Alpha-Gal Syndrome: From Tick Bite to Anaphylaxis, Clinical Pearls and Unanswered Questions

Alpha-gal syndrome has transformed our understanding of food allergy, linking tick bites to delayed anaphylaxis to mammalian meats. In this episode, we explore the epidemiology, immunologic mechanisms, diagnosis and management of alpha-gal syndrome with expert Scott Commins, MD, FAAAAI. Join us for practical clinical pearls and emerging insights into this unique disease.

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Transcript

Rebecca Saff, MD, PhD, FAAAAI 0:11

Hello and welcome to Conversations in the World of Allergy, a podcast produced by the American Academy of Allergy, Asthma & Immunology. I am your host, Rebecca Saff. I am a board-certified allergist and immunologist who always enjoys learning more about the exciting field of allergy immunology. This podcast uses interviews with leaders in the field to keep you up to date on new developments and to review core topics. We'll be revisiting one of the more mysterious IgE-mediated allergies today, Alpha Gal. This unique food allergy appears to be brought on by tick bites and can develop at any time throughout your life. After being sensitized, patients develop an allergic response to the sugar galactose alpha-1-3 galactose, or alpha gal, and can develop severe allergic reactions to mammalian meats, which are often delayed for hours after eating, making it tricky to diagnose. We are pleased to welcome Dr. Scott Commins today to tell us more about this. Dr. Commins is a professor of medicine at University of North Carolina who specializes in the patients with difficult to diagnose food allergies and allergic reactions. His primary research interest is Alpha Gal syndrome, and his lab uses the lens of Alpha Gal to study the role of skin and resident cells, including mast cells and basophils, in the allergic response. Dr. Commins, thank you so much for taking the time to join us today.

Scott Commins, MD, FAAAAI 1:18

My pleasure. Thanks for the invitation.

Rebecca Saff, MD, PhD, FAAAAI 1:20

We always like to get to know our guests a little bit before we start. Can you tell us a little bit about yourself and something you like to do outside of medicine?

Scott Commins, MD, FAAAAI 1:28

Sure. Well, I'd love to fish. I wish I had more time to fish. And I have been at uh Carolina now for almost 10 years after training and being on faculty at the University of Virginia for a period of time. I have two children, both college age, uh, and my bride Jenny. And we've been married for almost 25 years. And I really got into allergy because I enjoyed being a dad more than I thought I was going to. And I wanted to find a way that I could see adults and particularly kids, because I was training as an internist at the time.

Rebecca Saff, MD, PhD, FAAAAI 2:08

That's great. And what got you interested in Alpha Gal in particular?

Scott Commins, MD, FAAAAI 2:12

I really wanted to do something related to food allergy. And I guess training as an internist, I may have been perhaps more drawn to adult food allergy. And when I started fellowship, I was at UBA and Dr. Platts Mill's lab was just kind of getting into the Alpha Gal story. And it sort of fit for me that there was this kind of emerging food allergy that was initially appearing in adults that we really didn't know anything about. So it it kind of fit several of those interests for me.

Rebecca Saff, MD, PhD, FAAAAI 2:55

How would you describe what Alpha Gal is to a patient who's coming to see you?

Scott Commins, MD, FAAAAI 3:01

So Alpha Gal syndrome, I call it AGS for short, is really an allergic reaction that occurs due to a sugar carbohydrate alpha gal that's present in all forms of mammalian meat. And then sometimes you have to qualify, well, what's a mammal? We don't mean humans in this scenario, we truly mean non-human, non-primate mammals. So we're thinking about cows and pigs and sheep. So colloquially, it's a food allergy that is due to a sugar and it occurs in red meat, but also in the derived products from those animals as well. So it can include dairy and even some of the byproducts that are in medications or even devices.

Rebecca Saff, MD, PhD, FAAAAI 4:03

And so someone comes in with an unusual reaction, and you think this could be Alpha Gal. How do you start evaluating it?

Scott Commins, MD, FAAAAI 4:10

Well, the part of the Alpha Gal story is that the reactions are delayed. So one of the things that often happens is people don't really have an awareness that the hamburger hot dog that they ate for dinner is causing the symptoms that they're developing at midnight or 1 a.m. And so one of the initial clues to an AGS diagnosis is this kind of middle of the night symptoms, often awakening people from sleep. And beyond that, it's very inconsistent. So people can eat red meat and not react every time. And so you get confused if you're someone who has AGS because you may start to suspect that it's beef or pork, but then you eat it again and nothing happens. And so I think about Alpha Gauss syndrome a fair amount for people who have middle of the night stuff and they've been thinking about it, but it doesn't, they can't really find a good explanation. And then if they're outdoorsy too, because of the tick bite connection, that's often when I will bring up the idea of a delayed allergy to red meat and see if it might fit in their history, and then we run the blood test to try to confirm it.

Rebecca Saff, MD, PhD, FAAAAI 5:45

So how does a tick bite sensitize us to a sugar? I mean, it's kind of a very unusual thing to happen. What do we know about that?

Scott Commins, MD, FAAAAI 5:54

So this, I mean, the short answer is we're still working out the the molecular mechanism there, but it's pretty clear that ticks, whether it's all species or some, but ticks can carry alpha gal sugar uh or epitope in their salivary glands or their saliva? And so when a tick bites a human, some people develop an IgE response to the alpha gal that's present in the tick saliva. There's a lot of unanswered questions within that framework, including, you know, do all life forms uh or life stages of the ticks carry alpha gal? Are there different levels of expression? Are these different among different tic species? Why doesn't everyone react or develop IgE after a tick bite? Do you have to so there's a lot of work still to be done, but the general framework is that in the field of allergy, we know that going through the skin can be a fantastic way to make an IgE response. And so there in the tick saliva, alpha gal is present. There probably are some specific alarmins that are present in the tick saliva as well that that from sort of an ectoparasite perspective skew the immune response of some people to be TH2, and we end up making IgE to the alpha gal sugar.

Rebecca Saff, MD, PhD, FAAAAI 7:38

So you're saying I was always taught, you know, it's primarily the lone star tick, but you're saying that actually many tick species can may have this ability.

Scott Commins, MD, FAAAAI 7:46

Correct. So in the US, we totally are focused on the lone star tick. I I think the story goes beyond that, but we have the best evidence for the lone star tick. It's aggressive, it's expanding, and it affects a large portion of the US. But certainly, if you look in Europe and Australia, South Africa, and even South America, there are tick species in each of these places that have been associated with Alpha Gal syndrome. The exact same blood test for Alpha Gal IgE turns positive in each of these locations for those patients, but it's a different tick species in many of those areas.

Rebecca Saff, MD, PhD, FAAAAI 8:31

And so what is the epidemiology in the U.S. at this point? You know, it comes across, we think of it being more the middle of the country, but we're certainly seeing expand it north into the New England area, I think into the upper Midwest. Where should we expect to see this?

Scott Commins, MD, FAAAAI 8:47

Really, to take a large paintbrush to this, anywhere almost east of the Rockies, uh, to be honest with you, absolutely. We the initial thought was kind of a southeastern type focus, but really over the past several years, as you mentioned, this has expanded up the east coast. I mean, there are case now, case reports now in Maine. We know that Martha's Vineyard is heavily affected. And when we look epidemiologically from sero surveys, we have cases in the Great Lakes area. And so extending west, I think once you get to the Rockies, then my understanding from the tick experts is that high elevation, the Lone Star Ticks don't do as well in the drier temperatures. So there are fewer cases on the West Coast for sure, and many of those cases we think probably involve travel. Um, although there are probably at least one really good case from uh Washington state of Exodus Pacificus potentially causing AGS in a patient. So my sense is as much as we're focused on the lone star ticks, and those those ticks probably create, let's say, 95 plus percent of cases, there may be other smattering of cases here and there that are caused by different ticks even in the US.

Rebecca Saff, MD, PhD, FAAAAI 10:19

So when we suspect someone has Alpha Gal syndrome and we get the blood test and it turns out it's positive, how closely does that test align with the symptoms? So a higher number is going to be more significant than a lower number. If it's negative, are there are there false negatives?

Scott Commins, MD, FAAAAI 10:37

So the titer of the alpha gal IgE does not correlate well with symptoms at all, actually. It seems to correlate much more closely with the recentness or remoteness of the tick bite. And I should say too, you know, we when we say tick bite, I think our minds typically go to this picture of an attached adult tick that's feeding and engorging itself. But really, we like patients to think much more broadly about this. So often I will say tick bites, chigger bites, or seed tick bites. In my mind, that the jury's still out on whether chigger bites properly can cause alpha gal syndrome. But the problem when you get to these tiny little larval seed ticks is that they are really a challenge to see and they itch like crazy. And so there's a lot of confusion around seed ticks and chiggers. So we try to get people to think more broadly about that. So you could easily get a couple hundred seed tick bites if you're in the wrong place at the wrong time, and your alpha gal IgE may be greater than a hundred, would be what the clinical lab report might say, but you may only have hives and some gastro distress when you eat a full hamburger. So the titer itself doesn't really seem to correlate with symptoms per se. I think the second part of your question, we definitely know of some false negatives where people have a really solid history of the kind of textbook middle of the night hives or um gastro distress, trouble breathing, angioedema that correlates really well to their exposure to red meat, and yet their blood test is negative, the skin test doesn't work that well, so it's also um negative. And when we challenge those people in the clinic, we've had people who four or five hours later start getting uh signs and symptoms. So you you have to think that the test isn't perfect, it it probably picks up the large majority of people, but I think we have some pretty good evidence that there are false negatives.

Rebecca Saff, MD, PhD, FAAAAI 13:01

And why is the reaction so delayed? What's going on that makes it happen hours later rather than kind of what we would typically think of in a food allergy within you know 30 to 60 minutes?

Scott Commins, MD, FAAAAI 13:12

Well, the short answer is that is still a work in progress. The the general thought in the field is that the fat content is really important in generating these reactions, and and the fattier the meats seem to correlate to the more severe reactions. So when you think about our absorption of lipids, you know, they form chylomicrons, and we think that probably protects the alpha gal sugar. So in this scenario, we're thinking about a glycolipid. So the fats from pigs and cows certainly can have alpha gal as a sugar on it because they have the machinery to do that. And probably the fat gets absorbed. It takes a it takes a while for that process to happen. And in a human, we actually fat enters our bloodstream through the thoracic duct in our neck. So, you know, you've got to like specifically traffic the lipid particles through the intestinal barrier, then through the lymphatics. That whole process takes about three or four hours. So the general thought is that the lipid, the glycolipid, is really the allergenic portion of this or that's causing symptoms, and that that the delay really correlates to the appearance of lipid in the bloodstream. If you think back about the initial story with cituksimab, those patients would react to satuximab within minutes of it being infused and it was going IV. So there's clearly something to the delay that has to do with the absorption or processing of the food.

Rebecca Saff, MD, PhD, FAAAAI 15:10

Is there any other sugar that's known to do this?

Scott Commins, MD, FAAAAI 15:14

Not to my knowledge. We have we've thought that why would Alpha Gal really be the only one? Like it's probably the first that we've identified where you know allergists have kind of downplayed carbohydrates for a while. And we really everything in the field kind of focuses on protein-based allergens. But my sense is that Alpha Gal is probably somewhat unique in that we as humans don't make it, and the food products from these mammals specifically have alpha gal, so there is that portion. There's going to be other sugars that would also fit that bill. And they're probably, if if we fast forward five years from now, you and I may be having this conversation, and we may be talking about two or three other carbohydrates as well at that point. I I don't I don't think that the IgE response to Alpha Gal per se is is going to be unique.

Speaker 16:21

Do you mentioned ceteximabs? So there's these certain medications that we have to be careful of in patients with alpha gal syndrome. If someone has alpha gal syndrome, what medications do they have to avoid? And do they always have to avoid them or does it depend?

Scott Commins, MD, FAAAAI 16:35

I don't know that we could go through all those. Um so it's a real challenge. This my nebulous answer is really points to a big issue in the field, and more than the field, just to the management and of Alpha Gal syndrome and for patients dealing with this. There are a tremendous number of inactive ingredients in medicines. And that's really my pause because these can be magnesium state or gelatin, some of the polysorbates, they can have mammal sources or origins, but that portion doesn't really have to be declared because they're an inactive part. So as long as it's magnesium state, the FDA is fine with it. It doesn't really matter on the packaging. The manufacturer doesn't have to say what the origin of that magnesium state is. So it's it's an incredible challenge for patients that are sensitive to that degree where, I mean, there may be lot to lot variation in the source of some of these inactive ingredients. So you start to think, well, I'm fine with this capsule, but they can later change the the source, and now all of a sudden you're reacting to the same capsule. So things that have gelatin for sure, we're we are wary of and often require a call to perhaps the drug manufacturer or to an outfit like pill clarity to try to help the patients understand the risks. There are, to your question, there are a couple of things that come up over and over again. Heparin is one of them, it's clearly made from mammals. I think the other thing that comes up a fair amount are twofold. One is pancreatic enzymes, those tend to be just porcine-derived pancreatic enzymes. And the other thing is armor thyroid, which is really truly derived from the mammal thyroid gland of typically of pigs. And in those scenarios, we've had plenty of patients react to those medications, but the full list is a is a real challenge.

Rebecca Saff, MD, PhD, FAAAAI 18:54

So if someone has very mild symptoms and has a low titer, would you challenge them to those medications or would you just say, I'm afraid we we need to avoid that?

Scott Commins, MD, FAAAAI 19:04

Most people in that scenario, I kind of use dairy as a little bit of a bellwether. So if someone can have milk or cheese in their diet and they have Alpha Gauss syndrome, then they're not reacting to trace amounts. Generally, in the hierarchy of things, if someone can keep cow's milk-based ingredients in their diet, I'm less concerned about a gelatin capsule. There may be other times where if it's going IV, like if you're going to get fully anticoagulated with heparin, you might you might change that paradigm a little bit. But in general, if there is some dietary exposure to dairy that's tolerated, I think a lot of the medication-derived exposures become less of an issue.

Rebecca Saff, MD, PhD, FAAAAI 19:59

And one question we've gotten on the consult service a number of times is these biosprosthetic valves, um, and how safe are they in patients with alpha Gauss syndrome?

Scott Commins, MD, FAAAAI 20:08

Yeah, you and I probably could spend 30 minutes on the valve uh aspect too, but because there are a lot of nuances to that. The valves, look, valves are an issue for sure because if you look at the literature around these porcine and bovine derived valves, it's pretty clear that even with their fixation processes, that the alpha galmoiety survives. So you're putting a valve in when someone has IgE that clearly recognizes an epitope that's that is going to be present. I think the the issue gets muddy because often when you're getting a valve, you're also getting fully anticoagulated with heparin. And so in hindsight, I wonder some of the quote-unquote valve reactions that we were so worried about early on. And look, people had anaphylaxis perioperatively or periprocedurally. In hindsight, I think you have to question was that heparin or was that the valve? And the timing can be really a difficult one to sort out. And then now you add in the approval of omolisgiumab or Xolair for IgE-mediated food allergy. So these patients have AGS and now they need a valve. Well, one of the things that we are thinking about and and actively doing is maybe you you think about how Xolair can benefit both the food allergy portion for these folks, but also perhaps help with some of the potential valve ramifications and One of the questions that we don't know when you talk to the cardiothoracic surgeons, there is a percentage of early valve failure that seems to happen across multiple, like across any center, all comers. And it's not clear to me that we know why there are people who fail early. And probably there's multiple causes for early valve failure, but we've obviously been thinking with others that maybe the alpha gal IgE as a pro-inflammatory process could explain some percentage of early valve failure. And now you have Xolair entering the equation and the conversation. And so it does become a these become long visits with patients and trying to talk through the ramifications and figure out the best steps.

Rebecca Saff, MD, PhD, FAAAAI 22:57

Have you had success with Xolair in treating Alpha Gauss syndrome?

Scott Commins, MD, FAAAAI 23:02

Yes, we have. And we'll have a poster at the at the upcoming 2026 AAA AI meeting about this. And it has really seemed to work quite well for patients, particularly those who are very fairly sensitive to Alpha Gal and have a lot of trouble, particularly eating out, even though they practice an appropriate avoidance diet, may order the right thing at the restaurant and ask all the right questions. There's just a fair amount of lack of awareness, I think, and cross-contamination can produce symptoms for these folks, even though they're doing the best they can to avoid. And we've really found that in a lot of instances, Xolair improves quality of life for patients with AGS in a way that nothing else has prior to now.

Rebecca Saff, MD, PhD, FAAAAI 24:05

So when you go about recommending food avoidance to patients who have had maybe a reaction to meat, what are the things you discuss with them in terms of the different levels of risk with different foods? And does that change over time? Are you more likely to lose, for example, your sensitivity to milk before you're able to introduce meat, for example?

Scott Commins, MD, FAAAAI 24:25

Yeah, the foundation of this is a red meat avoidance diet. And when we talk through the idea that pork, even though it had this campaign as the other white meat, is mammalian derived and needs to be avoided as well. So it's a discussion of that. And then also the idea of maybe non-intuitive exposures like sauces and gravies, where you have flavors, fat, what have you, lard, suet derived from mammals that is kind of used as a way to create an uh you know a flavor-enhancing thing, but it's an exposure for these patients that they often don't do well with. And it is it is a fairly long conversation. Some people certainly already have a sense of having figured it out, but occasionally, you know, even in those folks, when they're trying to do the right thing and get chicken sausage, for example, often there's a pork casing to that that is completely derived from the intestines of a pig and can cause some pretty impressive symptoms, uh, as we've seen. So that portion is a fairly long conversation. And then dairy is kind of the second part of that discussion. I tend not to pull dairy from someone's diet if they're doing okay with it. And and that probably has two reasons. I think one, first and foremost, is that it seems to give patients a little more wiggle room. If if often we've seen when people are incredibly strict in terms of their avoidance, that seems to produce a phenotype where the slightest exposure gives them symptoms. Where other patients who who kind of kept dairy in their diet never seem to become as sensitive. And the other part of that is also just that when you take away red meat as a class of foods, if you can like patients still want to then be able to have cheese, for example, and I think appreciate being able to do that if they don't have symptoms. So it seems to be both from a sensitization and the standpoint of allowing them then to maybe create a little desensitization, if you will, and then also just the fact that they seem to prefer having dairy in their diet.

Rebecca Saff, MD, PhD, FAAAAI 27:16

So it's almost like the baked milk and someone with a milk allergy or baked egg and an egg allergy, maybe gives them a little bit more wiggle room in terms of eventually tolerizing.

Scott Commins, MD, FAAAAI 27:26

Yeah, that's how I've thought about it in my mind. We don't have as obviously, we don't have near as good of trials as there are in the baked milk, baked eggs scenario, but it is something that we're hoping to do uh over time because I that's how I conceptualize it.

Rebecca Saff, MD, PhD, FAAAAI 27:44

Yeah. Is there any besides the getting the dairy products, is there a something of a ladder that you do at all with patients who their titers are going down, or do you tend to just challenge them at some point?

Scott Commins, MD, FAAAAI 27:56

It's kind of a nuanced approach. I have, I certainly have ladders that we use for dairy reintroduction and then eventually for red meat reintroduction. And some people are exquisitely sensitive, and you don't even need the ladder because they'll react, you know, at a certain certain food product at a certain dose almost every time. But we really tend to handle that on kind of a one-on-one basis, and admittedly, have even done some staggered reintroduction, not always in the clinic under a full challenge, like the traditional food challenge model. Some of that's because with the delay in Alpha Gauss syndrome, like you can't just incrementally feed someone, you know, every 15 or 20 minutes the next dose of egg because you got to wait so long. So I think sometimes these ladders really help patients in a non-office environment, kind of help them to understand like where they may have opportunity to include a little bit of butter, a little bit of cheese, etc. And you know, you got to be careful, obviously, that you're not doing that for the most sensitive patient who's had recurrent anaphylaxis, but I think in the right scenario, it has worked pretty well.

Rebecca Saff, MD, PhD, FAAAAI 29:25

It can make such a difference in someone's life if they don't have to be quite so careful with every ingredient. So it gives them that peace of mind as well. How do you do these challenges in something with such a delayed reaction? What's your do you have people eat before they come in? Do you have people eat and then just wait in the clinic all day? How do you typically do this?

Scott Commins, MD, FAAAAI 29:44

I think the most typical is come in early, eat the challenge food in the clinic and wait. That being said, for someone who's local who's titer has been downtrending, maybe they've had a couple of accidental exposures that have not given them symptoms. In those scenarios, sometimes we'll have them wake up and eat early at their house, let's say, you know, before the clinic would be open, and then within two hours have them appear in clinics so that at least we get like a little bit of a head start. Uh and for some for some folks, that I think has worked pretty well, but that does tend to be folks who are more local.

Rebecca Saff, MD, PhD, FAAAAI 30:29

And do you have all patients with Alpha Gal syndrome carry epinephrine?

Scott Commins, MD, FAAAAI 30:35

I always go with all, but generally, yes.

Rebecca Saff, MD, PhD, FAAAAI 30:39

Yes. Um, are there patients who you know have more mild symptoms where you're not as inclined to have them necessarily be quite as careful?

Scott Commins, MD, FAAAAI 30:50

Yes, there are some patients who I think there's two scenarios here. One is they may have symptoms that really kind of resemble like chronic hives. There seem to be a group of folks who, no matter how large their exposure, they are going to get skin-related manifestations. It almost in some ways, to me, reminds me of our patients with bad atopic derm who, if they have a food allergy, they often don't necessarily have anaphylaxis, but their their skin will will really flare, you know, for a couple of days or a week or two after an exposure. There are people with AGS who seem to fit that bill where they they have a significant food exposure and they get they get hives only. And then I think the second group that comes to mind would be the people who really get gastrointestinal only symptoms. So there's a group of people with AGS who test positive, they have IgE to Alpha Gal, and they have a history of tick bites, etc. But their symptoms are gastrointestinal pain, abdominal cramping, nausea vomiting, diarrhea, and little else. They don't have hives or itching or angioedema or respiratory distress, lightheadedness, nothing cardiovascular. And those patients, that seems to be their manifestation. I think, you know, with epinephrine, it's I feel like it's often a loaded conversation. In many of my patients, I advocate for them to have epinephrine because to be honest with you, they're outdoorsy people, they have countless insect stinging and venomation exposures. And I frankly feel better with them having access to epinephrine. Um, but I recognize that not everybody wants that. And if they fit one of those two scenarios, then I think it does become a risk-benefit discussion.

Rebecca Saff, MD, PhD, FAAAAI 33:12

If someone is able to avoid tick bites, how quickly can you see the titer come down? And does it tend to be consistent that in most patients it comes down about this, or is it very widely depending on the patient population?

Scott Commins, MD, FAAAAI 33:24

The titer will fall pretty quickly. So even if someone has been referred to me and has an alpha gal IgE at the time of diagnosis, if it's been a couple of weeks or a couple months since that, we often recheck it because it will routinely fall fairly precipitously if the tick bites have been recent. The rate of that decline, if you were like mentally graphing it, does not continue to be exponential. It eventually levels off, and sometimes the last say two units of IgE that they're testing positive to seem as though it takes forever for that part to go away. There clearly are different kinetics where some people, this IgE to alpha gal will linger for years, but the highest I've ever seen is 1,286. We had to keep diluting it and diluting it, and eight years later, that patient was undetectable. So it clearly can completely go away. And whether you call it, you know, remission or resolved, unfortunately, if they get more tick bites, that alpha gal IgE can certainly return. And we've seen that happen where someone completely goes away, they're eating beef, pork, lamb, etc., they get more tick bites and the whole thing starts again.

Rebecca Saff, MD, PhD, FAAAAI 34:53

And oftentimes it I imagine it would be hard in some of these people to say, avoid ticks completely because they want to be outdoors.

Scott Commins, MD, FAAAAI 35:01

That's right. They like to be outside, and it's just a real challenge to be completely tick bite-free for years and years.

Rebecca Saff, MD, PhD, FAAAAI 35:07

Absolutely. So, what do you think are some of the most unimportant unanswered questions still remaining in alpha gas syndrome?

Scott Commins, MD, FAAAAI 35:15

Yeah, I think there's a few. I mentioned this idea of the gastrointestinal-only symptoms. So, one kind of easy answer is why do some people get this like GI-only version of AGS, but others get the full systemic version that we typically think of with food-based uh IgE-mediated anaphylaxis. And I I'm not sure that we really have an understanding at the moment of why that happens. The the GI only folks do seem to have a slightly lower alpha-gal IgE, but that may just be that it takes them longer to truly come to the attention of an allergist because often they've been told they have IBS for years and years. I think one of the elephants in the AGS room currently is the potential for a link with cardiovascular disease. So there's been two publications that associate an alpha-gal IgE with cardiovascular ramifications. One is uh an unstable plaque or atheroma, and the other is uh more related to like uh an MI. And I think this those two publications really weigh on a lot of patients and trying to understand is there some sort of cardiovascular overarching risk with the formation of IgE to Alpha Gal? And I I think that is something that we we as a field um need to answer, and I think many of us are are working on that. I think the other things that come to mind for me in the unanswered realm include the idea that there's some patients that have Lyme disease who are treated appropriately and effectively, but yet still have this constellation of symptoms. And in some ways, those symptoms, such as fatigue and flushing and brain fog, are similar to the things that you and I may hear about from our patients that have mast cell disease. And there does seem to be a group of people that have alpha gal syndrome who equally develop fatigue and flushing and brain fog and random hives and difficulty with some of the foods that are not at all mammal-based, but that we might more think about as kind of on the histamine side of things and understanding what it is about tick bites that leads to potential activation of mast cells. And is there some sort of final common pathway that is distinct from whether you have an infection of Rocky Mountain spotted fever or alpha gal syndrome or erlicosis or Lyme disease, but there's something about the tick bite itself that may be activating potentially mast cells, potentially basophils, et cetera. I think that's a real unanswered question for us as well. Obviously, if people are focused on treatment too, and and so for us, one of the real limitations there has been if we were going to take an approach like you and I kind of talked about with either like a baked baked milk theory or even like an OIT-based approach, one of the issues has really been how do we standardize Alpha Gal to where we are giving like a known dose or quantity? And and so it turns out we have real problems in the field producing alpha gal, like making enough of it to be able to create a therapeutic out of the sugar itself. And so I think what we really need to do is look for like a cell-free glycoprotein or glycolipid synthesis system. There are folks that are working on this. Mike Jewett and Ariel Timms have published this idea in a N-acetyl glucosamine pathway. But we would love to do something like that in the alpha-gal world to be able to have enough antigen or allergen to try to manipulate or treat that IgE uh-based allergy. Um and then I think finally is just if the tick bite itself is skewing people to make a TH2 IgE type response, you know, we're having more and more tools in our AI toolbox related to inhibiting that TH2 response. So are there things that we could do with current biologics that could potentially help treat that portion of the tick bite response itself?

Rebecca Saff, MD, PhD, FAAAAI 40:50

I wanted to circle back. So, one of the things we often have a question of is that an alpha gal gets sent for some reason and it's positive, but the patient actually hasn't had any symptoms. Like they're eating meat and they don't have any problem. And so I've also read the studies about heart disease. Wondering like, is it is it wise to avoid avoid, have patients avoid? We know that that's actually not good for tolerance. And in general, our food allergy hat would say, if you can keep something in the diet, you really should to maintain tolerance, but never sure exactly what to do with those patients. Um, it's often in the setting of medication that I've seen it sent, you know, there's a concern for a reaction, we send it, it comes positive. It's not clear if that's the culprit or not. What would you advise those patients?

Scott Commins, MD, FAAAAI 41:36

This is a big issue in the field at the moment. So I'm glad you brought that up. This idea of sensitization, right? Um, as we like to call it, it in some ways I feel like it's just we should just say it's a false positive, but I think we don't know, right? Um, I treat it the bottom line up front, I treat sensitization in the same way I would potentially treat it for someone if they turned up a peanut or shrimp IgE and they eat those foods fine. I would just say keep it in your diet. I I think what we don't know is, at least in the alpha gal allergy space, are those people that are positive, do they go on to become someone who is truly allergic at the next tick bite or the next set of seed ticks exposure? We're working on that now, and it requires following people who are positive longitudinally when they were initially positive without symptoms, right? Sensitized, do they but later become truly allergic? So we hope to have an answer to that in the next few years. But currently, I ask people to continue to eat the meats that haven't bothered them or the dairy that hasn't bothered them. But we see this a lot now where providers have added the Alpha Gal IgE to like their tick-borne illness panel, which to me is not the correct way to be doing it. We, you know, in the allergy field, we know that our testing should be used to confirm what we clinically suspect. And I think the Alpha Gal IgE is that same way. So there definitely are patients where sometimes the crux of their visit is telling them, look, I don't think you have Alpha Gal syndrome. I think someone perhaps well-intentioned sent this Alpha Gal IgE. You're an outdoorsy person, you turn positive. In some populations, literally 20 to 30% of the people in a given area could be positive, but no symptoms whatsoever. So, and that data has been repeated. And I think we have a fairly established track record that that can be true. And that helps us to reassure patients. You know, hey, you're probably in this 25-ish percent of people who in our area just test positive because you're outside, you get an occasional bite, but I wouldn't stop eating the red meats or pull dairy out of your diet at this point.

Rebecca Saff, MD, PhD, FAAAAI 44:14

Very good. Is there any other take homes that you want to make sure that you leave people with?

Scott Commins, MD, FAAAAI 44:20

I think all these podcasts are really helpful. So I'm gonna plug my own, which is called Questions People Ask. And the first episode is a slide deck of me going through what I want my alpha galallergic patients to know, and for it to be a resource for those who per perhaps are diagnosed with AGS and may not be close to an award-certified allergist immunologist to ask for expert opinion. And then the second episode of Questions People Ask is a deck of slides for providers who may have questions about AGS and want to go into details about some of this from a very clinical standpoint.

Rebecca Saff, MD, PhD, FAAAAI 45:05

That's fantastic. Yes, we can link to the show notes to the podcast, and I am excited to listen myself. I didn't know you had a podcast. That's fantastic.

Scott Commins, MD, FAAAAI 45:13

It's still in the production process, so it's not officially out yet, but I hope like within a couple weeks.

Rebecca Saff, MD, PhD, FAAAAI 45:21

Well, people can look for it. That's wonderful. Thank you so much.

Scott Commins, MD, FAAAAI 45:24

Yeah, thank you. My pleasure.

Rebecca Saff, MD, PhD, FAAAAI 45:28

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