Long COVID and the Functional Medicine Approach to Care

Kalea Wattles, ND

For many patients who test positive for COVID-19, symptoms improve or resolve within days to weeks. However, for some, symptoms persist for much longer. This is known as long COVID or post-COVID-19. Symptoms of long COVID range in number and degree but often include extreme fatigue, joint and muscle pain, and memory or concentration problems. Long COVID research is a developing area of investigation with many details not fully understood. What is the functional medicine approach to long COVID symptomology, and what are the most effective known interventions?

Elroy Vojdani, MD, IFMCP

I think the most important thing is that there's no magic bullet or magic diagnosis for long COVID. I think we've seen over the last few years, people kind of bring that up, especially in the clinical offering space, there's one thing, one test, one drug, one this, one that; we know in functional medicine that things don't work that way. Long COVID is no different. There's no magical answer; you've got to just get to the work the way that we do. If you have a roadmap of all of the possibilities, it helps to narrow that. So I hope that this helps people kind of understand specific areas they need to look into if they're troubleshooting.

Kalea Wattles

In this episode of Pathways to Well-Being, we welcome functional medicine expert and researcher Dr. Elroy Vojdani to discuss long COVID, it's symptomology, and how personalized treatment plans that address root causes may help to manage this health disorder. Welcome to the show, Dr. Vojdani.

Elroy Vojdani

Thank you so much for having me.

Kalea Wattles

Well, I think we're all talking about long COVID again, and someone like me who's a primary care doctor, I really want to understand, how can I look for patterns or predict the type of patient who might struggle with long COVID symptoms? Will you talk to us a little bit about the long COVID persistent symptomology and what determinants you have found that can suggest the potential for this development of long COVID?

Elroy Vojdani

Absolutely. The most important skill for all of us in the clinical space is that really good history taking, that relationship that we build with our patients. So to me, that's always the most important piece of data that I can gather when I'm trying to determine are we dealing with long COVID or not. And from a clinical perspective, the hallmarks of long COVID are greater than three months of a combination of fatigue, dyspnea on exertion, or exercise intolerance, and some type of neurocognitive disturbance like brain fog. Oftentimes, joint pain and muscle pain myalgias will accompany that. But I think those three are typically found in virtually everybody who's suffering from long COVID. So you got to sit down, ask questions, make a timeline, and put those pieces of information together and say, "Is this a possibility or not?" And if the answer is yes, then I think you continue down that diagnostic line.

Kalea Wattles

Very helpful, and you have a recent publication in Viruses, and your research has investigated some of these potential biological factors that are involved in long COVID, and we know that might be viral persistence, reactivation of dormant viruses, autoimmunity, or disturbance in the gut microbiome. We're kind of doing a tour of the functional medicine matrix thinking about this. Will you elaborate briefly on some of these topics? And I think I'd like to start with gut dysbiosis and how this might be related to long COVID symptoms.

Elroy Vojdani

Yeah, absolutely. So the article that we published in Viruses with my dad and Michael Maes was really meant to be a summary of where we were to date and a summary of a lot of the research and publications that we had up until that point. So, kind of going back in time to where that research started, one of our bigger initial papers was published in Frontiers in Immunology in January 2021. What did we do in that study? We took monoclonal antibodies against spike and nucleocapsid protein of SARS‑CoV‑2, and we did a cross-reactive experiment with human tissue, basically trying to map out if, essentially what the cross-reactive epitopes were between spike nucleocapsid in human tissue. The theory was at that point, to remind you, this is pretty early in the pandemic where we're doing this research, is that there's a significant autoimmune cascade that is triggered in a significant portion of post-COVID patients that's contributing to their symptom set. And we found really striking cross-reactivity to certain tissues. One of them was mitochondrial tissue, another one was thyroid tissue, blood-brain barrier, neurological targets, and then another big cross-reactive antibody that we saw there was zonulin. So kind of brought up the idea that in the post-COVID state, you're dealing with an autoimmune component against maybe neurological tissue, mitochondria, explaining the fatigue, and then with the zonulin component the presence of intestinal permeability actually triggered by the viral infection itself. 

Several papers have come out since then continuing to argue that and also showing that there are specific dysbiotic pictures found in long COVID, post-COVID, also particular dysbiotic pictures that would make someone more susceptible to a severe infection of COVID. And I think the most fascinating pieces of literature so far show antigen persistence in the mucosal barrier for post-COVID patients, meaning that either infection or production of let's say spike or nucleocapsid can exist for years in the gut mucosa following the initial infection, which leads to that dysbiosis and leaky gut.

Kalea Wattles

So are we thinking that those who had a dysbiotic microbial environment before they had a COVID infection are at greater risk for having persistent symptomology?

Elroy Vojdani

That's one of the theories for sure, that if you had intestinal permeability going into it, this next hit to zonulin would represent a marked expansion of that inflammatory cascade and process in the gut, and then it would just keep rolling downhill from there. That is definitely one of the theories.

Kalea Wattles

Very interesting how you mentioned this autoimmune cascade that affected mitochondrial function and thyroid function. And of course, we'll see some remaining fatigue with those body systems affected.

Elroy Vojdani

Yeah, absolutely. I think overall, the role of mitochondria, both directly damaged by COVID, may be damaged prior to the infection from COVID and then also damaged in an autoimmune perspective following that, holding them back from being able to repair themselves. In my mind, it’s probably like the center of the multi-layered onion that is long COVID here.

Kalea Wattles

Right, and on the same line, thinking of autoimmunity, let's say someone has an existing autoimmune thyroid disease. Are you seeing a worsening of those symptoms following COVID infection?

Elroy Vojdani

Yeah, there's probably several I consider signature autoimmune diseases that if they existed prior to the infection, you see a pretty dramatic heightening of the autoimmunity afterwards. Hashimoto's would be one of them, without question, Graves as well too. Inflammatory bowel diseases seem to have a very heightened activity initially after the infection. And rheumatoid arthritis, I think, tends to be flared quite a bit afterwards as well too. But Hashi's definitely high up on that list.

Kalea Wattles

Yeah, that makes good sense. Will you talk through this viral persistence or viral reactivation? Does that mean other existing viral co-infections, I'm thinking EBV, things like that, that they are reactivated in the setting of COVID infection?

Elroy Vojdani

Yeah, so there's two potential scenarios. One would be SARS‑CoV‑2 viral persistence along with what's called super antigen activation. And what does that mean? In certain individuals with different immune genetic haplotypes, they seem to struggle with the ability to clear the SARS‑CoV‑2 infection, and they will get persistence of the infection for years. Again, studies saying that the antigens can be persistent in gut mucosa for two, two and a half years. There are studies that show viral RNA present within T cells for several years following an infection as well. So there's one subgroup because of genetic weaknesses in a particular part of immune defense will end up with just a persistent COVID infection. Another subgroup will have the acute infection, clear it appropriately, but it will create enough of an immunological imbalance that latent viruses will have an opportunity to reactivate. Epstein-Barr virus being the one that we talk about the most, but HHV-6 is also implicated in that as well. Certain studies in long COVID will argue that 60 to 70% of long COVID patients will have EBV reactivation, which in the literature would be measured by the presence of an early antigen, an IgG early antigen to EBV. So it looks like a huge piece of people that are suffering from long COVID have that, not the viral persistence portion of it, but actually the viral reactivation, so other viruses waking up following the infection.

Kalea Wattles

Wow, this is fascinating stuff, and I think clinicians, we all have those patients that have this history of all kinds of viral parts of their story. When we make the timeline, they've had all of these viruses. How can we prepare that type of patient knowing that COVID is a part of the ecosystem out there? Is there anything that we need to consider, any special considerations for that specific kind of persona almost?

Elroy Vojdani

Yeah, I think the most important question to ask in that scenario is, "Why was that individual so susceptible to a very common virus tipping things into such an uncontrolled place," right? So what do we know about that? And this is where I think functional medicine is perfectly suited to answer these questions because we're in the mindset of asking a "why" question from a whole body perspective. And quite frankly, very few other people are going to ask that question. So, if you kind of dive in and look at why, let's say not in the long COVID state, but just let's say the general population, why are certain individuals so triggered by EBV and others aren't? There's a whole slew of explanations for that. There was an article that was published just a couple weeks ago that showed specific immune haplotypes are incapable of dealing with an acute EBV infection. And it looks like those are the ones that are going to be susceptible to something like MS being triggered. But just open up the functional medicine toolbox, and you'll have all the other explanations for it. Somebody who had preexisting immunological burden is going to be primed for EBV creating a problem where otherwise they wouldn't. So did they have intestinal permeability? Are they dealing with chronic emotional stress? Do they have some type of environmental toxin exposure? All the things that we learn about in our functional medicine training pertain perfectly to this question.

Kalea Wattles

Yes, I can see clearly how functional medicine is particularly well suited to answer these questions. And thinking about all of the antecedents and triggers and mediators that might contribute to viral susceptibility or severity, let's start to layer on this piece of metabolic health, and will you help us understand how comorbidities, things like diabetes, obesity, how that can also potentially contribute to the development of long COVID?

Elroy Vojdani

Absolutely. So this is going to involve us opening our biochemical understanding once again. So I think one of the earliest signals in the early days of the pandemic was that individuals with certain comorbidities were much more prone to severe COVID or life-threatening COVID. And since then, those same comorbidities have been known to be the same risk factors for the development of long COVID, and what are they? Primarily metabolic dysfunction, obesity, I think, being at the top of the list. So you kind of like break down obesity and you look at the mechanisms of viral defense and what are the connections between those two. In other words, how does an obese individual end up in a situation where their viral defense is inefficient for what it's being faced with and therefore will suffer the consequences of that? 

So in metabolic dysfunction, let's say insulin resistance, type 2 diabetes, we have a situation in which cells are incapable of receiving adequate chemical energy into a cell. So their glucose transport from the plasma into a cell to be converted into ATP is dramatically hindered by the insulin resistance. The end result is that the mitochondria for those individuals are much more inclined to be running on aerobic glycolysis or anaerobic... Sorry, anaerobic glycolysis instead of oxidative phosphorylation. So again, going back to kind of basic biochemistry, when someone is running on anaerobic glycolysis at the mitochondrial level, the amount of ATP that they produce per molecule that comes in is dramatically less. They're producing two to four ATP versus when somebody is working through oxidative phosphorylation, they're getting somewhere between 30 to 36 ATP. So huge differences in the amount of cellular energy being produced for the amount of food energy coming in, essentially. 

Now, mitochondria are extremely fascinating in that the amount of energy produced will actually dramatically change the balance of reactive oxygen species being produced at the mitochondrial level. In other words, for a mitochondria to go through anaerobic glycolysis, to have to produce those two ATP, there are massive amounts of reactive oxygen species that are beginning to be produced at the mitochondrial level compared to someone who's going through oxidative phosphorylation, who have a much smaller amount of those reactive oxygen species necessary. So person A in metabolic dysfunction, insulin resistance, type 2 diabetes is in a massive deficit of antioxidants because of the massive production of reactive oxygen species from that energy dysfunction. Person B who is metabolically healthy has plenty of antioxidants because they're not producing so many reactive oxygen species to create the same amount of ATP. Mitochondria are incredibly sensitive to oxidative balance, so person A will end up further damaging their mitochondria by having to produce this ATP in this inefficient manner because the reactive oxygen species that they're producing through the energy chain will end up going back into the mitochondria and damaging the very fragile DNA. The next thing that you know, you have mitochondria that are basically stuck in a permanent dysfunctional state. And the fascinating part of it is that they also are inhibited from mitophagy. So when you kind of look at what that means from an immunological perspective, the damaged mitochondria in the insulin-resistant metabolic dysfunction individual leads to what we call permanent inflammasome activation, which is a pro-inflammatory prothrombotic state with a handcuffed immune system because of a lack of antioxidants. And if you look at what happens to somebody with severe COVID, it is exactly that, it's viral persistence with an uncontrolled prothrombotic and proinflammatory state. 

So the metabolic conditioning equaling the mitochondrial conditioning equaling the immunological function is the linear progression of how someone with metabolic dysfunction means immunological dysfunction. And of course, we term this now immuno-metabolism, because through our understanding of COVID, the link between metabolic health and immunological health has now been seen as one-to-one with the mitochondria at the center of that discussion.

Kalea Wattles

Well, that's a lot for us to chew on and digest. And we'll talk a little bit more about therapeutics, but I have to just ask, because it sounded to me like some of these immuno-metabolic changes, it sounded like they were somewhat permanent. Can we get someone out of this cycle if we replete their antioxidants and we start to address the metabolic dysfunction? Can we reverse this and course correct?

Elroy Vojdani

Yeah, absolutely. I think that's something that I've seen in my clinical practice and many other practitioners have seen in their clinical practice. One of the most important interventions for somebody that is suffering from long COVID is to not just fix their metabolic dysfunction but take it to as close to perfection as you possibly can. And in doing so, you can restore mitophagy, and by restoring mitophagy, you can clear out those damaged dysfunctional mitochondria and replace them with fresh, newly functioning mitochondria that now have the capacity to go back into oxidative phosphorylation and basically reset this entire mess. So when you start diving into the literature and you say, "Well, what works for a long COVID?" Everything that we preach is the foundation of functional medicine, which is lifestyle intervention. There's evidence there that it works already, which makes perfect sense when you look at the mechanisms.

Kalea Wattles

Okay, what a relief. And we're gonna come back to some of these lifestyle changes, but I wanna work us through the kind of the therapeutic order here. So we've gathered our information, we've listened to our patient, we've heard their symptoms, we've heard their history, now we should start doing a little bit of an assessment. Are there some biomarkers that we should order? When the patient comes in, they're clearly having symptoms. We've talked about autoimmunity and metabolic dysfunction and chronic inflammation. When that patient comes into the office, what's on your lab order list?

Elroy Vojdani

So, I think this is where you see that long COVID can be a mixture of many things, and you've gotta put on our appropriate Sherlock Holmes hat and ask the right questions and then get to the right data points. So it could be anything from cardiometabolic dysfunction, a chronic inflammatory immune dysfunctional state, as we mentioned, viral persistence of SARS‑CoV‑2, you have to look in some people, in fact the majority of people, for EBV and HHV-6 viral reactivation. We hit on the gut dysbiosis portion of it and intestinal permeability. There is a significant portion of long COVID patients who have very specific neuro-autoimmunity. So, if you start kind of walking up the ladder here, the next steps beyond cardiometabolic health in general, intestinal permeability, the things that I would consider the staples of functional medicine. If you need to, you start escalating the ladder into the specific mechanisms, which would be neuro-autoimmunity and then the mitochondrial dysfunction component, and then whether any other autoimmune diseases have been triggered by the infection itself. So, forgive me, that’s another very lengthy explanation, but that just speaks to the complexity of what long COVID is.

Kalea Wattles

Nothing simple about it, right?

Elroy Vojdani

No.

Kalea Wattles

So it sounds to me like there’s a mixture of some blood work, and then in the setting of dysbiosis, is this a situation where a comprehensive stool analysis would be appropriate?

Elroy Vojdani

I typically will do a comprehensive stool analysis along with some type of serological assay for zonulin, antibodies to zonulin and LPS would be how I would cover the gut picture there, the fasting triglycerides, insulin, glucose, are a good start on the metabolic side of things. And then if you're looking at the viral reactivation, make sure that the EBV and HHV-6 panels are done to completion. EBV is a little bit complicated. Most often it's an early antigen IgG that's gonna be present, but that's not everything. And then with HHV-6 and IgM and IgG level, and then from there you can get even more complicated if you need to.

Kalea Wattles

We could keep adding things. What about something, I'm just thinking about even an hsCRP, would that be indicated in this situation just to get an understanding of what's happening with inflammation?

Elroy Vojdani

I think that the generalized inflammatory state can be persistent for some people, but it tends to be relatively low yield once you're getting three months out. I still order it on everybody, of course, because let's say the person has periodontal disease and you don't know about it, you're gonna catch that with a persistently elevated CRP or something like that, right? So it's high yield, not always specifically relevant to long COVID, but maybe gives you some of the important antecedents.

Kalea Wattles

Right, right. This theme of mitochondrial dysfunction has come up again and again. And would you be willing to speak a little bit about this overlap between long COVID and what we might call chronic fatigue syndrome?

Elroy Vojdani

Yeah, absolutely. For those of us who have been involved in the research space for chronic fatigue syndrome, myalgic encephalomyelitis, I think that the parallels between long COVID and CFS were apparent, I think, from the beginning. In other words, I think most of the literature would argue that chronic fatigue syndrome was a spectrum disorder that had all these different spots in it, just like long COVID. And if you really want to break it down, it's probably virtually identical in as far as all the different pieces that can be a part of CFS, and then also looking at long COVID. Again, the bulk of CFS is kind of centered around the idea of a combination of mitochondrial dysfunction along with some type of chronic viral issue, whether it's viral persistence or viral reactivation. So those two themes definitely present within both of those, and I think the dominant theory in both of them.

Kalea Wattles

Well, let's now bring another condition into the mix because we're drawing all these parallels. Is there a connection or some overlap between long COVID and mast cell activation syndrome?

Elroy Vojdani

Great question. Mast cells being such an important primal, and oftentimes, as we see in functional medicine, unnecessarily aggressive part of the immune system, it makes very logical sense that it's a big part of this. I think when we see our mast cell patients, we're seeing a lot of brain fog, we're seeing a lot of fatigue, we're seeing a lot of gut issues, and that clinically overlaps with mast cell activation quite a bit. I think that there's one study that has been done that basically looked at the overlap of symptoms in mast cell patients and long COVID patients and basically theorized based on those symptoms that it is likely a significant role player. My biggest wish as both a clinician and researcher is that somebody one day develops a great mast cell activation panel out there so we could finally nail this diagnosis and not just contemplate it, I think, as much as we do.

Kalea Wattles

Well, we'll put you to the task of developing that. We've talked about that on this show a couple times, and our guests have always said it's so hard to screen for and to diagnose, and that's one of the biggest limiting factors. So yes, we'll check back with you later to see if you've made progress on that front. From your clinical experience, let's move into talking about some of these lifestyle-based approaches, because like you said, the functional medicine approach is particularly well-suited because we'll ask questions and remain curious and we'll start with that foundation of lifestyle. So I'd like to touch on nutrition and exercise and sleep quality and all of these things we think about for a really well-rounded approach. But first, let's be specific to the gut because we've talked about the role of gut dysbiosis. What are some of your favorite strategies to support a healthy and diverse gut microbiome so that we can create some resiliency in our body knowing that viruses are out there?

Elroy Vojdani

I think oftentimes you're going to spend the majority of conversation trying to reshape what it is the individual puts inside of their body, right? And to me, that's absolutely that highest yield. So I'm not sure what your clinical experience is, but mine is definitely that it takes multiple visits to get people to continue to perfect and adopt the mindset that they're a complex machine and they need to be fueling themselves appropriately. But certainly, if you want to consider the presumption that intestinal permeability is present in these long COVID patients, which I think is a good presumption, and that dysbiosis is gonna follow that, basically executing an anti-inflammatory diet, like the core diet, or a paleo diet, or an autoimmune paleo diet, whatever your flavor of doing that is basically one that removes the common antigenic triggers of intestinal permeability, number one, and then number two, provides a robust phytonutrient spectrum for the growth of the microbiome in a positive direction is paramount, right? In doing that, you are going to heal intestinal permeability, you are going to support the growth of a healthy microbiome. And the fascinating part of doing that is that downstream from that is immune regulation. Because remember, T regulatory cells in adults predominantly live in the gut mucosa. And from that immune regulation, you get mitochondrial restoration. 

So thinking of these kind of gut-centric diets as being gut centric I think is missing a little bit of the point that this is whole body immuno-metabolic intervention when you're executing these diets for people. So remove the inflammatory antigens, we all know them, gluten, dairy, grains like corn, you can go on and on, you can personalize that, or you can do an elimination diet. And then from there, we focus quite a lot on fiber as being fuel for the microbiome, but I think the appreciation for phytonutrients and antioxidants being incredibly potent. Prebiotics is I think where we are now and I think where the future is gonna be. So those nutrients from your veggies are where you get that.

Kalea Wattles

All right, eat the rainbow. We'll keep going back to that advice, it's gonna be a good one here for a variety of reasons. While we're exploring these lifestyle interventions, I wanna get your thoughts on exercise because I have felt challenged by this before. When we have a patient who comes in, they're already fatigued. And I know exercise will help them, but they are tired. And so that seems the fatigue itself is a mediator of their inactivity. What advice do you have when it comes to being physically active when you're dealing with long COVID or you're fatigued?

Elroy Vojdani

I agree with you, it's probably the biggest challenge on the clinical front.

Kalea Wattles

It's so hard.

Elroy Vojdani

Yeah, I mean, you imagine, try to put yourself in their shoes and try to imagine the same situation, they're so tired, they don't really want to get out of bed, and you're telling them to go for a 30-minute jog, it seems pretty unrealistic. But first of all, I educate them and say that there's literature that supports that even an exercise-only approach can improve, if not fix, long COVID. Exercise is so much more than I think what it looks like on the surface, right? It is brain supportive, you get dopamine, it helps your mood, you're already in a very difficult depressive state because of the long COVID. So it can help with your mindset, it relieves emotional stress. And the most potent inducer of immune precursor cells from the bone marrow has been proven to be weight-bearing exercise. So these people need as many immune stem cells as they get. So I tell 'em, "Listen, the only way that we're gonna get those things that we need is we start exercising." And I give them a slowly escalating week-by-week program that's written out six weeks at a time and try to continue to escalate that for them as their tolerance increases. 

Remember that mitochondriopathy is at the center of this as well. And what style of exercise really suits the mitochondria? It's gonna be zone 2 or zone 3 exercise, which puts the least amount of oxidative stress on them while trying to help them rejuvenate. So I will start them with something as simple as, give me five minutes up and down the block, and then tomorrow, give me six, and then the day after, give me seven, and we will just escalate that for a couple of weeks until they're walking for 30 minutes. And then from there, just continue to try to ramp things up into a brisk walk, light jogging, yoga, try to get the weightbearing in there at some point. You just have to start with the minimal that they're willing or capable to do, and just very slightly increase it, get those hormetic stresses going and let them adapt to it.

Kalea Wattles

Very approachable. I'm a big fan of the zone 2 training, so that seems like a great plan. And I imagine that as they're more and more active, energy is improving, it's motivating, and they're able to kind of pick up on that momentum. So that's great. Let's keep layering on here and talk about sleep, because in functional medicine, we know how important sleep is for our brain and our immune system, but do you find that you have to have this conversation quite regularly with patients who are dealing with viral illness or recovering from long COVID symptoms of refocusing on what seems to be a simple intervention, it's sleep?

Elroy Vojdani

Absolutely, it's probably one of the most common disturbances that you'll see in the post-COVID state. Even acutely post-COVID, people have dramatic sleep disturbances. And again, the first thing I do is try to educate them and I'll say, "Listen, COVID has a very significant neuroinflammatory component." In addition to that, sometimes let's say it triggers viral reactivation or neuro-autoimmunity. Those are their own contributors to this neuroinflammatory state. This is something that is physically happening to you. Unfortunately, it becomes a self-fulfilling prophecy. In other words, if you continue the sleep deprivation, it makes everything much worse. So we've gotta do something to make sure that we're pushing against that. So I preach, obviously, sleep hygiene to its max in these people, blue light blocking glasses after seven, nothing stimulating, try to only read, keep away from screens. That's not always possible, but I'll try to do that with everybody. Some type of mindful meditation practice immediately before we go into sleep, and then I think a lot of times, people will need sleep-supportive supplements in this situation, theanine, magnesium, melatonin, which has the dual purpose of being immune regulatory as well as helping them to restore their sleep.

Kalea Wattles

Mm-hmm, so it sounds like poor sleep habits make you more susceptible to viral illness, and then the neuroinflammation that results from COVID-19 infection can then further exacerbate sleep deprivation. Is that correct?

Elroy Vojdani

Absolutely!

Kalea Wattles

Wow, we really gotta get sleeping, everyone. We've covered some really important lifestyle factors. Now let's talk about supplements. Are there some supplements, you mentioned a few that you're using for sleep, but are there some that you're using with regularity to address things like micronutrient insufficiencies or just frank deficiencies that might play into the prolonging of COVID symptoms?

Elroy Vojdani

Yeah, I think that there are some that are so well documented that they're to me a little bit shocking that they're not universally applied. I mean, the data surrounding vitamin D3 deficiency, and not only susceptibility to COVID but long COVID, is concrete at this point. So obviously, you're maximizing vitamin D levels. We could argue what that would be, but certainly well above what's considered a low normal would be better for them from an immune perspective. The next place I go to after that are these really wonderful multifaceted mitochondrial support products that are out there now in the functional medicine world. Again, consider that immunometabolism is at the center of post-COVID, and mitochondria are the focal point of that. If you're providing mitochondria with the nutrients that they need, they're gonna be in a better situation. They're gonna produce less reactive oxygen species, their function will be better, and immune stress will decrease following that. So I'm typically, as a second layer, putting them on one of the companies out there who have a great mitochondrial multivitamin, acetyl-L-carnitine, ALA, CoQ10, PQQ, all the things that mitochondria love. Usually after that, I'm tailoring it to what the personalized investigation really says are the important buckets for them. So make the presumption that they've got the mitochondrial deficiency. And from there, what are the unique pieces of their long COVID, and fix that. If it's metabolic, I'm all for giving supplements that can help improve insulin resistance like berberine. If it's viral reactivation, you want their T cells and their natural killer cells functioning as strongly as they possibly can. So astragalus, echinacea, elderberry, mushroom extracts, vitamin C, zinc, quercetin, NAC, we've got a lot of things in our toolbox in that front. And then if it's the gut stuff, lots of things that can be used in that space. My personal favorite is using serum bovine immunoglobulins.

Kalea Wattles

Yes, so many tools in this toolbox in terms of lifestyle, and we've got our supplements. Now, I'm just coming freshly off of a large integrative health conference and an exhibit hall full of the fanciest high-tech things that we could choose from. Is there a role for some of these hormetic therapies like sauna and red light and hyperbaric oxygen therapy? Give us your sense of if those things should be part of our plan.

Elroy Vojdani

Isn't this like such a fun time to be practicing in this space? It's like a new tool…

Kalea Wattles

Fun time to be alive.

Elroy Vojdani

It is a really fun time, you know? Yeah, I mean, if someone is perfecting all of the important foundations of functional medicine and they want to do more, we have those conversations for sure. I think that there's enough robust literature centered around sauna that it seems to fit the long COVID picture really well because it has that immuno-metabolic benefit for people. Cold exposure, probably got less data to it, but people love it. It certainly has a humongous dopamine response afterwards. And a lot of times that just gets people engaged and going and feeling good. Hyperbarics too, they've got their own early data in that space. Red light therapy's probably a little bit behind, but so many people just swear by it anecdotally. These are all things that when people, when I've given them a report card for everything else that they're doing, and I'll say, okay, now we can move on to other things if you want to. And there are even fancier things out there. A lot of people are using methylene blue as a hormetic stressor in this space, right? I'm aware of many people getting cultured mesenchymal stem cells now for long COVID with some anecdotal clinical success, it's just never ending.

Kalea Wattles

It's never ending. My personal group chat with my doctor friends, it's full of conversation about methylene blue, so I'm glad you brought that up. But I like where you took this, that we're gonna focus on the foundations and then the strategies that are well researched and we've been using them and they're tried and true. And then, of course, there’s always something to up the ante if we want to, and I think that that’s very well said. All of these things, I think the ultimate goal is that we create resiliency in our immune resiliency. And will you take a moment and just describe to us what that means to you? Is it that you can engage in the world and you can encounter whatever pathogens, but you’re able to overcome them and return to homeostasis? Will you just define that term as you interpret it?

Elroy Vojdani

Yeah, absolutely, immune resiliency is having the reservoir to be able to meet the stressors of the environment and be able to recover to your baseline without issue, if you just want to break it down to its most simplistic definition. I think it’s pretty evident that we’ve lost that recently in society. Even more evident, I think, since COVID has come around. I mean, we’re filled with stories in the clinical space, I’m sure you are too, with viral infections that didn’t really seem to be such a big deal before. RSV comes to mind, right? RSV was something that obviously children struggled with, but hearing about RSV being so devastating to adults is relatively new. I mean, I have patients who have what I call “long RSV” now in the clinic, they basically look exactly like long COVID patients, but RSV was the documented trigger, and that all speaks to a lack of immune resilience and inability to rebound from the stressor you’re facing.

Kalea Wattles

Mm-hmm, so as we think about all of these drivers for lack of resiliency in our immune system and these predisposing factors, what can we do in terms of prevention? You’ve mentioned a lot of things with metabolic health and inflammation and autoimmunity, but if we wanna start making the right choices to have a protective effect on our health, what can we do for prevention now?

Elroy Vojdani

I think it goes back to those basics again. It’s boring, I think, to kind of hit on sleep and movement and connecting with people, taking care of yourself, eating well, but you have to be a master of those things. I think in today’s world, it’s just the reality. We are getting hit with more environmental insults than ever before as a species, and the only way to meet that threat is to up your game, and you have to do it across the board.

Kalea Wattles

Up your immune game, I like that. What’s something that you do, it doesn’t have to be the most important thing, but what is one thing that you do for your own health to promote immune resiliency in your own body?

Elroy Vojdani

I’m a fanatic about sleep, diet, and exercise. I mean, if I think a lot of people would comment, if they saw how much I am a fanatic about those things, but I know a lot of clean eaters, and I'm definitely the cleanest among them, and I'm religious about exercise and religious about sleep. I do very much practice what I preach. I think those things are the most important. Since I've done well in those realms, I do sauna and cold plunge every day as well too, and I love them to death. But those to me are just icing on the cake.

Kalea Wattles

Icing on the cake, certainly. Well, for any of our listeners who are feeling excited about this topic, what do you hope that our listeners will take away from this episode as they head back into the real world?

Elroy Vojdani

I think the most important thing is that there's no magic bullet or magic diagnosis for long COVID. I think we've seen over the last few years, people kind of bring that up, especially in the clinical offering space. There's one thing, one test, one drug, one this, one that; we know in functional medicine that things don't work that way. Long COVID is no different, there's no magical answer, you've gotta just get to the work the way that we do. If you have a roadmap of all of the possibilities, it helps to narrow that. So I hope that this helps people kind of understand specific areas they need to look into if they're troubleshooting. But overall, this is just another example of us doing our work in functional medicine, and the answers will come from that.

Kalea Wattles

I really took that away as I was listening. It seems like the best way to take care of ourselves, either before or after a COVID infection, is to bolster and build fortitude within all of our body systems. So, like you said, we can meet these challenges and return to balance. Would you say that's true?

Elroy Vojdani

That is absolutely true.

Kalea Wattles

Wonderful, well, Dr. Vojdani, thank you so much for spending time with us today and sharing these clinical insights and your experience. We know that you'll keep an eye on the emerging research on this topic, and we'll look to your expertise, and you'll continue to share all of the most important and relevant clinical information with us. So thank you so much for spending time with us today.

Elroy Vojdani

My pleasure, thank you for having me.

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