Episode 3: Advancements in Evidence-Based Research and Nutraceutical Approaches to Managing Long Haul Syndrome with Dr. David Brady

Dr. David Brady: There you go. You got it.

Evelyne L.: Thank you so much.

Dr. David Brady: It’s a mouthful. I know. Sorry.

Evelyne L.: It is a mouthful. Thank you so much for joining us today. We are going to be talking about long haul COVID. Hot topic. A lot of people are suffering. What is long-haul COVID syndrome? I know there are multiple names for it. And what is the prevalence in the US?

Dr. David Brady: Yeah, good questions. The data, we’re getting new data all the time and picture’s not getting better looking, unfortunately it’s getting worse, but long-haul COVID syndrome or sometimes just called long-haul syndrome, sometimes called PASC, P-A-S-C, which is sort of the more the medical terminology for it, but it’s basically people who had acute COVID. So they had an infection with from SARS-CoV-2 virus, and they had all of, usually all of the typical acute symptoms, more like a respiratory kind of flu type of illness. But when they recovered from the acute phase of it, and by and large, most of the respiratory classic symptoms of acute COVID resolved. Not everything resolved. They ended up with persistent symptoms that just never quite went away. And that symptom list is pretty long. But the most prevalent things would be fatigue, particularly post exertional fatigue.

Pain, ongoing kind of weird pain. Pain that is hard to typify. It’s not necessarily just in the joint, it’s not necessarily just in the muscles. It’s kind of a vague achy pain. Often around the rib cage, like a costochondritis type of weird pain. Chest pain, often they have elements of what we call POT syndrome, postural orthostatic tachycardia or hypotension where they get a rapid heartbeat or tachycardia intermittently for no specific reason, not just because they’re exerting themselves just sort of out of the blue often in the evening. So there seems to be a temporal component to it. They often will get dizzy when they stand up quick like a postural hypotension and a myriad of other symptoms are common, a weird neurological phenomena, almost like a neuropathy or a buzzing or a pain in the distal extremities.

Also, part of that POT syndrome is like a Reynaud’s phenomenon where all of a sudden their hands in feet go ice-cold for no reason. Again, no rhyme or reason to it at all. Brain fog certainly a big part of it. And then there’s a whole laundry list of potential symptoms that are not as prevalent, like persistent minor cough, shortness of breath, but those things are not as common in the vast majority of long haul syndrome patients.

Evelyne L.: And what is the prevalence right now? Do we know how many people who have had COVID develop symptoms?

Dr. David Brady: Well, the Brooking Institute did a study of this within the last 12 months, and they put the number in the United States at about 16 million people with long haul COVID or persistent symptoms as a sequela to having SARS-CoV-2 infection. And of those 16 million, about 4 million are in prime age working years. So that’s a big impact on the economy, which is less people in the workforce, but also people not only not in the workforce, but then consuming a lot of healthcare resources, maybe being on public assistance. So it’s a big, big financial impact to the country. And of course it’s not isolated. It’s in the United States. When you run those numbers globally, they’re massive.

Evelyne L.: So in 2020 long haul COVID was not well understood though patients were sharing that they had these symptoms, which were not unlike long haul symptoms of other viral infections. How have things changed now three years later?

Dr. David Brady: Well, a lot has changed. We understand a lot more about long haul syndrome, although we still have not unlocked some of the major questions that still persist. But this is not the first time we’ve had long-term sequela or people have gone on to have chronic illness after an acute pathogenic infection. And predominantly, not exclusively, but predominantly post viral infections. There was reports of similar phenomena way back even in the early 20th century with some of the viral outbreaks that had happened, influenza and Spanish flu and things like that. And then the latest kind of parallel or analogous situation to it was about 20 years ago or so, we had SARS-1. And SARS-1 luckily it was not nearly as transmissible, it was more severe actually and more deadly, but it was not as transmissible. So there was not nearly as many people affected. But of the people who were affected, and particularly those who were hospitalized, many of the healthcare workers who cared for those patients came down with postviral myalgia, postviral fatigue.

And at the time, they’re usually just labeled as chronic fatigue syndrome or CFS/ME, which by the way is a postviral syndrome in and of itself. That’s just a much broader blanket term for people who have a post-infectious syndrome from a multitude of potential viruses or pathogens. Classic fibromyalgia is another example of a disorder that has all the harm hallmarks of a postviral sequelae.

But this long haul syndrome with SARS-CoV-2 has impacted way more people because the virus was just so transmissible and it affected so many people that when you get a percentage of them that go on to develop long-term chronic symptoms, those numbers end up being very, very large. We do know a lot of things about it. We still do not know a lot of things about it, but it’s interesting, that first viral wave, that spring of 2020 seem to be the worst from the standpoint of causing long haul syndrome. It’s not that later variants like Omicron and Delta did not cause any long haul, but does not seem that they caused as much long haul or as severe persistent long haul syndrome as that first wave of the virus did, unfortunately.

Evelyne L.: And especially with the respiratory symptoms. What are the current major gaps in the standards of clinical care? And I have some thoughts on this because I know at various hospitals like where I am, they have created long haul COVID clinics, but clinicians are still working in isolation. So if you have this symptom, you go see this doctor. If you have lung symptoms, you go see the pulmonologist and then they don’t talk to each other.

Dr. David Brady: Yeah, I don’t see it as there is really a standard of care established at this point for long-haul syndrome, either in conventional medicine or in complementary or integrative medicine. I think a lot of people are trying a lot of things that seem to make sense, even if it’s through rational hypothesis, but not yet necessarily hardcore outcome data and people are trying to do the right thing, but there’s been no coalescence around a gold standard of care. You’re right. In conventional medicine models, it’s a highly fragmented specialist kind of dominated architecture of the medical system. So you tend to get routed to whatever specialist your symptoms tend to line up with. The problem with long-haul COVID syndrome is there’s so many symptoms. What specialist do you send them to? Because you can send them to a pulmonologist, you can send them to an endocrinologist, you can send them to all these other types of specialists, a gastroenterologist, many of them, and they’re going to treat it through their kind of myopic tunnel vision of their specialty.

And this really is a very complex condition that I think needs the type of healthcare provider that can look at it from a much more global holistic perspective and have enough understanding and skills in those different domains to be able to do the right thing. And therefore, I really do think that highly qualified, very high-end integrative functional medicine physicians, may be the perfect kind of captain of someone’s healthcare journey to help them when they have long haul. It doesn’t mean you would not have to utilize some other specialist at times but you really do have to look at it through a larger, wider lens.

Evelyne L.: Right. And look at all the root causes and how everything correct ties together. You said earlier that we still have so many unanswered questions around long haul syndrome. I’d love to know what some of those are and do we understand the pathogenesis right now of long haul COVID?

Dr. David Brady: No, not really. There’s a lot of hypotheses, but there’s no absolute proof even at the fundamental level. Well, we know this is a downstream sequelae of at one point having an acute infection with SARS-CoV-2, and we know a lot about how SARS-CoV-2 acts and how it gets into tissues and some of the sinister things it does in the micro vasculature and micro clotting and all, and how it affects mitochondrial function and all these other things.

But we still have not answered the fundamental question of what creates this persistence of symptoms in this virus that has supposedly resolved from its acute phase? So is it some reservoir in the body of actually replicatable virus? Is it living deep in tissues and replicating itself? Some people believe that’s the case, although it’s not proven. We’ve seen reservoirs of virus persist for a long time, for instance, in the gastrointestinal tract and the enterocyte shedding spike protein, or is it just somehow the virus programmed our own cells machinery to make spike protein and other proteins that key the immune response again, or is it that the original viral infection caused a dysregulation or an imbalance in the immune response that persists?

So it pushed the immune system into a hyperactive frenzied state that got stuck in a locked loop pattern even without more virus being there? I’m not sure any of those are incorrect. I think they all could kind of be in play, and they may not all be in play in every subject. There’s variations, there’s shades of gray to long haul. But fundamentally, that is a question that ultimately does ideally need to be answered. But as far as the mechanisms of whatever those three things I said are true, how then is the dirty work done in the tissues and how does it make people feel the way they do? We know some about that, but they’re still definitely missing. There’s gaps in our understanding of it for sure.

Evelyne L.: Right. Very interesting. I want to talk about the links and associations between long haul and things like immunological cytokine patterns. And actually, I remember from our Cassie talk when Bruce Patterson spoke, he talked about the different metabolomic signatures in long haulers, whether it was post infection or whether they had underlying EBV. Can you talk more about those different presentations?

Dr. David Brady: Yeah. Dr. Patterson has done some interesting work. He is been one of the more active researchers and clinicians in this space from the beginning. Most of his work is centered more around cytokine signatures than wider metabolomic patterns. But he has found some interesting things. His background started in HIV, so he was very versed in how viruses do their dirty work, especially very complicated viruses that have persistence. And he noticed, for instance, early on when he was doing cytokine testing that a certain cytokine called CCL5 or RANTES it’s called as well, tended to be elevated in these long haul syndrome patients. And that’s the case in HIV as well. So that’s was the genesis of why they tried some of the therapeutics they did. For instance, a antiviral drug known as Maraviroc or Selzentry, I think is the trade name.

It’s used in HIV cocktails because it pushes down CCL5. It’s a CCL5 inhibitor. So they use that to see, Hey, if we see this cytokine that’s inflammatory high, if we can use an agent to push that cytokine down, do the patients feel better? Oftentimes that’s work out the way you would hope it was. Right. When you’re basically, and I understand why this happened, we were just trying to look for anything and people were trying to look for anything. So if you see atypical patterns on testing, like cytokine testing, Hey, do we have any agents that can normalize that pattern? And maybe if we normalize those cytokines, the patient normalizes. It doesn’t always work out as clean and linear as that. Right. It’s complicated. There’s more to it than one cytokine or even a couple of cytokines. But he did find specific patterns when they used machine learning and things to kind of mine a lot of tests being done on long haulers who got long haul from the virus, and people had persistent symptoms, let’s say after an immunization for COVID.

And he also looked at other subjects that had long-term fatigue and myalgia. So chronic fatigues, fibromyalgia, you want to know, everyone wants to know what’s different between them and the chronic fatigues that had it long before COVID was around and long haul syndrome patients. And you see things that you would expect in any immune activation syndrome that involves tissue inflammation. So things like IL6 and IL10, and TNF-alpha, interferon, gamma, these are all commonly high, but not absolutely predictably high in every long haul patients.

And actually other follow-up work done by other researchers really show that while some of those classic markers of inflammation that we look at on the cytokine pattern were higher to some degree than in normal patients, there were other ones that popped out more, particularly interferon-beta, which is interesting. And interferon-delta. So most people look at interferon gamma and TNF-alpha. So these other ones were popping out and cortisol actually was one that popped out. And then there are other certainly patterns in metabolomics that we see mostly the byproduct of disrupted energy metabolism and mitochondrial function that would be predictable.

Evelyne L.: I want to go back for one second. With cortisol what specifically are you seeing?

Dr. David Brady: Well, elevated cortisols were found in most of the early research. Now, if you follow these people long term, sometimes they will follow that typical pattern of early elevated cortisol, and then long term they will go down into a low cortisol state when their adrenal reserves are exhausted. Like you see classically in a chronic fatigue ME patient that’s chronic way years out, they will often tend to have low cortisol and low adrenal reserve.

Evelyne L.: And then in the metabolomics, what patterns are you seeing within Krebs cycle and other metabolites?

Dr. David Brady: A multitude of them, but probably the most predictable one and the most researched one by a couple of different groups showing this same pattern is that the long haul subjects tend to, they leave or abandon fatty acid beta oxidation very early, and they go into carbohydrate metabolism and they tend to be locked into an anaerobic dominant carbohydrate energy production. So what that means is they generate a lot of lactic acid and they don’t complete the task. They don’t get glucose down to pyruvate and then down to acetyl CoA and down Krebs cycle using oxygen and make lots of ATP. They kind of get stuck in that more anaerobic dominant quarry cycle.

They make a lot of lactic acid, which is an acidic waste product and makes the muscles achy. And then when you’re in that metabolism, you’re not making as much ATP. You’re particularly fatigued, particularly on exertion. So post exertional fatigue, usually you see high lactate and brain fog is classic in that, and those are two hallmark symptoms of long-haul syndrome. So there’s definitely mitochondrial energy, metabolism dysfunction that you see, but that doesn’t mean that that’s the cause of long haul syndrome. It’s a downstream right effect of it. There’s bigger things at play, but that’s a big part of why the people feel the way they do.

Evelyne L.: Yeah. Have you noticed in your work with patients that when you do the metabolomics and/or the cytokine panels before and after whatever you’re using, which we’ll get into that you do see those things resolve?

Dr. David Brady: You can see changes. The problem is the same things that change it in one patient don’t always change it in another. It’s not like a very linear, “Oh, we got this wired now. You’ll see this, this, this, this and this marker high 95% of the time in a long haul patient, you just give them this, this, and this, and they get better.” It’s just not behaving like that. Yeah. It’s very elusive and I think with a lot of complex chronic disorders, the body’s dysfunction can almost jig and jag around. It can run a slalom course around what you’re trying to do to mitigate the problem, and it’s almost like you plug this hole in the dike and another one pops open. Right? Right. It’s like playing whack-a-mole sometimes, metabolic whack-a-mole is what we call it. So you’ll seemingly repair certain elements of their metabolism or biochemistry, and you may get incremental improvements and symptoms, but sometimes those improvements can prove fleeting. There’s an atrophy of the effect of the therapy, and then they end up back in a flare or a crash, and we don’t fully understand why that happens.

Could it be that they’re getting more pressure into the system by being exposed to another pathogen of some sort? We’re all being exposed to viruses and bacteria and fungi and all these different things all the time, particularly if we’re traveling or getting on an airplane and things like that, and we suppress them and we don’t even know what’s happening in the background. Long haul patients aren’t so fortunate anymore. They get any kind of pathogenic load, microbial load, it seems to just flare up this whole bird’s nest of metabolic dysfunction and they go into a flare and they feel a lot worse. So they’re very fragile from an immune and a metabolic standpoint because of this chaos that’s going on in their body, which is a complicated thing because it really involves a lot of things, including micro microvasculature dysfunction and inflammation and profusion difficulties. It gets to the heart and the core of metabolism really, and they’ve got some serious problems in it.

Evelyne L.: I have so many questions popping in my head while you’re talking. Since we were talking about lab testing, have you found any correlations or has there been research on correlations between certain genetic SNPs and a propensity toward developing long haul COVID?

Dr. David Brady: That’s a good question. There’s a lot of people doing a lot of metadata mining on different SNP patterns or different genomic patterns in general on long haul patients versus patients who didn’t develop long haul or similar things were being done on trying to find how could we genetically somehow predict people who, when they get acute COVID, would go down the really bad path to acute respiratory distress syndrome and need into the ICU and potential catastrophic outcome. We definitely noticed patterns in different genetic lines. For instance, you saw what happened in early in the pandemic in Bergamo, Italy, devastating to that whole region, and they’ve a pretty clean genetic pool. In other words, they’re mostly of Italian descent on both sides of the family. There’s exceptions to this, but generally much more so than the United States, which was, it’s much more of a mixed bag genetically at this point, they were pretty solidly of one genetic line.

And even though they tended to smoke a lot, they also walked a lot. They weren’t obese, they ate generally good foods, but they had devastating outcomes. It ripped through there and killed a lot of people. And we saw that translate into people of Italian heritage having more problems, whole families being wiped out, for instance, even in those who had immigrated to the United States. And what’s different about the genes that and their immune response that maybe made that happen. I still have yet to see definitive answers on what those were. It’s complicated.

There’s lots of genes, lots of SNPs and complicated patterning to try to figure out. I think at some point we will, we’ll know more about that. But I think just anybody that had genetic propensity toward a baseline mitochondrial function, energy production that was less than optimal, people who are more susceptible to immune dysregulation. So people with autoimmune type of genetics and autoimmune HLA patterns and things like that, I think are more susceptible to this type of immune insult from a virus than triggering inflammation and autoimmune phenomena in the body. Because we definitely see autoimmune phenomena as a result of this viral infection, particularly in certain genetically susceptible people.

Evelyne L.: Very interesting. You’ve brought up mitochondrial dysfunction, I think twice now. I want to talk about that connection between long-haul and mitochondrial dysfunction. Can you elaborate on that?

Dr. David Brady: Yeah, that’s a common hallmark of all these postviral syndromes that there seems to be wreckage that happens in mitochondrial function, in energy production of ATP. And it’s complicated biochemistry for anyone who remembers studying it and the nightmares of trying to remember all those intermediates and enzymes. And unfortunately, most doctors took the exam and then promptly went out on a bender that night and forgot it all and never to visit it again. But in functional integrative medicine, we don’t have that luxury. And in clinical nutrition, we live in those pathways all the time. And we definitely see dysfunction there like we talked about on metabolomics, we can see it. We can see that down in the really efficient energy payoff metabolism that’s oxygen dependent in Krebs cycle. And within the mitochondria itself, we get a lot of stacking up of those intermediates, and ultimately it’s because they’re not getting much past the anaerobic metabolism that happens outside the mitochondria.

So you see these high Peruvian levels and lactic acid levels, and that’s just not an efficient way to make energy. You can make enough to survive. You can’t make enough to feel good and have good energy. And that’s what everyone goes into if you overexert yourself. If you go out and run sprints and you’re not used to it you go into oxygen debt and you’re going into that anaerobic metabolism. You’ll build up lactic acid and you’ll feel it in your muscles for a few days and you may even feel fatigued for a few days. But these people live in that place. They don’t just go there when you do something you’re not used to doing and you’re not conditioned to do, they’re kind of getting by on that metabolism and there’s a price to pay for that. All these acidic waste products make all your tissues ache.

You’re not making a lot of ATP, so you’re tired and you got brain fog and ATP is the currency of energy in the body. It’s needed to make everything work. And part of that is an element that doesn’t involve the mitochondria directly, but indirectly. And that is in order for the mitochondria to make energy well, even if all that biochemistry was perfectly capable of working well, you have to signal it to go at the right pace that involves thyroid function. Oftentimes, these people end up with thyroid dysfunction and in a hypothyroid state or in an autoimmune induced hypothyroid state. But the other thing you must do is you must deliver oxygen to the tissues. It’s like a bellows on a fire. When you squeeze that bellows, you see how bright that fire gets. The fire is the mitochondria and the oxygen blowing on it that’s coming from your blood cells.

And fundamentally at the heart of it, the main way that SARS-CoV-2 does its damage is through wrecking the vascular system and profusion. So if you’re left in a state where you have endothelial dysfunction, small vessel inflammation, and you cannot profuse tissues well, in other words, you can’t offload the oxygen into the tissues to make the mitochondria do their thing, you’re going to be in a state of oxygen debt in the tissues and you’re going to be tired and you’re just going to have energy problems. It’s functionally like being profoundly iron deficient, anemic, but you’re not. But you can’t get the oxygen off. And there’s been incredible studies on this. Even researchers at Yale and Harvard teamed up, that’s like the Yankees and the Red Sox making one baseball team. They’re a little bit competitive with one another. But when long haul started unfolding, there’s two researchers, jet Singh and David Strom, I think Yale and Harvard guys, and they were two of the only people that had really advanced metabolic testing labs with all the metabolomics proteomics, but also functional pulmonary studies and things like that, PET scans.

They basically had everything at their disposal and they ran exercise physiology and performance type of research, but they applied this to long haulers. And when they looked at how the skeletal muscle of long haulers was performing metabolically, it looked like cardiac tissue with ischemic heart disease or angina or heart attack, and it had all the metabolic characteristics of it. And they list probably about 10 or 12 of those. But some of the big ones were, again, the high lactate levels in the blood and oxygen coming back to the heart or returned blood to the right side of the heart, should basically be deoxygenated because it should have left its oxygen in the tissues, delivered its payload, got back to the heart to be pumped through the lung to get more oxygen to deliver it again and go around the loop again. The blood coming back to the heart was still full of oxygen and they were not pumping enough blood.

Their myocardium were not working optimally. So the volume of blood they were pumping was lower, but the blood returning was still full of oxygen and the blood volume that was leaving the heart less than would be expected was coming back to the right side of the heart. The blood that came back was oxygenated, but some of it was missing. So it’s what they call leaky vessel syndrome. We’re talking about leaky gut syndrome, leaky brain syndrome. Well, these people have leaky vessel syndrome, so the vessels are not in great shape in the small capillary beds and the blood is getting out leaking into the interstitial tissue, but the oxygen is not getting delivered where it needs to go. It’s very complicated. It’s a vascular biologist dream or nightmare. I don’t know. But they’re hard at work in the research trying to figure this out for sure.

Evelyne L.: Have you found anything in terms of medications, nutrition, lifestyle or other interventions that specifically help with this part of it? The vasculature part?

Dr. David Brady: Yeah, we’re doing things that are known to help with endothelial dysfunction, so things that lower oxidative stress, things that also treat what’s called the endothelial glycocalyx. So that little kind of slimy carbohydrate mucopolysaccharide layer, that kind of these little ciliary looking slimy things that you can only see under electron microscope, very, very thin, but it’s almost like the protective slime that keeps the stuff from sticking to the inside of the blood vessels and keep from clotting and kind of protects that one cell lining thick endothelium, which is very, very important to have proper function and produce nitric oxide and make all the physiology work. So that can be degraded in an insult like SARS-CoV-2. When you get this massive inflammation and all these cytokines running around, you’ll get oxidative stress, endothelial dysfunction, disruption of the glycocalyx. But in long haul syndrome, it seems to be a persistent, not as bad as in cytokine storm and organ failure and death in acute COVID, but on a lower level, but a persistent type of basis.

So we’ll use things like there’s certain seaweed extracts from monostroma that can treat the glycocalyx. Other just mucopolysaccharide type of agents, even things as common as glucosamine sulfate, chondroitin sulfate, all of those molecules, n-acetyl d-glucosamine. These can all be helpful. Polyphenols are very helpful. So things like resveratrol, red grape extract, even bioflavonoids like quercetin can all be very helpful not only in the context of vascular health, but also in general to lower inflammation and do other things that are good in long-haul syndrome. But it’s not like they undo all the damage. They help, but it’s not curative of it at this point.

Evelyne L.: Right. And I want to talk about labs again, going back for a moment. Have you seen changes in… Well, we know there are changes in the GI microbiota. Have you seen patterns?

Dr. David Brady: There are definitely definitely patterns in the microbiota that we see in people with chronic disease in general, but also in long haulers. And you get a shift in the compositional signature of the microbiota more toward an inflammatory dysbiotic state. So we get higher levels when you look at it, not organism by organism, but at the phyla level, like groupings of organisms. Most of the bacteria and the human intestine fall into one or two phyla. The Bacteroides are the firmicutes and the firmicutes and the Bacteroides are kind of the competing clans. It’s like the Hatfield’s and the McCoy’s of the gut. You want to make sure one is not overrunning the other, they’re with imbalance to one another. They all have enough members, but not too many members. But you don’t want one to get imbalanced with the other. And that does happen in long haul.

And just in chronic inflammatory disease in general, you get an elevation of the Bacteroides and a lower percentage of firmicutes. So that ratio shifts and that pushes the whole GI environment toward an inflammatory type of environment. So inflammatory cytokines and metabolites from the bugs themselves that can upregulate immune function and kind of keep the fire burning of this immune dysfunction. It happens in autoimmune disease as well. So rather than get kind of hung up on this study showed this specific genus and species of bug higher, and it’s really the bigger picture. It’s a slanting toward an inflammatory bias in the gut. You can see changes in keystone commensal organisms like akkermansia, faecalibacterium prausnitzii tends to be low, which these are important things to maintain the mucus layer on the lining of the gut so it’s healthy. These things make butyrates and other things that keep the gut healthy so that stuff gets disrupted.

And fixing the microbiome and the gut ecology and gut health in general is part of what you need to do in a long hauler for sure. By the way, it was one of the more predictive things of outcomes in acute COVID. People who went into it with a healthy microbiome, not in a dysregulated dysbiotic inflammatory state and not with leaky gut we’re much less likely to have a devastating outcome. It wasn’t quite as predictive. You know what the most predictive thing was? Vitamin D status, higher vitamin D status was the most shielding thing that’s been found yet in the literature. You don’t hear about that much in mainstream media, but that was… And that was reproduced in multiple countries on different continents, wasn’t just a local phenomena.

Evelyne L.: So let’s get into some things that you have worked that you’ve found in the literature that colleagues have used. We obviously know there’s not a one size fits all, but what are some of the evidence-based drug nutritional lifestyle and complimentary interventions that you recommend? And do you want to also share the personal patient story that you have?

Dr. David Brady: Yeah. Well, I have a lot of personal patient stories. I have a lot of long haul patients because I’m a functional integrative medicine doc. I deal with complex chronic disorders. So they come to docs like us usually after a whole bunch of other docs and a whole bunch of other providers. So they’re never easy cases. But a big part of my practice also centered in people that had had classic fibromyalgia or chronic fatigue and ME. So because of the similarity in relationship with long haul COVID, obviously the long haulers then started really coming in. And I have a personal story with my wife, my lovely wife, unfortunately as a long haul sufferer for three years. And she got it in that first wave when she got her acute COVID infection, it was I think the end of March or very early April, 2020.

We were in Connecticut. I’ll put it into context. No doctor’s offices were open. They were all shut down. Everything was in lockdown. The hospitals were full and there were cooler trucks outside with dead people in them. It wasn’t a good time to get really sick. Basically, the last place I wanted her to go to was to a hospital. At that point, people were getting kind of rushed into ICU ventilated bad outcomes. It wasn’t good. So I did everything I could to keep her out of the hospital at home. I mean, I brought oxygen setups and IVs and Hemealumens and blood ozone and everything you can think of from our practice into my house to treat her. And with the help of a couple of colleagues, we kept her out of the hospital, but she went on to develop long haul, unfortunately. And she was very typical of a patient that developed long haul that it became persistent.

And a big problem in that it was in spring of 2020 was that first wave. And she was a former professional dancer, Broadway level dancer, super fit, really good body composition, ate very well. Her nutrition was great. She took lots of supplements. I couldn’t keep up with her. She could beat me in an arm wrestle, a leg wrestle, going upstairs, whatever. I couldn’t keep up with her just really metabolically fit. And she’s the one that ended up with long haul. And when we looked at this in retrospect, we said, “Hey, with acute COVID, the predictor of bad outcome was often being overweight, having COPD, having diabetes and hypertension and comorbid conditions, being older.” Looked at the long haul patient demographics, wait a minute, they’re younger, they’re healthier, and really skewed toward professional athletes, triathletes, dancers like my wife. Why did the fittest among us get long-haul syndrome?

And there’s some really good hypotheses on why, and some of it goes back to that research I talked about at Yale and Harvard. When you look at SARS-CoV-2, it really penetrates into tissues as most people know by now through ACE2 receptors, the people who are great athletes, part of the reason they’re great athletes is they’re really good at onboarding oxygen in their red blood cells, carrying it and delivering it. They’re good at blowing the bellows on the fire. They get more energy out of the same metabolic input that than average people, and they could stay out of oxygen debt longer. The great bicyclists like Lance Armstrong was known to have one of the highest transport of oxygen known to mankind. And it’s no reason, despite all the other things, right, but still there was a basis of incredible athlete there.

So these people have higher density of ACE2 receptors and they’re vasculature, and they were better. They got oxygen into the tissues better. And I think the virus used that in a bit of a way. Their fitness and ACE2 receptor density and their profusion functionality worked against them in this circumstance, which is really odd.

Evelyne L.: Fascinating.

Dr. David Brady: Yeah, it is fascinating. So back to your question though, what kind of things are we using? What evidence-based things? Well, I’ll couch it first of all, to say all of it has limited evidence because it’s so new. But doctors started right away trying to use things that made sense based on what we mechanistically knew about SARS-CoV-2 and what it does. And then based on the symptom profile of what these patients were ending up with and experience with chronic fatigue and ME and other disorders that have gone before.

So you brought up Bruce Patterson, through his research and through some of his colleagues in group ended up some of these protocols using off-label drug applications. No drugs had been developed specifically for long haul. But for instance, there was a cocktail that is quite popular still, but was very popular for a while, was using a low dose statin, Pravastatin usually, and a pretty low dose, like 10 milligrams. So it didn’t usually cause more muscle, more fatigue. That’s one of the problems with statins. And combined with that drug I mentioned before, maraviroc, the CCL5 inhibitor. Using them in combination and the statin was not being used to lower cholesterol. It was being used because statins have an inherent immune modulating anti-inflammatory component to especially in deep tissue inflammation. And they actually worked on a mechanism known as fractile, the fractile pathway.

And that is involved in endothelial inflammation and small blood vessel inflammation and damage. So there was a rationale on why those medications were picked and me and combined actually. So this cocktail of low dose statin and maraviroc was used and some people benefited from it for sure. Functionally seemed to get better. Most of them, not better by the way, but better enough to make a difference. Now this is just my personal experience, many of them then that again, that benefit seemed to atrophy over time and they ended up back kind of where they were. And this has happened with other drug interventions. A lot of drugs that were totally for something else have been thrown at this fluvoxamine common SSRI antidepressant. And when you look at it, I think it’s a Sigma one receptor antagonist. It’s an anti-inflammatory as well.

A lot of these drugs have anti-inflammatory effects in addition to what they’re known for. And it also affects really deep tissue inflammation. And it seemed to improve a lot of these patients. But again, not all of them incrementally, sometimes not persistently. But I will add that fluvoxamine is unique in the SSRIs. It’s not a class effect across all SSRIs. It’s only fluvoxamine. Other medications, low dose naltrexone, which had been used for many years in autoimmune disorders and in immune dysfunction was used. Antihistamines seemed to help a lot of the symptoms that long haulers have. So hydroxyzine beta blockers are used a lot to control the POTS, the tachycardia and anti-anxiety medications. So anxiolytics, even those in the benzodiazepine class, you got to be very careful with them. But some of these people they’re so amped up, insomnia, couldn’t sleep nighttime, like wired and tired type of thing.

You see it a lot in them. And if they can’t sleep, it’s hard to get them better when they can’t sleep. But a lot of them have significant problems sleeping, getting to sleep, and staying asleep. They’re just in a hypervigilant kind of state, particularly at night, which is they get to tachycardia at night. It’s really kind of bizarre. And then just a myriad of other medications have been thrown at it from antibiotics to antivirals. Something like Acyclovir for instance. You mentioned other infections, kind of taking the opportunity of the person being down and out with immune dysfunction. And then this other infection that they’ve controlled for many years that was a stealth infection, let’s say Epstein-Barr virus, cytomegalovirus, herpes simplex viruses, Lyme, Babesia, all these other tick-borne illnesses. We see flare ups of those in long haul syndrome. So not only are they dealing with all the metabolic issues of the long haul syndrome itself, now they’re dealing with this other pathogen taking the opportunity to flare up and cause its own bunch of metabolic mess.

So sometimes antiviral drugs have helped certain ones, but you can’t throw all these drugs right at everybody. So you got to kind of triage it, figure out what is the most dominant symptoms and how does a specific patient present and then make your best assessment at what might move the dial on them. And then you have to try it. You have to clinically manage and follow them to make sure they’re not suffering any side effects of these things. And generally they’re safe if used right. Paxlovid was another one that was used more in acute COVID to lower the severity and the duration of it. It was thrown at long haul COVID with varying success.

Evelyne L.: What about nutraceutical interventions?

Dr. David Brady: Yeah, we use a lot of nutraceutical interventions, and some of it is aimed at the mitochondrial dysfunction. So all of the normal suspects of helping energy and mitochondrial functions. So anything from nicotinamide riboside to ubiquinone or ubiquinol or CoQ10 as many people know it. A molecule called GG or Geranylgeraniol, works in tandem with CoQ10, high-dose L-carnitine because of that lactic the fatty acid oxidation problems. So L-carnitine will take fats and shovel it into the mitochondria to burn more efficiently as energy. So we see high, we talked about metabolomics. You see high metabolites that are indicative of fats not being burned in the mitochondria, suberate, adipate, ethyl malonate, these other things. So we give high dose L-carnitine. Some of the things I mentioned before when we were talking about vascular dysfunction, definitely things like an arterial cell or a monostroma, these mucopolysaccharides to help the glycocalyx.

But these polyphenols work on a multitude of ways from stabilizing the immune system balance to endothelial dysfunction, vascular integrity, gut health. So again, resveratrol, red wine, polyphenol, quercetin, curcumin, luteolin. People use these a lot in nutraceutical intervention, but melatonin is a great immune modulator, high dose vitamin D. There’s nothing yet that’s curative. There’s things that help us get the patients feeling better functionally doing well. But if anyone at this point says they have the cure or they have the protocol that cures long haul, challenge them to put up your objective information that you indeed have that because I haven’t seen it yet. And I’m pretty much in touch with most of the big players in long haul, whether it’s in research or clinicians and we’re all trying a lot of things and getting some success, but there’s nothing that’s like universal. Oh, this is it.

Evelyne L.: Well, there probably won’t be right, because there’s so many-

Dr. David Brady: I’m hopeful there will be.

Evelyne L.: … mechanisms. Okay.

Dr. David Brady: And here’s why. Because for most of my 30 year career in practice, we’ve dealt with so many patients with chronic fatigue in ME and classic fibromyalgia, chronic Lyme, and all these things where conventional medicine just didn’t offer them much. They just said, “Nothing else we can do for you,” or “Take this Prozac,” or whatever. Back when I first went into practice, they were just overtly discounted and thought of his hypochondriacs and it’s all in their head. Give them a them a SSRI give them some Prozac and send them on their way. That changed over time. And then it got more to be, “Well, we know there’s actually something going on and they’re really sick, but we don’t know what the heck to do about it. So we’re not sure what to tell you.” But now the numbers are so big with long haul syndrome and it’s affecting the economies.

It’s affecting country’s preparedness. Even military can’t. Between the obesity epidemic and long haul COVID, they’re having a hard time finding fit enough young people to even serve in the military. A matter of national defense urgency. That gets the government’s attention. The economic impact certainly gets the government’s attention. It also gets pharma’s attention. And big academic researchers attention because there’s a lot of government money now, and there’s a lot of potential financial reward. If you find the magic pill that cures this, I’m not sure it’s going to be quite that easy. But if you find a viable treatment, and at this point, I don’t care what it is, I don’t care if it’s a pharmaceutical, a nutraceutical, I don’t care if it’s cobra venom, I don’t care if it’s me doing a rain down outside my practice. I just want something that helps these people. But if you get it, there’s a lot of money in curing it.

So with big money opportunities go big money investments into research. I hate to be that cynical, but I’ve seen it play out like that for 30 years. But I think there’s enough research and attention being paid to this at the highest levels that I think there’s a much higher chance that you’re going to get something coming out of the research pipeline, particularly with all the new science we can do, and looking at metabolomics, proteomics and trying to uncover what a underlying mechanistic foundational things that are targets to go after. I’m hopeful there’s going to be a cure and fairly soon, and I’m hopeful when there is, it’s not only curative or significantly impactful in improving long haul, but it will also be a big answer for people with chronic fatigue and ME and classic fibromyalgia and chronic symptoms of Lyme.

Because I really think most of this metabolic wreckage and havoc, this dungeon of bad metabolism that these people fall into, it’s a common dungeon. I just think there are different trap doors to get into it. There may be variations of it, but I think fundamentally you can get into this mess from having Lyme, from having Babesia, from having SARS-CoV-2, from having bad Epstein-Barr virus, whatever it may be. So I’m hoping whatever the ultimate therapeutic agent that really moves the dial in these patients, that that positive effect will be conserved across all those patient populations. And that would be transformative.

Evelyne L.: That would be. All right, I’ll change my stance to, I’m hopeful

Dr. David Brady: And I can’t guarantee that, but I’m hopeful. Pharma these days, by and large is not in the business of making things that cure things. They’re in the business of making things that manage things.

Evelyne L.: Right.

Dr. David Brady: It’s a better business model if you have to buy it every month to get the effect. If you take it once and it cures you, not that great. There’s been some instances of that recent in the last bunch of years of hepatitis C treatments. But you saw when they first came out, they were hundreds of thousands of dollars.

Evelyne L.: So in the meantime, when you are working with patients, how do you determine, do you it based on say, what symptom is bothering them the most? And then you’ll try a few things for that. And then-

Dr. David Brady: It’s partly-

Evelyne L.: … sequence it that way.

Dr. David Brady: It’s a lot of things. It’s their medical history background, and most we can tell about their genetics and lineage and their risk factors. It’s any preexisting conditions they had coming into it. But largely it is the triaging of their symptoms and what’s wrecking their life the most. What variation of long haul do they have, if you will. But also, what does the data say? What do the metabolomics say? What are the proteomics say? What are the genetic SNPs say? What do the inflammatory markers and the cytokine say? So that’s definitely a big part of it. But in the end though, it’s still, you use all those things to make your best judgment, but then you have to make a therapeutic intervention. And the proof’s in the pudding, do they get better? Do they feel different? And we try to not only use, “Hey, how you feeling, “but objective assessments.

Repeating labs that were abnormal or using questionnaires that have had some validity studies done on them, on functionally, how they’re doing. That’s really important stuff. And we’re starting to use with some significant success, regenerative medicine therapies. So we use various injectable peptides, exosomes, stem cells. Some people are doing plasma exchange that’s used even very conventionally in autoimmune disorders to kind of clean out the blood, if you will, of some of these antigens that are creating this storm. There’s different variations of plasma exchange and amino and different plasmapheresis, some that’s done in the US, some variants done overseas.

Patients are traveling a lot to get this treated, to get regenerative therapies that may not be available or approved in the US, whether they’re different types of stem cell treatments, different types of plasma pheresis treatments. And I’ve been in contact with a lot of patients who’ve had a lot of that done. Many of them have gotten better, some of them have gotten better, and there’s been a stickiness of the improvement. Others, they slide back or have to keep getting these therapies. Some people don’t get better from them at all, and they’re not cheap.

Evelyne L.: Yeah. I have one more question about long haul COVID for you. I want to go back to POTS for a moment because I do get asked about it a lot. I know you mentioned the medication part, but what do you do on the nutraceutical side for that? I know I suggest electrolytes-

Dr. David Brady: The biggest thing-

Evelyne L.: I know that’s not the only thing-

Dr. David Brady: Lots of salt and electrolytes and hydration are the biggest. But a big part of POTS is also affected by, well, I just mentioned one hypovolemia, not getting enough hydration, not having enough water volume in the system when you stand up to keep your blood pressure up. And electrolytes play a big part of regulating that. Most of them need salt, not only electrolytes, but even more salt in their diet. I probably have cardiologists all over cringing here, listening to that because of the hypertension thing. But these people are not hypertensive, they’re hypotensive.

And nutraceutical, adrenal glands have a big part to play that whole right autonomic response and keeping your blood pressure up, especially when you stand up real quick. So things that improve adrenal function, so adaptogenic botanicals, and with these patients, they tend to be in a hypervigilant kind of state. So I tend to use adaptogens that are not overtly stimulating. So instead of, rhodiola and panax ginseng or Chinese or Korean ginseng, we will use things like ashwagandha, which is Withania Somnifera, it’s a little bit sedating. American ginseng or panax quinquefolia. We use German chamomile, just kind of things that are good for adrenal function, lots of vitamin C, enough phosphorylated, B vitamins, all important.

Evelyne L.: Thank you. We love to ask every guest on conversation some more personal questions. So transitioning here, but what are your top three favorite supplements?

Dr. David Brady: Oh, top three. If I was stranded on a desert island what would I want with me?

Evelyne L.: Yeah.

Dr. David Brady: That’s a difficult one. Because that puts it in a different context, because I’d be worried about getting a cut and getting an infection and things like that.

Evelyne L.: Okay then no.

Dr. David Brady: It’s just living in the day to day world right? I would say definitely vitamin D, because I’ve just seen too much data on it, more than a vitamin. It’s a hormone, it’s an immune simulator. So important to immune balance and bone health and a million other things. I think as of now, we know it interacts with over 500 gene targets or something like that. So definitely vitamin D. I would probably say overall, I would say some form of fish oil, fatty acid type of thing, just because of its diversity of effects. It’s mildly blood thinning. And we didn’t get into that, but the whole micro clotting, vascular end of it.

So we use a lot of things like nattokinase syrup, peptidase, all these different kind of natural enzymes that can thin the blood a little bit, almost act like a baby aspirin. Sometimes we need to use stronger anticoagulant agents in some patients based on what the testing says on their bleeding times and other coagulation factors. But things like fish oil can be very, very helpful in that. So I said vitamin D, fish oil, I don’t know. Can I pick a multi, some sort of multi-vitamin? I don’t know, yeah.

Evelyne L.: Sure.

Dr. David Brady: Yeah. But a good one.

Evelyne L.: Yes. And what are your top health practices for your personal health and wellbeing?

Dr. David Brady: I really think the two most important things. Well, let’s say the three most important things, then I’ll land at three. It’s got to be eating a good whole fresh food diet. I mean, you can’t eat modern junk. Garbage in, garbage out. And I see a lot of patients make this mistake. You can’t exercise and yoga and meditate your way out of a crappy diet. You got to eat real whole good foods, and you got to eat a diversity of foods. You got to eat in a decent macronutrient balance. If you just eat a bunch of science foods that you can’t pronounce the chemicals on the label or through convenience foods and always pre-prepared foods, you’re just not going to be healthy. So not that I’m perfect, not that I don’t have my indulgence is, but I try to eat real whole fresh foods.

Foods that you could have got in that basic form a hundred years ago. It may not be the same of the way they grow crops and all that. I get that, but organic when I can. But just whole real food. So that’s number one. Number two is sleep. If you’re not getting enough sleep. But it’s not only the quantity of sleep hours, it’s the quality of the sleep. So all these wearables and things, I think the biggest advantage into actually is the sleep metrics. So being able to show people, “Hey, you’re not getting into deep delta wave sleep. You’re not restoring yourself at night.” You may be sleeping 10 hours, but you’re never getting into delta wave sleep. You’re not restoring yourself.

And what’s one of the most common complaints of people with chronic fatigue, long haul, unrefreshed sleep. They can sleep 14 hours. They get up, they feel like they didn’t sleep. They’re not going into delta wave restorative sleep, so they’re never restored. So their tissues just aren’t regenerated. So good diets, sleep, and then it’s kind of cliche, I know, but trying to control your stress level and realizing that only you have the capability to modulate and control your response to external factors. So someone else’s bad behavior or something they say to you doesn’t have to command an unhealthy response from you. And listen, it’s hard for me. I’m from New Jersey.

I’m an Irish guy from New Jersey. It doesn’t take much. But as I’ve gotten older, I’ve really learned that you really need to… You’re responsible for how you react and control and react to external circumstances. And you just get all mad about everything all the time. It’s not good for you. You got to put things in perspective.

Evelyne L.: Last question for you. What is something that you’ve changed your mind about over all your years in practice?

Dr. David Brady: I’ve changed my mind a lot about my ability to be right.

Evelyne L.: Care to elaborate on that?

Dr. David Brady: I think doing what we do and kind of being in the position, doctors almost have to have that default ego to that we’re smart. We always know what’s right. We’ll figure it out. And you need that, and it’s important, but it’s also important to maintain some humility in it and realize that sometimes you got to just look at it again from a different lens that we’re dealing with really complicated stuff. And it’s getting so complicated now with omics and things, you can’t even all parse it yourself. I use medical informatics platforms and all kinds of things to chunk up and we’re going to be using AI. We already are using AI, but you got to humble yourself and check your ego at the door and be able to look, I’ve gone into patients who I’ve seen for a long time, like really chronic complex injury patients or complex disorder patients.

And I’ll go in and I’ll put out my hand, shake their hand and go, “Hello, Mrs. Jones. I’m Dr. Smith.” And they go, “Well, I’m not Mrs. Jones. And you’re not Dr. Smith, you’re Dr. Brady.” “Yeah. But today I’m not Dr. Brady. Today, I am Dr. Smith, and you’re a whole new patient. And we’re starting this all over again because what we’re doing is not getting you there.” So sometimes you just need to talk to a colleague. You need to think that maybe I didn’t look at all this right. And go back to the beginning. And I think when you’re younger and more cocky in practice, you probably don’t do that as much.

Evelyne L.: I like that. Thank you for sharing. Yep. Well, David, this has been a pleasure. Thank you so much-

Dr. David Brady: Likewise.

Evelyne L.: … for your expertise. I learned so much from you, so thank you for everything that you do.

Dr. David Brady: You’re welcome.

Evelyne L.: Thank you for tuning into Conversations for Health. Check out the show notes for the resources shared on today’s episode. Share this podcast with your colleagues, follow, rate and leave a review wherever you listen. And thank you for designing a well world with us.

Speaker 1: This is Conversations for Health with Evelyne Lambrecht, dedicated to engaging discussions with industry experts, exploring evidence-based, cutting edge research and practical tips.