The Hidden Link Between Long COVID, Lyme Disease & Hypermobility with Dr. Ina Stephens

[00:35] Dr. Linda Bluestein: Welcome back to the Bendy Bodies Podcast. I'm your host, Dr. Linda Bluestein, the Hypermobility MD, a Mayo Clinic-trained expert in Ehlers-Danlos syndromes. Today, I'm thrilled to welcome back Dr. Ina Stephens. Dr. Stephens is a specialist in infectious disease, a physician of integrative medicine, and the associate medical director of the UVA Health EDS and Hypermobility Disorders Center. She has become one of the leading voices in multidisciplinary care for EDS, POTS, mast cell activation syndrome, and complex chronic illness. In this episode, we will be talking about the intersection of the immune system with connective tissue. This podcast is for education only, and it's not a substitute for personalized medical advice. Stay to the end for a hypermobility hack. Here we go.
[01:20] Well, I am thrilled to be back with one of my absolute favorite people, Dr. Ina Stephens. How are you today?

[01:27] Dr. Ina Stephens: I'm doing really well. How are you?

[01:29] Dr. Linda Bluestein: I am great. I am so excited to chat with you. I always love our conversations and I know that this has been such a requested topic in the hypermobility and EDS community, and you are just the perfect person to talk to about it. So this is going to be really fun and exciting.
[01:47] We know that infections and chronic illness can be so interconnected in ways that I think a lot of people don't necessarily appreciate. I think a lot of patients are starting to appreciate it, but clinicians are a little slower to catch on. And there are people who can point to a viral illness, COVID infection, mononucleosis, a tick-borne infection as the moment when their health changed forever. But it's not clear — are these infections actually causing these conditions, triggering them, or are we simply revealing something that was already there?
So Dr. Stephens, as both an infectious disease specialist and an EDS expert and someone who cares for patients with all of these conditions, you're so uniquely positioned to help us sort through what's fact, what's theory, and what are some misconceptions. So first, what are the most common questions you hear from patients about infections as they pertain to EDS-related conditions?

[02:44] Dr. Ina Stephens: Thanks, Linda. I think that these are really important questions and really important topics to bring up, and I get asked these questions all the time by both patients and providers. The number one question that I actually get asked by patients is, is there such a thing as a post-infectious syndrome? Is this infection actually causing a problem, or could it be related to my problem? I've read about it — is there a post-infectious phenomenon?
[03:22] And I have to say, the most important thing for them to understand is that not only is the answer yes, but we have seen this before historically for a very long time. I can give so many examples of infections that are related to illness — chronic illness or acute illnesses.
[03:49] One of the first things I say to patients is, nobody remembers this, but I would like you to remember the 1917 Spanish influenza outbreak. What happened right around that time and during that time? Well, there was a whole slew of patients — some of the literature says up to 40% of patients who potentially had the Spanish influenza, the 1917 outbreak, developed something called encephalitis lethargica. Now, encephalitis lethargica sounds pretty similar to myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS. It's not too dissimilar. There are obviously similarities and some great differences. And we do not have absolute proof that this was cause and effect — we do not have autopsy specimens from 1917, we do not have PCR and DNA data from 1917 — but there's a lot of causal relationship, a lot of association.
[08:10] And then there are the ones we see all the time: acute rheumatic fever associated with strep; Enterovirus D68 and the association with acute flaccid myelitis; Guillain-Barré and influenza and Campylobacter. And even post-infectious reactions to gram-negative bacteria like Yersinia enterocolitica, Salmonella, or meningococcus with post-infectious reactive arthritis.
[08:10] We know that infections can set off immune cascades. They can set off immune reactions. They can set up shock, and they can set up persistent infections. They can also cause your own body to produce autoantibodies. All these infections can do different things at different times and to different people. So the quick and dirty answer is, is there such a thing as post-infectious phenomenon? My answer is absolutely yes. And we could talk about that in detail if you'd like.

[08:10] Dr. Linda Bluestein: Yes, absolutely. Because I think so many patients are aware of this, but I think a lot of clinicians are not. So I hope that we have a lot of clinicians listening to this episode because I think it's going to be really important.
[08:10] I know that you are — if I'm remembering this correctly — in charge of a clinic called the Diagnostic Dilemma Clinic that deals especially with complex patients. Tell me a little bit about that because that is so fascinating to me, because so many of us get really nervous and scared with really complex patients. But you, in this setting, you're asking for the most complex patients, it sounds like.

[08:10] Dr. Ina Stephens: Yes, that's correct. And I love complex illness. I mean, I went into infectious disease — and I think I said this the last time — what so intrigued me about infectious disease was just the mind-boggling detective work that went along with it, with patients that came in with unknown symptoms. How do you get to the bottom of that? You really have to take a very detailed history and physical. And to me, that is such the art of medicine, and it's such a fascinating part of medicine. If you really listen to the patients, a lot of times you can get the answers. Lab tests, physical exam, imaging — those are supplemental and can be helpful. And I use them quite a bit, but a lot of times you're hearing the answer from the patient.
[08:10] So the Diagnostic Dilemma Clinic — I created that actually as kind of an offshoot of the infectious disease clinic. We have an infectious disease clinic at UVA for outpatient referrals. A lot of these patients will get referred for a kind of simple infection, maybe something like a chronic recurrent Staph aureus infection, an MRSA infection, and how do we deal with that? That's fairly simple — cut and dry, maybe an hour of an appointment. But then there are those patients who have all these vague symptoms and maybe fever is part of it. So fever of unknown origin, which is usually defined as fever for 8 or more days for no real reason, no specific markers, or they have vague symptoms and they're being evaluated by their pediatrician with still no good answer, no good treatment options. Those are the patients that I would get referred to the Diagnostic Dilemma Clinic.
[08:50] One thing that I noticed over the years is that a lot of these patients fell into categories of post-infectious phenomenon from different types of infections. And you can help diagnose that, potentially help treat it. Not all of them are treatable, but there are ways to support healing for some of the post-infectious phenomenon. With all that said, a lot of those patients also presented with symptoms of hypermobility spectrum disorder, Ehlers-Danlos — symptoms of basically every body tissue and body system being affected, and nobody really put it together. So to me, the Diagnostic Dilemma Clinic was like the foreground of where I started seeing all these patients. And the more you see them and the more you diagnose them, the more they get referred.

[09:46] Dr. Linda Bluestein: How do you work these patients up? So they tell you, "I was fine until I got COVID," or "everything started after I got EBV or something like that." What do you actually do in this setting in terms of how you're approaching the workup?

[10:03] Dr. Ina Stephens: Every patient is a little bit different. So there's no absolute cut and dry approach I do with every single patient, but obviously a really in-depth history and physical is going to be key. When I say in-depth history, I go from top to bottom. If "now" is "I've been feeling this way for years," that's still now — that's still history of present illness. I'll literally start from the head: do you get headaches? Do you get dizziness? Eye pain? And I work my way down the body to really include every body part. I get a complete review of systems so I really understand what they're dealing with and how long they've been dealing with each issue, what the manifestation of each issue is, whether it's intermittent, what kind of pain goes along with it.
[10:59] And then obviously this includes their past medical history. Is there any chance these patients are potentially immunocompromised? Is there something I need to know about? A really in-depth family history — is there a family history of autoimmunity? A family history of congenital infections? I can go on and on. Obviously a history of hypermobility in the family, I always ask about. A very in-depth family history is very helpful.
[11:23] I ask a lot about their social history. What are they able to do? If they're having a litany of complaints but they're still able to kind of get up and do what they need to do versus they haven't been able to literally get off the couch in about a year — that's a very different patient. And I may have to do a completely different evaluation from there.
I also ask them about their lifestyle. What are they putting into their body? And that is not just food — that's stimulation, screen time, sleep, exercise, how they're healing their body, what they're doing to their body on a daily basis, and what's their support system.
[12:51] And then I do a very in-depth physical exam. A lot of patients will say, "Wow, nobody ever really looked at my ankles that way," or "nobody actually really looked at this part of my body that way," because I think there are clues in the physical exam that are sometimes overlooked.
After that, I do some targeted lab work. I look for classic inflammatory markers and not-so-classic inflammatory markers. Most patients will have come in having gotten maybe a baseline CBC and a sed rate or a C-reactive protein, but maybe I'll look for a few of those second-tier studies as well — like Sjögren's antibodies or cyclic citrullinated peptides, which can be a sign of rheumatologic disease even if everything else is normal.
[13:25] Then I look into a number of different serologies for different infectious agents, mostly targeting agents that I could potentially treat if they haven't been treated already — things like Lyme disease, Bartonella, babesiosis, some of the tick-borne illnesses. If they haven't been treated for them, they probably deserve treatment. That may not help some of the post-inflammatory phenomenon that could be going on with these agents, but at least get rid of the agent first and foremost.
[14:06] And I do look for a number of viruses. I look for SARS-CoV-2 titers and nucleic acid, the nucleocapsid antibody — how high is it? If they tell me they had COVID once back in 2020, they really shouldn't have significantly high titers. Maybe they've had repeated infections, maybe a persistent infection. Same thing with Epstein-Barr virus — I look for reactivation of EBV.
[14:41] Then I look at some baseline allergies, because a lot of these patients come in with symptoms of potentially mast cell activation, which is very, very common. And I diagnose that quite often in patients with post-infectious phenomenon, but I want to make sure I'm not missing a regular IgE allergy. So I'll get RAST testing for the major trees, molds, grasses, and some of the foods. If they come up significantly positive to Timothy grass, they may actually deserve immunotherapy.
[15:26] And I look at a lot of vitamin levels. A lot of our patients — especially patients who've had a prolonged infectious phenomenon — are probably not eating well and could be vitamin deficient, could be having problems with processed foods. So I look at iron levels, ferritin levels, different vitamin levels. Vitamin D is tremendously important in terms of inflammation. You just had Dr. Planikoff on a couple of weeks ago, and he spoke for an hour — you could talk for hours on vitamin D. It's a very important anti-inflammatory. And most of my patients who are sick and spending a lot of time indoors have very low vitamin D levels and are really not helping to treat their inflammation. So that goes into a little bit of the workup.

[16:38] Dr. Linda Bluestein: That's perfect. And I want to come back to treatment of reactivated EBV and some of these other things, but I want to continue on first on the workup. You mentioned something that I want you to explain a little bit more — you said something about congenital infection. Can you explain what that is and why it's important?

[22:52] Dr. Ina Stephens: I think I was really meaning a history of childhood recurrent infections, not necessarily congenital infection, because that's a little bit different. As a pediatric infectious disease specialist — and I'm sorry if I misconstrued that — a congenital infection is usually an infection that the mother acquires while pregnant and that affects the fetus. A classic example would be congenital cytomegalovirus. If a mom develops primary cytomegalovirus in the first or second trimester of pregnancy, the infant can develop an infection of the entire reticuloendothelial system. They could end up having problems with microcephaly and significant neurodevelopmental delay — it very profoundly affects the newborn.
[22:52] That's different from somebody who may have a primary immunodeficiency that presents in childhood. So when I ask about family history of recurrent infections, I'm asking: is there somebody in the family who had recurrent ear infections, sinusitis, pneumonia, bone and joint infections, meningitis? Am I worried about something called SCID — severe combined immunodeficiency — or common variable immunodeficiency, or do I have to work them up for certain immunoglobulin deficiencies like Job syndrome or Bruton's syndrome? There are many, many primary immunodeficiencies that need to be taken into consideration. So I will look into that. That's more what I was talking about.

[22:52] Dr. Linda Bluestein: What about long COVID? Have you observed, amongst your patients — and I know there is some research on this and we need more for sure — what have you observed in terms of patients with joint hypermobility, with or without a full diagnosis of EDS and a connective tissue disorder, developing persistent symptoms after COVID?

[22:52] Dr. Ina Stephens: I have spent a lot of time thinking about this because it's a great question and I get asked it all the time. The answer is yes, I see this a lot in my hypermobile patients.
[22:52] Some facts about long COVID. About 10% of the general population will develop a long COVID symptom or a long COVID-type syndrome after acute COVID infection. There were about 7 billion COVID infections thus far since the beginning of the pandemic, and about 700 million cases of long COVID have been identified. Now, remember, we do not have a specific biomarker for long COVID — it's a clinical diagnosis. There's really no case definition that is perfect, because 60 to 100 different body symptoms or systems can actually be part of the long COVID syndrome. So when I'm saying 700 million patients have developed long COVID, I think that's probably understating the actual number. They say anywhere that long COVID develops in 10 to 57% of patients who've had COVID.
[22:52] Now, who's the 57%? There was a really interesting study that came out in October, put together by the NC3 Consortium, that looked at hypermobility in relation to long COVID. The outcome data shows that patients with hypermobility — whether it's hEDS or hypermobility spectrum disorder — actually have a 4 times greater likelihood of developing long COVID than the general population, 4 times more likelihood than someone who is not hypermobile.
[22:52] So when I am looking at a patient in my office with hypermobility, I always ask them about trigger onsets. Did they notice they got worse after a certain point in their life? And I often get, "Actually, yes, I was doing well in college until January 22nd, and then everything went downhill." And, oh, what happened? "Well, everyone was sick. I had a bad sinus infection." Were you tested for the flu or COVID or RSV? They may not have been, but they can pinpoint it to that time. And then all of a sudden everything went downhill. That's a very, very common presentation.
[22:52] I have had patients who will come in and say, "I never really had any problems until I got COVID," or "until I got this horrible illness that nobody could identify." And when I examine them, they absolutely meet the criteria for either hypermobility spectrum disorder or hEDS. And they will say, "Well, I never really was that hypermobile, I never noticed that this was a problem of mine," but they absolutely have the same overlapping symptoms.
[22:52] So a big question I get asked a lot is: what was the trigger? Is it because I was hypermobile and there's something wrong with me and that's why this virus caused this in my body? Or was I just fine and then this virus did this to my body? That's the big chicken-and-egg question. I think it's probably both. If you are hypermobile — even if you really don't have many symptoms early on — there may already be some connective tissue dysregulation, some connective tissue laxity, some extracellular matrix immune dysregulation causing some sensory-neural issues. We know that they can already have some mild autonomic dysfunction without even really knowing it. Some mild mast cell activation. I have patients all the time who say, "Oh yeah, I get hives all the time — I've been doing that my whole life," and they never thought anything of it. So they've already been kind of set up, and then they get a virus and it kind of puts them over the edge.
[24:08] Or there is a question: can this virus cause immune dysregulation within the connective tissue, setting off the mast cells and then causing underlying connective tissue dysregulation? I think until we absolutely know what causes hypermobile Ehlers-Danlos syndrome, we're still going to be questioning this. We don't know if hEDS is caused by a primary collagen defect. We've been looking, looking, looking. Is it polygenic? Is it because you're a certain HLA haplotype and you're predisposed and developing autoantibodies? There are so many potentially underlying issues. And because it's such a hugely variable population of patients, we don't even know that every patient with hEDS has the same underlying pathophysiology. So it's a very difficult question to answer until we find out. There are a lot of unanswered questions here. I think this is a tremendous area of research, and I'm excited to see where it's going.

[25:39] Dr. Linda Bluestein: Yeah, I definitely think that what we're currently calling hypermobile EDS — this phenotype — is most likely more of a final common pathway, that we're getting there different ways. Because there's just so much variability. While we have the common threads that lead us to have the same diagnosis, there's also just so much variation.
[26:04] I'm curious — I've had patients exactly like what you're describing, where they say, "I was doing fine, I got COVID, and then the wheels fell off the bus and all these things happened and my connective tissue started to fall apart." Have you also seen this with mold? Because I've also seen patients who say, "Yeah, I think I was fine until I lived in a moldy apartment."

[26:28] Dr. Ina Stephens: Absolutely. We know that post-infectious phenomenon can happen with basically any infection. It can happen with any virus — anything from COVID to enteroviruses, to Coxsackie viruses, to Zika virus and HIV. It can happen with bacteria: as I mentioned, with strep you can have permanent damage with acute rheumatic fever, and you can develop an antibody reaction to some of the staph enterotoxins. To parasites — Giardia, Cryptosporidium. And obviously with fungi — Aspergillus, Saccharomyces, Cryptococcus — you can develop a post-infectious phenomenon.
[27:21] What really occurs is that any one of these infectious agents can cause immune dysregulation in the body. All of them can cause disruption with interleukin-1B, interleukin-18. They can all elevate TNF-alpha. You can have dysregulation of your T helper cells. We see that with spirochetes — Lyme disease can cause problems with, basically, alteration of the ratio of your Th1 and Th2 T helper cells, which causes a problem with your T cell response and how you're able to fight other infections. All these different agents can do some real underlying damage to the immune system.
[28:17] And we haven't even talked about what can happen when any of these agents — particularly something like COVID — do to the mitochondria of cells. There are so many different mechanisms that cause problems in the body that can lead to these post-infectious symptoms. I just named a few: immune dysregulation and mitochondrial dysfunction. But the onset of sensory-neural inflammation, particularly involving the vagus nerve and autonomic dysfunction, is seen probably in 90% of patients with long COVID — what we call PASC, or post-acute sequelae of COVID-19.
[29:14] This goes back to the question of why do patients with hypermobility have an increased likelihood of developing it. The recent NC3 Consortium paper that came out in October 2025 showed that patients with hEDS and HSD who have one or more comorbidities — whether autonomic dysfunction and POTS, or mast cell activation, or both — their likelihood of developing PASC goes up even higher, because they already have that dysregulation going on.
[29:56] So that was a simple answer to your question about mold — yes, mold can turn this on too.

[30:10] Dr. Linda Bluestein: None of it's simple, right? None of it is simple. We will definitely track down that study and link it in the show notes because people are going to want to see that.
[30:19] Before we go to our break, I want to ask about the mitochondrial dysfunction and fatigue. I think a lot of people don't necessarily appreciate how many people with hypermobile EDS and HSD would comment that fatigue is a life-altering problem for them until you start seeing more patients. I feel like 90% of my patients have problems with really severe fatigue. There are probably many different mechanisms, but what are the top ones when it comes to these post-infectious syndromes?

[31:02] Dr. Ina Stephens: You're absolutely correct about this — fatigue is a huge problem. And I will take that one step further and say it's the what we call post-exertional exhaustion or post-exertional malaise, or PEM. It's that "I'll try to exercise, but then 24 hours later I can't move — I just can't get off the couch. I'm exhausted. I need to sleep 2 days after working out or maybe just doing something for an hour." That post-exertional malaise is almost like your body has been completely run down and can't do anything.
[31:43] I think this really goes to the piece where particularly COVID causes mitochondrial damage. And we know that a lot of other viruses and infectious agents do this. Some of the interesting data came out of autopsy specimens — a study that looked at autopsy specimens of patients who had passed and who had long COVID. They looked particularly at the nervous system and the vagus nerve. And what they saw was spike protein throughout the vagus nerve, throughout the myocardium, throughout the brain, in different areas — central, peripheral, in the lymph nodes. So we know that there was persistence of viral RNA. And number 2, the mitochondria were damaged in a number of these cells.
[32:41] What does the mitochondria do? The mitochondria are your body's energy warehouse. It literally takes the food you've eaten that has been broken down in your bloodstream and GI tract and breaks it down even further to produce adenosine triphosphate, or ATP. ATP is your power energy for your body. The more ATP you produce, the more energy you're going to have, the more your muscles are going to grow, and just the better you're going to feel. Well, if your mitochondria are not able to take that food and successfully make it into ATP, you're going to be exhausted. You're going to have muscle atrophy. Your muscles won't grow as well. Sarcopenia is probably one of the highest risk factors for aging, dementia, weakness, cognitive decline, problems with focusing, and overall post-exertional malaise.
[33:56] And when you have mitochondrial damage, it's not just that you're not able to make new mitochondria — you're also having the mitochondria set up their own inflammatory cascade with their own cytokines and chemokines. So you're getting even more inflammation, which just increases the risk further.
[34:24] Do we have a great therapy for this? We have some — which I can talk about. There are some supplements, and some promising-looking supplements, that can actually help with mitophagy — kind of getting rid of old mitochondria and helping the body make new mitochondria, or giving mitochondrial support. I think that's a huge part of the treatment plan for anybody who has a post-infectious phenomenon.

[35:01] Dr. Linda Bluestein: That is a perfect lead into our break. We're going to take a quick break, and when we come back, I really want to dig into this more — the mitophagy, helping our mitochondria, supplements that can help with fatigue, sleep, and muscle development. So we're going to take a quick break, and when we come back, we are going to talk about what you can do about all of this.

[38:04] Dr. Ina Stephens: Well, I think I want to start with the best I try to do first, which is to diagnose what their post-infectious phenomenon is. If I can kind of pin it down — well, I think this is long COVID, or this is post-acute sequelae of COVID-19, or this is reactivation of Epstein-Barr virus, or this is untreated Lyme disease — is there an affecting player we still need to get rid of? As I said, I always look at other tick-borne illnesses, because when a patient comes in and they say, "Well, I just got treated for Lyme disease, so I know it's not Lyme" — that is true. The Lyme spirochete is exquisitely sensitive to antibiotics. However, 2 things. Number one, it's not getting rid of a potential inflammatory cascade that has already happened — and that in itself needs to be quieted down. And number two, when you have one tick bite, that's the one tick we found. There are millions of ticks around. So there are potentially other ticks you may have been exposed to, and there are different infections carried by ticks, including Bartonella, babesiosis, STARI, alpha-gal — I can go on and on.
[39:53] So I try to look for the underlying infection and treat that first. Then we go to: how can I build the body back? How can I quiet down the inflammation so we can start regenerating some muscle tissue?
[40:10] I'll always start with the simple and the most effective, which is dietary guidelines. I look at what people are eating. My ear is out for pro-inflammatory foods and highly processed foods, which have a lot of dyes and a lot of chemicals. And just in case anybody was ever wondering, dyes and chemicals can turn on mast cells like nobody's business. So getting rid of dyes in food, getting rid of chemicals in food. I also look at their medications, because some medications for some reason are bright blue or bright red — and you may be reacting to that dye or another excipient in that medication. I had one patient where it turned out to be the silicon dioxide in her pills that she was reacting to, and once we took that out, her mast cells quieted right down.
[41:23] When I talk about dietary changes, I don't put them on a diet — "diet" is a four-letter word. It's more guidelines, food substitutions, getting whole foods in, higher fiber foods to feed your microbiome. COVID-19 can cause GI gut dysbiosis and microbiome disarrangement, and it is so important to have your microbiome doing its work for you, creating the neurotransmitters that it needs to create. Feeding the microbiome with fiber and short-chain fatty acids is exceedingly important. And foods that are very high in omega-3 fatty acids. I also usually put them on a kickstart of an omega-3 fatty acid supplement.
[42:22] As I said, vitamin D — I actually usually start everybody on vitamin D even while I'm checking their level, assuming they're going to be low. I usually start them on 2,000 IU a day, feeling like that's what they just need to be alive, and we may adjust it depending on the level. I don't think there's any patient I've actually really lowered that dose for. Some I've increased — maybe 5,000 a day for a few months.
I always start with magnesium as well. Most of our diets are magnesium deficient, and there are different formulations. Magnesium glycinate and magnesium L-threonate go straight to the blood-brain barrier — they help with calm, muscle pain, sleep, and muscle ache. Magnesium oxide and citrate are really great for constipation. So it can be a combination.
[43:20] When I'm talking about helping to build the mitochondria, there are certain enzymes and compounds that can be really, really helpful. One of the first ones is coenzyme Q10. Coenzyme Q10 is an enzyme that's actually naturally produced by the body — we get it from food, but most of us don't eat enough of it to really help. It's actually a cofactor that helps with the electron transport chain in making ATP. So it actually helps with the production of ATP, and a lot of patients will feel just an increased boost in energy after starting on it.
[44:07] The other one I usually start is acetyl-L-carnitine. L-carnitine in and of itself is also a mitochondrial supporter — it works with helping to create more ATP from the mitochondria. The acetyl part crosses the blood-brain barrier, so it could potentially help with some of the inflammation going on in the CNS. And we know there's certainly a lot of damage with COVID in the CNS — in the hippocampus, the medulla, the whole brainstem, spinal cord, and the periphery, including small fiber neuropathy. Acetyl-L-carnitine can also be used to make acetylcholine in the brain. So it's definitely part of the compound set that I like to include.
[45:17] Another set of compounds I sometimes suggest is in the nicotinamide family — NMN, NAD+, and NAC. These are all cofactors that help with improving mitochondrial health, improving the production of ATP, and moving along the electron transport chain. Your body can naturally produce some of these, but not all of them, and some people produce more than others.
One important thing to note about NAC is that it is actually the precursor to glutathione. Glutathione is especially helpful if there's been reactivation of Epstein-Barr virus, in terms of helping the liver to detoxify and to get rid of free radicals. So glutathione is particularly important — something I would give to basically almost every patient with reactivation of EBV. And since NAC is a precursor to glutathione, sometimes I use both NAC plus glutathione, depending on the patient and whether I've found reactivation of Epstein-Barr virus.
[47:24] And there are some others that are more experimental. There is a very interesting compound called urolithin A. Urolithin A actually helps with mitophagy — it is one of the top compounds that gets into the cell, removes the damaged mitochondria, and allows space for fresh mitochondrial growth. Your body won't regenerate mitochondria if it's filled with damaged old mitochondria, and the removal of damaged mitochondria doesn't work very well after a post-viral infection. So having something to help remove it so you can make new mitochondria is really important, and urolithin A seems to kickstart that whole process.
[48:25] Urolithin A is usually produced in our own microbiome, but you have to have a really healthy microbiome to produce it — and only 30 to 40% of the population actually does. You need to have the right amounts of Bifidobacteria, Proteobacteria, and Clostridium. If those aren't in the right amounts, you're not going to produce urolithin A and you need it from an outside source. The outside sources include berries, mostly pomegranates — but really, really high-dose pomegranate, like a room full of pomegranates. So it's not easy to get that kind of dosing. There are some interesting studies looking at urolithin A compounds and supplementation. Right now I think they're still very experimental, but the research seems very exciting. And it is quite expensive, and it really only looks like there's one brand out there that seems to be efficacious.
[50:00] Could I prescribe glutathione? Yes, I actually can. And I'll tell the pharmacy I want it in liposomal form so it's orally absorbed really well. I could actually even give it IV if needed.
[50:33] Then there are some other novel therapies — and some not so novel — that I use for patients. One of the not-so-novel therapies that I use quite often, and I know you do too, for patients with post-infectious phenomenon due to long COVID or other agents, or just severe hypermobility and comorbidities with chronic pain, is low-dose naltrexone. Low-dose naltrexone works in numerous ways that we don't quite even fully understand. One way it works for pain is it blocks the mu receptor in the brain, so your body starts pumping out its own natural opioids. But it also decreases inflammation throughout the body. It restores something called the TRPM3 ion channel in natural killer cells — and that can be damaged in patients with long COVID. So restoring this ion channel in the natural killer cells can actually help decrease inflammation. And it is also, very interestingly, a mast cell stabilizer. I don't know exactly the fine details of how it causes mast cell stabilization — I'll punt that to you or to Dr. Anne Maitland — but it does seem helpful with quieting down the mast cells and preventing them from degranulating.
[52:26] And then there's a lot of speculative and interesting other medications and products that people have asked me about. I think it's very specific to what etiology is causing your post-infectious syndrome. For example, if we know it's COVID, could a prolonged high dose of an antiviral like Paxlovid help? Well, we don't know — there are studies going on right now looking at this. Paxlovid is a combination of 2 antiviral medications, ritonavir and nirmatrelvir, and it can be unpleasant. So to just say to a patient, "here, take this for a couple of months," I don't know. There are ongoing trials with that.
The same question comes up with reactivation of Epstein-Barr virus. People have asked about antivirals — high-dose ganciclovir, or maybe valacyclovir, which is acyclovir but more bioavailable; or tenofovir, which is pretty toxic; or foscarnet. There are studies going on. To me, I don't feel like there's enough data yet. And I always take the risk and benefit of every medication and therapy very seriously. A lot of times I will say to a patient, "I want you to read all you can about low-dose naltrexone and get back to me next week and let me know if you want me to start this." I'm not just going to recommend and start it without patient input. I think it's very important that the patient has their own informed decision-making. Some are really no-brainers with very little risk — coenzyme Q10 is probably high on that list. But something like urolithin A, which hasn't been fully studied yet and is pricey — those all require a risk-benefit discussion with the patient.
[55:58] And this goes along with some of the other medications that have been looked at, including biologics and monoclonal antibodies for long COVID, for reactivation of EBV, for a number of these different post-viral, post-infectious phenomena. I don't know if there's enough data yet to say let's go for it. IVIG is also in that category. Right now IVIG is not FDA approved for long COVID, but there are some anecdotal studies and some good case reports and some interesting data that it may really help with autonomic dysfunction and with small fiber neuropathy. I offer it to patients and say: risk-benefit, pricing, insurance, how much are we suffering? Because these patients are suffering. My responsibility is to make sure they are informed about what could be helpful, what the side effects are, and to come to a shared, informed decision.
[57:30] The last medication I'm going to put into this category is the GLP-1s. There's a lot of data on how incredibly helpful the GLP-1s can be outside of treating obesity. And even at very, very microdosing — practically a hundredth of the dose — for patients with mast cell activation. I do that too. I think it can be very helpful. It could be the tiny little tip of the iceberg that just pushes the patient over the edge to finally feeling well, and at that little microdose it almost has no side effects. But higher doses that have been implicated in treating long COVID do have side effects. And these medications are often not covered by insurance and can be very expensive. So informed decision-making is really, really important.

[58:49] Dr. Linda Bluestein: That was fantastic. And I was making more notes as you were talking, so I'm going to go in reverse order for a few points of clarification before we have to wrap up.
[59:04] The first one is LDN and the ion channel you were mentioning for natural killer cells. Is this the mechanism by which LDN can help your immune system? Because I observed this absolutely clinically — before I started taking LDN, I would get so much more sick than my husband. I would get sick all the time and he would hardly ever get sick. And knock on wood, I don't get sick like I used to since I started LDN. I definitely have observed that amongst so many of my patients. And I was just curious about what you were mentioning with the natural killer cells.

[59:47] Dr. Ina Stephens: Yes. It helps reactivate the natural killer cells that may have been disrupted or deactivated by the inflammatory cascade that can happen after a viral infection. Remember all those interleukins, all the cytokines, the chemokine storm — those all have effects on your interferon and your natural killer cells, and they disrupt them completely. In a sense, you become almost immunosuppressed. Not the same as a congenital or inborn error of primary immunodeficiency, but it can be very, very detrimental. You're susceptible to just about everything. And your natural killer cells are your number one fighters against viruses.

[1:00:32] Dr. Linda Bluestein: And then when you were mentioning NMN and NAD and NAC — nicotinamide, vitamin B3, which is also niacin, correct? I've heard that nicotinamide also helps with basal cell skin cancer, which I've been struggling with a lot, so I've been taking that. But I know there are some people who actually get NAD+ infusions or subcutaneous injections. Do you think that is more beneficial than the oral preparations, or is there not really a substantial benefit there?

[1:01:17] Dr. Ina Stephens: Ooh, tricky question. And the reason that's a tricky question is because we don't know the answer. There's not enough data. What we do know is that NAD+ is not well absorbed orally. NAC is absorbed better, but what it looks like is that you actually need a pretty high dose — some people would say 600 milligrams, but the data probably supports more like twice that, around 1,200 milligrams. And 1,200 milligrams of NAC a day is expensive.
As for intravenous absorption versus oral — nobody really knows; it's just not been well studied. I've heard some very interesting anecdotal reports. I know people who go and get these at wellness spas and say they feel great afterwards for about a week. But I really don't know, and I don't think the research is there. And I'm not going to dismiss it and say it's not doing anything, because I do know that these compounds do some real good in the body. But is there some placebo effect happening after you get a big intravenous dose of something? It doesn't happen that quickly — muscles don't suddenly grow. So I am not too sure.
[1:02:59] And that really gets to my core principle as a physician: first, do no harm. Intravenous medication at those doses — we don't know if that could potentially be harmful down the road. We haven't studied it long enough. And it's very expensive. I would say start low with oral preparations of good supplements, in combinations with other things. And the combinations of other things that really need to be done — which I haven't quite gotten into but is probably one of the most important things in terms of healing the body — is exercise and helping that muscle grow.
[1:04:16] So a big one is creatine monohydrate, which a lot of people know about and many take. I take that every day. But it really doesn't work unless you are exercising. People will say, "Yeah, I took my creatine today." And I'll ask, "Did you exercise?" "Oh no, I'm not exercising right now, I'm just taking my creatine." Well, that's just raising your serum creatinine. We really, really have to include exercise to help muscle hypertrophy. Muscle growth is what's going to help utilize all these compounds, get them into the cells, help the mitochondria, and make more ATP. I think muscle growth and exercise is one of the most important aspects of healing a patient — more than any supplement they can take orally or intravenously. And so many of these patients already come in muscularly deconditioned because they've been feeling so bad. Getting them back to giving their muscles the power they can give the body is, I think, more important really than any supplement. I hope that makes sense.

[1:05:43] Dr. Linda Bluestein: Yeah, that does make sense. And I think it's so tricky when people do have PEM or post-exertional malaise — finding those sweet spots, because it's not just "go do more." Really gradually trying to push that envelope a little bit can be really challenging. Putting all these things in combination — maybe for some of those people, it's because they're so deficient in glutathione that that's why they have so much post-exertional malaise, and until they replenish that, they're really not going to be able to make much in the way of gains.
[1:06:18] And a couple other quick clarifying questions: with the glutathione you mentioned liposomal form and also infusion. It's hard, right? Because you can go to an infusion center and they have a conflict of interest, wanting to give you the infusion. Are there any particular nuances there that you want patients and clinicians to be aware of?

[1:06:44] Dr. Ina Stephens: Absolutely, and I'm so glad you asked me to clarify that. I have only used glutathione infusions for patients with acute infectious mononucleosis due to EBV who are hospitalized — patients with severe hepatitis, severe swollen adenopathy, a big spleen, who are hospitalized and very sick. I will give them intravenous glutathione as part of their regimen while they're in the hospital with support. That is really the only time I've ever used it. So I just mentioned it does come in IV formulation, but I do not use it for just supplemental therapy otherwise. In that context I'm giving it orally and making sure that it's liposomal, because the liposomal form helps with oral absorption.

[1:07:29] Dr. Linda Bluestein: And when it comes to coenzyme Q10, you talked about the importance of that — it's something I also prescribe or recommend quite frequently. What about ubiquinol, the active form? Does it matter if it's ubiquinol versus CoQ10, or are there any nuances there that you want people to be aware of?

[1:07:53] Dr. Ina Stephens: I don't think it makes that much of a difference. I think what really makes a difference is that you're getting it from a reputable company and that you actually have the right amount of product in what you're taking. What I tend to do is write a prescription for coenzyme Q10. When I'm getting it through the pharmacy, I know they're getting coenzyme Q10 — they're actually getting the product. Otherwise, if you walk into a vitamin shop and pick up whatever's on the shelf, it could say ubiquinol, it could say coenzyme Q10, and I don't know how much of the active ingredient you're actually getting. I think that if you get ubiquinol and it's 100% of the actual compound, it's probably just as good — but I can't prescribe that.
[1:08:47] So I try to prescribe as many of these supplements as I can, for a number of reasons. First, I want to make sure the pharmacy is putting in the actual substance into those capsules. I can pretty much guarantee that if it's going through a pharmacy I know and am comfortable with — sometimes I'll use a compounding pharmacy or our UVA specialty pharmacy. And number 2, when I prescribe it, there's a chance that insurance will pay for it even though it's a supplement. So those are both important reasons.

[1:09:31] Dr. Linda Bluestein: No, that's critically important information, and something that was also on my list. I have one last question before we go to our hypermobility hack, and that is vitamin C. That's not something you mentioned as you were going through.

[1:09:47] Dr. Ina Stephens: Vitamin C is very important and I didn't mean to diss it by any measure at all.

[1:09:53] Dr. Linda Bluestein: Vitamin C is feeling really dissed right now.

[1:09:59] Dr. Ina Stephens: So dissed. Vitamin C is hugely important. It's really important for inflammation — it's an anti-inflammatory. We probably get most of what we need from what we eat, but not always. If you can get it through a multivitamin, or when a patient is sick — and this is actually part of my hack — upping the ante in your regimen, increasing the amount to maybe 500 to 1,000 mg a day of vitamin C for a period of time while you're ill, because it can really help with cell repair and decreasing inflammation.
[1:10:37] The other thing that is so important — and I mentioned this a little bit earlier — is iron. I look at ferritin levels, and ferritin levels really should be nice and robust. A lot of clinicians out there say, "Oh, if your ferritin level is 20 and you're not anemic, you're probably fine." I don't think that's the case. I think you need a ferritin closer to 50 to really kind of quiet things down. Now, too high a ferritin is no good either, so you want the Goldilocks sweet spot right in between.
[1:11:13] But why am I bringing this up? Iron is not absorbed unless you're taking it with vitamin C. So you really need that vitamin C cofactor to help that iron be absorbed into your red blood cells and hemoglobin appropriately. Vitamin C is very important. Sorry — didn't mean to diss you.

[1:11:36] Dr. Linda Bluestein: I was thinking about this because I had a patient recently who was following a carnivore diet and she was diagnosed by her PCP with scurvy.

[1:11:44] Dr. Ina Stephens: Scurvy. Oh my gosh.

[1:11:47] Dr. Linda Bluestein: Isn't that crazy? In this day and age. And sometimes when I post things on YouTube, I've had people say, "Oh, I love my carnivore diet," but of course there are risks associated with any of those things. So I was so curious to ask about that.

[1:12:03] Dr. Ina Stephens: That's a really important point. When I ask my patients about their dietary habits, the first thing I say is, "Are you on a diet?" And I always clarify — "Are you vegan? Vegetarian? Lactose-free? Gluten-free? What are you eliminating from your diet?" Because there are pros and cons to every single one of those approaches. "I'm paleo this week, or I am vegan." Well, maybe you're missing some really important nutrients.
[1:12:35] And I don't want to diss vitamin B12. If you're vegan, vitamin B12 — and I check for these levels; I check for B6, I check for B12 — these are really important cofactors in our entire neurologic chain. Most whole food diets will have enough, unless there's something inherently wrong with your absorption system, which is why I check things. But a lot of people eliminate things from their diet and then they're missing some major nutrients. In a sense, that patient is malnourished.

[1:13:21] Dr. Linda Bluestein: Those are great questions to ask people, and you've given us so many great points. I feel kind of — like you were saying about dissing vitamin C — I feel like I'm being greedy by asking you for a hypermobility hack, because you've given us so many great hacks already. I'm sure people are also taking notes, rewinding, playing certain parts over again so they make sure they get all of this great information. Do you have an additional hack for us?

[1:13:50] Dr. Ina Stephens: I think there are 2 things I want to mention — one is a hack for the patient and the other is a hack for the providers.
[1:13:56] The first hack for the patient is: if you know that you are already hypermobile and you already have an underlying connective tissue issue, or autonomic dysfunction, or mast cell activation, or whatever you are dealing with — if you get hit with a virus, or let's say your best friend is starting to cough in your face, you want to up your ante on your regimen. You want to boost your body and put it in the best place so you are going to be on defense, because that virus can potentially take you down.
[1:14:39] People always ask me, "I flared — why did I flare? I've been doing so well and then I flared." Well, what causes a flare? I would say personally, as an infectious disease specialist, 85% of the time it's due to some kind of infection that was coughed in your face or flew your way somehow. Other things can cause flares — anything that causes trauma and stress to the body. A concussion can cause a flare. A car accident can cause a flare. A really stressful psychological event can cause a flare — we know what stress does to the body. Stress can absolutely set off mast cells. But infections cause a very systemic stress on the body.
[1:15:29] So when you know that you're getting sick or you've been exposed to some kind of illness, up the ante in your regimen. Whether that's making sure you're increasing your fluids and your salt if you have some baseline autonomic dysfunction, really trying to decrease the inflammation with your lifestyle, going back to that whole foods anti-inflammatory approach, getting your sleep in, seeing if you can exercise now while you're still feeling well — getting your body in the best shape it can be. Because it may take a big hit. That is hack number one. Seriously.
[1:16:10] And one other thing I wanted to throw in, because people have asked me — why do concussions cause flares? And why can trauma to the head cause immunosuppression? There's actually been some really interesting data that patients who have had a CNS insult — whether a really bad concussion, a car accident, brain surgery, something going on — their body actually becomes immunosuppressed to LPS, which is lipopolysaccharide on the outer coating of gram-negative rods. So they actually are more susceptible to developing an infection with gram-negative bacteria. And gram-negative bacteria can kill you, but even a regular gram-negative rod in your bloodstream can set up shock and cause an immune flare — Yersinia, Salmonella, those can all cause post-infectious phenomenon like arthritis and more. Just be aware that head trauma can have effects on your whole immune system. Your whole body is connected — I think that's the take-home message with that one.
[1:17:40] The other hack is for clinicians. I get referrals to the Diagnostic Dilemma Clinic, to the EDS clinic, to the autonomic dysfunction clinic, and a lot of times the note says the patient has normal labs, they're doing fine, I don't know what's wrong with them — and almost implying, "I think it's a lot of anxiety. You just help them out."
[1:18:13] My answer for the hack for the clinician is: normal labs just mean normal labs. That's all it means. It does not mean that you know what's going on with this patient. Maybe you need to dig a little deeper. Maybe there are some labs that you haven't looked into. Let's just pick mast cell activation as the perfect example. "Oh, your tryptase is normal and your urinary histamine and leukotrienes and prostaglandins are normal, so you don't have mast cell." I'm sorry that you're still hiding out and you're vomiting with a migraine — deal with it, it's probably anxiety. I don't think that's the right answer.
[1:18:57] Just because there's a normal lab does not mean that the patient doesn't need to be treated or that there isn't something else going on. It just means that we haven't figured out the correct biomarker — science hasn't figured out exactly how to diagnose this issue. We don't have a biomarker for long COVID. We don't have a biomarker for hEDS. So keep your mind broad and open, look at the patient in front of you, and try to heal the patient who may have normal labs. And that's still okay. I don't mean to sound like I'm on my high horse — I actually think that's just how I practice medicine, and I think it's really important.

[1:19:41] Dr. Linda Bluestein: I love that. You just said: clinicians, try to heal the patient who may have normal labs. I mean, I hear people all the time say "I checked everything." Well, you couldn't possibly check everything — there are just so many different labs. And it's a snapshot in time. Normal imaging and normal labs do not tell the whole story.

[1:19:46] Dr. Ina Stephens: And it's funny you say that. There's one more thing — the 2017 EDS criteria, which of course we're developing new criteria for, due out in December. When I'm going through the 2017 criteria with every single patient that comes in, and I get to criterion 3 — we have to rule out everything else — I look at them and I laugh. I say, "So what should I do? Should I order 50,000 labs on you?" And they laugh too, because you can't rule out everything else. I can't do that, and physicians can't do that. We are doing the best we can. And even if we could order every lab in the big thick book from the Mayo Clinic, you're still going to miss stuff, because we don't have all the testing available and we don't know that much science yet. We're still catching up.

[1:21:13] Dr. Linda Bluestein: And also the more things you check, you can get things that are artificially elevated or that lead you down the wrong path. The more things you check, the more false positives you might get too.
So, Dr. Stephens, this has been such a fantastic conversation. I just love chatting with you — I could do it indefinitely. So we'll have to get together again for a part 3. Before you go, where can people learn more about you?

[1:21:45] Dr. Ina Stephens: The first thing I'm going to say is that we are in the middle of developing our UVA EDS website. So if it doesn't look great right now, please don't diss us — it's coming. It will have descriptions of all the providers we have. We're working up to having 6 providers in the clinic seeing patients — physicians and physician extender providers, nurse practitioners. It has a bio for all of us and discusses the other clinics we're involved in. You can find me on the UVA Integrative Medicine site and the UVA Infectious Disease site. And I have a couple of YouTube videos doing some medical yoga.
[1:22:50] We're also going to be having on our website — and I should definitely mention this — some up-and-coming clinical trials. We have a lot of research going on. We have 2 protocols that have recently been approved, and we're going to be starting to collect data there, looking at a lot of what we talked about today, looking at a lot of different biomarkers, tissue markers — not only in blood but in tissue specimens. Looking at all different aspects of comorbidities related to EDS, including mental health, anxiety, and neurodivergency. So we're really being very open to, I think, a lot of the questions that are out there and that a lot of patients have been asking us about.

[1:23:40] Dr. Linda Bluestein: Well, I just love what you guys are doing. It's amazing. And it all started with you and the incredible work that you're doing. So thank you so much for making such a huge difference in the community.

[1:23:53] Dr. Ina Stephens: Oh, thank you. Thank you, Linda. And you too. I feel the exact same way. Huge honor to be here.

[1:24:33] Dr. Linda Bluestein: Thank you for listening to this week's episode of the Bendy Bodies Podcast. If you'd like to go deeper, I share additional education, clinical insights, and resources in my newsletter, The Bendy Bulletin, which you can find on Substack at hypermobilitymd.substack.com. You can also help us spread the word about connective tissue disorders by leaving a review, sharing this episode, or sending it to someone who needs it. These small actions truly make a difference in raising awareness about these conditions that are still widely misunderstood. And don't forget, full video episodes are available every week on YouTube at Bendy Bodies Podcast.
[1:25:07] As many of you know, my passion is helping people better understand and navigate symptomatic joint hypermobility. In addition to my clinical and educational work, I offer one-on-one coaching, professional mentorship for healthcare professionals, and expert witness services. If you'd like to learn more, please visit the services page at hypermobilitymd.com. You can find me, Dr. Linda Bluestein, on Instagram, Facebook, TikTok, X, and LinkedIn, all @HypermobilityMD.
[1:25:34] As part of our collaboration with the UVA Health EDS and Hypermobility Disorders Center, we also want to share a few helpful resources. For questions or appointment inquiries, you can contact them at [email protected]. That's the letter R, [email protected].
[1:26:05] We love bringing on guests with unique perspectives to share. However, these unscripted discussions do not necessarily reflect my views or opinions. Furthermore, perspectives expressed within Bendy Bodies media, including this podcast, do not reflect the views or opinions held by Human Content Inc. Although we may share healthcare perspectives on this podcast, no statements made on Bendy Bodies should be considered medical advice. Listening to or watching this podcast does not constitute a doctor-patient relationship. Please always consult a qualified healthcare provider regarding your own care. For information about the Bendy Bodies program disclaimer and ethics policy, submission verification and licensing terms, HIPAA release terms, or to get in touch with us, please visit bendybodiesboutcast.com. Bendy Bodies Podcast is a Human Content production. Thank you for being a part of our community, and we'll catch you next time on the Bendy Bodies Podcast.