This Podcast Will Kill You - Ep 162 Allergies Part 2: Shots, pills, & pens

Episode Date: January 14, 2025

Yes, the world may be out to get us with allergens around every corner, but we’ve got some tricks up our sleeve to help us cope. Our allergy treatment toolkit includes an impressive suite of tools, and in the second episode of our two-part series on allergies, we focus on three in particular: antihistamine medications, allergy shots, and the epinephrine auto-injector (aka the EpiPen). We take you through how exactly each of these work, trace their development from concept to product, and highlight some of the most promising areas of allergy treatment research today. Have you ever wondered why we have so many different types of antihistamines? Or thought about what the Cold War has to do with the EpiPen? Then this is the episode for you. 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 Samantha. I am 42, and I've never really paid much attention to allergies. I am allergic to mosquitoes, but my allergy has lessened in severity as I've gotten older, and I really don't even take many precautions anymore. And I haven't acquired allergy to penicillin that I've had since I was a child. I moved to Florida five years ago and had my first interaction with a fire ant. I was leaving work, and one fell down my shirt and stung my chest. It hurt and was itchy, but I didn't give it a second thought. And it really was just a funny story to tell my coworkers.

I don't even think I had a welt to the next day. About two months ago, I was mowing my lawn in flip-flops. And I know you're not supposed to do that, but it is Florida and it's August. And I really don't like wearing shoes and socks. I felt something itchy on my foot. It didn't hurt. And when I looked down, I only saw grass. So I brushed my foot off and just went about my business.

That evening, the top of my foot started to turn red and swell. It was itchy. It just looked like maybe a bug bite or I'd brushed up against some plant that I shouldn't have. The next day, though, I had two little white postules form and the red area had doubled in size. I still wasn't really worried, but by the afternoon, my foot was much more swollen and still very itchy. And several more white postules had formed. I went to a clinic, and they gave me a 10-day round of antibiotics and told me, to go to the ER if it got worse. By the time I got home that evening, part of my foot had kind of a yellowish tent,

and I wasn't sure if that was from the bite or whatever I had interacted with or because I had been driving or because I had been standing that day. So I just went back to the ER to be sure. There they said it looked like ant stings. And a few days later, I was out mowing my lawn again. Yes, still in flip-flops. I had not yet learned my lesson. and I mowed over a fire ant hill that was hidden in the grass. And then I stepped on it. I immediately

felt pain and itchy. When I looked down, my foot was covered with hundreds of ants all over my left foot and ankle. They were on my right foot. They were all over my mower. When I went to brush them off, they got on my hands and stung my hands. I was able to get them off. I moved away. The pain subsided really quickly, but I was definitely feeling the itch. After I regained my composure, I realized I was fine. I finished mowing and weed-wacked my fence line. When I went inside, I put ice on my feet and sat down for a few minutes. By now it had been about 20 minutes since I had stepped on the ant-hill. And I noticed that I was itching on my bra and my waistline, but I figured, you know, I just saw a whole bunch of insects and people get itchy after they see insects.

So I went to take a cold bath, and when I got undressed, I saw red patches all over my skin, chest, trunk, down my arms, down my legs, front and back. And I was like, oh, a rash, because I've never had hives that I remember. So I didn't realize right away that that's what that was. I was in the bath for about 15 minutes when I started coughing and having difficulty taking deep breaths. And I said, this is not normal. I need to go to the ER. So I drove back into town and it's about a 30 minute drive to get to the ER from my house.

And they took me back pretty quickly into a consult room. And I was chatting with the nurse while they were starting IV. I was in good spirits and everything. And then all of a sudden my vision started to get blurry. I texted my friend, I need you, ER on 43rd. And after that, I don't remember much. But here's what I do remember. I said several times my vision is blurry.

I'm going to be sick. I need a bag. I'm going to throw up. The nurse said several times, take a deep breath and try to stay calm. I told her that my hearing was fuzzy. It sounded like I was underwater. I said, please help. I'm going to be sick. And I remember an oxygen cannula going on my nose. I remember the nurses trying to wheel me out in the chair that I was in, but hitting a door or a wall several times. They were having difficulty maneuvering the chair. My body convulsed. I don't know what that looks. I don't know. looked like, but it felt terrifying. I heard someone say something about 50-somethings of Benadryl. I felt a sharp jab in my arm, followed by pain. And after a while, I was able to open my eyes. I saw my friend had arrived. And I said, to no one in particular, well, that was fun. And no one laughed. So I realized it was maybe more serious. A doctor came in and explained that my blood pressure had dropped to 86 over 54. My heart rate had dropped to 47. And I had had a false positive to something. So they had to do a CT with contrast. After a couple hours, they discharged me with prednisone, doxycycline, famidine, and epinephrine pens. Obviously, I don't go walking through my yard,

barefoot, orange flip-flops. And I carry my epipens in a cute little fanny pack. It kind of stinks, but dying is worse. That's my allergy story. Thanks. My parents found out that I was allergic to peanuts when I was 18 months old. After rubbing bits of a peanut butter and jelly sandwich all over myself, as babies do, I broke out in hives and was rushed to the hospital where my allergy was confirmed. From that day forward, I was taught to have the utmost caution around peanuts. And I did.

I've been lucky enough to only really go into anaphylactic shock twice. Because it's been so rare for me, I never truly knew what all the warning signs could be for an episode, only that if I got hives, I had a very short amount of time to use my EpiPen and get immediately to a hospital. And while that advice was helpful for my first run-in with anaphylaxis, it unfortunately wasn't enough for my second.

In February 2023, I was visiting friends in San Francisco, and we went out as a group for dinner for dim sum. I made sure to ask the waitstaff about peanuts and inform them of my allergy while ordering, as I always do when dining out. After my friends and I confirmed, in both English and Mandarin, that all of the food we ordered was safe, we dug in. As soon as the meal ended, I felt a bit flushed. I went to the bathroom, and I couldn't see any hives or swelling. So I attributed the flesh to digestion and a bit of anxiety and carried on.

About 10 minutes into the walk back to our Airbnb, I started to feel a little winded, and five minutes after that, I started to feel faint. I figured that I must be having an asthma attack, since I couldn't really explain this constellation of symptoms otherwise. I pulled one of my friends aside and asked her if we could sit together at the nearest bus station while I called an Uber. back to the Airbnb since I didn't think I could make the last 10 minutes of the walk. As soon as we sat down, I started to throw up, and I was unable to stop. At this point, I still didn't know what my body was reacting to, and I was starting to dip in and out of consciousness. The friend I'd pulled aside and a kind business owner from the corner

store called 911 when I was no longer verbally responsive. And it was only then that we learned from the 911 operator that I was in the middle of an anaphylactic episode. I had an epipen on me, but before the operator could finish telling my friend how to use it, an ambulance arrived and gave me a double dose of epinephrine, saving my life. While we will never know with 100% certainty whether my reaction was due to cross-contamination or peanut butter mixed into a sauce and forgotten, what we do know is that I took every step possible to avoid exposure to peanuts, and for whatever reason, it wasn't quite enough this time. I'm incredibly lucky and grateful for my friend and that business owner, as by the time I'd

realized something was seriously wrong, I'd lost the motor skills to do anything about it. Since then, I've told as many people as I can about the different presentations of anaphylaxis with the hopes of saving another person's life. After 28 years of caution, I still, almost died of anaphylaxis. So I would urge anyone else with a fatal allergy to please stay aware of the different presentations of anaphylaxis. And I would urge everyone else to learn how to use an epipen, just in case. Just terrifying. There's so many different ways that allergies terrify me. And these are both just incredible stories. And I'm so glad that you're both okay. Okay. Yeah. Yeah. Thank you so much for sharing those stories with us and with our listeners. We really

appreciate it. And yeah. Wow. Yeah. Thank you. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. We're bringing you part two of our allergies episode. We are. I am really excited for this. I got to say. Like, yeah. Antihistamines and other allergy treatments, I feel like have become so much a part of our daily lives or our medicine cabinet. Our medicine cabinets, 100%. But how do they work? And also, Erin, the first time I heard of allergy shots, my mind was first like, do those work? How does that actually work? I, this is not accurate, but I feel like, I'm really curious about the history of allergy shots because they feel a little bit like homeopathy, even though they're not, like they're not,

but it's a little bit like that, right? It's like give the smallest little dose and then. Yes. So it's, yeah. Treating like with like. I mean, it actually does have its roots in homeopathy, which I'm not going to talk about, but that is kind of the way that it all started was like, oh, if a lot hurts you, then a little bit, maybe you'll get used to it. Right. Yeah, but it actually works in this case. It actually works. I know. Yeah. So we will talk about how it works and where it came from and all the things for all the treatments, well, most of them at least, for allergies today. That's what we're focusing on is how last week, if you haven't listened, by the way, to last week's episode, it's all about what are allergies, what are they even,

how do they work? Where did they come from? Evolutionarily, why are we stuck with these things? Yeah. It's a great episode. Check it out. But this week we're talking about what do we do about them once you have them. What do we do about them? But before we get into all of that, we've got some very important business to get into. We do. It's quarantini time. Erin, what are we drinking again this week? Well, of course we're drinking the allergy shot. This week especially. Yep. It is, it's a shot, right? Like, what else could we have done? We could have called it oral immunotherapy. Just kidding. It is not, but that's what you call it when you give someone, oral allergy shot. Good one, Erin. That's a great one.

Why, thank you. In The Allergy Shot is, it's a pretty simple concoction of rum, orange juice, pineapple juice, and quantro. Delish, check it out. The recipe's already posted on our social media channels. So if you're not following us, there you definitely should be. Also, did you know we're on TikTok? We are. We are.

We have videos there. On our website. This podcast will be. kill you.com. You can find so many varied things, right? You can find the notes for each and every one of our episodes, which has the sources in case you wanted to read more. You can find links to our bookshop.org affiliate account, our Goodreads list, music by Bloodmobile, links to our Patreon, links to merch, links to savings in case you're like, oh, I heard a discount code for this podcast. What was that product? What was that code? Check out our website, this podcast, will kill you.

You can find all sorts of things. Transcripts. Did I mention that? Transcripts. You can find them. We've got them. Well, then. With that, should we get started?

I think we should. Let's take a quick break and begin. It feels like we need to start this section off with the briefest of reviews of how an allergy works. You know, just to be thorough. So we're going to basically do my whole episode from last week in like one paragraph. You ready for this? I'm ready. In allergies, you get exposed to an allergen, which is almost always some type of protein.

It gets into your bloodstream. Your immune system decides to do a wacky thing and start making these IGEE antibodies in a process known as sensitization. And then the next time that you're re-exposed to that allergen, these IGEE antibodies, which happen to be bound to these cells called mast cells and basophils, They bind to the allergen, causing those cells to burst open and spew forth all of this inflammatory junk, and our immune system goes hog wild. So in mild cases of allergies, this might lead to inflammation just near the sight of exposure, like itchy, runny, watery nose and sneezing when you breathe in cat dander,

itchy eyes when you get dust might gunk into your eyes, or upset stomach and vomiting if you eat a tree nut. And in the worst case scenarios, this inflammation triggers an extensive immune response that affects the whole body and can cause anaphylaxis, where we see swelling in the mouth and throat and lungs that leads to airway constriction and difficulty breathing. We see dilation of our blood vessels leading to blood pressure drops, which is sudden and dangerous. And this is an emergency life-threatening scenario. Was that a good summary of allergies in 30 seconds? Yeah, it made me want to ask more questions and that I was like, Erin, this is not about allergies. That was last week.

You had your opportunity. Now is time for the medications part. Right. So that's the question we're trying to get to today is what the heck do we do about these? How do we treat them? It's probably logical to most people that the treatment is going to vary in part depending on the type of allergy and the severity. across the board, the first answer that most people will get on how do I deal with my allergies is, oh, avoid allergens.

And A, that's not always possible. And B, sometimes there's not really that much data that it's helpful. Like in the cases of things like dust mites, like you can do all these things and there's not necessarily that much data that it helps your allergies that much because they're ubiquitous. They're everywhere. Right. So once this allergic response kicks off and starts to. run away like a boulder down a hill, what do we do about it? There are three main, like,

categories of treatment options that we'll talk in detail about. And then there are some others. And then at the end of this episode, we'll talk about the really exciting, more novel treatments. But the three main treatments that we'll focus on today are anihistamines, allergy shots, and epipens. That's a brand name. So I should say epinephrine auto-injectable device. Can we say EpiPen because it's such a mouthful? Okay. We can say EpiPen. Not sponsored EpiPen. Okay. We'll also give honorable mention to steroids and I'll talk about them a little bit as well. Honorable mention. I love it. One of the most important classes of drugs just gets an honorable mention for allergies. I know. I know. Well, you know, you got to make choices here, Aaron. It's a podcast.

It's true. It's true. Okay. So, and, Anihistamines, let us start there, shall we? Anihistamines are things like diphenhyramine. That's your Benadryl. Again, I'm going to say a lot of brand names this episode, which is not typical for us, but that way people know what we're actually talking about. Also things like hydroxazine. So these are the types of anihistamines that people might think of, that they're like,

oh my God, if I take that, I am knocked out. They make you super sleepy. Yeah. And then you have all these other anihistamines, things like satirazine, Zyrtec, Phecophonidine. I think that one's Allegra. Loradidine, pretty sure that's Clareton. I could have gotten those mixed up. Who cares? All of these types of medications, they're called anihistamines because they block histamine. Simple as that. So histamine is one of the many, many compounds that our mast cells are spewing out when they burst open and really, least inflammatory juices in response to an allergen. So that is why we can use anihistamines in cases of allergic responses because you have a ton of histamine floating around and it is very

involved in the symptoms that we see. Histamine does literally so much in our body, Erin. It is involved in regulating our gastric secretions in our guts. Histamine is involved in the regulation of our sleep wake cycle. You might only think of melatonin. It's way more complicated than that. Histamine's involved. Well, I guess that makes sense considering that some of these knock you out, right? Uh-huh. Yeah, I will talk about why only some of them. But in the case of allergies, histamine is involved in things like vasodilation. So it helps to cause vasodilation of our blood vessels. It also is involved in the smooth muscle constriction that we see, like bronchospasm that we see an asthma, but also in the cases of anaphylaxis and allergies. It causes increased vascular

permeability, so that leakiness of our blood vessels, which again, in the context of an immune response, is forcing all of your blood and all of the immune reactants in your blood to the area for help, right? That's the idea. It also is a big part of the itchiness that we feel. And so antihistamines are really useful in reducing the itchiness from allergies and other things that cause itch when it's a histamine-related itch, don't ask me how and why again. I was going to ask again, I was like, I just asked this a few episodes ago. I know you did. Why do we itch?

Why do we itch? I don't have an answer. But histamines involved in the case of allergies. And so specifically, the anihistamines that we use for allergies, they tend to, there's a bunch of different receptors for histamine, and they're numbered like one through four. So the antihistamines that we use for allergies block a receptor that histamine binds to, specifically the H1 receptor. So what happens then is that we're still releasing histamine. There's still plenty of histamine floating around when you're having an allergic reaction if you take an anihistamine. But it just can't

do its job because that receptor is blocked by the medication. And so this is also, like, an even wider class of medications because since there are multiple types of histamine receptors, something that you might take for like acid reflux might be something like pepsid or famotidine. That's an H2 blocker. So it blocks different receptors of histamine. But sometimes, if someone is having really severe allergies, they might need multiple types of histamine blockers. So they might be on a whole camaraderie. Is that a good word? I don't know. A whole bunch of of these medications. Okay.

Could I ask a question about histamine receptors? So there are multiple histamine receptors that do different things so that like if your body's like, hey, we need a histamine response because of this allergy or because of this thing, then come join this receptor. Right. That's exactly how it goes, right? Yeah, pretty much. But the histamine molecule itself is always the same, but it's the anihistamines that are

different to match those different receptors. Exactly. So histamine, think of it as one, one histamine, and this histamine binds to different receptors usually in different parts of our body. So like we have different receptors in our guts than we do in our brain than we do in our blood vessels. And so the medicine that you take is going to block more or less specifically these different types of receptors. But like I said, there are different versions of these, right? So the things like Benadryl or Hydroxazine, these are called first-generation anihistamines. And these, there's a few downsides to these compared to the newer ones that we use,

like the Zyrtex and the Allegra's, etc. First is that they don't last as long, so you have to take them more frequently throughout the day because their therapeutic effect is only a few hours, as opposed to like 12 or 24 hours. But they also are able to cross the blood-brain barrier, which is why Benadryls and things, make people so drowsy because histamine is important in your brain.

Histamine crosses the blood-brain barrier, but the medication can also do that and then block those receptors and then cause sleepiness in your brain. They also tend to be a little bit less specific. So you said like, okay, these different medications are blocking different receptors. Yes, but some of them are better at that than others. And so some of these older anihistamines block a wider range of not just histamine receptors, but other things as well, which is why they tend to have more side effects

across the board and interact with other medications. The newer anihistamines that we use for allergies, which are called second generation anihistamines, Zertexylogra's not sponsored, these don't cross the blood brain barrier. And so they have less sedating side effects. They're more specific for those H-1 receptors, and they tend to last longer so you can take them. maybe once or twice a day. Okay. How do you know which ones to take? Oh, I don't know if I want to answer that question. I have answers to that question, but it feels like a doctor question. This is not an advice podcast. This is not, I have a lot of like those caveats in this episode in particular. We are not your doctors. This is not medical advice, but it really will depend.

All of these anihistamines can be used to treat a lot of the symptoms. of allergic reactions, right? They're not treating the allergy at all. They're just treating the symptoms by blocking histamine from having an effect. But so no matter what the type of manifestation, be it allergic rhinitis, hives, food allergy where you're not having anaphylaxis, of course, itching, all of these symptoms that histamine is involved in in the whole suite of allergic reactions that we talked about last week, they can help be mediated by anaphymins. histamines. Which one you choose will depend on what your allergies are and which one you respond better to because some people respond better to some than others. What's really interesting is

especially when it comes to things like Benadryl, some people have like paradoxical effects where it makes them really agitated, especially kids, which is why it's usually not recommended to give kids those because they can either be way too sedating or make them super hyper, which is not fun. but all of these can potentially have a role. And sometimes people will respond really well to one for a long time. And then it will just like stop working. Yeah.

And then they have to switch to another one. Why? Why? We don't really know. Okay. But you can get used to a certain end histamine. Absolutely. Yeah.

And is it just because all of your receptors are so saturated that then your body is like, well, I'm just not going to, like I'm going to upregulate my receptors or what is it? We don't really know. But for some reason, at some point, that particular type of anihistamine for some people might not work as well. And if they switch to another one, which all of these are just different shapes of molecules binding to the same receptor, then it usually will work for them. But across the board, anihistamines are rarely the only thing that he's used to treat allergies. So let's keep going, shall we? Yeah.

Steroids, honorable mention, have a role to play in the treatment of allergies. Allergic rhinitis especially. So like nasal and eye and like your face symptoms from allergies really benefit from specifically nasal sprays that have glucocorticoids. And the reason is because steroids are general anti-inflammatories. They are blocking not just histamine. they're blocking your whole inflammatory response. Right.

So they're incredibly effective at calming down the inflammation in this tiny area that is your nasal passages. And they tend to be very safe and well tolerated because even though steroids might sound scary, in the case of nasal sprays, they're not super well absorbed systemically. So they're really locally treating this inflammation. So they're really awesome and like generally recommend. as first-line treatment for things like allergic rhinitis. Not all nasal sprays are steroid nasal sprays.

Okay. And so I think it can be really easy to get confused between all the different types. And there are some nasal sprays that you can really only use for like a day or two at a time before you start having pretty severe side effects from the nasal spray. Wow. Like what would those side effects be and why? It's because they're not steroid. So they're working in a way to just, like, constrict your blood vessels.

It's for when you have, like, really bad, like, sinus infection or something and you just need to dry up your sinuses. Right. They'll do that. But then they can cause, like, rebound, worsening of symptoms, and blah, blah, blah. So those are not what I'm talking about. The types of medicine I'm talking about are things like Flonase and Nasakort. Those are the, like, brand names in the U.S., but they're things like Fluticazone and Mometazone. Those are the steroids that are in it.

there are also anihistamine nasal sprays that people can use, which again are going to do the same thing as your oral antihistamines except locally just in your nose. Same thing with eye drops. There are anihistamine eye drops. Those tend to be less effective than steroid nasal sprays because they're more specific. They're only targeting the histamine rather than a more generalized inflammatory response the way that steroid nasal sprays are. It doesn't mean there's no downside to steroid nasal sprays. The biggest side effect tends to be that it can increase the risk of nosebleeds for some people. Okay. And they usually take some time to work. So they're not like automatic. It takes several days for that steroid to build up in your nasal passages to actually then reduce that inflammation.

Got it. We use steroids also topically for things like eczema or other allergic dermatitis type reactions. So topical ointments and creams that contain steroids are phenomenal. But in terms of oral medications, like we were talking about the scorched earth philosophy. Yeah. Ra, that's steroids. Like, right? They're just wiping out your entire, like, immune response.

Indiscriminate. Exactly. So in cases of severe allergies or a severe allergic reaction, then yes, there might be like a short course of steroids, but they're really not a great option for long-term treatment for oral steroids. Another honorable mention, I will say it so that no one. one gets mad that I didn't, is a medicine called Montalucast. Singular is the brand name. Okay. It's controversial enough that I'm not going to go into it, but it's used mostly for asthma

plus allergic rhinitis. So when you have both of those things together, this, unlike anihistamines, blocks another inflammatory bazge called leukotrienes. Bejouge. Bejouge, isn't that? You find it in the index of a medical textbook, right? Yeah. It's one of the other things that your mass cells spit out in the case of allergies is a leukotriene. And so this medication blocks some of those. But it has a potential for more severe side effects. And we're learning more about the like neuropsychiatric potential side effects of this medication. And so it is used, but not as commonly and in very more specific indications compared to these other medicines we're talking about today. Okay. Which include, for the next one, allergy shots.

Yeah. So how does an allergy shot work? Allergy shots are something that we use really for, again, a wide range, but as far as all allergies go, a narrow subset, and yet it is a wide range of different allergies. Mostly inhaled allergens, things like danders, mites, cockroaches, pollens, also beastings. fire ants and other venoms. And this process most often is done subcutaneously. So it's called subcutaneous immunotherapy, S-C-I-T. And essentially what happens is the person has to go usually weekly, sometimes even more frequently, like a couple times a week to start. And an allergist will inject teeny tiny amounts of the thing that they're allergic to underneath their skin.

It's just like iocaine powder in the princess bride, but it works. I don't. I have watched that movie, but I don't remember. Can you tell me that? He's building up a tolerance to iacane powder. Oh, Wesley. Okay. Now I do remember.

Yeah. So he doesn't die. He puts it in both of the drinks. Yeah. Yeah. I do remember that now. Yeah. Thank you.

It's just like that, Aaron. That's how allergy shots work. It is literally what that is. So you start out weekly or multiple times a week. and then you slowly are building up the amount of allergen that this person's being exposed to, and over time you space it out to less frequently every couple of weeks, every month, every few months, and this goes on for usually a couple of years, at least many, many months. And then eventually you can stop doing the shots altogether and people don't have allergies

or have significantly less of a response to allergens. Erin, why does that continuous exposure results in decreased sensitivity rather than increased sensitivity? It's a really good question. I think if we fully understood why this works, then we'd have a lot better treatment for all of our other allergies, and we don't. But we do know what is happening. So what is happening is that this very minute, really, really, really small amount, but frequent and repeated exposure, what it does is it kind of retrains our immune system and it induces a level of tolerance. So the way that I think of it is this repeated exposure over time trains our immune system to be like, hey, listen, remember in last week's episode we talked about door number one and

door number two and how allergies they're opening too much of door number two? So what this process is doing is telling our immune system, listen, like, we've opened up enough of door number two. Like, we've done it. It's overplayed, chill out with that over-response. And then what our immune system does is it starts to shift to the production of IGA and IGG antibodies and away from the production of IGE antibodies. And what do IGA and IG do? Well, they don't trigger this mass cell type response, right? It means that our bodies can still see and flag these allergens because we have these other antibodies to them, but we're never going to trigger that severe immune response unless you have IgG antibodies. And so we are shifting production to where we can be like, yes,

immune system, recognize this, you can remember this allergen, but you don't need to freak out about it. Okay. Unsurprisingly, this can also backfire and can induce anaphylaxis because you are literally exposing somebody on purpose to something that their body has already been trained to identify an attack. So it's like Owen Grady is training velociraptors. That's like the process of, have you seen Jurassic Worlds? No. Really? I stopped at Jurassic Park 3.

Okay. Well, everyone else is going to know what I'm talking about. imagine someone trying to train a velociraptor, right? Like it might work because they're very smart, right? And so they might learn, okay, don't attack this thing. But you also could get your arm bit off. And that is why allergy shots are always done in a very highly regulated and monitored setting under direction of an allergist.

And it's not something that people do like at home. Right. And you have to wait in the office and make sure, you know, a certain amount of time. Yeah. Now, there also are newer options. to do this without having to poke somebody. And this process is called sublingual. Usually it's called sublingual immunotherapy.

And that's when you are exposed to the allergen under your tongue. And so it absorbs into your mucous membranes of your mouth rather than under your skin. It's approved for some allergens, a smaller subset of allergens than subcutaneous immunotherapy. And again, we don't know exactly why, but is it because absorption isn't as good, whatever it is. We don't have as good of protocols for all the allergents. for sublingual immunotherapy. But it is possible for some. So especially for kids, that's a great option because getting shots is scary. But you can't get shots for food allergies. Oh, Aaron. Or can you? You're right. So everything that I just talked about, it's for the types of allergies

that mostly are like allergic rhinitis or rhinoconjunctivitis or venom's toxins. It's not for food allergies. And it's not for lack of trying. There have been so. So many studies where people have tried to use subcutaneous immunotherapy or sublingual immunotherapy for food allergies. They haven't panned out, mostly because especially with subcutaneous, people were just having really severe reactions. So, like, the reactions were more severe and then more dangerous, and so nothing ever got approved.

Asterisk, because we'll talk more at the end of this episode about some newer therapies that are similar to this. for food allergies. What a teaser. Wow. I know. But until very, very recently, like this year, really, the only real advice for people with food allergies was avoid it. Avoid it, avoid it, avoid it, along with an EpiPen, which brings us to our third and final medication that we use to treat allergies.

Epinephrine auto-injector. There you go. I am really interested to hear the history of this. It's a good one. But what I'm going to talk about is like, what the heck is in an epiphen or an epinecter? Well, it's epinephrine. That's easy. Yep. Epinephrine, the other name for it that people might have heard of is adrenaline. And so epinephrine or adrenaline, it's literally the same thing, two different names. Why? It's bizarre. I mean, it's like a little bit in the history, but mostly it was just

like someone like this and someone liked that. That's what I figured. Two different people came up with that. Okay. Yeah. We picked one. This is a hormone that we make in our bodies. And this hormone is our like fighter flight hormone. It's our fight or flight response hormone. So epinephrine is the thing that makes your heart pound when you get anxious. It's the thing that makes you feel jittery when you're feeling jittery when you're anxious or when you're nervous or when you're super excited. Epinephrine acts on these receptors in our body across our entire body called alpha receptors. And these receptors are present on our blood vessels. And they serve to constrict our blood vessels. Anaphylaxis, like we talked about last week, dilates our blood

vessels. So when we give this drug, we constrict them. Boom. Logic. But epinephrine does even more than that. It also works on these receptors called beta receptors. And we have a lot of these on our heart. And when epinephrine binds to these receptors on our heart, it makes our heart beat faster. and it makes our heartbeat harder. So it's pumping blood through these more narrowed vessels. It also, through these beta receptors in our lungs, relaxes the muscles in our airways to reverse that bronchoconstriction or bronchospasm that we see.

So that is why epinephrine is the medicine. It is the medicine to treat anaphylaxis, like point blank period, this is what you use. Okay, I kind of have a silly question. There's no such thing. Okay, well, so let's say that you know that you are really, really allergic to bee stings. Mm-hmm.

And you see a bee. Presumably, does that mean that your adrenaline would shoot up? Would that make you less likely to have an anaphylactic reaction? Aaron, that's not a silly question. That is such a fun question. Or like a snake bite. You see a snake and you're like, oh, and then it bites you and you're freaked out that the snake bit you. and then your body is like anaphylaxis time and then your body is also like but we just saw a snake so

Aaron this is such a fun question in the context of the history and like the toxin hypothesis from last week yeah I have no idea I have absolutely no idea I like I don't even know how you would study that like if someone is anxious before they yeah I have no idea how you would study that because But we can't even do like placebo-controlled trials on epinephrine because it would be unethical, right? Mm-hmm. Mm-hmm. And how durable is an adrenaline spike? Right.

Bras. Versus anaphylaxis, et cetera. Right. And is it just that in anaphylaxis, do you just not have enough endogenous adrenaline? Are you just not making enough epinephrine? And that is why, right? Mm-hmm. Because here's the other thing.

And this is where epinephrine gets a lot of. little bit weird. These beta receptors, they also do vasodilation, which is what is happening in anaphylaxis. So if you give someone some epinephrine, but not enough, like a lower dose of it, then those effects can override and be stronger than the vasoconstriction effects on the alpha receptors. And so the dose is actually really important in epinephrine. Okay. So each epipen contains a dose specific to the person that it is prescribed for? Absolutely not. Aaron, that would be personalized medicine, and we don't have that. Wait, so...

An epinephrine auto-injector, Epi-Pen, I will throw out other trade names, Annapen, Emerade Fastject, that's what one is called in German. Love that. These devices are fixed dose injectors. In the U.S., they're mostly in two doses. For kids, they're 0.1.4. milligrams, and for adults, they're 0.3 milligrams. That's it. Those are the two dose options. And you get prescribed them based on weight. So babies and small kids are going to get the small dose. Everyone else is

going to get the big dose, which means some people might be overdosed, some people might be underdosed. But across the board, I know your face is like, that sounds horrible. Why? Yeah. But it's also like across the board, even though there are potential side effects, how long those side effects last are usually not that long. And so these are the doses that are considered across the board safe. And so you give the dose that is closest to that person's weight based on their weight. Why would we not have a finer system for doing this? Oh my gosh, Erin. That is a question for pharmaceutical companies and who's making the most money off of this. And I do not have to do. There's already price gouging going on like with epipens or epinephrine auto injectors.

Excuse me. I don't know which companies are doing the price gouging. but does happen? I don't have an answer to that. But these doses work for most people. When I say like underdose or overdose, it's not a large segment of the population. It's more likely that somebody might be underdosed, but at least you're still buying time.

Okay. It's also the case that many people, regardless of whether it was the perfect, like, weight-based dose or not, might need more than one. Because this epinephrine doesn't last for very long. The effects are very rapid onset, but transient. And so a lot of times they will help, but then that's not enough.

So you're going to need multiple doses. People might even need an infusion of epinephrine running over a really long time period, like multiple hours before their body is really out of the woods. Wow, yeah. So in general, one of the benefits of these auto injectors is that they are standardized across the board. So no matter what pen you can find, if someone needs one, you can use it, right? It's the same dose for everyone. So it's easy in that way.

They're also designed to deliver the epinephrine directly into the muscle. And we usually use the thigh muscle because it's a nice, juicy, beefy muscle that has a ton of really good blood vessels and really good blood supply, which means that the epinephrine gets delivered in a really predictable way to the blood, as opposed to intravenous, which you can have much higher side effects, plus then you have. you have to find somebody's vein, which in an emergency isn't easy to do. And subcutaneous administration, so just putting it into the skin or like just under the skin rather than into the muscle, what happens is that you have so much local vasoconstriction from the medicine that you don't have as much penetration quickly into the bloodstream. So it doesn't work quite as well. Still better than nothing.

And seconds matter. Seconds absolutely matter. Yeah. These pens also are designed to work through clothing. So they can be delivered incredibly rapidly. You don't have to worry about exposing someone's thigh. You just can get the medicine in. How do you know when to use one?

That is a really good question, Erin. And that is, it is not something I can fully answer. And there have also been studies, and there's a paper that I'll link to in our sources, about like pros and cons of at what point in an end. allergic response. Like, do you wait for things to get more severe or do you not? And the thing is that even when there are cases where, yeah, maybe you could have waited, the side effects of epinephrine generally are less severe than the risks of weighting. So usually across the board, the recommendation is if you have a known, like especially if you've ever had anaphylaxis before, or if you have had

severe enough reactions where maybe it's not anaphylaxis, but you're really at high risk of anaphylaxis, then the recommendation is once you see signs of a systemic response and not just like, oh, just one hive or something like that, then you give it. Because the risks of waiting often outweigh the risks of the medication itself. Okay. But again, it's going to be, I'm not your doctor. This is not medical advice. Also not medical advice, I feel very strongly that everybody should learn how to use one of these pens, even if you don't have allergies because allergies are so common. So there's lots of great YouTube videos out there.

Most of them are really similar, even though all the pens look different. Some look like a box. Some look like a pen. Never, ever, ever, ever put your finger over the top. Anyone. You hold it like it's a, I don't know, a turkey leg. is that not like a I honestly I can't think of anything else so that's perfect

thank you why you hold a turkey leg you're not going to hold it with like you're not going to hold the end over the top of the turkey leg you can you can die that way anyways and we'll talk more about other newer options for epinephrine administration because also injecting your like shoving a needle into your leg or your child's leg that's traumatic. Yeah. So there are some really awesome newer options.

But one of the biggest issues, you mentioned cost, Aaron. These pens can be incredibly expensive. I went on good RX and I looked them up. And the cheapest one I could find in the U.S. is $140 for two pens if you don't have insurance or if your insurance doesn't cover. That's not cheap. No, it's not cheap.

But an even bigger problem in terms of access is that according to the World Allergy Organization, of a survey of all of its member states, this type of epinephrine auto-injecture is only available in 60% of the countries that they surveyed. 60%. And then I would still imagine, like, you know, we talked about, oh, do you wait, do you not wait?

How do you know when to? And I wonder for how many people cost is a factor in that. 100%. Because then if you use it, and they also degrade within 12 to 18 months, so they have to be replaced. So you need a new one, even if you don't use it. You have to carry it with you all of the time because you have no idea when you might be exposed to something that could give you an anaphylactic reaction.

I mean, it's, it is, they are life-saving medication and it is incredible and we need better options and more affordable options. So we'll talk about that a little later. But Erin, first, tell me, how did we come up with all of these different medications? Oh, yeah. There's a lot of story to cover. So let's take a break and then I'll get started. If you look in my bathroom cabinet, you will find among a million other things like cough drops and ibuprofen about 10 different types of anihistamine medications.

Wow, that's a lot. It's a lot. Yeah, drowsy, non-drowsy, generic name brand in a cold medicine combo. Ten is I don't really think it's an exaggeration. Maybe it's more like eight, but it's honestly there's a lot. I'm ready for when someone visits during ragweed season and asks if we have any Claritin or Wallaton, which is what we actually have, which is the Walgreens version. No, it's Walgreens. Okay.

I don't know if we would go through a Costco-sized thing of Claritin. Costco AllerTech have gone through many, many a bottle of children's AllerTech. My husband gets allergy shots every Saturday. I think he's actually down to every other Saturday because they seem to be helping. Yep. And while I don't personally own an EpiPen, I probably should, just in case, I have family and friends who do. Considering the extremely high prevalence of allergies around the globe, it's not all that surprising that medicine has put together a stocked and diverse toolkit for dealing with this condition. But it is pretty amazing, even considering the limitations of these treatments, because even though allergies were only described and linked to an exposure roughly 100. 150 years ago, even though we don't have a full grasp on why we develop allergies in the first

place and how to prevent them entirely, we do have effective treatments. And plenty more promising ones on the horizon. So what I want to do today is talk about the big three, as we've already discussed, to pay them homage, right, in order of their development. So we'll start with allergy immunotherapy, aka allergy shots. I love that that was first. Oilers, I know. Anihistamines and epinephrine auto-injectors, aka your epipens. Okay.

And let me just acknowledge that these treatments are not perfect, right? They don't work for everyone. They aren't the only ones out there, and there is certainly room for improvement. Because allergy remains a debilitating condition for many people, even with these treatments available, or even with the threat of allergies out there, right? But in most respects, allergy treatment is a huge medical thing. success story. And it's one that I'm excited to tell in three chapters. Chapter one, thank you vaccines. In last week's episode, I mentioned that English physician John Bostock was the first to

describe allergy in 1819, hay fever, and that it was Charles Blackley in 1870 who first linked hay fever to a specific exposure, in this case, grass pollen. Blackley's evidence was pretty compelling. He stuck grass pollen up his nose out of season to show that it still caused symptoms. He correlated pollen counts with prevalence and severity of hay fever symptoms. And his conclusions were simultaneously corroborated by a physician in the U.S. who was inhaling ragweed to induce his symptoms. Wow. Sounds really pleasant, right?

Honestly, hardcore. Like, good for you. Very hardcore. I would not subject myself to that. Sorry. Despite this, many scientists still doubted that grass pollen could cause such a response and that it must be some undescribed microbe or good old hysteria. Fortunately, others were convinced enough to take matters into their own hands like William Dunbar, who as a hay fever sufferer himself, was personally invested in understanding what caused his seasonal symptoms. So Dunbar confirmed Blackley's findings by injecting undiluted grass pollen extract into himself and his colleague who also had hay fever.

It's just like a shot of undiluted straight up grass pollen. Oh my God. And then he was miserable. Yeah. Yeah. Both he and his colleague had awful systemic reactions. Like I can't imagine. And instead of that experience dissuading them,

from pursuing this area of study, they were like, more. We must keep doing this. Oh, my God. And granted, they didn't inject themselves with like full-on pollen again. Instead, they took the diphtheria antitoxin approach, and they tried to produce pollen antiserum by injecting horses with grass pollen. Huh. They then turned the serum into powder, which could be applied to the eyes and nose prophylactically

during hay fever season. Did it work? Results were mixed. Okay. Some people got worse. They developed a sensitivity to the horse serum itself, something that had been known to happen with other serum antitoxins. Dunbar didn't give up hope, though. And he took one of these patients who had developed the sensitivity and started them on a pollen exposure journey.

Over many weeks, he injected teeny tiny amounts of grass pollen extract alternating with horse serum, trying to get them desensitized to both. And at the end of 15 increasing dosages, the patient had become much more tolerant of pollen. During that first hay fever season, they reported much more mild symptoms compared to previous years. Wow. Dunbar published his results in 1903.

1903. Wow. Right? And he wasn't even necessarily the first to try out this concept. A few other small reports came out in a five or so year. years before. But it was Dunbar's paper that would catch the eye of one young researcher, Leonard Noon. Noon was on board with hay fever being caused by grass pollen, specifically, quote, a soluble toxin found in the pollen of grasses. It is also undoubted that hay fever

patients sometimes become cured of their idiosyncrasy. The most reasonable explanation of this phenomenon would seem to be that the cured patients have had the good fortune to develop an active immunity against the toxin to the action of which they have been liable for so long, end quote. I love this, Erin. And so using this logic, Noon rounded up some human volunteers and tested their sensitivity to pollen by dropping a little bit of pollen extract into their eye. Oh God.

Sounds horrible. And also, I just wanted to note that the pollen had been collected by his sister, which I just love. Like, I love that detail so much. He's like, hey, sis, go out. No, no, no. This grass. Just this one.

Yeah, yeah, yeah. Okay, collect it all. Just like, just bring it back to me. It's cool. He has a glass tube is fine. Yeah. And then in the winter and spring, outside of hay fever season, he proceeded to administer very precise doses of this pollen extract to his two groups,

those with and those without hay fever. And he increased the concentration of these doses slowly over the weeks. He experimented with different intervals between injections and found that longer intervals could actually make the patient become resensitized and shorter intervals seemed to meaningfully reduce symptoms. Unfortunately, Noon was not able to see his experiment to the full conclusion, nor would he live to see his landmark research honored in the decades to come as the first allergen immunotherapy trial. Noon had tuberculosis And over the course of the study, he grew sicker and sicker And he eventually had to turn his work over to his friend John Freeman to finish carrying out Noon published what would be his last paper, prophylactic inoculation against hay fever, in 1911

And he died two years later at the age of 35. Oh, that's so sad. Yes, it is. Freeman continued this work for the next few years and showed, that using this immunotherapy approach, in 30% of participants, hay fever was effectively cured. Wow. In 35%, symptoms were greatly improved, in 24% slightly improved, and only 12% had no improvements whatsoever. Wow. It's pretty impressive. Yeah. Noon and Freeman's work was truly foundational for the field of immunotherapy. Not only did it demonstrate that long-term improvement was

possible for at least one type of allergy, it also provided a roadmap for healthcare practitioners to try this out on their patients and for researchers to tweak the protocol, testing it out with other allergens, developing a combo shot, improving safety, standardization, and so on. And I'm not going to go into those later improvements. Instead, I wanted to focus on these early years because I want us to consider the timing. The time from description, identification, of cause and effective treatment happened lightning fast for hay fever in science years. But if we place it in the context of what else was happening in the science world at the time, it's clear to see why, or at least partially why.

Vaccines. Although the smallpox vaccine had been around since the late 1800s, no other vaccines were developed until the end of the 19th century, around the 1870s and 1880s, which is right when Blackley's work on hay fever came out. And with the growing number of vaccine success stories and the development of antitoxin, everyone with a remote interest in microbiology or immunology began trying their hand at developing a vaccine. And using the germ theory framework to describe what happens with an allergen exposure,

along with the concepts of immunity, immunization, susceptibility, toxin, antitoxin, and so on, It seemed entirely reasonable that if vaccines worked for pathogens, introduce a little bit to prevent someone from getting sick in the future, then maybe that could work for allergens. Vala, allergy shots. Yeah. So, in a sense, we have vaccines to think. That is so interesting, Erin. I really love that.

I just can't believe how old it is. Like, it makes sense. But it's also like, I just can't believe it. It's also just like so, so, so interesting immunologically that it works and that it works the way that it does. And like it just, it makes me have so many more questions about our immune response and like tolerance versus resistance. You know what I mean? Oh, tolerance versus resistance is such a fascinating question. It really is.

And it's like, oh. Yeah. Yeah. And it doesn't work like vaccines in a way either, right? Like vaccines sensitize you to. Exactly. It is like the opposite of vaccines, but also the same as vaccines, right? Because it is, it is shifting your immune response to be an IGG response, which is what we see with vaccines. But it, but they, A, didn't know that, of course. And B, like, it is because you already had an abnormal. Well, is it abnormal. We don't know. But you had this IgE response and you're having to shift it. So it is, it is tolerance rather than this, like, primed ability to. resist in the future. What? What? I know. It is so weird. It's weird and I love it. I love it. I love it. Are you ready for our next chapter? I really am. Okay. Chapter two, thank you

pharmacology. Just as allergy shots were a product of their time and the excitement surrounding vaccines, antihistamines came out of an era that saw the birth of modern pharmacology. By the mid to late 1800s, the fields of chemistry and biochemistry had made huge technological advancements that allowed scientists to isolate and refine more and more compounds, especially those from living organisms. The goal of this work was basically to understand how stuff works, link a compound to its function. Then, if a certain compound did something interesting or helpful, like quinine treating malaria, you could take steps to either isolate larger, quantities of it from natural sources or try your hand at producing it artificially.

It sounds like a straightforward process, but in reality, this type of work often led researchers down unexpected roads, which is exactly what happened for Henry Dale and George Barker. Okay. Dale and Barger were working at Sir Henry Welcom's research lab in England, like of Welcome Collection, Welcome Library, when they turned their sites to Ergett. Welcome became interested in the commercial potential of Urget as a medication to speed up labor during childbirth and reduce postpartum bleeding, both of which Erget had been shown to do, but no one really understood how. I love this. We talked about Urget way back in a dancing plague.

Dancing Plague, that's right. Yeah, we should do just an Urget episode, really. Okay. I mean, we say like we could make anything into an episode. So, like, I don't know. I mean, this could have been three additional episodes. Let's be real. But Urgett on its own is not something you really want to mess with.

And so the key was to find the compound that had these desired effects, isolate it, and then turn it into a medication with fewer side effects than straight up Ergit. So Dale, Darger and another researcher Laid Law began this process of isolating various compounds from Ergit. and then injecting them into various animals. One compound in particular caught their eye. Beta, I'm going to try to say this, beta imidazililethulamine, or as we know it, histamine. Okay. I'm so glad I don't have to say that again.

It was brutal. Histamine had been isolated previously, but Dale and Laidlaw were the first to look into what it actually did. And what they found was pretty compelling. It caused all the things you talked about, Aaron, vasodilation, the contraction of smooth muscles in the airways, in the uterus, in the intestines, it increased heart rate and stimulated contraction. Overall, injection with histamine induced a response in animals that looked a whole lot like anaphylactic shock, which they pointed out at the very end of their 1910 paper as a possible avenue for future research.

Wow. Oh, 1910. 1910, I know. Anaphylaxis, by the way, had only been described eight years prior in 1902, which is pretty early, by Rochet and Portier. Dale and Laidlaw's paper went a long way towards linking histamine and allergy slash anaphylaxis, but the connection wasn't quite complete. This compound from Urget can cause this reaction, but does it have biological significance? Like, is this something that animals regularly encounter?

Right. The answer to that would arrive in 1927, when Charles Best of insulin fame, he was one of the people who, yep. Yeah. He isolated histamine from liver and lungs, showing that this compound is produced regularly in animal tissue and that it plays a strong role in allergy and anaphylaxis. This is so fun, Erin. I can't tell you how much I love learning this stuff that I've never learned.

about like where we got anihistamines from. I know. I just also I love, I think it's so fascinating to read about that, that period of science where it was just sort of like throwing a dart and being like, cool, let's check out this compound. Yeah. And it does this thing. Let's look at this microbe. It's just everything.

Yeah. Yeah. Open questions. So many. Once this link was made between animals produce histamine on the reg. and it seems to be linked to allergy and anaphylaxis in some way, then the logic followed that if you could find a way to block the action of histamine, you could reduce those unpleasant and deadly effects that it caused.

But how do you do that? Yeah. You look for compounds that bind to histamine receptors, blocking histamine from binding. I mean, straightforward when you say it like that. Straightforward, right? Easy enough. I mean, but in a way, it was only 10 years. after best isolated histamine from animal tissues that the first antihistamines emerged.

So it was 1937 is when Daniel Beauvais, who identified the first antihistamine and then was later awarded a Nobel Prize for his efforts. 1937 is when that happened. Wow. And they were on the market by the mid-1940s. Wow. I know. That's so much earlier.

Same. I think of the 1950s as like medicines didn't exist, which I know is inactored. We barely had antibiotics. Yeah, that's true. But yeah, first antihistamate, I feel like Benadryl was 1946, something like that. Wow. Yeah. That is so cool.

And again, these are the first generation. Right. I could tell a whole separate story about the research that followed from this first generation of anihistamines, you know, how we discovered the second generation. all the different receptors, the recognition that they could help with things like motion sickness, the discovery that some anihistamines could have potentially harmful cardiac side effects, the identification of their sedative effect. I mean, there's a lot more to the history of antihistamines.

I would read that book, Erin. Well, I'll have to save that story for another day because we've still got the last of the big three allergy treatments to get into. and that is the epinephrine auto-injector slash the EpiPen. Love it. Chapter 3. Thank you, Sheldon. Sheldon? Sheldon.

Okay. The Epipen is one of the most powerful medical devices you hope you never have to use. It has saved countless lives from anaphylaxis since its initial introduction, and millions of people around the world rely on epipens to save their lives from severe. allergic reactions. We owe the existence of this amazing device to two separate but equally crucial developments in medicine, the discovery of adrenaline slash epinephrine, and the invention of the auto-injector. Let's begin with adrenaline, again placing ourselves in the late 1800s, when alongside the fields of vaccinology and pharmacology, the study of hormones was also kicking off. Two researchers, George Oliver and E.A. Schaefer ground up a bunch of adrenal glands from various animals,

swirled them up with some alcohol and glycerin, and injected it into dogs just to see what would happen. Oh, my goodness. Okay. Yeah, not great. This idea didn't come out of thin air, though. Several other researchers had attempted something similar, but no one had thoroughly characterized a typical response. Usually it was just death. Yeah. Because it was like not very purified. Right. Hormone extract.

Lots of ways that that could kill a dog. Just saying. Yeah. Yeah. Absolutely. Oliver and Schaefer were the first to actually say, okay, this is what happens. Okay. They noted that the dogs receiving the adrenal gland extract had elevated heart rate,

vasodilation, increased blood pressure, and reduced respiratory rate. It's kind of a messy suite of symptoms. Yes. It's not necessarily. Your adrenal glands are. messy. Yeah. There's a lot of stuff going on there. They make a lot more than just adrenaline. Yeah. Inducing this type of response, they recognized, could come in handy. But first, you needed to find out exactly what was triggering this response or the different parts of this response.

Several researchers set to isolating the responsible compound, and in 1901, Jokichi Takamine would ultimately claim the title, calling the substance adrenaline, which, Park Davis and company later owned by Pfizer patented in 1903. What? I don't know. Is that, yeah, yeah, I know. So that's why we call it epinephrine because. Trade name.

Yeah. Once people were able to synthetically produce adrenaline in 1906, it quickly became one of the most studied hormones over the first few decades of the 20th century as researchers sought to identify possible therapeutic targets. among those asthma and hay fever. Since at least 1859, physicians had observed that, quote, asthma is immediately cured in situations of either sudden alarm or violent fleeting excitements, end quote.

When you're activating the sympathetic nervous system, Aaron. Uh-huh. And so researchers figured, look, here's this thing, adrenaline, that causes the same sensations as sudden alarm or violent fleeting excitements. maybe we injected into people with asthma and hay fever and just see what happens. And in the first few years of the 1900s, that's exactly what Solomon Solis Cohen, Jesse Boloa, and David Kaplan did, finding that both oral and injected doses of adrenaline relieved symptoms of both conditions. But a major question remained. Well, I mean, several major questions remained.

Like, what is adrenaline doing at a cellular level? But for the purposes of this history, The main unanswered question was, what is the best way to get adrenaline into someone? As a treatment for hay fever and asthma, you really had to get adrenaline into someone as fast as possible to be effective, which meant injection, specifically intramuscular injection over oral tablet or other kinds of injections. But how many people are lucky enough to have a syringe and vial of adrenaline on hand during an attack? And even if you are, like drawing up the liquid into the needle while your throat is constricting, not an ideal delivery system, especially when, as we talked about, every second counts. By the 1930s, researchers had developed nebulizers, which helped to solve the problem for people with asthma. But getting adrenaline into someone going into anaphylaxis was still a huge challenge. fortunately a solution was on the horizon, but it wasn't initially created with adrenaline in mind.

During the Cold War, a big fear was that troops would encounter nerve gas, which acted rapidly to incapacitate or kill, like nerve gas would be within seconds, right? And so the military was understandably very motivated to find a way to deliver an antidote as quickly as possible. Oh my gosh, Aaron. I know. Sheldon Kaplan, an engineer working at Survival Technology Incorporated. What a name for a company. What a name. Survival technology. Does it still exist? But Sheldon had just the thing. One of his projects at the company was redesigning the Astropen, which was an auto injector that had limited usefulness since it used stainless steel to hold the medication rather than glass, which was thought to be too frowning. And I think that this was developed with astronauts in mind. Okay. But again, you could only do certain medications because some medications when they come into contact

with stainless steel, not a good thing. Right, they interact. Yeah. Okay. But this problem didn't stop Sheldon. He rebuilt the pen entirely using glass and developing a system to carefully calibrate the dose. Sheldon's new pen was called the combo pen. Okay.

And this is what the military used to deliver antidotes to nerve gas. Wow. But Sheldon saw the great potential that this pen had outside of the military for the general population. He reworked it to contain adrenaline, epinephrine. And the world's first epinephrine auto-injector developed in 1976 was officially approved by the FDA to treat anaphylaxis in 1987. Wow. I know. He had the vision, right? He saw this and was like, there's so much more that we can do with this.

Wow. Yeah. The EpiPen would go on to become a household name and make pharmaceutical companies billions of dollars, thanks especially to price gouging yet again. But Sheldon Kaplan never received any money for his invention, even though his name is on the patent. And I bet that most people have never heard of this incredible inventor whose work and brilliance, has saved untold lives. Oh, wow. So let's give it up to Sheldon Kaplan. Give it up for Sheldon. Oh, my goodness. And there have been so many interesting developments. And you talked about different delivery systems, like a box versus a pen, you know,

and there have been studies looking at, well, if you conceal the needle, it makes people more likely to use it because it's less scary. Also, I am sure, and like, I don't know enough about the history of development of other medications, but, like, we use similar types of delivery systems. for so many medications now, it's not just epinephrine, right? It's even all of the ozempics of the world. Mm-hmm. Is the non-brand name, right?

Like all of these kinds of medications, insulin pens, like all of these things that have the ability to deliver a fixed dose amount in a way where you, in a lot of cases, have very minimal contact with the needle part of it. Wow, that is so interesting, Erin. Yeah. So all from Cold War.

nerve gas, the genius of Sheldon Kaplan. I love it. I know. How fun, Erin. Yeah. Also, 1987. I don't know if that feels earlier late. I don't know, but I'm, I love to know that date. Yeah. I don't know how I feel about it. I'll search my soul. Yeah. Same. Yeah. Well. Well, Aaron, that was a quick tour through the histories of some allergy treatments. And I know that we've got a lot of interesting potential on the horizon. And so I'm going to turn it over to you to let us know where we might be going with allergy treatments today. I will do that right after this break. So we talked already, Erin, because you asked, like, well, allergy shots, food allergies,

what's up? Okay. Well, let me tell you. There is a very new, and by very new, I mean it was approved in the U.S. in 2020. Oral immunotherapy, O-I-T, as opposed to SCI-E. or S-L-I-T for subcutaneous or sublingual. This is oral in your mouth immunotherapy for peanut allergy. It exists, Erin.

Yes, nice. Peanut allergy affects in the U.S. 1.2% of the entire population and 2.5% of kids. And peanut allergy specifically is associated with like a disproportionate amount of anaphylaxis cases that end up in the emergency room. And so that is why peanut allergies. has been the one that people have been studying to try and come up with treatment for. So this new treatment that exists, I didn't even write down the brand name because I didn't

and now I forget, but it's a powder and it's made from peanuts. Like it's just made from peanut protein, Aaron. But it's used as oral immunotherapy in a very similar type of desensitization therapy. And the difference between this and just feeding a kid peanuts to try and desensitize them are a few things. One, it's been very well studied to be safe and well tolerated. Two, it is made to have a very specific and predictable level of allergen exposure, right? That is why it is approved and safer than just trying to eat peanuts to desensitize yourself. Right.

And the therapy regimen itself seems pretty complex. It is multiple exposures per day. it is daily exposure. It's not like subcutaneous immunotherapy where you just go like weekly exposures or something like that. And so it often starts in an allergist office or in your physician's office with these monitored, very well-controlled exposures and then has to continue at home where you're doing this every single day, often multiple times a day, and then every time that you increase the dose, which happens slowly over weeks to months, every time you increase that dose, you've got to go back to your Allerogist office to do that safely under guidance to make sure that you don't have an anaphylactic

reaction. But it exists, Erin. And okay, so what is the success rate for this? Great question. Not perfect. I don't have an exact number. The biggest downside with this and another medicine that we'll talk about in a minute is that it doesn't seem to produce as long-lasting effects as allergy shots do. Okay. But it does have significantly increased tolerance for peanuts. Does it mean that somebody is going to no longer have a peanut allergy? No. Does it mean that they're going to be able to accidentally have peanuts or to have a little

bit of peanuts in something they didn't know had peanuts without having a severe reaction or dying? Yes. And that is huge. Right. And I imagine that it probably helps to then reduce a little bit of the anxiety and fear of a peanut exposure. Exactly, Aaron.

Exactly. And along those same lines, there's another new medication that is really exciting. And mere months ago, February 2024 was approved in the U.S. for treatment of food allergy

more broadly. Not just peanuts. And this is called omelizumab. This is a monoclonal antibody. Anytime you see a medication like on TV that ends in Mab, MAB is monoclonal antibody. Wow, I just made that connection.

So this is a medication that targets, wait for it, IGE antibodies. So we are using an antibody, an IGG antibody, to find and target IgE antibodies in our body. What? What? I know. That's wild. It's, it's incredible, Aaron. It's so interesting. I love it. And it's so, like, the, the way that you do this is very similar to allergy shots in that people had to be getting shots multiple times. You don't do like a small dose and build up kind of a thing, but you have to have multiple doses over a pretty long time period. The study that I read that was

the phase three trial of this drug before it got approved was like 16 to 12. 20 weeks. And then they were even checking like if we went for longer, would it have a better effect, et cetera. And what's incredible is that this showed in this trial where they took people who had at least two food allergies. So peanut allergy plus at least one other. And the ones that they ended up studying were egg, milk, cashew, wheat, hazelnut, walnut, walnut. That's just what happened, people who happened to be in the trial. Sixty-seven percent of people with multiple food allergies, including peanut, were able to tolerate by the end of the study at least 1,000 milligrams of peanut protein, which is equivalent to four peanuts, four peanuts. So that also, I think,

gives you a sense of just how little peanut it takes for many people with peanut allergy to have severe reaction, because in order to be included in the trial, they would have reacted to less than 100 milligrams of peanut protein. That's wow. Right? Yeah. So by the end of the study, 67% of people were able to tolerate at least four peanuts worth of peanut protein.

44% of participants tolerated up to 25 peanuts by the end of this trial. That's awesome. It's incredible. And they saw similar results for cashew egg, milk, wheat, hazelnut. Some of these were statistically significant. some of them weren't, but here's the other thing I want to say. I feel like in a recent episode, we talked about the difference between, like, is it significant clinically?

Is it significant statistically? Yeah. So 67%, depending on who you are, that might sound like a lot. Like, okay, there's like a almost 70% chance that if I have food allergies, if I can get access to this medication, I might not be as allergic as I am now. But that means there's also like a 33% chance that I wouldn't, right? but if you break down that 33%, there was like a portion of those people who did respond to the medication as in before they maybe would respond to like one milligram or like a couple of milligrams

of peanut protein and by the end they didn't react until they hit maybe 300 milligrams of peanut protein. So it wasn't statistically significant for the purposes of the study, but that might be the difference between I take one bite of a cookie and I realize I'm starting to have a mild reaction and I can stop versus I take one bite of a cookie and all of a sudden I'm going into anaphylaxis. So clinically, that is still significant. There was about 14% of people in the study who were true failures, as in they did not, sorry, they weren't failures, but they did not have any improvement in their response to this medication. Which is interesting in an

itself. Like, why not? Why are some people, why does the treatment work for some people, but not others? Exactly. And so we don't know the answer to that because it does not work for everyone, but it works for a pretty good proportion of people. So this was just approved. And again, like you mentioned, Erin, the potential that this has to improve the lives of people, even though it does not mean that they're not having an allergy at all. And we still don't know because this is so new and these trials weren't that long. How long is this tolerance going to last? We don't know. Are you going to have to get this medication again? If so, is it going to work as well? There's still a lot of unanswered questions. But this medication has been shown to be safe

and to be effective in increasing tolerance to so many of these food allergens, including these multiple food allergens. And that has just such a huge potential for impact on not only alleviating anaphylaxis, saving lives, but also on reducing that anxiety. And that's something that's not, like, maybe we didn't even emphasize it quite enough in last week's episode, just how severe that amount of stress can be. Right. To never know when you are going to be exposed and how severe your reaction might be, who's going to believe you at a restaurant and who's not. Right. The fact that there are people who are like, I don't believe in allergies, I mean, it's like not surprising given just the current state of everything in the world, but what?

I know. I know. And it's not just food allergies, too. Like we talked a little bit last episode about allergic rhinitis, how it can contribute to things like difficulties in schools, anxieties. All of these allergies have been shown to have significant effects on people and their families, especially for families with kids with food and other allergies. It can lead to social isolation. Like, it's a, these are big deals. And so the fact that we have treatments that can help to alleviate that is major.

And there's one more that I want to throw out there. And that is nasal epinephrine. Oh, nice. Even newer, Erin, this medication was just approved in August of 2024 by the FDA. Awesome. This is a no needle way to get epinephrine straight into your bloodstream in the case of an anaphylactic react. and I found it on GoodRX for only $199, which is pretty surprising considering it's not generic because it was just approved. This is a really exciting, like really, really exciting medication.

And I'm sure there's a really interesting history of this because I will link to a really cool paper that went into like what it took to be able to develop this because we needed not only the type of nasal sprayer that could spray out a fixed dose of a medication. So that technology had to develop. we also then had to develop a medication that could help other medicines be more well absorbed by your nasal mucosa so that we could more reliably get. Remember I said how like if it's absorbed into your skin, it's not going to work as well as in your muscle? So we had to have another medicine to help it get into your bloodstream. And so we have that now. And so nasal sprays for so many medications, I think they're going to just take off. And so this is one where now there is a, nasal version, which means that it's going to be easier for people to use, no needles,

easier to give your kid because you don't have to poke them, which means kid might be less afraid of it. Like, there's just so many incredible things that are now possible because there's a nasal spray version of an Epi pen. It's called Nephi. But all of these are new treatment options. What we still don't have is prevention. Aside from what we talked about in last week's episode, the leap trial and the eat trial, which I looked at back up, stands for, requiring about tolerance. And these are big deals because we know that early exposure, repeated exposure, can reduce the risk of food allergies, especially peanuts. But for other types of allergies, we still just don't know. There's a lot of work being done. Does treating

eczema early in life help to prevent allergies? Studies are so far pretty inconclusive. But there's a lot of people doing so much incredible research, trying to understand what are those immunologic triggers and what can we do to try and prevent these allergies from starting in the first place? At the same time that we're trying to develop better treatments for people who already are living with allergies. It's an exciting time in the world of allergy research. It really is. It seems like there is going to just be more and more incredible developments and we're going to look back at this time and go, oh, wow, we didn't have Like we have so much right now.

Yeah. But we're going to have so much more in the future. I know. To bring people hope. It's pretty exciting. Relief. If you want to know more to learn so that you can be one of those future researchers, oh my gosh, thank you.

We'll direct you to some sources. Oh, wow. I have so many for this. I don't even know where to begin. So I'll just shout out a few in particular and list the rest on the website. I'm going to shout out that one by Noon and CanTab from 19. 11 called prophylactic inoculation against hay fever. For the anihistamine and histamine section, I'll shout out a paper by Ostrom from 2014,

called the history and progression of treatments for allergic rhinitis. And then for the epinephrine auto-injector, how about a paper by Arthur from 2015, titled Epinephrine, a short history? I have also a number of papers. A couple that I really liked that were more broad overviews was a paper from 2008 from Nature Reviews Immunology. called treatment strategies for allergy and asthma. And then an update from 2023,

also from Nature Review's immunology, called Allergin Immunotherapy, Past, Present, and Future. But I have a whole bunch more specifics on anihistamines, more specifics on food allergy treatment and epinephrine. You can find the list of the sources from this episode and all of our episodes on our website, this podcast, we kill you.com, under the episodes tab. Thank you again so much to the providers of our firsthand accounts

and for being willing to relive those experiences through sharing your story. Yeah, thank you so much. We really appreciate it. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Tom Brifogel and Leanna Scuylachi for the audio mixing. Thank you to everyone at exactly right. And thank you to you, listeners. We hope that you enjoyed this two-parter and that you learned a little bit or a lot of bit about allergies

and how they work and why we treat them. I've certainly learned a lot of bit. Me too. And a special thank you, of course, to our lovely, generous patrons. We appreciate the support that you give us so, so very much. We do. We do. Well, until next time, wash your hands.

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