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Simmaron Celebrates Ten years of Innovative ME/CFS Research

March 4, 2020

“We envision a world where ME/CFS is treatable and well-understood. To get there, we are scientifically redefining ME/CFS.” The Simmaron Research Foundation

Dr. PetersonIt’s been ten years since the Simmaron Research Foundation for ME/CFS opened its doors. Dr. Daniel Peterson, one of its founders, was restless. Ever since people with a strange, debilitating illness began knocking on his door in the Incline Village outbreak in the mid-1980’s, he’d been focused on ME/CFS. Since then he’d been patiently collecting data and samples – including precious spinal fluid samples – and biding his time until the researchers were ready – and now he thought they were.

With the formation of the Simmaron Research Foundation, Peterson was given the opportunity to put his experience and samples to the test. It turned out that the ME/CFS research community was very interested in what he had to offer.

Research

A Special Partnership

Since its founding, the Simmaron Research Foundation has enjoyed a special relationship with Dr. Mady Hornig and internationally renowned virologist Dr. Ian Lipkin at the Colombia Center for Infection and Immunity. Dr. Lipkin’s interest in chronic fatigue syndrome (ME/CFS) – which began with Dr. Peterson – dates back to 1984. Dr. Lipkin talked about that and his search for more resources in a 2014 video.

 

Simmaron’s Signature Research Effort:

The Cerebral Spinal Fluid Studies

Simmaron’s signature research effort over the past ten years has involved the most intense and potentially difference-making exploration of the spinal fluid yet done in ME/CFS. Bathing the brain, the cerebral spinal fluid provides a unique access to an organ many believe plays a central role in ME/CFS.

Dr. Peterson’s dogged accumulation of cerebral spinal fluid samples over the years paid off in two unique studies. With recent studies providing more evidence of neuroinflammation in ME/CFS, Simmaron’s early decision to commit a substantial amount of resources to spinal fluid investigations is looking prescient indeed.

A gateway to the brain - the cerebral spinal fluid

Simmaron’s signature research efforts have focused on the cerebral spinal fluid – the gateway to the brain.

The first study published in 2017 assessed more cytokines, used more sophisticated statistical analyses (logistic regression/network analysis) and was larger (n=91) than past ME/CFS spinal fluid studies.

The studies started with a collection of samples from many of Dr. Peterson’s sickest patients, which Dr. Hornig called “unparalleled” in their breadth and rigor.

Simmaron sent off two sets of spinal fluid samples – one to Mady Hornig and Ian Lipkin at the Center for Infection and Immunity (CII) for a pathogen and cytokine study and another smaller set to Griffith University researchers in Australia to assess for immune abnormalities.

The CII added a set of multiple sclerosis patients to the mix to produce one of the most interesting studies in years. Few studies had compared MS and ME/CFS patients, and none had assessed the crucial immune factors present in the spinal fluid.

The cytokine levels in both the ME/CFS and the MS patients differed widely from those of the healthy controls. Interestingly, both ME/CFS and MS patients demonstrated reduced cytokine levels – a fascinating finding given the similar finding in the blood for longer duration ME/CFS patients. That finding prompted Dr. Hornig to speculate that, “I think what we’re seeing is an immune system exhaustion over time.”

Despite both diseases demonstrating the same general trend towards immune exhaustion, they differed markedly in the cytokines affected. The cytokines highlighted in ME/CFS suggested an allergic type of reaction – similar to that found in central nervous system infections – was present.  Cognitive decline and aging – two themes in ME/CFS research – as well as reduced neuron production were also highlighted.

The fact that the alterations in the immune factors in ME/CFS were almost as extreme as those found in multiple sclerosis – a disorder characterized by severe central nervous system dysfunction –  suggested that a significant pathological process was indeed occurring in the central nervous systems of ME/CFS patients.

A Hunch Pays Off – The Peterson Subset

“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.” Mady Hornig

Next, Simmaron and the CII turned to an unusual subset of patients. Dr. Peterson has long asserted that a classical (infectious onset) subset of patients is present in ME/CFS, and is different from what he called a “complex atypical” subset of patients.

Dr. Peterson’s believed his typical “classical” ME/CFS patients came down with a flu-like illness from which they never recovered. His atypical patients, on the other hand, tended to be sicker, have more cognitive problems, have more severe comorbid diseases (autoimmune diseases, cancer), tended to have unusually severe neurological symptoms (such as seizures), and had experienced things like blood transfusions, exposure to infectious agents during international travel, etc.

Many of these illnesses appeared long after the ME/CFS diagnosis. In fact, at the time of diagnosis Peterson reported that the atypical patients looked like a typical ME/CFS patient but felt that some other underlying central nervous system process was underway.

Peterson subset

Dr. Peterson’s intuition that the atypical patients were fundamentally different saved the spinal fluid study – and pointed to a new subset.

Dr. Peterson was so sure, in fact, that an atypical subset of ME/CFS was present – and probably bollixing up study results – that he requested that the group be assessed apart from the other patients in the first Simmaron/CII spinal fluid study. Peterson’s intuition turned out to be correct: the atypical group affected the results so thoroughly that it had to be removed from the first study.

The next study compared the atypical and typical patients. Using Peterson’s spinal fluid samples, The Center for Infection and Immunity (CII) at Columbia found that the “Peterson Subset” displayed a markedly different pattern of immune results: something quite different was going on in their central nervous systems.

Given how sick the atypical patients were, one might have expected their immune factors to be even more reduced, but instead they were increased. In stark contrast to the classical patients, the atypical patients had higher levels of virtually all the immune factors assessed.

Their immune presentation over time differed as well. Almost half their immune factors were lower early in the illness but as the illness proceeded, in contrast to the typical patients, the atypical groups’ immune systems actually revved up again.

Since the higher levels of cytokines in the atypical group would have negated the lower levels of cytokines in the “classical” patients, Peterson’s request that the atypical patients be set aside saved the biggest CSF study in ME/CFS history from a null result. Given the size and expense of the study, that negative result would have dampened interest in the immune aspects of the CSF in ME/CFS for years.

The study demonstrated how critical it is for savvy ME/CFS experts to work hand in hand with research teams to explore ME/CFS – and put the research field on the alert for the apparently very biologically different atypical patients.

The Gut

Since its inception, Simmaron has collaborated with the Columbia Center for Infection and Immunity on several gut studies, including, in 2017, the first study to characterize ME/CFS patients gut flora all the way down to the species level. Prior to this study, ME/CFS gut studies had identified genera, each of which contain many different species, some with very different characteristics. This time, Ian Lipkin used a new approach called metagenomic sequencing to get at the actual players in the gut – the bacterial species.

Simmaron collaborated with the Columbia Center for Infection and Immunity to produce the first study to describe the bacterial species present in ME/CFS patient’s guts.

For the first time, the gut flora of ME/CFS patients with and without irritable bowel syndrome (IBS) was assessed, as well.

Such dramatic differences in bacterial species showed up between the two groups that the researchers were able to distinguish the two simply by comparing their gut flora.

In 2018, Dr. Peterson participated in another innovative CII gut study. Melding together gut flora and metabolomic findings for the first time, Nagy-Syzkal and Lipkin found that ME/CFS and ME/CFS-IBS patients again displayed significantly different gut flora as well as metabolomic signatures.

While problems with fatty acid metabolism were present in both groups, the study found that ME/CFS patients with IBS had additional problems with ATP production and the urea cycle. Plus, the findings suggested high loads of bacterial toxins could be triggering IBS, and pathogens in the gut could be triggering ME/CFS in both groups. On the treatment end, the study findings suggested SMAse blockers might be helpful if the findings are validated.

For all the focus on metabolomics in ME/CFS, a gut microbiome analysis was better able to distinguish ME/CFS patients from healthy controls than a metabolomic analysis. That surprising finding suggested the gut may play a bigger role than we’ve thought in this disease.

Natural Killer (NK) Cells

Dr. Peterson was the co-author of the first NK study, over thirty years ago, to find deficient NK cell functioning in chronic fatigue syndrome (ME/CFS). Following a year-long collaboration between Dr. Peterson and Griffith University in Australia, Griffith found reduced natural killer cell functioning at all time points – indicating that NK problems in ME/CFS are consistent and pervasive.

Peterson’s next Griffith University collaboration found that small bits of mutated RNAs called miRNAs may be contributing to the problems with cytotoxic NK and T-cells in ME/CFS.

Immunology Workshop

In 2014, Simmaron hosted the first ever Immunology Workshop at the IACFS/ME International Conference:

Validating Treatment Successes

Making more effective treatments available for ME/CFS patients has been a goal of Dr. Peterson’s for years. Dr. Peterson’s focus on and his creative approach to infectious onset patients, in particular, has resulted in using and documenting treatments that other doctors might not try.

Dr. Peterson has reported that almost 30% of his patients test positive for active HHV-6 or human cytomegalovirus (HCMV) (via PCR, rapid culture, antigenemia), and a whopping 50% test positive for active Epstein-Barr virus (EBNA) infection.

Simmaron’s core work includes efforts to analyze the effects of little used immune treatments such as Cidofovir (Vistide), Ampligen and IVIG on ME/CFS with a goal of publishing treatment data.

Vistide

In 2013, Dr. Peterson reported on the results of the first retrospective analysis of Vistide’s effectiveness in ME/CFS. Few ME/CFS experts use Vistide but Peterson found that 70% of 65 patients treated from 2005-2012 for HHV6 and/or HCMV infection were either full (able to return to work) or partial (significant increase in functionality) responders; a very high rate of success in an illness characterized by a poor response to treatments.

Only 30% of Vistide recipients did not have a significantly positive response to the drug, and no serious side effects were seen; ironically the minor side effects seen were attributed to a drug, Probocenid, that’s used to ensure that Vistide is absorbed into patients’ systems effectively.

See Report From Paris: Peterson Reports Antiviral (Vistide) Effective in Treating Herpesvirus Infected Chronic Fatigue Syndrome (ME/CFS) Patients for more.

Ampligen 

In 2018, Simmaron and Dr. Peterson reached out to Maureen Hanson and the CDC to help with a project to assess the effectiveness of Ampligen. To this day, Ampligen still remains the only drug the FDA has assessed for ME/CFS. With no Ampligen trials forthcoming Peterson searched for ways to provide a boost for a drug he knows from long experience that can work very well.

Simmaron’s collaboration with Maureen Hanson and the CDC seeks to show why Ampligen is effective in ME/CFS

The novel project took advantage of a year-long lapse in Ampligen availability to assess changes in immune and other factors and symptoms at three time points: (1) while Dr. Peterson’s patients were on Ampligen; (2) when they were off Ampligen; and (3) when they went back on Ampligen.

The extensive testing included NK cell function, cytokine expression, multiple symptom surveys, an exercise tolerance test and Cornell-designed research protocols.  Besides demonstrating how Ampligen works, the study could begin to uncover which subsets of patients it works in.

Gunnar Gottschalk presented preliminary results from “The Workshop for Young Investigators” at the NIH’s ME/CFS Conference in 2019. He reported finding “significant and sustained clinical reduction(s) in both the physical and neurological symptoms following Rintatolimod (Ampligen®)”, including improvements in physical functioning, pain and energy after 6 months of treatment.

An analysis of the biological data is underway.

Next Up For Simmaron

Simmaron’s highest priority is publishing data on ME/CFS subsets and effective treatments – two factors which experience has shown are inextricably linked to one another. Simmaron believes the hidden subsets in ME/CFS have the potential to cloud or nullify the results of biomarker and research efforts as well as treatment trials. On the flip side, elucidating those subsets could produce breakthrough results. To this end, Simmaron’s work is strategically focused on helping the field break out of that conundrum.

Expanded Treatment / Subset Effort

Simmaron

The Simmaron Research Foundation is committed to scientifically redefining how ME/CFS is understood and treated.

Simmaron recently began fundraising for an expanded effort to analyze data from Dr. Peterson’s patients who’ve responded to treatments like Ampligen®, IVIG and cidofovir, as well as amino acid infusions, saline, etc. The goal of these studies is to biologically identify which patients respond to which treatments, and build a scientific roadmap for getting a first medication approved by the FDA for ME/CFS.

Maureen Hanson, PhD of Cornell, is leading the scientific arm of the study, the U.S. Centers for Disease Control is doing statistical analysis; and Dr. Peterson will provide the patients and the treatments.

Simmaron believes the rigorous data analysis being used in these efforts can provide a building block for designing rigorous placebo-controlled trials that have a stronger chance of approval, and ultimately attract pharmaceutical companies to the disease.

Spinal Fluid Study – Round Three

The second phase of the Simmaron/Columbia spinal fluid study now in progress expands the prior studies, and breaks new ground by including a metabolomics analysis. Metabolomics – the study of metabolic by-products – has suggested that a hypometabolic state akin to hibernation may be present in ME/CFS.  This study should shed light on both the metabolic and immune underpinnings of the neuroinflammation believed present in ME/CFS.

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11 Comments

  • Janet Blumberg

    March 4, 2020 at 10:37 pm - Reply

    Hi Cort — amazingly clear post on such technical subjects!

    I’m wondering if it still the case (at least as I understand it) that Ampligen cannot be prescribed for patients like us by our doctors? That to access it we would have to be in a trial or be able financially to go to an expensive private clinic? At least — I assume that going to a private clinic was how Laura Hillenbrand got access to the (unnamed) drugs she has signaled have been able to turn her CFS/ME condition dramatically around?

    • Cort Johnson

      March 5, 2020 at 2:28 am - Reply

      Since Ampligen is not FDA approved the FDA allows Ampligen to be provided only in a few clinics.d Dr. Peterson’s is one and I think Dr. Lapp’s former clinic is another but I’m not sure.

      If you have any information of how Laura Hillenbrand did that it would be great to hear.

  • Waiting

    March 4, 2020 at 11:13 pm - Reply

    There is a lot of really important information in here for the research community to follow up on, but this statement really hits home for me: “Simmaron’s highest priority is publishing data on ME/CFS subsets and effective treatments – two factors which experience has shown are inextricably linked to one another.”

    Subsets and effective treatments: yes, please!!! Effective treatments based on subsets rather than what we are currently left to — at best, and only for the most fortunate among us — being guided by our few, overworked ME specialists who have the clinical acumen & intuition, like Dr. Peterson, to help steer us in the right treatment directions.

    • Cort Johnson

      March 5, 2020 at 2:26 am - Reply

      So well said Waiting. (I can imagine what you’re waiting for :)) Ian Lipkin is always emphasizing the need, as Simmaron and Dr. Peterson does to tease out subsets. Dr. Peterson has been seeing this for years in his practice and that’s surely driving his desire to get the effectiveness of these immune treatments biologically validated.

  • Nikoli McCracken

    March 5, 2020 at 12:39 am - Reply

    I became ill in June 1981, while living in Denver. I was told I had “all in your head”
    for YEARS. Not too long ago, my regular physician ordered an MRI, spinal tap, and
    a PET scan. The neurologist refused to give it to me. He didn’t even have the courtesy to BILL me for the very brief appointment with him. Earlier I was forced to consult him, in order to ‘rule out MS (My eye surgeon refused to complete the eye surgery until a neurosurgeon ruled out MS)
    Same doctor bluntly told me I didn’t have MS. Which I could have told him. So there are still
    doctors out there who still think we are all hypochondriacs. Oh, right, I wanted to lose my marriage, my career, my $40,000 a year job which came with one million dollars of health insurance. Work I loved. When both of my adult kids, separately came down with ME/CFS,
    were were told: “It’s not genetic.” And I can hardly wait until they finall quite scrwing around
    with a medication which, even if it becomes available, costs $20,000 per person, per year.
    I’m really fed up. I’m 81.5 years old. I have now been sick for HALF my life!

    • Cort Johnson

      March 5, 2020 at 2:22 am - Reply

      Really rough, Nikoli. You are certainly not alone. The cure to all this is more and more research which will more and more validate this disease so that other people don’t have to go what you’ve gone through. Look at the spinal fluid results – the ME/CFS patient’s immune systems were almost as impaired as the M.S. patients. We have to keep fighting not just for us but for those that come after us – so they won’t have to go through this. That would a be a good legacy.

  • Janet Blumberg

    March 5, 2020 at 1:37 am - Reply

    Hi Nicholl —

    I am so sorry you experienced this. My experience was much the same. And in my case, it was the (male) neurologists of a certain age who were absolutely the worst of the deniers. They seemed to have an entrenched response that is hostile and aggressive in the extreme, against illnesses like ours. (Reactionary.) I too had to get a diagnosis from a neurologist, way back back when I had no idea what was wrong with me. He listened to my symptoms and responded angrily, “Fibromyalgia is NOT a diagnosis.” I hadn’t mentioned FM or even thought of it. So what does THAT tell you! Finally, many years later I traveled some distance to see a young woman neurologist who actually listened to me. In fact, she even took the 2015 IOS SEIDS Report literature with her and read it over the weekend and then did some research of her own. One of the most amazing days of my life was when she called me, out of the blue, to say yes, she would be happy to make the diagnosis.

    I’m a research scholar myself (not in medicine) aand so I could not believe that these university-trained medical professionals (who are supposed to understand and value scholarship and research) would not even be open to looking at such a Report as that — but over the years since it came out, none of my GPs or rheumatologists would do it. “Boutique research,” one called it. (IOM? NIH?)

    Anyway, I wanted you to know that you are not alone!

    And also, that maybe there’s a ray of hope to be found in a new generation of doctors.

  • Janet Flynt

    March 6, 2020 at 3:12 pm - Reply

    Thanks for this summary as it is clear and shows meaningful progress. And many thanks to Dr Petersen and the Simmaron team for sticking with us. The subset differentiation is very insightful and it will be interesting to see longitudinally how the immune profile changes for the atypical subset. Hopefully it will be a restorative path and not lead down the classical subset path as more health exposures and interventions arise. Also with the attention to CoVid-19 is anyone making the decision makers aware of this insightful research? With congressional appropriations the importance of immune system research for ME atypical and classical and … subsets could be of benefit. After all I surmise we are a higher risk severity group if exposed to CoVid-19 but have no data to support my surmising.

  • Adam

    March 8, 2020 at 7:30 am - Reply

    Guys, Ampligen is available in Brasil and it can be ordered from there by a physician. In Brussels, it is available and it shall be available in the USA too.

    My doctor told me that if I wish to get Ampligen, it can be done but it has downsides. First, it costs 3.000,-Eur/month (cca 3500,-dollars). Next, we do not have too much knowledge on Ampligen. It may even cause deterioration, altough it is rare. Finally, it shall be administered (intravenously) basically lifelong or with minor pauses only.

    This is why we experiment with BCG because it promises the same but it costs 1,-dollar and with a wellknown profile.

  • Adam

    March 8, 2020 at 7:48 am - Reply

    Vistide is also a risky drug. Not during the first one or two years but it shall also be administered continuously and they have not been tested in clinical trials for that. In addition, it costs also 2.000,-dollars/months in Europe.

    So, if you have proven reactivation, it is fine. However, CFS may be caused by various pathogens and the symptoms persist even after the initial infection. It is possible only if you have an underlying autoimmune response. This is why you have to be careful.

    IVIg may be applied even is autoimmune medical conditions. There are various clinical trials with CFS, results very mixed.

    Guys, patients shall not learn from patients but from doctors. Patients need doctors who are open to discuss possible treatment options, many of the aren’t licenced. Just as Nancy Klimas pointed out, we know a lot about patients and the disease. We need a medication which is already on the market (or available there) and which exerts an effect targeting pathogenic mechanism. This also shall be at a reasonable cost with favorable side effect profile.

    This is why we focus on BCG vaccine therapy, which may not work but which is a low cost therapy and targets the exact mechanism of CFS. Nancy Klimas pursues another course of treatment. Scheigebogen something else. All of them try to target the root of the disease.

    Prey for the success of all of these treatments !

    • Cort Johnson

      March 13, 2020 at 8:14 pm - Reply

      Agreed. Someone with an autoimmune manifestation does not want to be taking Vistide! Good luck with BCG!