All posts by Cort Johnson

Simmaron Research Foundation Study Targeting Roots of Immune System Breakdown in Chronic Fatigue Syndrome (ME/CFS)

June 13, 2014

Simmaron Research’s  new immune study builds on exciting research that is changing how we think about ME/CFS.

Twenty years ago  the internationally known virus hunter, Dr. Ian Lipkin of Columbia University, didn’t find Borna Virus in people with ME/CFS, but he never forgot the immune dysfunction he found.  Twenty years later he found more immune dysfunction in another study.

Isabel Barao, PhD, Simmaron Research Scientific Director

Isabel Barao, PhD, the Simmaron Research Foundations Scientific Director believes a genetic predisposition to immune problems could underlie ME/CFS

He doesn’t know why it’s there but he does believe that all ME/CFS cases – no matter what pathogen or other factor has triggered them –  devolve to a ‘common pathway’. The fact that pathogens of all types – from Epstein-Barr Virus, to SARS, to Giardia – can trigger ME/CFS suggests a core immune deficiency lies at the heart of the illness.

Every genetic study suggests an inherited susceptibility to Chronic Fatigue Syndrome is present. Dr. Mady Hornig of the Center for Infection and Immunity at Columbia University believes that a genetic predisposition in combination with an environmental trigger (such as an infection) occurring at just the right (wrong) time is probably key to coming down with ME/CFS.

For thirty or forty years you might be able to easily slough off this bug or that pathogen, but at some point for some reason the stars aligned; you were depleted in just the right way, the pathogen hit and with your immune system genetically predisposed to crack under the pressure – it did – and your entire system faltered.

gene strand

Simmaron is looking for the genetic roots of an immune system breakdown

Simmaron Research’s next pilot study is looking for that immune crack in the dike – the genetic underpinnings of the system collapse that occurred. Led by Simmaron’s Scientific Director, Isabel Barao, PhD, in collaboration with researchers at the National Cancer Institute and University of Nevada Reno, it will determine if your NK and B-cells and macrophages are genetically predisposed to respond poorly to a virus, toxin, or cancer cell.

Dr. Barao is studying whether people with ME/CFS have polymorphisms – unusual gene formations – that make their key immune cells less likely to respond well to viruses and other threats. That immune ‘hole’ many people have talked about with regards to ME/CFS could start here. We all know about the rampant NK cell problems in ME/CFS, but this study could help explain the B-cell problems recently uncovered in a German research study – and perhaps even shed light on why Rituximab may be working in some patients.

It’s the initial part of a projected three-part study that could end with drugs for ME/CFS. Once genetic alterations have been found, they’ll be correlated with immune findings. If that holds up, it’ll  be time to look for drugs to fix the problem, two of which are currently in clinical trials.

We-Have-Ideas

Support the Simmaron Research Foundation as it redefines how ME/CFS is understood and treated

Think about it. The high heritability rates in ME/CFS indicate genetic problems exist somewhere. Where better to look than the immune system?

This study is a no-brainer to me. It’s relatively cheap – it has a quick six-month turnaround – and the data it produces will lay the foundation for an NIH grant on topics they’ve  shown they’re willing to fund.

Help us redefine ME/CFS.  Support breakthrough science on immune deficiencies at Simmaron.

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS

Brief Report From Dr. Prigden on the Fibromyalgia Antiviral Trial – and the Future Chronic Fatigue Syndrome One

It’s not too much to say that if successful, the Pridgen antiviral trials for Fibromyalgia would be a paradigm changer – turning FM from a poorly treated central nervous system disorder to a  disorder characterized by a (hopefully) treatable herpesvirus infection.

Is it a breakthrough? The results look good so far - stay tuned!

Is it a breakthrough? The results look good so far – stay tuned!

Pridgen’s approach is new in several ways. Not only has no one targeted herpesviruses in FM before, but the  herpesvirus Pridgen is targeting, herpes simplex virus, is one no one has connected with either FM or ME/CFS before.

Pridgen has also combined an antiviral with an anti-inflammatory (with antiviral properties).  Rumors have abounded regarding the identity or identities of the drugs, but we won’t know officially which they are until the report is made.

The fact that we haven’t had a press release by now regarding the Phase II trial has lead to some concern. (Phase two trials are typically larger trials (1-several hundred people) that further assess a treatment’s efficacy and safety. Pridgen’s Phase II trial was a large multi-center trial.)

I contacted Dr. Pridgen to see what he could say at this point. This is what he said.

  • They hope to present their research mid-Nov
  • A press release will predate that
  • The treatment was statistically significantly effective in improving nearly every primary and secondary endpoint
  • The treatment was significantly superior to placebo (p<.oo1) (not sure which  endpoints)
  • The treatment was better tolerated than placebo
  • The results in the FM trial are good enough that preliminary plans are being made for toxicology studies that will allow them to move forward on a similar Proof of Concept Phase 2 CFS (ME/CFS) trial; i.e. they’re beginning to work on a similar ME/CFS trial.
  • They will be looking for government/humanitarian funding for that.

The Earlier Video

Check out a confident Dr. Pridgen as he talks about the Fibromyalgia trial sometime around April at a local news station.

 

Conclusion

It’s going to take longer for the final results than many had hoped but the news otherwise is good.  The significant improvement in almost all the endpoints is promising (and I would say somewhat unusual).  The fact that they’re beginning preliminary planning for an ME/CFS trial suggests that the FM trial went well indeed.

Still, we won’t know how significant the significant improvements are until the press and study release probably in November.

That will be frustrating to those who want to get going on treatments now, but my understanding is that this period – prior to publication – is a delicate period in the development of any drug. If that’s true think how much more so it is for a startup company that’s going to need to raise significant funds for the  big Phase III trial.  Publicly releasing the full results and the drug combo they’ve identified this far in advance of publication would be a mistake.

For more on Pridgen’s antiviral trial check out

Could the Epstein-Barr Virus – Autoimmunity Hypothesis Help Explain Chronic Fatigue Syndrome?

( Find a ‘quick’ summary at the  bottom of the blog)

 

The Epstein-Barr Virus Question in ME/CFS

We recently saw evidence suggesting that  increased viral loads of EBV (in whole blood) may be common in Chronic Fatigue Syndrome.We also saw that  ME/CFS patients  antibody responses to some proteins produced by EBV may be are impaired as well.

Those findings made sense given anecdotal evidence from doctors and study evidence from Dr. Lerner and Dr. Montoya indicating that  antivirals can be very helpful in some patients. Dr. Montoya’s recent review of anti-herpesvirus antivirals  indicated he believes they play a role but these results conflict with the Lipkin/Chronic Fatigue Initiative study which found almost no active herpesvirus infections in either Dr. Montoya’s or in the CFI’s study groups.

smoldering fire

Some researchers think the tests used by Dr. Lipkin are not sensitive enough to pick up the kind of ‘smoldering’ infection they believe is found in ME/CFS

How to reconcile these findings ? Kristin Loomis of the HHV-6 Foundation and Dr. Chia have stated that while the method Dr. Lipkin used to detect herpesviruses (in plasma) works very well in people with highly active herpesvirus infections, they do not believe it would pick up the type of smoldering, lower-level infection suspected in ME/CFS.

The existence of that ‘smoldering infection’ is, of course, controversial. It’s possible, even probable,  that most researchers outside this field including Dr. Lipkin do not believe that such a small infection could have such serious consequences.

Indeed, the ‘increased viral loads’ in the German study did not indicate a highly active infection was present, but they were still significantly higher in the ME/CFS patients than in the controls. Dr. Lerner, Kristin Loomis and others believes that’s significant and that’s the result they believe Dr. Lipkin would have received if he had used a different technique.

After XMRV it’s no surprise to see controversy in the pathogen field. The bottom line is that EBV is still a possible culprit in ME/CFS. Given that and the Rituximab findings suggesting that an autoimmune component may be present in ME/CFS, let’s look at a fascinating hypothesis that ties EBV infections and autoimmunity together and could have implications for ME/CFS.

Epstein-Barr Virus and Autoimmunity

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis. Pender MP. Autoimmune Dis. 2012;2012:189096. doi: 10.1155/2012/189096. Epub 2012 Jan 24.

If this hypothesis is right, Epstein Barr Virus – still the virus most closely associated with ME/CFS – has a very, very close connection to autoimmune disorders.

EBV

Pender believes an EBV infection of B-cells sets the stage for autoimmunity in people with impaired T-cell responses

About a decade ago Michael Prender proposed being exposed to EBV is a prerequisite for having autoimmune disorder. In doing so he tossed aside the usual EBV mimicry hypothesis; that proteins found in EBV confused the immune system into attacking the body and put forth a much encompassing idea. He proposed that EBV’s residence in B-cells – which are ground zero for an autoimmune response – was responsible for most types of autoimmunity. His hypothesis, a decade later, remains alive  and well.

B-cells produce antibodies and autoantibodies. As we learned in the Rose autoimmune talk, the production of autoantibodies primed to attack the body is a natural outcome of an immune system that must defend the body against microbes containing proteins that are very similar to those found in humans. The immune system has ways to deal with these autoantibodies and in most cases it succeeds. When it doesn’t you have an autoimmune problem.

An Admiring Look at a Virus

In some ways you’ve really got to give it up to Epstein-Barr Virus (EBV). EBV  just happens to be the only virus known to survive in B-cells. In fact, EBV doesn’t just survive in B-cells they are its home. Somehow B-cells have managed to thrive survive in the  very cells that are designed to attack them.  That takes a special kind of viral hutzpah..

Every time EBV infects a B-cell it tells it to reproduce and when the cells does, EBV inserts itself into the B-cell’s ‘germinal center’ where it will reside, largely untouched, for the rest of the B-cells life. Every time the B-cell replicates EBV hijacks its reproductive machinery to produce more EBV virions.

EBV

EBV – A remarkable virus

Because B-cells aren’t long-lived and because EBV can’t replicate in them when they’re pumping out antibodies, EBV has found ways to keep B-cells alive and in a state of latency for longer and longer periods of time.

EBV has found ways in induce B-cells to undergo what’s called ‘clonal’ expansion in which B-cells produces EBV infected clones of themselves. One way EBV does this is by tricking the immune system to believe an pathogen is present, thereby causing it to ramp up B-cell production.

Keeping the immune system on high alert, though, can cause problems. Think of our missile defense system. If it’s on high alert the risk of a catastrophic mistake  increases greatly, and here is where Pender and his hypothesis comes in.

Cytotoxic T-cells and A Numbers Game

“CD8+ T-cell deficiency would appear to be a general feature of human chronic autoimmune diseases. ” Pender et.al.

EBV infections in the body are usually tightly controlled by killer or cytotoxic T-cells (CD8+ T-cells). These CD8+ T-cells kill EBV infected B-cells when they proliferate.

cytotoxic t-cell

Pender believes reduced cytotoxic T-cell functioning plays a key role in EBV triggered autoimmunity. Some evidence suggest cytotoxic T-cell functioning is reduced in ME/CFS.

Pender and other researchers believe an inherited defect in cytotoxic T-cells that prevents them from controlling EBV may be behind a lot of autoimmunity. (A Simmaron Research Foundation project involves looking for inherited problems in T-cells, B-cells and NK cells killing capacity.) It turns out that a long list of autoimmune disorders are, in fact, characterized by low cytotoxic T-cell levels.

In what is essentially a numbers game, Pender believes that poorly functioning cytotoxic T-cells allow more EBV infected B-cells to proliferate. Because EBV induces these B-cells to proliferate at a higher than normal rate the outcome of a less controlled EBV infection is simply more and more B-cells. That means more autoantibodies (remember they’re a natural feature) for the immune  system to filter out, and more possibility of a catastrophic mistake being made; i.e. a full-blown autoimmune or autoinflammatory disorder.

Cytotoxic T-cells and Chronic Fatigue Syndrome

CD8+ T-cells have not received a lot of attention in ME/CFS, but early evidence suggests they’re not working too well. A recent German study found a reduced frequencies of an EBV specific T-cells  in people with Chronic Fatigue Syndrome and an Australian  group found reduced cytotoxic T-cell (and NK cell) killing capacity in ME/CFS.

In fact, given the similarity in the killing systems in cytotoxic T-cells and NK cells, it wouldn’t be surprising to find the same dysfunction in both NK cells and CD8+ T-cells.  (If your NK cells aren’t doing so hot, it’s possible your cytotoxic T-cells aren’t doing so well either.)

If that’s true, your cytotoxic T-cells may not be taking out as many EBV infected B-cells as normal. That fits Pender’s hypothesis to a T.

Another Numbers Game

Timing could be everything in EBV, ME/CFS and autoimmunity.   An EBV infection in young children usually doesn’t cause symptoms. It turns out that infants have very high levels of cytotoxic T-cells that allow them to stop the virus in its tracks.

By age sixteen, however, those cytotoxic T-cell levels are a third of what they were at age two. That means that an infection which most infants wouldn’t even notice often causes infectious mononucleosis (glandular fever) and a greatly increased risk for ME/CFS and multiple sclerosis in adolescents.

from youth to old age

Being exposed to EBV later in life greatly increases the difficulty the body has in fighting it off. How many people with ME/CFS were first exposed to EBV later in life?

It appears that the Western fanaticism with cleanliness is pushing the date most children are exposed to EBV further and further forward. In the developing world most children are exposed to EBV by age three, and almost 100% are exposed by age ten, but some studies suggest about half the children in the developed world  have not been exposed to EBV by the time they’re ten.

As many as 50% of these children may come down with a symptomatic, infectious mononucleosis-like illness and during that illness as many as half of B-cells in their blood may become infected with EBV  –  producing a huge reservoir of highly active EBV infected B-cells.

The Jason Northwestern ME/CFS study estimates as many as 10% of college students will come down with infectious mononucleosis. The increased IgM antibody rates in the ME/CFS patients in the German study suggested they may have been suffering from a primary (first-time) infection as well.

Data is lacking on date of first time EBV infection in ME/CFS, but the German study with its high IgM levels  suggests a substantial number of ME/CFS patients may have encountered EBV later in life when their immune systems are less prepared to deal with it. Could ME/CFS in some people simply be the consequence of encountering EBV later in life?

Pender ties in other autoimmune factors, many of which are found in Chronic Fatigue Syndrome as well.

Heritability

Autoimmune disorders are have a higher degree of heritability than most disorders – an intriguing factor given that cytotoxic T-cell functioning is largely governed by heredity.  The heritability factor in ME/CFS and Fibromyalgia has not been the subject of many studies, but one study suggests that heritability may be even higher in these disorders than in autoimmune disorders.

Location and the Vitamin D3 Connection

Living further from the equator also increases the risk of autoimmune disorders such as multiple sclerosis and rheumatoid arthritis. Reduced sunlight and vitamin D3 could aggravate  cytotoxic T-cell problems thus imperiling control of EBV. It turns out that cytotoxic T cells contain more vitamin D3 receptors than any other immune cell.

Dr. Bateman was astonished at how low the Vitamin D3 levels were in her ME/CFS and FM patients but people with ME/CFS and FM probably get less exposure to sunlight than do healthy people. People who are bedridden, of course, get very little exposure to sunlight.

Gender

Cytotoxic T-cells are believed to be hormonally regulated (with increasing estrogen reducing Tc levels) and women tend to have fewer cytotoxic T-cells than men. The gender imbalance found in FM and ME/CFS as another.

Reduced cytotoxic T-cell functioning, high heritability, reduced vitamin D3 levels, and female predominance all appear to be present in ME/CFS and all fit Pender’s paradigm for an EBV induced autoimmune disorder.

Treatment

Rituximab

Rituximab is high on Pender’s list of treatment options for people with EBV induced autoimmunity

Pender’s treatment recommendations for EBV triggered autoimmune disorders are enticing given what we know about Chronic Fatigue Syndrome. They start with none other than Rituximab.

“Improvement of an autoimmune disease with rituximab therapy would be consistent with an essential role of EBV in the development of the disease”

Pender asserts an EBV triggered autoimmune disorder could be treated in two ways.

(1) Depleting B-cells with monoclonal antibodies such as Rituximab would reduce total B-cell levels which would reduce the levels of EBV infected B-cells and autoantibody production. ( Since Rituximab would also reduce the levels of non-EBV autoreactive B-cells a successful course of Rituximab does not constitute proof.)

(2) Boosting immunity to EBV – Getting EBV under control is another option.

  •  the gp350 vaccine – vaccinating young adults with recombinant gp350 has been shown to stop the development of infectious mononucleosis after EBV infection. If Pender is right, gp350 vaccination could be one way of cutting down ME/CFS rates in adolescents. This would simply require determining which adolescents have not been exposed to EBV and vaccinating them. Given that Jason expects perhaps as many as 10 percent of college freshman to come down with some form of infectious mononucleosis this would seem to be a really good idea.
  • using monoclonal antibodies against gp350.
  • Intravenous infusion of autologous EBV-specific cytotoxic CD8+ T cells after expansion in vitro
  • interleukin-7, which expands the population of functional virus-specific CD8+ T cells in chronic viral infection

Summary

  • Michael Pender, has proposedthat exposure  to Epstein-Barr virus, a virus that takes up residence in the B-cells, is required for autoimmunity.
  • All B-cells produce autoantibodies that would, if the immune system didn’t filter them out, attack the body.
  • EBV prompts B-cells to produce EBV infected B-cells which live longer and produce more B-cells than usual. Their longer lifespan and higher productivity means EBV infected B-cells also produce more autoantibodies than normal B-cells.
  • Pender believes high numbers of autoantibodies produced  by these B-cells overwhelm the immune system causing an autoimmune disorder.
  • The key problem in autoimmunity Pender believes, then, is large numbers of EBV-infected B-cells.
  • Since cytotoxic T-cells kill EBV-infected B-cells, a poor cytotoxic T-cell response may be the key, and indeed reduced cytotoxic T-cell responses appear to be common  in autoimmune disorders.   (Two studies suggest reduced cytotoxic T-cell responses are present in ME/CFS  as well.)
  • Because cytotoxic T-cell responses decline over time, someone exposed to EBV as an adolescent typically has a much more difficult time fighting off EBV than a young child does. (Could late exposure to EBV be a common feature in Chronic Fatigue Syndrome?)
  • ME/CFS shares  factors like low Vit D3 levels,  a high degree of heritability and gender predominance with autoimmune disorders.  All these plus the increased EBV viral loads, the reduced antibody response to the latent stage of EBV and the possibly reduced cytotoxic T-cell functioning suggests ME/CFS could very well fit Pender’s hypothesis of an EBV triggered disorder.

Conclusions

The role Epstein Barr virus or autoimmunity plays in Chronic Fatigue Syndrome is unclear, but Pender’s hypothesis suggesting that poorly controlled EBV infections cause many autoimmune disorders is intriguing given recent study evidence of increased EBV viral loads in ME/CFS.  Time will tell but the  reduced cytotoxic T-cell functioning, gender imbalance, the low Vit. D3 levels, the high heritability factors, and the positive response to Rituximab reported all suggest Pender’s EBV/autoimmune hypothesis is something we should keep an eye on.

Report From San Francisco I: The “Father of Autoimmunity” Speaks

March 31, 2014

When the "Father of Autoimmunity' went to medical school 'autoimmunity' was not believed to exist

When the “Father of Autoimmunity’ went to medical school ‘autoimmunity’ was not believed to exist

Dr. Noel Rose M.D., PhD is  the Director of the Center for Autoimmune Disorders at Johns Hopkins University. Dr. Rose has been studying autoimmunity for over sixty years  but he was a pretty darn spry 80-something at the conference.

When I got close enough to  ask him a  quick question I would have sworn he was a well-preserved sixty something. The bow tie,though, still apparently in  fashion in some medical circles, gave it away as did his statement that the medical schools of his day scoffed, yes, scoffed at the idea that the body could attack itself.

In fact, in 1956 Dr. Rose was the first researcher to introduce autoimmunity as a cause of disease. In an interview he stated

“They were skeptical. People weren’t really prepared to believe it because it seemed so bizarre that you would develop an immune response to your own body. We had all been taught in medical school that the immune response is only directed to what’s foreign. But now we know that isn’t true.”

He’s one of the few people who could can say they wrote the book on it because he did. He wrote the first book on autoimmunity and it’s still being revised today. (Get the latest 1300 page edition for a cool $215)

Dr. Rose probably didn’t appear to know a lot about Chronic Fatigue Syndrome, but he does know  a lot about autoimmunity and with the Rituximab trials putting that subject on everyone’s mind it was good to get a primer on it.

Dr. Rose started off explaining the basics of the autoimmune response by stating that it’s a completely  natural response. We’re all doing autoimmune responses all  the time.  The reason for that is that ‘we all'; that is all the organisms on earth,  share proteins and enzymes and that means that the immune system is going to, in its fervor to rid the body of a pathogen, will inevitably accidentally attack the body instead at times. That means we  come loaded from the get-go with auto -antibodies and  self reactive T and B-cells and also that  we have a built-in way of suppressing those cells.

It’s when that suppression system goes down that you have trouble.

Males and females generally have equal rates of autoimmunity until puberty when the hormones kick in. Rates begin to even out  more in seniors

Males and females generally have equal rates of autoimmunity until puberty when the hormones kick in. Rates begin to even out more in seniors

An autoimmune response can affect essentially any organ disease in the body, and while  autoimmune disorders can show up very differently, they also share many features. They’re common – they’ve been diagnosed in about 20 million people in the U.S., but probably closer to 50 million Americans have one. They’re ‘chronic’  (usually life-long). They mainly affect women and they’re heavily hereditary.

There are no known cures, they’re expensive – costing the U.S. about a hundred billion (gulp) dollars yearly, and, in contrast to cancer and heart disease, they are on the rise.  About 80 autoimmune diseases have been identified and more are coming.

To the question why there are so many autoimmune  diseases, he stated

 “We think it’s the fact that the immune system is always looking for new pathogenic organisms and being very broad in its abilities to recognize organisms that it also responds to things within our own bodies that are of the same or a very similar substance.”

 

The Sex Bias

Hormones clearly play a major factor in the female predilection for autoimmune disorders.  Rates of autoimmune disorders in children  prior to puberty are equal  in males and females and pregnancy can have a huge effect on symptoms, with some women feeling much better.

They’re believed to  mostly result when  a genetic weakness plus an endocrine effect (female bias) bumps up against an environmental trigger such as an infection. Bad genes account for thirty percent of  the risk which means that 70% of it is probably some chance environmental factor you would have surely avoided if only you’d known.

Known environmental triggers include viruses (in particular EBV), bacteria (streptoccocus), drugs, foods (excess salt), pollutants such as mercury, hormones, stress (important but hard to quantitate). Because the exposure usually comes months or even years before you come down with an autoimmune disorder finding, the triggering factor is  often very  difficult.

gene

Genes account for 30% of the risk for getting an autoimmune disorder. Environmental triggers (infection, toxin, stress, drug) are far more important.

Celiac disease is one of the few autoimmune disorders in which the triggering factor is clear: gluten. Gluten-free diets may be important for more than Celiac patients, however. Dr. Rose believes they  can help people with other kinds of autoimmune disorders.

“Interestingly,” he added, “the gluten free diet may also be helpful for people who don’t have celiac disease but who have other forms of autoimmune disease. It’s just speculative, but as gluten free diets are more available, other people are trying them and often feel better.”

If you have a family member with an autoimmune disorder your risk of developing one jumps over 10-fold (from  .4% to 7%). If your twin has an autoimmune disorder you’ve got a 30% chance that you will come down with one  as well.

Once autoimmunity gets going it usually causes more damage and inflammation and generates more autoimmunity. One of the common signatures is  multiple autoantibodies to multiple antigens.

Treatment

Like ME/CFS and many other chronic illnesses, treatment is focused on symptom alleviation not curing the disorder. Progress is being made, however.

 “We still don’t have a cure, but new treatments have been introduced in the past 15, 20 years for autoimmune diseases like lupus and MS that are remarkable and very much improved. As we understand more about the autoimmune response we find more ways of developing drugs that will intervene, that will benefit the patient by at least alleviating the symptoms even if they won’t cure the disease.”

Autoimmune or Autoinflammatory?

Some disorders that have a strong inflammatory component and look like autoimmune disorders  are not auto-immune disorders; they’re auto-inflammatory disorders.  People with the autoinflammatory disorders carry  loads of auto-antibodies, but lack the self-reactive T and B cells found in true autoimmune disorders.  With regards to treatment  it’s often  a distinction without a difference because both involve the  innate immune system and they’re often  treated the same way.

innate immune diagram

Problems with the innate immune system (NK cell, neutrophils, complement, histamine, etc. ) are behind autoinflammatory disorders

The term  autoinflammatory only showed up in the scientific literature for the first time in 1990’s. Autoinflammatory disorders involve dysregulation of the innate immune system (NK cells, dendritic cells, macrophages,etc.) that result in high rates of inflammation.

Autoinflammatory disorders originally included ‘recurrent fever syndromes’, then branched out to include some genetic disorders, hard to understand disorders like Crohn’s disease, and now may include such common disorders as type II diabetes, gout and atherosclerosis. The  decreased adaptive immune response and increased innate immune response found in autoinflammatory disorders suggest aging could be included in this category. (In the Conference we’ll see some preliminary evidence of increased aging in ME/CFS)

We don’t know if some  individuals with ME/CFS have an autoimmune or an autoinflammatory disorder. Rose didn’t appear to know much about ME/CFS but after his  talk I asked Rose what I thought was THE question; the question that was not given to him  during the Q&A session even though I wrote it out twice,  the second time at least semi-legibly, and  that was:

“What does a positive response to Rituximab in a gender  specific disorder tell you about autoimmunity or  an auto-inflammatory response?” The MAN said it meant it could be either.

 ME/CFS Autoimmune Studies Underway

 “We hope this study will identify a pathogen as a likely causative agent of the disease in order to focus future study. Dr. Elledge

dorsal root ganglia

One CFIDS Association of America study will target autoantibodies to the dorsal root ganglia that the Light’s believe play a role in ME/CFS

Besides the two Rituximab trials two studies, both using the CFIDS Association of America’s Biobank, will shed light on the role autoimmunity plays in  ME/CFS. One promising study lead by Dr. Elledge of Harvard University will determine what the autoantibodies present in ME/CFS patients blood are targeting and what viruses the antibodies present are associated with.

“…autoantibodies to brain and dorsal root ganglia have been demonstrated in chronic post-Lyme disease syndrome, an entity essentially identical with chronic fatigue syndrome/fibromyalgia” Dr. Cooperstock

Another lead by Dr. Cooperstock will look for autoantibodies to nervous system targets including the dorsal root ganglia that feature in some theories of ME/CFS.

EBV I: A Deficient Immune Response, Increased Levels of Epstein-Barr Virus Opens Up EBV Question in Chronic Fatigue Syndrome Again

A Long History

Although altered EBV-specific antibody titers have been repeatedly demonstrated in CFS, no clear evidence for chronic EBV replication has been obtained so far. Authors

Perhaps the most common viral trigger for chronic fatigue syndrome (infectious mononucleosis, aka glandular fever) or Epstein Barr Virus (EBV) is a herpesvirus almost all adults have been exposed to and carry, usually in latent form in their cells.

conflicting signs

Conflicting results have made it difficult to determine the role EBV plays in ME/CFS. Will this German study signal a change?

EBV infection was proposed as the cause of chronic fatigue syndrome not long after the disorder became prominent in the 1980s, but inconsistent study results in the 1980s and 1990s followed by Straus’s 2000 paper (which suggested the search for herpesvirus infections in ME/CFS was over) put a damper on EBV research efforts.

From 2000 to the present only Dr. Lerner with his stream of positive studies (but sometimes challenging study designs) and Dr. Glaser published fairly consistently on EBV in ME/CFS. Recently Dr. Lipkin stated (unpublished) he found no evidence of active EBV infection using high throughput sequencing in the plasma of hundreds of ME/CFS patients.

Despite study inconsistencies, EBV has remained a pathogen of interest in ME/CFS. Both Lerner and Glaser have produced evidence suggesting that a defective form of the EBV virus may be causing the symptoms in some people with ME/CFS. Recent studies suggesting that EBV triggers autoimmune disorders are intriguing given the successful ME/CFS Rituximab treatment trials.

EBV’s ability to reactivate during stress and in hypoxic conditions may have implications for its possible role in ME/CFS as well. A recent laboratory study suggesting that high rates of oxidative stress can reactivate EBV and that antioxidants (including NAC, catalase, and L-glutathione) might be helpful in reducing EBV reactivation is intriguing given the high rates of oxidative stress found in ME/CFS.

Now, in a surprising turn, German researchers have not only put the spotlight back on EBV, but have dug deeper into EBV, ME/CFS, and the associated immune response than any group has before.

The Study

“Taken together, our study provides clear evidence that deficiency of EBV-specific immune response is present in CFS” The authors

The adaptive part of the immune system, the one that takes time to kick in, comes in the form of B-cell produced antibodies that lock onto proteins the virus produces and cytotoxic T-cells that attempt to the kill the virus. (B-cell’s attack the virus in the blood and cytotoxic T-cell attack virally infected cells.)

broken

Ohio State researchers believe a defective form of EBV that is spewing out proteins may be causing ME/CFS

Noting some unusual findings in their lab, these researchers looked at these antibodies and T-cells to see if people with chronic fatigue syndrome were mounting an effective immune response against EBV. They also looked for direct evidence of an active EBV infection.

EBV replication occurs when the virus produces proteins in a sequence that allows it to build another virus. One theory, developed by Dr. Lerner and a group at The Ohio State University (that includes Drs. Ariza, Glaser, and Williams), proposes that EBV undergoes ‘abortive replication’ in some people with ME/CFS. In abortive replication, a defective form of EBV produces early proteins, but is unable to produce later ones. The Ohio State group believes continual production of these proteins is causing a chronic inflammatory state in some people with ME/CFS.

Results

First, the German researchers found evidence of primary EBV infection or reactivation (increased IgM antibodies to a late EBV protein in @15% of patients vs 3% of controls) in significantly more ME/CFS patients than controls. The fact that this could be a ‘primary infection’; i.e. it represents the first time these patients are exposed to the virus is intriguing. A primary infection of EBV early in life usually leads to nothing more than a cold; a primary infection later in life can have serious consequences including infectious mononucleosis.

Having found evidence that an active EBV infection was more common in people with ME/CFS than controls, they looked to see if a reduced immune response was responsible for that.

The first hint of a reduced immune response to EBV in ME/CFS came in the form of a lack of antibodies to EBV-produced proteins VCA and EBNA1.

But first, a short antibody primer:

antibody

Antibodies attack pathogens in the blood; cytotoxic T-cells attack them in the cell

Antibody Types

  • IgG antibodies are ‘memory antibodies’ that travel through our system looking for evidence that a pathogen is present. Once your B-cells have mounted an attack against a pathogen, they are always present in our system. Therefore, IgG antibodies are not evidence of an ongoing infection.
  • IgM antibodies are attack proteins associated with a pathogen. High IgM titers to a viral protein generally reflect a primary infection.

With two types of antibodies being manufactured against a range of viral proteins the situation becomes complicated, but a healthy immune system should produce an array of both IgG and IgM antibodies that can detect (IgG) and inhibit (IgM) pathogens (found outside cells) at different stages of their lifecycles.

As they dug deeper, the German researchers found holes in the immune response to EBV in ME/CFS patients.

Immune Holes to Epstein-Barr Virus Found

Immune Hole #1 – reduced antibody response

Evidence of a impaired B-cell response to EBV first came in the form of missing IgG antibodies to VCA and EBNA in 13% of ME/CFS patients compared to 4% of controls. This indicated that 13% of their ME/CFS study population did not have some of the memory B-cells needed to detect an EBV infection.

Increased IgM antibody responses in ME/CFS (17.5% in ME/CFS vs 4% in controls), on the other hand, suggested active and perhaps primary EBV infections were more commonly found in ME/CFS patients.

All told, 30% of the ME/CFS patients either had reduced IgG (EBNA-IgG) or increased IgM (VCA) responses to EBV.

That finding prompted a deeper look, and a much larger study that found no IgG response to a protein expressed during latency by EBV (called EBNA-1 protein) in 10% of IgG positive ME/CS patients. This indicated that the immune systems of approximately 10% of the ME/CFS group were unable to detect a very early stage of EBV latency.

EBV

The EBNA-1 protein featured in many of the tests helps EBV maintain its latency in B-cells

Latency – For EBV to maintain itself in the body over time, it needs to be able to maintain itself in B-cells in a process called latency. EBNA-1 is a protein that helps maintain EBV’s viral genome in the earliest stages of latency.

The authors noted that people with severe infectious mononucleosis and chronic active Epstein-Barr virus disease have similar findings (although it’s not clear why, given that EBNA-1 is not involved, so far as we know, in replication).

That brings up the question of how many people with ME/CFS would have fit into the category of severe mononucleosis at the time they got ill. The Dubbo studies found that more severe infections greatly increase the risk of coming down with ME/CFS.

Immune Hole #2 – reduced frequencies of two B-cell antibody producing cells

Intrigued by the findings, the German researchers dug deeper into the immune response to EBV. They took blood (PBMCs) from ME/CFS patients and then stimulated it with CpG, SAC, and PWM for seven days, and found reduced frequencies of B-cells producing antibodies against VCA and EBNA-1, and for the first time they found evidence of immune deficiencies in most people with ME/CFS.

No less than 59% of ME/CFS samples had a diminished response to a later stage EBV protein (VCA) produced during the late stage of lytic replication, and a whopping 76% of ME/CFS samples had a diminished response to the EBNA-1 protein. With the VCA finding we have evidence suggesting many people with ME/CFS may have trouble controlling EBV replication.

Calling the findings ‘remarkable’, the authors suggested that either the memory B-cells associated with these EBV antigens had been lost or had failed to develop into antibody-secreting cells.

Immune Hole #3 – Reduced T-cell response to EBNA-1

A similar deficiency in the T-cell response to EBNA-1 indicated that both arms of the adaptive immune response to Epstein-Barr Virus, the B-cells and the T-cells, had difficult recognizing and responding to this protein.

Citing other disorders such as HIV, they suggested that persistent EBV reactivation in ME/CFS had driven the T-cell response in ME/CFS into ‘exhaustion’. (A similar suggestion has been made with regard to natural killer cells that attack pathogens early in an infection, which use killing methods similar to those employed by T-cells.)

Further analysis suggested that T-cell suppressor cells which decrease B-cell responses were not responsible for the B-cell suppression found. Normal B-cell responses to herpes simplex and cytomegalovirus suggested that the deficient B-cell responses were associated with EBV and not other herpesviruses.

cytotoxic T-cell

Lower cytotoxic T-cell responses to EBNA-1 could be associated with an increased risk of autoimmune disorders

Immune Hole #4 – reduced T-cell response to EBNA-1, reduced T-cell responses to EBV

Next they explored T-cell induced cytokine production. The T-cells should produce an array of cytokines against EBV. About 20% fewer ME/CFS patients (70% of controls vs 50% of ME/CFS patients) were able to mount an IFN-y response against EBV.

Looking specifically at the latency associated EBNA-I protein, they found the startling result that no ME/CFS patients mounted an IFN-y response against it.

They also found that ME/CFS patients produced significantly lower amounts of the pro-inflammatory cytokine TNF-a in response to EBV. Finally, a lower percentage of patients produced IL-2 as well. The reduced cytokine production suggested cytotoxic T-cells, one of the big guns of the adaptive immune response, were not being strongly activated in response to EBV.

Immune Hole #5 – Reduced frequencies of EBNA-1 specific T-cells

The researchers dug deeper still. Next they stimulated the blood (PBMCs) of ME/CFS patients and healthy controls (n=40) with the EBNA-1 protein, expanded the cells in the presence of IL-2 and Il-7, and then checked the T-cell response to them. Specific types of T-cells should be produced to attack EBV, but reduced frequencies of EBV-specific T-cells occurred in about 50% of the ME/CFS samples. That again suggested the cytotoxic T-cell response to the EBNA-1 protein was substantially reduced in ME/CFS.

Direct Evidence of Active EBV Infection

“Remarkably, in line with this finding we could provide evidence of enhanced viral load of EBV by detection of EBV DNA in a significantly higher proportion of patients compared to healthy controls.” The authors

Using a real-time PCR test in the whole blood that looked for ‘low-copy’ numbers (<1,000-2930 copies/ml) they found evidence of increased EBV viral load in 7.2% of 290 ME/CFS patients. When they dug deeper and did the same test in PBMCs in a subset of patients, they found that a whopping 55% of patients (vs 13% of controls) tested positive for EBV.

The viral loads were far below those found in other EBV associated illnesses such as infectious mononucleosis or post-transplant EBV infections, and there was no evidence of lytic replication (i.e., full replication of the virus), but something the authors called ‘latency-associated replication’ was common in people with ME/CFS, yet not in healthy controls.

The Lipkin Study

Using PCR the German researchers found much higher rates of EBV infection in PBMCs vs whole blood and no evidence of EBV infection in plasma.

plasma-blood

Was looking for EBV in plasma somehow a mistake?

Neither the Lipkin CFI ME/CFS pathogen study nor the CFIDS Association of America BSR study found evidence of EBV infection in ME/CFS. According to Russell Fleming’s transcript of the Lipkin talk, the CFI study looked in the plasma of both the Montoya and the ME/CFS experts’ samples.

Whole blood contains plasma, red blood cells, white blood cells, and platelets. Plasma makes up 55% of blood volume and contains water (90%), proteins, nutrients, waste products, clotting factors, hormones and carbon dioxide. It does not contain red or white blood cells or thrombocytes.

EBV DNA has certainly been found successfully in plasma before and plasma has been used to track EBV activation. Serum/plasma EBV PCR kits are available for purchase. Researchers search and find EBV in plasma frequently.

Dr. Chia, however, reportedly stated he believes the use of plasma rather than blood was a serious mistake, and the Germans were able to find evidence of EBV activation in blood but not in plasma.

EBV (and CMV and HHV-6) are ‘cell-associated viruses. The only times their DNA escapes the cells is when the cell dies (and the DNA goes into the plasma) or when the virus is replicating. Otherwise the virus sits in a latent or semi-latent state in the cells
Medical dogma states if you can’t find EBV in the plasma, the infection is not active. EBV DNA can be found in the plasma when EBV replication rates are high, as sometimes occurs in transplant patients, but it’s not likely to be found in the smoldering infection believed present in ME/CFS. Many researchers do not accept the idea of a smoldering infection that pumps out proteins which trigger an inflammatory response.

The German researchers are deepening their study of EBV and ME/CFS and currently evaluating antibody responses against a broader variety of EBV peptides derived from 8 different proteins. They are also quantifying the levels of memory B-cells targeting EBNA-1 and VCA.

Conclusion

“We think the altered pattern of the specific immune response to EBV may be suitable as a diagnostic marker for CFS.” Authors

ball of string

The harder they looked, the more they found …

It was if these researchers kept pulling a string that got longer and longer. First their interest was piqued by some paradoxical antibody findings, then they found widespread deficiencies in some antibody responses and T-cell responses, and finally they saw evidence of an active EBV infection in the blood of 55% people with ME/CFS (vs 7% of controls).

Much is still unclear. The EBNA-1 protein that the immune systems of ME/CFS patients had trouble responding to is associated with ‘early latency’, not EBV replication. The authors’ reference to ‘latency associated replication’ is unclear given that latency is not usually associated with replication. When asked what importance their findings have for EBV reactivation or EBV survival or  more severe casesof infectious mononucleosis in ME/CFS, the authors stated they can’t answer those questions yet.

Some researchers believe, however, that reduced cytotoxic T-cell responses to EBV increase the risk for autoimmune disorders. (We’ll be covering that possibility in the next blog.) These findings also suggest that the proposal by Lerner and the OSU group of Drs. Ariza, Glazer, and Williams that an abortive lytic process (smoldering EBV infection) is present in many people with ME/CFS may be correct.

While it will take more work to determine what these findings mean for ME/CFS,  the broad range of dysfunction  found and the high rate of active EBV infection (in plasma) would appear to put this pathogen back into play in a meaningful way in ME/CFS.

Simmaron’s Immunology Workshop at IACFS/ME: Redefining How Chronic Fatigue Syndrome Is Diagnosed and Treated

Immunology Primer For Practitioners

I’ve been going to IACFS/ME conferences for eight years now and I’ve never seen a Workshop like this. This is a Workshop that could change how Chronic Fatigue Syndrome patients are tested and treated in the upcoming years. Called the “Immunology Primer for Practitioners“, it’s chaired by Dr. Daniel Peterson.

key

Standard immune tests for ME/CFS patients could change viewpoints and unlock new treatment opportunities for many.

It’s mission: to produce bulletproof recommendations for immune tests that will guide both the diagnosis and treatment of chronic fatigue syndrome. Doctors are interested, patients are surely interested, and Dr. Unger from the Centers for Disease Control (CDC) is interested, so Simmaron Research is seizing the moment.

Recognizing the opportunity and realizing that a consensus recommendation of experts would carry the most weight, Simmaron gathered 12  experts (sponsoring half of them), including nine immunologists, to produce ironclad recommendations.

Redefining ME/CFS Indeed

The Simmaron Research Foundation is committed to ‘Scientifically Redefining ME/CFS’ and  few things could change the landscape more rapidly for patients than the CDC including immune tests in its ME/CFS management guidelines.

We know common blood tests reveal little or nothing about ME/CFS, but  immune tests may not only be very revealing, but may open the door to a new conception of ME/CFS in the medical community, and to a whole swath of treatments most MD’s know little about.

Producing Real Change

vision

Simmaron is committed to funding work that alters how the medical profession sees and treats ME/CFS

In order to produce real change you need to get at the ‘levers of power’ and, like it or not, the CDC is one of those levers. The CDC is trusted by gatekeepers in the medical field. It’s recommendations matter. As we know, for better (in this case) or for worse (in the past), they get spread around.

Dr. Unger’s interest in immune test recommendations from ME/CFS experts is just the latest in a series of transformative moves at the CDC.  Instead of holding ME/CFS experts at arm’s length, Dr. Unger has embraced them. She has visited many of the experts’ centers, and her multi-year, multi-site clinical assessment study is bringing the insights of ME/CFS experts to the fore at the CDC and other agencies for the first time.

The Latest in Immune ME/CFS Research

Besides the recommendations, the Workshop will provide education for clinicians on the immune system in ME/CFS, overviews of immune findings, and insights into cutting-edge ME/CFS immunological research. We will hear highlights from the Australian NCNED teams intense focus on natural killer cells, learn what the  CDC is currently researching, uncover what very severely ill ME/CFS patients’ immune system looks like, understand how herpesvirus infections might be linked to autoimmunity and more.

The immune system features prominently in this years IACFS/ME Conference

The immune system features prominently in this years IACFS/ME Conference

Underscoring the strong immunological focus in this IACFS/ME Conference, Dr. Peterson’s session follows an opening presentation by Dr. Ian Lipkin.  Dr. Lipkin described evidence of “ongoing stimulus to the immune system” and a different immune profile  patients ill less than 3 years have compared to long term patients last fall on a conference call hosted by Dr. Unger.

Dr. Klimas’ panel the next day will go deep on “The Latest Research in Immunology”, including results from Dr. Lipkin’s collaborative research, the CDC’s genomic study, and Dr. Marshall’s natural killer cell research. Her panel follows the Plenary Session with Dr. Noel Rose, Director of the Center for Autoimmune Research at Johns Hopkins.

It is a pivotal time in ME/CFS, and immunity and autoimmunity are coming into focus. Simmaron seeks to take these groundbreaking sessions into clinical practice with consensus.

Simmaron Research Foundation Moving Forward

Yes

Redefining ME/CFS step by step

This is just one of the Simmaron Foundation’s efforts to redefine Chronic Fatigue Syndrome by taking advantage of the expertise and experience of Dr. Peterson and his fellow practitioners.

That effort began with Dr. Peterson’s retrospective analysis of treatment success using Vistide in selected patients and will continue with further analyses of the effects of other immune-based treatments, like IVIG and Ampligen.  Dr. Peterson will also be participating in the B-12/MFTHR trial this spring.

In order to address a critical need for more expert  ME/CFS clinicians the Simmaron Foundation has also funded a practitioner to learn from Dr. Peterson. Bringing expertise and research to patient care is Simmaron’s mission.

Support the Simmaron Research Foundation’s Work to Scientifically Redefine ME/CFS

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“Immunology Primer for Practitioners” Panelists

  • Daniel Peterson, M.D., Owner, Sierra Internal Medicine, Incline Village, NV, Simmaron Research Scientific Advisor
  • Sonya Marshall – Gradisnik, BSc (Hons), Ph.D. , Professor of Immunology, Director, National Centre for Neuroimmunology & Emerging Diseases, Griffith University, Australia
  • Sharni Hardcastle, Ph.D., Research Assistant and Practical Demonstrator , Bond University, Gold Coast, Australia
  • Nancy Klimas, M.D. Ph.D., Professor of Medicine and Director, NSU COM Institute for Neuro-Immune Medicine Director, Miami VAMC Gulf War Illness and ME/CFS Research Program
  • Paula Waziry, Ph.D, Assistant Professor, Neuro Immune Medicine, COM, Nova Southeastern University, Miami, Fl
  • Konstance Knox, Ph.D., Founder, CEO, Coppe Healthcare Solutions
  • David Baewer, M.D. Ph.DMedical Director, Coppe Healthcare Solutions
  • Isabel Barao, Ph.D., Research Assistant Professor, University of Nevada, Reno, Simmaron Research Scientific
  • Gunnar Gottschalk, B.S., Simmaron Research, Incline Village, NV
  • Troy Querec, Ph.D., Associate Service Fellow, Centers for Disease Control and Prevention, Atlanta, GA
  • Dennis Mangan, Ph.D., Former Chair, Trans-NIH ME/CFS Research Working Group, Office of Research on Women’s Health, U.S. National Institutes of Health
  • Mary Ann Fletcher, Ph.D., University of Miami Miller School of Medicine Professor of Medicine, Microbiology/Immunology and Psychology
  • Elizabeth Unger, M.D. Ph.D., Chief, Chronic Viral Disease Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases. Centers for Disease Control and Prevention, Atlanta, GA

 

 

 

Michael VanElzakker Ph.d Talks – About the Vagus Nerve Infection Hypothesis and Chronic Fatigue Syndrome (ME/CFS)

 An Interview with Michael VanElzakker Ph.d

light bulb

Van Elzakker’s hypothesis could explain several of the mysteries associated with chronic fatigue syndrome

Michael VanElzakker’s Vagus Nerve Infection Hypothesis (VNIH) for Chronic Fatigue Syndrome may be the most intriguing hypothesis to come along in the last twenty years.  If it’s correct it could explain several mysteries including how a virus might trigger the disease and then seemingly disappear, why the Lipkin study failed to find an active infection, why cytokine studies have trouble finding evidence of the ‘never-ending cold’, why when antivirals work they often take so long to do so.

It’s raised a lot of interest. Now Michael VanElzakker ‘sits down’ and answers some questions about it.

Background

What is your background? When did you get interested in this subject and start  developing this hypothesis? 

I am a neuroscientist. I mostly focus on posttraumatic stress disorder (PTSD), which I consider to be very different from CFS and a separate arm of my research interests (although there are many interesting overlaps between the views of CFS and PTSD within our culture).

sick person

A sick friend prompted his interest in this disorder

However,  I got my bachelor’s and master’s at the University of Colorado – Boulder, at a time when the Psychology & Neuroscience department there was very focused on psychoneuroimmunology-related phenomena. Some of the many research programs there related to neuropathic pain, cytokines, and the vagus nerve. All it took was for someone who was thinking about CFS to be exposed to these different literatures and to start fitting them together.

I started thinking about CFS because I have a sick friend. She got sick back when CFS was viewed even more skeptically than it is today – I remember one MD referring to it as “yuppie flu.” I knew that my friend was not malingering – why would she be? She had to put her life on hold. It was pretty devastating.

The focus on the vagus nerve is simply because that organ is responsible for symptoms during “normal illness” that strongly overlap with CFS symptoms.

Testing the Theory

Apparently imaging techniques are not able yet to find localized infections in the vagus nerve. How far are they from being able to that? Is there interest in developing those kinds of techniques?

You reported that  PET scans have shown ‘promise’ in identifying activation of the microglia – a prominent part of your theory. (The VNIT proposes chronic microglial activation causes the vagus nerve to send signals to the brain that result in flu-like symptoms.)  It seems that we could settle the VNIH theory right now if PET scans showed clusters of infected areas around the vagus nerve. How effective are PET scans at doing something like this now?

I’ll answer these two questions together. As far as the effectiveness of PET scans finding local vagus infection: We don’t know. That’s part of what my group is trying to work on. There are a lot of technical problems that will require pilot testing.

PET Scan

Most PET scans are done of the brain. VE would like to do one further down in the vagus nerve area

One of the big problems is that PET scans cost thousands of dollars per hour. It’s difficult to convince funding agencies to give us money to pilot test a method so that we can even begin to ask questions about a hypothesis that may or may not be accurate. But I’ve got some really good people on my team and we’re working on it.

There’s interest because of this hypothesis, but most imaging of the vagus nerve thus far has been at the level of the brain, trying to understand the mechanism of vagus nerve stimulation for epilepsy or depression. We’re trying to image it farther down.

If someone made an animal model of the hypothesis, that would help raise interest. I laid out a protocol in the paper for creating an animal model; I hope somebody with a rat lab takes the idea and runs with it. I’m not jealously guarding these ideas, I put them in the paper in the hopes that other groups would work on them too.

You suggested that future CFS research  use radiolabeled antibodies to localize clusters of specific virus types. This is done to find tumors. Is it possible to radiolabel antibodies so that they pick up clusters of infection in the body?

Yes, it is. But there are several problems to this with regards to the VNIH of CFS. One is that antibodies are specific, but CFS could be caused by a number of different pathogens. So, we could flood someone’s body with radiolabeled antibodies against HHV-6, but maybe in that specific case, their symptoms are caused by HHV-4 (Epstein–Barr).

Another problem is that some of the pathogens that might be most likely to cause CFS are found in the vast majority of humans. So, radiolableled antibodies against HHV-1 would find a signal in most people, but only cause CFS if the viruses are in a vagus (para)ganglion. And the vagus nerve is so highly branched, that could be all over the trunk. Another problem is that antibodies cannot always get inside ganglia, which are immunoprivileged. But despite all of that, I still think it’s a research program that is worth pursuing.

Treatment

Herpesviruses apparently love to set up house in the sensory ganglia, but you suggest that antiviral drugs might have trouble getting to them and destroying them there. Why is that?

drugs

Antivirals may take much longer to work in ME/CFS because they have difficulty accessing the vagus nerve where the viruses are present

Similarly to how the central nervous system has a blood-brain barrier (BBB), peripheral nervous system ganglia are immunoprivileged. According to the hypothesis, the frequent failure of drug therapy and also one’s own immune system to eliminate infections within vagal ganglia and paraganglia is just like how some drug doses and antibodies do not penetrate the BBB.

You noted that behavioral/stress management therapies such as CBT are moderately effective in about 30% of people with chronic fatigue syndrome, and that CBT resulted in lower viral loads and improved immune functioning in HIV. Why would this be?

Stress causes a cytokine response. So, if someone who doesn’t like public speaking is giving a presentation, their immune system is generating a cytokine response. If such a person even thinks about giving a presentation, they are likely to generate a cytokine response.

People with CFS have an authentic reason to be concerned about any activity that requires physical exertion, and it’s called post-exertional malaise: worsened symptoms after exertion.

According to the vagus nerve infection hypothesis (VNIH), there is a physiological reason behind post-exertional malaise: Exercise provokes muscle tissue to produce the proinflammatory cytokine IL-6, which would then exacerbate the ongoing  local cytokine response within vagus nerve ganglia or paraganglia. That’s the hypothesized mechanism behind post-exertional malaise.

The CBT practitioners in the infamous PACE study were focused on avoidance/fear of activity because they began with the assumption that CFS is psychological. They think the fear of activity itself is the cause of CFS; I’d say that fear of activity is justified, but like all fear, it can become dysfunctional. For the vast majority of their patients, CBT did not help. The three out of ten that found some slight improvement may have used CBT to figure out exactly what level of activity they should be worried about. So, the moderate improvements they reported in a minority of patients were probably related to stress reduction.

In patients with HIV, reducing something like stress that taxes the immune system is bound to help a little bit.

I understand that this is a really charged topic among CFS advocates, and there is a lot of misinformation out there. Just to be clear, cognitive-behavioral therapy (CBT) does not get at the root cause of CFS. CBT offers coping strategies and is not a cure. But I can’t think of a single medical condition that isn’t exacerbated by stress. CFS is no different. Having a chronic illness is stressful and it makes one’s life complicated and there’s a grieving process. CBT is for those parts of the illness. It’s intended to help people solve problems and to challenge dysfunctional patterns. If you’re seeing a CBT practitioner who views CFS as a psychologically-based illness and is approaching your CBT that way, fire them. Find someone else.

While CBT can help people with serious and chronic medical problems, it should be used as an adjunct and not a primary treatment. It would be crazy, for example, for a doctor to prescribe CBT instead of chemotherapy for cancer. But chemotherapy is a known, empirically tested treatment for cancer. CFS doesn’t have such a thing yet.

stress

Behavioral practices like CBT that reduce stress can be helpful in immune mediated diseases such as HIV and ME/CFS, but are adjunct, not primary therapies

Without a cure, the next best thing is to focus on quality of life. I am very much focused on finding an explanation for CFS, which would then lead to a cure. I have hypothesized that CFS is a neurological illness triggered by a foreign pathogen infecting the vagus nerve. But the fact is that stress has profound impact on immune system function. CBT for CFS patients can reduce stress, which is one mechanism of action to improve symptoms.

I should also say – CBT sometimes gets conflated with graded exercise therapy as well. Some studies have combined these two techniques but they are not the same thing. In the paper I gave an example of a treatment regimen that included graded exercise therapy.

Again, to be clear, if the VNIH is correct and some combination of glial inhibitor, antivirals and vagus nerve stimulation can be used to quell symptoms, then and only then does it make sense to begin graded exercise therapy. At that point, the root cause of CFS symptoms has been dealt with, and the next priority is to deal with muscle deconditioning which is not an insignificant factor in ongoing symptoms.

I absolutely do not condone forcing still-sick patients to exercise if it’s making their symptoms worse. This should be obvious.

Others

The heart rate variability evidence suggests the parasympathetic nervous system (vagus nerve) is under-activated in ME/CFS while the sympathetic nervous system is over-activated.  The SNS activation, in fact, may be due to the PNS’s inability to rein it in.  The increased heart rate at rest, for instance, could be due to be due to the inability of the vagus nerve to slow it down. In your theory, though,  the vagus nerve appears to be activated by the localized infection.  I’m a bit confused.

ANS

Is an infection contributing to the autonomic nervous system problems in ME/CFS?

This has to do with the fact that the vagus nerve is a mixed cranial nerve, meaning it has both sensory (afferent, or towards the brain) and motor (efferent, or away from the brain) divisions. Its parasympathetic influence over the body results from efferent activity; its function in detecting peripheral infection and triggering sickness behavior results from afferent activity.

However, terms like over-active and under-active are a bit too simplified – what matters is that the nerve is able to respond and signal appropriately, to be able to create a functional signal-to-noise ratio.

Researchers have been looking for cytokines in ME/CFS for decades. Sometimes they find them, sometimes they don’t. When they do find them sometimes research groups find similar cytokines and sometimes they don’t. The one constant is that they keep looking. You mentioned that lung infections are also not associated with increased cytokine levels in the blood.  Are there many other infections like this?

Well, to be more accurate, it’s not necessarily that lung infections won’t show a cytokine response in the blood. It’s more that we cannot be certain to find a cytokine response from a local infection – that is, any local infection. If a lung infection were severe enough, you might find cytokines in the blood. Cytokine studies are quite prone to false negatives, and it’s a mistake to infer from a negative cytokine blood test that there is no cytokine response happening anywhere in the body.

In studies that look for cytokines in blood, there are 3 relevant questions:

  1. Is there any cytokine response in the first place?
  2. Did that cytokine response diffuse into peripheral blood?
  3. Did the method of detection work?
IL-1B

VE notes the difficulties present in finding a cytokine response in an infectious disease

The question we’re interested in is #1, however it’s a big assumption that the answers to #2 and #3 are “yes” when we infer from a negative blood test that there is no cytokine response.

Those of us who think that CFS is not psychologically-based tend to think there’s an immune dysfunction of some sort. People have been looking for cytokines because they are an obvious potential link between the immune system and CFS symptoms, but a lot of studies have ignored how cytokines work.

If a research group is unfamiliar with the cytokine literature they may have also made some easy mistakes in the cytokine assay – the actual lab methods for looking for these proteins.

For example, cytokines are relatively labile, meaning unstable. If someone who didn’t know any better stored their blood samples in a refrigerator instead of a -80° freezer, you can bet they did not find cytokines. If blood samples went through freeze-thaw cycles, the cytokines will also start to denature (break down). There are definitely a lot of really good researchers who have looked into cytokines, but the literature can get muddied pretty easily by bad studies. And because the symptoms are systemic, most people have been thinking in systemic terms (i.e., not thinking about a localized infection causing CFS).

In general, I’m skeptical of any attempts to find a “cytokine profile” for CFS or any other infectious disease. That doesn’t mean it can’t be done, but it’s difficult. Cytokine responses are very complex, they interact with each other and they change in daily and hourly rhythms. You could study one individual and not find a “cytokine profile” unless you took several samples a day for many days.

Response to the Hypothesis and the Future

This is a really intriguing theory. Kristin Loomis of the HHV-6 Foundation was excited by it.  Have you gotten much response from it? 

I’ve actually been really pleasantly surprised by the response. I’ve had the idea for quite a long time, and spent a lot of time and effort trying to set up a collaboration with a rat lab, to create an animal model. To make a very long and frustrating story short, nothing worked out.

people networking

The response to VE’s hypothesis has been very positive; he is working on putting a study together to test his hypothesis

I’ve been telling anybody who would listed about the hypothesis. It’s not like doors were getting slammed in my face, but most people simply didn’t have a background in the different literatures that the hypothesis ties together.

It wasn’t until recently that I discovered this unique journal, Medical Hypotheses, so I made some time to write up the idea. It gave me a forum to really give people the background they needed to understand the idea, and allows people to check the citations themselves. Based on past experience, I thought I’d have to keep cold-calling researchers to push the hypothesis. But it really took off right away.

I put it up online for free, and it’s been downloaded over 1000 times there; I don’t know how many people have downloaded it from the publisher through a university or hospital subscription. I’ve heard from researchers from 5 continents. Somebody translated the paper into Dutch and put it up online.

The week the paper came out, Anthony Komaroff contacted me, we’ve been in contact since. He finds the hypothesis to be “provocative and plausible” and shares my hope that functional imaging can help to shed some light on it. I’ve been in contact with a lot of other well-known CFS researchers, and I think the idea is at least changing the way that some people think about the problem.

VanElzakker

Van Elzakker will be at the IACFSME conference with a poster presentation of his hypothesis

I also know that the paper is already being taught at some universities and medical schools, so hopefully it will at least get young scientists to start thinking about CFS. I hope people start to think about new CFS findings through the lens of this hypothesis because in my experience, it explains a lot of phenomenology.

Even if the hypothesis doesn’t turn out to be accurate, or is only partially accurate, I hope that it gets us closer to effective treatments that are actually attacking the root causes of CFS symptoms and not just helping people cope with them.

Some reports suggest you’re engaged in a pilot study. Can you comment on that?

On the record, I’d just say that I’ve put together a really great team to pursue the VNIH and that Dr. Komaroff is part of it. There are a lot of technical issues but we’re hoping to use functional imaging to gain enough preliminary data that we can pursue it further.

 

 

One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome

Big Theory

It could explain the Chronic Fatigue Initiatives pathogen study results.  It could show how an infection could cause chronic fatigue syndrome, and then seemingly disappear.  It integrates two of the biggest players in ME/CFS; the autonomic nervous system and the immune system. It focuses on the herpesviruses. It includes sensory nerves, an increasingly hot topic in ME/CFS/FM, and it follows an  established model of fibromyalgia.

light bult

If it’s correct VanElzakker’s hypothesis could explain a lot about chronic fatigue syndrome

It’s the Vagus Nerve Infection Hypothesis (VNIH) for chronic fatigue syndrome, and it could change how this disorder is viewed, researched and treated.

Created by Michael VanElzakker, a Tufts neuroscientist,  the VNIH proposes that nerve loving viruses trigger a difficult to detect  immune response which produces the fatigue and other symptoms present in chronic fatigue syndrome.

Location, Location, Location

VanElzakker proposes that an infection triggers ME/CFS, but if his theory is right the most important thing about that infection is not what it is but where it is.   That ‘where’  is the biggest nerve in the body; the vagus nerve – a ‘wandering nerve’ that stretches over much of our torso and sends its roots into most of the organs of the body.

The vagus nerve isn’t just any nerve; it’s the nervous system’s immune conduit to the brain. VE believes that an infection there doesn’t need to be large to cause havoc in the brain; it just needs to be present.

In some ways, vagus nerve appears, in fact, to be ripe for infection in ME/CFS. As it ‘wanders’ through the body it comes into contact with virus havens such as the esophagus, stomach, lungs and spleen, all of which have likely at one time or another harbored the herpesviruses (HHV6, HHV-5 [cytomegalovirus], HHV-4 [Epstein-Barr virus]) that have been thought to be associated with ME/CFS for decades.

Most humans carry several of these herpesviruses in latent form unless some stressor or biological event allows them to become reactivated.

virus

Van Elzakker suggests ME/CFS is caused by localized infections associated with the vagus nerve

VanElzakker believes that upon reactivation these viruses replicate and move outside the nerves where they run into glial cells that attempt to gobble them up.  The glial cells perk up remarkably in the presence of viruses, releasing all manner of pro-inflammatory and neuroexcitatory compounds (proinflammatory cytokines [IL-1B, IL-6, TNF-a], glutamate, prostaglandins, nitric oxide and free radicals. )

Receptors on the vagus nerve that sniff out these alarm signals tell the brain an infection is present, which then shuts the body down by sending out  signals  (fatigue, flu-like symptoms, pain, etc.) that slow the body down, tell it to stop moving, stop eating, stop thinking.

Because these infections are localized right on the main immune conduit to the brain, VanElzakker believes they don’t need to produce the outsized cytokine response researchers have been looking for.   All they need to do is tweak the vagus nerve and let it and the brain the do the rest.

You don’t need a ‘big’ infection to produce ME/CFS; all you need is a little infection  in the right place.

The Key Component – Glial Cells

The glial cells that surround and protect the vagus nerve are the key. Once thought to be mere structural scaffolding for the nerves, these cells  (e.g., astrocytes) are  now known to regulate nervous system signaling, a fact that’s been borne out in chronic fatigue syndrome’s sister disease,  fibromyalgia.

Immune system

VE believes pathogen triggered,but localized immune system activation around the vagus nerves may be causing ME/CFS

Glial cell  release of cytokines, glutamate, free radicals, etc.  in the dorsal horn of the spinal cord causes  increased pain sensitivity and allodynia in susceptible individuals. At some point the constant production of these excitatory substances  causes  a switch to get flipped sending the pain response spiraling upwards instead of shutting down.

At its most extreme (allodynia), the nervous system can interpret even the slightest touch as eliciting pain.   The pain response  system at this point, as VanElzakker, puts it,  has become, ‘pathological’.

That model of pain production has been solidly documented. VanElzakker proposes the same process  causing pain sensitization in the dorsal horn is  causing fatigue and other symptoms in chronic fatigue syndrome, except this time it’s associated with glial cells surrounding the vagus nerve.

A New Model of Fatigue

There is no  reason to suspect  that vagus-nerve associated glia would function any different than pain associated glia. VanElzakker

Nobody knows what a herpesvirus infection  of the vagus nerve would look like,  but VanElzakker doesn’t see any  reason it should look any different  from an infection in other parts of the body.

shingles

Herpesvirus infections of the trigeminal nerve cause shingles. Do herpesvirus infections of the vagus nerve cause chronic fatigue syndrome?

We know a  herpesvirus infection of your trigeminal nerve gets you shingles and chronic pain.  Researchers believe a chronic infection in the dorsal horn of your spinal cord will can  get you fibromyalgia and allodynia.  Would  an  infection of the vagus nerve get you sickness behavior and  chronic fatigue syndrome?

There’s a good chance it might.  Animal studies indicate that fatigue/flu-like symptoms go gangbusters when the vagus nerve gets infected. In fact, it’s  possible  the flu-like symptoms associated  with infections wouldn’t even exist without the vagus nerve.  Rodents with their vagus nerves cut don’t act sick even after they’ve been infected with a pathogen; the fevers, fatigue, the desire for isolation – are gone.

What if the vagus nerve receptors were…ceaselessly bombarded with these cytokines?  The symptoms of sickness behavior would be severe and intractable.

If the glial cells surrounding the vagus nerve function the same way they do in the dorsal horn, a lingering or even a ‘smoldering’ infection (aka Dr. Lerner’s theory), could trigger the similar type of hypersensitive reaction in the vagus nerve. In this ‘immune sensitization’ model, it takes only very small amounts of cytokines to trigger fatigue and flu-like behavior.

In fact, VanElzakker suggests chronic fatigue syndrome and fibromyalgia could both be ‘glial cell diseases’.

How to Have an Infection That Doesn’t Show Up in the Blood

“Cytokines Responding to a Local Infection Stay Local” VanElzakker

If VanElzakker is right, the  same group of viruses are wreaking  havoc in different locations in different ME/CFS patients.  The problem is it’s just darn hard to get at them.  You can’t find them in the blood and you sure as heck can’t biopsy the vagus nerve.

A series of fascinating studies exploring how central nervous system infections cause chronic nerve pain may, however, illuminate what’s happening in ME/CFS.  First, researchers mimicked a localized nervous system infection by dropping an HIV protein known to activate glial cells  into rodents’  spinal cord.

mouse

The vagus nerve is the immune conduit to the brain; mice studies suggest it plays a key role in producing ‘sickness behavior’

They found that the glial cells  reared up and starting producing pro-inflammatory cytokines to take care of the intruder. Not surprisingly,  the rodents looked and acted sick – the cytokines were doing their job to keep the animal down and isolated – but  no trace of those cytokines could be found  in their bloodstream.  Only if the animal’s spinal cord was sampled near where the ‘infection’ was  it possible to find any evidence of increased cytokine levels.

If VanElzakker is right, then blood  cytokine levels in ME/CFS are a function of where your vagus nerve is infected. If it’s infected in your  abdominal area, you might find cytokines in the blood, but it might be hard to find them in your spinal fluid. If your vagus nerve is infected near your brainstem you might find cytokines  in the spinal fluid, but you probably won’t find them in your blood.

Wherever the infection is there’s a good chance you may not find cytokines in the blood  at all.  This isn’t a  completely surprising fact or even restricted to the vagus nerve infections; cytokines in  mice with lung infections, for instance, showed up only when the lungs themselves were sampled.

Next Steps

VanElzakker suggests animal studies to better understand infections of the vagus nerve and to ultimately to build a chronic fatigue syndrome rodent model would be helpful.  Magnetic resonance imaging (MRI) may be able to detect viral lesions in central nervous system tissues. It is not yet known if  PET scans can detect the activation of a different type of glial cells; the satellite glia that are in vagus nerve ganglia and paraganglia, but special PET scans might be able to be used to assess microglial activation.

Cadaver studies of people who had ME/CFS definitely aren’t his first choice, but they could find activated glia, inflammation and viral infections of the vagus nerve and associated structures.  Finally,  novel protocols should be developed to assess the vagus nerve and brainstem functioning in ME/CFS.  The severely ill should be given a prominent place in future studies.

 

prescription drugs

If VanElzakker is correct different treatments could be in store for people with ME/CFS

A New Treatment Approach

“Glial cell inhibitors could become standard treatment for CFS (caused by CNS vagus nerve infection)” VanElzakker

Glial Cell Inhibitors

If VE’s theory is correct then glial cell inhibitors to stop the immune activation, antivirals to attack the pathogens, vagus nerve stimulation and surgical alteration of the vagus nerve might be possible treatments sometime in the future.

Glial cell inhibitors have a good safety profile, have been helpful at curbing neuropathic pain and are not used much in chronic fatigue syndrome or fibromyalgia.

ibudilast

If VanElzakker is right then Ibudilast, a drug in clinical trials now for another disorder, is a possibility.

Ibudilast (AV411/MN166), a drug used mostly in Japan, knocks down glial cell activation by inhibiting the production of a proflammatory cytokine called macrophage-migration-inhibitory factor (MIF)  and TNF-a.  Reduced levels of TNF-a could provide a bonus by increasing the breakdown of  a excitatory neurotransmitter called glutamate that may be helping to keep your central nervous system on edge.

Ibudilast is also  known to have neuroprotective and vasodilative effects and is usually used to treat asthma and stroke. It’s ability to suppress glial cell activation has made it useful in the treatment of neuropathic pain, and it’s currently undergoing clinical trials to treat neuropathic pain in Australia.  Ibudilast can also prevent viral activation of the microglia.

The NIH is funding Ibudilast trials in the US to see if it’s effective against drug addiction. If successful the drug could be available here for off-label use in ME/CFS  in three or four years.

Other general microglial inhibitors exist (minocyline, pentoxyfilline, propentfylline) but have undesirable side effects.

Antivirals

Stopping glial cell activation may be easier than getting at the viruses themselves.  Herpesviruses living in the sensory ganglia may be protected from antiviral drugs and antibodies.  (One new herpesvirus drug may be coming on the market soon, however.) Alternately, viruses other than the herpesviruses could be infecting the vagus nerve.

Behavioral Therapy

VanElzakker also notes that while behavioral therapies are not curative and may only apply to a subset of patients, they can help moderate symptoms and improve quality of life in some.

Conclusion

The VNIT may be able to explain more puzzling aspects of chronic fatigue syndrome than any other.  Next up we talk with Dr. VanElzakker about how he got interested in ME/CFS and what his theory may mean for this disorder.

 

Big Antiviral Trial Could Usher in New Treatment Era for Fibromyalgia

 A New Approach to Fibromyalgia

Infections are a common trigger for fibromyalgia (FM), and fibromyalgia patients are experience many ‘sickness behavior’ symptoms, but we haven’t usually associated FM with viruses or immune system problems.

woman questioning

So it’s going to be Fibromyalgia that gets the really big antiviral trial ….

That’s been changing  recently. A immune biomarker has been proposed. Small fiber neuropathy - possibly caused by immune dysregulation – has been found. Dr. Dantini has been treating FM with antivirals for years.  The immune system’s starting to get some respect in FM.

Now, in a surprising twist, it’s going to be fibromyalgia rather than chronic fatigue syndrome, that’s getting the big, placebo controlled, double-blinded multi-center antiviral trial.

Last year we heard that Dr. William Pridgen in  Alabama was getting his ducks in a row for a major antiviral trial. Four weeks ago in an email exchange he confirmed that the money – $3.3 million dollars – all gathered from ‘angel investors’ is in  hand, and the four-month 143 patient trial began  in early October.

Pridgen’s Innovative Med Concepts biotech startup is producing the study.

A Different Path

The pathways researchers and doctors take to get to disorders like FM or chronic fatigue syndrome are nothing but diverse, and it’s worth taking a look at how Dr. Pridgen, a surgeon, came to fibromyalgia. (Dr. Julia Newton’s pathway to ME/CFS was through elderly people experiencing dizziness and, to her surprise, a great deal of fatigue.) Dr. Pridgen’s pathway to fibromyalgia was through the gut.

Pridgen saw a pattern emerge in his  treatment of thousands of patients with chronic gastrointestinal issues that intrigued him. A patient would get better, but then experience a stressful event that would send him/her back into the soup.  They would get better, but during the next relapse they would stay sick longer and their recovery period would be shorter. Eventually they would be sick all the time.

virus

Shorter and shorter relapses over time in his patients lead Pridgen to conclude that a virus must be involved.

The problem, he thought, had to be some sort of pathogen that was steadily increasing with every recurrence. Giving his patients antivirals helped, but problems remained. Then he found that adding an anti-inflammatory (which also had anti-viral properties) reduced their fatigue, gastrointestinal complaints, depression and anxiety markedly and improved their energy.

An observational study indicating that the combination drug approach had a 90% ‘efficacy rate’ led Pridgen to start a company, enlist investors and create the large treatment trial.

Pridgen’s theory fits glove and hand with several other fibromyalgia/chronic fatigue syndrome theories. As with Van Elzakkers’ vagus nerve infection theory for ME/CFS, Pridgen’s theory begins with a nerve loving virus that takes up residence – for life – in nerves in the sensory ganglia found across the body.

Instead of HHV6 or EBV Pridgen believes herpes simplex viruses, are the key in FM/ME/CFS. Other than a 1993 theory proposing herpes simplex virus was at play in ME/CFS, interest has been scanty. HSV-1’s ability to affect many of the genes and gene pathways suspected of playing a role in nervous system disorders such as Alzheimer’s, Parkinson’s, depression, chronic fatigue syndrome and autism, however, lead one researcher to propose it could play a role in all of them.

HSV-1 has been found in the esophagus, stomach and duodenum of the gastrointestinal system. In fact, HSV-1 was proposed to  cause ‘recurrent functional gastrointestinal disorders’ such as IBS, as far back as 1996.

Pridgen’s patent application indicates that he believes that stressors and  peptides and hormones released by the sympathetic nervous system and HPA axis  set the stage for herpes simplex-1 reactivation. Pridgen proposes that repeated HSV reactivation can  kill the sensory nerve cells ( small fiber neuropathy?) and destroy part of the nerve ganglion.  (Stress induced HSV-1 reactivation has been documented in laboratory animal studies.)

Once  these neurons and ganglia are damaged, Pridgen believes they send out signals that ultimately muck up the pain processing centers in the central nervous system. The over-generation of neurotransmitters such as glutamate, Substance P, serotonin, norepinephrine, dopamine, brain-derived neurotrophic factor (BDNF) involved in this process then causes central sensitization.

Antiviral Plus

Pridgen proposes to stop the viral reactivation and the central sensitization with antivirals; an approach that’s been tried before in chronic fatigue syndrome, but not in the way Pridgen’s doing it.

connections

Are two ‘antivirals’ better than one? We’ll find out sometime next year.

One of Pridgen’s patent applications suggests that one of his unique insights has been to combine valacyclovir (valtrex) with an anti-inflammatory, Celecoxib (Celebrex) that has antiviral properties.  Other combinations are being tested and Pridgen stated  they have not released the make-up of IMC formulation used in the trial. It’s not clear, then, what drugs at what doses were used in the study or which will prove most effective. 

Celexcoxib (Celebrex) is a non-steroidal antinflammatory (NSAID) COX-2 inhibitor usually used  in the treatment of osteoarthritisrheumatoid arthritisacute pain, painful menstruation and menstrual symptoms. It down regulates the activity of inflammation producing  cells.

Pridgen proposes that the  two drugs hit the virus at different stages of its life-cycle. Pummeling the virus with that one-two punch, he believes, will finally stop the virus from reactivating.

Pridgen and Duffy are looking for herpes simplex virus, but other herpes viruses could be affected by this treatment. We won’t know if they are until further studies are done.

Inflammation Gone Awry

Pridgen and his partner, molecular virologist, Carol Duffy will also attempt to develop a diagnostic test for fibromyalgia using cytokine arrays they believe will document high levels of  pro-inflammatory cytokines and low levels of anti-inflammatory cytokines.

Like VanElzakker, Pridgen believes the body is over-reacting to the virus.

“It’s basically exaggerating its reaction to the virus. Any little stress reactivates the virus, and, rather than the body saying, ‘Oh, this is just a virus I’ve been living with this since I was five,’ the body keeps saying, ‘Oh, my God,’ and throws on all this inflammation, and that gives these people this pain.”

“There is a theory that all pain, one way or another, is inflammation,” Duffy says. “It’s inflammation gone awry.”

Not just Fibromyalgia

Pridgen and Duffy have their eyes on more than Fibromyalgia.  Pridgen’s provisional patent proposes this treatment will work for chronic fatigue syndrome, irritable bowel syndrome, chronic pain, chronic headache, chronic neck pain, chronic back pain, chronic depression, chronic clinical anxiety disorder, post-traumatic stress disorder (PTSD), brain fog, cognitive dysfunction and chronic interstitial cystitis.

Celebrex – The Antiviral?

We don’t hear anything about Celecoxib as a virus fighter in ME/CFS, but some evidence suggests it could be efficacious against herpes simplex virus. The ability of COX-2 inhibitors to decrease prostaglandin production is believed to push the immune system towards a Th1 (antiviral) response and away from the Th2 response often found in ME/CFS.

stop sign

Pridgen believes Celexicob’s antiviral properties, in concert with Valtrex, will knock down the herpes viruses causing FM and ME/CFS

Celebrex was shown to reduce stress induced herpes virus reactivation in the nervous systems of mice.  Another study found that reactivation of HSV-1 in mice was associated with upregulation of COX-2 gene expression in their nerve ganglia.  HHV-6 can also induce COX-2 expression.  Both COX-1 and COX-2 are needed for viral replication.

(One mother found that VIOXX (now off the market) reduced her daughters IL-6 levels and eliminated the ‘panic attacks’  she’d experienced following a central nervous system infection.)

(Aspirin and flavanoids, vitamin E and fish oils also inhibit COX-2. The efficacy some ME/CFS patients experience from using omega-3 fatty acids could be due to antiviral effects.)

Tissue Biopsies

Along with treating the virus, Pridgen and his partner, molecular virologist Carol Duffy, will be using PCR to test for the virus, not in the blood, but in gut tissue samples.

One of the most intriguing aspects of the Pridgen-Duffy study is the search for HSV-1, not in the blood, but in the tissues. We know the Chronic Fatigue Initiative’s Pathogen study  failed to find evidence of viral infection in the blood. Now, Pridgen and Duffy are testing gut samples for herpes virus simplex in their study.

First PCR will be used to search for herpesviruses in both the control and FM gut samples. Then antibodies will be used to determine if an active infection is present.  In subsequent studies, electron microscopy will look for the herpesviruses particles themselves.

In preliminary studies 18/19 fibromyalgia patients with gut issues contained herpes simplex virus DNA in their gut tissues. No other herpesviruses were found. Immunoblot testing indicated that an active infection was present in eight of nine positive biopises.

Dr. Pridgen reported in an email they are still trying to determine  the optimum doses and cautioned everyone to wait until the results of the phase three trial are done before starting this treatment.  He also stated he feels  they are ‘very close’ to helping many people with this condition.  The results of trial will be released mid-year, 2014. 

Conclusion

breakthrough arrow

A successful trial could usher in a new era of treatment for fibromyalgia and perhaps chronic fatigue syndrome

Pridgen and Duffy’s big multi-center antiviral trial in Fibromyalgia is nothing if not exciting in its scope and approach. Pridgen’s ability to come up with over $3,000,000 in startup funding suggests he and Duffy have got some solid data backing their trial up. .

If they results are positive, Pridgen and Duffy could usher in an entirely new way of treating both fibromyalgia and chronic fatigue syndrome.

Aussie Immune Study Raises Questions About Chronic Fatigue Syndrome Research Definition

December 12, 2013

The more specific requirements of the ICC however, may select patients that are less clinically diverse. This could improve detection of immunological findings in CFS/ME.      

Study authors.

How much of a difference the International Consensus Criteria (or any definition) makes is a major question in chronic fatigue sDr. Marshall-Gradisnikyndrome.

Dr. Sonya Marshall-Gradisnik’s team in Australia, who just celebrated the grand opening of the National Centre for Neuroimmune and Emerging Diseases at Griffith Univeristy, examines this question in a recent study. Dr. Marshall is a leading ME/CFS researcher, as well as a member of Simmaron’s Scientific Advisory Board.

Proponents of using a more restrictive definition such as the CCC/ICC believe that winnowing out a homogeneous group in research studies  could be the key to figuring out ME/CFS.  Once ‘non-ME/CFS patients are eliminated, core factor will pop out and be quickly replicated.  It’s an enticing vision.

netOthers worry that a more narrowly focused group might miss some legitimate ME/CFS patients. The ‘wider net’ approach, may have been embodied in the ‘empirical definition’, which grabbed a large set of ‘CFS’ patients, from which subsets could conceivably have been winnowed.

This strategy would have the benefit of applying to a larger population (up to 4 million in the US), and might work well if the funds and will had been available. Without that commitment that  strategy runs the risk of producing almost meaningless results.

A recent publication by Dr. Sonya Marshall-Gradisnik’s team compares the immune functioning of ME/CFS patients meeting the International Consensus Criteria vs. those meeting the Fukuda/1994 CDC definition, giving us a start on determining the pros and cons of a more narrow vs. a broader approach to ME/CFS research.

Fukuda/1994 CDC Definition

The fact that few research papers in the last twenty years used something other than the 1994 Fukuda definition to define their participants means that virtually all the findings in ME/CFS from the natural killer cell dysfunctions to low blood volume to exercise intolerance, etc., have all been found using the Fukuda definition. By putting all researchers on the same playing field, the Fukuda definition has played an important place in the history of ME/CFS research, but its vagueness and its inability to highlight what many believe to be the key symptom in ME/CFS means it almost certainly allows several questionable subsets into research studies.

The Study

Sixty-three participants including 41 people with ME/CFS and 22 controls answered questionnaires and gave blood samples. The blood samples were assessed for immune functioning. All patients had been previously diagnosed with chronic fatigue syndrome at the National Centre for Neuroimmunology and Emerging Diseases, a top ME/CFS research lab (and soon to be clinic) led by Dr. Sonya Marshall-Gradisnik in Australia. (Dr. Marshall-Gradisnik serves on the Simmaron Research Foundation’s Board).

Results

The breakdown was fascinating. Seventeen people met the Fukuda criteria but not the ICC, and 18 people met both the ICC and the Fukuda criteria. Five people — over 10 percent — of the ME/CFS patients met neither criteria. This was one small study, but it did suggest that a large percentage of people that doctors identify with ‘chronic fatigue syndrome’ may not meet the ICC, and another substantial subset may not meet either criteria. It does not bode well for a more restrictive approach to ME/CFS.

Natural Killer Cells

It was no surprise to see reduced NK cell functioning show up in both the ICC and Fukuda groups. This reduced natural killer cell functioning is believed to inhibit the ME/CFS patient’s ability to clear new infections and/or stop recurring infections. (Interestingly, reduced NK cell function was not associated with alterations in the cytotoxic factors – granzymes and perforin – that NK cells use to kill cells, as has been seen in the past. The authors suggested, however, that this might have been due to the small sample size.)

Immune Suppression Enhanced in the ICC Group

Both groups demonstrated immune suppression, but the immune suppression was significantly increased in the ICC patients. The increased prevalence of two inhibitory or suppressive immune factors in the ICC group suggested a) they were a distinct group, (b) the promise of more abnormalities showing up when a more restrictive definition was used was fulfilled and c) that their immune system was having more trouble than the Fukuda group’s in becoming properly activated. Treg or T regulatory cells or ‘suppressor’ T-cells are rather new to the scene in ME/CFS, but this is the third study showing significant increases in these cells. That suggests they may play an important role in chronic fatigue syndrome. High levels of Treg cells could be suppressing natural killer cell functioning in ME/CFS.

the word reduced

Both groups exhibited reduced immune activity, but more immune suppression was found in the ICC group

KIR Receptors – High levels of ‘KIR’ receptors on the NK cells of the ICC group (but not the CDC group) could further suppress NK cell function. The presence of two ‘profoundly’ inhibiting factors suggested the ICC group’s immune systems were getting particularly hammered. (Increased levels of an ‘activating’ NK cell receptor were also found. The authors felt this resulted from an attempt to balance the ‘overwhelming’ inhibitory signals from the two inhibitory receptors.) (Receptors on the surface of a cell greatly influence what the cell does. NK cells that are dotted with inhibitory receptors, for instance, can be easily turned off. Conversely, NK cells with few inhibitory receptors will be difficult to turn off.) The authors suggested, but could not prove, that the ICC group carried genes that promoted a tendency towards NK inhibition.

Hitting Home – Physical Functioning Affected

One of the vital questions regarding the abnormalities in ME/CFS is how much they matter. Ironically, THE immune finding in ME/CFS, poor NK cell functioning, didn’t pan out in this regard. While low NK cell functioning was associated with poorer health in the healthy controls, it didn’t appear, at least in this small study, to be correlated with poorer health in the ME/CFS groups. Decreased CD39+ and altered KIR receptors were, however, ‘strongly’ associated with poorer health in the ICC (but not the Fukuda delineated patients). This  suggested that immune suppression was having an impact in the ICC delineated patients.

Touchy Situation Ahead

The increased  amount of immune suppression in the ICC group suggested that the ICC criteria did select a more immune-challenged set of patients and that group should be set apart for separate study. The immune findings in the Fukuda group (low NK cell functioning/increased Tregs) were nothing to sneeze at, however. Plus, the high percentage (almost 50%) of patients meeting the Fukuda criteria, but not the ICC criteria indicated that group cannot be ignored. The ten percent of people with ME/CFS that met neither criteria suggested an important subset of people who are sick, but don’t meet either criteria, may be present. The fact that all the study participants were identified by ME/CFS researchers/doctors working at an ME/CFS lab suggested they were indeed ME/CFS patients. These researchers proposed that both groups should be included in studies. Since all the people that met the ICC also met the Fukuda/1994 CDC criteria, starting off with the Fukuda criteria and then examining the ICC criteria patients could achieve this.

Conclusion

“These findings are highly suggestive of a need to incorporate both the 1994 CDC and the ICC in future clinical research”

Study authors

With a new research definition coming up on the docket, it was good a see a study examining a prominent candidate — the International Consensus Criteria.

casting a net

With this study suggesting both definitions have merit, determining how wide or narrow of a net to cast in the research definition will not be easy.

The IOM contract for a clinical definition was really just a prelude to the big problem looming ahead, which is creating an appropriate research definition.

Since the research definition defines what types of patients participate in a study, its use can fundamentally alter how a disorder is viewed or researched.

The suppressive nature of the immune dysfunctions found in the ICC group suggested, to my mind, that they might be ‘Fukuda plus’ patients dogged by increased levels of immune suppression.

This study gave no clear answers. It suggested that patients that meet the Fukuda criteria but not the ICC criteria are an important subset of ME/CFS, but it also suggested that segregating patients meeting the ICC criteria could help uncover more immune abnormalities.