused on the EBV patients. Thus the statistics regarding prevalence included EBV, Ross-River and Q fever patients not just EBV patients; the prevalence figures probably do reflect the rate of post-infectious fatigue and ME/CFS after a serious infection.