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BackTable / ENT / Podcast / Transcript #212
Podcast Transcript: Allergy Immunotherapy & The Microbiome
with Dr. Jennifer Villwock
Could the key to more effective allergy therapies lie in the nasal microbiome? In this episode of BackTable ENT, Dr. Jennifer Villwock from Kansas University Medical Center discusses the intricacies of treating allergies and sinus issues with hosts Dr. Ashley Agan and Dr. Gopi Shah. You can read the full transcript below and listen to this episode here on BackTable.com.
Table of Contents
(1) The Allergy & Microbiome Connection
(2) Why Microbiome Diversity Matters
(3) How Immunotherapy Affects Microbiome Health
(4) How Microbiome Research Influences Clinical Decisions
(5) How Diet and Air Quality Shape Your Microbiome & Impact Sinus Health
(6) Sublingual vs Subcutaneous Immunotherapy
(7) Allergy Testing Methods: Skin vs. Blood Testing
(8) The Future of Immunotherapy, Probiotics & Sinus Microbiome Research
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[Dr. Ashley Agan]
We have the pleasure and honor of having a mutual friend, Dr. Jennifer Villwock on today. We've got some interesting stuff to talk about, so we'll just dive right in. Dr. Jennifer Villwock is a Professor in the Department of Otolaryngology Head and Neck Surgery at Kansas University Medical Center, where she's the vice chair for research. She is also the Section Chief of Otolaryngology Kansas City Veterans Affairs Hospital. Her clinical practice focuses on rhinology and allergy. Her research interests are in personalized medicine in pain and olfaction.
Her work is currently supported by the NIH and Department of Defense research grants. She's here today to talk to us about the sinus microbiome, allergy, and the impact of allergy immunotherapy. Welcome to the show, Jen.
[Dr. Jennifer Villwock]
Thanks for having me.
[Dr. Ashley Agan]
Jen, can you first tell us a little bit, for those of you who may not know you, can you first tell us a little bit about yourself and your practice?
[Dr. Jennifer Villwock]
Yes. I'm an academic rhinologist, but a big part of my practice also involves allergy, which makes a lot of my clinical focus on inflammatory disease, because so many of the patients that are on that Th2 allergy pathway, they have allergic rhinitis, oftentimes they have nasal polyps, and they may or may not have asthma that has either been not diagnosed or inadequately treated. That's a lot of the patients that I see in practice.
[Dr. Ashley Agan]
Before we get into our topic today, I just wanted to give you a shout out, because you are the program director for the AAOA educational meeting in Vail this year, yes?
[Dr. Jennifer Villwock]
Yes. Lots of vowels involved there. Yes.
[Dr. Ashley Agan]
Did I get them all right? AAOA.
[Dr. Jennifer Villwock]
Yes. Correct. Yes. The American Academy of Otolaryngic Allergy. Really what that organization is focused on is helping folks provide comprehensive care within otolaryngology, recognizing that airway inflammation and allergy is something that impacts not just the nasal sniffles that we all think about, but it has correlations to the ear, to the throat, our chronic cough patients, there's so much that's going on there. How does that impact sleep apnea? Yes, I have the pleasure of being the course director for the upcoming course in Vail.
It's our explorers course. Traditionally the spring course has been called the advanced course where we go over topics like the basics of immunotherapy, how to deliver it safely, sublingual immunotherapy. All of those sessions are still available, but will be online this year as pre-work. That way in the actual in-person course, we can focus on some of these up and coming, have a robust knowledge and evidence-based, but have only really been delved into more recently. We can really provide the most contemporary information when it comes to allergies impact on otology and sleep apnea, pediatrics, cough, all of those things. For anyone who wants to deepen their practice or sees these challenging patients where you're like the usual things aren't working. What do I do now? It's a great course to consider attending.
[Dr. Ashley Agan]
That's awesome. Jen, can you tell us the date?
[Dr. Jennifer Villwock]
27th to the 29th.
[Dr. Ashley Agan]
March 27th to 29th in Vail, Colorado.
[Dr. Jennifer Villwock]
In Vail. Yes.
[Dr. Ashley Agan] T
hat would be a great meeting to attend to deepen your knowledge based on how allergy affects basically beyond allergic rhinitis, right?
[Dr. Jennifer Villwock]
Correct.
(1) The Allergy & Microbiome Connection
[Dr. Ashley Agan]
That's cool. Very interesting. Great. Then today we're talking about the microbiome as it relates to allergy. I guess maybe we can just start with talking about just basics in setting the stage. When you're thinking about allergy as it relates to the microbiome, in pre-reading for this, I saw articles that talked about both how sublingual immunotherapy can affect the gut microbiome as well as looking at the nasal and sinus microbiome and so tell me more.
[Dr. Jennifer Villwock]
Yes. You're like, so what's up with all that?
[Dr. Gopi Shah]
Which bugs are we worried about?
[Dr. Ashley Agan]
Before you even do that, can you just explain in general what is a microbiome? Where do we have them? Just give us the basics first.
[Dr. Jennifer Villwock]
Yes. We have a microbiome everywhere. Anywhere that basically our body is interacting with the outside world and even internally, there's an active microbiome there. I think for most people, the most common one that we hear about so much, and I think part of that is due to marketing of different supplements and other things, is the gut microbiome. I think a lot of our patients, especially our sinusitis patients are very well aware of the importance of the gut microbiome because they're treated with antibiotics, sometimes very routinely, and they experience all of those GI type symptoms, which sometimes can be worse or become chronic and overshadow some of the original reasons that they came to see us.
There's a skin microbiome. We're going to talk a little bit about the sinus microbiome. I think we're really in a time in science, at least, where there's a lot of interest in figuring out, well, how do all of these things really relate? To your point, well, how is it that sublingual immunotherapy, the benefit of it is supposed to be, it stays on the mucosal surface, low risk for side effects, et cetera, but somehow it's changing the gut microbiome. What's happening? Also, I think that we're going to be learning a lot more in the coming years about, well, what are the side effects and how long are there changes to the microbiome with the different treatments that we offer, whether it's antibiotics versus immunotherapy versus steroids, et cetera.
I think for a lot of patients, especially, I always picture my recalcitrant patients who are like, "I've done everything I think I'm supposed to do" and they're not getting better. I'm really hopeful that as the evidence emerges, we'll have more explanations and hopefully understanding those mechanisms will lead to better treatments.
[Dr. Gopi Shah]
I always think about bacteria when I think about the microbiome, but technically it's also parasites and viruses and non-human cells. We have way more non-human cells living in us and on us than we do human cells.
[Dr. Jennifer Villwock]
Yes, absolutely. I think for most of the scientific disciplines, it's the study of the bacterial microbiome that has the most literature, but you're exactly right, there's bacteria as well as viruses, as well as fungi, bacteriophages. There's all sorts of things that are happening in that complex interplay that we can neither see and oftentimes we don't have the optimized ways to even test for all of those things.
[Dr. Ashley Agan]
Are these protective or do they ever not help us?
[Dr. Jennifer Villwock]
Yes, so for the most part, you can think about, I guess, two different states. One is the healthy state where we know that our microbiome, it is in fact protecting us. There's a lot that begins even at the fetal level in terms of recognizing what is self, what is safe, et cetera. There can be things that happen very early in development that are linked to the atopic disease and other diseases going forward because of the dysregulated immune system, not recognizing things as it's supposed to, et cetera. On the normal side of things, everything is running in sync.
All these invisible players that we can't see, it's all working. We're staying nice and healthy. Then you get to the dysbiosis side, meaning something just isn't right here. There's a variety of ways to assess or test for that. You can look at the overall number of different species. You can look at the overall proportions. We can compare those versus disease states and look at also things like metabolites of that whole bacterial microbiome. How is that causing differences in the products, et cetera that are excreted? Dysbiosis is associated with a lot of different things.
It certainly can be associated with different atopic or allergic diseases, which is where a lot of my interest is. There's also a lot of implications for things like irritable bowel disease. There's a whole emerging body of literature about how when your microbiome isn't optimized and you're in thatdysbiosis state, there's more inflammatory products that are made. Then how does that play into other things that we know are related to inflammation like autoimmune diseases, multiple sclerosis, Parkinson's disease, Alzheimer's? There's all sorts of research in all of those other fields as well.
[Dr. Ashley Agan]
The microbiome in the gut is different than in the sinuses or are they similar? Then do we have a microbiome in the middle ear? I just think of mucosal linings that are all connected.
[Dr. Jennifer Villwock]
Yes. There's a microbiome everywhere. To your question, there have been some studies looking at, for example, sublingual immunotherapy that has been administered and it has changed the microbiome in the gut, which I think you alluded to in the beginning. Follow-up studies have showed, oh, actually the proportion of bacteria in the nose mirrored the change that happened in the gut, which again seems like, well, how is this happening? I don't think anybody has the answer to that, but it does show how all of these microbiomes and all of these hidden pieces are really connected in terms of human health.
(2) Why Microbiome Diversity Matters
[Dr. Ashley Agan]
When you're studying microbiome changes, tell me, is there an optimum diversity constellation of bacteria or we're just looking at, oh, they seem to have more of this before when they had worse symptoms and then we did this treatment and now they have less of this one bacteria after we did. Is there a standard? Like we know that you should have this, if you had a recipe, we want this much staph and this much strep and blah, blah, blah. I think that's the hard part when I'm listening to other podcasts with people talking about it.
It seems like that we don't quite know what are we striving towards? It's just, we're just noticing, oh, some people who have more of this seem to have this problem. We're noticing some patterns, but I feel like that makes it hard to study it, maybe.
[Dr. Jennifer Villwock]
Yes, it does. I think it gets really complicated in the sinuses as well, because we know that there are some folks that are colonized with bacteria that we typically perceive to be pathologic, but they're not causing them any symptoms. Then how do you separate out, well, are those really healthy control people or are they in their separate little category? Then to your point, to do a study, like how many of these little categories are we going to have? Because we know that there's so much variability and there's been a number of recent, like in the past 5 to 10 years, different systematic and narrative reviews that try to summarize we're generating all of this information. What does it really mean?
For most studies, when you're looking at populations of people that have chronic sinusitis, you see a decrease to no change when comparing to control subjects and things like the diversity and the richness. You sometimes see differences between your disease state and your control group, but not always. Yes, it gets very challenging to know, to your point, well, what is truly the best mix? I think that what we'll see is that's highly location, demographic, disease state, symptom state dependent in a way that we're not going to have a great recipe for everybody.
I think that's also, sometimes when things get complicated in my mind, I'm like, let's just not focus on the complicated part. Let's find another little tidbit that we can focus on and that's a little bit easier. That's why I'm a person that tends to go down rabbit holes if you guys have not already learned that about me. One of the things that I think is really cool is that yes, there's all this microbiome, different bacteria, proportions of different stuff in the sinuses. We also know downstream there's things that are going to happen or be produced that are either going to be pro-inflammatory or not pro-inflammatory.
I think about that a lot in the context of the allergy patients that I treat because we know that as we do things like immunotherapy and we're actually retraining the immune system, we're expecting decreases in certain cytokines and cell populations, et cetera, that are going to correlate with decreases in symptoms. The decreases are the things that all the new biologic medicines are focusing on. Like we're shunted towards the allergy side of things. We know we're going to have more things like IL-5 and IL-4 and IL-13. There's biologics for all of those things now.
The other thing that we know is going to happen as we make allergies in the atopic pathway better is we're going to have increases of anti-inflammatory cytokines. Those are things like IL-10. Going back to the microbiome, we know that sometimes when there are these shifts in the microbiome, it also leads to increases in anti-inflammatory cytokines like IL-10. Now, rather than getting lost in all of the weeds of like, oh, well, what's the proportion and how do we manipulate it, et cetera, sometimes in very specific contexts like allergy, you can think about, well, if I'm treating people, regardless of what their microbiome is, it should shift towards a less inflammatory state and I should be seeing some of these anti-inflammatory cytokines as a result.
[Dr. Ashley Agan]
The take-home point is diversity is probably better.
[Dr. Jennifer Villwock]
Yes, diversity is probably better.
[Dr. Ashley Agan]
Don't worry about the exact amount of proportions.
[Dr. Jennifer Villwock]
Yes, exactly. There have been some studies that show overall healthy folks have a preponderance of a couple of specific species. I don't think we know enough about it to say this should be how everybody is assigned on these microbiome parts.
(3) How Immunotherapy Affects Microbiome Health
[Dr. Ashley Agan]
You just talked to us a little bit about the biologics and how that might shift certain anti-inflammatory cytokines in the microbiome. Are we ever doing too much one way, whether it's immunotherapy, biologics, that we just said diversity and the different types of cells in the microbiome is protective. When we do treatments, are we ever doing too much to cause it to shift towards just IL-10, which may or may not be the only thing we want in the microbiome and in our sinuses?
[Dr. Jennifer Villwock]
Yes, that's a great question. I actually I'm not aware of any literature showing or any studies that have been done actually on a lot of these newer biologic medications and how they might impact the microbiome. That's a great question, because we know we're fundamentally altering the different immunologic pathways. I feel I guess, if we're talking about, well, how do we feel about immune system manipulation when it's in the context of pharmacologic things versus immunotherapy? I would say that my hesitations in terms of any sort of long-term side effects are much less on the immunotherapy side of things just because it's been documented to be so safe for so long.
We know that we're manipulating, yes, the differentiation of different cells. We want higher populations of their T regulatory cells, et cetera. It's in a much more, at least in my opinion, physiologic context, than just saying we're going to introduce something that's going to block these particular cytokines and artificially shunt things one way or the other. My hypothesis would be that there's less of a risk for pushing people towards that dysbiosis using things like immunotherapy.
[Dr. Ashley Agan]
Yes, I think of that, too, because in my mind, when I think about, for example, like sublingual immunotherapy, I think about little kids who are always putting things in their mouth and sampling their environment. That's them, like when you think about hygiene hypothesis and if you grew up in a less hygienic environment, then you did your own sublingual immunotherapy by sampling the environment, being exposed to stuff. Maybe if you didn't have that exposure, you now we're doing that in a different way later in life, being like, here, let's have a little dust, have a little grass.
Yes, it feels more like you're just tapping into the body's natural way of going down that pathway of tolerance. Is there a certain state that you want your microbiome to be in to be more or less responsive to immunotherapy? If you have a patient that, for example, history of allergies, history of chronic syntheses, maybe they've been on lots of antibiotics at this point because they've been treated for lots of six weeks of whatever antibiotic, twice a year. We've done oral steroids, we've done, rinses with steroids and allergy medications. We've done all that.
Now we are thinking, immunotherapy. Does a patient like that who's had lots of different types of medications, potentially surgery, how that might affect the microbiome versus somebody that really is naïve to a lot of that, starting immunotherapy, do you think of them differently and sort of how that microbiome might play a role in how responsive they are?
[Dr. Jennifer Villwock]
That's a great question. I think the honest answer is that we don't have great predictive mechanisms right now to know who's going to be a good responder and who isn't. There are some folks who have done research investigating, we're going to start someone on immunotherapy. We know that IL-10 in particular is something that we can analyze from the saliva as well as the serum. We should be seeing a pretty quick uptick of that particular cytokine. Maybe, if you're able to assess that early on in the immunotherapy course, taking a step back, recognizing that most of the time we're going to recommend that people be on immunotherapy, whether it's subcutaneous or sublingual for a treatment course of three to five years.
It's automatically a long buy-in. I talk to patients about that all the time, and one of the things I counsel them on is, well, we're trying to retrain your immune system. It's just like training a small human, or a small pet. You can't just train them consistently for like three to six months and then be like, "Oh, they're going to behave for the rest of their life." We know that you have to continue to train these little creatures for years if you want that consistent behavior that you're looking for and the immune system is the same. To your fundamental question, well, wouldn't it be nice if we had an early way to say this person's probably going to be a great responder after six months to a year, versus just saying, well, I guess we'll see how you're doing as things go on and potentially and tweak your recipes or reassess.
IL-10 is a potential candidate for that. As you mentioned, there's a lot and our patients are complex. The patients that we see in clinic are not the ones that are presented to us in the textbooks or on the in-service exam, right? Where it's a very, here's the patient, it should be a relatively clear answer. Those are not the folks that are coming to us in clinic. There's so much that's going on there. there's been studies, Dr. Hauser et al. did some 8 to 10 years ago looking at the microbiome in the sinuses after surgery. Yes, and it does take several weeks to months to normalize.
Then the question is, well, did it normalize back to a pathologicy state or did it normalize all the way back to normal? How would we know that? I think there's still a lot of information to be found. I do think that immunotherapy in terms of allergy immunotherapy for appropriately selected patients is certainly an option, and certainly represents an avenue for potential improvement. The reason that I say inappropriately selected patients is that there's a difference between allergy sensitization that we can detect on testing and actual clinical allergy.
Really, your best allergy test is your HNP. It's talking with the person that's in front of you. Then we seek to quantify and correlate those symptoms with the things that are prevalent in our area that we know are most likely to be contributing to those allergy seasons. Then we have to do our double check and say, well, do the symptoms correlate with what's prevalent in our area? Are the symptoms happening at the time that we know that those antigens are most prevalent? If the symptoms are always in spring, but they're only sensitive to ragweed, you might say, oh, that doesn't quite make sense because weeds are a fall antigen. All their symptoms are in spring.
Even if the test says that they have sensitization, you're not going to treat them for an allergy that they don't have any symptoms during that time. There have been studies that have shown like, yes, allergy immunotherapy can help in addition to the traditional surgical options that we offer people. There was a recent study investigating the utility of adding sublingual immunotherapy to patients with nasal congestion, and they were all appropriately selected who were undergoing septoplasty and turbinate reduction.
They compared, well, what happens to the folks where we just optimize the architecture, we do our septoplasty turbinate reduction, and what happens to them where we do that, but we also do sublingual immunotherapy. The folks that were treated with sublingual immunotherapy had better outcomes in terms of reduction in nasal obstruction, et cetera, long-term. There's a lot to continue to think about.
(4) How Microbiome Research Influences Clinical Decisions
[Dr. Ashley Agan]
When you think about dysbiosis, maybe whether it be like in the nasal microbiome or the gut or what have you, is that part of your clinical decision-making? When you have the patient in front of you and let's say, you talked earlier about how you're at the end of the road and you've done all the things, you've reached in your toolbox and you're like, we do this, we do this, we do this. How do you think about it when the patient is in front of you? Are you culturing the inside of the nose? Has the research made it to the bedside or is it still mostly in papers right now?
[Dr. Jennifer Villwock]
I think a lot of it still remains in the realm of papers. It's certainly something that I think about because I think we'd be doing ourselves a disservice not to think about it, at least to keep it in our mind. Like do I really want to put this person on like their fifth oral antibiotic course, type thing. I think this is where it becomes really important to have shared decision-making conversations with your patients. As you guys already know about me, I'm an over-explainer. I go into all these rabbit holes. I present people way more information than perhaps is helpful for them, but I want them to understand my thought process.
I absolutely have these conversations with folks about, well, for a lot of these situations, we're in a state of equipoise in terms of we have these different options. There's not clearly one that's superior to another, because if there was, obviously I would offer you the superior one, and these are all the things to consider. That's a conversation about, well, do we do another round of oral antibiotics? Do we just bring you in for more frequent debridement's? Do we do topical antibiotics? do we want to do allergy testing not to satisfy your curiosity, because just knowing what you're sensitized to is not helpful, but to potentially then pursue that three to five-year treatment course to see if this can get you some added benefits.
One area that I hope will experience a renaissance is investigations into topical probiotics for the sinuses, which was a hot topic maybe 10 years ago or so and has nosedived, but personally, I would love to see a resurgence in the research in that realm, because I think that it's an area that's really needed.
[Dr. Ashley Agan]
I do remember conferences several years back where this was a little bit, the whole microbiome was hot, fresh, and in front. Then I remember patients asking, well, and usually patients will ask, should I take a probiotic if we're going to do whatever antibiotic? Should I be taking a probiotic regularly because I have all these infections? What are your thoughts on oral probiotics for sinus disease or allergy symptoms?
[Dr. Jennifer Villwock]
In general, I would say they're in that category of unlikely to harm, may help. I do make it part of my standard practice with patients to anytime I'm prescribing an oral antibiotic, I also counsel them about not just some of the topical probiotic pills and things that you can get, but also foods that you can eat that are naturally fermented. They're going to have a probiotic mix within them and to increase their consumption for all the reasons that we talked about. Do I think that it is plausible that oral probiotics that impact gut health may at the same time be impacting our microbiome elsewhere?
I think it's definitely possible. I think that that's something that hasn't been studied, but I would put it in the realm of possible. If patients are getting additional benefit from that, then I think that's great. I don't know how I would tease that out in a clinical context, but I think certainly for gut microbiome protection, I do talk to patients about that for sure.
(5) How Diet and Air Quality Shape Your Microbiome & Impact Sinus Health
[Dr. Ashley Agan]
If we think of different external factors that affect our gut health, I immediately think of dietary factors. We think of, especially with allergy, food allergy, I guess, per se, which definitely is not my realm, but people will ask, especially if they're bringing their kid in for chronic congestion, runny nose, should I cut dairy out? Should we try not doing gluten? Should we not try-- Do you feel that some of the dietary changes affect potentially whether it's the gut, the microbiome, I don't know if this is a little bit too naïve, the microbiome in general for our bodies, or specifically sinus microbiome, if it affects the gut that then affects the sinus, do you think those modifications work in that mechanism, I guess, or do we just not know yet?
[Dr. Jennifer Villwock]
I think that conversation can become very complicated because there's true IgE-mediated food allergy, which should have very clear, very reproducible symptoms. Then you also have the lactose intolerances of the world, which is not an IgE-mediated phenomenon. Then you can add another layer of complexity onto that because now there's all sorts of food additives and other things, which some people can be sensitive to as well. If you're interested in that topic, come to the AAOA Course in Vail. There will be some sessions on that are related to food-related sensitivities and additive sensitivities.
I think it becomes very complicated. A lot of times people will say, "Well, I looked online and I can order this test that's going to tell me if I'm allergic to all these different foods." Historically, a lot of those tests have not been super clinically helpful because there's a difference between a reaction that can be precipitated in a lab versus actually having that clinically relevant reaction to that. What I counsel patients on is that, "Well, if you're concerned about this particular food or food group giving you symptoms, the best way to figure that out is just to go on an elimination diet, then you can slowly add these things back in and see if there's a change in the symptoms."
Having tried an elimination diet in the past, it is super unpleasant and very difficult. I think it's a special patient who is so motivated that they're going to say like, "Yes, I'm going to eliminate corn, soy, wheat, gluten." There are so many things if you want to do it thoroughly that I think it can be a real challenge for folks. The flip side of that for your patient who's a child who has the sniffles, a lot of parents I think are really concerned about some of the side effects of our first line medications. Depending on where you buy your little thing of fluticasone, it's either going to say, do not use this for more than two months.
It's going to say, ask your doctor if this needs to be used for more than two months. I think that's another opportunity to have a conversation about, well, in children who are sensitized and allergic to many things, we know that early initiation of immunotherapy can help with a number of things. First, your allergen specific reactions that you're having now, it can prevent future sensitizations and it can prevent things like progression to asthma and asthma severity. I think it behooves you to have, even if you don't offer immunotherapy or allergy testing in your office, I think it behooves you to have that skillset in your mind so that you're not just playing this whack-a-mole, okay, we'll do Flonase for two weeks or two months and then they get better, but the label says to stop. Then they stop and now they're worse, and that's not really optimizing the health of that child at all.
[Dr. Ashley Agan]
Yes, no, that's a really good point. When I think diet is obviously frequently talked about when it comes to microbiome and it makes sense, because it's like we put things in our mouth and they're going down into our stomach and then bacteria are eating up some of it too or whatnot. What about other non-diet types of things affecting our microbiome, whether it be in our gut or in our nose or elsewhere? Things like exercise, environmental exposure, air quality, pollution, are those playing a role?
[Dr. Jennifer Villwock]
Yes, I think the data for those, I think is much more robust in, for example, the airway literature. There's a lot of studies on things like PM 2.5, which is particulate matter. The reason there's so much focus on 2.5 is because it's small enough that it's going to bypass our nose and sinuses and get right into the lower lung, lower airway. There's a lot of robust literature that's emerging about the impacts of particulates of that size and how they relate to cardiovascular health, pulmonary health, even factors like dementia. Certainly, there's tons of stuff floating around that we're breathing in allergies and irritant-wise. I think that most of the literature shows that a lot of those things are going to contribute to more of that pro-inflammatory state.
[Dr. Ashley Agan]
Do you think we'll ever get to the point where some of like we understand the microbiome enough in a patient to where now we're not just like, immunotherapy to modulate your immune system for sensitivity, but, oh, we're going to also have treatment parameters or tools potentially to get your microbiome back healthy and your sinuses? Do things like, and this might sound even more naïve or silly, but, do basic sinus rinses help us get our microbiome in check? Will we have something as basic and as broad as sinus rinses to something more specific where it's topical probiotics, for example, certain dosages or treatment parameters that can help us modulate somebody's sinus microbiome?
(6) Sublingual vs Subcutaneous Immunotherapy
[Dr. Jennifer Villwock]
I would hope so, because what we see in the context of immunotherapy for people is that, yes, we do see that there are changes in the nasal microbiome in response to immunotherapy as we've talked about more IL-10 and other of these anti-inflammatory cytokine, but some of the interesting results have also been that, well, yes, there's this shift. There's a clear difference between before and after treatment, but things don't necessarily normalize all the way back to your healthy control patients. Potentially either we tested too early.
A lot of these studies have only have tests have reassessed after about a year, but we know that the whole gamut of the immunologic changes takes several years to develop. I do think that it would be interesting to be able to say, "Hey, we know that your microbiome is slowly shifting towards the normal side, but it's not all the way there yet." To your point, maybe that's where different interventions can be done in terms of topical probiotics or other potential support mechanisms to say, let's keep trying to push that microbiome towards what seems to be a more healthy diversity and proportion of these different bacteria.
[Dr. Ashley Agan]
You had mentioned that immunotherapy, it affects the microbiome in a positive way. Is that for sublingual and subcutaneous equally? Is there a difference? Does one do it better than the other?
[Dr. Jennifer Villwock]
I don't think one does it better than the other. Most of the studies, again, show that we're in equipoise between sublingual and subcutaneous in terms of all of the different ways that they're immunologically mediating allergy, as well as the symptoms that patients have. For the most part, the main distinction between the two is route and if they're going to be able to adhere to the treatment. I always tell folks, "The immunotherapy that's best for you is the one that you can do." If you're the person that's going to be able to come into the office every week and that's your preference, subcutaneous is what's typically going to be covered by insurance.
If that's the route that you need to go and you can commit to that, great, you should do that. If you want to go the sublingual route, there's two different options. There's the FDA-approved sublingual tablets, and those are done at home per the protocol. Those may or may not be covered by insurance because they're FDA-approved. It's one of those like, well, I don't want to co-pay and blah, blah, versus our sublingual aqueous immunotherapy, which we have to counsel folks that, technically this is off label. It's not FDA-approved. It's been used for decades, but it will not be covered by your insurance. Then here would be your out-of-pocket cost. I present folks with all of those options because it's whatever works best in the context of their life in terms of what they can commit to for that three to five years.
(7) Allergy Testing Methods: Skin vs. Blood Testing
[Dr. Ashley Agan]
Just from a testing standpoint, do you have a preference of skin testing versus blood testing?
[Dr. Jennifer Villwock]
Yes, my preference is for skin prick testing. This is another, I want to over-explain, but I will try not to.
[Dr. Gopi Shah]
No, do it. We got time. Let's do it. Unpack it.
[Dr. Jennifer Villwock]
For me, my preference is skin testing. If you have gone to the AAOA courses or you have been or seen allergy practices for oncologists who do skin testing, you'll see that there's a number of different ways to do it. The classic way is intradermal testing, where you make your little wheel, you wait, you measure. You start at your most dilute, and then you ramp your way up to see where your endpoint is. That's very time intensive. A compromise between like, we still want great results, but we can't be playing this intradermal. I'm going to be here for a thousand years' game.
That's the modified quantitative testing, which is basically a blended technique that where you do a skin prick test first, and then based on the results, then you place a single intradermal that gets your endpoint. The endpoints are just relevant for subcutaneous immunotherapy. If you're doing sublingual, it's not really a consideration. You can do skin testing that way. Or you can say, "I just don't really want to do this intradermal thing. We're just going to do skin prick testing." Then that's all you do with one of the divided plastic devices. You do it per the manufacturer's instructions.
That is versus specific IgE testing, which is done exclusively in a lab context where you're looking to quantify the amount of specific IgE for the allergens that are relevant in your area. There's different companies have different panels because they're supposed to be reflective of what's popping in your geographic area. My preference is skin testing. I believe that it's a little bit more sensitive, but that's another question of, well, what is reasonable for the patient to do? Sometimes you have your patient, optimized-ish. They're not great. They're not where they would like to be because if they were, you would not be pursuing allergy testing.
They're better than they were when they first came to see you. Then if you talk to them about skin testing and you're like, "You're going to need to hold all the stuff that makes you feel not terrible in preparation for this test," sometimes they will be like, "I cannot do that." In which case you say, "Great, we have another mechanism for you." For folks that are willing to hold the appropriate medications for the prescribed amount of time, then I do try to encourage them to go through with the skin testing.
[Dr. Ashley Agan]
The degree, on the blood tests, the degree of severity that it shows, some patients will be like, "Oh, whoa, this one's really high. That must mean I'm really allergic to this." Maybe it doesn't even match, maybe they're not symptomatic during that season. What does that conversation go like? I think it's really hard with the skin testing, it can be reassuring because if there's a big wheel, they're like, "Oh, I see it. I'm really sensitive to that." On the blood testing, I think sometimes it can be confusing trying to explain those results.
[Dr. Jennifer Villwock]
Yes. The blood testing will usually give you, a quantitative readout, and that'll translate that into a class. Typically, the higher the class, the classes are meant to correlate with what your endpoint would be. The higher the class, the more sensitive that person is. I think it all comes back to the conversation about, well, there's a difference between what you're sensitized to and what you're displaying symptoms to. Would it be the wrong answer to treat you for this thing that you're highly sensitive to?
You could find a way to justify it, but in my heart of hearts, I want you to feel better when you're exposed to the things that are giving you symptoms in these discrete seasons. It makes more sense to treat you for the stuff that you're actually displaying symptoms to versus something that's just a lab result that we don't really know what to do with it.
(8) The Future of Immunotherapy, Probiotics & Sinus Microbiome Research
[Dr. Ashley Agan]
It makes sense. Going back to the sinus microbiome or for allergy testing, if our listeners wanted to learn more about the microbiome, immunotherapy, allergy treatment, do you have any studies or reading or podcasts that you recommend? Granted, for any of our listeners, you still have time to register for the Vail meeting, which sounds like it's going to be amazing because you're the program chair for it, the course director, which is awesome. Do you have any recommendations?
[Dr. Jennifer Villwock]
Literature searches are my love language. I have so many.
[Dr. Ashley Agan]
What keywords are you typing in? Are you using Wikipedia or ChatGPT ever for these as well?
[Dr. Jennifer Villwock]
Yes. I've had some instances where I have been very unimpressed with what ChatGPT has told me. I am primarily just using good old PubMed.gov and Google Scholar. If you put in keywords like sinusitis, microbiome, immunotherapy, nasal microbiome, you'll find all sorts of stuff that comes up. I'm trying to focus more on the more contemporaneous literature, you can filter down so that you're not getting 10,000 million different hits just by searching for within the past 5 to 10 years, particularly if you're interested in probiotics and those other things.
Those will pull up some of those papers that Gopi and I were talking about in terms of this being more of a hot topic 8 to 10 years ago. The other thing that is nice is as we're having so much more literature in this area, if you're doing your lit search, you can also click the box that says just show me reviews, because that'll give you a nice synthesis of everything that has already been published in hopefully a very digestible format.
[Dr. Gopi Shah]
I love a good review article.
[Dr. Ashley Agan]
Anything on the horizon to be on the lookout for? Do you think if you could gaze into your crystal ball, how do you think this is going to translate into clinical care 10 to 20 years from now?
[Dr. Gopi Shah]
Are you going to have beakers and vials of topical probiotics that you're going to be testing and producing?
[Dr. Jennifer Villwock]
I am hopeful that others, not necessarily me personally, will take up the mantle of how efficacious or not. Sometimes it's helpful just to know like these don't work, so let's stop revisiting it.
[Dr. Gopi Shah]
Cross it off.
[Dr. Jennifer Villwock]
Yes, but I think the topical probiotics is an interesting question. I think continuing to do studies on changes in the nasal microbiome after immunotherapy, whether it's subcutaneous or sublingual, in our allergic rhinitis as well as our nasal polyp and other patients will be very helpful. Most of the studies that have been done are relatively small. We do see signal in the noise in terms of, yes, there's differences in the bacterial compositions and things start to normalize with immunotherapy, but a lot of times those are limited to 40, 50, 60 patients. It's hard to really say this is valid for all the populations that we treat. Then on the horizon, there's a technique called intralymphatic immunotherapy. Have you guys heard of that one?
[Dr. Ashley Agan]
No.
[Dr. Jennifer Villwock]
The goal is to say, well, we know all this immunologic shenanigans that's happening in the lymph nodes, et cetera. Why don't we just give our immunotherapy to the lymph node? There are folks who are currently studying and there's been a number of clinical trials investigating, yes, what happens if we deliver our immunotherapy via targeted injection into inguinal lymph nodes? That circumvents some of the three to five-year treatment because a lot of times these protocols are just three-ish injections that are spaced out over a number of weeks and seeing, can we get the same immune tolerance effects?
I would be particularly interested in knowing who the ideal patient is for this. There's some issues in terms of, well, it's not as simple as just being like antigen into the lymph node. It matters like how it's packaged, what it's attached to, all of those things impact how your immune system is going to recognize that antigen. I think more information about the ideal way even to deliver intralymphatic immunotherapy and then, of course, really assessing symptoms, microbiome changes, IL-10 levels, et cetera after that treatment.
[Dr. Gopi Shah]
Cool. This was fun.
[Dr. Ashley Agan]
Yes. Thank you so much, Jen. I learned a ton. Are you on social media? Remind us if any of our listeners want to reach out to you.
[Dr. Jennifer Villwock]
I used to be on it and now my enthusiasm is quickly waning more and more every day.
[Dr. Ashley Agan]
All right.
[Dr. Jennifer Villwock]
I'm always happy people want to reach out via email or other mechanisms. Come find me at the Vail course or at CAUSM, any of those places. I'm happy to nerd more about any of these topics.
[Dr. Ashley Agan]
Just go to the website for the AAOA to register for the course, I assume, right?
[Dr. Jennifer Villwock]
Yes. You can still register and then you'll have access to the different pre-work lectures. You can see the whole itinerary. You'll see there's nice little breaks in there for skiers so that you're not in beautiful Vail but not able to take advantage of the surroundings.
[Dr. Ashley Agan]
For the operate skiers. That's good.
[Dr. Gopi Shah]
Is there a deadline to register? Can you register all the way up until the course?
[Dr. Jennifer Villwock]
Yes. You can keep registering. Yes.
[Dr. Gopi Shah]
Cool. Awesome. Well, thank you.
Podcast Contributors
Cite This Podcast
BackTable, LLC (Producer). (2025, February 25). Ep. 212 – Allergy Immunotherapy & The Microbiome [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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