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Jill Brook: Hello, fellow POTS patients and beautiful people who care about POTS patients. I'm Jill Brook, your horizontal host, and today we're so happy to welcome back Dr. Robert Groysman for his third appearance on the POTScast. Dr. Groysman is a board certified anesthesiologist and pain medicine physician, and long COVID specialist.

He is the founder of the COVID Institute in Plano, Texas, where his interest in the field grew out of both his clinical work and his own experience with long COVID. He has published the seven volume Long COVID Handbook, plus a number of peer reviewed journal articles. So today we're gonna have some listener Q&A about some of those, and discussion of some of his newest ones.

And Dr. Groysman, thank you so much for coming back.

Dr. Robert Groysman: Of course, it's my pleasure.

Jill Brook: You have published so much on long COVID, and we just love talking to you and we have a lot of questions that are in from listeners. And [00:01:00] so maybe just as a refresher, I will remind people that last time we discussed your proposed model of long COVID as a network disorder comprised of different interacting mechanistic domains that can include the, the main ones being dysautonomia, mitochondrial impairment, endothelial or microvascular dysfunction, gut dysbiosis or barrier disruption, mast cell signaling, and neuroendocrine dysregulation.

Plus, you had some secondary amplifiers, like immune activation, viral antigen persistence, autoantibodies, neuroinflammation, and small fiber neuropathy. So depending on the exact patient, any combination of these mechanisms could be at play, likely exacerbating one another, and accounting for why long COVID can present so differently, but keep having these kinda same [00:02:00] common themes. And did I summarize that properly?

Dr. Robert Groysman: You did. And, and, and really, it, it, it goes even further into this. So it's not just how many of these mechanisms a person has, or someone suffering from long COVID has. It's how much each is contributing relative strength, that's number one, and number two, how they interact with each other.

And they have effects on each other, not one way. So, one, one of these nodes, one of these mechanisms will interact with another, but that one will also interact back. So all of these create almost impossible odds on number of combinations you can have. So, that's why long COVID pretty much looks different in every single person.

But you do notice patterns. There, there is some similarity that goes from one long COVID patient to the next, and that's why these six are forefront as, as [00:03:00] primary, as primary nodes, with others being secondary amplifiers.

Jill Brook: Great. Okay. And for listeners we'll put a link in the show notes to this paper, but this is in the Frontiers in Medicine. This is the hypothesis and theory article called Long COVID as a Network Disorder: A Mechanism-Anchored Framework for Biological Stratification and Therapeutic Targeting. And we did talk about it last time, but a lot of questions came in 'cause people were very interested in this. And so, so that's why the first question that came in, it came in from a lot of different people, was could you just sort of give an example of a long COVID patient that you had, and talk about them using this framework?

Dr. Robert Groysman: So this paper in particular is meant to define the mechanism anchored network as opposed to focusing on symptom clusters. Many of the papers out there, if you look back even, even back to [00:04:00] 2021, because I've read all these papers, and they, they fall into two different categories.

They'll fall into the symptom clusters where, where they'll, they'll group patients based on similar symptoms and they'll group, let's say, four or five symptoms together, and this is one group, okay. And that's how they define their cohort. And the other types of papers look at phenotypes. So they will say, for instance, cardiac and gastrointestinal as, as one group of phenotype.

Not specific to any symptom, but they have, they have issues with those two areas, as an example. Okay? I wanted to take this to the next level. Instead of looking at just symptoms or phenotypes, I wanted to look at endotypes. So what are endotypes? Endotypes are biological mechanisms. So, so these can be explained by the biology.

And if you group patients by [00:05:00] biology, something magical happens. You notice that these mechanisms come out. Okay? And each patient that has this issue with the biology is gonna be the same as the next patient that has the same biology.

Jill Brook: Mm-hmm.

Dr. Robert Groysman: So that is the whole point of this model, is to pull out... We're not looking at symptoms, we're not looking at phenotypes. Phenotypes are what you can describe, right? Symptoms are what patients describe. Phenotypes are what doctors describe. It's what they see. You have a rash, dermatological, right? You have, you have chest pain, a heart, or, or, or a heart issue. That's cardiac. I shouldn't use chest pain 'cause that's more symptom.

But I, I think I'm making the point here. I'm talking about what is actually going on, and the way we get to this is with triggers and timing. This is my third paper that's just about to be published. The abstract is out, [00:06:00] but not the main part of the article.

So what I did was I greatly simplified this, okay? What I do, I cannot put into a paper. It would be the size of an encyclopedia, unfortunately, to explain how I do everything and how I come up with with the results I come up with. So I had to simplify it into easier to understand terms in order for it to be, you know, to be a paper, not, not a book.

So, this paper, the, the network model explains how, how it's defined, the definitions. And this trigger timing paper describes how to use it in a, in a more simplistic way. Like I said what I do is a, is, is a bit more complex than what the paper shows, but it gives you a gist of, of the basics.

Jill Brook: So am I understanding correctly that one of the challenges with the long COVID and other populations that are similar is that [00:07:00] we might have 20 symptoms, but those symptoms are not specific to any one mechanism necessarily. So I could have fatigue, but that's not gonna tell you whether I have MCAS or ME or mitochondrial problems or dysautonomia because they all have fatigue.

Dr. Robert Groysman: So that, that's the problem, though. So, so a, a paper or a study that looks and studies, let's say, brain fog, they group brain fog patients together as, as one cohort, as one group. The problem is, is there's distinct biological differences between each of these patients. In one patient it could be endothelial.

There's a blood flow issue. In another, it's gonna be dysautonomia, and it's a regional blood flow. So you're getting enough blood to the brain, but it's not going into the right places. In the mitochondrial dysfunction group, your neurons are one of the most active cells in your body, and if your [00:08:00] mitochondria are not working, they're not generating sufficient levels of ATP, you're gonna have brain fog from that, right?

Most people wouldn't think that gut, your gut could cause brain fog, but it absolutely can, multiple ways. Number one, there's communication through the vagus nerve. Okay? So, messages get sent up to the brain from your gut, not just your colon, but your entire gastrointestinal system. That's number one.

Number two, if you have leakage of toxins or bacteria or other pathogens they will get close to the brain. They don't have to cross the blood-brain barrier. They just have to be close to it. And the cells inside the blood-brain barrier will activate just from them being close. One of these things is called LPS or lipopolysaccharide.

This is normally present in healthy, normal gut, okay? This is part of gram-negative bacteria, and when you eat, [00:09:00] it's gonna kill off some of these bacteria, and the LPS normally would stay in, in the lumen of the gut and go out in the stool. Not a problem. If you have leaky gut, though, this stuff can get into the bloodstream and, like I said, it doesn't need to cross into the brain to cause problems.

You can cause neuroinflammation just by being close or near that area. Your blood-brain barrier is not a physical barrier, per se. It is alive. It is an organ, and it has cells in there patrolling, okay, that if they sense something harmful, they will activate the alarm. So you don't actually have to get into the brain to cause inflammation, to cause that, that type of reason.

That is a good reason for brain fog, okay? Neuroendocrine. I mean, a thyroid controls your metabolism. It is your pacemaker for your metabolism. Your body drums and beats to thyroid, okay? Low thyroid, [00:10:00] guess what? Brain cells are not gonna be firing as fast. Okay? A completely different reason for brain fog.

So just imagine all these brain fog patients, okay? They're there to, to be studied for brain fog, but they have completely distinct biological endotypes, which means that each one needs a completely different treatment approach, completely different. You can treat gut very differently from endothelial, from mitochondrial.

All these require completely different treatments.

Jill Brook: Right, which is why you make a point in your paper that for, especially for treatment studies, it would be important to group them by endotype and not just by symptom clusters.

Dr. Robert Groysman: Right. So, so let's look at, at this study, right? And there's several of these, right? So th- they, they, they pick a treatment, they create a hypothesis. If you give this, if you give this supplement or, or medication for this length of time, we expect it to help with brain fog. Except what is the problem here?

[00:11:00] What is this exactly treating? What is this supplement and medication treating? Is it treating mitochondrial? Is it treating endothelial? Is it treating gut? Does it matter? Yeah, it matters. If you have two patients in your brain fog study that are gut caused, okay, and the rest, let's say, are mitochondrial, I'll make this really simple, but the treatment you're doing is, is, is for gut.

So when you do the study, you're gonna have a negative result. Only two of your patients responded.

Jill Brook: Yeah.

Dr. Robert Groysman: Not the other 10. So it makes it look like it didn't help, but, but what are you really studying? Brain fog is not a symptom. It is a result. It is a consequence, right? So you need to target the endotype, not the consequence.

Jill Brook: Mm-hmm.

Dr. Robert Groysman: And this is just one example. I can, I can make this for any, any symptom. So this is why I don't care about symptoms except to identify the endotypes. I [00:12:00] don't go after symptoms. I don't treat symptoms. I go after the endotypes because that is where, if you treat those, magically the symptoms disappear, because they are the consequence of the endotype or the, the mechanism that's broken.

Jill Brook: And so another thing that comes to mind is that you might have a symptom that is caused by more than one endotype.

Dr. Robert Groysman: Yes. And that's often the case. Yeah, and that's often the case. So it's like peeling back an onion. You have to peel it layer by layer, treating each of the endotypes until the symptom goes away, and it will go away because it is being driven by these endotypes.

Jill Brook: Mm-hmm. Okay. Now I imagine that listeners might be thinking, "Well, oh my gosh, well then on the one hand, I love that Dr. Groysman not only says I'm not imagining my symptoms, but that he can explain it in six different ways why I have these symptoms."

Dr. Robert Groysman: Well, more, more than six different ways, but yeah.

Jill Brook: But [00:13:00] that kind of gets to your next paper, which maybe we should mention it now because it, I think it addresses this problem, right? Because somebody might be saying, "Oh my goodness, well then how the heck do I figure out if this symptom is coming from one mechanism or the other mechanism?" How do you, how do you tell?

Dr. Robert Groysman: So the way I start is by looking at triggers, and what I'm talking about triggers is what causes your symptoms to get worse. What are the circumstances? Now, some common ones are standing. That usually refers to orthostasis, right? A lot of people when they stand, they get lightheaded, they, they get tachycardic, or they even pass out.

Heat is another one. So, shower is a good example because it combines both standing and heat. Some people, though, sit in the shower, so we can isolate just the heat. Or if you're in Texas or anywhere where it's over 100 these days you know what heat does to you. You don't feel good during heat.

But not everyone goes through this, okay? There's only certain endotypes that respond to [00:14:00] this, okay? What are some other ones?

Jill Brook: Well, I would say that one that we get questions about pretty often is eating as a trigger.

Dr. Robert Groysman: Yes, and that's a big one. So this one can involve three endotypes. And depending on what it triggers, what the symptoms are when it triggers helps me determine which of the three endotypes it is, and it could be all three. So, you know, post-meal alters your regional blood flow, so more blood is supposed to go to your gut than, say, to your muscles because, well, it's not needed. So if there's a impairment there your gut is not gonna function well. So what I'm looking for is what actually happens after you eat.

Jill Brook: Hmm.

Dr. Robert Groysman: So that's a trigger.

Jill Brook: Okay.

Dr. Robert Groysman: Okay. All right? There, there's, there's several others, but the point is, is between the triggers and timing, when does it happen? Is it worse in the [00:15:00] morning?

Is it, is it better in the morning? Is it worse at night? So these patterns plus monthly patterns. Does it happen around a certain time of the month? So all, all these all these give me a lot of clues, and then I also look at the relief. What makes it better?

What are you doing that's making this better? So I combine all those with many other factors that I use to, to get to the endotypes. Once I get to the endotypes, we treat the endotypes. If I'm not sure, let's say the questions are maybe a little fuzzy, unclear or, or, or it goes into the gray area. It could be, but maybe it isn't. So I, I test it then.

I will test them. I will test each endotype and see the response.

So that, that's essentially how my method works, and that's what it will show in, in the timing trigger paper. I assign different values [00:16:00] to each trigger, okay? So, a trigger that triggers one thing could be for instance, a three times for one, for one of the endotypes, but only a one times for another endotype.

Jill Brook: Okay, so if you have an actual scoring algorithm.

Dr. Robert Groysman: I do. It's, it's not, it's not pure scoring. It's, it's just used to, to create the framework. But like I said, there's a lot more involved. I'm not trying to be cryptic or anything. It's just, it's just very complicated to explain.

But yes, it starts, it starts with scoring. Basically each each trigger that's positive goes towards the score of each endotype in a particular way. Not every endotype. For instance, like heat would go towards mast cells and dysautonomia big time, maybe small contribution to mitochondria. Okay? Just as example. Okay? So this is just to get the framework first, and [00:17:00] then we start digging in deeper.

So these, these six that I look at, plus the amplifiers, a lot of them are broken down into what I call sub buckets. So these to me are buckets. What goes into dysautonomia, what goes into mitochondrial, what goes into endothelial and so forth. And then underneath that, I break it up even further. So I, I'll give you an example.

In dysautonomia, dysautonomia is a very umbrella term. Okay? So what do we have on there? Well, we have POTS, right? Which is also an umbrella term, which has another stuff underneath that, right? But we also have inappropriate sinus tachycardia, which goes under dysautonomia. We have vagus nerve dysfunction.

We have fight or flight or adrenal surges. All of these fall under dysautonomia. Okay? And you can have multiple different pieces from the sub buckets and still be under dysautonomia.

Jill Brook: So that makes a lot of sense. And I guess getting back to your food [00:18:00] example.

Dr. Robert Groysman: Yes.

Jill Brook: I'm wondering how much does the timing tell you? So for example, one thing that comes to mind is, you know, when we eat, we try to figure out, okay, was that a mast cell reaction that I had? Was that a gut dysbiosis reaction that I had?

Was that setting off my POTS because it was too much carbs? How do you start to pull that apart?

Dr. Robert Groysman: I, I don't treat it in isolation even though I'm discussing it in isolation here. So, like I said, I want to see what happens after a meal. Doesn't matter what kind of meal it is, okay? And then we start digging into reactivity, sensitivity. Then I look at other connecting things, like sleep. So, even though I'm talking about it in isolation, it really isn't.

Like we said earlier, everything is connected. Everything is connected. Long COVID looks confusing if you look at it from the, the, the huge picture that it is, but if you, if you know where to look [00:19:00] and which, which doors to open, it becomes very predictable.

Jill Brook: And so I guess we had a question about that. So part of your buckets look a lot like other syndromes, and we had one question about whether your mitochondrial bucket is basically ME/CFS, or does it not necessarily have to be full-blown to count in your mitochondrial and bioenergy buckets?

Dr. Robert Groysman: So that's another paper that's gonna be coming out. So I don't wanna talk too much about that. But what I will say is no. So first off, long COVID is not ME/CFS. It does not require you to have post-exertional malaise or even fatigue. In fact, long COVID doesn't require to have any particular symptom or symptoms. All it requires is the onset of symptoms in proximity to the virus, to being sick, okay? And for it to last at least three months, 12 [00:20:00] weeks. So those are really the only requirements. ME/CFS has other requirements, which are, at least if we're using the, the US classifications, right, from 2015 that would be post-exertional malaise is a must.

You must have delayed onset crashes that last a certain amount of time that are not relieved by rest or, or, or doing anything else. It just has to run its course each time. There's sleep disruption, right, which is part of the diagnosis for ME/CFS. And usually one or more cognitive findings such as brain fog are enough to diagnose ME/CFS.

Of course, it has to have lasted for six months or longer. That's one of the requirements. But none of these are required for long COVID. Mitochondrial dysfunction does not mean post-exertional malaise, and mitochondrial dysfunction does not mean [00:21:00] ME/CFS. And we know this because there are kids who are born with essentially damaged mitochondria from birth.

So all of your mitochondria that you have in your body comes from your mom, from the egg. Sperm does not contribute any, any organelles or anything, just the DNA. That's it. Everything else comes from the mom's egg. So it's chock-full of mitochondria. And from those mitochondria, we make every other mitochondria or mitochondrion in our bodies.

They're all clones, okay? So if, if there's already a a defect in the mitochondria in the egg, and that replicates in the baby, so the baby's never gonna have normal mitochondria.

Jill Brook: Right.

Dr. Robert Groysman: No matter what you do, it's never gonna have normal, so we know a lot of information about mitochondrial diseases from congenital causes of mitochondrial problems, right?

So, not everyone develops ME/CFS, right? So [00:22:00] some some children who have mitochondrial disorders don't necessarily have ME/CFS. So, just having mitochondrial dysfunction is not enough.

Jill Brook: Okay.

Dr. Robert Groysman: Post exertional malaise, again, is a consequence. It's not a symptom, it is a consequence, and is, and is a convergent consequence of multiple mechanisms that, that we're seeing here. Okay? So it, it's not necessarily coming from mitochondria itself. It can come from a stressor from dysautonomia or from mast cell or from neuroendocrine or any of the others. And, the convergence of all of these is what triggers the post exertional malaise. My second paper, the, the fragile mitophagy paper, explains one particular subtype.

So this does not explain post exertional malaise as a whole. This explains a subtype. Okay? What I'm, what I'm [00:23:00] trying to explain here is why the delay. Why doesn't the activity, whether it's mental or physical or emotional or social, why doesn't it cause the problem right then and there?

I mean, if the mitochondria are not working right it should happen right then and there. Why is there a now- several hours delay or the next day or even three days later?

That's what this paper attempts to explain. And what, what I'm trying to to say here is, is the problem is not necessarily that the mitochondria are dysfunctioning.

The issue is in the cleanup process. So damaged mitochondria in your cells get tagged. There's a chemical tag that's put on them that says, "I'm bad. I'm not working well, you know, get rid of me." Except my proposal here is, is that despite that, they don't get cleaned out, so they start to accumulate.

So think of a [00:24:00] hoarder's house, okay? You know, you got stacks and stacks of stuff, and you wanna bring in a new couch. Where are you gonna put it? So where are you gonna put the new mitochondria if you don't have the space? The cell is chock-full of trash, so all that trash has to be removed. So why the delay?

Well, the cleanup process starts, but it doesn't finish, so you have bits of mitochondrial DNA, and bits of oxidized lipids, and other danger signals that are sitting in the cell, okay? This creates inflammation, okay? Because your cells, when they see double-stranded DNA, which mitochondria have they assume virus, okay?

And, and they treat it just like a viral infection. So the response of your immune system is the same as basically like the cell was infected.

Jill Brook: Okay.

Dr. Robert Groysman: So it creates a lot of [00:25:00] inflammation, and this is going to amplify all the other mechanisms, all the other endotypes.

So, this is my my hypothesis of why it's delayed, okay? That's not gonna explain all of all of post-exertional malaise, and I have experimental evidence for this, but I can't really post or do anything with it because of IRB and stuff. So, I'm limited with that.

Jill Brook: Well, hopefully we'll revisit that when, when are able.

Dr. Robert Groysman: But all, all I can say is is that I, I have proof. I have proof that this happens.

Jill Brook: So we hear a lot about the term mitophagy.

Dr. Robert Groysman: I prefer mitophagy.

Jill Brook: Mitophagy. Okay. So, so can you say what that is and why people are talking about it, and is that relevant to what you're talking about?

Dr. Robert Groysman: Autophagy, as you said, I call it autophagy it's just my, my accent, I guess, is turnover of the entire cell. So, whether it's damaged, [00:26:00] whether it's cancer, whether something's wrong with the cell your body tags the entire cell and says, "kill it." But here's the important part, kill it in a way that doesn't cause inflammation.

So, there's multiple ways to destroy a cell. Some are inflammatory, like, an infected cell, for instance will be killed with prejudice. And it will cause collateral damage, and it will be inflammatory. But there's a way to to kill it in a way that does not signal inflammation.

So that's what autophagy is. It is destruction of the entire cell. You can, you can destroy any portion of the innards of the cell if they're damaged, and it could be anything. Any of the organelles can be damaged, and they go through a destruction process. Mitophagy, in particular, focuses on mitochondria destruction, but any, any of the [00:27:00] organelles undergo a similar process.

Jill Brook: But even though it sounds bad, it's good, right?

Dr. Robert Groysman: It is good. It's, it's supposed to happen. So if there's a damage to one of the organelles like mitochondria your body doesn't throw it out. It breaks it down and into its component pieces and just rebuilds a new one from from the materials, okay? But the problem is, is if you can't break it down it sits in the garbage disposal system, and it just sits there.

And another one adds because another one gets damaged, and you do this all the time real, real time you do this every day all the time. Your mitochondria wear out, and they do. Any organelle wears out just like the shocks or the tires on your car, and you have to replace them, and that's what your body does.

Your cells do that, too, and it's not a bad thing. It's supposed to happen. The problem is, is if you can't do it, and you, you don't completely break down the [00:28:00] mitochondria. Well, it takes up space. I mean, a cell wall has a finite amount of space, so if you keep cramming in more mitochondria that are damaged but not producing fresh ones, you see the problem here.

There's no room to put the fresh ones. You, you essentially have you know, a garbage dump in, in, in your cell because you can't get rid of the garbage. So, that's part of what this hypothesis talks about.

Jill Brook: Okay, okay. So I think what you're saying is in your model, everything is connected to everything, and so there's a number of different ways by which you can get these mitochondrial problems, and you don't just have to have ME/CFS. So, so those of us who don't have post exertional malaise might have been thinking, "Well, that, that mechanistic domain must not apply to me."

Dr. Robert Groysman: No, absolutely [00:29:00] not. You could still have mitochondrial dysfunction and not have post exertional malaise.

Jill Brook: Okay.

Dr. Robert Groysman: That's, that's the sub-bucket, okay? Just because you have mitochondrial dysfunction does not mean that you have post-exertional malaise. And I just showed you that example of, you know, kids who are born with essentially damaged mitochondria, they're not all in post-exertional malaise category.

You're not, you're not basically guaranteed to have ME/CFS just because you have damaged mitochondria.

Jill Brook: Okay, and so we'll come back to that bucket when you can talk more about it. We're excited for that. But I know that, that our audience focuses largely on POTS, and so we get a lot of people write in questions wondering how do you think about POTS? How does POTS fit into your network model, and what are the different things that can make POTS worse?

Dr. Robert Groysman: So POTS, like I said, POTS is an umbrella underneath the umbrella of dysautonomia. And [00:30:00] fundamentally, the, the issue comes down to not having enough blood, blood oxygen reaching the brain, okay, when you're upright. Bottom line, that is the end result no matter which form of POTS you're talking about, whether it's an issue with the heart, whether it's an issue with the blood vessels, whether it's an issue with the blood volume.

The main, the main problem is there's not enough oxygen and blood reaching the brain. That's what it comes down to, okay? So that is the goal. That is what your brain is trying to do, and it's the most important organ in the body, or so it thinks. So it's going to do whatever it takes to, to get the blood over there, and if it can't, guess what?

You're gonna fall down and lay down, and blood flow is restored, right, since you're no longer standing. But the end goal is achieved. So it's gonna do whatever it has to to get blood and oxygen flowing to the brain, okay? So the [00:31:00] treatment here is figuring out why the heart rate is going faster. Sometimes it's compensatory and necessary, but that's not the problem. It's not that your heart is going fast that's the problem. It may be because not enough blood is reaching the heart.

So your heart is trying to compensate by trying to deliver more oxygen and blood to the brain, which is always the end goal, right? So what does it do? It's gonna pump harder and faster.

That is compensatory. That is good. If you slow that down or stop it, guess what's gonna happen? It's gonna make symptoms worse, because you haven't solved the original problem. All you did was stop the compensation that was happening. So it's important to understand and know if, if the response is compensatory or not, maybe you shouldn't be treating the heart rate, is what I'm saying.

That may not be the problem. If you fix the problem, the heart rate goes back to [00:32:00] normal because it's compensatory, it's no longer needed, so you don't need to go fast anymore, or hard. But if you treat all POTS by lowering the heart rate, you're gonna be sadly disappointed because those patients with compensation are gonna feel a lot worse by slowing the heart rate down, okay? So this is how I break it down. You know what the end goal is, right? Is to supply oxygen and blood to the brain. That's it. That's what the whole point is, and you have to figure out what's wrong.

Is it the blood volume? Is it the vascular tone? Is it the heart? I mean, heart can be primary, and you can have tachycardia, and that is causing POTS because you're not getting enough blood to the brain. But that's not compensatory here. It's it's primary to the heart. So, so it's important to split those up, okay? And once you know that, it's easy to treat. You know what to do, once you [00:33:00] identify the actual problem. So, so that's essentially how I treat POTS. I had fairly good success with it. We don't, we don't do the roulette wheel of try this, try that. You know, whatever, whatever the arrow lands on.

I, I hone in on the problem and I treat the problem, and lo and behold, it works, because you're treating the problem. I mean, it's, it's, it's kinda unfathomable that if you actually treat the cause, it, it fixes the problem.

Jill Brook: Okay, so I'm gonna combine our next question with a sort of a follow-up to the POTS question. So, so we've had some guests in the past who have suggested that Mast Cell Activation Syndrome might be a common upstream driver of POTS, and we also had a question come in about your whole model in general, that one patient took your model to their physician, and their physician thought that Mast Cell Activation Syndrome could account for a lot of the, the [00:34:00] mechanistic domains or could be upstream.

Dr. Robert Groysman: Any one of these nodes can explain the majority of symptoms. That's the whole point and problem. If you just focus on the symptoms, you miss the underlying endotypes. So I can explain pretty much every symptom using just one of these nodes. I can explain it with dysautonomia, I can explain it with mitochondrial, and so forth.

But that's the, that's the problem, is if you don't know what the underlying endotype is, then what are you treating? Yeah, of course, if you just look at mast cells, yeah, it looks like it could cause most of these symptoms, of course. But I can do the same thing with gut, and the same thing with dysautonomia.

And frankly we could look at Lyme, we could look at EDS, we could look at traumatic brain injury. We could look at so many other conditions that will replicate the majority of the symptoms. But what are you treating? If you're treating symptoms, you're not treating [00:35:00] anything. So that, that's what it really comes down to, is what is causing these symptoms?

And you can't assume it's just mast cells, or just endothelial, or just mitochondrial, or, or even immune dysregulation, or viral persistence. You have to figure out what is actually driving these loops, okay, I, I keep bringing up loops. I know we talked about loops last time. So all these loops set up because of the interactions between the nodes.

Okay? And these can become self-sustaining loops. So you don't actually need the problem anymore to have, to have the loops. Let's say mitochondria miraculously treats itself and becomes normal. You could still have the same problem continue until you break that loop.

That's another element to this that again, it's, it's difficult to explain, but there's layers upon layers here.

And yes, you can take any one [00:36:00] of these nodes and explain most of the symptoms. I've done it. So this was the problem. When I first started it was dysautonomia. Everything was dysautonomia to me. I was doing stellate ganglion blocks, and patients felt better. So long COVID was just dysautonomia. But then other things start creeping up, and I couldn't explain it with just dysautonomia.

That's why I started looking for other mechanisms, other endotypes. And as time went on it, it settled on these six. Now, like I said, there's other, there's other mechanisms, there's other endotypes, and if you pick the right person one of these can become primary instead of the others. But consistently, patient for patients, this is across thousands of patients, these six come up more often than the others.

Not to say that you can't have somebody with, you know, immune activation, and they have fevers going on all the time, or they have viral persistence that's evident, or there's [00:37:00] a, an autoantibody issue. So any of these can, can become a major source for this particular person, but not for the global part of long COVID.

If you look at global, these six come up over and over again in the majority of long COVID patients. So I don't limit myself to these six. What I'm saying is, is that these six are the ones that you see pretty much every time. And in some patients, they'll have one of these other amplifiers become primary, and it's a little different.

ME/CFS works a little different. This model is slightly different for ME/CFS, okay? So I haven't published that, but the mechanisms are different, okay? Because it, it works and sets up differently than long COVID. Different virus, different viruses, damage different, different systems in different ways.

So that's how that's how I do this. And specifically for long COVID and ME/CFS, [00:38:00] the problem is is it spans every single organ system. So which doctor should be treating it? Cardiologist? Endocrinologist? Neurologist? Immunologist? Rheumatologist? This is not an infectious disease problem, okay?

There's no more infection. But the problem persists. So, so yeah, so here's the problem. I think it needs its own specialty. I think these chronic illnesses that are body-wide, every system is affected, needs its own specialty. It doesn't really fit in into any of the normal specialties we have.

Jill Brook: Yeah. And what, which is why we're lucky that you have agreed to come back a number of times so that we'll have time to go deeper on each of these topics. Today we're doing sort of an overview before we start doing deeper dives. But, but a couple of the other questions that came in, I think you sort of addressed, which is somebody asked about viral persistence, and how they [00:39:00] have a doctor who keeps giving them more treatments trying to treat the original virus, thinking that it must still be there.

But what you're saying is that that might be there or it might not be, but it wouldn't be necessary for these other loops to have gotten enacted.

Dr. Robert Groysman: So, yes, you, you don't actually need any of these mechanisms to remain active. Once the loop sets up and becomes entrenched, you don't actually need the, the original input. I use the, the Hatfield-McCoy analogy. You know, the feud lasted many, many years, and in future generations they likely didn't remember what the feud was about, but they still kept it up, right?

They still hated each other. They're still shooting at each other. So, the point is, is you don't need the original insult to, to continue the fight. And yes, there are some patients that are gonna have true viral persistence. In other words, the virus is still replicating [00:40:00] and, and going. But the majority of these patients that have been found have been immunocompromised.

So, HIV, right? Full uncontrolled HIV, organ transplants where their immune system is severely suppressed, bone marrow transplants. You get the, you get the gist. Or some kind of congenital autoimmunity problem where your immune system just doesn't work right. In those patients, you may never recover from COVID.

The COVID infection just continues. But that's a different situation. When we're talking about viral persistence, we're really talking about two different things, okay? We're talking about remnants here, okay? So bits and pieces of virus, pieces of RNA, pieces of cell wall.

Basically, the gunk that's left behind after the war is over, the battlefield. And these still can persist in some cells, mostly immune cells, but they're also found in some gut cells, which was the last paper that was released. And because they're in there, they [00:41:00] can continue the inflammatory reaction, even though nothing is really going on, the, you know, because the junk is not removed. See the, see the theme here? The junk is not removed it's continuing to stimulate. So it's not just mitochondria, it's other things that can persist because your cells are not able to process the, the junk. So, that's, that's one. The, the other one is what they call reservoirs, right? Viral reservoirs. So here's the thing, viral reservoirs do exist, but they have not been proven in long COVID. So a virus has to have some strategy to remain active or to remain in your body without being destroyed, and there's really only several ways to do this, okay, that we know of.

Number one, HIV, right? It incorporates itself into our genome. It actually writes its, its, its genetic code into our DNA so that it always produces more of itself. That's one strategy. [00:42:00] The other strategy, for instance, is, like, hepatitis. Hepatitis B and C. C, as you know, can persist for a long time. How does it do this?

Well, it just replicates very, very, very slowly, so slowly that it gets under the radar of your immune system. That's strategy number two. Strategy number three is go to sleep. That's herpes family viruses, right? All of the Epstein-Barr, all of the herpes simplex, CMV, zoster, right? Varicella zoster. All these are herpes family viruses.

They have the ability to go latent. They can go to sleep for 20 years, and they're still fine. They're not incorporating into our DNA, but they stay in your cells sleeping, okay? And with the right event, it's triggered, and it goes back to work. It starts replicating. So these are the three main strategies that viruses use to stay in our bodies.

Long COVID, COVID, SARS-CoV-2 has not shown to have any of these properties, [00:43:00] any of these three properties. It doesn't replicate slowly, it doesn't go latent, and it doesn't incorporate itself into our DNA. So my question to you is how is it still there if it doesn't do any of these three things? So, so it has to make sense.

You have to have a mechanism to explain how a virus stays in your body without being touched by your immune system, right? So, an active virus is going to display its markers on the cell. The cell gets marked, it gets killed. So it doesn't do any of these three things is my point.

It doesn't use any of these three mechanisms that we know of. It has not been demonstrated in the last six years. I mean, I know we're going on seven here, but nobody has demonstrated any, any of those three mechanisms, not once, not any paper, not any study. What they found was bits and pieces of virus, you know, remnants, but that's not the same thing as saying you have live virus in [00:44:00] there that's capable of replicating.

That just means that you have trash in your cells or in your tissues that wasn't cleared out.

Jill Brook: And did you say that you had written a paper about that in the gut?

Dr. Robert Groysman: Not me. This was a paper that was just released this month.

Jill Brook: Oh, okay. Okay

Dr. Robert Groysman: On the gut where they, they looked at cellular basically colonocytes in, in the gut, looking at the cells themselves, and they found bits and pieces of virus.

Jill Brook: Oh, okay.

Dr. Robert Groysman: So remnants, junk.

Jill Brook: Okay.

Dr. Robert Groysman: But yes, but having those, that junk there will cause inflammation because then they don't belong there. And that can cause problems in itself, but you don't need actual live virus to have long COVID.

Jill Brook: You can have the entire, every bit of, of the COVID virus long gone, but all of the loops that were set into place are just still going.

Dr. Robert Groysman: Right. I mean, you still have to repair [00:45:00] the damage, but even if you repair the damage, some of these loops remain, so you need to break the loops.

The longer the loops remain, the harder it is to break them later. So, I try to make sure that patients know that treating early has much better success rates.

It just, it just takes more work to break the loops later if you've had it for more than a couple of years. It's not impossible. It's just more difficult

Jill Brook: Okay. Okay. Gosh, we have so many questions, and it's so amazing speaking to you. You're so knowledgeable about so many things. But I, I lost track of the time, and I know we need to let you go. But I, I'm very excited that next time that we speak to you, that we'll go deeper on some of these things. So if I could ask one more question before we let you go. A lot of patients who have what is called, you know, the triad or the septad or the pentad are seeing what, you know, resembles their own situations [00:46:00] even if they didn't get it from COVID.

So do you think that your model applies to people who got the same set of issues, but not really from COVID?

Dr. Robert Groysman: Yes. I, I don't just treat COVID, like I said, or long COVID. I treat ME/CFS as well, and I treat post-viral syndromes in general. But we can even go even further out of that. There's several conditions that would replicate the majority of what we're seeing because these mechanisms interact the same way, but the damage is done by a completely different process. So yes, it, it's applicable to a lot of things and even other conditions, non-infectious. And by following the endotypes as opposed to symptoms, I think you know, we may get into some cures potentially. I, I mean, it's not a promise, obviously. It's gonna require a lot of, a lot of research into those [00:47:00] conditions and into their endotypes, which I have not done, but I do think that it's applicable to a lot of other conditions too.

Jill Brook: Yeah. Yeah, it feels like it. And so like I said we're so grateful that you have agreed to come back on a regular basis and talk about this until we've kind of gone through. There's so much to your model, and there's so much we haven't talked about yet.

Dr. Robert Groysman: It's, it's never ending though. I, I'm telling you, this is never ending. There's always something new I discover, and I have to figure out how it incorporates into the rest of the model. But I, I do wanna reiterate that this is a hypothetical model. It hasn't been proven yet even though I do believe it will eventually be based on all the evidence that I have.

I mean, I didn't come up out of this out of thin air, obviously. I have a lot of proof behind it. But bottom line is the way science works is you come up with a hypothesis, and then you prove it or disprove it. So all of these [00:48:00] papers are what's called falsifiable. You have to have a way to disprove the, the hypothesis, otherwise it's not a hypothesis.

So, that's all built into the papers that I write. You have to have an ability to prove them false.

So that's the difference between a hypothesis and pseudoscience, which does not have to have any proof or ability to prove that it's wrong. A true hypothesis should be able to be falsified. And, you know, maybe not all of it is right, I don't know. But we'll, we'll find out if somebody decides to actually empirically test it, and if it's, if it's proven, it's gonna be a theory. That's how this works in science and medicine, and pretty much anywhere else. I'm passionate about it, but I'm not gonna be upset if it's, if a part of it is proven false, because that's part of science.

We, we learn from successes and the failures. Maybe somebody can add something additional in the future. But my, my point is I wanted to start the process. This is where long COVID [00:49:00] needs to be. This is where ME/CFS needs to be, in my opinion. In my view, this is how you start a path to recovery.

Jill Brook: Yeah. Well, we're so grateful for you for starting this path. We will put links in the show notes to all of your papers that we have discussed, and to your Long COVID Handbook, and to your website. And at the end of the day, probably what a lot of listeners are wondering are, are your patients getting better?

Dr. Robert Groysman: I mean, from feedback that I'm getting, yes. I mean, I don't get feedback from 100% of my patients unfortunately, but the ones that do, do get better. I mean, I'm not gonna say that it's 100% I'm not gonna tell you that it's a smooth road and smooth ride, you know, you're going from A to B. There's gonna be some bumps in the road.

There's gonna be some, you know, some issues that need to be ironed out. But as a whole, yes, I do see the majority of my patients getting better. I'm not gonna tell you that they get back to 100% to where they were before [00:50:00] COVID, and that's never the goal. My goal has always been not a cure, but improving function and improving quality of life to get them to do at least the things that they love to do or have to do that they couldn't do before.

My biggest successes have been getting people out of bed. Basically, someone who is stuck in bed and they can't even go to the bathroom or brush their hair. To get somebody like that to walk around and up and about it's a tremendous quality of life improvement. We have a child that is back in school, could not attend school before, is back in social activities and clubs. Slowly, slowly, we're going slow, but we have a tremendous improvement compared to where he started from.

So, you know, for, for a kid, for a teenager you know, it's huge. If, if you, if you can't be around your friends, if you can't go to school... So, it's, it's, it's [00:51:00] it's life changing.

I mean, could you imagine losing your whole childhood because you can't do what a kid is supposed to do, the normal things that kids do? I mean, it, it, it scars you. It scars you. So the mom is thrilled, the dad is thrilled. I mean, you know, I'm thrilled.

It's really just about looking at things in a different way. So, you know, everybody can look at the same thing, but some people when they look at it, they see something different. So there's a pattern there that's not evident to other people. So, when I look at some of these things, I, I, I see things in a different way is the best way I can explain it.

And that's how this whole thing came about is, is just seeing, seeing these things in a different way, and also realizing that what was going on and what was currently being offered didn't work. So, that really motivated me to, to look for something [00:52:00] else, something that did.

Jill Brook: Well, Dr. Groysman, I'm gonna sign off because I have some burning questions that I have to ask you offline 'cause there's so much good stuff here. But thank you so much for your time here and for your work, and can't wait to have you back again soon. Okay, listeners, that's all for today. We'll be back again soon, but until then, thank you for listening, remember you're not alone, and please join us again soon.