Phoenix Rising: Vol.1, No. 6, Feb. 2006 By Cort Johnson

Phoenix Rising: Vol.1, No. 6, Feb. 2006 By Cort Johnson

(Please send submissions, comments and/or clarifications toPhoenixcfs@yahoo.com)

Phoenix Rising is a monthly newsletter committed to elucidating current CFS research, describing important events, telling patient stories, etc. Please contribute to Phoenix Rising.

NEWS

The CFIDS Association of America publishes Special Issue on the Science and Research of Chronic Fatigue Syndrome. This is the kind of thing only a national organization like the CAA can produce – it’s chock full of insights straight from many of the top CFS researchers. Its a great way to get up to date on the latest research in CFS. Everyone should have a copy. You can get one for $12 (or you could fork out a little more money and join the organization). The press release from the CAA is given below.

“After months of collaboration with researchers from around the world, the CFIDS Association of America is proud to publish the Science & Research of CFS. This special, double-issue of the CFIDS Chronicle covers the scope of research on chronic fatigue syndrome, profiles key investigators, highlights current best treatment practices and shares stories about patients and families coping with the illness. Topics include research developments, epidemiology, etiology, the immune system, the brain, sleep dysfunction, pediatric CFS, overlapping conditions (such as Fibromyalgia), clinical care practices and more. It’s the first wide-scale attempt to cover the state of CFS research and key findings to emerge from nearly two decades of investigation into this illness.“

Copies are available through the CFIDS Association’s web site at www.cfids.org for just $12 ea (plus shipping). Visit https://www.cfids.org/special/default.asp to browse a complete listing of articles in the Science & Research of CFS, including links to several online samples.

MERGE, the dynamic UK CFS research organization has produced a DVD titled “Biomedical Research in ME/CFS” that discusses the issues and challenging CFS research. This short, 30-minute lecture by the Chairman of MERGE, Dr Vance Spence, also provides news of MERGE’s latest research efforts.

Copies are available from the MERGE headquarters (suggested donation £5.00 to help towards production costs and p&p). This is the first in a series of DVD’s MERGE will produce to energize research into ME/CFS. https://www.meresearch.org.uk/archive/dvdpresent.html

A DVD featuring a talk by Dr John Gow about his pioneering genetic study at the Glasgow University is now available from The ME Association. Dr. Gow is only researcher to examine the entire genome of CFS patients.

The two-part DVD, videoed at the association’s annual medical conference last September, also includes a medical panel discussion led by MEA medical advisers Dr Charles Shepherd and Dr Anne Macintyre, and pediatrician Dr Rashmin Tamnhe.

Dr Gow has identified nine gene sequences among a list of 100 possible biomarkers which could lead to drug treatments being developed. The ME Association is the major funder of the present stage of the study. The next stage – if funding can be found – will be a clinical study.

The price of the DVD is £5 (inc UK postage – overseas delivery, please inquire). Copies may be obtained from The ME Association, 4 Top Angel, Buckingham, MK18 1TH. Make cheques payable to The ME Association. Copies can also be obtained by credit card order – phone 01280 818964. Please allow seven days for delivery.

(I was unable to get a website address for this DVD; if anyone has one please let me know).

ACAM Conference on Infection and Chronic Illness: Integrative Approaches to Lyme Disease, Stealth Infections and Inflammation, will take place from May 3 – 7 in Dallas. The three objectives of the conference are to:

The Keynote speaker is Mark Levine, MD (Chief, Molecular and Clinical Nutrition Section, Senior Staff Physician, National Institutes of Health). Other speakers include Garth Nicolson and John Martin. https://www.acam.org/DALLASabout.html

P.A.N.D.O.R.A. (Patient Alliance for Neuroendocrineimmune Disorders Organization for Research and Advocacy, Inc.- that’s a mouthful!) is proud to announce the 5th Annual Inspiring Hope Through Awareness Neuroendocrineimmune Disorders Conference, April 29, 2006 9:00 am to 3:30 pm, Emma Lou Olson Civic Center 1801 N.E. 6th Street, Pompano Beach, Florida. Conference fee: $15 tax deductible donation. The key note speakers are Roland Staud, MD (Fibromyalgia Session) and Nancy Klimas, MD (Chronic Fatigue Syndrome Session).

For more information visit www.pandoranet.info or call 954-783-6771

Dr. Kerr working on drugs for CFS – Dr. Kerr, the physician in charge of the very (very) large gene expression study now taking place in the UK, is beginning to formulate drugs that he thinks, based on the his gene expression results, will help CFS patients. If all goes well he should be able to start testing these drugs in about a year. This man is moving fast! Meanwhile the gene expression results suggest an already existing immunomodulator drug (unnamed) may help CFS patients as well. (To read the story Click here.)

RESEARCH

RESEARCH – Unless otherwise noted the research summaries are by Cort Johnson, a CFS patient, whose ‘expertise’ such as it is, extends mostly to subjects of CFS pathophysiology. Submissions from others with knowledge of other fields (psychology, epidemiology, etc). or of any aspect of CFS pathophysiology are gratefully accepted. Comments, suggestions, clarifications, etc, negative or positive, only add to the editors and others understanding of CFS. Please send them to Phoenixcfs@yahoo.com).

Research Summary:

Rating The Months Research – The thesis of this newsletter is that the most important studies deal with the pathophysiology of CFS. Each month is graded according to the following criteria;

A – several difference making papers on CFS pathophysiology

B – a difference making paper on CFS pathophysiology plus several important ones

C – several important papers on CFS pathophysiology

D – 1 or no important papers on CFS pathophysiology but several on other aspects of CFS

*F – no important papers on CFS

Research Rating – A ‘F’ for the month – that’s really bad but in this case it’s is misleading. We had 11 papers but little pathophysiological stuff – mostly a lot of clinical, psychological and cognitive stuff. Going by our criteria – papers have to have CFS in the title – this month got an F. It was saved, however, in a big way, by a group of papers not specifically on CFS but that may greatly contribute to our understanding of it. January in the end turned out to be a very good month for CFS research.

THE PAPERS

Paper of the Month – every month the editor picks out what he, based on his admittedly limited understanding of CFS, believes to be the most important paper published that month for an in-depth examination.

THE DUBBO STUDIES PART I : A MODEL OF POST-INFECTIVE FATIGUE EMERGING

EPSTEIN-BARR VIRUS

The Dubbo studies are a series of studies funded by the CDC and the Australian government that examine what happens to people as they come down with CFS. These researchers are following cohorts of people exposed to exposed to pathogens (Epstein-Barr Virus (EBV), Ross-River virus, Coxiella burneti) known to put them at risk for CFS. Because these studies focus on producing an infectious model of CFS they may or may not reflect processes occurring in CFS patients with a different type of onset.

The three studies reviewed here focus on Infectious mononucleosis (IM), an EBV caused disease found in adolescents and adults. IM is a particularly apt disease to study in reference to CFS. Like CFS it is characterized by extreme fatigue, and like CFS, viral loads cannot explain the lingering problems found. Two studies have shown that about 10% of healthy young adults that come down with infectious mononucleosis (IM) still experience disabling symptoms, in particular fatigue, six months after the disease’s onset. Since the CDC has stated that almost all the chronically ill patients in the Dubbo studies met the criteria for CFS they will be referred to as CFS patients in these overviews.

There’s a lot at stake in these studies. The proponents of the ‘biopsychosocial’ model of CFS propose that it mostly occurs in people who for one reason or another just cope poorly with disease. If these studies find no differences between the people who get ill and stay ill and those who recover from the infection, then the case of the CBT proponents will be enhanced. If, on the other hand, these studies find that the still ill patients undergo unique physiological changes in response to infection then not only will the ‘biopsychosocial’ model of CFS take a hit but the beginnings of unique disease process may be uncovered.

Cameron, B., Bharadwaj, M., Burrows, J., Fazou, C., Wakefield, D., Hickie, I., Ffrench, R., Khanna, R. and A. Lloyd. 2006. Prolonged Illness after infectious mononucleosis is associated with altered immunity but not with increased viral load. Journal of Infectious Diseases 193, 664-671.

At least two general possibilities could explain the ongoing debility of the still ill or ‘CFS’ patients in these studies; they could have trouble eliminating the virus, or they could display an response to the virus that persists after the virus has been eliminated. This study examined both possibilities; it examined the viral loads to see if the CFS patients were unable to eliminate the virus, and cytokine levels to see if the CFS patients had a different response to the pathogen. Pro-inflammatory cytokines such as TNF-a, IL-1b and IL-6 are known to cause the symptoms of ‘sickness behavior’ (malaise, fatigue, aching muscles, etc.) so similar to those found in CFS that commonly occur during the early stages (acute phase) of infectious illness

Immune Response – The successful resolution of IM appears to derive from an individual’s ability to mount a ‘broad-based’ cytotoxic T-cell response to EBV. Studies have found that increased levels of EBV specific cytotoxic T-cells are paralleled by declines in the levels of circulating EBV.

Viruses usually enter cells, use the cell’s RNA machinery to produce more viruses and then leave the cell and swarm through the bloodstream looking for more cells to infect. Large numbers of circulating viruses (virions) in the blood stream indicate virus replication is in full swing.

An examination of the cytotoxic T-cell response found that neither people who recovered or who didn’t recover from IM, had a significantly different T-cell response; both groups were able to fairly quickly produce large numbers of EBV specific T-cells that were able to eventually knock down the infection. The researchers also examined how well the immune system responded to the production of two EBV proteins associated with EBV replication. The proteins viruses produce help it to assemble new virions. The T-cells should take note of these new proteins and react by producing a pro-inflammatory cytokine, IFN-7, that helps to regulate the immune response. Both the still ill and the healthy IM patients reacted similarly to the presence of these viral proteins; these patients did not appear to be ill because of their inability to mount an immune response.

Because cytokines can be responsible for many of the symptoms associated with infection, the researchers also examined the two groups to see if the ‘CFS’ patients demonstrated increased or prolonged levels of pro-inflammatory cytokines. The cytokine levels of the ‘CFS’ patients did not, however, differ from those of the recovered patients.

The humoral branch (B-cells) of the immune system has long been thought, because of its delayed appearance, to play a relatively minor role in EBV suppression. Indeed, the antibodies produced by B-cells (IgG anti-EBNA – Epstein-Barr nuclear antigen) appear to signal the beginning of the latency phase when EBV takes up its lifelong residence in B-cells. The presence of anti-EBNA antibodies is believed to be associated with the period of convalescence that follows the acute immune response.

Here, however, a difference was found; the humoral response occurred earlier and was stronger in the CFS-like patients. The researchers posited this meant EBV was able to mount a quicker attack in these patients. They noted that although the both sets of patients mounted an equally powerful cytotoxic T-cell attack that it was ‘somewhat slower’ in the CFS-like ones. They suggested that the earlier humoral response in CFS patients may have been due to enhanced Th2 immune responses. CFS patients have long been thought to display an enhanced Th2 immune response. Cytokines produced during the Th2 immune response activate B-cells, among other things, and increased B-cell activity and antibody production is one of the hallmarks of the Th2 immune response. Interestingly EBV is able to produce a cytokine, IL-10, that induces a Th2 response.

This was not enough to satisfy the authors, however, that a cause had been found for the protracted illness seen in these patients. None of the critical factors involving EBV suppression; the cytotoxic T-cell response, IFN-y production, or the cytokine response were found to be altered. Neither the viral load in the bloodstream or in the cells themselves was higher in the chronically ill patients; they appeared to have successfully resolved the infection! Based on this data authors were unable to determine why these patients were still so sick.

Almost coyly, however, they suggested in the last sentence of the paper, that they did have a idea where the problem lay but aren’t going to share the details of it with us yet. They stated “we propose that alternative neurobiological mechanisms triggered during the severe, acute illness and sustained in the absence of peripheral inflammation underpin prolonged illnesses after EBV infection”.

This suggests the problem lies not in the immune system but in the nervous system (probably the brain) and that it is triggered during the initial phase of the illness and then sustained even after the infection has been resolved. It suggests this team has found markers of nervous system dysfunction both early in the illness and later on in the CFS patients.

Indeed Lloyd later in an interview said “We believe that the parts of the brain that control the perception of fatigue and pain get damaged during the acute infection phase of glandular fever. If you’re still sick several weeks after infection, it seems that the symptoms aren’t being driven by the activity of the virus in body, it’s happening in the brain.

“It’s not too big a leap of faith to say after that, it’s in the brain, because of the nature of the symptoms – it’s fatigue, it’s pain, sleep disturbance, concentration and memory difficulties and mood disturbance. They’re very much brain symptoms.”

While the Lloyd team did look at many of the parameters of EBV infection and the immune response their research was not necessarily conclusive. They did not, for instance, search for the antibodies to the early EBV enzymes the Glaser’s believe are creating havoc in CFS patients. It is also possible that the virus could have been vanquished in the periphery but became established in the brain.

Several studies have suggested that immune activation may be occurring in the brains of CFS patients. These include the increased white blood cell levels in Natelson’s cerebrospinal fluid study, a distinctive proteome that could reflect glial cell activation in the Baraniuk cerebrospinal fluid study, and the increased choline levels seen in the basal ganglia in several magnetic resonance spectroscopy studies. Albashi believes HHV-6A infection of the CNS contributes to the symptoms seen in CFS (see The Pathogens in CFS, Part I, HHV-6). The Kauschik/Kerr and Vernon gene expression studies have found evidence of both central nervous system and immune dysregulation in CFS. Hopefully the Lloyd team’s next paper explaining their rather cryptic comment will be out soon.

The next Dubbo study examined the gene expression patterns in chronically ill and recovered IM patients. Oddly enough, at first glance at least, it appeared to come to a conclusion opposite than that of the Cameron study¼

Vernon, S., Whistler, T., Cameron, B., Hickie, I., Reeves, W. and A. Lloyd. 2006. Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr Virus. BMC Infectious Diseases 6: 15.

This study found that the gene response in the chronically ill IM (or CFS) patients differed early in the illness, and this difference appeared to reflect the ability of EBV to better evade or exploit these patients immune systems and replicate in the body.

Amazingly all eight of the genes more highly expressed in the CFS-like patients in the early stages of the IM were involved the activation of a phase of the cell cycle. The cell cycle is invoked when cells begin to proliferate. I believe EBV induces B-cells to proliferate in order to create the B-memory cells it hides out in. Four of the genes differentially expressed in the chronically ill group were involved in parts of the immune response EBV is known to evoke or exploit. One, an interferon stimulated gene (ISG20) is evoked by cells infected with viruses. Another, involved in apoptosis, is evoked when the immune system kills off infected cells by invoking their suicide program. Three of the genes were involved in a cellular process called the cell cycle that EBV hijacks in order to replicate in the bodies cells.

An analysis of genes that were upregulated both early and late in the disease process found that over half of them were involved in fatty acid metabolism and mitochondria functioning and several of these genes are known to be associated with increased EBV activity. One of the early proteins produced by EBV (BRLFI), for instance, induces the infected cell to produce an enzyme, called fatty acid synthase (FAS), that produces a fatty acid (palmitate) found in cellular membranes. EBV uses the FAS enzyme and palmitate to awake from latency and begin replication in the cell. The authors noted that the active ingredient in green tea (epigallocachetin gallate) has been found to inhibit FAS activity and EBV replication. The authors posited that the mitochondrial abnormalities found may have been responsible for the immune alterations seen in the first study. Indeed, EBV infected monocytes display reduced production of TNF-a, an important pro-inflammatory cytokine.

The tight fit between the genes found and EBV replication was impressive and suggested increased EBV replication had occurred in the CFS patients. Indeed the authors stated that the gene expression changes seen

“potentially implicates a failure of the host to adequately control viral replication.“

Unfortunately the very small sample size (5 CFS patients) impeded the researchers from doing a more thorough gene expression analysis. Because they had to pool both the late and the early gene results we don’t know, for instance, if the mitochondrial activity was induced early or late in the disease process or both. The number of genes assessed (3,800) was also quite small for a gene expression study. These factors, however, make the impressive results found all the more startling. Hopefully larger follow up studies are in process.

Why was the patient sample so small? The researchers followed the cohort of IM patients that presented themselves in the township of Dubbo, Australia over a period of time. Either they didn’t realize that so few people would get IM or they simply were satisfied with such a small study. Since only about 10% of IM patients come down with ‘CFS’ the researchers must have known that their odds of getting an adequate sample size were small. We can be thankful to the CDC for pursuing such innovative studies yet one can only rue their decision not to commit the resources needed for this investigations results to have been other than ‘preliminary’. These studies take a long time; the Dubbo studies have be ongoing since 1999 – will it take another five years to get other than a ‘preliminary’ study?

How to explain the differing results from the two studies? The first study suggested the CFS patients successfully contained the virus; the second one suggested they did not. One explanation might involve the range of the different studies. The Cameron/Lloyd study looked strictly at peripheral indices of infection and immune activation while the Vernon study examined the gene expression of immune cells that are able to reflect both peripheral and central processes. Could the Vernon study be picking up evidence of a CNS infection or disruption? Is the fact that EBV is able to infect the central nervous system important?

EBV may be a factor in another fatiguing disease of the central nervous system, multiple sclerosis (MS). A recent study found that EBV infection was a risk factor for MS. Most intriguingly, those at the highest risk of MS encountered EBV later in life; i.e. they came down with infectious mononucleosis. (Sooner or later most people get exposed to EBV. If you do so as a child you usually have a mild infection, if you’re an adolescent or adult you have a good chance of getting infectious mononucleosis and if you get infectious mononucleosis you apparently stand a pretty good chance of getting CFS (1/10) and may have an increased (but still low) chance of getting MS.

The next paper from the Dubbo group, which looked at gene expression during the early (acute) phase of infectious mononucleosis may give us some clues as to what could go wrong in the chronically ill patients.

Vernon, S, Nicholson, A., Rajeevan, M., Dimulescu, I., Cameron, B., Whistler, T. and A. Lloyd. 2006. Correlation of psycho-neuroendocrine-immune (PNI) gene expression with symptoms of acute infectious mononucleosis. Brain Research 1068, 1-6.

Most gene expression studies have focused on genes found in immune cells in the blood called peripheral blood mononuclear cells (monocytes and lymphocytes). This seems fine for examining immune activity in CFS but what about uncovering information on metabolic or nervous system processes? How in the world can one get information on these processes from immune cells?

Researchers at the CDC recently demonstrated – to their surprise – that almost 2/3rds of 1600 genes known to mediate psychological – neuroendocrine – and immune (PNI) processes were expressed in PBMC’s. This indicates gene expression in the PBMC’s does give a credible snapshot of the biological activity in the body. PBMC gene expression analysis has, in fact, been described as being a kind of molecular biopsy of the body.

This study examined the expression of 1058 genes known to be engaged in PNI processes. First the researchers assessed the symptom presentation of people with infectious mononucleosis. Then they correlated the symptom expression data with gene expression data in order to determine which genes may have contributed to which symptoms.

It is important to note that they did not look at gene expression in CFS patients; this study simply examined what happens to the body to create the symptoms of infectious mononucleosis. Since CFS and infectious mononucleosis have such similar symptoms, however, it is possible that this study uncovered genes involved in generating the symptoms found in CFS. Because this study did not differentiate between chronically fatigued and recovered patients some genes that could be uniquely upregulated in CFS patients may not be presented here. We don’t know if they examined these genes in the second Dubbo study or not. This study, then, does give us a preliminary idea of what might have gone wrong in CFS.

The researchers must have beamed at their results. No genes were significantly associated with fever, malaise or irritability/depression but they found a nice tight fit between gene expression and fatigue, sleep disturbance and neurocognitive problems. This means there is little doubt that these genes play a role in causing these symptoms.

Surprisingly, none of these genes were directly involved in cytokine production. Many researchers believe the symptoms (i.e. sickness behavior) seen in the early stages of an infection are cytokine related. This is an important finding. Skeptics of a physiological interpretation of a post-infective fatigue state have been able to point to the conflicting findings in CFS cytokine studies to assert there is no evidence of an aberrant physiological process. But what if we’re looking in the wrong place? This study strongly suggests that cytokines are not the only agents involved in producing ‘sickness behavior’.

Sleep Problems (Hypocretin/orexin) – How nicely this gene fits this symptom! Low hypocretin levels occur in narcoplepsy, a disease characterized by extreme sleepiness during the daytime and insomnia at night. Narcoleptics get about as much sleep as everyone else but they can’t get it in one shot – they are unable to stay awake or asleep for significant periods of time.

Hypocretin is produced by neurons that extend throughout the brain with especially heavy concentrations in the hypothalamus and brainstem – two regions of interest in CFS. The hypocretin system regulates the roles the monaminergic (dopamine, serotonin, histamine) and cholinergic systems play in producing ‘vigilance’ or alertness. Injecting hyporexin into the brains of rats results in increased wakefulness for hours, probably through the induction of histamine. Researchers have recently demonstrated that glutamate drives neuronal hypocretin activity. Some believe increased glutamate levels could play a role in cognitive as well as other problems found in CFS.

This seems like a strange finding though; increased hypocretin mRNA in EBV patients would lead, one would think, to increased alertness. High hypocretin levels at night, however, could lead to insomnia and that could theoretically lead to increased daytime sleepiness. A disturbance in the hypocretin system by EBV could therefore play a role in the extreme daytime sleepiness found in CFS patients.

Fatigue (MEF2C) – Remarkably, one gene (MEF2C) accounted for almost 2/3rds of the variance associated with fatigue in these patients! A further analysis found that this gene was highly expressed in infectious mononucleosis patients with high fatigue and hardly expressed in patients with low fatigue (p<.0015). It was also highly correlated with muscle/joint and cognitive problems. This is an important gene!

So what is MEF2C? MEF2C is a transcription factor, a protein that regulates gene activity; transcription factors enter the nucleus and then either promote or inhibit the transcription of DNA into mRNA. Many CFS patients know of the STAT transcription factor that regulates the transcription of immune genes. One of the genes MEF2C activates promotes the expression of a key viral protein (BZLFI) important in the EBV replication.

This doesn’t appear to tell us much about the fatigue found in infectious mononucleosis patients, though. About half of the IM patients – those without fatigue – did not have high MEF2C levels. Since there is no evidence of increased viral replication in the more fatigued IM patients MEF2C’s role in producing fatigue during IM is something of a mystery.

MEF2C also plays a role in muscle generation. A recent paper reported that MEF2C upregulation induced the cardiac muscle cells in mice to elongate or hypertrophy, a finding which appears to implicate MEF2C overexpression in cardiomyopathy (heart disease). MEF2C also plays a critical role in the survival of the endothelial cells that line the blood vessels. There is growing evidence that vascular problems may contribute to CFS. This study groups was examining immune not endothelial or cardiac cells but as we have seen all sorts of genes are present in immune cells. Could high MEF2C expression over time contribute to the vascular or cardiac problems in CFS patients?

Neurocognitive Problems (VACHT) – VACHT is a transporter takes up acetylcholine from the synapses of the nerves and returns it for use in the neurons. Many of the acetylcholine containing neurons occur in a part of the brain called the basal ganglia which some CFS researchers believe is disrupted in CFS (See Choline on the Brain?). Could VACHT be overexpressed in order to make up for low acetylcholine levels in the basal ganglia? Acetylcholine blockage in the brain has been shown to cause memory loss.

As was stated it is unclear if any of these genes are chronically upregulated in CFS patients; none of the gene expression studies have thus far stated they are. We don’t know, however, if they have been tested yet – the gene studies only specify which genes have an altered expression, not which ones are normal.

Conclusions – The Dubbo Studies and EBV – At this point we are unable to build a coherent model of post-infective fatigue out of these studies The Lloyd study found evidence of a somewhat delayed immune response and perhaps an initially stronger pathogenic attack in the still ill IM patients but it did not find evidence of increased viral activity or an prolonged or aberrant immune response.

Lloyd has indicated the problem lies in the brain and, importantly that it occurs early in the infectious process. Could the slightly delayed immune response and/or increased pathogenic attack in the chronically ill patients give EBV an opportunity to make it to the brain? The Vernon study clearly suggested the still ill IM patients had trouble shutting down EBV replication. Is that replication occurring in the periphery or in the brain?

And what about EBV? Does it play a special role in CFS or not? Is it just one of many pathogens that can trigger CFS or does it have certain features that make more dangerous than others? Is its ability to infect central nervous system cells important or necessary? Are CFS patients at special risk from neurotropic pathogens? Several of the pathogens of interest in CFS (HHV-6, EBV, some mycoplasma’s, coxsackie B) can infect the CNS.

“Two hundred fifty-three subjects have been enrolled and followed for at least 12 months¼ Protracted and disabling PIF (post-infectious fatigue)/CFS, characterized by fatigue, musculo-skeletal pain, neurocognitive difficulties, and mood disturbance, occurred in 12% of subjects at 6 months and in 9% at 12 months. We specifically identified CFS in 11% of participants at 6 months. (Look at these numbers; if 10% of the subjects got CFS then we have about 25 people with CFS¼ spread among three diseases¼ .three studies/three papers – 8 patients a study! This is great stuff but it looks like we are in store for more preliminary findings!

The risk of PIF/CFS was similar for all three agents, and although each of the acute infectious diseases had unique clinical features, the PIF/CFS phenotype was uniform and independent of the initial infection. (What an interesting statement – unique clinical features but a common endpoint – CFS. These studies looked two very different kinds of pathogens; viruses and bacteria. Since the immune response to each is likely to differ this appears to suggests that something rather fundamental in the immune response or in the reaction to the immune response goes awry in CFS patients.) PIF/CFS was predicted largely by the severity of the acute illness rather than by demographic, microbiological, immunological, or psychological factors. This ‘severity of the acute illness’ appears to refer to how debilitating it was, e.g. people who got really sick had the best chance of getting CFS. Since the amount of pathogen present was not a factor the problem appears lies in the body’s response to it. Since the immune response does not appear to be the problem either, it seems we are probably left with the body’s response to the immune response. Since the immune system interacts closely with the brain the most likely candidate here appears to a problem in the brain triggered by the immune system). These infections clearly can have an etiological role in triggering CFS, and it appears that host response to infection (rather than the specific pathogen) determines the occurrence of PIF/CFS).“

Ongoing Studies – the Dubbo studies have also investigated, using the same methodology, the disease process initiated by another virus, Ross-River Virus, and a bacteria, Coxiella burneti. Although the CDC sites states proteomics is being employed all three studies none of the EBV studies have thus far used it. They are all complete and should be published shortly. See Eye on the Researchers.

THE SOURCE OF FATIGUE IN DISEASE IDENTIFIED?

CFS is not the only disease with mysteriously severe levels of fatigue. Cholestatic liver disease, multiple sclerosis (MS) can also result severe, unrelenting levels of fatigue. Researchers and clinicians have for years puzzled over the cause of the fatigue seen in some of these patients. Two papers published last month suggest, remarkably, that not only does the same process cause fatigue in both diseases but that the same agent does as well. There is some evidence this agent may be at work in CFS as well. .

Kerfoot, S., D’Mello, C., Nguyen, H., Ajuebor, M., Kubes, P., Le, T. and M. Swain. 2006. TNF-a secreting monocytes are recruited into the brain of cholestatic mice. Hepatology 43, 154-162

Aspinall, A. and D. Adams. 2006. Sickness behaviors in chronic cholestasis” an immune mediated process? Hepatology 43, 20-23. .

From 50-85% of biliary cirrhosis patients experience severe fatigue. Cholestatic liver diseases (CLD) are characterized by reduced bile flow from the liver. The most prominent CLD, primary biliary cirrhosis, an autoimmune disease is, like CFS, predominantly found in women. Researchers have postulated several causes of this fatigue including stimulation of the vagus nerve endings in the liver, HPA axis abnormalities and increased heavy metal (manganese) accumulations in the central nervous system (CNS). This paper, which elucidates a unique way the immune system affects the brain, may be a breakthrough in this area, and, as such, may provide a model for other diseases with immune/neurological component. (Severe fatigue is found in several autoimmune diseases (rheumatoid arthritis, lupus, MS).

The advent of ‘sickness behavior’ (malaise, poor cognition, muscle aches, fever) during the acute phases of infection, has long indicated to researchers that the immune response can effect the central nervous system. Unraveling just how it does so, however, has been difficult. The brain, after all, is heavily guarded by a ‘fence’ called the blood brain barrier (BBB) that blocks the flow of most immune mediators, including cytokines, from penetrating it. Somehow researchers have had to find -how- cytokines or other immune agents in the periphery make it into the brain and alter it.

They have posited at least four means of surpassing the blood brain barrier; (1) the stimulation of nerve (parasympathetic) fibers in the affected organs (in this case the liver) could induce the brain to act differently, (2) immune mediators could stimulate the endothelial cells lining the blood vessels in the brain to release inflammatory agents such as prostaglandins into the brain, (3) cytokines could bypass the BBB and access the brain via regions called the circumventricular organs that are largely devoid of an intact BBB, (4) a leaky blood brain barrier (BBB) could allow immune agents into the brain.

Now researchers appear to have uncovered a fifth way for the immune system to affect the brain. In cholestatic liver disease (CLD) cytokines and endotoxins are released that induce the endothelial cells lining the blood vessels in the brain to recruit immune cells called monocytes into the brain. These monocytes then produce cytokines that affect the brain.

How does this occur? First a pro-inflammatory cytokine called tumor necrosis factor-alpha (TNF-a) produced during CLD prompts the endothelial cells to produce adhesion molecules called P-selectins that attract monocytes and other white blood cells to adhere to the blood vessel walls. (ndothelium). Adhesion molecules, which play an important role in the immune response, attract white blood cells to a site of infection or trauma. Once monocytes attach to the blood vessel ways they are able to burrow into them and then emerge on the other side in the brain. For a reason that is not yet clear once inside the brain they are somehow given the signal to activate and they begin pumping out TNF-a. This study found that the fatigued CLD patients had increased rates of TNF-a producing monocytes in their brains relative to the non-fatigued CLD patients.

The monocytes were found in the regions of the brain that are subject to inflammatory processes. Aspinall and Adams propose that chronic glial cell and astrocyte activation due to monocyte activation and TNF-a production could lead to neurodegeneration. Despite the intriguing findings in this paper Aspinall and Adams note that the severe side effects of the current anti-TNF-a therapy (e.g. infliximab) largely preclude them from being used.

Could this be occurring in CFS? Who knows? But the endothelial cell connection is intriguing given the mounting evidence of vascular dysfunction in CFS. Could a disruption in the endothelial cells lining the blood vessels be causing both vascular abnormalities in CFS and the central nervous system problems?

There is the issue of the blood brain barrier (BBB). Could a leaky BBB be the weak link in CFS patients? Could an unusually leaky BBB in CFS patients give cytokines and pathogens a straight shot into the brain? A recent study finding that a process akin to cortical spreading depression (CSD) occurs in the brains of CFS patients intriguing in this regard since cortical spreading depression increases the permeability of the BBB. Baraniuk et. al. speculated whether increased histamine production in the brains of CFS patients results in a leaky BBB. One study has found increased sensitivity to histamine in the blood vessels of the skin.

Fascinating stuff! We aren’t done with TNF-a, however¼ ..

Heesen, C., Nawrath, L., Reich, C., Bauer, N. Schulz, K-H and S. M. Gold. 2006. Fatigue in multiple sclerosis: an example of cytokine- mediated sickness behaviour? J. Neurol. Neurosurg. Psychiatry 77, 34-39.

Fatigue is the most disabling symptom found in a significant subset of MS patients. Even after many years of research the cause of MS is unclear but the central process is clear; MS patients over time display increasing demyelination of the nerve fibers in their brain. This leads to progressively reduced signals to the body (periphery) and a decreasing ability to orchestrate one’s movements.

This study examined the cause of the severe fatigue sometimes present in MS. That fatigue in MS is not associated with the severity, type or stage of MS suggests that an altered host response is causing it. Since the immune system is known to be activated in MS and some aspects of immune system activation are known to cause fatigue, the immune response become a target of MS researchers interested in fatigue.

These researchers looked at whether the response to an immune stimulant (phytohemagglutin) differed between the fatigue and non-fatigued MS patients. They found that fatigued MS patients displayed increased IFN-y and TNF-a production relative to the non-fatigued patients. Intriguingly, TNF-a levels were moderately correlated with fatigue and disease activity and strongly correlated with increased daytime sleepiness. Daytime sleepiness is commonly found in CFS as well. The authors suggested that daytime sleepiness may, in fact, be an indicator of a ‘cytokine mediated fatigue syndrome’.

What an interesting idea and what an apt choice of words – ‘cytokine induced fatigue syndrome’ – so close to ‘chronic fatigue syndrome’, so easy to change the first word¼ .

Given the role TNF-a may play in inducing fatigue in both CLD and MS it is obviously time to take a closer look at this important cytokine.

TNF-A in the brain – But how does TNF-a in the brain cause fatigue? This is still unclear. Intriguingly given the findings of aberrant serotonergic activity in the brains of CFS patients some evidence suggests TNF-a may impair brain serotonergic activity.

TNF-a in CFS– Like many other immune measures studies examining TNF-a activity in CFS patients have had mixed results. A 2000 study indicated that a process designed to inhibit TNF-a production in the body is impaired in CFS but about half the studies examining TNF-a levels in CFS show normal levels while the other half show increased levels. Two studies using a more accurate test, TNF-a production in response to an immune stimulant (lipopolysaccarides, endotoxins), found either normal or reduced TNF-a production in CFS while one early study (1991) found increased TNF-a production. While TNF-a levels were not increased in CFS relative to controls in a recent study the response CFS patients had to TNF-a was. Instead of having higher levels of TNF-a CFS patients appeared to display an exaggerated response to it. (What a twist that is! A similar situation occurs when rats with cholestatic liver disease respond to negligible amounts of the IL-1B cytokine with severe fatigue.) To further complicate matters CFS patients showed reduced not increased cytokine production in response to a psychosocial stress test. Gaab posited that high levels of stress over time lead to a supersensitization to TNF-a and other cytokines in CFS.

REPORT FROM….DOWN UNDER

By Jonathan Wilson

(If you’d like to file a report from somewhere in the world please e-mail me at phoenixcfs@yahoo.com. Reports done thus far; Portugal, Australia, Belgium and Israel.)

Q. How well is CFS known in Australia? If you mention you have CFS to someone do they know what it is? What is their general impression of it?

Most people are aware of CFS as a psychiatric condition but almost are totally ignorant of ME. It sounds serious so many people tend to associate ME with MS so their ignorance can be bliss. I tend to use ME as the descriptive term with those unfamiliar. The prohibitive factor is that those with ME including me have difficulty saying Myalgic Encephalomyelitis so CFS is the unfortunate default response. Although, in a ME/CFS support group I’ll use CFS as i t is far less offense from a co-sufferer.

When CFS is used in this context then the standard response is “I get tired too”, or “Your mind is a powerful tool”. Until I was well acquainted with the science and politics and able to hammer them with the facts then I was better off walking away. In the early days of illness my ‘fight or flight’ response was too impaired so I endured the abuse and discrimination. Interactions with others that didn’t suffer or understand was humiliating on most occasions. For six months I didn’t socialize except on-line as I learnt to defend myself and the condition.

Does the Australian government recognize CFS as a disability?

The Australian government…do(es)acknowledge the degree of incapacity that is the result of the condition yet without acknowledging the condition itself. This is most odd because the precedent has been set in New South Wales for sufferers of HIV-AIDS receive an additional component to their Disability Support Pension. We in Australia are being marginalized by the support mechanisms that are supposed to assist us. Quality of Life is not an objective of the Australian government. Sheer existence may be a consideration but only if you can ‘contribute to society’. It sure isn’t conducive to emotional health. So the answer to this question appears to be ‘No!’.

Are people who have CFS able to get government support?

Unless the sufferer has a supportive doctor the chances are close to zero. The Australian Medical Association’s collective opinion is that the condition has a psychosomatic etiology. For many including myself I had to spend some time seeking employment or obtain a medical certificate for this exemption to claim a government support benefit.

Some sufferers including myself would like to sue the (Medical) Association for there medical negligence but it’s my understanding that Australian law protects them. We are the weakest link and they attacked that link.

I may be lucky to be an Australian but I’m sure not proud of my Government’s treatment of the disabled and their record tax surpluses in recent years.

In your experience how well informed are doctors about CFS?

Possibly two percent of the medical profession have some training on ME/CFS that is not tainted by pharmaceutical companies. Most of them get the Journal of the Australian Medical Association (JAMA) so they are consistently fed misinformation. There is probably more training occurring from patients teaching their doctors or at least increasing their doctor’s interest in the issue. I’ve attempted to influence a few doctors but unless I take a full medical journal article and sit with them while they read it then there hasn’t been change…I’ve been to about twenty-five doctors to validate(my CFS)etiology. I would like to be referred to a toxicologist and a neuropsychologist but most doctors see this as an “unnecessary expense”.

What kinds of treatments are available in Australia for CFS?

Any pharmaceutical available… if you can tolerate them. And they are mostly government subsidized which is great if you suffer one of those condition that it works for. Regarding ‘alternative therapies’ you can get them in Australian but the price is far too much for those who need it them. None of those are subsidized. As the two main areas of supplementary support are phosphorylation affecting the Krebs Cycle and glycosation that increases intracellular glutathione levels.

Are alternative minded doctors readily available or do you mainly have access to more traditionalphysicians.

There are alternative doctors available but the waiting lists are anywhere from one to four months, and this applies to about two percent of medical practitioners. Some of them have trumped up malpractice charges made against them so they don’t know how long they will be able to practice medicine at all.

Do you have a sense of how active the CFS’community’ is there? Are there many support groups?

As we all suffer with the condition the most we get up to is Internet based so that is hard to measure. The other thing is that every man and his dog has a website these days so finding decent doctors websites is useless unless you know who you are searching for. The organizations and support groups have no rating system for these doctors so we are largely left to our own devices which is unproductive with cognitive and memory impairment.

Most ‘supportive’ organizations are dysfunctional to a large degree. Some organizations are quite good. One support network claim that between five to ten percent of the Australian population is affected by these types of illnesses. Within the various communities either on-line or local groups there may be ten-thousand in total. I would guess that there are about 30 to 60 support groups around Australia including on-line.

Is there much research that you are aware of occurring in Australia?

In regards to government funded research, most revenue goes to cancer therapies due to it’s specificity but with multiple organ conditions it is too diverse to bother with. Considering that alternatives therapies tend to be more effective there isn’t much interest in products that are non-toxic.

Jonathan Wilson