Dr. Nancy Klimas discusses groundbreaking approaches to understanding and treating ME/CFS and Long COVID. She emphasizes the importance of a holistic view of the body, exploring issues like immune senescence, oxidative stress, and latent viral reactivations. Highlighting an innovative nebulized antioxidant-antiviral treatment, Dr. Klimas explains its potential to restore immune function and improve patients’ quality of life. She also underscores the critical need for further research into biomarkers, immune dysfunction, and vascular issues.
Guest – Professor Nancy Klimas PhD
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Podcast Overview:
- Holistic Approach to Health: Dr. Nancy Klimas underscores the need to view the body as an interconnected system rather than treating organs in isolation.
- Immune Senescence and Dysfunction: Long COVID and ME/CFS patients experience immune system “hibernation” caused by oxidative stress, similar to aging effects but in younger individuals.
- Innovative Treatment: A nebulized antioxidant-antiviral therapy shows promise in restoring immune function, reducing oxidative stress, and improving quality of life in severely ill patients.
- Delivery Mechanism Benefits: Inhalation offers rapid drug delivery to the bloodstream, bypassing digestive barriers and reaching the blood-brain barrier more effectively.
- Latent Virus Reactivation: Reactivated viruses like Epstein-Barr (EBV), CMV, and HHV-6 play a significant role in patient symptoms, varying individually.
- Biomarker Research: Dr. Klimas collaborates with researchers to identify cytokine patterns and other biomarkers to improve diagnosis and treatment tracking.
- Call for Further Research: Emphasis on the need for larger studies and NIH support to expand understanding and validate treatment efficacy.
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Podcast Transcript:
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E26: A Potential Treatment & Biomarkers for Long COVID ft Prof Nancy Klimas
[00:00:00] Funmi Okunola: The information in this podcast is provided for informational purposes only. You should not use any information discussed in this podcast and related materials to make medical or healthcare related decisions. Always consult your physician or other qualified healthcare providers with regards to diagnosing and managing your medical condition. Any medications or treatments, including any discussed in this podcast, should be initiated and managed by a qualified healthcare professional.
Funmi Okunola: [00:00:00] Welcome to Long Covid – The Answers. Today’s Episode is “Potential Treatments and Biomarkers for Long COVID” with Professor Nancy Klimas. I’d like to introduce Professor Nancy Klimas, MD.
Dr. Klimas has forty years of professional experience and has achieved international recognition for her research and clinical efforts in Complex Chronic Disease, notably Myalgic Encephalomyelitis or Chronic Fatigue Syndrome, Gulf War Illness, Fibromyalgia, and most recently Long COVID. Dr. Klimas is Professor Emerita at the University of Miami’s Miller School of Medicine where she practiced for thirty years.
She is the Director of the Institute for Neuro-immune Medicine, Assistant Dean of Research, and Professor of Clinical Immunology at the Dr. Kiran C. Patel College of Osteopathic Medicine in Florida in the U.S.A. She chairs the Department of Clinical Immunology at Nova Southeastern [00:01:00] University. Professor Klimas is a past president of the International Association for ME/CFS and a past member of the Health and Human Services CFS Advisory Committee, the VA Gulf War Illness Research Advisory Committee, the National Academy of Medicine’s ME/CFS Clinical Case Definition Working Group and has served on several NIH advisory panels.
Professor Klimas founded the NSU Institute for Neuro-immune Medicine where she directs a group of eighteen inter-disciplinary scientists and clinicians who are working to discover and implement innovative strategies that effectively treat or prevent Complex Chronic Disease. Welcome, Nancy.
Nancy Klimas: Thank you very much. I appreciate the introduction. Well, that’s a lot.
Funmi Okunola: So, yes, I wanted them to know that you did have a long career.
Nancy Klimas: Yes, I did have a long career.
Funmi Okunola: I wanted them to get a really good picture of that. So, do you have any conflicts of interest to declare?
Nancy Klimas: No. I’m a [00:02:00] Professor. I don’t own anything.
Funmi Okunola: Okay. I invited Professor Klimas to be interviewed today, not just because of her reputation for producing outstanding research that has furthered our understanding of a number of Complex Chronic Diseases, such as ME/CFS, Fibromyalgia, Gulf War Syndrome and now Long COVID, but also because some of her latest work is hope for biomarkers and treatments for Long COVID.
First, I’d like to explore some of the features of your recent research paper entitled “Identification of CD8 T cell Dysfunction Associated with Symptoms in Myalgic Encephalomyelitis Stroke, Chronic Fatigue Syndrome and Long COVID and Treatment with a Nebulized Antigen Stroke Anti-pathogen Agent” in a retrospective case series published in ‘Brain Behavior and Immunity Health’ in March of this year.
Before we dive into the findings of the paper, I think we need to explore some of the background pathophysiology that it is [00:03:00] based on. So, can you please remind our medical audience and inform our non-medical audience what a lymphocyte is?
Nancy Klimas: Sure. So, your white blood cells break into two large groups, and lymphocytes account for about half of your immune system. They recognize something that’s come on board, like a pathogen, a virus, and then they create an army of cells that are very specifically directed at that virus, particular bug, and the majority of your immune system is like a well-trained army of cells that can target something very specifically.
In the background, about 10% of your lymphocytes are this other army that’s sort of more general and can do anything – it just sees things as self and non-self. Those are your natural killer cells – very important cells. It’s called your ‘innate immunity’. So, you have these two, one, two, one, two sets of cells that together have a very sharp and [00:04:00] directed point, and then this more general way of cleaning up. It’s a pretty darn clever system. I think it’s pretty amazing.
Funmi Okunola: I agree. What is the difference between a T cell lymphocyte and a B cell lymphocyte?
Nancy Klimas: It’s an important difference, and you need both of them. The B cells are the starting point for antibody which is a protein that circulates like when you get a vaccination. You’re making antibodies against something, and it’s grabbing it up before it can enter a cell and cause damage while the T cell is orchestrating a response that includes something called a ‘cytotoxic T cell’ that can find a cell that’s infected and making virus or whatever, and kill the source, so kill the cell itself. So, one’s cleaning up the loose stuff that’s running around re-infecting other cells, and the other one’s grabbing the cell that’s actually making the virus to begin with.
Funmi Okunola: Right. Nancy, can you please talk [00:05:00] about interferon nuclear gamma and tumours in the tumor necrosis factor alpha and their relationship to the CD eight T cell or T killer cell, and a fully functioning human immune system.
Nancy Klimas: There’s more than one kind of interferon. But interferon gamma is one of the interferons that is a direct antiviral, and it’s often elevated when your immune system is busy fighting a bug, a virus, I should say, whereas tumor necrosis factor is the beginning of a cascade of inflammatory cytokines that make a lot of inflammation. So, TNF, Tumor Necrosis Factor triggers a whole cascade of interleukins and other cytokines that result in inflammation in the site that it’s being activated. It’s not antiviral, but it is a part of the inflammatory response.
Funmi Okunola: Okay, and these two chemicals, what are they [00:06:00] produced by in our bodies?
Nancy Klimas: Well, the interferon is mostly being made by lymphocytes, whereas tumor necrosis factors are being made by a number of different types of white blood cells – more than one. What matters is that they’re being made and that they’re being made correctly, and they’re regulated, right, and they go away when you need them to go away, and they trigger on when you need them to trigger on. So, it’s not so much what the cells are doing as it is that they’re working correctly.
Funmi Okunola: Okay. Can you please talk about latent viruses and how our immune system keeps them at bay?
Nancy Klimas: Absolutely. It’s so important. We’re children. We have a host of viruses. I have a four-year-old granddaughter, and man we have had some serious series of infections just since school started in the fall.
About every third week something’s back in this house, and that’s typical when they’re young and they haven’t seen much in their immune system. Every bug that comes along grabs them, and [00:07:00] then they bring it home to grandma. So, thank you very much. But most of the viruses in our system are come and go viruses – like most cold viruses, you get them, you get rid of them, they don’t stick around.
But there are some viruses, particularly families of viruses, that once you have them, they never go away. They become latent – you keep them forever. Specifically, but not just, the herpes family viruses. Herpes simplex is a cold sore virus. Herpes zoster is the chicken pox virus – that’s shingles.
That’s miserable when you’re my age, but actually, that’s a good example. So, my little granddaughter, four years old, if she brought home chicken pox, for which she’s been vaccinated so let’s hope not, but if she brought home chicken pox, she would have a generalized rash and a miserable fever, and it would last a week or two and it would go away.
Now she has got a latent infection. I had that latent infection when I was three or four or five [00:08:00] years old. So, in my life now my immune system is quite a bit older than that. I won’t say the exact number of years, but hell, a lot, and over time my immune system becomes less and less, fewer of that army to help protect me.
So, I’m at risk for my chickenpox virus to reactivate, and when it does it reactivates in the cell that it was infecting at the time, which in the case of shingles is the nerve endings – the sensory cells, and that’s why it’s such a terribly painful reactivation thing because when it reactivates it makes a rash exactly where those nerve endings are, and that’s where you see those patches because it’s in just this one area the way that nerve broke up into its little branches. That’s what pops open with the virus.
So that’s a reactivated virus shingles. My granddaughter would have had the primary infection, chickenpox, and it did take fifty, sixty, seventy years for the immune system to get stupid enough to let it back out again.
Funmi Okunola: [00:09:00] Nancy, can you briefly explain free radicals, antioxidants and oxidative stress?
Nancy Klimas: We’re all over the camp here. This is fun. They so matter, and if you’re trying to understand Long COVID, you’re absolutely right to be bringing up all this language because you can’t look at this disease through the silo of any one of these things.
You actually have to have the big, broad look, what I call the ‘quilt’, when you’re putting all the patches together, and then stand back and see what the picture is. That’s what you’re looking at with Long COVID. So oxidative stress and free radicals matter so much to the Long COVID patient because the mitochondria, which is your cell’s energy box that’s inside every cell, there’s a whole bunch of mitochondria that are busy making energy.
To move that cell they make it work, provide the energy for that cell. Whenever you make energy, you use something up and you spit off a free radical. A free radical is like a little electron that’s like garbage that’s [00:10:00] left over at the end of making energy, and it’s snapped up in that system by an antioxidant.
So, oxidant, the electron, antioxidant, the thing that grabs it, and like a perfect figure eight, you make electrons, you grab them, you recycle them back into energy, and it just works perfectly. The average cell, the healthy cell, has just as much antioxidant as it does have oxidative stress, and it cleans it up, recycles it, and keeps using it.
It’s a very efficient system, but when it gets out of sync, when that figure eight turns into something puny on the antioxidant side, the free radicals accumulate and now all kinds of things can happen. Initially, the cell recognizes it’s in danger and it puts some distress signals out and essentially puts that cell into hibernation mode.
It says, “Oh my God, we don’t want to die. So at least shut down,” and it shuts the cell’s function down. If it kept on going, it would kill the cell. So oxidative stress [00:11:00] is very damaging to cells. It’s a very big player in Long COVID. It’s also a big player in neurodegenerative illness and other kinds of things.
It’s not just this one disease that does that, but it’s a treatable point. So, in clinical land what we like to know is what can we fix? So, if we know that oxidative stress is a great big player, we’re going to try really hard to clean up the oxidative stress and give the system enough antioxidants to be healthier. Won’t fix it all, but it might help. It depends on the tissue.
So, let’s take the immune system for a moment because it starts tying together your viruses that are reactivating. We just started to talk about particularly this herpes family virus. There are more viruses than that. Just say that the immune systems got this thing it’s got to deal with, and it’s trying to clean it up. So, a whole lot of the immune system is [00:12:00] activated.
Maybe 40, 50, 60% of the cells are turned on when normally maybe only 10 or 15% would be turned on. That’s a lot of energy production. That’s a lot of free radicals. It’s a lot of cleanups. So, there’s oxidative stress in the immune system, okay, and these cells in the immune system that are becoming less and less efficient because that’s not good for a cell, and it’s the catch 22. If I can’t clean the virus up, it’s going to keep on reactivating, and there’s another catch 22 in the immune system. It’s the activated cell that makes the virus. So, the more you activate the random cell, the more likely you’re kicking out the Epstein Barr virus, for instance.
Two catch 22’s. The cells don’t work as well, and when they’re over activated, they’re making more virus anyway. You’re triggering virus production. If it’s in the muscle, which it really is in Long COVID and in ME/CFS, it’s a different kind of damage, but what it does is it damages the muscle.
There’s a great paper by Dr. [00:13:00] Wust, WUST, from Amsterdam. This amazing paper in ‘Nature’ January this year where he did muscle biopsies before and after exercise challenge, and he showed the next day after a minor exercise challenge, the kind we do in the lab just to try to learn things, not putting people on thirty minutes of bike, more like two to eight minutes, really a little bit, and yet there was muscle breakdown, necrosis, inflammation, too few mitochondria, a whole lot of oxidative stress, all this stuff you could demonstrate in a very visual way with this before and after needle biopsy of the muscles.
So that would be the muscle. I just worry like crazy about the brain because cognitive fog is the thing that makes people stop. I’ve seen my ME/CFS patients and my Long COVID patients go to work feeling just awful, but they can’t work if their brain doesn’t work, and that often stops them. So oxidative stress in the brain and exercise, it’s a very aerobic [00:14:00] space, your brain, it’s really working, and it uses a lot of energy second only to your muscles.
It’s pretty quick to clean up, pretty quick to accumulate free radicals and have oxidative stress and some very nice images of that using MRS spectroscopy that show lactate which is when you get a cramp in your muscle because you were running. You might remember those days back when there’s too much lactate building up in your muscle and getting a Charlie horse or a cramp in your muscle.
Well, that happens in your brain. That’s a great big deal. Things don’t get into the brain that easy. It’s designed that way because you don’t want toxins to get in there very easily. The brain has a barrier system, so when you talk about interventions that help, you’re trying to think of ways not just to get them on into the muscle, but also into the brain.
Funmi Okunola: Thank you so much. That was a fantastic explanation and a good learning point for me in a really good way that I’ve learned how to picture that, and we looked at the [00:15:00] muscle necrosis paper earlier on in this series with Todd Davenport, but I will provide a link for it in this Episode as well.
In your opinion what are the similarities between ME/CFS, Gulf War Syndrome, and Long COVID?
Nancy Klimas: It’s such an interesting area. I’ve been doing this research for a long time. Clinically, you can’t tell them apart they couldn’t be more identical. They have post exertional relapse. They have body pain, muscle pain, cognitive fog, a lot of metabolic disorders, weight gain, all the things that happen when your system goes out of whack. So, our group thinks of these chronic illnesses as homeostasis, meaning the normal healthy body is in a balance.
If you get a little sick, and you get a little out of balance when you’re well, you fall back into the old balance. But in the diseases that we’re studying it [00:16:00] would appear that when they got the initial insult, the acute infection, or in the case of the Gulf War veterans, the toxic exposure, they didn’t just get a little sick. They climbed up the mountain and they fell down into this other side, and they’re in this new well. But it’s a balance, a sick balance, but a stable balance. So, they can’t get from where they are stuck back into this spot just by drawing a straight line. There’s a mountain between them, and they have to climb up the mountain and fall back into the old balance.
One of the main areas of research in our group is how to use computational biology which is like AI only I think that gives the computers too much credit because there are some really smart people who know how to do this stuff, but AI’ish, what they call machine learning now, machine learning ways of putting all these systems and all the knowledge you can get from measuring a lot of things, and we use that exercise-induced relapse. That’s the thing that teaches us the [00:17:00] most because you put someone on a bike, and you measure bloods before during and all the way through after into the next day. Then you measure every gene that’s turned on and off, every cytokine that’s expressed, every endocrine thing that’s going on, all the cells, their function, the way they’re expressing things.
It’s a ridiculous amount of data. It’s three million bytes of data per time point times nine time points over twenty-four hours, and you give that to these computational scientists, and they say, “Oh, that’s not much data” which is pretty cool, and they figure out what comes first, second, third, and fourth over the course of the twenty-four hours for the relapse to evolve.
Then they can project – what’s my favorite part – they do in silico (meaning in the computer) clinical trials, and they do it by randomly hitting any button anywhere in any order at any degree. So, they don’t have to have any hypothesis whatsoever because they’ll [00:18:00] run five supercomputers for three weeks, then they’ll just randomly do it all.
It’s Chaos Theory, and they apply it. I don’t get it. I’m not going to try to explain it, but it’s pretty damn cool because in the end they give back to me, the clinician, what is the sequence of things, what button you have to push. So, for instance in Gulf War Illness we did this, and we have an animal model, which we don’t unfortunately have for ME/CFS or even Long COVID yet.
So, in the animal model it said you have to reduce inflammation in the brain. This made sense to me because the brain’s grand central station for everything. Then you have to do something to make the adrenal gland behave more normally. It’s very blunted in these illnesses, all three illnesses.
Essentially, they gave us not just the targetable points, but they actually used the computer to find the right drugs. So, we used the TNF inhibitor. In this case we’re using Interocept, which is Embril in [00:19:00] our experimental design, and then we used a drug that blocked the adrenal gland so that when we unblocked it the biofeedback loop from the brain said, “Oh my God, I need more cortisol! Go, go, go, go, go.” So, the really loud shout out from the hypothalamus and pituitary down to the adrenal saying, “Get off your ass and work!”, and it did.
So, in the animal we actually (on the very first experiment that they predicted for us) rebooted a chronically ill animal with the equivalent of ten years of human illness back into normal homeostasis and back into health. That was very exciting.
You asked me what’s similar about these three diseases. They all got started with a neuroinflammatory insult. At least part of what went on was that you made inflammation happen in the brain, and you made it in a way that it didn’t go away – that it was chronic.
So, a chronic neuroinflammatory insult at which point the normal very [00:20:00] subtle fine tuning of the brain couldn’t be heard. I like to say for those of you who have ever hung out with seriously nerdy people, there’s a CB radio where you had to keep playing around with it, and it was making so much noise until you got just the right spot where you could actually hear people talk – you know, the background noise.
Well, the background noise in the brain is loud enough to disrupt the normal hypothalamic and pituitary axis. So not just the adrenal glands blunted, the thyroid glands blunted, the testosterone levels are low, the estrogen, ask women with these illnesses what’s going on with their periods, and they will tell you, “Boy, is everything all messed up!” That’s because, and even in ME/CFS in particular, menopause happens eight to ten years early because of these kinds of disruptions.
So, then again back to the quilt. Look at the whole thing and you say, “Oh, endocrine inflammation, yeah, [00:21:00] cell dysfunction, poor immune function, yeah, viral reactivation.” It’s not one or the other or the other. All these things are all touching each other and interplaying, and to try to get them back into right you have to return the normal feedback loops that control inflammation, and that reset, these types of processes that just keep us in fine form most days, I’m going to say there’s the mountain, and the math is trying to figure out how to climb the mountain and drop it back in.
Funmi Okunola: Gosh, that explanation is amazing! And you have an amazing team there that you’ve talked to, to summarize, and it’s really interesting to hear you say that.
Gulf War Illness, Long COVID and ME/CFS to you seem virtually identical. But I think the big revolution we’ve had in this field of medicine that you’ve been practicing in for forty years is something positive [00:22:00] that’s come out of the pandemic in that everybody caught one virus at once, and it resulted in a proportion of people developing ME/CFS type Long COVID illness.
So we could say categorically that one virus caused neuroinflammation in the brain which shut down or because the brain, as you say, controls all of our endocrine and hormone producing organs, shut them down or caused them to go awry resulting in a Long COVID presentation, whereas with ME/CFS, the population that’s predisposed to getting that probably has many different viruses that have caused it, and we couldn’t pinpoint which one.
Nancy Klimas: This gave us an opportunity, as you say, and also to set the timeframe as 2020 and forward because the other thing that’s been hard in ME/CFS is the duration of illness. You have people who have been ill for twenty years, and they’re going to be different than people who have been ill for three years which we’ve shown that as the illness evolves all this immunologic muck up [00:23:00] makes you more prone to autoimmunity. So ten, twenty years down the line you might have a bunch of autoimmune panels that look a little awry that weren’t like that in the first three years. The cytokines in the first three years are very inflammatory as compared to later on when they tend to not get normal but quiet down a bit, and there are other ways that duration of illness matters.
One of the advantages as you say in Long COVID have this same trigger. We have this relatively similar duration of illness in the population to look at. Now the flip side of that is the ME/CFS patients can teach us a lot about duration of illness that you don’t want to experience but do need to know, right? Because if we don’t fix this thing, what’s going to happen at ten years and twenty years? I know that I’ve got people out ten, twenty, thirty years. You don’t want to be those people. You want to be people that are getting better. But there are differences. I don’t want to pretend like they’re exactly the same because there are differences.
We’re doing a great big study that [00:24:00] the CDC’s funded comparing ME/ CFS data that we got before the pandemic to a brand new Long COVID cohort that we’re evaluating, and like I say, clinically, you’d be hard pressed to see them to be much different, but biologically, are we going to see the same thing?
That’s the question. We don’t know, but as a clinician I could say looking at people and doing big workups that micro clotting endothelial dysfunction thing that is Long COVID is much more prominent than a ME/CFS, and very dangerous…. (There was a ) paper out just in the last month or so showed the cardiovascular events in people a thousand days Post COVID being as high as people who had suffered a prior cardiovascular event.
Now, there’s people who already had a heart attack or already had coronary artery disease. The rate of a cardiovascular event was as high in Long COVID as what these other high-risk people would be. [00:25:00] That’s scary. It was also the blood type, which I thought was really weird. I’m trying to figure that one out.
If you were a type O, you were good. AB myself, I’m not so keen on that, that little vision of that! The Long COVID people do have another layer of important mediators. Maybe they were there in ME/CFS but just not as bad. The other thing about ME/CFS is that we had practically no money to spend on this field. In Long COVID the first wave of money was 1.15 billion dollars. We had years where we had for the whole field, three million dollars – for the whole field! I think the peak year was twenty million. The average year in the last five or six years was more like thirteen or so. In other words, with many zeros off.
So, what you do is you do a study with fifty people in it instead of five hundred, right? because the kind of funding that you have is all pilot, pilot, pilot funding, and not the much more [00:26:00] expensive ‘knock it out of the park’ funding. Still, there have been knock it out of the park people, and one of those is Dr. Systrom. He’s a Harvard Professor, and he’s done a study where, again, using the bike as the challenge, but in a very invasive way, he drops a line into the heart, into the pulmonary arteries, into the peripheral vasculature, and he measures very directly your cardiac output, your cardiovascular resistance, your oxygen extraction from the tissues, but in a huge number of people, fifteen hundred people.
That’s a ‘knock it out of the park study’ where you just have to believe his results because no one’s ever going to reproduce a study of that level. But it’s really extraordinary, and he did a big one in ME/CFS, and then he did one in the last year, Long COVID, that looked like it was coming up the same way.
But this is what he found – a couple of really important things. One is something called peripheral shunting. What he’s calling peripheral shunting is [00:27:00] what you would call really poor blood flow in the most distal of your blood vessels. That when you look at your blood – there’s the arteries, and then they go down to arterioles, they’re skinnier, and then they go into the capillaries, that blush of capillaries.
It’s that blush that’s missing its blood flow. That means the tissue is not getting oxygen. So, go back to Dr. Wust’s study with the muscle biopsies where he saw necrosis and oxidative stress in the tissues because they weren’t getting oxygen, right? So, when he pushed them over the limit of their ability to extract oxygen from the blood that they’re not getting, then they have to make the energy themselves, which is incredibly good at making free radicals when the cell has to generate its own energy without the help of oxygen or glucose.
It really makes a lot of free radicals, and then boom, you start having tissue destruction. So, he showed Dr. Wust the necrosis and the torn-up muscles. [00:28:00] Dr. Systrom said “I get that there is this group of people that have shunting where you can measure the blood going into say the hand and the measure coming out of the hand, and the same amount of oxygen going in is out that didn’t pull any out to didn’t use it because the capillary beds didn’t get it,” and he said that people with small fiber neuropathy had that in particular. That was an important thing because we have been thinking small fiber neuropathy, which causes Fibromyalgia, which many of our patients have. We’ve always thought, well, that is an autoimmune condition, and Dr. Systrom’s data would say, “Well, maybe not. Maybe the issue was that you starved the fibers of their oxygen, and you have ischemic damage, you didn’t get blood flow, then they broke down and it was the breakdown of the tissue that let the immune system see it and then start creating antibodies to it. Then maybe the original insult [00:29:00] was actually the lack of blood flow all the way out to the tip of the skin where these small fibers sit.”
That’s a really important study. Another one that makes you think perfusion, perfusion, perfusion. If there’s one thing you could do for our patients that would really help them in their brains, in their muscles, in the small fibers of their skin, it would be to assure them blood flow.
Oh, the other thing that Dr. Systrom’s data showed, and we did this a long time ago, about twelve years ago, a similar paper in ME/CFS, it showed that while the cardiac output looked okay, the blood volume itself is not okay. The amount of blood going into the heart and filling the heart is too low. So that means even though the muscle is good and it’s pushing it back out again in the right amount, the right ratio, if what goes in goes out, too little is going back out again, and that’s going to affect perfusion too.
We did a study like this, [00:30:00] and before us there were several really stellar groups that did this too in ME/CFS where you measure actual blood volume. You do that by taking a tube of blood and labeling the red cells and labeling the plasma with something else and letting it circulate, and then take another tube of blood and then it’s a nuclear medicine study – they measure these isotopes and tell you to the CC how much plasma volume you have and how much red cell mass you have, and you think you just see this on a CBC. You think these people are anemic, they don’t have enough blood. That’s not true because the CBC is a ratio. This is your red cells, this is your plasma, this is your CBC ratio, your hematocrit. It’s a ratio. But if your plasma volume is low and your red cell mass is low, you still get the same hematocrit.
So, when you run it through a CBC machine you can’t see it as anemia, but when you do the whole body’s plasma volume with one of these studies, they’re short like 20%. It’s a huge amount – it’s a whole liter of [00:31:00] blood. That’s a lot, and if you’re saying to a POTS patient (Postural Orthostatic Tachycardia) the dysautonomia piece, when I stand up with a normal cardiovascular system that knows how to compensate for standing up, 40% of my blood volume is from my belly to my head and 60% falls below my belly button. In a POTS patient, 60% of the blood falls below their belly button. If you’re a liter short, you’re operating your lungs, your brain, and your heart on a liter of blood. That’s not very much. So, you can imagine what that must feel like to somebody who has Cognitive Fatigue in a total body core, exhaustion, my liver, my kidneys, my lungs, my heart, not getting enough perfusion.
So, I’m an immunologist, and I always laugh at if I looked at me forty years ago doing this work back then I was just thinking [00:32:00] through the eyes of an immunologist, it’s all your immune system.
If the immune system would just work and not be so inflamed and kill the viruses, we could just make this all better. But now through my many years of work and working with inter-disciplinary groups, and particularly with integrative medicine doctors, I have a much better perception of what you’ve got to fix. You’ve got to make perfusion work, and you’ve got to make oxidative stress better, and if you don’t do those two things, trying to drive energy out of a broken system will only break it more. God forbid you put people on an aggressive exercise program or even a modest exercise program if we know that their muscles aren’t getting perfused.
So, we have to convince the doctors that we’re trying to train to look at those muscle biopsies from Dr. Wust because that is like “hello” these muscles are going to break down if you push them too hard. You can’t make them; you don’t want necrosis. That’s a bad thing. So how do you get the blood to flow? And what’s wrong with the [00:33:00] vasculature that it’s shunting this blood away from the tissues? And why do we have this low blood volume situation that needs to be corrected? So, to me that’s first. Then you try to fix the other things.
Funmi Okunola: That was a fantastic explanation, and also a justification as to why we need to look at our bodies as a whole.
As you said, we have a medical system which is looking at things in silos and organ systems separately, but we have a body that works synergistically, and you’ve just given an excellent example of how it works – synergistically, and I suspect the work that Professor Resia Pretorius is doing clues into that because she talks about how SARS-CoV-2 has a huge endothelial and coagulation effect in the body.
That would be the reason why you’re not getting that tissue perfusion because if it’s pro-coagulative, the virus is pro-coagulative effect. Also, the cardiovascular paper [00:34:00] that you mentioned, we looked at that a few weeks ago with Professor Erica Spatz. Yes, that’s a very interesting paper.
So, can you please explain using the two cases featured in your paper, if you’d like, how the nebulized antioxidant or antipathogen treatment provided relief for the people with ME/CFS and Long COVID in your study?
Nancy Klimas: So, I’m just one cog in the group that’s trying to do that. I’ve been trying very hard to help this group with this very novel kind of treatment approach get through the next steps that they have to do to become more successful in that research.
So, essentially somebody in private practice used this product and said, “Oh, my goodness, look, I’m getting clinical responses!” and then called in the academics to try to help them understand why and how to move forward, and I was just one of those academics that got called in late. I wasn’t the early one.
I didn’t design it. I get to scratch my head and figure it out. The medication [00:35:00] is a combination of things that work together well. Mostly in medicine we study things one at a time, and put them in combinations, and a study A versus B versus C versus A plus B versus B plus C versus A, B, C.
To do a study like that it’s just dragged out. It takes five, six years to go through all these different steps before you even got there. So, they come along with a compounded set of medications that are antioxidant and antiviral and designed it in a very clear way that they should work together better than separately.
Then you have to deal with that you’re breaking down the usual way of going about drug trials. But these are all nutraceuticals. They all have that category of being generally regarded as ‘safe’. What’s different about them is that they’re inhaled rather than taken orally. Think about where COVID has done some of its biggest damage in the lung, and you would see why it might’ve started that way. But [00:36:00] then I think the surprise was that they got nice neurocognitive effects, that they got general better health in addition to any direct effects on the lung. They were getting all these other effects which is to say that the ability to deliver a drug to the bloodstream through the lung is really dramatic.
The bloodstream is really, really close. Think about that’s where you do oxygen exchange, right? The really thin membranes there that are right next to where the red cells are, where the blood is flowing, and then it’s pulling that into the bloodstream more quickly, more effectively than say swallowing something that has to deal with digestive enzymes and thick GI walls and poor absorption, and maybe not have any absorption when it gets to the blood-brain barrier.
So, I think it’s very interesting that the delivery method was perhaps as important as the combination of things that are in that mixture. If you look at the [00:37:00] case reports, I’ve had the opportunity to speak with the people in those case reports, and they really were the housebound, bedbound, sick, very, very sick people that were able to maybe not be cured but have a much more reliable quality of life. In fact, I’ve seen both of them at meetings, and doing things that you would never have expected them to be well enough to do if you knew them before they had the intervention.
So, it’s an exciting thing. We’ve worked with that company to try to help them find the financial backing they need to move their product. I think it’s in front of the Recovery Initiatives list of things we’d like to move forward. I don’t know if it’s going to move along or not, but it was certainly submitted to them both last year and again this year. So, we’ll see if it gets picked up.
Funmi Okunola: Oh, that’s really good because that was going to be my next question.
Getting back to how it works.
So, basically, this medication was antiviral, antioxidant, and [00:38:00] what you seem to identify with the T killer cells or CD8 cells as they’re called in the body, were somehow dysfunctional in the ME/CFS and Long COVID patients. So, this medication helped the CD8, or T killer cells, to function again, and I guess reduced the toxic free radicals that their cells couldn’t get rid of, is that correct?
Nancy Klimas: It’s even more exciting than that because I think I described before where this over-activated immune system goes into hibernation because of oxidative stress and other things, and that’s basically called ‘immune senescence’. It’s something we see as we age, but this is happening in very young people – immune senescence.
What this intervention did was basically wake them back up so that they could function again, and then once they function, they’re much better at clearing infections. So, what [00:39:00] they’re clearing, of course, this depends on the individual. If your Epstein Barr virus is reactivated or your CMV or your HHV6, or as some of our earlier studies right now might suggest that COVID itself is either persistent or some of its antigens persist.
Funmi Okunola: Yes, and why that’s important is because something like 96% of us get EBV from mono whether we know about it or not, or glandular fever, as it’s called in the UK. I think nearly 100% of us are exposed to cytomegalovirus. There are all kinds of herpes diseases, and there’s other viruses as you said earlier.
They sit latently in our spinal cords, and our T cells normally keep them at bay. But obviously if they become dysfunctional because of SARS-CoV-2, they run riot, and in certain people, some, one, all of them, and cause them to get ill, and this nebulizer reverses that situation. [00:40:00]
Nancy Klimas: Yes, so, mostly right. It all just depends on the virus – where it’s sitting.
So, for instance Epstein Barr virus is in the immune system. It’s in the B cells, but it’s also in your parotids and your salivary – the dry mouth misery that people get. That’s in part EBV, dry eyes. It’s in the tear ducts. CMV is also mostly in the immune system, but there’s other viruses, some that are in the GI tract, the enteroviruses, coxsackievirus, and others.
There’s a lot of important latent reactivated viruses at play, and everybody has a different set of cards, reactivation, and it even comes and goes. I think probably the most common one of all of them is HHV 6, which is your three-day measles virus – roseola, it comes and goes.
If you follow people over multiple blood draws, you’ll almost always find it by PCR, meaning it’s really there. I can find the actual virus, not just the antibody to the virus, but the virus. But if I go [00:41:00] on any given day, I might miss it. So, some of our studies have to be careful to be longitudinal studies that are trying to capture patterns over time.
Anyway, whether this particular treatment clears them or not, we hope so. It’s a very small experience. This is a case series, and we don’t know everything it’s able to do. We hope so, and I would like to do that work. I would very much like to find that out.
Funmi Okunola: Well, it’s exciting, I think, and really hopeful, and I hope the NIH does work with you so that you can do bigger studies, and we can have a greater understanding and possibly successful treatment for Long Haulers.
Please tell us about the biomarker that you feel could be relevant that’s come out of this research.
Nancy Klimas: Oh, there’s a number of biomarkers. This is the work of Lisa Sellam at the University of Massachusetts, and she’s amazing. Then Maddy Hornig who’s at Columbia has worked hand in hand and has done some of the other biomarker work related to this. There’s a [00:42:00] cytokine pattern that Dr. Hornig, I and Lisa have worked on together.
Funmi Okunola: So, thank you, Nancy for such a great, informative, and educational interview.
Nancy Klimas: You’re welcome. Happy to be here.
Funmi Okunola: Thank you. All right. Please join us for next week’s Episode of Long Covid – The Answers.
Funmi Okunola:
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SHOW NOTES:
Professor Nancy Klimas is interviewed about the mechanisms behind how a nebulised medication caused a remarkable recovery from symptoms of ME/CFS and Long COVID in a small group of individuals and her objective to gain the ability to extend this research into a larger population of people with the hope of finding a viable treatment for these diseases.
REFERENCES
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Bloemers FW, van Weeghel M, Schomakers BV, Coelho P., Wüst Rob.C Muscle abnormalities
worsen after post-exertional malaise in long COVID. Nature communications. 2024
