+100%-

One of the things I enjoy about the TLC podcast (The TLC Sessions – Living with Long COVID ) from Noreen Jameel and Emily Kate Stephens (besides their English accents) is the short bit in the beginning of their podcasts where they discuss what’s going on with them.

There’s something about hearing about the trials and tribulations (and occasional successes) of people with long COVID (them), or any of these diseases, that is surprisingly relieving and heartening. Color changes in the toes, horrific crashes, hair falling out, heart palpitations, pain everywhere, etc. The need for a “shitometer” to measure how bad it was was reminiscent of the “small old shitty baseline” (SOSB) term coined in ME/CFS years ago.

You could tell that something was up with one of them – she was just a little slower – and it turned out that she had overdone it and was in a great deal of pain. How easy it is to relate to relate to that.

The Klimas Interview

Listen to Geoff’s narration

THE GIST

THE BLOG

 

How nice that they reached out to Dr. Nancy Klimas – a longtime chronic fatigue syndrome (ME/CFS) doctor and researcher. Dr. Klimas, a clinical immunologist, has been jabbing away at chronic fatigue syndrome (ME/CFS) since it came on the scene decades ago, and the Institute for Neuro-Immune Medicine she runs at Nova Southeastern University in Florida is one of the few large centers dedicated to understanding and treating ME/CFS and other complex, chronic diseases. Besides ME/CFS, Dr. Klimas has done an enormous amount of research on Gulf War Illness (GWI) and is now in the midst of a large long-COVID study. Her computational modeling program that uses supercomputers to understand ME/CFS and find precise treatments for it is, to my knowledge, unique in the country.

Dr. Klimas's big team

Dr. Klimas’s big team

THE GIST

  • Check out Geoff’s narration of the GIST below the introduction.
  • The Living with Long COVID (TLC) podcasts features two women with long COVID talking about their experiences and talking with researchers and doctors Recentlly they had on Dr. Nancy Klimas – a clinical immunologist and longtime ME/CFS doctor who runs the Institute for Neuroimmune Medicine at NovaSoutheastern University.
  • Dr. Klimas is coming at these diseases from a neuroinflammatory perspective. She described the five horsemen of these diseases as immunology, inflammation and neuroinflammation, energy production, oxidative stress, and perfusion (blood flows). Each of these facets of ME/CFS has made big strides recently.
  • Jarred Younger thinks that the neuroinflammation will become a done deal over the next year. Evidence of increased oxidative stress has been found in a dazzling array of tissues and compartments including the muscles, the blood, metabolites, red blood cells, plasma, lipids, and lastly, and perhaps most importantly, in Shungu’s series of NIH-funded studies – the brain. Evidence of impaired energy production has been found in T-, B-, and natural killer cells, in numerous metabolomic studies, the muscles, the mitochondria, and during numerous exercise studies. Dramatically reduced blood flows to the brain have been found.
  • For Dr. Klimas, it all – the reduced blood flows, the high energy needs, the oxidative stress, and the inflammation – shows up most prominently in the brain and that’s where she focuses much of her treatment focus.
  • Dr. Klimas talked about putting the pieces together to make a quilt which she’s been trying to do by using supercomputers to model the system interactions occurring in these diseases. She sees a bunch of highly connected systems (neuroendocrine, immune, and autonomic nervous systems) that are interacting together to hold ME/CFS/FM/GWI and long-COVID patients in their stuck place. Her goal is to bring the systems of people with ME/CFS, long COVID, Gulf War Illness, etc. back into “homeostasis”; i.e. back into their happy place.
  • Using computational analyses Klimas’s team developed a new treatment approach – a two-stage effort involving etanercept (neuroinflammation) and mifepristone (reset HPA axis)  – that’s being tested in GWI and will be tested in ME/CFS.
  • The first major factor she goes after is oxidative stress. She believes high levels of oxidative stress are hampering energy production. You can’t fight the oxidative stress in these diseases simply by giving people handfuls of antioxidants, you have to use right antioxidants, and for Dr. Klimas that means antioxidants that can get across the blood-brain barrier and get at Dr. Klimas’s main target – neuroinflammation; i.e. inflammation in the brain.
  • Quercetin and luteolin are two nice options: they’re strong antioxidants and mast cell stabilizers that can get into the brain. NAC is an antioxidant that can get into the brain as well. (Shungu’s ME/CFS study showed that NAC can reduce oxidative stress in the brain.) Dr. Klimas also recommended a supplement called D-Hist, NeuroProtek.
  • The talk then turned to a small T-cell exhaustion paper by a T-cell expert named Liisa Selin, in which Dr. Selin and Dr. Klimas found “severe deficiencies” in the ability of T-cells to produce cytokines like IFN-γ and TNFα that play a major role in pathogen suppression. Dr. Klimas noted that the T-cells are probably becoming worn out from being activated at all times and that the T-cells found in ME/CFS are reminiscent of “early aging”. A T-cell of a 40-year-old with ME/CFS might look more like that of a healthy 80-year-old.
  • The paper also provided preliminary evidence that a nebulized anti-oxidant, anti-pathogen product called Inspiritol may be able to reduce T-cell exhaustion and improve symptoms in ME/CFS. (A Stanford researcher, interestingly enough, found that oxidative stress – as Dr. Klimas – was exhausting T-cells as well.).
  • When asked about low-dose naltrexone, she said, the studies showed that it was “a little bit better” than the FDA-approved drugs for fibromyalgia but was a lot safer, and her clinical experience is that it helps most people. They start at 1.5 mg and then go up to 3 mg and then up to 4.5mg. (It wasn’t mentioned in the podcast, but Jarred Younger appears confident that he’ll be able to get a trial of a potentially more powerful form of LDN called dextronaltrexone going later this year. (see video in blog).
  • When asked about amytriptyline, Dr. Klimas called it a “messy, old-fashioned drug with a tremendous history” that’s about 100 years old. At a low dose, “it’s pretty good with pain”, is a “pretty decent antihistamine” and is an anticholinergic that can help with dysautonomia. Using it for too long might increase the risk for dementia or cognitive defects, though, and she’ll use it for a while to get things under control (even up to a few years), but that’s about it.
  • When it came to viral reactivation Dr. Klimas reported that HHV-6 is the most common kind of herpesvirus reactivation she sees. Lastly, Dr. Klimas talked about the incredible monoclonal antibody cases series that she, Dr. Pepe, and others wrote up about that demonstrated how they quickly sent three long-term long-COVID patients into remission.  She is about to begin a clinical trial.
  • A “What’s Up Doc” talk with Dr. Klimas is coming up. Register for Dr. Klimas’s Institute of Neuroimmune Conference on May 10th on the Institute’s Events page. Listen to the Institute of Neuroimmune Medicine’s “Hope and Help for Fatigue and Chronic Illness” podcasts.
I remember how worried I was attending my first ME/CFS conference decades ago that the experts in this neglected and rather fringe field of medicine might not be up to snuff. Thankfully, they turned out to be a serious and, I thought, impressive bunch.

ME/CFS still doesn’t get much respect, though. The RECOVER project, for instance, doesn’t appear to have listened to our experts much, and a good deal of long-COVID research has been reinventing a wheel that was formed over the decades in ME/CFS. Research funding is still in the pits. It’s clear that in the medical community’s eyes, long COVID is where the action is. It’s certainly where the money is. ME/CFS is still the odd man out.

I didn’t realize until I listened to the podcast how much I yearn for ME/CFS to achieve the kind of legitimacy it deserves. I fully know how good Nancy Klimas is – she’s been an uncommonly articulate representative of this field for decades – but what surprised me was the feeling of pride that swelled up at how well she represented us in the long-COVID space. One of them called her a “powerhouse’, and she was.

The Talk

Please note that this “overview” contains some information not included in the talk and may not reflect Dr. Klimas’s views. 

Dr. Klimas laid out an interesting approach to ME/CFS and long COVID. A clinical immunologist, she first and foremost, is coming at these diseases from a neuroinflammatory perspective. She described the five horsemen of these diseases are the immunology, inflammation and neuroinflammation, energy production, oxidative stress, and perfusion (blood flows).

It’s interesting, looking at them, to see how our conception of these diseases has changed over time. The immune system has always been a big deal in ME/CFS research, but it’s only been in the past couple of years that it’s become pretty clear that neuroinflammation, problems with energy production, and the blood vessels are alive and kicking in this disease.  Slowly but surely we’ve gained ground.

Next, a brief look at where we are with these “five horsemen”.

Neuroinflammation

neuroinflammation

Jarred Younger believes that over the next year the neuroinflammation finding will be a done deal in ME/CFS.

The small 2014 Watanabe study provided the first direct evidence of neuroinflammation in ME/CFS. Since then, a meta-analysis highlighted the “neuroinflammatory features” found in ME/CFS. Rather remarkably, ME/CFS and Gulf War Illness (GWI) showed up next to neurodegenerative diseases like Parkinson’s, Alzheimer’s, etc. in a review of neuroinflammatory disorders. The authors of the paper did not pull their punches when they remarked on “the unbearable physical and mental fatigue can remain in the ME/CFS patients for decades.”

At least three studies have found neuroinflammation in fibromyalgia and multiple studies have done so in GWI. With new studies coming out over the next year, Jarred Younger believes that neuroinflammation will soon be widely accepted in these diseases.

Given the increasing interest in treating neuroinflammation in neurodegenerative diseases, recognizing that these are neuroinflammatory diseases should open up more treatment options over time. The neuroinflammatory review paper offered up polyphenol curcumin, monosodium luminol (MSL), minocycline, Q10 (CoQ10), Bacopa monnieri, Tai Chi, yoga, and interestingly, sildenafil (Viagra). Viagra, which can improve blood flows to both brains (:)), may be able to reduce neuroinflammation, and has been shown to increase brain oxygenation. Future potential treatment options could include stem cells, nanoparticles, exosomes, and intranasal administration as possible.

Oxidative stress

High rates of oxidative stress have been found across the body.

Oxidative Stress

High levels of oxidative stress may be the most consistent finding in ME/CFS, but it’s always been considered a kind of side issue. That may be changing with the recognition of how widespread it is and the role that mitochondrial damage could play in enhancing it. Evidence of increased oxidative stress has been found in a dazzling array of tissues and compartments including the muscles, the blood, metabolites, red blood cells, plasma, lipids, and lastly, and perhaps most importantly, in Shungu’s series of NIH-funded studies – the brain.

A major hypothesis paper that linked oxidative stress, inflammation, mitochondrial dysfunction, impaired metabolism, pathogens, and cell death together appeared recently. Noting that impaired hydrogen sulfide metabolism can produce a hypometabolic state similar to that seen in ME/CFS, Bindu Paul, proposed that next-generation hydrogen sulfide-based antioxidants will be much more effective in these diseases. In a 2022 paper, Paul proposed that ergothioneine (ET), a sulfur-derived stress vitamin and antioxidant whose levels decline during aging, might be helpful.

Energy Production

low fuel

Problems with energy production have been found in many compartments of the body

Impaired energy production, has, not surprisingly, always been a concern in this exertion-challenged disease, but only in the last couple of years have how widespread these problems are become apparent. Evidence of impaired energy production has been found in T-, B-, and natural killer cells, in numerous metabolomic studies, the muscles, the mitochondria, and during numerous exercise studies. Chris Armstrong believes the research findings now clearly indicate that a dirty fuel source – amino acids – are preferentially being used to produce energy in ME/CFS.

Blood Flow Issues

Likewise, while we’ve known for ages of the startlingly low blood volume that can be, it’s only been in the last five years or so and the development of better technology that the Visser/Van Campen/Rowe team has been able to show how dramatically impaired blood flows to the brain are. Evidence of microcirculatory problems has shown up, as well, and of course, long-COVID findings have put a new focus on blood clots and blood vessel functioning.

The Key Factor – the Brain

For Dr. Klimas, it all – the reduced blood flows, the high energy needs, the oxidative stress, and the inflammation – shows up most prominently in the brain. In a recent talk with Health Rising, Dr. Clauw – a fibromyalgia and nociplastic pain specialist – noted that all the symptoms of these diseases are symptoms produced by the brain.

In a big surprise, Dr. Klimas called long COVID “a touch more complicated, maybe, than ME”. Thinking of ME/CFS – the disease triggered by god knows how many different pathogens or other insults – as perhaps a bit less complicated than long COVID was startling (and a bit of good news for ME/CFS sufferers.)

It made sense, though. Compare an Epstein-Barr virus-triggered case of ME/CFS that targets the immune cells with a coronavirus-triggered case of long COVID which targets the ACE-2 receptors on the endothelial cells lining the blood vessels and you can see how complicated long COVID can be. Any blood vessel in the body is a potential target.

Putting the Quilt Together

Quilt

The computational goal – putting the ME/CFS, long COVID, GWI quilt together.

The huge question, of course, is how to put the genie back in the bottle in these very complex diseases. ME/CFS researchers were probably not surprised at how complex long COVID has turned out to be, but long-COVID researchers have been. Many of them have been working with colleagues in other fields they’ve never had contact with.

Dr. Klimas called it putting the little pieces together to make a quilt – and she, of all researchers, has been most dedicated to trying to put that quilt together and she’s trying to do that in an unusual way – by using supercomputers to model the systems that are interacting with each other.

The goal is to get back to “homeostasis” (your happy place :)) where all the systems are working together to produce health. During an infection, the body moves out of its normal homeostatic equilibrium to fight off the infection. When the infection is cleared, the body should move back into homeostasis but, in these diseases, gets caught in a now stable “sick point”.

The Big Picture

The goal is to move it back to a healthy homeostatic state. The findings in this diseases clearly show, Dr. Klimas believes, the outlines of the sick homeostatic setpoint. All these illnesses, feature highly connected systems (neuroendocrine, immune, and autonomic) that are interacting together to hold ME/CFS/FM/GWI and long-COVID patients in their stuck place.

Dr. Klimas’s group models these interactions, identifies potential targetable points for treatment, and then runs hundreds of thousands of virtual clinical trials using every substance under the sun to find drugs that could impact the system. They’re even able to use 3-dimensional structures to look for drugs that target specific locations on proteins and molecules. Her computational researchers give her the results which typically include a bunch of toxic or very expensive drugs that wouldn’t work, but mixed in that bunch are possibilities that can work – drugs or supplements.

It was Gulf War Illness funding that got Klimas’s team to get to this point. Remarkably one in three Gulf War soldiers came down with GWI, and for a very simple reason: they were slow metabolizers who were unable to detoxify the tremendous levels of toxins (Sarin gas, oil well fires, pesticides) they were exposed to. Interestingly, pathophysiologically, they look very much like people with ME/CFS and long COVID: they exhibit high levels of oxidative stress, inflammation, and problems with energy production; i.e. they had a neuroinflammatory illness – similar to what people with ME/CFS and long COVID have.

Klimas’s team came up with a new treatment approach – a two-stage effort involving etanercept (neuroinflammation) and mifepristone (reset HPA axis) which is in phase I trials. As to the identical ME/CFS trial for which they have funding – which always seems about to begin – it still has not begun and Dr. Klimas said it was getting IRB approval. (Dr. Klimas said that GWI has about 35 clinical trials going (all apparently funded by the Department of Defense).

The RECOVER Initiative

question mark

Does the Recover Initiative simply need more time to get its act together? (Image-by-ElisaRiva-from-Pixabay-.gif)

Dr. Klimas did introduce a way for long COVID, ME/CFS, and similar diseases to move quickly: build a clinical trial network across the country like happened with HIV/AIDS. Once that was done, it took a couple of years to come up with the first good treatment and ten years to come up with definitive treatments – and that was in the 90s – and medicine has moved a long way since then.

Dr. Klimas didn’t want to comment on how well the RECOVER Initiative is doing, but she did note that it’s essentially duplicating that effort. It’s created dozens of clinical centers, has a clinical trials network, has centralized depositories and databases.

Her message seemed hopeful. Nobody was studying “postviral” illnesses prior to ME/CFS, and building an effort like this from scratch isn’t easy. It takes years to build that kind of infrastructure and find the right teams. Her remarks were reminiscent of what former National Cancer Institute chief Vincent DeVita said about the development of the National Cancer Institute Centers. They were a big mess for a while, but they did work things out over time. Hopefully, the same thing is happening with RECOVER.

There’s no reason it shouldn’t. The RECOVER money pot was so big that over 200 institutions applied to be part of it, and as Suzanne Vernon said years ago, a lot of “really sharp” people are a part of it. ME/CFS, Dr. Klimas still thinks (she’s been saying this for years), should be part of the network.

“The Death of Cancer” – and Ultimately ME/CFS, FM and Long COVID? A Review of Vincent DeVita’s Book

Still, Dr. Klimas did ask what is the use of basic science if it doesn’t move the needle on treatments, and we’ve seen no evidence yet that the research being done in RECOVER is anything other than very basic.

Treatment

Low-Dose Naltrexone (LDN) – When asked about low-dose naltrexone, she said, the studies showed that it was “a little bit better” than the FDA-approved drugs for fibromyalgia but was a lot safer, and her clinical experience is that it helps most people. They start at 1.5 mg and then go up to 3 mg and then up to 4.5mg.

It wasn’t mentioned in the podcast, but Jarred Younger appears confident that he’ll be able to get a trial of a potentially more powerful form of LDN called dextronaltrexone going later this year.

 

Amytriptyline – When asked about amytriptyline, Dr. Klimas called it a “messy, old-fashioned drug with a tremendous history” that’s about 100 years old. At a low dose, “it’s pretty good with pain”, is a “pretty decent antihistamine” and is an anticholinergic that can help with dysautonomia. Using it for too long might increase the risk for dementia or cognitive defects, though, and she’ll use it for a while to get things under control (even up to a few years), but that’s about it.

Antioxidants and Mast Cells – Mast cells are major players in these illnesses – and she has one of the mast cell pioneers – Theo Theoharides – on her team. (See mastcellmaster.com.) Mast cell activation syndrome (MCAS) is very, very common in her patients. Given how hard it is to test for it, the best way to diagnose it is to treat it and see if the treatment works. Check out Dr. Theoharides on mast cells below.

 

Interestingly enough, though, reining in the mast cells is not her first objective. The first of the five horsemen she goes after is oxidative stress. She believes high levels of oxidative stress are hampering energy production. Since the mitochondria are major drivers of oxidative stress, the cells “hunker down” and turn down their energy levels in order to avoid being damaged. .

While too much oxidative stress means our antioxidant systems are getting overwhelmed, Dr. Klimas stated that you can’t fight the oxidative stress in these diseases simply by giving people handfuls of antioxidants. You have to use right antioxidants, though, and for Dr. Klimas that means antioxidants that can get across the blood-brain barrier and get at Dr. Klimas’s main target – neuroinflammation; i.e. inflammation in the brain. Anything that attacks inflammation in the brain will attack inflammation in the body.

Quercetin and luteolin are two nice options: they’re strong antioxidants and mast cell stabilizers that can get into the brain. NAC is an antioxidant that can get into the brain as well. (Shungu’s ME/CFS study showed that NAC can reduce oxidative stress in the brain.) Dr. Klimas also recommended a supplement called D-Hist, NeuroProtek.

T-Cell Exhaustion, Early Aging, the Herpesviruses, and Another Treatment Option

The talk then turned to a small T-cell exhaustion paper by a T-cell expert named Liisa Selin, in which Dr. Selin and Dr. Klimas found “severe deficiencies” in the ability of T-cells to produce cytokines like IFN-γ and TNFα that play a major role in pathogen suppression. Vishnu Shankar at Stanford also recently found evidence of T-cell exhaustion in ME/CFS that he traced to oxidative stress as well. He believes exhausted T-cells may be overstressing the mitochondria causing them to break down and produce more oxidative stress. It feels like we are starting to put the pieces together.

The Vampire: Is the Immune System Sucking the Energy Out of People with ME/CFS? – the NIH ME/CFS Conference Pt. I

The paper also provided preliminary evidence that a nebulized anti-oxidant, anti-pathogen product called Inspiritol is able to reduce T-cell exhaustion and improve symptoms in ME/CFS.

Inspiritol – A New Investigational Drug Announced for ME/CFS and Long COVID

Dr. Klimas noted that the T-cells are probably becoming worn out from being activated at all times and that the T-cells found in ME/CFS are reminiscent of “early aging”. A T-cell of a 40-year-old with ME/CFS might look more like that of a healthy 80-year-old.

The idea of early aging has cropped up a couple of times in the ME/CFS literature. While the idea that early aging is taking place is rather daunting – if not particularly surprising – it may also provide a window into new treatment options. On one of the Unraveled Patreon podcasts, Dr. Kaufman said he believed that longevity research could be really helpful in ME/CFS, and, Dr. Eleanor Stein will talk about why she believes longevity research will help inform ME/CFS in our upcoming “What’s Up Doc?” series.

Exhaustion

Has Liisa Selin found a biomarker of T-cell exhaustion?

With that, Dr. Klimas turned to the Epstein-Barr virus (EBV) reactivation that occurs in long-COVID patients during the initial illness and later, and of course, the EBV reactivation that’s been seen in ME/CFS for decades. Given the overwhelming interest in EBV, it was interesting to hear Dr. Klimas call another herpesvirus – HHV-6 – the most commonly reactivated virus in ME/CFS. A recent paper highlighted HHV-6 activation in both ME/CFS and long COVID. Personally, tests suggested that HHV-6 was much more reactivated in me than EBV.

On Dr. Klimas’s way to stating that a crippled immune system has let the dogs out, so to speak, in ME/CFS, she also referenced John Chia’s enterovirus findings.

Monoclonal Antibodies to the Rescue?

Then it was onto the incredible monoclonal antibody cases series that Dr. Klimas, Dr. Pepe, and others wrote up about how they sent three long-term long-COVID patients into remission in a week. (Dr. Klimas said Dr. Pepe has 15 more patients with similar stories.)

The study used a monoclonal antibody called Regeneron which is no longer effective against the more recent coronavirus variants – and is almost, but not completely, unavailable. Dr. Klimas has funding and was able to get some of the drug. She hopes to start a 20-person trial by May.

Unfortunately, we didn’t get to hear about the possibility of using monoclonal antibodies against EBV or HHV-6 in ME/CFS, but Dr. Klimas said pharmaceutical companies were eagerly awaiting the result of the 20-person trial. Why RECOVER is not doing a spate of experimental trials to assess treatment possibilities like this is beyond me.

Three Severely Ill Long COVID Patients – Three Rapid Recoveries: Monoclonal Antibodies, LC and ME/CFS

 

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