This Podcast Will Kill You - Ep 161 Allergies Part 1: Pollens, nuts, & bugs

Episode Date: January 7, 2025

Sometimes it seems like the world is out to get us: bees in our garden, pollen in the air, nuts in our brownies, any number of other things that could trigger an allergic reaction ranging from itchy eyes and a runny nose all the way to anaphylaxis. Why must our bodies react in such over-the-top ways to these seemingly innocuous substances? In the first episode of our two-parter on allergies, we explore that very question. From the biological basis of an allergic reaction to the potential evolutionary significance of allergies, from the history of their discovery to the global status of allergies today, we cover it all. Tune in today! Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAu  See omnystudio.com/listener for privacy information.

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My name is Caitlin. I'm 32 years old. And for most of my life, I hadn't experienced. severe allergies or allergic reactions to anything except for cats sometimes. I went to school in Nebraska and after college I got a job in Denver and moved. The first year living in Denver was awesome. I got really into all the outdoorsy things that Colorado has to offer, like camping and hiking and skiing.

But about a year into my time in Denver in the spring of 2017, seasonal allergies and hay fever hit me unlike anything I had ever experienced before. Every day that spring, I remember, I would wake up with a sore throat, hives, and swollen eyes. My eyes would have allergic conjunctivitis and chemosis, which is when tiny bubbles form on the surface of your eye from all the allergens and pollen in the air. I had a constant runny nose and couldn't breathe. I had a lot of sinus infections. I also couldn't hear very well because of all of the post nasal drip that would happen and settle in overnight. I was beyond exhausted all the time and unable to go outside.

much at all. Every time I would leave my house, I would get hot, painful hives on any part of my skin that was exposed. I remember taking cold showers all the time to try to keep my hives from spreading all over my body. And at the time, I was only using over-the-counter allergy medications, which only helped a little bit. I worked downtown in an office. And so writing the train into the office, interacting with coworkers and clients and wearing business casual clothing, was incredibly uncomfortable and embarrassing sometimes. And this is all before COVID times, and I was still really new at my job, so asking to work from home was a challenge. I was also really bummed because I couldn't eat a lot of fruits that grew on trees where you typically eat the skin because the

pollen grows with the fruit instead of on the hard outer layer. So fruits like peaches and apples were off limits because I would break out in hives on my neck and face and sometimes experience breathing issues. And sadly, Colorado is famous for their palisade peaches, and And I could never have them, even though it was my favorite fruit growing up. Unfortunately, things got exponentially worse the following fall due to a mold issue in the rental house that I was living in. I was exposed to penicillium mold spores, which had a compounding effect on my already maxed out immune system. And I ended up developing severe asthma. I was playing roller derby at the time, and I remember showing up to practices and scrimmages,

feeling like I was breathing through a wet cloth draped over my nose and mouth, and felt like I would pass out after one, warm-up lap. I was devastated. I didn't know what was wrong with me, and I was trying so hard to get into the sport and develop a community in my new place, but I was not able to keep up at all. I ended up taking a leave of absence to avoid further damage and started seeking professional help. I had skin testing done in January 2018, and it was pretty awful. Almost every single allergen that they had tested me for came back with a flaming positive. After this, I was introduced to my allergist and met my immunotherapy team. I got started with allergy shots by doing a procedure called a rush treatment to try to get my body as close to my maintenance dose for

allergy shots as soon as possible. I was not able to finish the entire rush treatment because my body started to go into shock, which is actually typical for the procedure. After that, I began regular allergy shots every three weeks for the next five years. I was also put on a prescription strength antihistamine, two over-the-counter antihistamines, two inhalers, and an epipen. And an epipen. And a epipen in the event I went into anaphylaxis. I was not allowed to eat or touch anything that would cause any sort of reaction, and I had to avoid being outside on high pollen days. Springtime was always the worst for me due to the presence of tree pollen, and I would always see more intense reactions during that time of year to my allergy shots. Fortunately, I completed my immunotherapy in July 2023 and had been

pretty good ever since. I'm still on the prescription strength antihistamine and one of the over-the-counter antihistamines for any allergies that might pop up. as well as both inhalers for the now permanent asthma. But overall, things are pretty manageable for me. I remember asking my allergist, why now? Why did allergies hit me now and here and like this? And never before in my life. And she explained to me that I'd probably experience what they call a honeymoon period when I first moved to Colorado.

My body is non-reactive to the new allergens because it had never seen them before. But almost always a second time around or the following season that your body encounters the allergen, it overreacts and produces an excessive histamine response. This whole experience has been a very long and painful journey and it took a huge toll on my mental health at the time. I'm not entirely sure how long I'll be without allergic reactions, hopefully forever, but I still get hives from time to time. Everyone's body reacts differently and sometimes you become allergic to new things that you weren't before. Every reaction I do have now is manageable. My asthma is still very much there, but I've learned to live with it.

And I'm also really excited to report that I can have features and apples again. Life has been completely changed because of this experience. I'm so fortunate to have the support that I do, and I cannot thank my medical team and my family and my friends enough for taking such good care of me throughout those five years. I've learned so much about something I never even thought twice about for two-thirds of my life that ended up having a major life-altering impact on me. The human body is so intensely weird in particular sometimes, but I'm so grateful that I was able to get through this experience and to be where I am now, even with the lasting effects

it has left me with. That sounds truly miserable. Yeah. Truly miserable. Oh, my goodness. I always think like, oh yeah, I have seasonal allergies sometimes. I barely do. Yeah. I have the hint of a seasonal allergy. I know. And to deal with it. The lecroy of seasonal allergies. The lecroy. I know. And to deal with it just like, oh, my goodness. Yeah. All. Yeah. And when it's everywhere, it is inescapable. You can. and not ever escape it. Yeah. Yeah, you just breathe it in.

That's brutal, but I'm glad that you're finding some more relief now. Thank you so much, Caitlin, for sharing your story with us. Thank you. Oof. Hey. Hi, I'm Erin Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you.

And today we're talking about allergies. Today and next week. Today and next week. You know, what do we get ourselves into here, Aaron? The same thing that we always do, Erin, which is a very, a very large topic. Yeah. Yeah. Here's the deal, everyone listening.

Here's what it's going to go like. This week, we are going to talk about allergies. I'm going to call it capital A allergies. That is, all of them. Food allergies, seasonal allergies, all of the allergies. What does that mean? What is an allergy even? We'll talk about it.

And we'll talk about how we figured out what are allergies. Why do we have them? those kinds of things. Next week, we'll focus on what do you do if you have allergies? And how did we figure that out? How do we treat them? And what are some of the options in that respect? That's the way that we're trying to split it up.

We'll see how it goes. I think it'll go great, Erin. You have nothing to be worried about. I'm so worried. You always do an amazing job. I'm so nauseous. She gets nervous every time. She's so nervous all the time.

And I'm like, you do a great job. As soon as we start, thank you. As soon as we start to record the biology section, my stomach every time goes like, so it's already there. But I'm looking forward to it. I think there are going to be a great couple of episodes. There's a lot of stuff that we're getting to explore from sort of this big picture perspective on allergies that we haven't really, although we have covered allergies or allergy-related conditions like asthma in the past,

I think this is a fun opportunity for us to kind of go, okay, let's take a step back. What are the patterns that we see? How does this work across the board? Right. Really big picture here. Yeah. Yeah. But before we can start on that, it's quarantini time.

It is. Erin, what are we drinking this week? We're drinking the allergy shot. Yeah. Pretty straightforward? Pretty straightforward. But we won't talk about allergy shots other than this today. talk about them next week. It's true. What's in the allergy shot, Aaron? You know, it's just a little

tropical delight, you know, it's got some, it's got some rum in it. It's got some tropical fruit juices, like some pineapple, some orange. It's delicious and it's a small contained thing. So, you know, it's great. We'll post the full recipe for the allergy shot quarantini and the non-alcoholic placebo rita on our website. This Podcast Will Kill You.com, as well as on all of our social media channels, which if you're not following us on social media, you really should be because, you know, there's some pretty good content if we do say so ourselves. And we do. We do every time. If you haven't checked out our website yet, check that out. It's phenomenal. This podcast will kill you.com. We have sources from all of our

episodes. We have transcripts from all of our episodes. We have a link to our bookshop.org affiliate account and our good reads list. We have links to Bloodmobile who does our music. We have so much merch. We do. We have more things. We have more things. The website is a great, magical place. Check it out. New pictures. New pictures. promo codes. This podcast, wKhawekow.com. Check it out. And then one last thing before we get started with the actual content of the episode. And that is to please rate, review, and subscribe. It really does help us out. And we appreciate everyone who has ever left a review or subscribed or rated, you know. Yeah.

Also tell your friends. Yeah. Maybe they're not listening yet. And then you would have something else to talk about. Like allergies. Like allergies. Speaking of. Things to talk about.

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now available in Canada too. That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. This is either going to be very shocking to people listening or entirely unsurprising, probably for long-term listeners, but it's actually a little hard to put a very strict definition on the word allergy. Erin, there is a paper that I found that was the evolution of the term allergy.

I think I read that paper. Yeah. I think I read that paper. I tried not to read history and evolution papers, but I think I did read that one. But we will do it, in part, because we have to, because we're doing an episode on allergies, so we have to tell you what we're talking about.

But I think that by the end of this and next episode, everyone will appreciate that, like, the deeper you get into the weeds, the more messy this idea of allergy really becomes. But we'll try and keep it a little less messy and just cover the general basics. So the American Academy of Allergy, Asthma, and Immunology, and the UK's National Health Service, and most other, like, major medical and public health organizations agree on the basics of what an allergy is. An allergy is an abnormal over-the-top immune response to substances that typically do not,

and really kind of should not cause any substantial immune response. Erin, you're smiling, which I know means that the should not maybe doesn't apply, but that's the way that I think about it. There's some discussion. We'll get there. I can't wait. But so these substances, the stuff that our immune system is recognizing and reacting to in this over-the-top way, these things are called allergens. And we've talked a lot on this podcast about the idea of antigens.

Antigens are just the stuffs that our immune system sees and recognizes and then responds to. Allergens are just antigens. They really are just antigens. The only differences and the reason that they classify them differently is that they are stuff. And first of all, they're usually almost always proteins, except as we talked about an alpha gal, when they're not. but they're almost always some type of protein. And for most people, these things that we call allergens, our immune system sees them, but usually goes, ah, forget about it. Like, just ignore that one. But in people with allergies, these specific kinds of antigens that we call allergens

trigger a severe hypersensitive response. So let's talk about how that ends up happening. Okay, real quick. So all allergens are antigens, but not all antigens are allergens. Exactly. It's like all squares are rectangles, but not all rectangles are squares. Got it. So let's see how that ends up happening. We went over the basics of this actually very recently in our alpha-gal episode, but we're going to go over it again, because the basics of this are applicable to essentially all types of allergies with an asterisk, because there are a lot of things that people might call allergies that don't fit this mold. But when we're talking about allergies for this episode, this is the type of process that we're going to be talking about,

is the pathway I'm about to explain. And here it goes. The pathway starts with an exposure, and then there's a process called sensitization, which is making these specific type of antibodies called IGE antibodies, and we'll get there. Then there's re-exposure, and then there's an allergic response. So we can go into detail on each of those parts. First, of course, we have to be exposed to an allergen. And we can be exposed to an allergen in so many different ways. It can be in the air so we can breathe it in. And they often call those aero allergens because if we don't have confusing terminology for every single thing, then what are we even doing in medicine? Or it can be in our food. We can scratch these allergens into our skin, a tick could spit them into us, as we recently learned.

We could rub them into our eyes any way that they get in. Eventually, these allergens make it into our bloodstream. And as soon as they make it into our bloodstream, our immune system is all over it. So let's say, as an example, it's cat dander. There's a specific protein called F-E-L-D-1 or F-D-1 that's in cat skin, saliva, and urine. And that's the thing that's the allergen in cat-dander. So once cat dander makes it into our bloodstream, a whole bunch of cells, like our macrophages, our dendritic cells, blah, blah, blah, all these immune cells, they find this stuff, all of these allergens and antigens and the cat dander protein. And they bring it to our T cells. And our T cells are the ones, Aaron, went back to my vaccines episode notes. Great episode.

To be like, how did I explain this once upon a time? our T cells are the ones who are the way that I think about it is they're kind of responsible, and this is an oversimplification, for either doing something or like not doing much of anything. They're going to be the ones who like open a door or don't open a door to make the rest of our immune system react or not react. They're like the major part of the decision tree where it's like, is there going to be a cascade of events after this? Or do we shut it down right now? Exactly, exactly. And it turns out that we have a lot of different kinds of T cells in our bodies.

And depending on what they're reacting to, what they find, they can open one of many doors in our immune system. And which door they open fundamentally changes all of the downstream immune response that we see. So when T cells open, say, door number one, they're going to release. a whole bunch of cytokines, right? These inflammatory things that will help our immune system to, let's say, find bacteria or viruses and target them and eliminate them. If T-cells instead open a different door, call it door number two, then they release different cytokines, different inflammatory stuff, and then they're maybe going to look for worms or parasites or something like that. Now, of course, in reality, our immune system is doing all of these things and opening all the doors at the same time and there's more than just two.

But it turns out that what happens in the process of allergic sensitization, this is our second step in the pathway, is that the proportion of doors that our T cells are opening is skewed. And it's skewed towards door number two. So it just so happens that when our T cells decide, when they see an allergen, to open a whole whole. whole bunch of doors number two, it ends up telling our B cells, which are the ones that make antibodies, to produce a specific kind of antibody, and that is IGE. And that's the sensitization step of an allergy formation. And we talked about these IGEE antibodies in our Alphigal episode, but antibodies in general are like flags that our immune system uses to recognize and respond to harmful stuff more quickly. We have to see a pathogen or an antigen or an allergen make an

antibody, and then the next time we see it is when that antibody does its job. And we talked about this particular IGE antibody that it's different from the ones we think of that we use for something like vaccine responses because they're bound to cells like our mass cells and our basophils. So, sensitization, we're making these weird, kind of weird, IGE antibodies. Once we've been sensitized, then we have to see that allergen again. We have to be re-exposed to that same allergen. So you made IGE against cat dander, and then you go back to your friend's house who has a cat. And because this IgE is all over our mass cells, it's going to find and bind to that cat dander

protein. And that binding of the massed cells to the allergen triggers a reaction that causes those mass cells to burst open and spew forth a whole bunch of highly reactive inflammatory stuff. It's things like histamine, leukotrienes, a bunch of things called interlems, all of this stuff that tells our immune system, something really serious and horrible is happening, and everyone needs to get on board. It activates our immune system in a really extreme way, and it can do this on both these short time scales, like immediately, these immediate responses, but then it also triggers these longer term, like, delayed responses as well as the rest of those inflammatory stuffs are floating around our body.

that's the actual allergic reaction okay okay um question question what's your question so iGE is involved in this allergic pathway and also parasites but yeah you'll get there we'll get there yeah but there are so many different types of antibodies so is is iGE generally associated with the speedy almost immediate response and the other antibodies, like, why, what do they do? Yeah. Not to turn this into an immunology episode, but like, what do they do? Yeah, so all antibodies are serving as ways to quickly identify and respond to very specific antigens, right?

So each different antibody, we have like bagillions of antibodies in our body. All of them are responding to one specific protein or one specific car. or a dehydrate or whatever it is, one specific thing. But things like IGG antibodies, the way that I think of them, and immunologists might tell me this is not a great way to conceptualize it, but the way that I think of them is they're more like a flag. So they attach on, they find like a bacteria or something, and they attach themselves to it. And then our other immune cells, as they're floating around, they see that flag, that IGG flag, before they see the bacteria. And they're like, oh, hey, guys, that's an antibody flag, so we should find that thing, right? And then they can go and find all the bacteria

that have all these flags on them. The difference with IgE is that it's not just a flag. It's attached. It's not free floating. It sometimes can be, but it's not free floating in our bloodstream. It's attached to these cells. And something about the process of when that antibody that's attached to a cell attaches to its antigen, that we call allergens in the case of allergies, It triggers this response in the mast cell itself that causes an explosion of the inflammatory stuff that's inside of that mass cell. And we don't see that with other types of antibodies because they're not bound to cells. So it's like a longer process, even though it's all much quicker than like making the antibodies the first time that you're ever exposed to something. And compared to IGE is the response to other types of antibodies.

generally speaking, more directed, more precise. Or is it also the systemic sort of like just, again, scorched earth, I think is the phrase that I used in Alpha-Cal. Yeah, that's a really, it's a really good question. I think it's tough because the antibody response itself, even in the case of IGE, it is very highly specific, right? Like your IGE is only attaching to cat dander protein. Yeah. But yes, because you have this then immediate release of all these general inflammatory stuff, you see a quicker onset of a more widespread reaction than you would potentially with other

antibodies. Right. Because you just don't have that. It doesn't mean that you don't have like a widespread immune response in other scenarios, because we definitely can. That's how you could end up with like sepsis from a bacterial infection in, blah, blah, blah. But yeah, it is not that same antibodies kind of causing the problem here, I guess, is the way that you can think of it. Right, right. It's just bizarre. It is. It's a really

weird and interesting, especially like, I know you're going to talk, Aaron, about the kind of evolution of this. And, like, it is really, really interesting and weird to think about why we evolved this type of response. It's really interesting. Especially when it seems like It can come at a great cost. It can. When it kind of runs away. So there's such a huge range of allergic responses, right? There can just be like itchy nose.

It can be coughing. It can be whatever. Yeah. What determines whether the response to an allergen is mild versus extreme all the way to anaphylaxis? So let's talk about what the different responses can be. Because we are talking really generally about this big picture allergic. response. And the symptoms that you're going to get will, in large part, depend on the type of

allergen that you're exposed to and how you are exposed. So if it's a cat dander protein, for example, or even like a ragweed pollen, or a dust mite, or cockroach leg fuzz, or whatever, then you are being exposed to these aero allergens, right? So you are breathing them in for the most part. So then where you're going to get this inflammation from this immune activation might largely be in, say, your nose. So you might have an itchy nose. You might have sneezing. You might get a runny nose. Maybe your eyes will start to itch or water because the cat dander is getting into your mucous membranes in your eyes and triggering inflammation in your eyes. If, on the other hand, we're not talking about an aero-allergen, maybe we're talking about something like a peanut protein or a

soybean protein or a wheat protein. You're eating that. So then you're being exposed through your gut mucous membranes or maybe through your mouth because there's a whole thing called oral allergy syndrome where you have this type of itching, watering, numbness, tingling just in your mouth. But if it makes it down into your guts before you're having allergy response, then maybe you're having nausea. You're having vomiting. So it depends in part in the way. way that you're exposed. Is it through your respiratory system? Is it through your GI tract? Is it limited to one mucus membrane like your mouth or your eyes? But then there's more than that, right? Because while this is, in some ways, a localized exposure, unless it's through your skin,

then it is still a systemic response. So in any of these cases, in any way that you're exposed, through your skin, through your eyes, through your guts, you can also see skin manifestations. And most classically in allergies, we'll see these as like wheels or hives. And hives are those red, raised, usually irregular-shaped kind of puffy splotches. And you can see those sometimes where you're exposed. Like if you are eating something that you're allergic to, you might start with hives around the face or the mouth, but very often and very quickly they can become generalized. It might start with, say, puffiness around a bee sting, but then spread to be hives across your whole body. And those kind of skin reactions can happen from any allergies. They can

happen from cat dander allergies and from peanut allergies. And then you mentioned already, Aaron, the most severe thing that can happen with an allergic reaction is anaphylaxis. And just like the idea of allergies, the definition of anaphylaxis, it's not one perfect universal definition. But mostly we think of anaphylaxis as when, in the case of allergies at least, because you can get anaphylaxis without allergies, but it's when an allergic response is affecting multiple organ systems and becomes very extreme. So it's when these mast cells and our basophiles are sending out so much inflammatory material that our whole body's immune system starts to react.

What this causes is massive vasodilation. So your blood vessels are getting really wide. And that makes sense because these immune markers are telling your body, hey, there's something big going on. Send us all your blood. Send all of the white blood cells. Send all of the blood to us.

So vasodilation sends all of your blood different places. But that also causes swelling, in part because when our vessels expand, they get more leaky. So fluid is going to leak out. And if you get that swelling in a place like your throat or your mouth or your lungs, it can make it really difficult to breathe. That's why anaphylaxis, when it causes that throat constriction, is a severe life-threatening emergency. It can also be life-threatening because when our blood vessels expand, that causes a drop in blood pressure. because your blood vessels are now wide open, and because of physics, when you have a pipe that's wider, the pressure inside it is going to be lower. And that, again, is a life-threatening emergency if your blood pressure drops really quickly.

So that is, like, the ways that allergies can manifest, right? And it's such a huge range and so many different ways that you can be exposed, which can cause, like, any and all of these. But why? I have so many questions. Because first, why do some allergens trigger, say, anaphylaxis more commonly than other allergens? Yeah. What are those? Bees.

I mean, peanuts is the most classic, right? And a lot of times it is the food allergies that, like tree nuts, peanuts, things like that, that are even more likely. But people can absolutely be stings or another one, venoms in general, really commonly cause anaphylaxis. It doesn't mean that you can't have an anaphylactic reaction to something like cat dander. There are absolutely people who have severe reactions

to something like cat dander. But I do not know the answer to that question. And that was something that I had so many papers. And none of them really even tried to answer that question. Like what is? about particular allergens that are more likely to cause a severe reaction versus a less severe reaction. I don't know. Right. But then it also is individual differences. So like the genetic component of allergies. Right. So that's the other big question, right? It's why some allergens

and why some people? Why do some people develop allergies and other people don't? And we still don't know, but we have a lot more information at least about that part of the question. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works.

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You deserve the peace of mind of having Wi-Fi that's got your back. Xfinity. Imagine that. Allergies are really both environmental and genetic diseases. So you have to have a certain genetic susceptibility. in order to develop allergies to begin with. But that doesn't mean there's a single gene or a couple of genes or even like a few genes. There's like bocillions. That's an exaggeration. But there's a really wide range of genes that are associated with an increased risk of allergies. And for the most part, we don't know

like what they are or how they work. Like why do these genes that we might see in association with allergies, do they cause allergies or why is there that association? Right. And is it allergies or is it the degree of your reaction or is it which allergies or is it, yeah, all these things? And in all of the literature, a thing that I want to get into, even though I already regret it, is that one of the biggest known risk factors for allergies is this idea of something called atopi. I had such a hard time wrapping my head around this idea. I know. And we can't not talk about it. So I'm going to try. So atopic diseases, this idea of an atopic disease, it includes asthma, eczema, or atopic dermatitis, and allergies, which includes all of our allergies. So food allergies, allergic rhinitis,

or like hay fever, those seasonal allergies, all of that. And the word atopi or atopic, it's like, it's not specific. It doesn't, like, that word in and of itself anymore doesn't really mean much. And some people mean it to mean this type of IGE response, but it's not that simple. But the point of it is, is that these big four diseases, and there might be a couple others that probably are under this umbrella, but like eczema, asthma, allergic rhinitis, and food allergy. If you think of these big ones, there is something about them that links them all together. And we think that part of it might be an underlying genetic susceptibility that makes someone more susceptible to all of these at once. But really, in a lot of the literature, it's described as this atopic march. You probably saw that in papers. and that's because when we see these four diseases develop through life, there's often a progression

from one to the next to the next. And there's a lot of different theories as to why that is and what is this relationship between these four big diseases. So I'm going to go over what the thoughts are about what the relationship is here. So one suggestion is that it's allergens that cause all of this. And it starts by allergens causing atopic dermatitis or eczema, which is usually the first thing that we see, like even in tiny babies who don't have asthma and they don't have any food allergies yet or anything. They have eczema first thing. And so one hypothesis is that you start by getting exposed and sensitized to certain allergens and first develop atopic dermatitis or eczema. And then down the line,

because you have been exposed and sensitized, you then might develop asthma or other allergies as a result of this allergen exposure. That's one hypothesis. Another one that people seem to really, really like is that eczema is the start of this. An eczema causes breakdown in the skin barrier, and this breakdown allows for allergen exposure through the skin. And, And that, and I like this too in part because of, we've already talked about on our alpha-gal episode, the idea that when you are exposed to something in an abnormal way, i.e. through breaks in your skin, that that exposure is what predisposes you to this abnormal immune response, i.e. the development of allergies. So that's one hypothesis. And then there's a third hypothesis,

which is that there's not necessarily a causal relationship between eczema and allergies and asthma, but rather there's an underlying genetic or immunologic pathway that kind of pins them all together. And eczema just happens to be the first one that we see. Right. None of these three hypotheses are mutually exclusive. And none of them fully explain the story, right? Because there are plenty of people with eczema who don't have any other allergies. plenty of people with allergies who never had eczema. Asma, oof, really doesn't fit well into this

story, even though there are really strong relationships between allergic rhinitis and allergic asthma. It's really interesting, and I kind of like the idea of just the threshold being lowered for that pathway to be initiated, where it's like, oh, you know, once it's down, once you travel down that road once, it's so easy to go back down that road over and over again. Exactly, exactly. And these are not the only hypotheses. There's a lot of other ideas as to like what ends up causing or what are the risks that are contributing to the development of allergies. A lot of it might be like environmental exposures starting as early as in utero, causing things like DNA methylation or these like epigenetic changes that changes our susceptibility to asthma, allergies, etc. Then we also can think of the microbiome. Got to love it. How does that affect our risk of allergies, asthma, etc.?

We don't know, right? But we know that all of these things, and I know, Aaron, you're going to talk more about this, so I swear I'm almost done. We know that all of these things contribute. We just don't understand how, which means that we don't yet know how do we prevent all of this. And that is like next episode. We'll talk a lot more about that idea because that's like where a lot of the future research is going. And there may not be, I think, one unifying cause, right? 100%. Because one of the questions that I had when reading about these allergies and just like in general life is some people develop allergies at a very young age and those allergies stay with them for the rest of their lives.

Some people develop allergies at a very young age. and then over time, they no longer have those allergies. And that's most true for food allergies. Yes. So it's also really interesting to think about, like, when are you more likely to develop what type of allergy? Because food allergies, you're more likely to start developing when you're younger. Allergic rhinitis, usually not until you're older.

But then, yeah. Some people can develop food allergies later in life. I have several friends who developed food allergies in their things. 30s. Yeah. And like what? Yeah. Well, and food allergies also, I think, gets so much more confusing because there's also a lot of other, like, food intolerances or sensitivities that some people might classify as allergies and other people would not classify as allergies. So a really good example of this is something called F-Pies, which stands for food protein-induced anteriorocolitis syndrome. And this is on a lot of, like, allergy websites classified as an allergy, but it is not

an IGE-mediated response, but it causes severe, like vomiting, diarrhea, sometimes bloody diarrhea in babies that are exposed to certain foods. And most kids outgrow this. And then in adults, there's a lot of different ways that you could become intolerant of different foods, some of which might be IGE-mediated and some of which are definitely not IgE-mediated. And some of which are definitely not IG-mediated. And so that's where what I said, like, the deeper you get into the weeds, like, what's an allergy, what's not an allergy, it can get confusing. So, yeah, allergies are very interesting. Erin, tell me. Yeah. Why? Can I ask you why? You can ask. Okay. Let's see if I can answer right after this break. Allergies are so ubiquitous these days that we don't often stop to

think about just how weird they are. Like, here's this extreme thing our body does in reaction to a seemingly innocuous substance, like pollen, like a peanut, and that reaction can at times kill us. Yep. It's not the peanut or the shrimp itself doing the harm. It's how our body responds that inflicts the damage. Friendly fire. Whether it's seasonal allergies to ragweed, environmental allergies like to cat dander, food allergies, like to tree nuts, or some other type of allergy. We all know someone who has allergies or we have them ourselves, and we wished we didn't, at least speaking for myself. At the least, allergies are annoying, disruptive, and at the extreme, they can be deadly. Why do our bodies react in this way? What have almonds ever done to us?

And on top of that, has it always been like this? In this first episode of this two-parter on allergies, I want to explore those questions, the significance of allergies in an evolutionary context and a little bit of how our knowledge of allergy has changed over time. Ultimately, I want to try to get at whether allergies are increasing in frequency and why that might be, sort of unifying all of this. Yeah. And then next week, I'll pick it back up at how we devised ways to deal with the self-attack

using medications, allergy shots, the EpiPen, and so on. Almost universally, allergy, or an allergic response, is described as an overreaction, as an exaggerated response to an innocuous environmental trigger, like pollen, like dust mites, like peanuts. Since scientists first characterized allergies in the late 1800s, early 1900s, they referred to the phenomenon as an idiosyncrasy, a biological contradiction, where our bodies harm us in an attempt to protect us. But more recently, some researchers have called into question two assumptions that underlie this premise of allergy. Number one, that this reaction is always an overreaction.

And number two, that the substances triggering an allergic response are truly innocuous. Oh, I can't tell you how excited I am about this. I read, I'm full disclosure, I read one paper that talked about some of the, like, evolutionary hypothesis of the worms and things that I was like, this is my favorite thing I have ever. Yeah. Because you're right. Like that is the, that is an underlie, I said it at the very top. This is how we define an allergy. And those assumptions, no one that I have read or spoken with has ever questioned. And I love questioning it. It's important, right? Like, yeah. Maybe it is an overreaction. And it is in some certain situations, like definitely an overreaction as in it is out of proportion to the threat that whatever that thing causes. Right.

But maybe not all of the time. Right. Right. There has to be a reason that that response exists. Exactly. So just calling it a straight overreaction makes our immune system seem dumb. Right. A little overprotective, like stop helicopter, yeah.

Allergies are incredibly widespread, and they have grown in prevalence over the past century. More on that later. They're so widespread that it's difficult to just discard them as a quirk of the immune system, as our immune system being dumb, as just an overreaction with no benefit to that overreaction. As we all know, an extreme allergic reaction can be deadly. And while maybe that reaction is just a peculiar aspect of our immune system, might it also be that there's a very good reason that we still possess it? And importantly, are those two scenarios mutually exclusive? Or is it both a quirk and an advantage? Since the early days of allergy research in the first decades of the 20th century, allergies were labeled a modern disease, a quote-unquote pathology of progress.

the natural consequence of us living what was perceived to be increasingly unnatural lives, sedentary lifestyles, spending large amounts of time indoors, the growth of cities, consuming processed foods, using chemicals in the home and the environment, and so on. Allergies are not the only disease said to result from industrialization and development. If you remember back to our gout episode, that was another one. Yeah. And in the case of allergies, there might be a lot. be something to it. So, Erin, you talked about how when someone is exposed to an allergen like a dust mite,

their body begins producing IgE antibodies, which is part of what triggers this rapid cascade of symptoms. As it turns out, our body ramps up production of IgE in response to another external threat, helmuth parasites. So dust mite, hookworm, very similar initial responses. One major difference, though, is in the long term. In people who are chronically infected with helmuth parasites, that IGE production eventually scales down, and the entire inflammatory response is suppressed, in part by the parasite itself, which allows these parasites to kind of fly under the radar. That suppression doesn't happen in an allergic response.

Right. Instead, it can just ramp up and up and up until anaphylaxis. And so when researchers described IgE antibodies in 1967 and began linking them to different exposures to things like allergies like parasites, a hypothesis emerged that we have this exaggerated allergic response and increasing rates of allergies in regions where parasitic infections are low because those parasites are not suppressing the immune system. So fewer parasites, more allergies. and more parasites, fewer allergies. Essentially, the hypothesis goes, improved sanitation and treatments for parasites, reduced exposure to those parasites, which makes our board immune system go into overdrive,

overreacting to any stimulus, aka the hygiene hypothesis or the old friend's hypothesis. Now, this might be part of what's going on, because some studies show that regions with higher, rates of chronic parasite infestation tend to have lower rates of allergy. And in experiments using mice, those chronically infected with helmets are protected from developing allergies. Pretty compelling evidence. Also, some of the genes associated with asthma are also associated with increasing susceptibility to some parasite infections. So these genes might make you both more

likely to develop asthma and more susceptible to parasite infections. The hygiene hypothesis does have some compelling support when it comes to allergies or allergy-like diseases. But in recent decades, some researchers are starting to question whether it's the only thing going on. If you look at the vast array of substances that trigger an IGE response, only a tiny portion of them are helmets. The rest are various pollens. nuts, animal products, venoms, chemicals, so very many different things that we encounter regularly that are not helmets, that are not parasites. It's not just worms. Yeah. If the IGE response evolved in response to helmence infections alone, why can it be so deadly? Wouldn't that have been

selected against at some point in its hundreds of millions years old evolutionary history? Because the IGEE response is very old. Not if the benefits outweigh the costs, not if there's a reason to maintain it. As to what that reason could be, how do toxins sound? Love toxins. Aaron, you know that. I know you do. I know. You love a toxicologist. You love toxins. I do. In 1991, Marjorie Prophet introduced the toxin hypothesis of allergy. And this hypothesis suggests that the IgE-mediated allergic response evolved to protect us from immediate danger posed by toxins. So a strong IgE allergic response, like you described, Aaron, is usually very rapid onset, generally speaking, within seconds or minutes of exposure. And it's often accompanied by things

like a sudden drop in blood pressure, vomiting, tearing, diarrhea, coughing, all things that would help to expel a toxic substance or slow it down from reaching vital organs. Oh, that is such an interesting. Oh, how did I never think about that? I, how did, like, it's amazing. It's just like, oh, yeah. Oh, you get something in your eye, your body's like, get it out of your eye by watering the heck out of it. Right. And allergies do the same things. Yeah. Oh, I like that. I like that. I hope there's support for the cybothesering because I like it. It's fascinating. Yeah.

And, you know, I was asking in the biology section, okay, well, the IGE response versus other types of antibody responses. And the allergic response, this IGE-E-mediated response, is very different than that caused by exposure to a pathogen, like a virus or a bacterium. And this allergic response wouldn't really be effective against those infections. which our immune system deals with by killing rather than expelling, which is what it does to allergens and multicellular parasites. Huh.

Uh-huh. Profits suggest that some of the allergens that we think of as innocuous, like pollens, like haydust or shellfish, may not be as harmless as they seem. Pollins contain phenolic acids or alkaloids, both of which can cause organ or nerve damage. hay dust can be contaminated by pathogenic fungal spores, and shellfish can have toxins from algae or plankton. I think fungi are not well respected in this regard, in that they trigger a similar, especially some like aspergillus and things like that that commonly can infect grains and blah, blah, blah. Sorry, but I love this. I'm really excited. Yeah, no, and there's also a lot of, like, I am not getting into asthma here because we did an asthma episode.

And so that's a whole separate literature in many ways, but there are links between, like a lot of these papers that talk about the evolution of allergies also group asthma into that, which is entirely reasonable. Yeah, like we talked about, atopies. The atopic disease. And there have been a lot of links with asthma and fungus as well and fungal experiments. So, super interesting. But being able to rapidly recognize and deal with these toxic threats, like these alkaloids, like these toxins from algae, that could be vital to our survival, both from an immunological standpoint, as well as just us experiencing that deeply allergic response

and wanting to avoid exposure in the future. Are allergies a signal to us? do they teach us which plants or foods to stay away from? Erin, I can't tell you how much I love this idea because you know what it feels like to me? It feels like the difference between like what is a weed and what is a desirable plant. Like are allergies responses to things that they shouldn't be or actually are they responding to something that we should be because we shouldn't be having so much grass? Like, you know what I mean?

I just... Yeah. Oh, I... Wow, this is mind-blowing to me. I think, yeah, me too. I, because I had never really considered, I always was just like innocuous substance, overreaction. Yeah. And, like, in some cases, yeah.

But peanuts can be contaminated with fungus a lot, Erin. And they also might be, like, these different foods or these different allergens might be the compound structure. itself could be similar to something else. Something that is much more toxic, right? I've been wondering that too. Yeah. Yeah. It's an interesting idea.

We love it. But is there support for it? Is there? I hope so. Yes, there is. And is it like the most compelling support in the world? I don't know. There are mice studies, lab studies, etc.

But still, but still. So there were a couple studies from 2013 that found that mice that had previously been exposed to venom, one study. used a beasting and the other used snake venom, the mice that had been previously exposed, were more likely to survive a big second dose of venom that should have been fatal, compared to those who did not receive that initial dose. Suggesting that that big IGE response in the second exposure might be helpful rather than detrimental. Mm-hmm.

And of course, this doesn't explain why a beasting in humans can lead to a fatal anaphylaxis response, because clearly that is very harmful. Some researchers suggest it's too much of a good thing, kind of like sickle cell anemia and malaria. We're having one copy of the gene protects you from malaria, but two copies leads to disease. While most experimental studies looking at this toxin hypothesis have focused on things like bee stings,

other epidemiological studies have taken a broader view of toxins and how they can harm us, such as cancer. There's no clear pattern. when it comes to allergies and cancer. But some studies have shown that higher rates of allergies is linked to lower rates of cancer. But I would imagine that that depends on the type of cancer and the other lifestyle and genetic factors. Right. And is it like, is it environmental? No, that's interesting and weird because there's so much environmental cancer exposure, blah, blah, blah.

And then environmental allergy, oh, that's so weird and interesting. Yeah. Isn't it interesting? And so while the hygiene hypothesis or the old friend's hypothesis and the toxin hypothesis of allergy can help to fill in some of the gaps as to the why of allergies, the complete picture is not yet clear. Yeah. How can we take what we know about helmets and allergies and apply it to treatment, right? Can we make an allergen tree of life to predict the groups of antigens that people are likely to be sensitive to? Does it have to do with evolutionary distance? The farther away something is on that evolutionary tree of life, does that mean that we're more likely to initiate an immune response to it?

The future of allergy research is exciting. And to understand where we go from here, we also have to take a look at where we've come from. Yeah. Are allergies changing? And if so, what is driving that change? Uh-huh. Today, allergies are one of the most common diseases across the world, affecting 10 to 30% of the global population and up to 50% of people in some regions. For years, that number has been on the rise, which is why you'll hear people refer to this as an allergy epidemic, sometimes broken down into two waves.

The first being respiratory allergies like hay fever, and the second being food allergies. Of course, allergies themselves are not a new phenomenon. IGE antibodies evolved around 300 million years ago, allowing for this allergic response, and we have evidence of allergies from ancient times, descriptions of fatal be stings, what could be allergic rhinitis, and of course, asthma. But the heyday of allergy awareness, pun intended, really only began in the 1800s with the first description of hay fever in 1819 by John Bostock, and the first case series, published in 1873 by Charles Blackley.

These observations didn't seem to be a case of, cool, there's finally a name associated with this condition that we've noticed for a long time, but a recognition of a truly emerging phenomenon. Huh. Like one summer day in 1875, your nose starts running, and your eyes start itching, and you're sneezing all over the place, and you find all of your friends and family are similarly affected,

and you're just complaining about it, you form groups to talk about it. But just a few years ago, no doctor had ever heard of such a thing. The sudden increase in hay fever in Europe and North America around the late 1800s resulted from changes in agricultural practices. Changing which crops were planted. So planting more pollinaceous, if that's a word, it's not. I don't think my word document is telling me there's a red underline, it's angry, But it's the only thing I could think of pollinacious grass varieties to feed the growing cattle herds and an increase in farmed land in the U.S. leading to higher ragweed growth.

This marks the beginning of the first wave of the allergy epidemic late 1800s. You said this is 1800s. Okay. Yeah. That's way further back. I mean, it feels like I should have expected, but like, I don't know. I mean, it's hard because, like, people generally associate asthma with the first wave, and that's like 19-11. 1960s is really when those cases started to super ramp up.

Okay. But if we're talking about allergic rhinitis, it really is like 1880s roughly. Interesting. There had been in decades previous descriptions here and there, but not like sudden recognition of this, whoa, everyone is experiencing. Yeah. Interesting. Yeah.

In 1906, Clemens von Pirke coined the term allergy to describe the hypersitivity reaction in serum sickness. So when someone was given antiserum, let's say for like diphtheria to treat their diphtheria infection, but they had extracted that antiserum from an animal, like a horse that they had caused the infection, got the antibodies, all of that. We should do an episode on serum sickness. Sorry, but it's interesting, terrifying. But yeah, then people got real sick from that. And by that time, so around the early 1900s, Other work had shown how anaphylaxis can happen, how animals negatively react to the introduction of a foreign substance, and the concept of an allergic response mediated by your immune

system began to gain traction. Because up to this time, germ theory had a pretty tight hold on many explanations of disease. And so the recognition that it was actually our immune systems causing these allergic responses, like the callist coming from inside the house, took a bit of time to gain traction. Von Pyrke combined a bunch of observations from hyposensitivity, hypersensitivity, food allergy, hay fever, beasting reactions, serum sickness, and so on, to create this organized concept of allergy as it relates to immunity, and it created momentum for more research in the area,

even if it was initially papoed by, like, a lot of his peers. Classic. Classic. The first decades of the 19th century saw the formation of allergy research groups and clinics across the globe. And as far back as 1936, the phrase, quote unquote, the allergy epidemic was used. Wow. Right?

Much earlier than I thought. Yeah. In 1946, ragweed hay fever was such a huge problem in New York City that city council started a ragweed elimination campaign. Hmm. The tides were changing and fast. Asthma, which prior to 1960 had been considered a rare disease, shot up in incidents, doubling in Swedish Army recruits from 1971 to 1981, huge rise, as did hospital admissions for the condition, which increased tenfold between 1965 and 1980 in Australia, the UK, New Zealand, Canada, and the U.S. 10fold for asthma. In the 1970s, after the discovery of IgE, researchers observed a sharp increase in allergen-specific IgE antibodies against environmental allergens, growing to over 50% of the population in some regions,

like I mentioned. And the second wave of the allergy epidemic, food-borne allergies, began much more recently, around 1990, as most papers I read. And that's the same time that asthma cases actually plateaued. One large study found that between 1997 and 2008, allergies to peanuts and tree nuts tripled. Tripled. Huge. Yeah.

Reports from Australia indicate a 10-fold increase in referrals to food allergy specialists and a five-fold increase in hospital admissions for food-related anaphylaxis. This is not just a matter of doing a better job of recognizing these allergies. No. Oh, especially not with food allergies because the reaction is usually so severe. Exactly. Yeah. What is driving this explosive rise?

Yeah. That is the billion dollar question. We don't fully know, of course. Here is what we do know. We know that while this is a global rise, the highest increases are seen in more industrialized countries. For instance, following the reunification of East and West Germany, in 1989, prevalence of allergy shot up in East Germany, where it had been much lower in previous decades. I think that's one of the most interesting examples, because it's so, like, discreet,

and, like, the regions are so close to each other. So it's, like, not, like, what is it? Because it's not just, like, natural environment exposure, clearly, like, weather or whatever. Right, right. The pollen is not, does not respect the Berlin Wall. Exactly. Yeah. Yeah. And on average, allergies are 20 times more common in affluent, quote-unquote, westernized countries compared to those with lower incomes. And we know that this rise is not limited to allergies or asthma, but it also is seen in other autoimmune or immune-mediated diseases.

We know that these diseases are not rising all at the same time or in the same place or at the same pace, which could suggest different mechanisms behind the rise in each of them. And this has been used to challenge the old friends or the hygiene hypothesis since countries that saw the biggest rise in allergies only did so beginning really in the 1960s, which was around 40 years after major sanitation changes, would have reduced waterborne pathogens, and anti-helmet campaigns had reduced parasite burden to almost nothing. So what could be going? on. Most of the predominant ideas fall under the hygiene hypothesis or, you know, the old friends hypothesis or the biodiversity hypothesis, which are kind of like more recent offshoots.

And both of these suggest that our allergies are a result of us not being exposed to as many or as diverse microbes and parasites that we used to throughout our evolutionary history. Why that would lead to more allergies depends on who you ask. Maybe it's that with D.E. decreasing family size, kids are not coming into contact with as many germs at a young age, although some childhood pathogens like RSV are positively associated with developing allergies. So it's like the right germs, right? Which germs? That's the, yeah. Yeah, it's layers, complications.

It's almost like our immune system is complicated. I don't know. Maybe it's that our use of antibiotics. at an early age disrupts our gut microbiome and primes us to develop allergies. Maybe it's that we spend more time inside and sedentary. Early childhood exposure to pets or farm animals seems to reduce the risk of allergies. And exercise reduces allergic inflammation. I found a study looking at babies born during COVID lockdown in 2020, and the study found higher rates of allergies in that cohort.

So it's like, again, the limited exposure to the outside world. Right. Maybe it's the chemicals in our soaps, food packaging, microplastics, pollution, ozone, cigarette smoke that disrupts our protective epithelial barriers and sends our immune systems into overdrive. If you think about it, the allergic response is kind of like a Hail Mary last resort option to protect us from toxins. after our skin or skin microbiota, after our guts or gut microbiota, our lungs and lung microbiota lets it get through, right? Like there are so many other layers of protection. And then maybe it's that once it makes it past all those layers, then we have this last ditch effort to protect us from whatever perceived toxin there is. Right. And if those layers are continually broken down

by some of the things that we encounter in our everyday lives, like, processed foods, all of these different things that all combined together to increase permeability of those barriers. Does that then lead to increased allergy? And I think that's one of the things that makes the, there's a lot of research being done on like, is eczema and the breakdown of your skin barrier that happens with eczema? Does it also result in this abnormal presentation of these toxins or of these allergens, right? Where it's like typically you shouldn't be able to be exposed to say cat dander through your skin because your skin should be able to keep cat dander out.

But if it gets in that way, does that predispose you to out? And cat dander might be a crappy example. I don't know. But like if you get peanut on your skin, peanut protein shouldn't be able to make it through your skin. If it does, does that trigger your immune response to think that it is something that is pathogenic? So that's one of those kind of ideas.

Right. Yeah. Novel exposure roots to these things because of a decreased barrier and permeability. Which is why I think the Alpha-Gal story is so interesting in that, like, because it applies so much to that. So yeah, I don't know. Yeah. It's interesting, Aaron. We don't have a single, simple answer for why tree nut allergies suddenly exploded in the past few decades. Although I do think that part of it is, at least from my reading, our response to them initially and how it was like, don't expose anymore. If there's a slightest bit of reaction, then it sort of, yeah. I am really curious. This is jumping so far ahead. I'm sorry, but I'm so curious to see what is going to happen in the next decade. Because it was our generation that has really high rates

of things like peanut and tree nut and all these food allergies. And it was our generation that very much was told by physicians do not expose your children because we don't want them to develop allergies. And it turns out, again, spoilers, that that was exactly the wrong advice. And now we know that because of these phenomenal studies. And so early introduction is now the recommendation. So what are rates going to be like in kids in five, 10 years? I'm super curious about all this. Like how the epidemiology is going to, is it going to change? I don't know. Is it something else? Yeah. Yeah. And, you know, like we probably won't. ever have one simple unifying answer to all of this.

I agree. And I will say also like the hygiene hypothesis or the old friends hypothesis or the toxin hypothesis or the epithelial barrier hypothesis, these things aren't attempting to explain away all cases of allergies or autoimmune diseases with one bottom line. Yeah. Instead, what they're doing is highlighting patterns of allergy, pointing out where we can look next. if it is certain detergent compounds causing a rise in asthma because of increased skin permeability, why and how? If it is a disrupted microbiome, what about it makes it disrupted? And how can we

restore balance? Right. If it is epigenetic effects, what are those prenatal exposures that increase someone's chance of developing allergies? While the complex nature of allergies makes all of this seem so overwhelming. The truth is that people are doing incredible research to answer these questions, to get at the underlying triggers of different allergies. And it really seems like we're slowly going to be able to put the puzzle pieces together, at least for some pictures, right? For some bits of the allergy.

Right. And come up with better ways to understand, prevent and treat allergies. I love it, Erin. Now, Erin, I'll turn it over to you. to tell us where we are with allergies around the world today. I'll give it my best shot right after this. So you told us already, Erin, that all of these allergic disorders from hay fever,

from seasonal allergies, from food allergies, they're all on the rise. That is certainly true. And they have been for a lot longer than I realized, apparently. When it comes to, I'll break this down into like the allergic rhinitis, which is more you think of as the hay fever,

the seasonal allergies, it's the runny nose and the blah, blah, blah, runny eyes. And I don't say blah, blah, blah, to discount it because it has pretty significant effects on people's lives, as we'll see. But a paper from the Lancet from 2011, which is old now, estimated that 400 million people worldwide are affected by allergic rhinitis. And this number is likely higher today as this, like all allergies, has continued to increase. But this varies a lot across the globe.

And while most cases of allergic rhinitis develop in like child or teen years, sometimes they don't. There's plenty of adults who don't develop seasonal or environmental allergies until much later in life. But overall, in some areas of the globe prevalence is as high as like 17 to 20 percent. those seem to be the highest percentage numbers that I saw. And across the board, even though in the international study of asthma and allergies in childhood, which is also now old because the phase three study finished in like the early 2000s, but in this study, the rates of allergic rhinitis were actually greatest in Latin America and African countries. But even there, the prevalence was higher in urban areas compared to rural areas.

And that pattern is true pretty much across the globe. Allergic rhinitis also has pretty significant burdens on our health care system. In the 90s, way back in the 90s, it was estimated to cost $1.9 billion U.S. dollars every year. And that increased to $3.4 billion in the early 2000s. And that's not even counting indirect costs, of which there are enormous indirect costs, things like missed school, missed work. Allergic rhinitis especially can result in things like poor sleep or sleep apnea. It can contribute, which can then lead to fatigue, memory problems, mood changes.

It can make school harder for kids. It is not a minor. We might think of it as, oh, it's just a runny nose. It is not just a runny nose. Right. Food allergies, we have much crudier data for. Which is interesting to me for some reason. I don't know why.

Yeah. I think it's, we have credit Europe, like, global data. Okay. But no doubt food allergies are absolutely on the rise. In some countries, as much as 10% of children have at least one food allergy. And food allergies are especially interesting because for some foods, up to like 70 or 80% of kids will outgrow their food allergy. And those foods tend to be things like egg and milk. But things like peanuts and tree nuts tends to be much less likely that kids will outgrow it.

Usually it's 20% or less of kids with a peanut or tree nut allergy will outgrow them. Then there's other food allergies like shellfish and fish, which not only do we have less data for the idea that early introduction can prevent sensitization for things like fish and shellfish, but it's also more likely that people don't develop those allergies and. until adulthood. Why? Why? Oh, you know, I have a quick question, actually. Yeah. Dose and relationship to response. Like, is it one, you know, one peanut, how much peanut or almond or shellfish shrimp tail, you know? So, yeah, maybe it's worth talking a little bit in more detail about this. So the study that showed that early exposure can reduce the risk of peanut allergy. The big one was called Leap, learning early about peanut allergy. And then there was another one, I think, called eat. And I forget what that acronym stands for. But these were

like really landmark studies that showed that early exposure, and early exposure meant like four months of life, but definitely earlier than 11 months of life. So before a baby turns one year old, you start with exposure to peanuts and you have to have persistent exposure. So it's not like give them peanuts one time and then you're good. These studies were consistent. exposure like two to three times a week, every week for the first five years of life. Okay. Wow. But in those kids, and in these studies, they took kids who were high risk, kids who either had severe eczema or had a known allergy to egg, or in some of the studies, it was kids

who had a family history of peanut allergy. So these were high risk kids, because we know that there's genetics in these associations. So in those kids, the reduction in risk of peanut allergy was like 70 to 80%. It was massive, massive reduction in risk. And so across the board now, the recommendation is early exposure, but it has to be that consistent exposure. So it's not like necessarily a one-time dose, like give this much peanut. It's really like start small, but continued exposure.

So like a little peanut on the finger when they're a tiny baby, continuing that until they're like eating peanut butter and their oatmeal like a couple times a week when they're kids. And that significantly decreases the risk. And so that data has now been extrapolated to a lot of the foods. It's thought that the earlier exposure to all of the main allergenic foods, and in the U.S., those foods are wheat, soy, tree nuts, peanuts, milk, egg. Oh crap, I should have written all of these down.

Fish, shellfish, and now sesame. That's the earliest edition. So early and consistent exposure to all of those is what's now recommended to try and prevent food allergies. And we don't know what happens when someone just develops an allergy, a food allergy at the age of 35. No, no. Is it all alpha-gallering? I don't know. It all comes down to alpha-gal. Is it the ticks? No, yeah. I don't know.

Is it a threshold thing? Like we kind of talked about, is it that maybe they had some level of an... Here's the other thing, Erin. Oh, my gosh. There is a proportion of the population who, if you test them, they develop these IgE antibodies, aka they are sensitized to various things. Be they aerow allergens like cat dander. Cat dander's a good example, because if you test...

kids who live in homes with cats, a higher percentage of them will have a degree of sensitization at a certain age, but a lower percentage of them will be allergic. We'll have that allergic response to cats. Interesting. And so, yeah, so like what is it about sensitization versus then who of those kids who are sensitized actually then will have allergies? We don't, we don't exactly know. So is there, is that what it is for adults who develop, say, a shellfish allergy later in life, that maybe they were a little bit sensitized, but it wasn't until that built up enough in their system that they had an allergic response. I don't know. Okay. But the quantity of exposure or the amount of allergen that they're exposed to can lead to really different responses

than some people, where some people are like, even the most minute amount can lead to these horrible reactions, whereas other people can have, there's a threshold where that causes that, I guess. Okay. A hundred percent. Yes. That is absolutely true. we don't understand why. Okay. So yeah, that's like what we know of. When it comes to the most severe outcomes, that is anaphylaxis, we again don't really have great data here because most of the data that we have is on hospital admissions for anaphylaxis. And not all people with anaphylaxis have to actually be admitted to the hospital. And also, it's not always allergies that cause anaphylaxis. But at least in some of the papers that I found, it's estimated that about

0.3% of the population of Europe will experience anaphylaxis at some point in their lives. Wow. Okay. Yeah, it's higher than I expected. And the data across the board is that, especially in most high-income countries, which is where we have data, incidents of anaphylaxis is increasing, which makes sense because allergies across the board are increasing. And, and, and, and, you know, anaphylaxis especially due to foodborne triggers is increasing. Anaphylaxis due to alpha-gal specifically is increasing big time. But mortality does not seem to be increasing, except in Australia, which some of the data has had increases in mortality associated with anaphylaxis.

So, yeah. Does that mean that we have developed better tools, or is that a tune in for next week to find out? That's a tune in for next week to find out. How do we treat it? That was my segue, Erin. You guessed it. I love it. So yeah, that's allergies for now, but I can't wait for next week to hear about how we figured out how to treat these things. And then we'll talk about how we treat them and what our thoughts are about preventing them in more detail. Next week. But until then, if you would like to learn more about things like these, the how allergies work, the IGE mediated response, the evolution of allergies, the rise in

allergies, we've got sources for you. So many. I have so many. And I highlighted two right here just because to list them all out would take another 10 minutes. So there's one by Dasher and Fernandez from 2019 titled Allergy in an Evolutionary Framework. I was all about the evolution of allergies. And then by Actis from 2021, does the evolutionary? epithelial barrier hypothesis explain the increase in allergy, autoimmunity, and other chronic

conditions. Fascinating stuff. For the biology of allergies, boy, do I have plenty of rabbit holes that you can go down. But I'm going to shout out like four or five main papers that are really high-level overviews. One is from the New England Journal of Medicine from 2001, so it's old but still good, and that is just called allergy and allergic diseases. There was one on titled Food Allergy from Nature Reviews Disease Primers from 2018 and another one titled Food Allergy from the Lancet 2002. And then two on allergic rhinitis, one titled Allergic Rhinitis from the Lancet, 2011, and one titled Allergic Rhinitis, Definition, Epidemiology, Pathophysiology, Detection, and Diagnosis from the Journal of Allergy and Clinical Imminology from 2001. There's so many. There's so many more.

going to read them all, but you can find them on our website. This Podcast Will Kill You.com under the episodes tab for this episode. And everyone we've ever done, they're all there. Thank you again, Caitlin, so much for sharing your story with us and really helping to illustrate that allergy to environmental allergens is not just a runny nose. No, it is so much more. Thank you so much for being willing to take the time and to share your story. with us and all the listeners. We really appreciate it. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Leanna Squillachi and Tom Brifogel for the audio mixing. Thank you to everyone at exactly right. And thank you to you, listeners. We hope you

enjoyed this episode and that you're stoked for next week to learn even more about allergies. Yeah. Why do EpiPen's work the way they do? I can't wait to find out. Yeah, me too. Got some reading to do. Thank you also to our wonderful, generous, amazing patrons. We really truly appreciate your support so much. Thank you. Thank you. Well, until next time, wash your hands. You filthy animals.

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