The Septet Model for ME/CFS and Long COVID

Welcome to the Gordon Medical Forum. ME/CFS and Long COVID don't fit the medical model of one problem, one organ, one treatment. And that's exactly why so many patients struggle with recovery. In this episode, Dr. Eric Gordon sits down with Dr. David Kaufman to discuss his septet model, a framework of seven overlapping, constantly interacting pathologies, and why knowing how to identify them and in what order to treat them changes everything. Thank you for joining us in here, Dr. Eric Gordon and Dr. David Kaufman. Welcome everyone. Today I'm going to have a very interesting and educational time for me and I hope for everyone else. I'm going to be speaking with Dr. David Kaufman and Dr. Kaufman is just the kind of doctors that we need in this world of ME/CFS. He is someone who has spent a long career in infectious disease and understanding immunology and how to treat people. Luckily for our world with chronic complex illness, he became very interested in it. We opened his clinic in 2017 dedicated to chronic complex illness and he continues to really, I don't use this word often, but to be a thought leader in that field. So, David, thanks for joining us and today we're going to talk about the overlaps and the differences between ME/CFS and long COVID, something that those of us in the field weren't surprised that they were going to be very similar because virus triggers a lot of people's ME/CFS, so maybe there was something there. But so tell me what's your thoughts on the overlap and how do you begin to parse the difference between them if you need to and when do you see it useful? So, the questions. Okay, thanks for bringing me on. I'm been excited to do this with you. So, to me, they're virtually the same. If we exclude the long COVID patients who have organ specific disabilities. So, I'm not including pulmonary fibrosis from terrible infection, ICU, etc., or cardiomyopathy developed during or after infection. I'm talking about the vast majority of long COVID patients who develop a presentation, a syndrome, a picture that is absolutely identical or nearly identical to ME/CFS. They meet all the consensus criteria for ME/CFS. It's a bend diagram overlapping nearly completely. And I don't think that's a coincidence. I think it is a high contrast graphic example of the fact that these are infection mediated chronic fatiguing illnesses. COVID, Zika, Dangae, ME/CFS after EBV. There's a subgroup that have other causes, but I think the similarity shouldn't surprise us at all. And the silver lining in the cloud here is long COVID is letting us or provides the opportunity. Hopefully that will continue, but provides the opportunity to do the research to finally understand the underlying causes of the ME/CFS type picture, the fatigue illness picture. Yeah, I said underlying causes and we'll get to the underlying physiology of them, because it's one of the things that I know that you have, as many of us, been frustrated that sometimes, finding the triggering cause, treating it doesn't always make the problem go away. So, on that note, what's been your experience with the people who come in and seem to have a, you know, you can name the infection that seems to precipitate the event, but what have you found in your experience with treating that? Yeah, so as you probably know, and probably many of your listeners know, I see ME/CFS and we'll encode it as simply a label. It's just like a label on a jar, okay. Just says you meet the criteria. It tells you and me nothing about how they got to this miserable situation, what's driving their illness. And I and many other docs have spent a lot of time looking at that and discussing it and recognizing almost in a kind of eureka moment. Wait a minute, I'm seeing all these patients and they all end up having pots and dysautonomia and MCAS. And started to develop a sort of hypothesis or a different way to look at the illness. So, I've used this, as you probably heard me talk about in the past, this notion of a septid, which is seven different types of pathologies that over and over and over, if you think of it, and you look for it, you will find it there in these patients. And the beauty of that approach is that it lets you, number one, it helps really to understand it. Number two, to explain it to the patient. Number three, it guides the workup and also allows you to have effective treatments to treat the things that are driving the illness. I'm not in any way saying I understand it all, that I know exactly why. And particularly the biggest challenge, as you know, is fatigue, the post-exertional malaise aspect of the fatigue. But the other conditions are diagnosable and treatable, and I can certainly walk through them if you want. Yeah, just briefly, I think that would probably be helpful for our listeners. So, in general, we'll find or I find anywhere from, I'll say four to seven of the things that I'm going to describe. So, a very significant percentage of ME and lung coveitations have connected tissue disorder, so-called hypermobility, hypermobility, EDS, hyperflexibility. It's got a bunch of different names, but at the end of the day, it's a connective tissue disorder and it does not have the genetic markers of the other alergagnolous syndrome. Okay, it's a home condition. It's probably about a six-hour podcast to think about and talk about why, why do these EDS patients occur, have these illnesses with such a higher level of frequency. It's a completely interesting topic, but anyhow. So, there's EDS connective tissue disorder, then there's dysautonomia, and I divide that from my own thinking into two pieces. One is POTS or hemodynamic instability, which translates at the end of the day into hypokriffusion of blood to the brain, the core muscles, and the organs. That is a major driver of illness, of symptoms, of fatigue, of brain fog. All of the symptoms you list under ME/CFS criteria, it's a major driver, and it's treatable. It's treatable. Okay, and then the other aspect of the dysautonomia is the gut GI manifestations, gut motility disorder, usually accompanied with small intestine bacterial overgrowth, and then increased gut permeability, so-called leaky gut, and that is the second major driver as far as I'm concerned. What leaks across that gut is lipopolysafride, which is dead bacterial cell wall debris. It's an endotoxin. It is what's used in the laboratory to mimic sepsis when they're trying to study things, so it gives you 90-apultent it is. In a SIBO patient with leaky gut, it's not causing sepsis. It's causing chronic 24/7 inflammation, causes a leaky blood-brain barrier, contributes to the whole picture, and probably contributes to the next topic, which is mass cell activation syndrome. I've done chart reviews of my own charts, and I've had other colleagues and friends do the same thing. At least 80% of my patients have MCAS, and probably they all do. The mass cell is aberrant and hyperstimulated by the toxins and antigens from the leaky gut, and also from infection. Mass cell activation syndrome is a multi-system, multi-organ inflammatory illness, which can be as confusing as hell to doctors and to patients. How could somebody come in with nine different symptoms, or a completely positive review of symptoms, most of the time they're told they're crazy, and they're not. It's really because mass cell releases of thousand chemicals, and they work everywhere. Auto-immunity. This is probably the weakest teeth in the sense that it's the hardest I find, and I'd love to hear what you think. Hardest one to prove, because we simply don't know all the antibodies to look for. We don't have a test. So it's well demonstrated in COVID and post-COVID, long COVID, that there's a definite large cohort of people who have autoimmune disease driving their long COVID. We don't always know the antibody, but we have many other positive tests that we find. I find the same thing in ME/CFS patients, and I think if we keep looking, we're just going to keep finding more antibodies. I wrote someone today, I think, that I had this memory from a meeting in London where somebody spoke a pathologist, and she was saying how she gets samples from all over the world for mystery patients, and she finds a new auto-antibody every week, every week. And I think that's true. If you look at the literature, almost every week, somebody publishes another paper with a, "Oh, we just found an antibody to, I don't know, eyebrows." You know what I mean? Making a joke out of sleep. So what do immunity? So number six is the biggie, chronic infection. Okay. This is another six-hour podcast. So by chronic infection, I am referring to not so often acute infection, but either ongoing chronic infection or more commonly infections that are reactivating. And it's a really important concept and topic is now well proven, well demonstrated, and finally accepted that in COVID, leads to very, very often reactivation of Epstein-Barr virus, of EBB. Okay. It's a crucial concept that this herpes family of viruses, and there are eight include, you know, EBB, CMV, HSV1, HSV6, which we get as kids. Almost every one of those gets infected. It never leaves our body. And basically, those viruses are so-called latent state in our cells, and they're simply waiting for your immune system, Thank you for your time. immune system to become disturbed and less active, less competent. And they just break out of jail and they reactivate. And I suspect that happened way more often than we think, but we have such an incredible immune system that quickly locks them back up. But in COVID, post COVID, low COVID, it becomes another driver of illness. I hate to go down the rabbit hole, but the other major infection that needs to be part of the conversation is tick-borne infections. You know, I have now become 100% convinced that because I see patients over and over and over, we're coming with long COVID or MECFS, likely it's one long COVID, they give me a history that's very consistent with a high exposure risk of tick-borne infections. They may say I never had a tick, but they also went camping and hunting and hiking and all that. And then they had a cat that scratched them or a dog that scratched them, etc., etc. And I run their tests and they come back with evidence of active infection, not antibodies. I'm not looking at antibody, active infection, but they clearly weren't sick before and they don't recall ever getting infected. And I think it's just another example of a disturbed, disturbed immune system allowing reactivation of infection. And there's other infections we could talk about, but that's the idea. And then number seven is, in a sense, the final common pathway for a subset of patients where their connective tissue disorder is so significant, made infinitely worse by the chronic inflammation for so long that they develop cranial cervical instability. And then that's a whole other chapter to discuss. I don't know that we need to get into that. Wow. I see a point. We can go down every one of these into the rabbit holes of life. I'm going to try to explain what I try to explain to patients every time I see them, but it's the circles. And that's what's so hard because doctors don't understand circles. Doctors want linear. You know, I always use it, the bullet wound, you know. And when it's single problem in a single organ, it has a single explanation. Yeah. And everything you describe is a circle. Okay. Every single one of them, you know, it just feeds back on a loop and, you know, like the hypermobility. I mean, this is just from most of these people. They just were good yogis and otherwise felt great, you know, that with the people, I was always jealous of. They could like, you know, do the cow and and do things and they were fine. But when you add, you know, toxins over time and then something that causes inflammation looks like they're mass cells then get activated and then this tissue starts getting more lax and that creates its own problems of, you know, eventually it can be cervical instability, but it can just be that, you know, their thoracic vertebrae are no longer holding place so well. So their sympathetic get up regulated and then their guts stop. It's right. I mean, you really bring up an important point, which I'm glad you're doing because I didn't say it. So if you think of it as seven things and I realize that's somewhat simplistic, but it's not quite helpful. It's helpful. It's good. It is seven things which are constantly interacting with each other. Your EDS connective tissue disorder helps make pots worse because the vessels become floppy. It makes the gut motility worse. You're in leaky gut, makes the M-cast worse. I mean, it all connects to each other and that's why it's hard to take care of the patients and also why it's so challenging and gratifying because you can make a difference. Yeah, but the thing we're trying to teach, I mean, you know, these episodes are for patients, but they're also for practitioners because we're just trying to increase the number of doctors that recognize because there are lots of good doctors out there who become pretty good. I'm seeing experts at treating pieces of what you're talking about and it works. Occasionally you get somebody comes in, you know, they got the tick bite and you know it and they all they have these symptoms and happen to year ago will treat it and they get better. It's really cool. You know, they treat mast cell or they treat mold, which is another just exacerbator of the immune activation, but if they don't see these patterns, they can't serve enough people and it's so far away from the medical model of that, you know, single cause, single disease and the beautiful treatment. But except the thing I always have to remind people is most of our beautiful medical treatments that I love, they're band-aids. They don't help the body get back to stability. Stay with us. We'll be right back. The Gordon Medical Forum is now online. Join us for events, workshops and webinars with medicines most innovative minds, giving you exclusive access to groundbreaking conversations, insights and solutions from leading pioneers in chronic illness treatment. Learn more at Gordonmedicalforum.com The other thing I just want to throw in about antibodies because this is I want you to think about. Okay. Well, it's because I'm always embarrassed because I have no head for names, but that wonderful German researcher who mentioned earlier, Dr. is it Shoggen-Shoggerwagge? Yeah, just amazing, amazing. But when I read her stuff, she was talking about this concept that intrigues me and when we think about it, is the body makes low, remember, when you do those antibody tests to any antibody, the normal level isn't usually zero. It's just usually less definitely. Exactly. Oh, interesting, right? So they're clearly your body, you know, what's that old saying, you know, God doesn't make junk, you know, and we have learned this over and over again in medicine, you know, junk DNA, junk, this. It just means we don't know it does yet. So these tiny low levels, you know, they probably are modulating the receptors maybe. And so maybe those antibodies go up because that receptor isn't working and the high, and this is my story and you guy want to hear yours about it. And maybe those antibodies eventually reach a level when the immune system begins to think it's a problem and then attacks the organ, but initially the low levels are just to modulate. I mean, that's a story. I have no idea of how to do it. I agree with you and it's interesting because I've had the same, you know, aha moment when I started looking at I was using cell trend panel from Germany. Yeah, yeah. And I remember ordering it. I really found it helpful. And then I would have this moment, real aha moment, I was looking at a report and said and realized, wait a minute, there's a normal level when he reports it when Harry, which is last name I forgot, when he reports it out, it's not greater than zero and that's abnormal. It's greater than let's say 21. Well, wait a minute. Why is 21 okay or 20? And I think you're right. I think it is a modulating system, which makes sense. If you think about evolution and receptors and triggers and receptors and neurotransmitters, why wouldn't there be a modulating system? Why would it only be on off? That's too simple and too ineligant and not not nuanced enough. So yeah, I agree. And then as that level goes up, it becomes or potentially becomes pathologic. And we don't always know that those antibodies are blocking the receptor and they may be actually the agonist provoking the receptor to overdo whatever that receptor does. Yeah. And my story is it eventually gets high enough that the immune system, you know, thinks there's a real problem and then they'll get your T cells and your natural killer cells involved. And then you have an organ that's not working well. But it's this rounding round that I just want everybody, doctors and patients to realize that it's not a one off kind of situation because that's how our minds work. As people say, like engineers, no offense engineers, they're brilliant, but it's your engineering circles. You're doing, you know, Buckminster Fuller's, you know, geodesic domes where everything connects totally. So you you go through these, I mean, is there a particular order? I mean, I'm sure there isn't. When the patients come in, what's your more or less order of treatment? I know it'll depend on the patient's presentation, but how do your mind kind of go to what's your normal cycle? So to use a overused expression, but I think it's very helpful. I go after the low hanging fruit, first low hanging fruit. It just so happens, I think that that low hanging fruit is the major driver of symptoms. And that's what makes the patients miserable. So if I can address those first, there's a greater chance I can help that person. And then we can deal with the bigger underlying issues. That's how I approach it. So what does that mean? If they have pots, that's treatable. And it's miserable. And I'll go after that right away. I mean, sometimes in the very first visit, if I'm suspicious of SIBO and leaky gut, I'll test it and I will aggressively go after that. I care about the GI symptoms, but that's not what's making them sick. My argument is it's the leaky gut and and those toxins and chronic inflammation. So I'll go after that. And then that third low hanging fruit is mass cell activation. And I will be quite aggressive trying to manage that because without fixing those three or at least modulating them, improving them, it's going to be very hard to go after their chronic infections and reactivated infections. And I think that's an important to understand. I don't think using tick-borne infections as an example, I will not begin treatment for a patient with Babesia or Bartonella or Borrelia until I've gotten adequate control of the first three things that I just said because they won't tolerate the treatment. They'll be miserable and they'll fire me or they'll hate me. Absolutely. In the early 2000s when we were doing this, everybody was having chronic heart curses, but now we know that it was mostly mass cell activation. I think it's so important for people to remember that. When you react badly to treatment, it's not necessarily the treatment is wrong, it's just the wrong order. So I think the low hanging fruit approach is very productive and practical and doable. And honestly, you know this and I know this, but this is for whatever physicians are listening. It's not magic. It's not rocket science. Physicians can do this. It's just a bunch of different drugs, which most the physicians are already familiar with. I understand physicians that are scared of treating tick-borne infections, chronic infection, but it shouldn't be that challenging to manage pots with beta blockers or I've ever been reminded of and it shouldn't be that challenging to prescribe a facsimine and whatever else you think is needed for SIBO and certainly for MESCEL doesn't take a lot to try taking an anti-histamine and pepsi. You know these are easy things to do. And give surprisingly good results for a lot of people and there are always folks who you know too sensitive, can't tolerate, but usually it's dosage and as our dear friend Dr. Affran always has to say it's probably the exhibits which I hate. Do you do make an important point in terms of going slow? You know don't start with a maximum dose of something just start slower and easy. Yeah, I love to organize mine. I've been working on that for a long time on Sunday. That was a great layout of the land of people with you know symptomatic illness and one last thing I want to throw in there about it is don't be attached to think that you have MECFS or you have long COVID or you have tick-borne disease because as Dr. Kaufman has been trying to tell you you may have all of them and it doesn't mean you have to fix all of them because the body is beautiful. You just sometimes move some things and your immune system will get back in control again. So let's talk a little bit about testing that you like. What are your favorite? Let me just say one thing before I dive into this please go not included in the septid model is probably the crucial piece for a good reason which is what's going on with the mitochondria. All right. You know the biggest challenge the biggest hurdle the holy grail whatever you want to call it in long COVID MECFS is post-exertional laser and I don't know about you I could do a really pretty good job for pots and sebowl and leaky gut and mess cell activation syndrome and ebv reactivation and babesian and partner etc but getting that p.e. m. fix and getting that fatigue really back to a normal level meaning lack of is the challenge of my life. Okay. Yes. And I think it will might a congeal dysfunction and I just sort of occur to me the reason I don't include it in a septid is partly the testing is is a different kind of world but more importantly I don't think we have a clue what to do for that. I mean we all try different supplements. Do they work? I'm just not sure and it's incredibly frustrating. Maybe later we'll discuss some of the things that I think might work which are newer on the horizon but it's a big piece I didn't want to leave it out. Oh no no no no please we'll come back to that because that's my one of my favorite things and first of all I have to go along with you that host exertion the lays is the hardest thing because you're right we have things we can do that are fairly predictably will work if you can tolerate the treatments for everything else you talked about. But p.e.m. is difficult and you know thankfully I helped a lot of people with it but not because I'm smart just because I got a lot of stuff to try and eventually something work. But when I'm thinking more and more lately. late to the game is going back to the thing that we talk a lot on these podcasts is underlying toxicity I think there's something about that underlying toxic load that the body tolerates. Then when you get the infection you lose the ability to compensate for that and I think the mitochondria might be the downstream effect but again. haven't healed enough people yet to come out with like oh that's it but that's my prayer so you definitely it's not very important just now which I think should be emphasized about the p.e.m. when you said you're unable to help some people. The work you do and the work I do and our colleagues do is all about trial and error and not giving up and trying new things and always looking for new things right so if you could see my. display here it is literally covered in stickies post it cover along the perimeter different drugs or supplements or something I read about to think i'm going to try that someday you know soon and that is the way we make progress and if it fails. 70% of the time and actually means it works 30% of the time and that's what matters so I totally agree with what you. If we can only get this message across to physicians that you know you're dealing with like we would love to have 90% but that 30 or even 10% and I think that's my prayer for AI is that this can help us figure out who those 10 or 20 or 30% are without having to spend all that time money and sometimes suffering because. In some people everything has a side effect that's why it makes this job a lot harder our good idea can mean a very unpleasant period of time for them so we want to be careful. But you're right what one of these days each one of your seven plus a few others we could. One for hours we should do that yeah I can go I know you know renamed and yeah I know but you got the biggies I mean that's the beauty of it you know I mean what people have to understand is because if you go too much into. This is enough in the weeds yeah but talking about testing because that's one of the ways I mean the history gives you probably a lot of this but still deciding on therapies the testing often helps aim so what are some of your favorite ways in. Yeah so like I suspect you I have a pretty big work up initially with a new patient. When I say big the the blood work up could easily be 30 or 35 tubes of blood which is daunting unlike the way I was trained and you were trained where we were told order one thing at a time and make a decision in order the next test in the next test. I've thrown that out as far as I'm concerned these patients have suffered too long into too many doctors who say there's nothing wrong with you you'll have to normal. I'm going to save time and just throw at that fish net it's not a thoughtless fish net but it is a fish net and that's okay so I look at the obvious you know routine stuff cbc metabolic panel etc I do a pretty extensive immunologic workup looking at tnb cell besides subsets. I do immunoglobulins subclasses which is really important over and over a patient bring a normal gg is part of their labs to me and then I do subclasses and they have two subclass deficiencies so looking for immunologic risk factors i can stop you different question you first of all there's four subclasses for that people out there and the range is our very wide that's why any immunologist will tell you that if one of them is just a little bit on the low it doesn't mean anything but. We often see one in three whoa do you make anything of that i think you mean something i'm not sure. Can sort of get the chapter verse of what it means but it may well be part of the reason that almost all of these patients have reactivated infections i mean if you look you find the other subclass i see. Is gg for elevated and i regard that as a as a marker for infection meaning ongoing chronic reactivated infection i can't prove that to you but that's what i think i'm learning when i see patients which is how you and i learn yeah again once another little advertisement for this is not academic medicine okay this is not a double blind who see about control study this is like. What they call anecdotal medicine and somebody told i heard that one so you know the plural of anecdote is not data but on the other hand anecdote is our guide until we can have enough money and time yeah medicine is made up of anecdotal case reports that's how we've learned so much eventually. ten or twenty years later it becomes evidence based but i'm not gonna wait ten or twenty years and i think it's. Cruel and unethical to ask our patients to wait. For evidence based guideline driven medicine i'm not saying those are bad but they're late in the game thank you any help show the lab work also includes viral sorology and about testing but also viral DNA testing you see our DNA testing. If there's a clear nutrition issue i will do pretty extensive vitamin levels and other nutritional parameters and then you know some hormone stuff i wrote things like that. Sure i'm leaving something out and then in addition i will do a three hour breath test for small intestine bacterial over using lactolosis substrate not because. And i do a saliva cortisol test to four points a lot of cortisol test because nearly all the patients have hyposolamic pituitary adrenal access dysfunction h pa dysfunction. And if you wake up in the morning with no cortisol level you're gonna feel like garbage so i will treat that so it's a very useful test and it's really interesting just a sort of a little anecdote how often. i'll do the slide of cortisol and then i'll discuss it with the patient comes back as a graph as well as numbers and i'll say well this looks like the up to somebody who takes two hours to get out of bed. They feel a little bit better by two in the afternoon but by five they're crashing and they'll look at me and say how did you know that because you can tell when you see their cortisol level you know any so those tests everybody does nasoline tests the stand test i live in breath with that test that's how i'm diagnosed that's how i. Titrate their meds how i manage their drugs crucial test they hate it but it's too important you give it 30 second on what that is for people i know they can see him online there's lots of but still just 30 seconds on. Sure somebody takes a blood pressure and heart rate lying down supine you stand up and you lean against the wall your shoe your heels are out of that eight inches you're supposed to be perfect. perfectly still your arms just hang down every 60 seconds every minute. The person takes your heart rate and your blood pressure with a cuff and writes down what you say, what you are feeling and what you look like. Are you getting spots? Blue, red, yellow, you know, blotchy and then also tells me what you feel after you lie down how you know how long it takes you to feel better because it's a very difficult test if your pot is uncontrolled. The reason for the leaning as opposed to just standing is that almost every patient with pots has learned consciously or unconsciously that the more they move the better they feel. So the classic piece of history question is, I'll ask, how do you feel when you're shopping in the supermarket compared to when you're waiting online to pay the cashier and they will say, I'm okay in the market, but when I wait online, I feel horrible because when they stand still, the blood starts to pool and so they start jiggling and moving and stuff like that. So this is to try to prevent that so you get more accurate read. And it's a hard test. I feel badly asked in patients to do it, but it's the equivalent of doing the tilt table test, which is quite sure. Yeah, it's the equivalent clinically to tilt table, but it's like doing serial MRIs. It gives so much information. And when you look at the test, are you doing any, you know, the T cell testing or what are you, what are you? Yeah, I'm doing a subset analysis. So we're looking at CD4, CD3, CD8, CD19, natural killer cells and getting an absolute count and a percentage count, which can be very helpful. Lots of times it's normal and that's fine. It's okay, but an awful lot of times it's not normal and it's another indicator of immune risk, immune dysfunction. Any ones that stand out that are more common in you, I'm pushing you because I need you have a background in immunology. So I'm digging. Sure. I mean, I often find surprisingly low levels or abnormally low levels of CD19, which is B cells, which is quite surprising. Normal people should not have abnormally low B cells. Okay. B cells are the cells, as you know, B cells make the antibodies. They make immunoglobin, they're the source of IgG and IgM. And I mean, I don't know the answer, but I think that that is a B cell exhaustion from constantly pouring out antibodies and then the system just starts to fail because they have this constant infection, antigen stimulation, infection reactivation and even toxins. I mean, you know, we are body makes a response to all this toxic overload and it takes a toll. It takes a toll on the HPA axis and on the B cells. I see T cell changes much less often except natural killer cells, which are almost universally not functioning properly in ME/CFS patients. Yeah. I like the idea of T cell exhaustion in COVID and B cell exhaustion here. I always tend to think that it's again part of the circle is that in a way I wouldn't be surprised if it was more an issue of the body sort of stopping a process that's not really working, if it keeps going, may cause tissue damage. I mean, these are stories. Please understand, folks. This is not quite science yet, but that's why you and I learn, you know, you're speculating and putting together what you know to see if you can come up with a hypothesis. I completely agree. So you've got your issues and so you're going to go after the mass cells, the C-B O kind of things early on in the process. Very old. Just quiet things down. Yeah. It's always so funky because you fix one and luck the others start to get a little bit better if you're lucky. If you look, you fix two, yeah, the whole intersection fix two and you really start getting some motion, which is exciting for people. So going back when long COVID started and or people actually pretty early on, people realize that COVID was not going away, that people who had symptomatic COVID, a lot of them weren't bouncing back as fast as they were. What were your initial thoughts? I mean, were you just going, oh, like this is MECFS or what were you thinking early on and curious your thought process? Do you mean what was I thinking about what was going to happen down the road in the future? Yeah. Yeah. Yeah. I'll try to monitor my language carefully. I thought we were really in force. Okay. You know, it became clear reasonably quickly as the long COVID issue surfaced, which happened within six months of the onset of the epidemic, I would say, that this was yet another infection mediated chronic fatigue illness. And if that is true and we had millions and millions of Americans getting sick, we were going to have millions of patients with long COVID and we still only have a few hundred doctors who can take care of that. That's part of the reason I tried to start spending some of my time doing education like you're doing with this podcast. You know, I have my podcast with Dr. Ruhoi. That was one of the drivers we were doing it to educate doctors. Mostly we have patients watching, but we have some doctors. It's why I'll do retwebinars. It became really obvious very early on in COVID that we were in for a disastrous epidemic of long COVID. And it's still true and I could launch into the politics, but I love it. Yes. Well, frustrations. Yes. Yes. Yes. That's not go there. So let's wander over to the favorite organ of all of us, which is the mitochondria. I know you've been involved in some really interesting work looking at different ways of trying to coax the mitochondria to come back. And I know people who listen to me, we talk a lot about the cell danger response and the idea that this is a compensation and it's not going to come back to you fix it, but that's not completely true because many times it's just if you do replace the right, not always nutrients, but cell signaling factors, the system will change. And I know you've done a lot of work there. So what's on your top list for like, well, first of all, how do you think about it? And then what's the top things that you keep trying to see if you can make the mitochondria decide that it's time to come out and play again, normally? So let me give you a little thought background on this. Okay. You know, I started doing MECFS complex illness in 2013. Okay. I had never ever done it. All right. I was an HIV doc in New York starting in 1980 for 30 years. For the first 15 or 20, that's pretty much all I did take care of dying men mostly, some women, but mostly dying men. It was just an amazing kind of experience. And I never saw patients that I thought, I mean, I must have missed patients, but none of them would I thought of as chronic fatigue patients. So then 2013, I started seeing these patients and this whole question of what is this fatigue in PEM became pretty quickly apparent that it was the challenge, the big piece. Okay. And I thought, all right, this is mitochondria, but I didn't know what the hell to do about that. I mean, I'm not Bob Navio. I don't know enough about that mitochondria. But it led me down a road, which I think has been for me at any rate, has been very, very helpful. And that the road is this. I also was reading at the same time a lot of literature and a lot of podcasts and a lot of other sources on the world of anti-aging and longevity. And again, kind of one of those extended prolonged aha moments for me saying, wait a minute, what I'm learning about here in this space in this universe is what's happening to my patients. You get sick. I'm old. I'm going to get sick, or I will get sick, or maybe I am sick from chronic inflammation as my body gets more and more in low grade inflammation and decrease function of autophagy and other cleanup processes. That's what's happening in our patients. This is my thinking now. I haven't proven this yet. One client made that leap or started thinking that way, the next step becomes obvious. Well, what are they doing in the longevity space? Let's look at metformin. Let's look at rapamysin. Let's look at connectlyphlosing. Let's look at acarbos. All those drugs are used and have been demonstrated to have an impact on lifespan and health span. Most of them work in a similar fashion that is improving insulin resistance, decreasing glucose intolerance, which then decreases inflammation, and most of them are having an impact at the mitochondrial level. And that kind of took off from there in terms of let's try these things. And I fully disclose that I don't have up until recently, any rate, till yesterday, practically, experimental data to say that it's correct. It's mostly been, as you pointed out, NF1 and anecdotal type stuff. And I think it's a really key piece and I'm hoping that it will continue to play out. I think this concept of in terms of the mitochondrial dysfunction, the concept of inappropriately down-regulated autophagy, which is this biologic evolved clean-up mechanism, waste management system in, in all of our bodies, is the cause of pathology, a cause of inflammation, which then causes more mitochondrial trouble and more other system trouble. And if we can up-regulate autophagy, just as we see in the longevity world, if we can do that in our patients, we will see benefit. And I think we are now showing that pretty clearly in terms of the rapamycin trial that I've been involved in, you know, along with some other docs and researchers. And it's very exciting because it may, you know, it may move the needle on the whole mitochondrial piece, plus these other things. Right. And I'm with you. I've always used the longevity space and regenerative medicine space as because that's what we're doing. I mean, actually, to be honest, that's what I started doing 30 years ago. And then I said, I stopped because I didn't, I couldn't tell what you needed. And at least when I treated sick people, I knew what they kind of, you know, they at least I told I knew what they needed. But now the circle is coming around. We're getting enough data between genetics and all these testing modalities that we have, that we can actually maybe be giving people the right thing to keep them alive instead of just giving a lot of people stuff. So once one physician or whoever it is looks at the literature and begins to accept that the knowledge in the regenerative medicine world, the anti-aging world, the longevity world is real and solid. Then you can take that information and begin to apply it to our patients and then opens up a world of interventions that you and I never thought of you, at least I never thought of using. Okay? I mean, did I think in my whole life I would be prescribing rapamycin? I mean, that's like to give transplants, you know? Yeah, it's incredible. Yeah. And just because my take on rapamycin is, I mean, I should one aspect. The reason I've been using it a lot more with since COVID came is I think it has effects on kind of getting the teeth, the teeth regs to start functioning better. And I really think that's a key piece for so many people is that the teeth regs like went to sleep or got knocked out, you know, something affected them. And I think that's why I think we see so many, you know, B cell craziness with these super high antibodies, like all of our patients have EVVs greater than 600s and CMVs greater than 10 and that shouldn't be happening in 50-year-olds. Maybe the CMV. And again, T-reg dysfunction is a characteristic of getting old of aging. Yeah. Right. That's why you see it. You're right. You're the old people. And that connection and the T-reg dysfunction is probably a function of the chronic inflammation caused by the downregulated auto, I mean, so I'll connect it down regularly with baffergy, with causes mitochondrial, dysfunction, etc. Yeah. Can you talk a little bit more about that study or is that not ready for prime time yet? Yeah, I can talk some of it. Actually, the paper just came out as a preprint. So, waiting its final pure review. So we give rapamycin in a target dose. And in simple terms, in the study, this is a rapamycin study. I was giving rapamycin before the study. I do prescribe it off study as well. But in the study, it's not placebo control. And there's basically two aspects to the study and that reported in the paper. The research laboratory, the lab work is looking at proteins that are markers for autophagy, either being upregulated or downregulated. And the hypothesis was that it's down regulated in our MECFS lung cobit patients. That has been demonstrated in this study, meaning the proteins demonstrated. When you give rapamycin, which inhibits emetor, that upregulates autophagy, and the protein related to the correlates with upregulation goes up. So now we have protein markers to prove the concept. And at the same time, over a series of months, patients complete validated questionnaires, MFI and SF36 fatigue, cognitive function, that kind of thing. And we can demonstrate that as those proteins reverse and autophagy goes up, their questionnaires demonstrate their improvements in symptoms. That's pretty exciting. You know? Well, the drug that has potentially nearly no side effects. Yeah, at the doses you're using. I know some of you know that five six to seven weeks. What's interesting is that, you know, I mean, this, you know, some of the bunch of people are now, you know, for a long time, have been using, you know, fasting to do the same thing. But for many people who are really ill, fasting is not much of an option. That's what people forget is that when you're might have, not sure you aren't working, you don't do well fasting because you live on glucose. Right. Right. Exactly. And you need your muscles. So they look you fast, you lose your muscles. Yeah. Yeah. That's really exciting. And I, before we wrap up, I remembered what I was put in my point was that we're seeing, it's not just along COVID, but even in people who don't have along COVID, if you happen to have, for some reason, measure, like their D dimers, they're high. And the rise in cancers. And, you know, I mean, like the autoimmune, I mean autoimmune disease, all these things are happening in the last five years. They've been happening for longer than that, but they seem to have escalated in the last five years. So the dance that COVID has done with our immune systems is, is incredibly complex. And so you better go keep working and figure it out so you can come back next year and tell me what you're doing because, you know, I realize there's so much more to talk about with you, but any deep thoughts that you want to leave people with about what your next moves might be in this world. I mean, I think the most important thing to say is in terms of MECFS prior to COVID, it's been a pretty hopeless world for those patients for our MECFS patients. Hopeless because it was ignored by mainstream medicine, ignored by the NIH and the government. No research funding or near zero patients were ghastled over and over. And, you know, long COVID has changed the game. And I think we are on the verge of really learning a lot that can make a lot of changes. I mean, just in the last six months, I'd say, you know, it's Rapa Myson and the GLP ones and GIP drugs or Zepatide and some of the other ones I mentioned, a plasma for esses, exosomes. These are huge game changers potentially. And so, I guess I want to end my piece with something optimistic. I think, you know, things are going to get better. I think so. I mean, I see it, but we're still unfortunately, you know, there's literally, he said, there's a few hundred doctors who really, maybe a thousand by now, who really are thinking about this in its multi-dimensionality, you know, and I'm so glad that you're out there. Your podcast, what's the name of the podcast? It's called Unraveled Understanding Complex Olmus when it's on YouTube. And we have like over a hundred hours of this stuff that we talk about. It's very unscripted. It's a little bit, Eileen and I can get a little crazy when we're talking, a lot of laughing. I mean, we really enjoyed doing it. I hope people find it helpful. Yeah, you know, I'm sure because you and the good doctor, Ruhoy, besides the years of experience, have the imagination and the willingness to keep thinking that is what this world needs. So I really recommend it. Anyway, so thank you. I mean, David, anytime talking to you is a pleasure. It's always a learning experience. Look forward to doing it more. Yeah, me too. I really enjoyed it. Eric, I look forward to it. Thank you very much. And that's a wrap for today's episode. We hope you enjoyed the conversation as much as we did. We love hearing from our listeners and one of the best ways to show your support is by leaving us a review on your favorite podcast platform.