PHOENIX RISING

In July, however, the NIH committed a significant amount of money ($4,000,000) to examine neuro-immune interactions in CFS. They did this by announcing an RAF (request for applications). . Since RAF’s are one time allocations of funding this doesn’t mean the annual funding for CFS will be increased in the future but it does provide enough money for 6-10 studies to examine this vital area of research in CFS.

Phoenix Rising will closely examine the winners of the NIH RAF to determine how well connected their projects are to CFS. Will they, for example, include CFS patients in their studies or will these be basic research projects applicable to any number of neuro-immune diseases? Will prominent CFS researchers be involved?

There the matter rested until in mid-July David was informed that not only was Lipoceutical Glutathione effective against HHV6-A in in-vitro tests but it proved to be the most effective of the 70 compounds thus far tested. Shortly after this, David, Rich, Kristin and the Scientific Director at the HHV6- Foundation, Dr. Ablashi, participated in an hour long conference call.

Since HHV-6 infects the brain it is important that an anti-HHV-6 agent be able to cross the blood brain barrier. Dr. Ablashi’s first question, whether Lipoceutical Glutathione would be able to cross the BBB, was answered positively when a computer search revealed a cancer chemotheropathy drug with a similar delivery system, was able to do so. It was in fact delivered to the same cells HHV-6 is believed to infect in CFS and other diseases. Further questions during the conference call involved what types of liposomal glutathione were available, etc. There is obviously now great interest at the HHV-6 Foundation in liposomal glutathione as an anti-HHV-6 agent.

On July 4, 2005, sometime between 2:30 am when his mother kissed him good night, and 6:30 am when his father came downstairs, Casey Fero died in his sleep. His heart simply stopped. Casey Fero was 23.

Casey was a charming, friendly kid with blue-green eyes. He was first diagnosed with CFS at the age of 9, then again at 15. He was plagued by headaches, cognitive difficulties, muscle weakness, and exhaustion. In addition to the symptoms of a serious illness, he had to endure doctors who did not "believe" he was "really" sick, and teachers who saw in him only a shirker. By the end of his short life, however, he was happy. He had just completed two years of community college and was looking forward to beginning courses at the University of Wisconsin. He had acquired a summer job. He had many friends, who came to his home for days after he slipped away to mourn the loss together. The family and Wisconsin CFS Association will honor Casey with a blood and tissue bank for CFS/M.E. victims.

In his mother's words, "Casey had bull dog determination. In his mind he had overcome all illness and if he just worked harder he could do anything.... Interesting, how he died so well, with so much enthusiasm to live."

Casey's mother, Pat Fero, President of the Wisconsin CFS Association testified before this Committee about a year and a half ago. Pat has had CFS since before Casey was born. She and Bruce sought diagnosis and treatment for Casey, but as he passed into adulthood, he no longer had a doctor of his own. Even at the University of Wisconsin, there were no doctors who "believed in" the disease or, for that matter, really believed Casey was sick. Casey carved his own therapy out of over-the-counter and mail-order supplements such as powdered whey protein and Co-Q-10.Seeing the supplements, the coroner originally told Pat that this would be their first "steroid" death. Even in death, the first response was that it could not be CFS, because CFS is not a serious disease.

Last Thursday, September 8, Pat received the coroner's report. The University of Wisconsin forensic pathologist found that: Casey died of myocarditis that is, his heart was infected with disease. There was inflammation, and the tissue was full of viral infection. Casey also had old fibrosis, indicating that the viral infection was not of a new onset.** The pathologist was "shocked" at this finding.

Casey Fero died of Chronic Fatigue Syndrome. Why?

Specialists on NMH said they knew of no cases where someone died from that condition nor had there been reason to suspect carditis was involved in NMH.Using an ultra-sensitive type of electrocardiogram, Dr. A. Martin Lerner of Wayne State University has found evidence that EBV and cytomegaloviruses in CFS patients has caused heart damage. I do not know whether this research has been replicated, but under the circumstances, it takes on a new importance. There is evidence that HHV-6 can infect the heart. Other possible culprits include Lyme Disease, mycoplasma, and Chlamydia. In 2003, Arnold Peckerman, Benjamin Natelson and others published their research finding that most CFS patients suffer from cardiac abnormalities "Abnormal Impedance Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome," in The American Journal of the Medical Sciences 326:2 (2003): 55-60]. The cause was left to further studies, but Dr. Paul Cheney has suggested viral infection. Clearly this research could lead to an answer to Casey's death, but it has no federal funding.

The harsh reality is that research on CFS, viruses, and cardiac abnormalities is under-funded, ignored, and at times outright dismissed by those charged with informing the public of the dangers of diseases. However, if you turn to the Myalgic Encephalomyelitis (M.E.) literature in Great Britain, there is evidence of deaths in both adults and teenagers from sudden heart stoppage. Ramsay wrote about such cases, and in correspondence with Dr. Malcolm Hooper I was informed that he, too, was aware of premature deaths from heart failure. Dr. Hooper has long been studying the hypothesis that M.E. is caused by an enterovirus (such as polio and coxsackie). There is no comparable research on enteroviruses in the United States (unless you count the sparse literature on post-polio syndrome).

Is this the price we have paid because in 1988 we rejected, instead of embracing, the robust research programs and existing literature in the M.E. community? Had we built on these studies, instead of squandering our time on measures of "fatigue" and a plethora of studies of CFS as a "somaticizing" disorder, where might we be today? For the past twenty years, had we been looking at this as a disease rather than a psychological disorder, would we now know enough to have prevented Casey's death?

And if we hadn't hidden what we already know from the public, would Casey have had a doctor of his own, perhaps even one that would have looked into the condition of his heart? Pat Fero came down with CFS before her son Casey was born. His entire life was lived under the shadow of this disease a shadow of widespread ignorance. Why? The pathologist was shocked to find heart damage. Why?

What is the virus that the pathologists found? HHV-6? Mycoplasma? Anenterovirus? Cytomegalovirus? EBV? Something completely new? Why is there no money for researchers studying these very questions? We need the public to be told NOW that there is a serious disease out there, and that nearly a million people in the United States have it. They need to be told of the uncertainty about cause, prognosis, and cure. They need to be told what they should be tested for to rule out other diseases.

And they need to know that patients die. Two months after Casey's tragic, untimely death, most primary care physicians know little more about the disease than they did on the day Casey was born. That is criminal. One year after this committee sent a list of suggestions (as is its task), to the Secretary of the DHHS, there has been no [effective] response. That is also criminal.

What does it take to impart a sense of urgency to this task? Does it take the tragedy of a young man's senseless death?

Hold Casey's memory high, like a banner. Take him to Congress, to the press, to the appropriate medical specialties. Let this be a turning point. Casey Fero died too young. Do not let his death be in vain.

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 - no important papers on CFS pathophysiology but several on other aspects of CFS

F – no important papers on CFS

N. Kaushik, D. Fear, S. Richards, C. McDermott, E. Nuwaysir, P. Kellam, T. Harrison, R. Wilkinson, D. Tyrell, S. Holgate and J. Kerr. J.  Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome.. Clin. Pathol. 58, 826-832.

Dr. Kerr has focused his attentions on immune system alterations in CFS. To this end he pioneered work that illustrated that not only do a subset of people with parvovirus B19 infection come down with CFS but that long standing cytokine dysregulations appear to contribute to their illness. Now he has turned his attention to gene expression in CFS.

This study of 9522 genes in 25 CFS patients and 25 controls found that CFS patients would be differentiated through the expression of 16 genes involved in a wide variety of processes.

The most important thing about this study, though, is not what’s in it but what it’s given birth to. The results were sufficiently encouraging for the Kerr team to embark on a larger, much more comprehensive study.

It has not been clear and indeed is still not clear how suitable PBMC’s are for gene microarray analysis. PBMC’s are not a preferred target in microarray studies. Most researchers concentrate on changes in gene expression in the lesion or wound associated with their study subject. Cancer researchers, for instance, study gene expression changes in tumors.

Like most other researchers examining gene expression in CFS the Kerr team focused on genes expressed in peripheral blood mononuclear cells (PBMC’s – lymphocytes, monocytes). We still don’t know how effective these PBMC’s are at guiding us to the source or sources of CFS. CFS researchers choose these cells with the hope that because they interact with virtually all systems of the body that changes in their gene expression will reflect changes found elsewhere. PBMC studies, then, are temporary expedients that will presumably be discarded when the actual injury in CFS is found.

Thus far, while there has been some general consistency (T-cell activation) in the findings of the various studies completed thus far, there has been more variance. The Kaushik study appeared to highlight differences in gene expression in genes associated with T-cell activation, mitochondrial activity and neuronal functions, the 2005 Whistler Study highlighted genes involved in ion channel transport and the 2005 Gow study illuminated genes involved in antigen presentation by MHC cells and inflammation.

Part of this variability may simply be due to the different sets of genes the groups have looked at; the Kaushik study examined 9522 genes, the Whistler study 3800 and the Gow study 33,000. Sample sizes were different as well, the Kauschik and Whistler studies contained 25 and 23 CFS patients respectively while the Gow contained only 8.

Researchers naturally hoped they would find a tightly knit group of genes signaling a central disruption in CFS. Instead they have mostly found a wide array of genes relating to disparate processes. In the Kaushik study, for instance, the highlighted genes were involved in neuronal, immune, brain or ubiquitous processes and were involved in processes scattered around the cell in the cytoplasm, mitochondrial, nucleus or the membranes. Attempting to divine a coherent picture of these widely varying genes may be difficult; the Kerr group stated the ‘involvement of genes from several disparate pathways suggests a complex pathogenesis’. Nothing is simple in CFS!

Although different studies have often found different trends there have been some general consistencies. Most studies, for instance, have found abnormal gene expression in genes involved in T-cell activation. It is encouraging, as well, that researchers have been able to establish linkages between abnormal gene expression and problems found in CFS. That is, while the patterns of abnormal gene expression found so far are complex they at least make sense given what we know about CFS. The NTE gene, for instance, found upregulated in the Kerr study is targeted by organophosphates and may relate to neuronal problems (and MCS?) in CFS. Several genes involved in mitochondrial activity could help explain the fatigue in CFS and one gene, EIF4F, which is responsible for the production of mitochondrial proteins and is often hijacked by viruses, could provide a bridge between immune dysfunction and poor energy production in CFS. Similarly the genes involved in immune activation could help explain signs of immune dysfunction in CFS.

It is encouraging as well that Kerr appears to be quite confident about his findings. The New Scientist reports he said his teams findings indicate that ‘a significant part of the pathogenesis resides in the white blood cells’ and that this new data ‘will open the door to the development of pharmacological interventions’. No cautious statements here, no proviso’s about a preliminary report, no cautious backpedaling, but instead a rather emphatic statement that a good part of CFS is due to disruptions in white blood cell activity and a promise, really, that this research will at least ‘open the door’ and give researchers a shot at developing suitable drugs for this disease. Let’s hope he’s right.

One reason Kerr may be feel so confident about his results is that early reports from his new study indicate the results are consistent, so far, with the old study. Importantly, the New Scientist also reports the Kerr team is finding protein analogues to the gene expression data. This finding indicates the up regulated mRNA expression is showing up in the protein production. This validates the gene expression findings and may provide possible biomarkers for CFS.

Kerr may also feel confident about his results because of the unusual rigor of the study. The microarray results were double-checked using real time PCR to ensure the mRNA they thought they were seeing was actually there.

In summary, there is much in the study for the CFS patient to feel good about. The next step, however, is the biggest. If the Kerr team can validate (and expand) their findings in their much larger study (47,000 gene products and 100 patients and controls we will have new opportunities for research, hopefully a much clear picture of where the dysfunction in CFS lies, and may be on the road to a biomarker for this disease.

The Kerr Studies - 'I am involved in studies of the pathogenesis of parvovirus B19, persistent virus infections and particularly CFS. I enclose an abstract which is now in press with Journal of Clinical Pathology. This provides very good evidence for gene differences in CFS patients and was presented at the recent meeting of the Society for General Microbiology in Edinburgh (Apr 4-7, 2005)http://www.sgm.ac.uk/meetings/past.cfm.  (Upon examining the expression of @ 9,500 genes in CFS patients and controls using gene microarray's, the Kerr group found 16 genes involved mostly in T-cell activation and neuronal and mitochondrial functioning,were differentially expressed in CFS) We are undertaking a programme of research into the molecular pathogenesis of CFS following this pilot study. First  a repeat of the microarray study, and then testing of CFS, normals, and several disease control groups to arrive at those gene differences which are only or mainly associated with CFS. We are also looking for biomarkers in the serum of patients. We envisage these studies leading to development of a diagnostic test and specific treatments which will target the specific molecular pathways involved in CFS.' 

From the CFS Research Foundation Newsletter (To subscribe to an online version of the CFS Research Foundation's Newsletter click here) - As Dr. Kerr alluded to above the next stage of the project is multi-factorial. First mRNA from the entire genome will examined in 50 CFS and 50 healthy controls. For the first time that I am aware of Dr. Kerr's research group will then compare the genes of CFS patients with a wide variety of control groups including people with depression, rheumatorid arthritis, osteoarthritis, MS and prolonged fatigue and healthy individuals with some fatigue on the day of testing. The researchers hope to identify both patterns of gene expression that CFS patients share with these other groups and those unique to them. It is important when searching for a biomarker to test a variety of control groups with similar disease processes in order to determine what you have found is unique to your particular disease. The group will then attempt to 'develop diagnostic tests and identify therapeutic targets'. (Exciting stuff!). In order to determine if there is any geographic variation in the gene expression the samples will be taken from six different parts of the country. 

The Kerr group will also examine how the genes change in people with CFS whose onset was synonymous with parvovirus B19, Q-fever and enterovirus infection. The researchers will attempt in a smaller group to correlate differences in symptom expression in CFS patients with changes in gene expression. Finally, changes in gene expression in 10 patients will be examined over time to determine how symptom expression correlates with gene expression.

As can be seen Dr. Kerr and his group have taken a creative and dynamic approach towards their genetic research in CFS. Projects of this scope are expensive, the cost of this research runs to over 1,000,000 pounds. The Kerr gene project has been ongoing for two years and funds are available for another year but about 650,000 pounds still needs to be raised. To find out how you can support Dr. Kerr's vital research click here. 

The Vernon Studies - The CDC is doing some marvelous work on CFS right now. The Vernon group at the CDC has complete gene and protein (!) expression data as well as neuroendocrine and immune data from the saliva, blood and urine from 170 participants of the Wichita study. Their challenge, now, as they put it is ‘how to integrate the large volume of data into an accurate model of CFS pathogenesis’. This is exciting stuff. The Vernon group has set itself a high goal indeed. Indeed, coming up with an ‘accurate model of CFS pathogenesis’ is heady talk for such a conservative and cautious organization. It was not so long ago that the CDC was being called on the matt by the GAO over their fraudulent usage of CFS research funds. The CDC states that analyses of at least some of this data will be published in 2005. (They have 2 months!) We should have another very important paper to forward to in the near future.

The Dubbo Group - The CDC sponsored Dubbo group in Australia is also tracking both gene and protein expression in a cohort of Ross River Virus, Q-fever and EBV virus patients who fail to recover and come down with CFS. The CDC report that the chief researcher of this study, Lloyd, spent the summer of 2004 preparing his results for publication indicates they should be published soon. (In fact they should have been published by now. Lets see, Lloyd finishes his papers and submits them for publication in Sept. of last year and its now, what, 14 months later? Where are they????)

Dr. Gow - in the U. K. has also embarked on a larger follow up to his study but money problems have been noted and it is unclear how large his study is.

Dr. Natelson in the U.S. is trying to get money together examine gene expression in spinal fluid samples he has.

This was not a fun article to read. It is not uncommon for studies to have different findings, and one sometimes sees opposing papers question each others interpretations, but it is pretty rare to find a paper specifically state other researchers made such a fundamental mistake that their findings were erroneous. That is what happened here. Unfortunately it happened to two well-known CFS researchers, Doctors Neil McGregor and Hugh Dunstan, both hailing from Australia.

Two papers by McGregor et. al. in 1996* claimed to have found extensive urinary acid abnormalities in the urine of CFS patients. Of these three metabolites stood out because of their correlation to symptom severity but because their makeup of two of them at the time was unable to be determined they were labeled CFSUMI and CFSUM2. The authors thought CFSUMI, in particular, was ‘a very important metabolite in CFS’ and that it warranted ‘further biochemical investigation and determination of its origin".

This was exciting stuff, I remember Dr. Cheney stating he thought these papers were of real significance. Although Dunstan and McGregor continued to publish papers on urinary acid metabolism until 2001 the expected follow up studies never arrived and the mysterious substances were never identified. Nothing more was heard regarding this topic until now, nine years later, when these London researchers reported CFSUMI and CFSUM2 were nothing but ‘artefacts of the sample preparation procedure’ (ouch!).

But is this situation is entirely resolved? If the substances were simply artifacts of the sample preparation process why did they show up in much, much (much) (p<.00003) greater amounts in the CFS patients sample and not the controls? (P<.00003 is an almost unheard of probability. It states there was a 1 in 33,000 chance the results were due to a random occurrence). And if CFSUMI was nothing but an artifact why was it related to CFS symptom severity? On the other hand, if it was such a significant metabolite, why was it never characterized?

This second paper by the same group presents their evaluations of urinary and plasma organic and amino acids in CFS and extends their critique of the methods McGregor et. al. used to measure urinary amino acids. It appears to be the most extensive exploration of metabolic products in CFS yet done. Control groups included healthy controls, depressed patients and rheumatoid arthritis (RA) patients.

McGregor et. al reported extensive amino acid abnormalities were found in CFS. Of the 16 amino acids measured in their study 8 were significantly different in CFS patients. None of these amino acid abnormalities reported were found in the Jones study. CFSUM2 was suggested by McGregor to be partially derivatised serine. McGregor et. al. also stated reduced urinary serine levels were associated with CFS. Neither plasma nor urinary serine levels were significantly lower in CFS patients in Jones study.

The Jones study found the levels of several urinary amino acids (B-alanine, hydroxyproline, histidine, methionine, cysteine, phenyalanine) were significantly lower in CFS patients compared to healthy controls. McGregor et. al. indicated B-alanine was significantly higher. Hydroxyproline was the most significantly reduced (p<.0001) amino acid. Interestingly given Dr. Cheney’s comments on organic acid abnormalities in CFS, the CFS patients in this study did not display a distinctive organic acid signature.

Low histidine levels in both CFS and RA suggested an active inflammatory state exists in CFS. Reduced hydroxyproline levels in both CFS (and FMS) suggests, intriguingly, increased risk of micromuscular injury due to reduced intramuscular collagen. The authors suggest these two abnormalities may provide a basis for the fatigue and muscle pain found in both CFS and FMS.

Jones et. al. reported that McGregor and Dunstan formed a company called Bioscreen in Melbourne, Australia (www.bioscreenmedical.com.au) that uses their methodology to uncover amino acid abnormalities and gastrointestinal flora in CFS, FMS, MCS, IBS, autism and many other diseases. Their website states they test 1000’s of patients a year. They also co-authored Chapters 7 and 9 in Chronic Fatigue Syndrome, A Biological Approach edited by De Meirleir and Englebienne.

Is the CFSUMI/ CFSUM2 story over? McGregor et al’s scientific credibility (not to mention their financial liability?) demands a substantive answer be given to the charges posed.

This is a remarkable paper by a group of researchers very much committed to the use of cognitive behavior therapy (CBT) in CFS. CBT has been used successfully and without controversy in many chronic disorders including HIV, heart disease, kidney disease, etc. The situation is different in CFS, a disease with no clear biological origin and increased rates of mood disorder. Some advocates of a psychological orientation towards believe CFS patients are nothing more than a subset of the population that is unable to cope effectively with disease. Some have suggested CFS patients are of a personality type that is unable to accept failure and that CFS represents a retreat from the competitive pressures of modern day life. They point out that psychiatric disorders are associated with poor outcomes in CFS. (They don’t note the obverse – that really ill CFS patients probably tend to have more mood disorders simply from the stress of coping with this disease). Others believe CFS patients are simply confused; they have become so focused on their symptoms that they employ a extreme practice of movement avoidance

Whatever their orientation towards CFS, many strong advocates of CBT assert CFS is worsened by poor coping skills. How can one argue with this? Who is trained to deal with a disease of this magnitude? Is anyone in any way prepared for the loss this disease entails? For the sometimes complete overturning of ones aspirations? Loss of financial security? The diminishment of ones social circle? Since they believe CFS is at least in part a psychological disorder it only stands to reason that patients with actual mood disorders (i.e. those most severely disturbed) would be more resistant to CBT. The flip side of this is that patients without mood disorders should have better results from CBT than those with them. If CBT really gets at the core of CFS and CFS is defined as disease of poor coping then those able to cope the least; i.e. those with mood disorders, should be helped the least by CBT.

That didn’t happen in this study. Patients with mood disorders were no more likely not to benefit from CBT than those with mood disorders. If this doesn’t invalidate a basic premise of CBT it at least invalidates the perceived wisdom concerning CFS and CBT. It suggests the success or failure of CBT is a function of other than ones psychological state. It opens up the interpretation that CFS is a very difficult disease to cope with, and that like other patients with difficult diseases the right kind of professional coping services may assist patients in coping with their disease. That is not unusual nor is unforeseen. This study puts CFS squarely back into the biological disorder camp.

This is the second recent paper that invalidates a psychological orientation in CFS. The first was a delicious study that indicated CFS patients had, contrary to the authors expectations, a lower than normal response to placebo. The authors didn’t seem to know what to make of that finding.

It’s encouraging to see CFS research spread to countries outside of the US, Europe and Australia. This was not a small study; it involved determining the type of fatigue found in all patients (n=1648) who visited eight primary care clinics over a 10 day period. CFS patients very rightly complain how they are stigmatized by the word fatigue but this study indicates how increasingly well defined fatigue is at least in the research community. Six different kinds of fatigue were delineated in this study: no fatigue, prolonged fatigued, physically caused fatigue, psychologically caused fatigue, idiopathic (unexplained) fatigue and CFS.

While chronic fatigue was common in this patient population (8%) CFS was not (0.6%). This indicates that even though none of the defining symptoms of the disease are unusual, and the definition is open enough to allow for many different symptom sets, the collection of symptoms found in CFS is still highly unusual and quite recognizable.

After rereading Orthostatic Intolerance Part II: Types and finding rather large parts of it almost incomprehensible, portion of this paper were rewritten. If you couldn’t make it through it (I almost couldn’t) you might want to try again.