All posts by Cort Johnson

Making Music – and a Difference – for ME/CFS

May 28, 2017

Making Music For ME/CFS

For the second time this month, the loved one of an ME/CFS patient has dedicated talent and sacrifice to raise funding for Simmaron Research and awareness of the disease more broadly.

Michael Jasper met Terry’s husband, Silvestre, 13 years ago and over time the two couples became best friends, even like family to each other but for a while they were a family with a mystery: Terry would mysteriously disappear at times. When the Jaspars were told she had something called “chronic fatigue syndrome” the explanation helped even as it obscured.

terri sylvestre

Terri Gilmete – in her scooter – advocating for ME/CFS

It wasn’t until Michael and his wife Marie saw a screening of “The Forgotten Plague” earlier this year that they really began to  understand what was going on. Terry wasn’t just tired – she was really sick! They’d seen her only on her best days, which unfortunately were few and far between.

“The Forgotten Plague” turned out to be a line of demarcation for them. They’d pounded Terry with questions about the disease after that. They now know the history, they know the neglect, they know the seeds of change that are sprouting now and they wanted to do something for their friend.

Several months later Michael asked for a meeting and when Terry was well enough Michael and his family broke the news: he was resurrecting his music career and wanted to dedicate the song “Beachwalk” to Terry and the ME/CFS community. He’d composed it years before, and when he and his daughter, Marissa, got to work on the album, it was the first song they’d worked on.

Michael told me that he’d played in the greatest garage bands that never made it. Along the way, he’d played and toured around the world with many figures in the music industry. Now as he re-emerged into the music scene he was putting those connections to good use – having them join him on the new album he and his daughter – who, having just graduated from college with a degree in music –  were going to release in December.  Merging old and new –  his old-school R & B and funk roots with her contemporary pop and dance sound – the album will have a unique sound.

Beachwalk-flyerBeachwalk’s melody described for him a simple pleasure that few people with ME/CFS could enjoy:  a relaxing walk on the beach, the sun overhead, the sand in their toes – a walk that left them relaxed and rejuvenated. Such an easy thing to contemplate for most people but just a dream for Terry and so many others.

For me I heard the keyboards, horn and guitar singing a song of triumph; a song celebrating someone finally making it to their beach after years of effort. It was an uplifting feeling.

Music for Simmaron

It was out of a vision of Terry, their good friend of many years, and others with ME/CFS finally taking their well-deserved walk on the beach, that Michael is donating 50% of the proceeds from the sale of Beachwalk to the Simmaron Research Foundation to help people with ME/CFS.

Please take a  walk on the beach with Michael Jaspar, his daughter Marissa  and other as they play for Terry Gilmete and others with ME/CFS to support Simmaron. You can find Beachwalk:

Check out Jaspar 3D’s Facebook page here. Michael didn’t stop his advocacy with Beachwalk – he’s fully engaged and promoting ME/CFS events on it – including the June 2nd Millions Missing Rally in Sacramento.

Millions Missing Rally & a Song in Sacramento on June 2nd

The problem, of course, is that people with ME/CFS aren’t able to walk far, if at all. They’re largely missing from the rounds of daily life – an absence dramatically evoked by the MillionsMissing rallies featuring ME/CFS supporters and their shoes.

Millions Missing

Terry Gilmete and Linda Tannenbaum

This Friday, June 2, patients and loved ones will gather on the steps of the Capitol in Sacramento for a MillionsMissing Rally and a live debut of the Jaspars’ Beachwalk.

The Sacramento Rally featuring Terry Gilmete, Michael Jaspar and others has a story all its own. The woman who organized it, Marilyn Yu, also created “The Forgotten Plague” screening which opened Michael Jaspar’s eyes and got him, his wife and daughter involved. In 2016, Marilyn, who’s had ME/CFS for three years, got West Sacramento, Elk Grove and Sacramento to do proclamations of their own. She’s gotten the Sacramento City buildings lit up in blue for the  past 2 years. The Sacramento Convention Marque featured May 12 as ME/CFS Awareness Day. Marilyn also created a virtual run last year in which she raised some money for Simmaron.

On May 18th, a number of California patients including Terry Gilmete and Marilyn Yu met with Senator Glazers and Moorlach to sponsor SCR-40 which proclaimed May 12th ME/CFS Awareness day and the month of May Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Month in California. Senator Moorlach passionately spoke of his friend’s daughter who’s been disabled from ME/CFS for 18 years.

The striking and, in many ways, beautiful California resolution resolved that…

  • WHEREAS, ME/CFS has been found by the National Academy of Medicine to be “a serious, chronic, complex, and systemic disease that frequently and dramatically limits the activities of affected patients,” leaving them with a lower quality of life than patients with multiple sclerosis, stroke, renal failure, heart failure, and other chronic diseases; and
  • WHEREAS, The lack of tracking for ME/CFS by the CDC and the grossly inadequate NIH funding for research based on disease burden have hindered progress in diagnosing and treating ME/CFS, such that there is no FDA-approved treatment for the disease; and
  • WHEREAS, ME/CFS is a tragic and disabling disease that destroys the lives of many patients and imposes a severe toll on their families, friends, and caretakers;
  • WHEREAS, The economic impact of ME/CFS in the United States is estimated to be $20 billion to $50 billion per year (CDC February 2016) and likely costs the California economy billions of dollars in health care costs, patient care, lost productivity, and lost tax revenues;
From Australian Rally

From Australian Rally

The Legislature hereby proclaims May 12, 2017, as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Day, and declares the month of May 2017, and each May thereafter, as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Month, to help spread awareness of the disease and the need for increased research funding, and to support individuals living with ME/CFS;…

On June 2nd, Michael Jaspar, Marilyn Yu, Terri Gilmete and others will all be at ME/CFS Millions Missing Rally in Sacramento at the CA State Capitol Steps-south side on June 2 from 11:30-1:30. A shoe exhibit will be on display from 10:30-4. The music will be an inspiration all our own in the ME/CFS community.

  • When: June 2, 2017, 10:30-4:00 shoe display, 11:30-1:30 rally and musical debut
  • Where:  CA State Capitol Steps-south side

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A Run for His Son…and Everyone: An ME/CFS Parent Steps Out

May 21, 2017

A run for his son…

Most people in their late 60’s probably aren’t running half marathons. Alex Ribaroff had run them twice before, when he turned 50 and 60, and he swore he would never do a half-marathon again.  But here he is, at age 67, three months into his training, on the verge of doing just that.

Tom Ribaroff ME/CFS

Tom was perfectly healthy until he came down with infectious mononucleosis at age 16

This time he’s not doing it to celebrate a milestone. He’s doing it to for his son, Tom.  Tom was a strapping young man – athletic, academically inclined and outgoing – when he fell prey at 16 to an Epstein-Barr virus (EBV) infection in the UK. Getting exposed to EBV as a child is usually a piece of cake but if you encounter it as an adolescent, it’s another deal indeed; it’s a very common trigger for ME/CFS.

Tom got hit so hard he had to leave school. Two months later, still not well but itching to get back, he returned – only to get hit harder by another bout. That was five years ago. Tom is at University now, he’s hanging on but everything other than academics – sports, exercise, socializing – is out.  It’s no way for a young man to get through college.

Tom and his family went through the same experience that so many other sufferers from ME/CFS have – the fruitless search for help – the suggestions to use CBT and graded exercise.

Slowly, Alex and his wife Denise learned more about ME/CFS, the many people affected, the few experts, its marginalization and it’s need for funding.  They’ve come to grips with the fact that their young son has a debilitating and chronic illness that many have not recovered from – and they decided to try and do something about it.

They’re raising money to support ME/CFS research. It’s not like they’re experts at this. In fact, they’re complete novices, but their burning commitment to help is pushing them to do things they’ve never done before.

When I asked them why they were stepping out like this, Alex and his wife described the helpless feeling they had watching their young son get sicker and sicker.   “You expect your children to be healthy” he said, and if they’re not then “you expect the medical profession to be able to do something about it.”  No one should have to experience that feeling around their children.

By chance, a year ago, a friend of the family sent them an article from the Guardian newspaper in the U.K., talking about the research advances being made by Mady Hornig and the Center for Infection and Immunity.

Hornig MD, and Ian Lipkin, a world-renowned pathologist, have taken a special interest in ME/CFS. The blood and spinal fluid studies they’ve done in collaboration with the Simmaron Research Foundation (SRF) and other groups found that ME/CFS patients first exhibit a pattern of high immune activation which is followed by immune exhaustion.  Their joint CII/Simmaron Research Foundation cerebral spinal fluid study found a degree of  immune dysregulation similar to that found in multiple sclerosis. (An expanded study is underway). Another joint CII/Simmaron Research Foundation study identified a new class of ME/CFS patients (“atypical patients”) who have unusual disease trajectories and test results). Their latest study found dramatic differences in the gut flora which may eventually lead to targeted gut therapies.

A conversation with Hornig led the Ribaroff’s to get in touch with Dr. Peterson and the Simmaron Research Foundation.  Only then did they feel that they had found a clinician who understood this illness and might be able to help them.

When they found out how many people’s lives are blighted by the disease, and how many people’s future has been darkened by the cloud of ME/CFS hanging over them, their focus shifted. The fight became about more than for Tom.  It became a fight for everyone who has this illness.

Banner-new-2017 from website

So, Alex at age 67 is now lacing up his running shoes for a half-marathon he didn’t ever expect to run again. He’s raising money for two groups – the Simmaron Research Foundation and Columbia University’s Center For Infection and Immunity-  that provided them with answers when they desperately needed them.

Alex Ribaroff

Alex was appalled by the helpless feeling he and wife had when Tom got sick. Now they’re doing something about that.

They’ve put the call for help far and wide to their friends, many of whom were shocked to hear the healthy, young man they’d known was struggling so much.  Jen Brea’s moving “TED talk” – now seen by over 1,200,000 people – proved to be a powerful introduction to a disorder many of them had never heard of.  Alex and Denise hope to raise $75,000 – the first $25,000 of which they will match.

The Ribaroffs are getting more involved. They’re going to meet with Dr. Peterson, Dr. Hornig and other luminaries at the London “Invest in ME” conference, to better educate themselves about global advances in research.

But first comes the run. In just two days Alex will put the memories of the last two runs aside and step out onto the track and run – for his son and everyone else with ME/CFS.

Please support Alex and Denise‘s commitment to help their son and many others with your donation to the Simmaron Research Foundation here.  (The Simmaron Research Foundation will receive half of the donations raised and will provide the other half to support Ian Lipkin and Mady Hornig in their ME/CFS work at the Center for Infection and Immunity.)  PayPal and Credit Cards accepted.

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Update: Sixty-seven year old Alex Ribaroff successfully completed the Bermuda Half-Marathon on the 25th of May 🙂

Columbia & Simmaron Gut Study Uncovers Another Chronic Fatigue Syndrome (ME/CFS) Subset

With their second myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) study published this month, Ian Lipkin and Mady Hornig’s Center for Infection and Immunity (CII) and collaborator Simmaron Research are on an ME/CFS roll.  As with all CII studies, this one combined unusual rigor and the latest technological advances to cast new light on ME/CFS – and possibly  produce yet another subset.  Longtime CII collaborators, the Simmaron Research Foundation and Dr. Daniel Peterson provided samples for both studies.

precision-gut-data-me-cfs

This study used the latest technology to dig deeper into ME/CFS patients guts than ever before.

Published this week, the new study combined microflora, metabolic and immune analyses in fifty chronic fatigue syndrome (ME/CFS) and healthy controls from four clinical sites (Dr. Peterson, Dr. Lucinda Bateman, Dr. Nancy Klimas and Dr. Susan Levine). A typically rigorous study  from the Center, it matched ME/CFS and healthy controls in numerous ways (age, sex, race, geographic site and season of sampling). The goal was to take the deepest look yet at gut bacteria and their effects on metabolic pathways and the immune system.

Species, Species, Species….

This was a gut study with a twist.  All chronic fatigue syndrome (ME/CFS) gut studies to date have used a process called 16 S rRNA sequencing to characterize the gut microbiome. Unfortunately this process, which focuses on one section of the bacterial genome, is unable to differentiate approximately 40% of the species within each bacteria genera.  Because different primers can also produce discordant results, results of 16 S rRNA studies can also vary from study to study.

These studies have been valuable; they’ve have indicated that something is off in the ME/CFS patients guts, and have given us some idea about the bacterial species involved, but because they can’t differentiate between some of the helpful or harmful species in a genera, they lack specificity.

Lipkin has changed the ways researchers identify pathogens

Dr. Ian Lipkin, Columbia Center for Infection & Immunity

Enter Ian Lipkin. It’s perhaps no surprise that technological ace Ian Lipkin would be the first to produce a study that really gets at gut species in ME/CFS.  (Lipkin has invented several viral identification tools). Lipkin used a more expensive tool called metagenomic sequencing which analyses the entire genome. It has even been used to identify species new to science.

Lipkin’s ME/CFS study identified more than 350 bacterial species.  How cutting-edge Lipkin’s approach was showed up when I asked him if finding 350 species was unusual. He said he couldn’t say; the technique hasn’t been used enough in other diseases to tell. He was confident, though, that the species the study identified were correct.

The study indicated that the guts of people with chronic fatigue syndrome (ME/CFS) were harboring  a significantly different flora than the healthy controls.  As in other studies, the relative abundance of species from one phylum (Firmicutes) chiefly defined the ME/CFS.

Moving from the top down, topological  analyses and prediction models found that the relative abundances of seven bacterial genera (Faecalibacterium, Roseburia, Dorea, Coprococcus, Clostridium , Ruminococcus, and Coprobacillus) differentiated ME/CFS patients from healthy controls as well.

Getting into the species level, four gut species in particular (C. catus, P. capillosus, D. formicigenerans , and F. prausnitzii) and four others (C. asparigiforme, Sutterella wadsworthensis, A. putredinis, and Anaerotruncus colihominis) mainly differentiated the ME/CFS patients from the healthy controls.

Thankfully, the study’s general conclusions jived with the results of past ME/CFS studies which also found reductions in Faecalbacterium and increases in Alistepes bacteria.

Another Study – Another Subset

Ian Lipkin and Mady Hornig are beginning to specialize in uncovering subsets in ME/CFS. Their studies are bringing scientific definition to Dr. Peterson’s and other clinicians’ long experience of clinical subsets. First they identified a short/long duration subset, then they uncovered Dr. Peterson’s atypical patient subset and now they’ve illuminated an ME/CFS-irritable bowel syndrome (IBS) subset.

Whether they had IBS or not, chronic fatigue syndrome patients had a different microbiome than the healthy controls. Topological analyses, however, indicated that having IBS, changed a great deal.

The relative abundance of four bacteria (Faecalibacterium species, R. obeum, E. hallii, and C. comes) were lower in the ME/CFS + IBS group than the ME/CFS – IBS group. One bacteria (D. Longicatena) that was increased in ME/CFS patients – IBS, was actually decreased in the ME/CFS + IBS patients. This appears to suggest that ME/CFS patients with IBS specialized in having lower abundances of “good bacteria”.

IBS-ME/CFS-GUT

Irritable bowel syndrome (IBS) added another overlay to the ME/CFS gut picture

Encouragingly some of those same bacteria are low in IBS studies. Low levels of these protective bacteria have been associated with gut hypersensitivity, bloating and discomfort in both animal and human studies.

That suggests that having inadequate levels of these bacteria may result in inflammation which attacks the gut lining and allows bacteria to escape to the blood.  Once in the blood the bacteria are believed to trigger a systemic immune response that may be able to affect the central nervous system.  Evidence of leaky gut has shown up in several ME/CFS studies.

Gut Triggers

Lipkin drew a possible connection between the flu-like onset in ME/CFS that many people experience and gastrointestinal infections that can precede irritable bowel syndrome. Studies indicate that gastroenteritis or the stomach flu increases one’s chances of coming down with IBS six fold – but does it also increase the risk of getting ME/CFS?

Lipkin asked if the same gut infection could trigger both diseases. Studies suggest yes. Even when treated, giardia infections can produce long lasting cases of ME/CFS. (Three years after being treated for Giardia, 50% of those affected still suffered from chronic fatigue and/or Giardia.) Tests indicated that their illness persisted long after they’d cleared the bug from their system. Dr. John Chia, of course, has long associated ME/CFS with enteroviral gut infections.

Several well-known ME/CFS patients (author John Falk, Tom Hennessey, Whitney Dafoe) experienced some sort of stomach flu before becoming ill. (I contracted Giardia about three years before becoming ill. Tests years later indicated it was still present.)

Metabolic Tweaks

We know that the bacteria in our gut affect our metabolism.  It’s in the gut, after all, where many of the metabolites that our bodies use get manufactured.  Next the researchers used a pathway analysis to try and determine what effects those differences might have on metabolic functioning.

Differences, Differences – Their metabolic pathway analysis indicated different metabolic pathways were accentuated in the different groups.  Vitamin B6 biosynthesis and salvage, pyrimidine ribonucleoside degradation, and atrazine degradation all appeared to be going gangbusters in the ME/CFS patients at large while the production of arginine, polyamine, unsaturated fatty acid (FA), and mycolate appeared to be significantly reduced relative to the healthy controls.

gut bacteria-IBS-ME-CFS

Are gut bacteria in contributing to the energy problems in ME/CFS patients with IBS?

The ME/CFS with IBS group looked far different from the ME/CFS group overall with projected increases in the production of fucose, rhamnose, atrazine degradation and L-threonine biosynthesis, reduced heme, AA and polyamine biosynthesis, and reduced purine, pyrimidine, and unsaturated FA metabolism compared to the controls. Of those pathways only the atrazine degradation and decreased unsaturated FA metabolism were similar to the ME/CFS patients without IBS.

Energy production has become a key area of study in ME/CFS but no study until this one has implicated IBS in that problem.  A mitochondrial pathway affecting the Krebs cycle was upregulated in the ME/CFS – IBS group and downregulated in the ME/CFS + IBS group.  The pathways affecting metabolites associated with the urea cycle (another metabolomic finding) also only effected the ME/CFS + IBS group.

Throughout the paper the authors cautioned that they didn’t know if bacterial issues in the gut might be causing problems with energy production or other factors.  The findings, though, lead the authors to speculate that some metabolomic findings could be caused by the inclusion of high numbers of  ME/CFS + IBS patients in their studies. That’s an intriguing question given that up to 90% of ME/CFS patients may have IBS.

Similarities – Problems with fatty acid metabolism proved to be one of the ties that bind: the reduced activation of those pathways in ME/CFS patients with and without IBS suggested that problems with fatty acid metabolism could be producing inflammation in both groups.

Enhanced vitamin B-6 synthesis was also a hallmark of  both the ME/CFS + and – IBS groups. Dr. Wessely, of all people, suggested way back in 1999 that poor Vit. B6 synthesis in ME/CFS could be causing central nervous system issues. A further analysis nailed increased atrazine  (a pesticide) degradation as a key factor in both the ME/CFS and ME/CFS + IBS groups compared to the controls.

Conclusion – Some important similarities in bacteria activated metabolic pathways are present in both ME/CFS patients with and without IBS, but important differences were found as well.

 Immune Study

Mady Hornig sits on the Simmaron Research Foundations Board. She and the Simmaron Research Foundation are frequent collaborators.

Dr. Mady Hornig, Columbia Center for Infection & Immunity

In a recent blog, Dr. Hornig pointed out that it’s clear that the bacterial communities in our gut shape our immune response. For all the bacterial differences found in this study, though, none were linked to changes in cytokine levels – a somewhat surprising finding since bacterial alterations are believed to produce their effects via immune activation.

Dr. Lipkin, however, suggested that too few short duration ME/CFS patients with upregulated immune systems were present in the study to pick up immune differences. It could also be that a bigger patient sample would have detected them as well.

Some important immune differences were found, however. One of the master pro-inflammatory immune factors in the body – TNF-a – was increased in the ME/CFS group.  Plus Jarred Younger’s big finding – leptin – plus another CXCL immune factor showed up in the ME/CFS + IBS group.  CXCL-8 has not been found in ME/CFS before but another chemokine CXCL-9 was significantly reduced in Dr. Peterson’s atypical subset, and in Houghton’s cytokine study

 Symptoms

The differences in gut makeup didn’t show up in immune system changes but they did appear to effect symptoms. Increased levels of  several species (R. gnavus, C. bacterium, C. bolteae, and C. asparagiforme) were associated with better vitality, health change, and motivation scores. Decreased relative levels of F. prausnitzii and C. catus were associated with worse emotional well-being scores, while levels of R. inulinivorans and D. formicigenerans were associated with improved motivation scores.

 A Focus on Faecalibacterium prausnitzii

good-bacteria-reduced-me-cfs

A good bacteria that was reduced in ME/CFS is also reduced in IBS, IBD, asthma, depression and other diseases.

F prausnitzii is not your ordinary gut bacteria. Making up about 5% of our gut bacteria, F. prausnitzii is one of the most abundant and consequential bacterium found in our guts. Unlike many other gut bacteria, F prausnitzii hangs out in and around our gut lining.    It mainly  produces short-chain fatty acids such as butyrate (remember the fatty-acid synthesis problem?) through its fermentation of dietary fiber. It also appears to have anti-inflammatory effects including  the induction of IL-10 and TGFB-1.

F. prausnitzii is considered a “clostridial microbe” – a bacteria that’s distantly related to the dangerous Clostridium difficile. While C. difficile causes inflammation, bleeding and sometimes death by diarrhea, other clostridial microbes such as F. prausnitzii work to soothe our immune systems and strengthen our gut lining. F. prausnitzii was recently highlighted in a Scientific American article “Among Trillions of Microbes in the Gut, a Few Are Special“.

Reduced levels of F. prausnitzii have been associated with both gut diseases  (irritable bowel syndrome (IBS), Crohn’s Disease, inflammatory bowel disease, ulcerative colitis) and others including asthma, psoriasis, and depression, of course, now chronic fatigue syndrome.   It’s considered a potential prime candidate in the treatment of inflammatory bowel disease.  It was the only gut species that showed up in a meta-analysis of irritable bowel syndrome gut studies.  It appears to be an indicator of general gut health.

Reduced levels of F. prausnitzii (and one other bacteria) were the strongest predictors of having ME/CFS in this study.

Treatment (Treatment?)

“Much like IBS, ME/CFS may involve a breakdown in the bidirectional communication between the brain and the gut mediated by bacteria, their metabolites, and the molecules they influence. By identifying the specific bacteria involved, we are one step closer to more accurate diagnosis and targeted therapies.” Ian Lipkin

One of this study’s strengths was it’s ability to identify specific bacterial species. A targeted prebiotic-probiotic approach could presumably use findings such as these to jack up the levels of beneficial bacteria in hopes of producing a healthier gut. In a U.K Times interview, Lipkin speculated that given the dire need for effective ME/CFS treatments, some people were going to try to do just that.

“The ME/CFS community is very eager to find solutions. I expect there will be people immediately trying to modify their microbiota. In the end we think all this needs to be done in a full clinical trial but there will be people acting on this.”

I asked Dr. Lipkin if we were ready for a focused pre and probiotic treatment for ME/CFS.  As always he warned against one-size fits all prescriptions for ME/CFS but stated that we were getting there….

 Getting there. Treatment for ME/CFS won’t be a one size fits all. We anticipate that some people will benefit from pre and probiotics.

He also provided an interesting teaser: some upcoming studies from his group will suggest that different types of ME/CFS patients will benefit from immune or neuro-modulating drugs.

 In work we are preparing now for publication we see clues that that some people will also benefit from drugs that modulate immune responses whereas others will benefit from drugs that modulate neurotransmission.  

A Growing Field

ME/CFS may not be ready yet for a targeted probiotic treatment but the probiotic drug field is growing. Like any new field it’s going through its growing pains. A startup named Seres, valued at $130 million when it went public last year, failed at a clinical trial aimed to treat C. difficile infections with drug derived  from human feces.

Theoretically it should have worked. OpenBiome says it’s successfully treated 15,000 cases of C. difficile infection  since 2012 using raw poop donated by volunteers. Seres simply provided a well characterized mixture of what it thought were the right bacteria species.

The NIH is helping to move things along, so to speak, by funding a fecal transplant registry that sequences the microbiomes of fecal transplant patients pre and post-transplant in an attempt to uncover which bacterial strains work best.

A recent small autism fecal transplant clinical trial, on the other hand, went swimmingly well. Like ME/CFS, altered gut microbiomes and irritable bowel symptoms are common in autism. (Bob Naviaux finds similar patterns of metabolites in both diseases.)

First the kids got an antibiotic, and a gut cleanse to clear the gut of bacteria. Then they got a dose of “standardized human gut microbiotia” (either orally or rectally) in combination with a stomach acid suppressant (Prilosec) for 8 weeks to repopulate it. According to a Medscape article “Fecal Transplants May Yield Lasting Benefits in Autism“, autism scores went down significantly.

Autism and gut tests eight weeks later indicated the improvements had persisted and that many of the new bacteria had permanently colonized the gut. A much larger placebo-controlled, double-blinded trial is being planned.

It’s clear that Dr. Lipkin believes that targeted pre and probiotic treatments will be able to help some people with ME/CFS. He’s certainly not alone in believing the probiotics are going to help with disease. Money is being pumped into several companies aiming to produce probiotic drugs. Here are some examples.

After a Japanese researcher identified 17 clostridial species  including F. prausnitzii that were able to halt runaway pro-inflammatory activity in mice, Vedanta Biosciences, a Massachusett’s company, pulled in $50 million in venture capital to produce live bacterial drugs to treat inflammation, infections or cancer. Vedanta asserts that the “here today, gone tomorrow” bugs found in yogurt are too transient to do much good.

Synlogic brought in $70 million over a couple of years to develop a “smart” bacterial based drug that responds to different conditions in the gut.  A San Francisco company, Second Genome, recently scored $43 million to develop a bacterial-based drug for inflammatory bowel disorder. The military gave Gingko Bioworks almost $2 million last year to produce a “probiotic vaccine” to protect U.S. troops against the bad bacteria they encounter overseas.

 Intellect and Compassion

Ian Lipkin has a reputation as a hard-nosed scientist but he has a strikingly compassionate side as well. He was one of the few doctors willing to treat AIDS patients early in the epidemic. While everyone who could left China during the SARS epidemic, Lipkin flew on an empty plane bringing medicines to China. In a Times UK article titled “Gut bacteria linked to chronic fatigue” Lipkin made a direct appeal to ME/CFS patients to hang on.

“We don’t think this could be a panacea. It is a complex disorder. But we do think there are a group of people who may be helped. It is our fervent hope to find real solutions. People become despondent and even suicidal. I want them to realize that we are working on this. Please hang on.”

Next Up for the Lipkin/Hornig Team

I asked Lipkin what was next for his group. After laying out his desire for a comprehensive and integrated approach to ME/CFS, he noted that despite the NIH’s increased funding, a thicker shoestring is still a shoestring and once again called for a much more funding.

We are currently putting the finishing touches on our NIH Collaborative Research Center proposal. And, we are integrating clinical, microbiome, metabolomic and gene expression data using mathematical programs with the goal of achieving precision medicine for the ME/CFS community. What we need is a moonshot akin to what will be done for cancer. Our challenge is to do it on a shoestring.

lab testing

The CII is one of probably 7 or more sites vying to become an NIH funded research center

Lipkin has the samples to do this. He and Hornig gathered samples at different time points over a year in many ME/CFS patients but inexplicably weren’t given the funding to analyze them. Had he finally gotten that funding yet?  It turned out that even with a successful research center application he will still need more money. (With the heavy administrative reporting needs baked into the research centers and the need to bring in outside researchers, $1.2 million is not going to go a long way).

 Wish we did.  In the event we are successful with our Center application—and that is by no means certain because many excellent teams are putting in applications—we will still be significantly short because there is so much to do. Continued community support is critical!

The competition will be intense indeed for those three NIH funded ME/CFS research centers. Applications are believed to be going in this week from at least seven groups: Ron Davis, Nancy Klimas, Ian Lipkin/Mady Hornig, Jarred Younger, The Nevada Center for Biomedical Research (formerly WPI), Dr. Montoya and Maureen Hanson. Others may be applying as well.

Conclusion

The Center for Infection and Immunity was able to distinguish ME/CFS patients with and without IBS from healthy controls using  analyses of their gut flora. Underlying alterations in gut flora were common to all ME/CFS patients but having IBS as well had a  major effect on the gut flora and possibly on ME/CFS patients’ metabolism.

Using a technique that was better able to identify more gut species than past studies, the group found marked differences not just in the gut flora of ME/CFS patients with IBS but in the metabolic pathways those differences are believed to effect. Problems with ATP production and the urea cycle might be more associated with ME/CFS + IBS patients while problems with fatty acid metabolism appear to be common to all ME/CFS patients. The study suggested that infectious gut illnesses might be common triggers of  both ME/CFS and IBS.

The Simmaron Research Foundation

Three studies – three subsets identified using clinical expertise, cutting-edge technologies, and precision medicine. With your support the Simmaron Research Foundation is  redefining how ME/CFS is understood and treated.

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Peterson’s Atypical Subset Opens New View of ME/CFS in Columbia/Simmaron Publication

“We now have biological evidence that the triggers for ME/CFS may involve distinct pathways to disease, or, in some cases, predispose individuals to the later development of serious comorbidities.” Dr. Mady Hornig. 

The Subset Makers

Simmaron Research | Scientifically Redefining ME CFS | #ShakeTheCFSstigmaOver the past couple of years the Simmaron Research Foundation and Center for Infection and Immunity at Columbia University and others have begun to pump out some long awaited subsets. This week, new findings were published by Columbia and Simmaron that define 2 subsets.

They’re not the usual suspects (infectious trigger vs non-infectious trigger; gradual onset vs acute onset). In fact, they involve subsets few would have predicted a couple of years ago. They suggest that we might be in for some real surprises over time.

Short Duration vs Long Duration Subset: Two years ago, the Simmaron Research Foundation collaborated with Ian Lipkin and other doctors to uncover a subset few had anticipated: short duration patients vs long duration patients.

The Atypical Patient or “Peterson Subset”:  Now comes a subset of atypical chronic fatigue syndrome (ME/CFS) patients (the “Peterson Subset”) that Dr. Peterson had long wondered about. These patients had ME/CFS but tended to follow a different course. Some had had unusual exposures (unusual infections, blood transfusions); others developed serious illnesses (cancer, autoimmune diseases, etc.) that Dr. Peterson didn’t see in the rest of the population.

Dr. Hornig talked about how the atypical subset came about. Like so many breakthroughs in medicine it took a careful and observant doctor/researcher to bring it about. This study, she said, was a testament to:

“Dr. Peterson’s clinical acumen, his long-term follow up of this patient population and his attentiveness to the full range of complex, serious medical disorders that might develop. The classical group had been followed for similar lengths of time but had not developed these more severe, serious comorbidities.”

The atypical vs classical distinction was pre-established by Dr. Peterson before the analysis. Based on his wide-ranging clinical experience, the atypical group stood out for either: 1) the presence of unusual precursors (triggers) of ME/CFS or; 2) the development of more unusual and severe comorbidities over varying (and often long-term) intervals after ME/CFS onset.”

atypical subset

The atypical group turned out to be quite different

Dr. Peterson felt the unusual outcomes weren’t just the result of chance: something different was going on – something that he felt as a doctor needed to be identified. What if, he thought, there was a way to identify these unusual patients before they started developing these significant illnesses. Then he could do more extensive cancer or immune screens and watch these patients more closely.

Plus, these patients could be inadvertently bollixing up the results of ME/CFS studies. Peterson was so sure, in fact, this subset was different that he had its effects assessed during the first Simmaron/CII spinal fluid study. Peterson turned out to be right: the atypical subset had such an effect on the results that it had to be removed.

The next step was a study comparing the two groups. Using Dr. Peterson’s spinal fluid samples, The Center for Infection and Immunity (CII) at Columbia found that “Peterson Subset” not only had markedly different immune findings but displayed a different pattern of immune results as well. Dr. Peterson is Scientific Advisor to Simmaron and Gunnar Gottschalk was its Research Manager.

Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations M Hornig1,2, CG Gottschalk3, ML Eddy1, X Che1, JE Ukaigwe1, DL Peterson3 and WI Lipkin. Translational Psychiatry (2017) 7, e1080; doi:10.1038/tp.2017.44; published online 4 April 2017

 The Atypical Subset

What does a typical chronic fatigue syndrome (ME/CFS) patient look like? Something like someone who suddenly comes down with a flu-like illness and never recovers. They may get better or they may get worse, but they don’t come down with cancer, an autoimmune illness, seizures or other significant illnesses.

An atypical patient, on the other hand, might have a history of viral infection (viral encephalitis) or have been exposed to unusual pathogens during foreign travel or had a blood transfusion before becoming ill. They also tended to be more severely cognitively impaired and had more neurological complaints.  They tended to suffer from severe diseases as well.

Many of these illnesses appeared long after the ME/CFS diagnosis. In fact, at the time of diagnosis these patients looked like a typical ME/CFS patient. This study suggests, though, that very early on, something different was happening in their central nervous systems.

The Atypical Patients in the Study (the “Peterson Subset”):

  • Atypical multiple sclerosis – 3
  • Other autoimmune/inflammatory disorders – 4
  • Cancer – 8 (brain-3, breast-2, lymphoma -2, pancreatic-1)
  • Infections – 2 (West Nile Virus encephalitis – 1; Unspecified viral encephalitis – 1)
  • Illness during foreign travel – 2
  • Illness after blood transfusion – 1
  • Seizure disorder – 6
  • Gulf War Illness – 1

Immune “Exhaustion”?

This “broadly based” immune study compared 51 cytokines and other immune factors in the cerebral spinal fluid of 32 typical and 19 atypical ME/CFS patients. These numbers at first glance may seem small but they’re actually quite large for spinal fluid studies.

The Simmaron Research Foundation/Center for Infection and Immunity’s prior studies suggested that typical ME/CFS patients’ immune systems went on high alert for the first couple of years of illness but then went into slumber mode. In fact, it was more than slumber mode: their immune activity essentially tanked – leading to the hypothesis that frantic activity of the first couple of years might have left their immune systems depleted.

autoimmune diseases

Autoimmune diseases were amongst the unusual comorbidities found in the atypical subset.

This study suggests that the “Peterson Subset” follows a markedly different pattern. The major burst of immune activity early on followed by equally dramatic downturns found in the typical patients is gone. Instead the study suggests that the immune systems of the atypical patients essentially started off low and stayed low.

Almost half the immune factors tested (IL1β, IL5, IL7, IL13, IL17A, IFNα2, IFNγ, TNFα, TRAIL (TNFSF10), CCL2, CCL7, CXCL5, CXCL9, CSF3 (GCSF), βNGF, resistin, serpin E1) were lower early in the illness in the atypical group.

As the illness proceeded, though, the pattern changed again: the atypical groups’ immune system actually revved up again.

When I asked if immune exhaustion was bringing the immune system down early in the atypical group, Mady Hornig replied:

 “We don’t know yet. Our additional finding of an interaction of diagnostic subset with duration of illness – wherein the atypical group showed a pattern of increased levels of immune molecules with longer duration of illness, as opposed to the dampened immune profiles in the classical group with longer illness duration compared to classical ME/CFS in the early stages of disease  (as we had seen in the immune profiling work based on plasma samples) – suggests that the response tends to be more suppressed at the onset of ME/CFS in the atypical group.”

Could that dampened immune response early in their illness be contributing to the illnesses the atypical group experienced later? Dr. Hornig again cautioned about the need to replicate the study but suggested it might.  A viral trigger could have blasted their immune systems or vice versa – a problematic immune system could have allowed a virus in …

 “However, dampening of inflammatory (so-called Th1/Th17-type) responses might be expected to restrict an individual’s ability to keep problematic microbes from replicating. Certain viruses – even common ones implicated in ME/CFS in some studies, such as Epstein-Barr Virus (EBV) – are well-known to be associated with development of certain cancers; however, only a fraction of those infected with EBV develop cancers.

It is a bit of a chicken-egg conundrum: EBV could alter immune responses of T/NK cells to increase cancer risk, or altered T/NK responses at the time of EBV infection could be the critical factor. Alternatively, reduced Th1/Th17-type immune profiles after infection – along with reduced T regulatory cell responses – might skew some individuals toward autoimmunity, raising the risk for more severe autoimmune diseases, including atypical multiple sclerosis or even autoimmune-mediated epileptiform disorders. But at this early juncture this remains only speculation.”

Epstein-Barr Virus (EBV) brings up the age and exposure question. It’s much more difficult for the immune system to corral or ward off EBV if EBV is encountered for the first time at a later age (during or after adolescence). That difficulty shows up as the months long fight to beat EBV called infectious mononucleosis.

A meta-analysis of studies examining many environmental risk factors for multiple sclerosis (including vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers) found that only three were associated with an increased risk of coming down with MS. Two of those concerned EBV (having had infectious mononucleosis, IgG seropositivity to EBNA). (The last significant factor was smoking).

Could a later exposure to EBV which resulted in infectious mononucleosis be the straw, so to speak, that ultimately broke the camel’s back for some of the atypical patients?

Dr. Hornig agreed that a study parsing out the rates of infectious mononucleosis in ME/CFS could be helpful but said it was hard to know at this point if IM played a role. She said that the CII group was investigating EBV further:

 “Hard to know (if late exposure to EBV is involved)- we are looking for clues suggesting greater risk for autoantibody-mediated disease in EBV and other virally-exposed subsets of ME/CFS. We do know that females have higher risk for autoimmune disease, but the sex skew only begins after puberty (when females might have come down with IM [Infectious Mononucleosis]).”

Poor Networking

Not only was less immune activation present earlier in the atypical groups but a network analysis indicated a weaker immune network was present as well. These network analyses assess the “wiring” present in the complex immune system.

Immune mediators called cytokines (and other immune factors) form these networks when they communicate with each other to drive an effective immune response.  While a central immune network was found in the typical patients, no such network connection was found in the atypical group.  That suggested a less robust immune response was occurring.

Pro-inflammatory Markers Down

pathogen

A less than robust immune response to an infection could play a role in the atypical group.

Surprisingly, the atypical group’s spinal fluid had lower levels of two pro-inflammatory cytokines, IL17A and CXCL9.  Given the atypical group’s increased neurological and cognitive problems one would have expected the opposite.

That suggested that the atypical patients might be more than different in degree; they might be different in kind. The TH17 pathway that underlies many autoimmune and inflammatory diseases, and which the authors believes may be contributing to the typical ME/CFS group, doesn’t appear to be in play in the atypical group. In fact, the authors suggested the researchers vigorously pursue “alternate, nonimmune mechanisms of pathogenesis in more complex, atypical patients with ME/CFS.”

Dr. Hornig suggested genetics might play a role or that a different kind of immune response; one that was a bit too weak early on to knock off a pathogen, was another possibility.

“I think it may rather be the kind of immune response (inadequate inflammatory responses that might serve to contain an infectious agent upon first exposure, with skew towards autoimmunity or permissiveness to later uncontrolled growth of abnormal cells – i.e., neoplasia) and its timing (too little early on, with some limited immune escape at later time points, allowing for some inappropriate inflammatory type responses after the infectious agent has already had an opportunity to set destructive processes in motion – but too little and too late to contain or eradicate the pathogen).”

That could set up what Dr. Hornig called a “smoldering inflammatory process”.

Cause(s)

What might be causing the immune systems of the atypical group to act so differently early on? Dr. Hornig warned that it was essential that the study results be confirmed by a larger study but suggested that different triggers (unusual infections) or genetic vulnerabilities  (environmental susceptibility, immune response, autoimmunity genes) or even one’s age at exposure could play a role.

Results Suggest Atypical ME/CFS Patients Should Be Screened for Cancer and other Diseases

As with any single study the results need to be validated in studies by other labs using other patients to be validated. If they are, though, they could help doctors and patients. Dr. Peterson said:

 “Early identification of patients who meet the usual clinical criteria when first diagnosed but then go on to develop atypical features would help clinicians like myself identify and treat these complex cases and even prevent fatal outcomes.”

Hornig and Lipkin suggested that atypical ME/CFS patients should be screened for cancer just as patients with paraneoplastic syndromes are. Paraneoplastic syndrome occurs when an immune response against cancer affects other parts of the body, often before a diagnosis of cancer is made.

How Common are Atypical Patients?

How many patients are “atypical”? In her answer to that question Mady Hornig called for more comprehensive studies to fully understand ME/CFS.

 “Though we know comorbidity rates in ME/CFS are thought to be high for quite a number of conditions (allergies, gastrointestinal problems), few studies have addressed this issue in a systematic manner.

It is rare to find physicians who specialize in this disorder, let alone follow the same individuals over time. Given the finding that prior to the development of these other serious comorbidities, all members of this subset met research diagnostic criteria for ME/CFS and would only later qualify as “atypical” based on subsequently developing comorbidities (over many years), we desperately need longitudinal studies that monitor for such issues.

The bottom line is that we don’t know what percentage of ME/CFS patients are “atypical”.”

It’s not clear what percentage of ME/CFS patients are atypical but they may  have already had a dramatic impact on ME/CFS research and treatment. Dr’s Fluge and Mella started the Rituximab saga in ME/CFS after noticing improvements in the fatigue, etc. of ME/CFS patients who’d come down with cancer; i.e. atypical patients.

Dr. Hornig has called the spinal fluid samples Dr. Peterson has collected over the years a “precious” resource, and she highlighted his persistence in collecting them over the years.

 “There also may be long-term cohorts at some ME/CFS clinical sites that might be available for closer examination, at least with respect to clinical patterns and disease/comorbidity trajectories. But most of these sites are unlikely to have cerebrospinal fluid samples (let alone plasma samples) banked in a repository for years!

The suggestion that biological pathways in the CNS already look different even before the onset of these comorbidities implies not only that screening and surveillance are likely to be important to ensure better long term care for individuals with ME/CFS, but also that treatment might need to be tailored differently in classical vs. atypical subsets.”

 Similar Issues Showing Up in Other Neurological Diseases

subsets chronic fatigue

Subsets are common in neurological diseases.

Gunnar Gottschalk, a co-author of the study and medical student is a former research manager for Simmaron Research Foundation. He’s been deeply immersed in ME/CFS research for several years and continues as a Trustee of the Foundation.  Gunnar noted that the neuroscience lab he is working in is studying similar issues in Parkinson’s, Alzheimer’s and other neurodegenerative diseases. It’s not that the same findings are present but that highly abnormal spinal fluid cytokine findings are showing up in all these diseases –  including ME/CFS.

Nor is this study’s general finding – that atypical patients can be differentiated from typical patients in ME/CFS – unusual in the neuroscience field.  Virtually every neurological disease, Gunnar said, appears to be studded with subsets. Different types of multiple sclerosis, for instance, have been identified using similar kinds of spinal fluid analyses.

Noting that developing animal models are critical to understand what’s happening in the brain, Gunnar said he wouldn’t be surprised at all if some animal models which have been developed at great cost for other diseases wouldn’t eventually be helpful in some ways for ME/CFS.

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Next Steps

This is not it for the spinal fluid and the atypical patients. Metabolomics and proteomics studies are next in Phase 2 of the study, which is being funded by Simmaron.  Gunnar noted that the cytokine studies can identify important pathways, but the metabolomics studies can provide more detailed results and he’s eager to see how they turn out.

Dr. Hornig has a long, long list of studies she’d love to do in ME/CFS. This is a disease, she feels, that is calling out for comprehensive studies. She wants to analyze blood, fecal and spinal fluid samples collected at the same time to assess what infection or environmental insult the patient is reacting to.

Comparing immune profiles in the blood and spinal fluid could, for instance, help tell her whether powerful immune cells are squeezing though the blood-brain barrier and wreaking havoc in the brain. Determining that immune cells from the periphery are in the brain would open an entirely new window on ME/CFS.

The gut is another area primed for research. Dr. Hornig pointed out that it’s clear that the bacterial communities in our gut shape our immune response. The TH17 profile found in some patients that tilts the immune system towards inflammation could derive from danger signals produced in the gut. Similarly the TH2 profile found in other patients that tilts them towards autoimmunity could come from the gut as well.

What Dr. Hornig wants is “system-biology” work that ties all these systems into a coherent whole. A gut level disturbance could, for instance, end up impacting virtually every system involved in ME/CFS – including the central nervous system.

“Further systems biology-type work will help us delineate how altered gut microbiota might translate into faulty signals – ranging from bacterial or human metabolites, including a range of immunity-modifying and neuroactive molecules, to immune molecules, to autonomic/vagal nerve axis effects – that then access the CNS (perhaps involving damage to the integrity of the blood-brain barrier to allow entrance of these aberrant signaling molecules) and disrupt brain function.”

In fact, Mady Hornig and Ian Lipkin do have most of the samples they need to begin this work. In what must have been one of the stranger NIH grant awards ever, however, the NIH funded the collection of an enormous amount of samples taken at four points over a year in 250 ME/CFS and healthy controls, but has not funded the analysis of these very same samples.

“In the more recent longitudinal NIH study we have no funding at all for laboratory studies, but have a unique banked set of well-characterized samples (oral, fecal and blood).” (bold added)

Having so many samples just sitting there is astonishing, and hopefully the second half of the study will get funded.

When I asked Dr. Hornig about funding the metabolomics and proteomics work she said that the metabolomics and proteomics assays had been run – but only for a subset of patients.  The CII, she said had funding:

 “Only for analysis of a subset of the Chronic Fatigue Initiative main study cohort samples (and this assay work is completed with analysis in progress) – not for the latest 125+ cases and 125+ controls based on the 1-year, NIH-funded study with 4 serial sample collections.

We don’t have any funding to follow up on candidates identified, including validation, quantitation and correlation with genetic, epigenetic and RNA-based assays.”

 A Foundational Approach To ME/CFS Proposed

foundational study

Large foundational studies are needed to take ME/CFS to the next level

Dr. Hornig went further, though, and called for a “foundational” approach to chronic fatigue syndrome (ME/CFS) that included national registries which would be able to tease out subsets and determine just what happens as people get ME/CFS.

“To support this sort of work on a larger scale, fundamental and foundational work is required. National registries of ME/CFS populations could be developed that would have the capacity to identify the range of preceding potential triggers to disease, to define comorbidities at the time of diagnosis, as well as to longitudinally track the new occurrence of comorbidities in ME/CFS populations over time.”

That is the kind of vision this field needs.  That is the kind of vision that should be able to excite NIH and other funders.

The Simmaron Research Foundation’s unique spinal fluid work with the CII has thus far helped to identify two potential subsets in ME/CFS.  Validating the atypical or “Peterson Subset” could lead to a new understanding of how ME/CFS works and open new treatment options for patients.  The SRF looks forward to further collaborations with the Center for Infection and Immunity and Mady Hornig and Ian Lipkin as it works to redefine ME/CFS biologically.

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Poll Note: The poll will only allow one option to be picked. One positive response suggests you may be an atypical patient. Keep in mind, though, that this is early research on subsets and further studies are needed to verify the findings.

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The Shift: Top Science Journal Asserts Shift in Attitude Towards ME/CFS Has Occurred

“Chronic Fatigue Syndrome is a biological disease” Dr. Ian Lipkin’s Center for Infection and Immunity at Columbia University

From NIH Director Francis Collins’ high profile blog “Moving Toward Answers in ME/CFS“, to the New York Times Opinion piece “Getting It Wrong on Chronic Fatigue Syndrome” exposing the failures of the PACE trial, to the coverage of the Australians’ search for a biomarker, the chronic fatigue syndrome (ME/CFS) community has been treated to some excellent press lately.

difference-maker

Influential journal suggests a shift is occurring in how researchers are viewing ME/CFS

Now comes a piece “Biological underpinnings of chronic fatigue syndrome begin to emerge” from the news section of Nature, one of the world’s most read and most prestigious scientific journals. The article, written by Amy Maxmen, proclaims that a “shift” from viewing ME/CFS as psychosomatic to viewing it as a real disorder has occurred.

The article is a far cry from some of sentiments of the “Life After XMRV” piece Nature did in 2011 in which Simon Wessely asserted that the patients’ reactions to that finding would lead another generation of researchers to avoid ME/CFS research.  (He rather memorably suggested that researchers would rather “work on images of Mohammed” than study it.) Even advocates for the disease, though, worried that the controversy would turn off researchers.  Others, however, felt that the XMRV finding would galvanize researchers to use new technologies to understand ME/CFS.

They were right. Wessely, it appears, was wrong.

World-Class Researchers Beginning to Take ME/CFS On

The Nature article makes it clear that a major cause for the shift occurring is the presence, for the first time ever, of world-class researchers willing to take ME/CFS on.

Dr. Ian Lipkin, an immunologist with an unmatched resume, has not only lent his name and prestige to this disease, but his Columbia team’s published findings  – two of which have outlined dramatic changes in immune functioning in ME/CFS –  have been at the center of this shift. The Columbia team’s findings have been built on collaborations with expert clinicians, including Dr. Daniel Peterson and the Simmaron Research Foundation he advises. (Check out the slideshow that dominates the website for Lipkin’s Center for Infection and Immunity (CII): one of the slides simply says, “Chronic Fatigue Syndrome is a biological disease”.)

Ron Davis, with his many awards and the stunning story of his son’s illness, is also reaching deep into the scientific world to find answers. The stunning picture of Davis holding the printed circuit he’s using to decipher ME/CFS could be a metaphor for the search for the answer to ME/CFS itself.  The answer is there in that maze somewhere, and it’s going to be technology – probably new technology – that uncovers it.

These two men, with their willingness to publicly take bold stands for this disease, have been at the forefront of the “shift” that appears to be occurring. Both men have had the ear of the NIH Director, Francis Collin.  Their credibility has gone far in helping the National Institutes of Health, the largest funder of biomedical research in the country, take a reinvigorated approach to ME/CFS.

Dr. Avi Nath

Dr. Avi Nath, National Clinical Center, NIH

Next, Nature cites the conclusion from the IOM report’s “expert panel” that  chronic fatigue syndrome is an under-studied physiological illness. Then comes mention of the intramural study led by Avindra Nath, the widely published and respected clinical director for the National Institute of Neurological Disorders (NINDS). An infectious neurologist, Dr. Nath is conducting the first intramural study in ME/CFS in decades at the National Institutes of Health Clinical Center. Dr. Lipkin and Dr. Peterson are advisers on this intramural study.

Others could have been mentioned: Mark Davis of Stanford, Derya Unutmaz of the Jackson Laboratory, Lasker Award winner Michael Houghton of the University of Alberta, Patrick McGowan of the University of Toronto and others new to the field.  As the names line up, you do get the idea that, as Dr. Nath told Nature, “Researchers are thinking deeply about how to build the field.”

Building the field, of course, is what the NIH’s recent decision to fund three ME/CFS research centers is all about. Yes, much more is needed, but this article, showing up in a highly cited journal, suggests that the tide may be slowing turning where it needs to turn the most – in the research community.

Ian Lipkin and the Center for Infection and Immunity Step Forward

 Ian Lipkin is featured twice in the article, first stating:

“We now have a great deal of evidence to support that this is not only real, but a complex set of disorders. We are gathering clues that will lead to controlled clinical trials.”

Lipkin has been a vocal advocate for ME/CFS

Lipkin has been a vocal advocate for ME/CFS

Three studies from Lipkin and Hornig at Columbia are expected to be published shortly with one to be published next week. Don’t be surprised if, based on Lipkin’s comments, the CII lays the groundwork for something the chronic fatigue syndrome (ME/CFS) community has been waiting for a long time: evidence of biologically determined subsets, or in Lipkin’s words, direct evidence that ME/CFS is made up of a “complex set of disorders”.

The Simmaron Research Institute / Center For Infection and Immunity Collaboration

Simmaron CII partnership

Simmaron and the Center for Infection and Immunity: working together to understand ME/CFS

In its efforts to scientifically redefine ME/CFS, the Simmaron Research Foundation regularly partners with Dr. Lipkin’s Center for Infection and Immunity. Recent efforts included the spinal fluid study which showed dramatic alterations in immune functioning in the brain, the immune study which differentiated short from long duration ME/CFS patients, and the gut study about to be published. Simmaron is currently collaborating with the CII on additional phases of spinal fluid research and more.

Stay tuned for a Simmaron/CII study that will help to reshape our understanding of what ME/CFS is and how it should be treated.

Simmaron

The Gut and ME/CFS

The gut with its immense effect on the immune system is proving to be a fertile area of research on ME/CFS (see below). Perhaps no other team has pushed the ME/CFS gut connection more effectively recently than Ian Lipkin and Mady Hornig at the CII.

The Nature piece tantalized us a bit with news from Ian Lipkin that one of those studies showing an unusual pattern of gut flora in people with ME/CFS and IBS will be published soon.

A quick look at what studies have told us (see below) about the gut and chronic fatigue syndrome (ME/CFS) suggests that reduced gut floral diversity, possibly characterized by increased numbers of inflammatory bacteria may be common in ME/CFS.

Importantly, every study that has looked for leaky gut – which involves the translocation of gut bacteria into the blood – where it could spark an immune response causing fatigue, pain and other symptoms – has found it.  Most intriguingly, the research suggesting that exercise may negatively affect ME/CFS patients’ gut flora and increase their leaky gut issues could help explain post-exertional malaise.

The Gut and ME/CFS – Recent Findings

  •  Exercise in ME/CFS produces changes in gut flora, leaky gut and Inflammation  – Shukla’s 2015 study suggests that exercise not only changes the composition of the gut flora in people with ME/CFS but results in increased levels of gut bacteria leaking into the blood (possibly causing inflammation and post-exertional malaise.) The fun didn’t stop there. The ME/CFS patients also had more trouble clearing the gut bacteria from their blood than the healthy controls.
  • People with ME/CFS have reduced gut flora diversity and leaky gut – Gilotreaux’s 2016 study suggests more pro-inflammatory and fewer anti-inflammatory gut species are present in ME/CFS, and provides more evidence of bacteria sneaking through the gut lining and ending up in the blood.
  • Gut bacteria/viruses are infectious triggers in ME/CFSNavaneetharaja’s 2016 review paper suggests that gut bacteria and/or viruses have been overlooked in the search for an infectious trigger in ME/CFS.
  • ME/CFS is associated with reduced gut microbiome diversity and increased gut viral activity – Gilotreaux’s 2016 case report of twins found reduced VO2 max, decreased gut bacterial diversity and increased gut viral activity in the sick ME/CFS twin.
  • Antibiotics can improve gut flora and sleep in some ME/CFS patientsJackson’s 2015 Australian study suggests that erythromycin improved the gut flora and sleep in about a third of ME/CFS patients but not in the rest.
  • Altered gut flora diversityFremont’s 2013 study shows increased abundance of the same bacterial family (Firmicuties) in ME/CFS as found in Shukla’s 2015 study.
  • Leaky gut is associated with an autoimmune processMaes 2013 study suggests that increased bacterial translocation (leaky gut) is associated with high levels of antibodies targeting serotonin. Patients with these antibodies had evidence of increased inflammation.
  • Leaky gut is associated with inflammation and symptom severityMaes 2012 study suggests ME/CFS patients are mounting a very strong immune response to intestinal bacteria found in the blood that is leading to increased inflammation.
  • IBS/leaky gut subset is present in ME/CFSMaes 2012 study shows one subset of ME/CFS patients (60%) has leaky gut and IBS while another subset does not.
  • Treating leaky gut in ME/CFS can reduce symptomsMaes 2008 study shows that treating leaky gut with natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc in conjunction with a leaky gut diet can significantly improve symptoms in ME/CFS

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Through the “Valley of Death”: Dr. Pridgen, Fibromyalgia and the Looming Trials

First there were the anecdotal reports – FM patients were not just getting better but some, and not just a few, were getting well using something entirely new – an antiviral protocol, of all things, created not by a pain specialist or rheumatologist but by a surgeon.

Aside from a few doctors in the U.S., no one was treating FM with antivirals and virtually no research had examined the role of pathogens in the disease. A PubMed search of fibromyalgia and herpesviruses pulled up just two herpesvirus studies – both done over thirty years ago.

Skip Pridgen fibromyalgia

Dr. Pridgen’s hypothesis that FM is a herpesvirus disease may be put to the test by the end of this year.

But here was Skip Pridgen, a Tuscaloosa surgeon, not just asserting that herpesviruses were the cause of FM, but that an unusual antiviral protocol consisting of a herpesvirus antiviral and anti-inflammatory with antiviral properties (celecoxib) was doing the trick.  Plus, he asserted that herpes simplex virus – a virus that has gotten no attention in FM’s sister disease, chronic fatigue syndrome (ME/CFS) – was the culprit.

Pridgen, who’s treated thousands of patients with gastrointestinal issues, came up with the protocol after he noticed that his FM patients with IBS seemed to get better and then relapse. Figuring that a herpesvirus might be responsible, he gave them a herpesvirus drug and was surprised that not only their GI but also their FM symptoms improved. When celecoxib had the same effect in FM patients with arthritis, the idea of a drug combo – IMC-1 – was born.

Pridgen and Carol Duffy – his research partner at the University of Alabama – believe the drug combo is effective because each drug inhibits the virus at different points in its replication cycle and they stop viral reactivation as well.  (Hitting a virus at multiple points is a strategy employed to stop HIV.)

Pridgen created a startup Innovative Med Concepts – and put together a pretty hot team (including a past Vice President of Pfizer) and some respected researchers for its Scientific Advisory Board (including Daniel Clauw and surprise, surprise former ME/CFS researcher Dr. Dedra Buchwald) and got a Phase II clinical trial funded and going. (Dr. Buchwald was a surprise because she was so darn conservative in her approach to ME/CFS…)

The clinical trials are where it gets really serious, though. For all the reports of Pridgen helping FM patients, they mean nothing to Pridgen’s hopes of producing an FDA approved drug. The trials are where the action is, and with the recent publication of Pridgen’s Phase II clinical trial in the Journal of Pain Research, we finally have something we can really get our hands around.

The Trial

A famciclovir + celecoxib combination treatment is safe and efficacious in the treatment of fibromyalgia. William L Pridgen, Carol Duffy, Judy F Gendreau, R Michael Gendreau. Journal of Pain Research 2017:10 451–460

Pridgen has been almost relentlessly upbeat in his assertions about the effectiveness of his new protocol and he and his co-authors don’t pull any punches in the title of their journal article which boldly states that “A famciclovir + celecoxib combination treatment is safe and efficacious in the treatment of fibromyalgia”.

Because the trial was distributed across twelve sites, it sampled a broad array of FM patients (and doctors). With 143 patients participating, it was a good size and was double-blinded (neither the patients nor doctors/researchers knew who got the drug or placebo), placebo-controlled 16-week study.

Six questionnaires were used to assess the drug combo’s effectiveness. The primary endpoint – the test the study really had to meet involved two questionnaires – a numerical pain rating scale (NRS) and a past week functional and symptom assessment questionnaire called the Fibromyalgia Impact Quotient (FIQ-R) score.

The first part of the FIQ-R asks how difficult it was over the past week to do things like walk continuously for 20 minutes, vacuum the floor, climb one flight of stairs, go shopping etc. The second part asks each patient to rate their pain, energy, sleep, depression, etc.

The study participants had to be off a variety of drugs (duloxetine, milnacipran, pregabalin, gabapentin, sodium oxybate, and opioids). Over ninety percent of the participants were women and their average age was 49.

Results

Functionality and Symptoms – The FM patients on the IMC-1 protocol showed a statistically significant improvement in their functionality and overall symptom scores on the FIQ-R test relative to the patients not on the protocol.  (The average patient showed a 2.2 point improvement on the eleven point scale.)  Functionality, symptoms and overall impact of FM all showed significant improvement on the drug.

Pain Assessment – Past 24 Hours – With regard to the other primary endpoint – the NSR measurement of pain, only when the data was subjected to “imputation” did the patients report statistically significant improvement in their past 24-hour pain. (Imputation analyses were used to account for missing data.)

IMC-1 was statistically significantly superior to placebo in most of the tests

IMC-1 was statistically significantly superior to placebo in most of the tests

Overall Improvement – Another test called the PGIC which asked patients about how much they had improved. Patients had to report that they were much or very improved to pass the PGIC test. About 35% of patients on the IMC-1 protocol reported they were much or very much improved at weeks 12 or 16 vs about 18% of those on placebo – a statistically significant result.

Another Pain Analysis – Responder analyses used to assess what percentage of patients received a 30-50% reduction in pain found that about 30% of FM patients reported a greater than 50% reduction in pain over the past 24 hours on the IMC-1 drug combo.

Fatigue – Two fatigue assessments (MFI, PROMIS fatigue short form) had differing results; the older MFI test showed no significant improvements in fatigue while the more recently developed PROMIS test showed that those on the drug combo received statistically significant reductions in fatigue.

Depression – The depression findings were intriguing given that one does not ordinarily link depression with herpesvirus infections. When the imputation analyses to account for missing data were performed, however, IMC-1 produced a highly statistically significant (P=0.003) reduction in depression. (This data was not in the published paper.) Since the HSV-1 virus hangs out in three different nerve ganglia in the body, knocking it down could conceivably affect many symptoms – including depression and anxiety.

Safety and Tolerability

With more patients off the drug than on the drug reporting side effects, the IMC-1 drug combo passed the safety test with flying colors. That finding was bolstered by the much higher dropout rates in the placebo arm compared to the drug arm.

The Phase II clinical trials reported on here is a proof of concept trial done to demonstrate that the drug probably works and is safe. Because these trials are also used to help manufacturers determine the best dose to use in a Phase III trial, Phase II trials are also more experimental.

The results were good but not spectacular. I asked Dr. Pridgen if he was satisfied with them. Considering that he felt that Innovative Med Concepts had a hand tied behind its back by the FDA he was:

Given that the FDA restricted our dose to that which we ultimately used, we were thrilled that we met statistical significance with our primary, secondary and even our exploratory endpoints. Being able to show statistically significant improvement in Pain, fatigue, depression, and a dramatic impact on IBS is truly unique. Honestly, I have never seen a proof of concept trial with this broad of an impact. Knowing that the recent toxicology results support our planned ideal dose, as you might imagine, we are incredibly confident in our Phase 3 trial. Dr. Pridgen

Pinpointing the Culprit

One of Pridgen’s and Duffy’s tasks includes demonstrating that herpes simplex one (HSV-1) – the virus they believe is responsible for FM – is, in fact, present. Pridgen reported that Duffy’s analysis of FM patients gut tissue is complete and that the data that emerged “far surpassed” their expectations. They are writing up the manuscript now.

Through the Valley of Death

Pridgen reported a couple of factors that may increase IMC-1’s effectiveness in the next trial. A higher dose will be used in the next trial and the screening process for the participants will be tighter to avoid the impact of confounding factors.

The huge Phase III clinical trials required for FDA approval are called the “Valley of Death” by some for good reason. Pridgen said that testing the drug combination – featuring two drugs that are already FDA approved – will require two 500-1000 person drug trials, each costing from $25-50 million. That’s on top of almost complete animal toxicology testing that’s been done and the large proof of concept Phase II trial.

Trials like that take some heavy lifting and Pridgen’s enrolled some top talent to get IMC-1 through the “Valley”. Rick Burch, the President of Innovative Med Concepts and the former Senior Vice President for Pfizer, oversaw divisions employing more than 6,500 employees and had a hand in launching Lyrica. As chief medical and safety officers, Drs. Michael and Judy Gendreau helped usher Savella to FDA approval.

Pridgen-IMC-1-valley-death

Pridgen hopes to get IMC-1 through the “valley of death” and into its final clinical trials by the end of this year

Pridgen reported that Innovative Med Concepts met with 14 companies (half pharmaceutical, half companies that could provide financing) at JP Morgan in January of this year. He expects the trials to begin in late 2017.

He’s confident enough of the drug’s success to expect to employ in the next trial what he stated was the toughest primary endpoint ever used in an FM drug trial – a 50% or more reduction in pain.

Will Pridgen’s approach revolutionize our understanding and treatment of fibromyalgia? Could FM really come to be viewed as a herpesvirus induced disease – and if it is – what would that mean for chronic fatigue syndrome?

Intriguing questions all. The rubber will really meet the road for surgeon turned drug developer and the many FM patients looking for better treatment options probably at the end of this year.

 More on Dr. Pridgen and His Approach to Fibromyalgia

Simmaron

Inflammation Test Could be Tailor-Made for Chronic Fatigue Syndrome: Are the Mitochondria To Blame?

February 12, 2017

“More than 90 percent of all noncommunicable diseases of aging are associated with chronic inflammation”  David Furman  – Stanford Institute for Immunity, Transplantation and Infection

Inflammation is a big deal in the medical world.  Even mild inflammation, if it’s consistently present, is known to increase one’s risk of getting cardiovascular diseases, diabetes, Alzheimer’s and many others. Standard tests for inflammation such as C-reactive protein or cholesterol, however, are often unrevealing. For instance, inflammation is a key driver of heart disease, but the first sign for many of heart problems is still a heart attack.

inflammation

Chronic, low levels of inflammation are found in many serious diseases.

Likewise it’s been said that chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are inflammatory diseases, but standard tests for inflammation often indicate that none is present. Dr. Montoya believes that current inflammation tests are missing a lot and that future tests will be able to detect the kind of inflammation occurring in ME/CFS.

Given that tests for inflammation are relatively crude, it makes sense that significant efforts would be directed to developing a better test.  It’s no surprise that Mark Davis at Stanford is involved.

Davis’s Institute for Immunity, Transplantation and Infection is spitting out interesting findings like there’s no tomorrow.  Coffee drinkers and dark chocolate lovers were recently pleased to learn that metabolites associated with caffeine and dark chocolate were associated with increased longevity and reduced inflammation. In fact, incubating cells with these metabolites  shut off their inflammatory response.

A 2015 study overturned decades of perceived wisdom that self-attacking or auto-reactive lymphocytes are mostly weeded out early in childhood. (They’re actually very common in adults.)  Davis upended another pillar of orthodoxy when he determined that environment – the microbes, toxins, foods, etc. that we encounter – have far more of an impact on our immune system than our genes. Davis found, for instance, that a single cytomegalovirus infection causes stunningly large and permanent changes to our immune systems.

Davis is bold enough to want to replace all mouse research forever (“Free the mice!”) with a human based approach using immune modeling. In 2015 the Bill Gates foundation gave him $50 million to figure out how to build more effective vaccines. Lastly and most importantly for us, Davis is one of the luminaries sitting on the Open Medicine Foundation’s Scientific Board.  A friend of Ron Davis, I met him at the Davis’ Palo Alto fundraiser a year or so ago. (He said when Ron Davis asks you to do something, you do it).

Davis may have come up with the best test yet for inflammation – an apt subject for ME/CFS and FM patients.  In fact this test sounds like it was made for people with chronic fatigue syndrome and fibromyalgia.

 Old Before Their Time?

The study originated in an attempt to quantify the link between inflammation and something perhaps pertinent to chronic fatigue syndrome and fibromyalgia – aging.  While the evidence is sketchy, it does suggest that people with ME/CFS and/or FM might be aging faster.  Decreased brain gray matter, shortened telomere lengths,  gait alterations, and the cognitive and sleep issues, could all reflect a group of patients who are aging a bit before their time.

The Study

Scientists develop inflammation test that may predict cardiovascular disease Cell Syst. 2016 Oct 26;3(4):374-384.e4. doi: 10.1016/j.cels.2016.09.009. Epub 2016 Oct 13. Defective Signaling in the JAK-STAT Pathway Tracks with Chronic Inflammation and Cardiovascular Risk in Aging Humans. Shen-Orr SS1, Furman D2, Kidd BA2, Hadad F3, Lovelace P4, Huang YW4, et. al. 

In this study researchers studied two groups of 40 individuals, one between 40 and 60 years old and one over the age of 60, for nine years. Every year they threw a battery of specialized immune tests at them, and at the end of the study assessed their cardiovascular health by measuring levels of atherosclerotic plaque, arterial stiffness and ventricular function.

Their goal  – to develop a better immune test that can predict cardiovascular risk due to inflammation much earlier than is currently possible.

“Wired and Tired” Immune Systems Spark Inflammation

They hit the jackpot when they measured immune cells responsiveness to cytokines.  Younger study participants demonstrated a quick and dramatic response to the cytokines- their T-cells went into a tizzy, but the older participants produced a more muted response.

Exhausted immune systems

Tired immune systems may be sparking inflammation

We usually think of immune activation as potentially bad – as a driver of inflammation, and  so it is at times. This study suggests, though, that the kind of immune activation present is the key.

The older persons’ immune systems were, in fact, overly activated – but not in response to the cytokines. They were hyped up before the cytokine test; i.e. they were mildly activated (“wired and tired”?) all the time.  When presented with a stressor, though, the immune cells pooped out.

If that pattern sounds familiar, it should.  ME/CFS/FM patients appear to have activated sympathetic nervous systems at rest which also poop out when they’re put under strain. ME/CFS/FM patients low heart rate variability (HRV) scores also demonstrate a less responsive system is present.

A cytokine responsiveness score (composed of 15 different cytokine responsiveness tests) indicated that the always-on-but-muted immune response to danger was not good news. It was associated with signs of atherosclerosis and the inability of the heart to relax between beats.

This study suggests that it’s not the big burst of immune activity that is perilous for most of us. A nice, sharp increase in immune responsiveness is actually a sign of health. It’s the always on, lower levels of immune activation that cause the inflammation that results in so much trouble for so many people – and perhaps in ME/CFS.

It suggests the system doesn’t have to be fully activated to create inflammation; it simply has to be exhausted. The reduced blood and spinal fluid cytokine levels Lipkin and Hornig found in ME/CFS smacked of immune exhaustion. The Columbia-Simmaron Research spinal fluid studies that published those results continue in an effort to characterize the neurological levels of inflammation and immune response and move us closer to treatments.

Several studies suggest that increased oxidative stress and vascular characteristics of people with chronic fatigue syndrome may put them at increased risk of cardiovascular issues.  Improperly functioning mitochondria can produce massive amounts of free radicals and thus inflammation, which in turn furthers hampers mitochondrial functioning.

A Mitochondrial Immune Connection?

Any discussion of “exhaustion” has to touch on the mitochondria.  It turns out that immune exhaustion may very well be linked to mitochondrial problems.

Early on Ron Davis suggested that energy problems in ME/CFS could be affecting the immune cells in particular. Immune cells typically don’t use a lot of energy until they come upon a pathogen, at which point they use enormous amounts of energy to transform themselves into fighting machines that attack the defender and pump out scads of cytokines.  If mitochondrial dysfunction is present it might very well show up in the immune cells in spades.

Armstrong and McGregor’s metabolomic findings suggested that ME/CFS patients were in energy depleted states similar to those found in inflammatory, sepsis-like conditions or starvation.  Their work suggested that energy depletion (immune exhaustion?) may be associated with inflammation in ME/CFS.

Naviaux believes the mitochondria provide our first and perhaps most precise reflection of immune health.  His insights into the mitochondria/immune interface has guided much of his work.

SMCI Tackles Mitochondrial-Immune Connection

The Solve ME/CFS Initiative is exploring the intersection between the immune system and the mitochondria in a slate of studies. In the “The Bioenergetic Health Index of NK Cells as a Diagnostic Tool for Chronic Fatigue Syndrome” Isabel Barao – an ME/CFS researcher who’s also worked with the Simmaron Research Foundation – will assess the energy index of NK cells in ME/CFS.  This new test, called the “Bioenergetic Health Index,was developed at the same University Jarred Younger is working at (University of Alabama at Birmingham).

low energy chronic fatigue

ME/CFS researchers are determining if low energy production is affecting immune performance

Another SMCI study “Metabolic Analysis of B-Cell Maturation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” will assess whether mitochondrial problems are affecting the B-cell problems that Rituximab may be fixing in ME/CFS.  Fluge and Mella – the originators of the Rituximab treatment regimen in ME/CFS – believe autoimmune processes may be attacking the mitochondria in ME/CFS.

A third study “HHV-6 Mediated Mitochondrial Modulation and Its Association to ME/CFS” will determine if HHV-6 infection is affecting mitochondrial energy production in ME/CFS.

The Stanford immune responsiveness test is not available yet. Too expensive for clinical use, researchers are trying to find ways to lower its cost. When the Stanford test becomes available it might not be surprising to find ME/CFS and FM patients scoring very low.

In the meantime ME/CFS researchers are avidly exploring the intersection between the immune system and the mitochondria.

Simmaron

Is Chronic Fatigue Syndrome (ME/CFS) a Brain Disease? The 2016 IACFS/ME Conference Pt. III

December 23, 2016

brain chronic fatigue syndromeRemember:  $100,000 Year End Matching Gift Opportunity: A generous donor will match your gift to Simmaron between now and December 31, 2016, doubling your impact!

Chronic fatigue syndrome (ME/CFS) may be many things: an autonomic nervous system disease, or a disease involving the mitochondria, or an immune disease, but the IACFS/ME conference made one thing crystal clear – this disease effects the brain. Given the recent metabolomic findings suggesting that a low energy or hypometabolic state is present it makes sense that the most energy intensive organ of all – the brain – might  be affected. Plus, recent evidence suggesting that the brain’s immune system may be particularly affected suggests that brain might just be where it all comes together for ME/CFS.

In Part III of our 2016 IACFS/ME Fort Lauderdale Conference Overviews check out what the Conference told us about brain in chronic fatigue syndrome (ME/CFS).

Dr. Natelson: The Bad News / Good News Presentation

Dr. Natelson was in surprisingly good spirits given that he was delivering what must have been some wrenching news.  His recent study indicated he could kiss about a decade of work and one really interesting hypothesis goodbye.

A number of his studies had suggested that ME/CFS patients without mood disorders had more brain abnormalities (MRI’s, spinal taps, neuropsychological testing, lactate levels) than ME/CFS patients with mood disorders. It was an unexpected and exciting finding that was backed up by several studies, but the crucial larger study found no difference at all.

It’s certainly a cautionary tale regarding the small, generally underpowered studies that permeate this disease. Dr. Newton appears to have gone through a similar process; a stream of publications on muscle and mitochondrial issues were unfortunately later negated by a larger follow up study. It shows we can’t count on findings until they’re nailed down by bigger studies.

The news wasn’t all bad. Natelson’s latest study validated the fact that the major antioxidant in the brain – glutathione (GSH) – is lower in ME/CFS (we can accept that finding) and ventricular lactate levels are higher than in healthy controls (we can accept that one as well). Both findings would seemingly fit in well with studies showing that aerobic energy production is blunted and that neuroinflammation is present.  (We can’t accept the neuroinflammation finding yet.)

Dr. Natelson, a neurologist,  believes pro-inflammatory cytokines are probably whacking glutathione in ME/CFS. He also believes that reduced cerebral blood flows are a solid finding.

Occult Patients. About half the ME/CFS patients in his study also had two or more brain abnormalities – a condition Natelson called an “occult encephalopathy”. Occult refers to hidden or concealed abnormalities that take special tests to uncover. Encephalopathy is a broad term that refers to a syndrome that affects brain functioning. Natelson, then, has evidence (in what appears to be a fairly large study) that a hidden brain disorder is present in about half the ME/CFS patients.

Now that Natelson has evidence that a brain encephalopathy is present in about half the ME/CFS patients, he hopes to use proteomics to find a biomarker in the cerebral spinal fluid (CSF).  He’s preparing a grant proposal. This won’t be his first go-around in the proteomics field. Natelson was the senior author of the 2011 Schutser proteomics study which cast doubt on the idea that chronic Lyme disease is a subset of ME/CFS.

Natelson has high hopes for proteomics – a technology that he believes will help uncover unique biomarkers. In fact, Natelson, neurologist that he is, believes the hunt for a biomarker should begin in the cerebral spinal fluid, and then move to the blood. Because ME/CFS is, more than anything, a brain disorder, the best biomarkers are going to show up in the fluid that bathes the brain. They’re present in the blood too, but are being obscured by all the other factors in the rich broth that the blood is. His plan, then, is to locate them in the CSF and then find them in the blood.

POSTER – Zeineh Replicates Stanford Study

Zeineh’s arcuate fasiculatus results made a big, big splash when they came out in 2014. It was just a small pilot study, but it was Stanford, and that was enough for media outlets from CNN to Bloomberg News, the San Francisco Chronicle, and WebMD to lead with the news that ME/CFS is real.

I vividly remember Dr. Hyde, who knows of what he speaks regarding brain imaging, standing up at the Stanford Symposium and saying that was the best presentation on brain imaging in ME/CFS he had ever seen.

The Zeineh findings were exciting for a number of reasons. One, Zeineh used cutting-edge imaging technology called diffusion tensor imaging (DTI) that had not been used in ME/CFS before.  (One of the benefits of working at Stanford, Zeineh stated, was access to the best technology in the world.) We’ve always hoped that as medical testing gets more precise it will uncover issues that haven’t been seen before, and that’s what happened here.

The arcuate fasciculus is a connective fibe

The arcuate fasciculus is a connective fiber.

We know that the gross nerve damage present in multiple sclerosis isn’t present in ME/CFS, but we also know that the Simmaron Research Foundation’s cerebral spinal fluid study suggests that immune issues in ME/CFS patients’ brains may be almost as severe as those in MS patients.  Zeineh examined the brain’s microstructure, and his findings suggested that atrophy in the wiring that connects the different sections of our brain together had occurred. That kind of damage would impede the free flow of signals across the brain – making it more difficult to think and process information.  (Many brain diseases are now considered primarily diseases of connectivity.)

After his first study was released Zeineh pointed to its potential importance stating

“Most CFS patients at some point in time have been accused of being hypochondriacs and their symptoms dismissed by others. And there is still skepticism in the medical community about the diagnosis. That’s one of the reasons these findings are important.” – Michael Zeineh

Zeineh’s findings also suggested reduced white matter and problems with the thalamus and basal ganglia were present.  He attributed the fasiculatus results to inflammation.

Leptin Again..…Not only did Zeineh replicate his past results, but his ability to correlate them (in a preliminary analysis) with cytokine levels suggested that inflammation was indeed responsible for the damage he found. The real surprise, though, was the cytokine that popped up; it was leptin. With all the different cytokine results floating around (See the IACFS/ME Conference Immune blog) it was shocking to see a familiar cytokine pop up – and leptin at that.

Nobody had connected leptin to ME/CFS until Jarred Younger’s Good Day /Bad Day study suggested a couple of years ago that it was driving the immune problems in ME/CFS.  (Younger is in the middle of a larger validation study now.) Younger believes that leptin could play a key role in the neuroinflammation believed to be present in chronic fatigue syndrome.  Now Zeineh’s (preliminary) analysis suggests that leptin may be causing the brain injury he’s found. Although these results are preliminary, these are the kind of results this field could really use.

Zeineh has moved fast; he published his first study in 2014 and he presented the results of this study in 2016.

POSTERS:  The Zinn’s Damaged Connectome

Talk about connectivity:  the Zinn’s and Lenny Jason’s latest study found problems with connectivity in spades in what must be one of the most damaged brain networks of all in ME/CFS –  the attention network.  (Talk about a good fit for fatigued, concentration-challenged ME/CFS patients.) The Zinn’s found that the different brain-wave bands in this network were not in sync; while two were increased, another was decreased. Their small study also found significantly increased activation of three brain-wave bands in the attention network during a task relative to healthy controls. That actually wasn’t good news; it suggested that ME/CFS patients had to work VERY hard to maintain their attention during that task.

Connectivity issues came to the fore in the Zinn’s next poster as well. We know that information processing is slowed in ME/CFS. We also know that different regions of the brain have to work together to process information.  Put those together and it raises the possibility that the slowed information processing in chronic fatigue syndrome could be the result of bad connections.

transmission line

Reduced connectivity was the theme of several studies

Again, the Zinn’s small study suggests it just might be. Their EEG results pinpointed one brain-wave band that was inhibited across the occipital (rear), parietal (top) and temporal (front) lobes (i.e. a good chunk of the brain). Even worse the signaling “hubs” most effected in ME/CFS constituted “the most electrically active” regions of the brain.

A regression analysis also suggested that the longer you’ve had this illness the less well connected these parts of the brain are. The Zinns referred to their findings as “widespread functional dysregulation in the connectome”.

At the conference, Marcie Zinn pointed out someone vigorously talking to a group clustered around their posters. “That’s Rex Cannon, she whispered. It turns out he actually wrote THE BOOK on the type of EEG analysis they’re doing. The Zinn’s and Lenny Jason had apparently invited him down to the conference and he was interested; in fact he was so interested in their findings that they’re now collaborating with him.

Byron Hyde – the Pioneer

The “father” of brain imaging research in ME/CFS, Bryon Hyde, didn’t present but he was there and provided a nicely illustrated booklet on his findings. Hyde said he had a new book coming out on ME/CFS soon.

Hyde has been using SPECT scans to diagnose and treat patients for decades; his experience indicates that hypo perfusion or low blood flows to different parts of the brain is common in ME/CFS. Furthermore be believes that low blood flows to certain parts of the brain are causing many of the major problems in ME/CFS.  Simply by assessing a SPECT scan he can probably tell you what kind of patient you are.

In the booklet he demonstrated how he’s able to tie certain SPECT scan findings to distinct problems ME/CFS patients face.

  • Autonomic dysfunction – patients with autonomic dysfunction always, in his experience, demonstrate reduced blood flows in an area above the insular cortex called the operculum. The insula regulates homeostasis; e.g. the autonomic nervous system. Damage to this area is associated with orthostatic intolerance, blood vessel problems and problems with heart regulation.

Hyde, long associated with ME/CFS and critical of exercise therapies, is able to find middle ground with regard to activity. The damage to the insula and therefor to the autonomic nervous system is too significant, he believes, for these patients to benefit from graded exercise therapy (GET), but he also believes that patients shouldn’t let fear keep them in bed forever either. Depending on how severely ill a person is, Hyde states that “a gradual, patient regulated increase in activity is necessary, both for the body and the soul”.

  • Muscle dysfunction – Patients with muscle dysfunction show low blood flows to the motor cortex (Brodman’s area 4 of the posterior lobe).
  • Cognitive problems  – Patients’ problems with information processing (which included everyone), speech comprehension, and processing visual and auditory information – all have left anterior temporal lobe injuries. These are found in all ME patients.
  • Lots of Stuff –  Patients with problems in a host of areas including learning, complex motor skills (driving?), sleep, alertness, multi-tasking, emotions, etc. demonstrate low blood flows to the anterior and posterior cingulate lobes. Most patients have injuries in both these areas.

Hyde believes the 1984 Incline Village/Lake Tahoe outbreak investigated by the CDC was a classic enterovirus epidemic. He asserts in the booklet that Stephen Straus’ blockage of a publication about this outbreak in the New England Journal of Medicine by Dr. Peterson and others had tragic consequences.  Hyde believes that pure ME is an enteroviral disease diagnosed using disease history, gastric or GIT biopsy and a SPECT scan.

If Hyde is right about enteroviral infections, some hope may be on the horizon.  Enteroviral infections are so difficult to treat given our limited pharmocopia that most doctors don’t even test for them. Hyde reported, though, that several new enteroviral drugs (Pirodavir, Vapendavir, Pocapavir, Plecoaril and Rupintivir) are in the early stages of being tested.

Hyde has a new book coming out on ME soon.

Brain Research Heating Up!

A gateway to the brain - the cerebral spinal fluid

A gateway to the brain – the cerebral spinal fluid. (See the arrows)

Interest in neuroinflammation in chronic fatigue syndrome (ME/CFS) is growing, and that means more emphasis on the brain. The problems Natelson and Shungu have described (increased lactate, decreased glutathione and reduced cerebral blood flows) are likely the result of increased inflammation and oxidative stress. At the IACFS/ME conference Dane Cook demonstrated that exercise not only impairs cognition a day later but that it also puts a whopping damper on ME/CFS patients’ brain activity.

After Zeineh’s mighty diffusion-tensor machine uncovered microstructural damage in one of the main connective pathways in the brain, his preliminary analyses suggest that inflammation (via leptin) was the cause. Meanwhile, different issues with “the connectome” in the brain showed up in the Zinn’s (soon to be published) studies. Their tagging of the alertness network made perfect sense.

The brain research is heating up! Quite literally. The Solve ME/CFS Initiative just funded Jarred Younger’s attempt to assess neuroinflammation in the brain using a new heat scanning technique. Younger believes areas of the brain associated with fatigue are going to be red hot (figuratively speaking) in ME/CFS patients.

All these interesting results mean an increased interest in examining our best gateway to the brain (short of a biopsy): the cerebral spinal fluid (CSF). As was noted, Dr. Natelson is eager to get underway with his proSR_Donate_6.9.14_1teome CSF study. Dr. Baraniuk is currently examining the exosomes – small fluid vesicles that contain inflammatory factors – in the CSF of ME/CFS patients to see if they’re adding to the inflammatory milieu there. The Simmaron Foundation’s new spinal fluid study, which is incorporating Dr. Naviaux’s metabolomic results, aims to duplicate and expand on its past CSF study.

That study showed a degree of immune dysfunction almost equal to that found in multiple sclerosis. Remarkably, almost half the cytokines in the ME/CFS patients were abnormal. No exercise was needed to tweak them. There was no need to filter for duration or severity either. Even at rest those cytokines were off, off, off.  That suggested that major and readily identifiable immune issues exist in the brain. It also suggested, as Dr. Natelson proposed, that the brain might just be the first place researchers should go to look for immune problems in ME/CFS.

Given the variable cytokine results often seen in this field, it was stunning to see the Simmaron Foundation’s CSF cytokine results essentially duplicate those found in the Lipkin/Hornig blood study. That got Ian Lipkin so excited that he flew all the way to Incline Village to promote it last year. Simmaron is raising money for that project right now.

Remember:  $100,000 Year End Matching Gift Opportunity: A generous donor will match your gift to Simmaron between now and December 31, 2016, doubling your impact!

SR_Donate_6.9.14_1

Is Chronic Fatigue Syndrome An Inflammatory Disease? The 2016 IACFS/ME Conference Overviews Pt II

immune-systemThe immune system’s complexity reared its head again at this conference as Dr. Montoya showcased some of the findings coming out of his large immune studies at Stanford.  Montoya’s assertions that chronic fatigue syndrome (ME/CFS) is similar to systemic inflammatory response syndrome and should be called an inflammatory disorder were intriguing indeed. It’s still, however, hard understand what is going on in the immune system in ME/CFS.

This is a long blog; if you just want the main findings a quickie overview is given at the end of it.

IMMUNE SYSTEM

Montoya’s huge (584 person!) and impressive immune studies –  the largest ever done in this disease – dominated several presentations.  The studies are bit unusual in that they contained about twice as many healthy controls (n=392) as patients (n=192).  Montoya posted an impressive list of 30 researchers he’s collaborating with at Stanford and elsewhere.

He spoke of a complex immune situation often characterized by both up and down immune activation, but which strongly suggested chronic fatigue syndrome is an inflammatory disorder.

Cytokine Study

Cytokines are molecules produced by immune cells that regulate immune functioning in many ways. Montoya tested many cytokines (51) but only two popped out in the first run of this study. That was surprising; large studies are particularly good at finding small but still significant differences, but this study found few differences between the ME/CFS patients and healthy controls than some smaller studies.

Lipkin and Hornig enhanced their cytokine study results by controlling for duration. The key for Montoya was severity. When he added severity to the picture, the immune findings popped out. In the more severely ill patients a rather eye-popping third of the 51 cytokines tested (leptin, CXCL-1, CXLC10, GM-SF, IFN-Y, GM-CSF, IL-4, IL-5, Il-7, IL-12p70, IL-13,  IL-17F, NGF, TGF-b, CCLI, SCF and TGF-a) – most of them pro-inflammatory in nature  – significantly increased.

Montoya proposed that TGF-b, traditionally thought of as anti-inflammatory, may have been acting as a pro-inflammatory cytokine. That cytokine has shown up in several ME/CFS studies before.

Interlude: Cytokine Results Still All Over the Map

The results were encouraging, but cytokine results in this disease are still all over the map. For years researchers have thought they MUST be involved in ME/CFS, but cytokine results have been stunningly inconsistent.

For example, while a 145 person Australian study did, like Montoya’s study, find increased levels of cytokines (IL-10, IFN-γ, TNF-α), none of those cytokines showed up in Montoya’s results.

igg-antibodyA 99 person study from the Klimas group measuring 16 cytokines found significant alterations in 10 of them (increased – LT-a, IL-1a, IL-1b, IL-4, IL-5, IL-6, and IL-12; decreased – IL-8, IL-13 and IL-15.) IL-4/5-were increased in Montoya’s severe ME/CFS group, but IL-13 was decreased in the Klimas study and increased in Montoya’s.

Wyller’s recent large study of ME/CFS adolescents found no cytokine differences between those diagnosed with the Fukuda criteria cytokine and healthy controls. A Japanese/U.S. study found no evidence that either sleep deprivation or exercise effected cytokine levels as well.

The large Landi/Houghton 179 person study of longer duration patients found mostly cytokine reductions instead of increases (reduced levels of IL-7, IL-16, VEGF-a, CX3CLI, CXCL9; increased CCL24). If most of Montoya’s group were early-stage ME/CFS patients, that might help explain the differences, but we don’t know that they were. (Montoya did state that he is going to filter for illness duration.)

The Lipkin/Hornig cytokine study found increased levels of 16 cytokines in early or late duration patients vs healthy controls (IL-1a, IL-1ra, IL-4, IL-12p70, Il-13, CXCL8, TNFα, SFASL, CCL2, CCL3, CD40L, MCP1, TNFSF10, SCF, CFS1, and resistin).  Only three of those (IL-12p70, Il-13, SCF) were found elevated in the Montoya study; thirteen were not.

An Australian study that tracked for severity in a different way from Montoya suggested that more severe patients do have higher cytokine levels. It found reductions in IL-1b, and increases in IL-7, IL-8 and IFN-y. Of those, IFN-y was increased in the Montoya study.

In a much (much) smaller cytokine study published earlier this year, Dr. Fletcher’s study suggested that dramatic shifts in immune functioning may occur over time. IL-a plays an important role in early ME/CFS and then declines. IL-8 levels were abnormally high early on but declined to lower than normal levels after a few years. Il-6 levels were low early on and elevated later. Ironically, the Montoya study didn’t find any of these cytokines elevated in his severely ill patients.

Conclusion (?)

Until cytokine results achieve more consistency they’re clearly not going to get traction in the medical world.  The inconsistency seems surprising as most of these studies are from good labs. It’s possible, though, that subsets are mucking up the issue. Filtering for duration is clearly needed, and Montoya’s study suggested that filtering for severity is as well. The Klimas group’s Gulf War Syndrome study suggested that  gender may need to be accounted for as well.

Dr. Peterson’s atypical patient subset may throw another loop into cytokine results. Peterson’s atypical ME/CFS subset group so dramatically affected cerebral spinal fluid results that it had to be excluded from the study altogether.  Could  this group be effecting blood cytokine results as well?

Researchers are not going to stop studying cytokines – they’re apparently too enticing – and it’s possible that studies underway may help us understand what is going on.  If Lipkin/Hornig can, in their study underway, replicate their cytokine results in different duration patients – that will be something. Ditto with several good day bad day studies underway. If Montoya can duplicate the Lipkin/Hornig duration results that would really be something. Time will tell.

It’s also possible that cytokine levels per se aren’t as important as we might think. Broderick’s models suggest that context is key; in the right context a factor can be important even if it’s levels are not raised.  His models suggest that treatments targeting just two cytokines might be able to enable ME/CFS patients to exercise again. (See upcoming IACFS/ME treatment blog).

Montoya’s network analysis indicated that Il-1B – an important regulatory cytokine associated with increased pain – was the most important factor 24 hours after exercise.  That certainly makes sense given what we know about exercise and pain.

Another possibility is that cytokines in the nervous system are more important than those in the peripheral blood. It’s thought, for instance, that cytokines must contribute to central sensitivity syndromes (CSS’s) such as fibromyalgia as well, but a similar issue with consistency apparently applies there. Staud has suggested that cytokines probably play a major in CSS, but only within the central nervous system.

No Biomarker Yet – An immune signature that shows up only in the more severely ill gives us clues about the illness but obviously isn’t going to work as a biomarker.  But what would happen if Montoya essentially shoved those people into a more severe state by having them exercise? Would adding exercise to the mix make the more moderately ill patients look like more severely ill patients?

Montoya’s Exercise Study

Would exercise make moderately ill ME/CFS patients in the throes of post-exertional malaise look like severely ill patients? The answer to that question was no.

Montoya’s maximal exercise test produced opposite results from the cytokine study done in patients at rest.  This time, exercise reduced the levels of four cytokines (TNF-a, IL-8, CCL4, ICAM-1) while increasing the levels of only 1 (CXCL-10).

Both TNF-a and IL-8 increase during exercise in healthy people, however. The fact that both went down in ME/CFS patients may be notable.  If immune exhaustion is present then perhaps one might expect cytokine levels to drop when the body is faced with an exercise stressor.

A 2014 review of exercise studies reported that while exercise does appear to effect the complement system and gene expression and increase oxidative stress in ME/CFS, it does not appear to effect cytokines. Montoya’s results suggested the opposite.

Genomics Study Suggests Chronic Fatigue Syndrome is an Inflammatory Disorder

At the Stanford Symposium, Montoya announced that the gene expression results indicated that ME/CFS was similar to a disease called systemic inflammatory response syndrome or SIRS. He repeated that assertion again; this time stating that ME/CFS was a “100% match” to SIRS.  (The abstract was a bit more cautious, stating that the gene expression results were “very similar” to it and similar diseases).

SIRS

SIRS has been called a
“cytokine storm”

The concept of SIRS came out of ten years of work at a Toronto trauma lab by Dr. William Nelson. SIRS is  a kind of cytokine “storm” – a term sometimes used in ME/CFS – which refers to a positive feedback cycle that results in higher and higher levels of cytokines.  SIRS also effects both pro and anti-inflammatory cytokine levels as well.

SIRS refers to a state of systemic inflammation after infection or some other insult and can result in organ dysfunction and failure. Intriguingly, given the Australian metabolomic group’s suggestion that the metabolomic results in ME/CFS are similar to sepsis, it’s closely related to sepsis.

SIRS has other manifestations that some may find familiar. Increased heart rates, lower or higher than normal body temperatures, rapid breathing rates, and low white blood cell counts found in SIRS have also been found in ME/CFS. The rapid breathing rates, by the way, are associated with either increased metabolic stress due to infection or inflammation or may signal inadequate perfusion because of the onset of anaerobic cellular metabolism.

Other possible links include fibrin deposition, platelet aggregation, and coagulopathies aka Dr. Berg’s findings in ME/CFS some years ago. Dr. Montoya’s immense gene expression study almost couldn’t have uncovered a more interesting disease to link to ME/CFS.  How serendipitous as well – if this all turns out – that Ron Davis and some members of his Open Medicine Foundation team have done an enormous amount of work on sepsis.

How is SIRS treated? In some ways (blood volume enhancement, anti-anaphylaxis drugs, selenium, glutamine, eicosapentaenoic acid, and antioxidants) that can be helpful in ME/CFS.

Epigenetic Modifications Point at Immune System and HPA Axis

Montoya’s epigenetic study suggested an infection (or some other insult) had indeed occurred in ME/CFS. Greatly increased rate of methylation in ME/CFS patients’ immune regulatory genes suggested some infection or other environmental insult had occurred.

Other epigenetic modifications were found to affect HPA axis genes.  Given the strong interaction between the HPA axis and the immune system, it wouldn’t be surprising at all to find that some event had tweaked both the HPA axis and immune genes in many ME/CFS patients. (The Montoya group is currently engaged in a promising HPA axis study.)

Other gene groups affected by methylation (epigenetic modification) include genes that play a role in, yes, metabolism.  One gene highlighted in a whole genome polymorphism study has been implicated in lactic acidosis (NUFS7). A polymorphism in this gene, which transfers electrons from NADH to CoQ10, could result in increased oxidative stress and reduced mitochondrial output.

Is Chronic Fatigue Syndrome an Inflammatory Disease?

Finding increased immune activation in severe ME/CFS patients, and with gene expression results a close match to SIRS, Montoya asserted that ME/CFS is an overactive immune disease and proposed that its new name should include the word “inflammatory.” Montoya results suggest this, but it’s hard to see how any consensus can be reached until we get more consistent results from the cytokine studies (???).

Pathogens

When asked about retroviruses, Montoya suggested there was no cheese down that tunnel. In several of his newsletters Montoya promised “exciting” new findings regarding pathogens but none were presented at this conference.

Allergy Study Reveals Intriguing Subset

Dr. Levine’s allergy study was, for me, one of the surprise highlights of the conference. This nice big study demonstrated how valuable a resource the multi-site ME/CFS experts centers are, and how valuable a tightly integrated network of research centers will be.

In one of the bigger ME/CFS studies to date, Levine queried 200 patients in five sites regarding the incidence of allergic symptoms/conditions and found that the presence of sinusitis and hives distinguished ME/CFS patients from healthy controls.  (My guess is that the presence of sinusitis is overlooked and understudied in ME/CFS).

allergy subset ME/CFS

An allergy subset appears to have increased pain sensitization as well

The fact that having either of those conditions resulted in patients experiencing more pain suggested that an immune process was ramping up their pain levels.   That hypothesis was strengthened when Levine found that this group also had a much, much higher incidence of migraine, tension headaches, back pain, neck pain, and fibromyalgia.  Plus they had more gut and inflammatory symptoms. Something clearly appeared to be driving a pain sensitization process in these patients.

What is the tie that binds these findings together? Levine suggested it might be mast cell activation. Plus, Dr. Levine noted that both mast cells and neurons secrete two factors: nerve growth factor and substance P, known to increase pain. Then there’s tryptase to consider. A recent study suggested that modification of a tryptase gene could be behind some cases of EDS, POTS, IBS, ME/CFS and FM. Another suggested mast cell activation may be occurring in ME/CFS

This is the kind of study that makes you wonder why the heck it hasn’t been done before. The study was surely not expensive, yet it might illuminate much about ME/CFS.  It was funded by the Hitchens Foundation.

POSTER: RNase L Returns? Novel Isoform of Ribonuclease L Shows up in Fibromyalgia

The idea that an important immune enzyme called RNase L had been broken into pieces and was not only no longer working properly but was actually causing channelopathies and other issues raised a great deal of interest in ME/CFS the 2000’s. At some point work on the enzyme stopped but RNase L was not forgotten.

In a surprise a Spanish group looked for and found the broken-up bits of the enzyme in fibromyalgia. The results were too variable for the 37 dKA form of the enzyme to be considered a biomarker but they did suggest that a subset of FM patients carried it.

Even more surprising was their finding of another broken up bit of RNase L (70 kDa) which was almost totally associated with the FM patients (p<.0001). They’ve create custom-made antibody to identify it and will apparently keep working on it.

PATHOGENS

POSTER: EBV Rides Again

We’ve heard so much about EBV over the years that we forget what a special virus it is. It’s’ true that almost everyone has been infected with EBV, and most have no problem with it, but EBV is no walkover.

When one is exposed to EBV later in life, it causes infectious mononucleosis (glandular fever) and is associated with several forms of cancer (Hodgkin’s lymphoma, Burkitt’s lymphoma, gastric cancer, nasopharyngeal carcinoma, central nervous system lymphomas). Evidence suggests that EBV infections result in a higher risk of many autoimmune diseases including dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, and multiple sclerosis. Lastly, while hardly mentioned in the medical world (ME/CFS is not even mentioned in the Wikipedia article) but foremost in ME/CFS patients minds, EBV is a well-known trigger of ME/CFS.

EBV must have a multitude of tricks up its sleeve to contribute to so many illnesses. The idea that it plays a major role in ME/CFS has risen and fallen over the years. Right now, that idea seems to be more in its descendant phase, but as Dr. Klimas’s study shows, it ain’t over until it’s over; EBV may still very much figure in this disease.

Micro RNA’s – small bits of RNA – regulate which genes get expressed. It turns out that EBV, tricky virus that it is, encodes viral miRNA’s of its own. (EBV was the first virus found able to do this. Given the immense amount of EBV research being done (over 25 studies published in November alone) that was perhaps no surprise.)

HHV-6

HHV-6 appears to contribute to symptoms in ME/CFS

Peripheral blood mononuclear cells (PBMCs) were collected from ME/CFS patients and healthy controls before, during and after exercise, and various tests were done to assess EBV miRNA’s.  Preliminary results suggested that ME/CFS patients’ cells express higher levels of EBV proteins than normal and thus might be more likely to support EBV reactivation.

Plus some strange features emerged. The immune cells in ME/CFS tended to be smaller and have less volume (Ron Davis has found something similar). Instead of forming a classic “pump” shape the ME/CFS nuclei take on a puckered and wrinkled look as if they were aged. Plus, when a key immune transcription factor called STAT I gets activated, presumably by the virus, it ends up in the wrong part of the cell – a pattern indicative of viral reactivation.

All of this suggests that EBV may be tweaking ME/CFS cells in strange ways and that the virus may still play a part in ME/CFS.

POSTER: A Better HHV-6 Test

It’s clear that herpesvirus tests leave something to be desired and Nancy Klimas’ group is attempting to find a way to improve the diagnostic effectiveness of the Elisa test. The current test are provide only  yes-infected or no-not infected answers and are particularly unreliable at the high and low ends of the spectrum.

This study, involving Dr. Govindan from Tufts University and four Florida researchers, used various statistical tests to see if they could develop a truly “quantitative” Elisa for HHV-6.

The intercept they developed allowed them to accurately stratify patients, and showed that the HHV-6 intercept they produced was negatively associated with physical functioning; i.e. the higher the intercept – the worse the ME/CFS patients physical functioning was. This suggested that a) HHV-6 does contribute to the symptom burden in ME/CFS, and b) that this new test could aid doctors in determining when to apply antiviral therapies.

POSTER: Enterovirus Brain Infection Found

Dr. Chia’s work to get the medical world to take enterovirus infections in ME/CFS seriously continues. He gave a workshop on enteroviruses and seemed to be in demand; every time I saw him he was engaged in conversation with a group of people.

His poster highlighted the possible effects of enteroviruses in the most dramatic way. It told the story of a young man who first developed gut problems and then severe ME/CFS. Tests for herpesviruses were normal, but his Echovirus antibody levels were sky-high.  Stomach and colon biopsies stained positive for enteroviruses but enterovirus RNA was not detected in his blood (it often isn’t).

Unfortunately, the young man failed to respond to either alpha or gamma interferon or to SSRI’s, benzodiazepines or acid suppressants. Repeated MRI’s of his brain and spinal chord were normal. Six years into his illness, at the age of 29, he committed suicide.

His ending was tragic, but his story was not over. His harvested brain provided clues as to what may have happened. Neither a brain culture nor an RT-PCR picked up signs of enterovirus, but a western blot found protein bands which were similar to those found in the young man’s stomach biopsies (but different from those found in tuberculosis and lymphoma).

Dr. Chia concluded that this finding replicated a similar finding dating back to 1994.  He concluded that the

“finding of viral protein and RNA in the brain specimens ….is consistent with a chronic, persistent infection of the brain causing debilitating symptoms. EV is clearly one of the causes of ME/CFS, and antiviral therapy should be developed for chronic EV infection.”

Like herpesviruses, most enteroviral infections are passed off quickly, but like herpesviruses, enteroviruses are also associated with serious disorders including polio, meningitis, myocarditis, hand, foot and mouth disease and others. According to Wikipedia, treatment for enterovirus infections is primitive, consisting mostly of relieving symptoms such as pain as they occur.

One hopes at some point an independent lab will take up Dr. Chia’s work and give it the replication it needs and he deserves.

Conclusions

The cytokine findings are disappointingly inconsistent, but the immune system is a vast place and gene expression, epigenetic modeling and other studies continue to point a finger at it.  The Montoya studies should tell us much, plus the entry of noted researchers such as Ian Lipkin and Mady Hornig,  Maureen Hanson, Derya Unutmaz, Michael Houghton and Patrick McGowan into the field ensure that we’ll be learning much more about the immune system in the years ahead.

Marshall-Gradisnik’s NCNED team is churning out immune studies at a rapid rate, Broderick’s early modeling  studies suggest an immune focused 1-2 punch may knock out post-exertional malaise, and Fluge and Mella are testing another autoimmune drug, cyclophosphamide, in clinical trials.

Both Fluge/Ron Davis believe an immune process may be targeting energy production in our cells, the same may be true for ion channels, and it’s now clear that an autoimmune process is producing POTS in some patients. Every microbiome study thus far suggests altered microbial diversity and/or gut leakage into the blood could be sparking an immune response.

The Simmaron Foundation’s expanded spinal fluid study should give us a better handle on what’s happening in the brain just as new techniques to measure the amount of neuroinflammation present in the brain come online.

Finally, it’s encouraging that researchers are getting serious about subsets – and finding them when they look for them.

Major Findings

  • Increased levels of pro-inflammatory cytokines are associated with increased severity in ME/CFS;
  • Exercise, on the other hand, appears to down-regulate cytokine levels in ME/CFS including several cytokines that are typically increased during exercise in healthy people;
  • Gene expression results suggest ME/CFS is very similar to a sepsis-like condition called systemic inflammatory response syndrome (SIRS) which shares some other characteristics with ME/CFS;
  • Epigenetic modifications suggest that events may have altered the expression of genes involved in both the HPA axis and immune systems in ME/CFS;
  • One subset of ME/CFS with sinusitis and/or hives also falls prey to other pain sensitization type disorders such as migraine, fibromyalgia, headache and back pain. Mast cells could be implicated;
  • A broken up form of RNase L, an important enzyme involved in fighting pathogens, showed up in fibromyalgia;
  • Higher levels of EBV proteins in ME/CFS patients’ cells plus structural abnormalities in their cells suggest EBV reactivation may occur more frequently in ME/CFS;
  • A quantitative Elisa test suggests that HHV-6 contributes to the symptoms of ME/CFS as well;
  • Enteroviral proteins in the brain of a young man with ME/CFS who committed suicide suggested that enteroviruses have infected the brains of some people with ME/CFS.

SR_Donate_6.9.14_1

 

 

The Pridgen Revolution? Dr. Pridgen on Bringing His Antiviral Approach to Fibromyalgia To Market

The Pridgen Revolution?

Almost three years ago, Dr. Pridgen threatened to turn the world of fibromyalgia treatment on its head. Few had connected fibromyalgia with viruses or even immune problems when Pridgen announced that a) FM is caused herpes simplex virus reactivation and b) that it could be treated with antivirals. Then he shocked a chronic fatigue syndrome community (ME/CFS) well acquainted with antivirals with his assertion that one antiviral drug was not enough.  (Pridgen believes the same process is going on in ME/CFS). Pridgen wasn’t done, though, instead of using the usual anti-herpes virus drugs he used an anti-inflammatory (Celebrex) that had antiviral properties as his second antiviral.

pridgen_skipPridgen was knocking down received wisdom at every turn. One would not have been remiss to think that he and his unusual protocol would, as other supposed cures have, disappear at some point, but he hasn’t.

Instead, touting his success with the drug combo, Pridgen embarked on the long and difficult task of bringing a new treatment to market. After joining up with a University of Alabama virologist, Dr. Carol Duffy, Pridgen formed a biotech company aptly named Innovative Med Concepts, hired an ex-Pfizer vice-president, put together a strong scientific board, raised the money for a Phase 2 trial, and embarked on toxicology testing.

The Phase II trial was successful enough for the drug combo to move forward. Then Innovate Med Concept got a break when FDA granted fast-track status to its IMC-1 formulation, allowing the drug combo to move forward as quickly as possible.  (Fast-track status is granted to serious diseases that have “substantial impact on day-to-day functioning.”)

Now comes the real work – raising money for some very, very expensive Phase 3 trials. It’s been about a year since we checked in. In an interview, I asked Pridgen how it was going.

The Pridgen Interview

The Phase II trial results were certainly quite good, but they weren’t spectacular.  How did the Phase II trial inform the Phase III trial and how will it be different?

We wanted to prove the concept first with a dose that we knew would be effective.  Additionally, we chose this lower dose, as it would allow us to begin without first performing the very expensive and time-consuming toxicology studies. We will be beginning the final 2 toxicology studies necessary to be Phase 3 ready, this month, and we expect to have these completed late this winter or in early spring 2017.

This was a year to prep for the big Phase III trials. How much money do you need to raise? Do you need to do one or two trials and how big does the trial or trials need to be? How much money do you need to raise?

Typically, two Phase 3 studies are required, the studies require 500-1000 patients per study, and these studies cost $25-50 million each.

One report suggested that some pharmaceutical companies have shown interest. Can you say anything about that?

drug-developmentWe have met with a dozen different pharmaceutical companies. All knew that we would be either forming a strategic partnership, or continuing the drug development ourselves once we near Phase 3 readiness. We will meet with these pharmaceutical companies to discuss a possible partnership at the upcoming JP Morgan meeting Jan 2017 in San Francisco.

We’ve seen a couple of high-profile Phase III trial failures recently. One may have been due to doctors misidentifying a side effect as something else and using a drug that interfered with the results. Another got excellent results in the Phase II trial but then didn’t meet its primary endpoint (but did meet some of its secondary endpoints) in the Phase III trial.  In another trial a very high placebo rate surfaced. What can you do to ensure that IMC-1 trial goes as well as possible?

We have actually been using a variant of this combination at my office for 2-3 years, so we are extremely confident in, not only its efficacy, but also know the combination is quite well tolerated and safe. Though providing the necessary optimal dose is incredibly time-consuming for the office staff, and complicated for the patients, we endure this hardship because of the dramatic improvement they experience.

Dr. Pridgen remains very, (very) confident in the effects of his protocol; he’s so confident that he anticipates raising the bar for the primary endpoint of his Phase 3 trials. Drugs have failed because they chose the wrong primary endpoint or too difficult of a primary endpoint, but Pridgen reports the study will use the most difficult primary endpoint to attain of any fibromyalgia trial to date:

Finally, because IMC-1 is so effective, we will use a primary endpoint that represents the highest bar ever used for any of the drugs previously studied for FM. We feel that this will negate to some degree the placebo effect.

We can see from studies and patient comments that the fibromyalgia population is pretty heterogeneous one. Some people do well on Lyrica – others do terribly. Low dose naltrexone works very well for some and others do poorly on it, etc., etc. The heterogeneity seen in the reactions to pain medications, in general, is pretty daunting. Is there any way you can target FM patients who are more likely to do well on the drug?

Again, Pridgen waxed confident in how efficacious this drug combination is. He believes his is the only protocol that gets at the source of fibromyalgia.

We believe IMC-1 is targeting the possible cause of fibromyalgia, not just modifying the body’s perception of pain.

Emedicine lists four antivirals (Famvir, Valtrex, Acyclovir, Penciclovir) used to treat herpes simplex infections. You’ve found that you need to add Celebrex to Famvir to get the best results in FM. Why do you think this is?

Penciclovir is not available in the PO form because it is not well absorbed, so it is a better topical agent.  Actually, Famvir turns into the active form, penciclovir, once it is acted on by human and viral enzymes. Celebrex is effective as an antiviral also. Herpes viruses are known to up-regulate the Cox-1 and Cox-2 enzymes to maximize viral activation. Though Celebrex (celecoxib) is known as a Cox-2 inhibitor, it actually has substantial Cox-1 inhibition.

viral-attack-cfsAre the herpes simplex infections harder in FM harder to get at than in other diseases? Do you need to reach into the central nervous system?

Essentially all adults have HSV-1, but we believe there is an immune defect in place in some patients, which results in an inability to force the virus into dormancy after an acute infection. In other words, patients with FM, have an ongoing HSV-1 infection, which we feel results in a chronic stress response. The meds can act centrally, however, the virus lives in the Trigeminal, and Nodose ganglia which are intracranial, but technically not in the CNS. The dorsal sacral root ganglia are the third major site (in the pelvis) where the virus resides.

Note: The herpes virus is known to hide out all three of these ganglia or cell bodies.

  • Trigeminal ganglia – is the largest and most complex of the 12 cranial nerves. The trigeminal ganglia provides sensations to the face and other parts of the head. It also sends signals that allow us to chew and even helps with balance. People with trigeminal neuralgia can experience high levels of pain when doing things like brushing their teeth or putting on makeup.
  • Nodose ganglia – are sensory ganglia or nerve cell bodies of the vagus nerve that are found near the top of the spine..
  • Dorsal sacral root ganglia – are associated with vertebrae in the pelvic area. The nerves emanating from them impact all areas of gut and pelvic functioning. In between bouts of genital herpes virus reactivation, the herpes simplex virus hides in these ganglia.

Like the other herpesviruses, almost everyone is infected with HSV-1, and when reactivated these infections can be pretty harmful. They’ve been shown to cause gastrointestinal and esophageal disorders, acute viral encephalitis, and approximately 25% of all genital herpes infections. Fibromyalgia is a bit different; it causes widespread pain, fatigue, sleep and sometimes mood problems as well as other symptoms- and is thought more of as a central nervous system disorder than anything else. Can you explain what the herpes simplex virus is doing differently in FM to cause this extraordinary range of symptoms?

The ongoing stress response affects nearly every system in the body. The immune response to this stress response over time affects sleep, mood, anxiety, thyroid, adrenal function, GI tract, HA’s and much more.

Dr. Duffy was reportedly writing up a paper on her gut findings. Can you tell us that the status of that is?

We have one last sample (of 60 total) to obtain to complete the study.

(At a conference Duffy was reported to find HSV-1 in 100% of FM gut biopsies and a protein found only in cells that are actively infected with HSV-1 in 80% of patients.)

With another year under your belt have you learned anything new treating FM using Famvir and Celebrex?

We have found that anything that was previously part of the functional somatic syndrome will improve on this treatment. At the risk of sounding like a snake oil salesman, we have patients who have chronic non-seasonal sinusitis, HA’s, brain fog, and even libido issues who swear by IMC-1.

Dosing – I also asked Dr. Pridgen about dosing information. He replied that the dosing information has to be proprietary right now. This is because pharmaceutical companies or other funding sources would not back a product composed of already approved drugs if the dosages were put in the public realm. Given the enormous costs of the Phase 3 trials, Pridgen’s drug combo would never make it to market without their backing.

That means FM patients will have to wait before Dr. Pridgen publicly reports on the appropriate dose. For many people this conversation is moot – their doctors would not prescribe antivirals now anyway. People seeing Dr. Pridgen or people seeing doctors in touch with Dr. Pridgen will obviously get the right doses.

If the trials are successful and the FDA approves the IMC-1 formulation everyone should be able to get a shot at these drugs.

Can you give us a timeline regarding the Phase III trial(s)?

They will start next year.

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For more on Dr. Pridgen’s antiviral approach to fibromyalgia: