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We are still suffering through this quagmire of existence with the Delta strain of COVID-19 on the rampage. Vaccinations are clearly proving to be a remarkable shield to hospitalizations and deaths, but 99% of the hospitalizations are occurring in the unvaccinated. So, unfortunately, the message is really still not being well received by enough people.

Today’s podcast will focus on an issue almost as frightening as dying from COVID-19 and that’s living with the long haul symptoms of COVID-19. In my medical practice, the only thing that has prepared me to care for and help these patients is my experience treating chronic fatigue syndrome for over two decades.

These two syndromes are very similar in their presentation and the suffering that they impose on the afflicted patients. My guest today, Dr. Amy Proal is a microbiology researcher at the PolyBio Research Foundation, and she’s been studying and has published numerous articles on chronic fatigue syndrome, also called myalgic encephalomyelitis, and is now applying her expertise to studying long haul COVID patients as well.

Dr. Proal has focused on the reactivation of viruses as a possible explanation for these symptoms in both of these conditions. So, it’s with great pleasure and interest for me that I welcome Dr. Amy Proal to the podcast.

I always like to start out with a little background on my guests because I’m always fascinated with how people get to where they are. And I was looking at your bio and I saw that you studied biology at Georgetown University, and then you went to Australia for your Ph.D. in microbiology. So, my first question is why did you go, as the Aussies say, “down under,” to get your advanced degree in microbiology?

Dr. Amy Proal:

It actually just happened to be the case that there was a mentor there who is friends with one of the researchers I already worked with, and they were really open to some of the existing actually papers or talks I’d already given.

And they were very welcoming and I thought it was a good program. And I thought it was cool too.

Dr. Dean Mitchell:

Yeah, it’d be abroad. It is. I trained in Israel for my medical studies and being in another country and especially with great scientists and physicians, in so many ways, it was a great experience for myself. I mean, of course, you can get great training here in the United States, but it brings a little added perspective. So, I was kind of interested. And I know it’s interesting, I think in PhDs, it’s really interesting. It’s like who your mentors and advisors are, are so critical as they are in every field, but especially now when you’re really working with somebody so closely that if you get a great opportunity, wherever it is in the world, it’s obviously worthwhile to take advantage of.

Dr. Proal’s Background & Personal Experience with ME/CFS

Dr. Dean Mitchell:

All right. We’re going to go into one other sort of background question. I know I saw it was really interesting to me that you’ve been doing research on chronic fatigue syndrome, myalgic encephalitis for such a long time. And especially, and I say this, especially with so many other institutions had given up, even the NIH, I think it was Steven Strauss who was looking at, I still remember this. He was pursuing about whether the Epstein-Barr is involved with chronic fatigue and so many researchers said, you know what? This is a dead-end for my career or whatever, but you actually clearly from your papers, continue to work, and seek some answers. So I’m just curious why you persisted in that?

Dr. Amy Proal:

Yeah, well, that goes into my personal story. I might as well describe that.

So I actually got diagnosed with ME/CFS myself in 2004. So that’s part of the whole way that I began to study the condition. So I was a college student at Georgetown University and in fact, there, I had an amazing mentor already. I was a pre-med student at the time. His name was professor Douglas Eagles. And when I was young, I got a lot of infections as a child. I don’t know why. I was vaccinated for it with MMR, but I got measles, mumps, and rubella on three separate occasions and was hospitalized for them each time. And I have also got Scarlet fever, a really bad case of pneumonia. It was very strange. It was a slew between the ages of three and five of really severe, almost encephalitic type conditions.

And I have a fraternal twin sister and she didn’t get any of those. And then after that, I was fine. So it seemed. I was really a healthy kid and very athletic through high school, tennis team captain, and all kinds of stuff. No problem. Then when I was at college at Georgetown, I started to feel a little strange, had trouble sleeping, had headaches, but every time I went to the student health center, they just told me you’re fine. I mean, it got a little ridiculous, the classic story of ME/CFS where after a while I really tried to up and say, I really don’t feel well. And I did get, you’re anxious. Your pre-med courses are too hard for you, which of course they were not. I was doing just fine. The kind of stuff where I was referred to psychiatric care if that. And then the last year of college in 2004, for me, at the very end, I got Mono Epstein-Barr virus and infection, and that really put me over the edge and I absolutely tanked so badly.

So I went to what really could be described as bedridden. I just lost all function, could hardly speak, was only able to be in a bed, could not tolerate almost any light, anything.

So I was very ill. And then from there, over time, and that’s part of my story. I began to think, well, did these infections that I’ve sustained as a child or, the Epstein-BARR that put me over the edge, do they matter? It seems like that would matter in my case.

I don’t know what else happened to me. And so even from my bed, to the extent that I could, I began to look into microbiology and just to look at the impact of chronic infection. I’ll be honest, I was a little, you could say, biased at the time.

I felt like I had such ongoing flu-like symptoms and so many continued symptoms that I knew Epstein-Barr virus, for example, was a persistent virus because herpes viruses by definition do not clear. So I was really interested early on in persistent infection. And whether in some sort of simple scenario, maybe the viruses that had contributed to my condition to my body had not fully cleared. And so in that capacity, I began to use totally experimental protocols. Anti-viral drugs and a treatment that seeks to stimulate the immune system post antibiotics in case there could be a bacterial component. I did this all experimentally and based on some protocols that were out there. Interestingly, you mentioned Dr. Jacob Teitelbaum, before that you interviewed separately for a podcast. And he was my first doctor.

Dr. Dean Mitchell:

Really?

Dr. Amy Proal:

Yeah. I was his patient.

Dr. Dean Mitchell:

Well, he went through it himself too. I always like to throw this line out when I’m talking to the public and they smile and I take it from Bernie Siegel, the Yale surgeon, humanistic doctor, when he said it, let me make sure I get this quote, right. He said, “Doctors are the tourists of the land, but the patients are the natives. They know the lay of the land, and you’ve been there and you’ve walked the walk. Who knows it better than you, what you’re experiencing and feeling?” So, yes.

Dr. Amy Proal:

Right. So even Dr. Teitelbaum was one of the people who kind of helped me in these early stages and I did begin to slowly improve. I published a paper on one of the treatments that I use. It’s difficult because it makes you feel worse before you feel better. It involves Herxheimer, which is a reaction in which if the pathogen is targeted, there’s a battle between the immune response and the organism. So it’s a difficult treatment, but it did help in my case. So I try to put that out there, put a case series out there. And beyond that, then as I started to improve, I became more and more interested in the phenomenon. And as part of what I was doing is I reached out to a lot of researchers at the time who were doing cool work on persistent infection. And in fact, researchers who had even really done good work on that topic in the 60s and 70s, for example, there was a researcher named Gerald Domingue who was an emeritus professor at Tulane. And he has these incredible, they just sit there in some sense, but there are incredible papers.

For example, one called Bacterial Persistence and Expression in Disease, which just goes into so much work in which, granted the tools that they had in the 60s and 70s for finding organisms and tissue were not perfect, but even then, if they really looked, if they got tissue samples from patients at autopsy, they were seeking to really find an organism in patients they were finding it and there were beautiful pictures, beautiful diagrams. So for example, I sought him out, we met over Skype, he taught me some of his methods, some of his thinking, and I grew from those, I’m going to call them old school researchers.

And then I was given the opportunity from my old mentor at Georgetown to visit the J. Craig Venter Institute that was running one of the earliest programs on prokaryotic sequencing. So we were moving into this new era, which is still part of what my work focuses on in which before the 2000s, most of the microbiology and biology work done was with staining, was with culturing and Petri dishes, which there’s still great work out there.

Dr. Dean Mitchell:

Right.

Dr. Amy Proal:

But we now understand that culturing, for example, a bacterial pathogen in a Petri dish, really only a fraction of organisms capable of persisting in the human body will be identified in that fashion. Some just don’t grow.

Many just don’t in a Petri dish. So we were missing a lot of organisms.

What happened is around the 2000s, the human genome was starting to be sequenced. That was Craig Venter, who sequenced the first human. And that was using computer-based technologies wherein simple terms you pull the genetic material out of a sample, and then you know that the sequence of a virus or bacterial pathogen, you know its genetic sequence.

And the computer can go through the base pairs of that and match those two pathogens in an organism, in a sample. Those tools revolutionized our ability to find organisms in the human body.

Dr. Dean Mitchell:

Well, just to jump ahead also, I can’t wait until this test is more commercially available. I read about it. I can’t believe it, I think it’s coming out of California.

But it was essentially one of the most difficult things as a doctor, especially in a hospital, is you have a patient that comes in acutely sick, doing blood cultures, you’re sending off for antibodies for different viruses, but apparently, I think there’s this test. I’m not sure again if it’s based on DNA sequencing or whatever, but they basically could tell you the pathogen based on the DNA sequence, right. I forgot the name of the test, but so it’s almost like the doctors don’t have to be such a genius, infectious disease, super specialist to say, oh yes, this is brucellosis or some unusual pathogen that would respond to an antibiotic if it wasn’t overlooked. Am I right on that?

Dr. Amy Proal:

I’m not sure. There is a company who I have great respect for. It was partially founded by Stephen Quake and it does, it uses a type of cell-free DNA sequencing, which is a method to identify-

Dr. Dean Mitchell:

So funny. I have his book here,

Dr. Amy Proal:

Perfect.

Dr. Dean Mitchell:

On Corona. He’s a smart guy.

Dr. Amy Proal:

He’s smart. Yeah exactly. So, and that’s great. It is still I’m going to say a challenge for clinicians. And this is one of the things that we face in research as well,

Because what I’ve come to realize over time in most researchers who study persistent pathogens, especially those that get involved in severe cases of chronic disease, the severe ME/CFS cases, they don’t necessarily persist in the blood or even in body fluids because that’s where the immune system is most robust and most likely to recognize them. So in the acute stage of disease, the early stages, they may be in the blood.

And so, for example, when you’re testing, especially for something, let’s say Borrelia and Lyme disease, acute Lyme, and the testing is far from perfect. But the earlier you test, the more likely you’re likely to find the organism there,

Or time though, it can be difficult because most pathogens, almost all of them have evolved mechanisms to, in simple terms, hide.

Dr. Dean Mitchell:

That’s a great point.

Dr. Amy Proal:

Yeah.

Having an Infectious Disease But Appearing Healthy | Harboring Dormant Infectious Diseases

Dr. Dean Mitchell:

I want to get into some of this with you because you’re hitting so many important things and, and what frustrates doctors and patients especially mine, which I wasn’t even playing, I didn’t know if we’d have time, but I want to get into that maybe later on.

I’d like to move on to something because I want to really understand this. And again, my background when I did my training was infectious disease, immunology, and allergy. And I was always fascinated with infectious diseases. It’s probably what drove me into medicine. But I want to understand something that I’ve always grappled with. It’s obviously common for all of us to be exposed to viruses. And Epstein-Barr again is one of them. There are people who don’t even know that they have been infected with Epstein-Barr. So many people have had exposure and have, if we do blood testing, have antibodies, IgG antibodies. Obviously herpes simplex, common cold sores.

It’s common. A lot of people may never have any manifestations like the sores, other people are prone to them. And of course, the one that causes more concerns is all before COVID and everything was herpes zoster, the chicken pox virus. Now I wonder if you could explain to me, cause I, as I said, this is what I grappled with.

How does a virus stay quiet, alive in a dormant cell, whether it’s neurons or whatever the tissue, when I guess I always picture viruses, obviously like, COVID that, what’s the best word it’s like parasitic almost in a, it has to infect new cells to stay alive? Is it just this class of viruses? Just so our listeners should know, Epstein-BARR is in the herpes virus class of viruses. Is it, are there other ones, but what is, how does a virus stay alive in tissue if it’s not infecting other cells?

Dr. Amy Proal:

Yeah, that’s a good question. And you’re right. And I think that’s one of, first of all, one of them, the fact that more than 90% of the human population harbors a herpes virus. So obviously,

There are people who appear healthy and have these viruses. So the question then becomes, when we start to notice that they’re potentially active in patients with chronic disease, what’s going on there. And so first of all, that brings us to the first major consideration, which is in a lot of diseases, and this has happened in ME/CFS as well, people say, “Oh, well, a person with a ME/CFS has Epstein-Barr virus, but so does that healthy person, so it must not matter.” And that is a dumb argument.

Because really, the question that we need to be asking is what is the virus doing? What is it doing? And what viruses do is express proteins, and this happens when they’re more active. So in simple terms, and this goes to your question about virus persistence viruses can remain often in an infected cell and they don’t replicate very much, they’re in a dormant or latent form. And the way that that occurs is that because they’re kept in check by the immune system.

Dr. Dean Mitchell:

But they survive in the cell? They’re intracellular, they’re inside the cell, they’re not like bacteria floating around in the blood and tissue in the bloodstream. So let’s just say, for example, with hepatitis or whatever, so that hepatitis B or C or whatever it is too, it’s just living in that liver cell, just hanging out. I mean, they can survive the RNA or DNA, whatever the cause of the viral disease, it just sits there. Okay.

Dr. Amy Proal:

Enough, yeah. There can be some cases, the intracellular…

Dr. Dean Mitchell:

They sort of coexist with the… Sort of like a symbiotic relationship, I guess. It’s not causing a problem, but it’s just kind of sitting there on the sidelines.

Dr. Amy Proal:

Enough, right? And what some of the viruses do as well is they’ll modulate the gene expression of the cell, and they’ll actually keep the cell from undergoing a pop ptosis, which is a form of cell death. So sometimes they’ll actually extend the life of the cell they live in to make it a more compatible home. So there are tactics that these viruses use to be able to sort of, once they get inside of well-located immune cell or it can be a neuron as well, somewhere in the body, they can try to prevent that cell from dying as quickly. They can just basically in simple terms, they can just hang out. Even then though, latent virus, latent is when they’re most controlled, even then sometimes express protein a bit.

Dr. Dean Mitchell:

They’re there, but the immune system knows that they’re there. So whether the immune system starts to go into attack mode or say, okay, well, I’ll leave you alone right now. You’re not causing enough irritation for me to keep you in check or do something.

Dr. Amy Proal:

And the immune system is actively containing the virus as well. So this is one of the things is if a person has a robust enough immune response, for example, we express interferon. They’re a type of cytokine. And they’re the most anti-viral cytokine that we have. So they target viruses in a number of ways and Bose interferon helped keep herpes viruses in latency. In other words, as long as those are being expressed by the immune system, it’s difficult for herpes virus to activate more in the cell that it’s in because the interferon will not get back down.

Dr. Dean Mitchell:

You know, what’s interesting. I’m going to take it from my clinical experience. I trained my residency and then my fellowship, and then late 1980s, early 1990s during the AIDS epidemic. And I’ll never forget, as a resident, you’re mostly doing. You’re giving medications, doing blood, you’re not supposed to be the thinker, but I couldn’t help but think it to myself at that time because it fascinated me. Where were these patients with AIDS catching toxoplasmosis? Where would they catch cytomegalovirus? And it wasn’t really, till years later, it dawned on me that these patients harbored these viruses. And they weren’t catching it from somebody else. It was just that their T-cell counts were so low that essentially their immune system said surrender. And these viruses rose and also caused these opportunistic infections. But again, that was a pretty dramatic example of the immune system taking a major hit.

Dr. Amy Proal:

It’s dramatic, but it’s important because really there’s a similar trend in a lot of chronic diseases where, and not everyone harbors toxoplasma, but actually it’s fairly common. You know, it’s not many, but 11% or more of the US population.

Dr. Dean Mitchell:

Yeah. If you have a cat you probably have Toxoplasmo.

Dr. Amy Proal:

Yeah. toxoplasma, which enters the central nerve, which puts it in the brain in the central nervous system.

Dr. Dean Mitchell:

I know. Or when I used to see cryptococcus. Again, I’m throwing these names out to the listeners, but these were unusual causes of meningitis, but we were seeing this on a regular basis. There was no way that all these patients were gathering and infecting each other with cryptococcus. It couldn’t be.

Dr. Amy Proal:

And honestly, another consideration is that a lot of these pathogens are passed from mother to child in the womb, right? So they’re inherited. So you end up you can just be born with CMB. You can be born with a virus that is inherited in the womb, which is a consideration. And I do personally think, I wonder, I’m not sure. I think people may harbor more of these pathogens than in previous decades, just because a global lifestyle does subject people. You travel to one country, pick up a parasite over there, you interact with someone and you get a herpes virus. We don’t live locally, and so there is potentially more chance for people to be getting some of these kind of growing somewhat pathogen load that can be exactly problematic under conditions in which the immune system struggles.

And that’s one of the things that’s similar to HIV AIDS is that in these diseases and even in ME/CFS, one of the trends we look at is you may have one infectious pathogen. For example, let’s say Epstein-Barr virus and it might not be a problem yet, but let’s say it’s able to express one or two proteins. Sometimes those proteins can interfere with the immune response. So every virus, the herpes virus is knocked down CD four T cell counts, CDA, depending on their activity, the immune system may become somewhat more slowed because you have that one pathogen. Now, if you get another infection, it might make it a little easier for that to stick around. For example, an intero virus, which is another pathogen, and that’s really implicated in the ME/CFS disease process. That virus has been found in gut reservoir samples from patients, even in two brain autopsy studies from patients with MECFS directly in the brain in the brain stem.

So each virus or pathogen that the person acquires can stifle the immune system in a way that makes it somewhat easier for each of the different hits to actually begin to cause more problems, a little like a snowball rolling down a hill where maybe you have the first thing and you’re alright, but as you accumulate more and the immune system becomes more way down each of the organisms. Then of course, those you can factor hits in that are not just direct infections. For example, say a person’s exposed to mold and they become populated with micro toxin or they have a really stressful event or they have an injury, all of that, anything else that’s compromising the immune system that’s debilitating. It can feed into that picture in which the pathogens begin to act more and express more protein, become more virulent and collectively add up to jive symptoms.

Dr Dean Mitchell:

Let me ask you this too. What a lot of times too, with viral infections, we tend to think of the tissue that it targets with human papillomavirus, HPV, that obviously could be the back of the throat or in women, the cervical area. Hepatitis the name lets us know affects the parasites, the liver. Epstein-Barr seems to be sort of a general thing, is that because it affects the bone marrow or what? It doesn’t seem to have a specific, well, maybe the spleen, but doesn’t really seem to have an organ.

Dr. Amy Proal:

I’ve seen BARR virus seems capable of persisting in most human tissue types. There’s a team in Japan that actually collected tissue from healthy patients at autopsy. And so these were patients who died from accidents or events that were not necessarily chronic diseases and even in their healthy tissue that they harvested. I’d have to look at the paper, but you can see that they’re looking at an ovary of thyroid blood vessel wall and EBV is in a significant number of those tissues and these are healthy individuals. So it seems capable of infecting a wide range of tissue types. Yeah.

Dr Dean Mitchell:

There is no test or maybe from some of the work you’ve done, that helps us get an idea of sort of an immune threshold. Whether it’s either an increased viral load or lower immunity as with AIDS or something else, we’re looking at CD four CD eight cells, stuff like that. Is there anything that you’ve uncovered from your work that would help a clinician be tipped off saying, Hmm, something’s going on here?

Dr. Amy Proal:

It’s a tough one because a lot of what’s happening in CFS is probably not happening in the blood. That’s one of the biggest problems with it. There was actually just a conference today on ME/CFS. It was a big trend, which is that the pathogens if they are persistent, impact the central nervous system the most, that’s the most likely scenario and there’s data suggesting that especially for intera virus. And so what we’re looking at, in fact, the herpes viruses are neurotrophic pathogens, which means that they infect nerves preferentially and their active lifecycle requires movement through nerve. So we, for example, are interested. I work with a researcher, Michael VanElzakker at Harvard MGH. And he wrote a paper several years ago, for example, that the Vegas nerve, which is a very important nerve.

So he actually hypothesized that in some patients with ME/CFS, the vagus nerve could be directly infected. We don’t, in other words, the nervous system may be infected. And we know, for example, that often patients can have gut reservoir of entire virus. And then Vegas may be a conduit by which a neurotrophic pathogen can reach the brain or central nervous system. So we’re very interested in, it doesn’t have to be.

Dr Dean Mitchell:

No, it’s interesting. I mean, it’s… The other question I was about to ask, jumping around a little bit, but when the CSF you just always wonder besides fatigue, why these patients complain of brain fog and as we’ll get to with COVID like why? And I guess you sort of started to answer that because this is directly affecting the brain cells. I mean, it’s the type of tissue inflammation going on there. I mean, it’s the biggest thing that people complain about aside from the fatigue, they’re like, even if I’m laying in bed, I can’t concentrate. I can’t even do remote work. Did you experience that if you don’t mind my asking you that yourself?

Dr. Amy Proal:

Absolutely. I remember being in class in one of my pre-med classes and the writing on the board just started gibberish. I’ve been there, it’s really scary. And it’s really disorienting, but yeah, well, what we look at is, what we’re interested in, of course we were doing more research on this. This is all part of, we started a nonprofit called poly by research foundation. And we were slowly working on a research program that goes in this direction, but we’re very interested in the dorsal activity of the dorsal brainstem in patients with MECFS and also with long COVID because the dorsal brainstem contains nuclei that control, first of all, what’s called the sickness behavior response.

And so what that is, is that the vagus nerve, again, branches throughout most of the trunk organs of the body, these chemo receptors that send inflammation, and that can be inflammation from an ongoing infection from gut microbiome issues and whatnot. And as long as there’s a pro-inflammatory environment, it will convey that to the dorsal brainstem, this area of the brain. And what that does is that signaling causes you to feel sick. It causes the feelings of the sickness of Malays, and that’s an evolutionary response to say, that’s why, for example, when you get COVID and it’s in your lung, let’s say Vegas picks it up. That’s why you go, you feel sick, you feel fluey. The virus doesn’t necessarily have to be there, but the Vagus is saying this sickness response is important.

Dr Dean Mitchell:

Yes, it changes your temperature and your pulse and all that stuff, right. To get in a more like recovery mode. Don’t push too hard.

Dr. Amy Proal:

Infection, whether it’s in the periphery or other issues that circuit doesn’t stop that continue a feeling of sickness and malaise continues. And the dorsal brainstem that has that, where the Vegas innovates also has a nuclei that are really important for autonomic nervous system functioning and other nuclei for pain and nauseous. So there’s this small area that over where these important nuclei control symptoms are the primary symptoms of MECs and actually long COVID as well, autonomic dysfunction, sickness, behavior, response, malaise pain. And so we’re interested in the Vegas two dorsal brainstem circuitry, and what can activate that, and what also matters is in that area of the brainstem, it’s dense with micro glial cells.

Dr Dean Mitchell:

You know, it’s interesting you’re saying all this, because when I had interviewed Kevin Tracy, about two years ago, I know he’s very involved with COVID now. Cause he’s also like a cytokine expert, but you know, what was one of those fascinating things was that he was dealing in his research, he developed this electrical stimulation unit to help people with auto-immune disease, which was fascinating. But the thing was, was that in a lot of these auto-immune disease too, besides the horrific joint pain and everything, they just feel so fatigued. I mean, it’s just that’s the initial complaint. So I do agree with you that the Vagal nerve it’s interesting could be one of the Trojan horses of this whole illness.

Dr. Amy Proal:

Do you think that’s one of the things that the infections and whatnot end up stimulating, and it becomes part of the disease process because as you mentioned before, we could go back to Epstein-Barr virus as an example, I’ve seen Barbara drives cancers. So in some case, it’s a oncogenic virus. Google it, Epstein-Barr virus can absolutely drive a tumor. So the question is, why is it doing what it’s doing in a particular patient? Why is it driving cancer in one person and perhaps other symptoms in someone else? And that depends your human genetics play into that. All of us have different human genes, human variants that also affect what pathways viruses can explore it and better take advantage of. But we do think that in ME/CFS viruses are probably stimulating this sort of vagus to dorsal brainstem circuitry. And that’s part of why you get some of the autonomic and sickness.

Dr Dean Mitchell:

Don’t also viruses get into our DNA? I mean when you get an infection, I think what they’re finding and stuff like that too. I mean, there’s so probably some of the nonsense what they call it, I guess, areas of the Tino or whatever, probably infections that people had hundreds thousands of years ago. And just it’s part of the thing.

Dr. Amy Proal:

I think you’re referring to human endogenous retroviruses and that’s fascinating. And we evolved with retroviruses that were incorporated into our genomes over time. This is looking at the course of billions of years and for a long time, those incorporated retroviruses they’re part of our genomes now, technically. So they’re like, oh, people are like, oh, then it’s not a problem, but it actually may be the case that they can activate and act more like the retroviruses they once were, especially if there are other infectious or inflammatory insults that sort of bring them. So that’s a big topic right now and lupus and other conditions is kind of…

Dr Dean Mitchell:

The reason being like, when you quote say hereditary, why is it in families and stuff like that too? And of course we say genetics, but then you start looking at… Anyway, that’s another whole fascinating, I’m going to ask you a clinical question. And I know you’re really not a clinician, you’re a researcher, but you

And what I find also, and I had to revisit this myself. Because patients will always come in, and I see chronic fatigue patients in my practice. I’ve been doing this over 20 years. They’re like, “I have Epstein-Barr. I have Epstein-Barr.” And then I’ll sometimes look at the bloods and I’m like, “Well, you just have exposure, like everybody else.” And what I found to be a really great paper was, in the same article of the Wall Street Journal that I found your name, they had David Hurley and I guess Geoffrey Gold published a paper regarding COVID associated with Epstein-Barr reactivation. So I wanted to ask you, if you’re comfortable with this, I just want to make sure I’m getting this right.

When I order routine bloods to find out if my patient has chronic fatigue, I’m getting the Epstein-Barr. They usually give you a panel. The viral capsid IgG, which just indicates someone’s been exposed, at some point, right? We don’t know when, but they’ve had some exposure. Epstein-Barr virus capsid IgM, which, I don’t know, it’s like an antigen and the antibody or something, I guess? Because it’s capsid, but that’s also called I think sometimes BCA IgM. Is that correct? Are you familiar with that? Yeah. Now that would either indicate obviously an acute infection or… well actually that indicates just an acute infection. So that’s not a reactivated infection. Are you familiar with that?

Dr. Amy Proal:

Yeah, I’m actually not totally sure how to interpret the clinical tests very well. But I do know that if you see IgM, that you probably are looking at a virus, the Epstein-Barr, that’s more persistent.

Dr Dean Mitchell:

Yeah. Because what Gold said in his article, I guess this is the thing I want to make sure that, again we’re going to get to the COVID in a few minutes, that has to do about reactivation, is that when they see the viral capsid, the antigen IgM, and they see the early, it’s a deceiving term, the early antigen D IgG. And if they get serum EBV DNA, which I’ve never seen in a blood test that I ordered panels, then they’re saying there’s reactivation. Because as I said, this gets way… you have this whole spectrum of patients coming in saying I have chronic fatigue. I have chronic fatigue and I have EBV, and I, like anything, if I was evaluating a patient with hepatitis, I really want to know is that… because chronic fatigue, and I tell this to patients and we’ve talked about this in my other podcast with Sarah Myhill and Jacob Teitelbaum.

I mean, it’s a syndrome, meaning a whole bunch of conditions run together, but there are probably people that it’s infectious. There are probably other people, it could be endocrine, or some people really autoimmune. I mean it’s part of my detective work. But I do treat people a little bit differently depending on what I think their underlying… I mean if I had heard a patient like you, I would have focused more on the infectious aspect in boosting your immunity. In fact, I use gamma globulin for patients and have had some nice success with that.

So one of the thoughts too, in all your work and again, maybe it’s not what you’ve really focused on, but there’ve been the people who say Emmy CSF is mitochondrial dysfunction, and there was also a doctor in Berlin, Dr. Carmen Shebergan I think, I’m just saying. She’s in Berlin. She believes it’s auto-immune and she’s found some auto antibodies. If you were in a debate, if I had you on a panel with them, you’re going to make your case versus theirs or it could be both.

Dr. Amy Proal:

I think… and I’ve had a couple of conversations with other researchers in the ME/CFS and long COVID communities, and one thing that we need to understand, the autoantibodies, which is what most of these teams are picking up on, to deem the condition purely auto-immune, you have to move into a paradigm now in which the human body is understood to not be sterile. And I mean not sterile by huge, we’re talking trillions of organisms in the human gut alone. And there are bacteriophage, which are viruses that infect bacteria. There are 10 times more of those bacteriophages than there are bacteria in any community. They’re all interacting, and now we realize as we were turning those computer based tools onto more and more human samples of blood, tissue types, the bladder, the lung, the pancreas, you name it. They’re not sterile. They all harbor interestingly, these organisms, most of human tissue and blood is not sterile.

Now within those, it’s interesting that what I call the dominant pathogen, the Epstein Barr, the Antero viruses, they’re members of those communities to a large degree. And what can happen is that under conditions of inflammation and imbalance, most organisms and human microbiome communities, they’re like the major viruses. The immune system keeps them in check in a commensal state, in a state of homeostasis when people are healthy. But if the immune system gets thrown off, they can collectively move towards a state of virulence, and part of what they do when they collectively move, whether it’s in the gut or in a different body site, is they express new proteins and metabolites. And those proteins and metabolites are often similar in size and shape to human proteins, human structures or human receptors and antibodies are notoriously poly specific. They’re flexible in the way they respond.

So one of the biggest concepts in the autoimmune community now that also considers organism, is molecular mimicry, which is that the immune system may fire on a viral protein, on a gut pathobiome protein. And then that has a similar enough size and shape to a human receptor, human structure. And it hits that as collateral damage. So one of the things that we’re trying to do is we’re working with a team in the background to create with… for example, the beta adrenergic auto antibodies that these things find in MECFS, there’s just proof of concept studies showing that real virus creates proteins that are similar in size and shape to those receptors. The parasites do.

So we’re working to create, and this is a long-term project, and some other teams are doing this as well, databases that better show the mimics between some of these so-called autoantibodies and all these organism protein and metabolite, because it really matters. Because what you deem an autoantibody may actually be targeted against the organism. And what it’s really important, one of the papers I wrote this past year, again with my colleague, Mike VanElzakker who is a neuroscientist. I think it’s probably one of the most important concepts for MECFS and many chronic conditions, is that viruses and most pathogens are obligate intracellular pathogens. And what that means is, by definition they must in fact pool from the host cell mitochondria, from the cells that they infect for their replications and nutritional needs.

Dr Dean Mitchell:

Wait, say that one more time. So they infect in the cell. I want to make this clear for listeners too and for myself. They effect in the cells. They do in fact get in the mitochondria, because that’s always been like a… you know, this whole thing about mitochondrial dysfunction in MECFS.

Dr. Amy Proal:

Right. So they’ll infect the nucleus or center of the cell, and they have the access to the mitochondria. And what they do is they pool from glycolysis and the TCA cycle. These cycles that our mitochondria grow through to produce energy for us, they pool, they hijack the mitochondria directly to pool substrates out of that nucleotides, lipids for their own replication. All viruses do this. SARS-Covid-2 does it. Every single one. And by definition then, the metabolic output of that infected cell is different. And that’s one of the most important concepts. It’s called immuno metabolism field right now.

Infections & Metabolic Output

Dr Dean Mitchell:

It’s interesting because I had never… again, I’ve heard very superficially from Jacob’s work Dr. Teitelbaum and Dr. Myhill, they all… just as clinicians, we don’t really have good tests. So that’s why again doctors don’t like that stuff. If they don’t have a test or something, they don’t want to just, put it out and say, oh you have mitochondrial dysfunction. Although I’ve learned from Dr. Teitelbaum, Dr. Myhill, that trying to replenish some of the substrates that are maybe diminished, or the need or augmentation could clinically help a patient. That’s why I recommend certain supplements like D Ribos and CoQ10 and Acetyl-L-Carnitine as boosters for the mitochondria and the patients feel better.

Dr. Amy Proal:

Yeah, I know. Exactly. You can try to sort of replenish what pathogens may be pulling from you, hijacking from you. But at the same time, what’s really important is for the field. And even for treatment, to consider that these topics are not separate. The infections impact the metabolic output.

Dr Dean Mitchell:

Okay. That’s critical. That is critical. Yeah. I think that might be one of the most important things that we bring out today.

Dr. Amy Proal:

It’s a new project.

Dr Dean Mitchell:

You sound like… because doctors tend to think, well if you have a reactivated infection you should be having fevers. There should be some demonstrable thing in a lesion, but what you’re saying, and I think I find that fascinating, is what a lot of these top clinicians have been seeing for years is that no, there’s something happening in the metabolism.

Dr. Amy Proal:

You could just have a metabolic problem, exactly, from an infection.

Dr Dean Mitchell:

Sure, and you would feel sick. Yeah. You’ll feel sick and horrible.

Dr. Amy Proal:

And now just, I can’t help, but mitochondria are also known to function as part of the innate immune response. So they actually fight back against this hijacking by creating their own compounds. So there’s this ongoing war between pathogen hijacking, mitochondria and mitochondria functioning as innate immune organelles to fight back. And that’s really a topic where, as we researched that, there should be clinical application to that, where we’re going to better figure out how we can either take advantage to strengthen the mitochondrial pushback on the pathogen or prevent the pathogen from being able to hijack. That should be able to hopefully-

Dr Dean Mitchell:

Anything you could throw out that you think would help a patient right now, someone who was in your situation years ago, that whether it’s a supplement or something, even a medication that would be beneficial. Because it almost sounds like… this was the question I was going to ask you originally, are people… because it doesn’t seem like they get a huge response to things like Valtrex or Ganciclovir. Because again, these are antivirals. Sometimes they help, sometimes they don’t, because essentially they’re trying to decrease the viral load. But on the other hand, what is it that could boost either the metabolic or the immune component that might give these patients symptomatic relief so they could function better?

Dr. Amy Proal:

Yeah. You know, I don’t know enough. I know some people are using Metformin, which is an interesting modulator that can even impact gut microbiome composition. If they’re seeing that Metformin has activity beyond its original scope. I do also know that there is a doctor today giving a talk about oxaloacetate I think, on its impact in MECFS. And I do know you have some of the substrates that can feed into the mitochondrial cycle of some of the lysosomal forms. But some of those substrates that I think some people use.

Long-Haul COVID-19

Dr Dean Mitchell:

Okay. I’ve used in my own practice. I do IB vitamin therapy. As I said, I mentioned that I do gamma globulin if I think somebody has got an infection. It’s amazing. I think it’s an underutilized. I know it’s hard to get, but again going back to your whole thing, I find patients with chronic fatigue syndrome, possibly even sometimes like chronic Lyme that as you were saying earlier, it’s not so much the active bacteria or viruses proliferating, it’s maybe somehow irritating the immune system, which is then setting off chemicals that are making them feel sick. And again, it seems to lower their inflammation, but it actually keeps their immune system strong.

So I want them to move on to COVID a little bit. And then obviously there’s going to be an overlap with what we just talked about with ME/CFS. And really, the first question I want to ask you, I started to just mention. This was pretty fascinating as I was getting ready for this podcast with you, which I’m really excited to do. And it’s been awesome so far. A paper came out that, this I thought was jaw-dropping, long-haul COVID symptoms were in COVID-19, that paper by Jeffrey Gold and David Hurley. And they were looking at EBV reactivation patients, and their statistic was 73% of these long haul COVID patients had evidence of EB reactivation, I think in the first three months.

Dr. Amy Proal:

Yeah, no, that doesn’t surprise me.

Dr Dean Mitchell:

That doesn’t surprise you.

Dr. Amy Proal:

No. Because I mentioned before the interferons, those anti-viral cytokines. Well the SARS-CoV-2 virus expresses at least 10 proteins that knock down interferon signaling. It’s one of the major ways that SARS-CoV-2 survives and does what it does. It knocks down. The SARS-CoV-2 survives better because it mutes that the response of these anti-viral cytokines and it can proliferate more, but those are also what keep the herpes viruses in latency.

Dr Dean Mitchell:

So these cytokines. These are. Yeah, just for our listeners to know. Cytokines. I guess maybe the best description are that they are celled hormones. Patients understand thyroid makes thyroid hormone. Adrenal glands make adrenal hormones. Well, certain immune cells make cytokines, which are really important. It’s a little bit under appreciated even by clinicians. Because we sometimes have difficulty measuring them. I’m doing a lot more of that in my office, but it’s essentially immune cell hormones. Right. And you know what’s interesting too. I read something, that children, this was really before the Delta virus. They tend to have higher interferon gamma levels. So I’m assuming that’s why they were thought to be less prone to illness than adults.

Dr. Amy Proal:

It’s an interesting theory because yes, a lot of times when we hear cytokine, we think of something negative and that is the case. It can be because if a cytokine response becomes too much, causes a lot of inflammation that can cause a lot of symptoms, but they’re also very important. They have their normal functional role, which is they’re sort of like attack molecules and they go after many of the pathogens, even SARS-CoV-2. And so by blunting this cytokine from being able to go after it, it’s like a battle move. SARS-CoV-2 inhibits the cytokine that would otherwise kill it. There’s always an arms race with these things between pathogen immune system that just really provides an atmosphere for the herpes virus. So we should say, wow, we’re no longer being regulated by these same interferons. Let’s adapt, let’s infect a new tissue. Let’s infect new nerves. Let’s create more protein.

Dr Dean Mitchell:

Do you think also… and I think I saw this in some of your papers. What I talk a lot with my patients, because I find there’s a lot of… like the whole function medicine community. There’s a lot of microbiome dysfunction. That’s why a lot of people get ill. I see a lot of people, what I call candida hypersensitivity, where they’re getting thrush in their mouth. The women are getting vaginitis, and there’s other areas. But you know, the microbiome we tend to associate with bacteria. I guess also probably fungi. And you mentioned, I think in one of your papers I was reading, that the virus, I think, I don’t know it’s called the biome or something, but do you think from your work, that some people who have, maybe, a more diverse and stronger microbiome are more resistant to infections in general?

Dr. Amy Proal:

Yes.

Dr Dean Mitchell:

You do?

Dr. Amy Proal:

So, one of the things that I’ve done with my papers and some of my research is, I always try to integrate the microbiome. These really robust and extensive communities of organisms in our tissue and blood-

Dr Dean Mitchell:

Right.

Dr. Amy Proal:

… along with the activity of the major pathogens, like the Epstein-Barr, because their activity is totally interrelated. So yes, what healthy people usually have. So, I’m an Olympic athlete. I’m seeded with organisms, and I’m functioning very well. That’s usually because the immune system is in good shape, it’s preventing organisms in those communities from being able to change their gene expression. They’re capable of acting more problematic but the immune system goes, “No, no, no. No, no, no.” Kind of like a teacher in a classroom. The kids in the classroom, if the teacher is there, pretend the teacher is the immune system. If the teacher’s there, the kids are all behaving-

Dr Dean Mitchell:

They’re behaving, they’re not jumping out the window.

Dr. Amy Proal:

Exactly. If the teacher leaves the room, though, those same kids can act up, and cause a lot of problems. That’s the way it is with these microbiome communities, is when the immune system is not in great shape, they can change. They can kind of collectively move towards a state called dysbiosis a lot, where they’re imbalanced.

Dr Dean Mitchell:

That’s a great analogy. I’ll have to use that with my patients. Because it did, it fascinated me. I’m a huge tennis fan, and so I heard you play.

But I was fascinated when Novak Djokovic came down with COVID. Again, clearly an elite athlete, fortunately got through quite well because a few weeks later, after quarantine, he was back on the tour, playing. And you see all these other people that are having a lot of varied responses. So you say to yourself, so interesting, because again, this is a virus, it shouldn’t discriminate between an elite athlete and a regular person. I mean, because again, we’re just talking about biology. But clearly it seems that it does, because these elite athletes must have a really good microbiome and immune system.

Dr. Amy Proal:

It can be one of the factors, and we wrote a paper on long COVID as well, it was recently published, and different biological abnormalities that may contribute, and there’s a big microbiome section. The reason for that is, I’m just going to give an example, the vaginal microbiome, when the vaginal microbiome is more diverse, when it’s in good shape, when it’s more balanced, it’s actually, they’ve studied it. In HIV, women who have a more balanced vaginal microbiome, even when they’re exposed to HIV, are less likely to get the virus. And that’s because, there’s a number of reasons. The organisms take up more niche space. It’s harder for the virus to find a place to be.

Dr Dean Mitchell:

No seat in the classroom.

Dr. Amy Proal:

Right.

Other organisms secrete … I think it’s lactic acid, or other compounds that make it more difficult for the virus to stick around. So those organisms, they’re all creating, and that’s the thing, they’re creating compounds. They create neuro-transmitter, they create protein, metabolite. That can actually, if it’s in a good state, sort of push back against the viral invasion, there’s no space for it, there’s no place for it. The other organisms almost like don’t want to let it in, in simple terms.

The same with the lung microbiome, which is really important for COVID. There are studies that have shown, for example, one team infected mice with respiratory syncytial virus [crosstalk 00:48:36] like that, and they showed that the mice, first of all, after getting the virus, the lung microbiome composition totally changes, but also, the mice with more robust microbiome to begin with can better fight back against virus.

So in other words, microbiome, to me, you name it, whether it’s in the lung, in the mouth, in the gut, in the bladder, anywhere, it’s a predisposition. If it’s robust, it’s harder for the major viruses to really take hold and infect that same body site.

Dr Dean Mitchell:

Is there a way to improve that? Or that’s still the mystery in medicine? Because I know people take probiotics.

Dr. Amy Proal:

Yeah.

Dr Dean Mitchell:

I don’t know. I call it the Wild West, or a state of infancy, because we don’t know. Because obviously each area of the body could require a different kind of microbiome. So I don’t think it’s harmful, but I can’t say this is going to be a game changer.

Dr. Amy Proal:

I do think that right now we can address gut and small intestine dysbiosis the most, and there actually are some good protocols out there. I think, for SIBO, small intestinal bacterial overgrowth, there’s a doctor, David Kaufman, and he reports that, I think, a good percentage of his NVCFS patients have SIBO and there’s good protocols for that now. They usually center on, you use an antibiotic, or sometimes a strong herbal anti-microbial, try to kill off organism there, and then you repopulate with yes, probiotic or fermented food, or other stuff like that.

There’s a couple different, especially for SIBO, protocol, that does seem to help patients improve a little bit. And I do think that can matter in these cases, because even if that’s just part of your case, let’s say the gut, or the intestine, and SIBO is dysbiotic, and all the organism is out of balance. The immune system gets so caught up in that mess, it’s like, “Oh, what’s going on?”

Dr Dean Mitchell:

Yeah. [crosstalk 00:50:28]. No, it’s huge. I’ll just have to add one thing. What I’ve found, because I’ve taken care of many patients with SIBO, but I have found that … I tell my patients this, I feel I’ve been a little more successful by treating what I call the candida overgrowth.

I think the candida growth is somehow involved with the SIBO, believe it or not. And I find that when patients go on the antibiotics, they feel better, but they relapse, and then they relapse. And when I treat the underlying candida imbalance, because again, a lot of times they have symptoms, either thrush, or bloating, dysbiosis, or toenail fungus, that they get more permanently better. That’s just been my clinical experience. I wanted to ask you one thing or two, going back to, again, some of the things with the anti-inflammatory treatments. Again, I don’t know if it’s come across in your research, things like low-dose Naltrexone, which Jared Younger, I think, promotes a lot. I think he’s in Alabama now, I think he used to be at Stanford. Do you see a place for that in this? I mean, have you …

Dr. Amy Proal:

Yeah. I don’t. And you know, I think Jared is looking at low-dose Naltrexone as a potential glial inhibitor, and I think we need a little bit more evidence for that. First, we do need a little bit more evidence that glia are activated in NVCFS, because there’s one small … for example, my colleague, again, Mike VanElzakker, he’s running a large PET study now, which is … that’s the goal, is to really try to document neuroinflammation. Whether or not the microglia are activated in the brains of these patients. But other than that, we’re relying on a … I think, a Japanese study, that’s small. There’s, I think, nine subjects, or something like that. They did find glial activation in NVCFS, but we do need some replication there. But assuming the glia are active, and assuming we further study low dose Naltrexone as a glial inhibitor, because we need more data on that, then that could be interesting.

Beyond that, though, I’ve always been interested in the low-dose Naltrexone mechanisms that must impact the immune system. I wish … I know that there are doctors who used, I’m going to call it LDN, low dose Naltrexone, LDN for short, they used LDN in patients with HIV, AIDS, and cancer. It helped with comorbid infection. It helped with [crosstalk 00:52:30], it helped contain fungal co-morbidity. And so, I know there’s a lot of people, there was one group at Harvard, for example, that was looking to see if it had an effect on T cell function.

There’s a lot of hypothesis out there as to what LDN does, and even the sort of original mechanism, where it seems to infect endorphin sickling. Well, endorphins are also tied to immunity in some sense, so I do also think there’s an immune component to LDN, where it’s probably an immune modulator that may actually better help people contain infection. And I’m not sure, but I really hope it’s studied more in that capacity because I know doctors who use it more for its potential effects on controlling infection than necessarily on even glial inhibition. However, if it did both, it’d be very interesting. So yeah.

What’s the Best Option for Chronic Conditions?

Dr Dean Mitchell:

I want to just go back to one last thing too, as we’re kind of wrapping up. This has been tremendous. The whole idea with the antivirals, as I mentioned earlier, the Valacyclovirs, which I know Valtrex has been used for Epstein-Barr, it’s used sometimes even in shingles, when people get an acute reactivation of singles, even now Remdesivir is being tried, and I’m hearing positive and negative response. I guess all that has to do with timing. Do you believe though, with viral infections, that antivirals … I mean, obviously, we see in HIV, it’s amazing. Do you think they could have a really good place? Like maybe even in COVID?

I keep on thinking, the same way it took David Ho, a brilliant guy, to come up and say, “You know what? We need a triple antiviral cocktail to knock this thing out.” Do you that something like that could potentially …

Dr. Amy Proal:

Yes.

Dr Dean Mitchell:

Yeah?

Dr. Amy Proal:

I think that the best thing that we could do for many, chronic conditions-

Dr Dean Mitchell:

Because people are being infected, already.

Dr. Amy Proal:

… is to develop better antivirals we have Valtrex, we have Valcyte. They’re okay. They’re not even perfect. Many of them are not even targeted to Epstein-Barr virus. We’re hoping … I mean, ish, but … if it were up to me, and I ran the National Institutes of Health, the first thing I would do, would be to create a program as big as what we’ve done for the MRNA vaccines, as big as anything, that just fast tracks research on new antivirals. There are so many new mechanisms, there are so many new potentials-

Dr Dean Mitchell:

Right. Because those drugs are old, in a sense. And when you look at HIV, I mean, I’m not really an expert in that anymore, but all of those protease inhibitors, and this that too, they clearly worked.

Dr. Amy Proal:

Yeah.

Dr Dean Mitchell:

I mean, these people are living full lives, with now a chronic condition and bringing the viral tires … they measure this stuff now. They’re basically down to nothing. That, if we had weapons for COVID, which is going to be critical, I mean, this is going to be the new epidemic of our lifetime. People just don’t realize, I mean, whether it was like polio, or other things, it could be decades. People could have some degree of suffering, but if we get before it gets to a pathological state where it changes tissue and everything, this could be the window to do that.

Dr. Amy Proal:

I couldn’t agree more. I actually, every time I see an antiviral even suggested for COVID, I get excited. One doctor presented at a conference today that they thought NVCFS patients who also had enterovirus infection might have responded to Remdesivir even for the enterovirus, it’s another RNA virus.

Dr Dean Mitchell:

Wow. Wow.

Dr. Amy Proal:

Again, there’s a huge potential for the development of new and better antivirals, and if we were to do that, I think we could really make a dent in these cases. And as you say, if we use them in the most preventative fashion possible, before things get too bad, there huge promise in that. So I agree, I’m with you. I hope that happens.

Dr Dean Mitchell:

Yeah.

I’ll tell you one last thing too, because again, I always think about these things. As horrible as it was when I was doing training during the HIV/AIDS crisis, I kept thinking to myself, “Something good will probably come out of this. Doctors and researchers, we’re discovering things about the immune system that we never would have known, or it would have taken decades more.”

And I think the same thing is going to happen with COVID, and especially regarding chronic fatigue, myeloencephalitis, and myalgic encephalitis, that this condition, this virus may uncover things about the immune system that could have been hidden for centuries, so …

Dr. Amy Proal:

I agree. It’s exciting. More teams are studying a virus than has ever occurred before. And so, exactly, when we learn from this virus, we can extrapolate to maybe other RNA viruses. So yes, it’s good. [crosstalk 00:56:53].

Dr Dean Mitchell:

Well, Dr. Amy Pearl, I want to thank you so much for taking the time today. I am so glad you’re on this, because I’ll sleep a little better at night realizing you and other researchers are really diving into this, and appreciate your time, and I hope we get to chat again.

Dr. Amy Proal:

For sure. Of course. Same.

Dr Dean Mitchell:

Thanks Amy.

About the Author – Dr. Dean Mitchell, M.D.

Dr. Dean Mitchell, M.D.

Dr. Dean Mitchell M.D. is a Board-Certified and Immunologist based out of NYC. He graduated from the Sackler School of Medicine and completed training at the Robert Cooke Allergy Institute in New York City. He is also a Professor of Clinical Immunology at Touro College of Osteopathic Medicine, a fellow of the American Academy of Allergy, Asthma and Immunology, and the author of Allergy and Asthma Solution: The Ultimate Program for Reversing Your Symptoms One Drop at a Time. Dr. Dean Mitchell, M.D. has also been featured in The New York Times, The Huffington Post, Fitness Magazine, Dr. Oz, and News NY 1. Dr. Mitchell also hosts the podcast The Smartest Doctor in the Room – a combination of a lively, personal, and in-depth interview with top healthcare specialists.