I have a number of slides that we're going to go through on the pathophysiology, epidemiology and definition of EOE, and then, you know, we'll open up for any questions or discussions that we want. So I'm going to start with the definition and history of EOE and also the epidemiology, followed by a little bit about the pathophysiology, at least our current understanding of it, and then we'll go through some of the clinical presentation and what we expect in terms of natural history of the disease, which is important, especially when we think about what treatment to choose and when to treat these patients. So for definition, EOE is defined as a chronic immune-mediated food antigen-driven disease. To define EOE, actually to qualify for EOE, there are two components to it, the clinical component and the histology component. Patients have to have symptoms related to esophageal dysfunction, most commonly dysphagia, swallowing symptoms, feeling food, getting stuck. And then they also have to have the pathologic component, which is the part where they need the biopsies from the esophagus showing inflammation, their eosinophil predominant. As mentioned before, the definition of increased eosinophilic infiltration in the esophagus is 15 eosinophils per hypo field on the pathology slide. And it is the peak value, so especially when you look at different fields of the slide, there may be different numbers. So the current definition is using the peak number, the highest number that you can see. And I think we're going to probably talk a little more about it later, especially with Rishi's talk with the diagnosis. But all you need really is just one of the samples, any one sample showing that 15 eosinophils per hypo field is considered positive, considered part of the definition of EOE. The other definition is that it needs to be isolated to esophagus, because now we're seeing a lot of patients with other eosinophilic GI disorders, and it might be a completely different phenotype if they also have high eosinophils in other parts of the GI tract. There are also other causes for eosinophilia, so it's important to also route other causes for high eosinophils in the esophagus. So what's a little bit of history of this disease? Basically, it was in the late 70s when the first case reports for EOE in adults were reported in the literature. And then it was in 1984, in the 80s, when the thought was that maybe EOE is just reflux disease, because as mentioned earlier, reflux can also cause inflammation in the esophagus, and it can also cause some eosinophils within the biopsies. So at the time, the thought is that, well, maybe these are all just reflux-induced. But later on, in the 90s, there are a few case series of EOE in adults, and describing a phenotype that might be a little bit different from what we see normally with reflux patients. And then it was proposed around the time that maybe it is a part of allergic condition related to food allergy. But then, even despite all these reports of cases, it wasn't until 2007 when the first consensus guideline for the diagnosis and management of EOE came out, and when we start trying to do things in a more standard manner. And then the second version came in 2011, and quickly we're having more and more evidence showing that EOE is really part of likely a food allergy or allergic conditions in the adults. And then the third consensus came out in 2013. And then, interestingly, the first biologic trial didn't start until about 2015, based on increasing understanding of the conditions. And then more recently, there are more consensus and guidelines that have been put together, not just by gastroenterologists, but together with allergists and other specialists, pathologists, they're part of a management team of this condition. And most recently, the AGA ITF EOE guidelines came out in the past couple of years as well. So a little bit about the epidemiology. How prevalent is EOE compared to other allergic or atopic conditions? Asthma, as we all know, it's decently common, it's about 7% to 8% of the U.S. population. About 40% of the population has some type of seasonal allergy. In contrast, the prevalence of EOE, it's about 34 per 100,000 patients, so it's really 0.034%, much lower than what we see in asthma or just seasonal allergies. This number might be changing, as I'm going to show in a couple of slides, we're really diagnosing more patients with EOE, so that might be going up. Now, looking at other eosinophilic GI condition, specifically eosinophilic gastroenteritis, that's even more rare, at least for now. Again, it's a condition that we're trying to understand more and more now, so we might actually diagnose more of them in the future as well. But importantly, when looking at EOE patients, over three quarters of them, at least in prior studies, show they have at least one allergic condition, some type of atopic disease, whether it's asthma, which is the most commonly reported in the past, or eczema or skin conditions or other allergic conditions. So they very frequently coexist. So that's certainly one of the risk factors you can look for in patients where you're suspecting EOE. Looking at, again, we're talking about the prevalence of other eosinophilic GI disorders, the prevalence on the lower side, about three to eight per 100,000 patients, depending on the location of the eosinophilic infiltration. Compared to EOE, it is much higher. It's about 45 to 100 per 100,000 patients, depending on where the study came from. So for now, among all the eosinophilic GI conditions, EOE remains the most prevalent one. There are some risk factors that might be associated with the risk of developing EOE. Some of them are some early life factors have been looked at. And a few that have really been found to be potential positive risk factors include any type of being exposed to any type of antibiotics, even as a baby. Maybe the mode of delivery has been thought to be related. Maybe patients who are requiring ICU admission may be exposed to certain factors or may be more predisposed to developing allergic conditions. What about in the family or genetic or other conditions? That are people who have EOE, are the family members more likely to have EOE? There have been a number of studies that look at this. In this study, they actually look at a patient who have EOE and they look at their either sibling or if they have siblings, they're twins. As you can see in this graph, the twins, either monopsychotic or disychotic twins, often EOE patients are much more likely to also have EOE compared to non-twins family members. And just looking at the sibling of an EOE patient compared to the general population, the risk is also higher. So it seems like there might be some factors predisposing people from the same family to have EOE. But then the question becomes, because this is potentially an allergic condition, is it a genetic factor or is it some sort of shared environmental factor? And some study have actually looked at that and estimated that maybe environmental factor play a big part because they're all exposed to the same type of antigen. And that had been to explain the familial clustering. And the thought is that if that's the case, maybe modifying the environment, the exposure early on may decrease the risk of EOE in the same family. What about the overall population, the age and gender of people who get EOE? As you see in this graph here, the main group of patients who get EOE are generally patients in around the 20s to 40s. That's the most common age group for EOE. And generally, the younger population, there's also a significant proportion of patients who are pediatric patients as well. Generally, you don't see them as much in the older population, although we do diagnose them sometimes, a lot of times, because they have a delayed diagnosis. They just have been having symptoms for a long time and never presented for evaluation. You can also see here that the darker bar, which is the male, compared to white box, which is the females, there's a much higher prevalence amount of male patients as well. Oftentimes, I tell people the typical patients that we see most commonly are Caucasian men in the 20s and 30s are the most common ones that come in with these symptoms and be diagnosed with EOE. One question is that we've been diagnosing a lot, is we've been seeing more and more of these patients. You can see in some of these studies here, the incidence and prevalence of EOE has been increasing throughout the years. The question has always been, well, are we diagnosing more of them? Because now we understand them more, we're teaching them more, and people are specifically looking for them. So we're doing more biopsies. Is that why we're picking up more EOE? There actually is another study, actually from Switzerland, that looked at their diagnosis of EOE over a 15-year period using two gastroenterologists and one pathologist, same people, throughout these 15 years. And in that, they also saw an increase between the first half and the second half of the study period, where there's about a four-fold increase of diagnosis of EOE. There was a study that went from, I think, the early 90s to the mid-2000s. So it seems like the increase in prevalence, in this instance, is not just because we're looking for it more, but actually there's an increase in the prevalence of EOE. So it seems like the increase in prevalence, in this instance, is not just because we're looking for it more, but actually there's an increase in patients actually being diagnosed with this condition or being affected by this condition. We talked about the fact that it seems like between male and female, it's at least three times more common in men. And EOE is found in about 2% to 7% of patients undergoing endoscopy for any reason. So it's a decently common diagnosis that we find. And specifically for patients coming in for swallowing symptoms with dysphagia, EOE is found in between 12% to 23% of patients coming in for evaluation for this diagnosis. So one of the things that we do is that I think a lot of us do more commonly now is patients coming in for endoscopy for evaluation of dysphagia, we pretty routinely would take biopsy from the esophagus to make sure that we rule out this condition. EOE is also the most common cause of food impaction. Food impaction is one of the common presentation of patients coming with EOE for the first time. So among all the different potential conditions that can cause food impaction, EOE remains the most common. So for patients that come in that we see in the ED for the first time with food impaction, we always want to look for potential EOE and get the biopsies. And EOE is not really just, it's really a global disease. It's not just in specific areas. I think probably 10, 20 years ago, initially it was thought to be more of a Western disease, but now we actually see that more studies are coming up from different countries that can really affect the worldwide population. But still, it's being diagnosed a little bit more in urban cities compared to more rural areas. And in an insurance database looking at this, it's estimated that the prevalence of EOE is about 8 per 10,000 patients, but there's obviously geographic variability depending on where you're at. So I think one of the questions is that because of all this data that came out in different time and different parts of the world, how common is EOE? And you can see that there's some study that shows that in the United States, there's how common is EOE? And you can see that there's some study that's shown globally maybe is as common as 1 per 4,000 patients to 1 per 100 in some studies. So I think depending on where the study is coming from and what population you're studying, the number might be slightly different. And obviously, we have shown that the incidence and prevalence are going up as well. So we might learn more about that, but it might be a little more common than we previously thought even compared to when I was a trainee. One of the challenges of diagnosing and identifying the true prevalence of EOE is that there are probably a lot of people that are not diagnosed who have EOE. And it's not uncommon. When we see these patients coming in, we diagnose them. It turns out they have been having symptoms for years, and they didn't even realize that's abnormal. And that's one of the reasons is that a lot of people develop adaptive behaviors which can mask their symptoms. So they are already subconsciously changing their eating behavior to adapt to it, and that's why they never came to the doctors. And on top of that, because the epidemiology we talk about, the population who commonly have them are male in their 20s and 30s, probably the population that are less likely to go to the doctors or complain about symptoms to start with. It makes the late diagnosis even more common. So some of these adaptive behavior that now we actually look for when we talk to patients we suspect with EOE are things like, oh, I always try to drink some liquid when I eat to help the food goes down, or they try to cut food into smaller pieces or even puree them to help eating. They tend to take longer to eat compared to their family members or friends, or they try to avoid certain food because they know that it's hard to get down. Sometimes they know that they chew everything for a very long time, or they try to avoid taking pills or tablets because it makes them feel uncomfortable. Some of these things that might not trigger them to think that that's something abnormal, but you have to really ask the patients to really try to get this information so that you can identify patients who are most likely at risk. What are some of the other risk factors that might be associated with EOE? There are actually a number of things that have been looked at. Aerial allergens, meaning any sort of environmental allergens, are something that has been looked at quite a bit. It's actually very prevalent in EOE. It's thought that the trigger for EOE might not just be food alone, but also other environmental allergens. In fact, there have been some studies that have shown that in adults, the aerial allergen, the environmental factors might play an even bigger role compared to children alone. We know that food allergens may directly trigger EOE, and that's why elimination diet is one of the ways to treat it. H. pylori infection actually has been looked at. And interestingly, it's inversely associated with EOE. So the patients who have H. pylori infections or history of H. pylori infection seem to have a lower prevalence of being diagnosed with EOE. It's not really completely clear why that is. It is possible that it is just an association where patients who have H. pylori infection might have certain behavior or have certain environmental factors that make them less likely to have EOE. We don't really completely know. I think that's something that we need to study a little bit more. Other infections, HSV has been talked about. Mycoplasma has been associated with EOE as well. Again, not completely clear why people who have had these infections may be more likely to have EOE later in life. So we don't really know if it's truly causing it or just happened to be associated. But certainly something else to be studied a little bit more as well. Also, immunotherapy, especially once you take by mouth, there are some thoughts that maybe that can cause or induce EOE in certain patients because you're taking medications that go through the esophagus that might modulate the immune system. Although, again, this is something that needs more study to see if it's truly causative or not. Proton pump inhibitors is interesting. It's been reported to potentially induce IgE antibodies to certain food and thought that maybe that can also trigger EOE. But as I think Rishi is going to talk about later, PPI is also a potential treatment for EOE as well. And there have been a lot of studies that have shown potential mechanism why PPI may help people go into remission for EOE. So the exact role of PPI in terms of risk of developing EOE is not completely clear, but it is an established potential treatment option for EOE. Climate, weather, environmental factors. Cold climate has been thought to be a potential risk factors because the incidence of EOE, a prevalence of EOE is higher in climate zones that are colder compared to more tropical or temperate zones. Even within the US, the Northeast actually has a higher prevalence of EOE compared to the southern part of the country. Again, not really sure why. Maybe it has to do with how aero allergens or environmental factors may affect how much you are being exposed to them because of the weather. But we definitely have seen that in even our own study that there's certain seasonal variation in how often we diagnose EOE as well. Population density might play a part. The odds of EOE is higher among more densely populated areas, specifically more urban cities. Again, maybe related to because of the density, the likelihood of being exposed to certain environmental allergens or risk factors. We talked about early life risk factors. Certain connective tissue disorders as well have been associated, things like Ehlers-Danlos syndrome, Marfan syndrome. And then celiac disease, which in itself is also an autoimmune condition. It has been associated with EOE, where EOE is more common in patients with celiac disease compared to the general population. The exact immune mechanism has not been completely elucidated yet. But the fact that they're both autoimmune conditions, it is not completely surprising that there might be a higher risk in that population as well. The other group that I've looked at, the next group, which is other autoimmune conditions, inflammatory bowel disease, is also another condition that's been looked at. Very little data so far, but there might be also an increased risk of EOE among this population. We definitely see patients who have an overlap, EOE and IBD as well. So now that we're going to more biologic therapy for EOE, it will be interesting to see how much we can actually use to treat both conditions. But then other conditions like rheumatoid arthritis, IgA deficiency, multiple sclerosis, thyroiditis, or some of the other ones have been associated as well. Just very quickly about the pathophysiology, just not to make it overly complicated, I think the main thing is that in terms of understanding of what causes EOE and how EOE happens, we know that it's in response to some sort of trigger, whether it's food or environmental allergens. And what happens when we're exposed to them is that it might activate certain inflammatory proteins. And there's a whole list of them, but we don't know how many of them And there's a whole list of them, as you can see here, but the key ones include IL-5, IL-13, eotexin-3, some of the key proteins which are responsible for recruiting, causing an increase of these eosinophils and other inflammatory cells to the esophagus. And when these inflammatory cells get deposited into the esophagus, that's when it can cause a lot of changes, remodeling and structural changes of the esophagus that leads to symptoms. So that's why a lot of the biologic therapy, therapy either once have been studied or once are being studied right now, really target those inflammatory proteins. So if you can knock those down or suppress them, then maybe you can prevent the recruitment of a lot of these inflammatory cells. And as we know, the pexin, for example, targets IL-5 and there are ones that are targeting IL-13 and other proteins that are being looked at as well. What about clinical presentation? I think we kind of went over that a little bit and we're gonna quickly go over an example case. It's a very typical case. 36-year-old man who came in with persistent dysphagia for six years, had five ED visits each time for food impaction. Either they're eating steak or something and they feel like it just got stuck and never goes down. And despite making changes in how they eat, including chewing carefully and drinking water with eating, he still has swallowing symptoms. And because of these, he's been often avoiding eating at business lunches and dinners. He also has a history of allergy, of atopy. And as part of the evaluation, the next thing you often do is doing an upper endoscopy. And what you can see here in this patient is that you see these narrowing, severe proximal esophageal stricture. So on the left-hand side of the endoscopic image, instead of like very smooth, straight tube going down, you see these ridges and narrowing. And these are examples of strictures that we see associated with EOE. And instead of just like one stricture or one ring, we often see with other conditions like reflux, you can often see multiple of these strictures kind of going down the esophagus. And it can be fairly severe. Sometimes there are ones that we'll see where it gets so narrow that we can't even pass the endoscope through. And on the right-hand side, it's actually a barium study, a radiology study, where you can even see the narrowing on the upper part of it. I don't know if I've actually had a... Yeah, so you can see here the narrowing right there that's associated with the stricture area. So these patients often have a pretty significant dysphagia. You can see that when the food are bigger, they are more easily being held up in that area where the strictures are. And I don't want to rehash a lot of these, but we kind of talk about it a little bit in the epidemiology part, often male and patients in their 20s, 30s, and 40s, or when they come in, frequent atopic history, commonly white patients, and often have family history of EOE or allergic condition. But most importantly, from a clinical presentation side, 70 to 80% of them had dysphagia. And honestly, for the 20 to 30% that said they don't have dysphagia, they probably do. They just don't realize that. The reason is that a lot of people might have had symptoms since they're a child, and that's what they're used to, how they're eating. And they always thought that that's how they should be eating. And as a result, they never knew they had a problem until they actually develop a food impaction. And I've definitely had a lot of patients, once we've treated them, we dilated them, we treated them, they go into remission, and they tell me, wow, I didn't realize that you can swallow this way. They didn't realize that this is how normal swallowing should be, because they just never knew. Again, about up to 50% of patients had at least one episode of food impaction in their life. So food getting stuck is very common. Patients might also have other symptoms like heartburn and reflux and chest pain, basically other esophageal symptoms as well. So not just dysphagia, maybe other symptoms associated as well. We talked about what we might find on upper endoscopy. They're typical of EOE. And ERAFs is actually a score that we now use to report these findings on a standard way. And ERAF stands for edema, rings, exudates, furrows, and strictures, which are basically the five common findings we see in EOE. First of all, you can see furrow on the left-hand side, which is this long tracks going down. You can see here, there's this long tracks going along the length of the esophagus going down. These furrows right here, those are what we call longitudinal furrows. Normally we shouldn't see that, but when we see that, that might be a sign of EOE. And sometimes you can see that without those ring-like structures as well. Edema on the right-hand side is basically when you see swelling from the inflammation. Normally you can see these little tiny blood vessels on the surface of the esophagus, kind of like the capillary we see under our skin. When it's swollen, when there's edema, you may actually don't see those marking as well, just because things are a little bit more edematous. And then you can see exudates, which are these little white spots. Those are basically oftentimes where a lot of these inflammatory cells, eosinophils, are concentrated, and they can cover different areas of the esophagus. So depending on how much of the esophagus is being covered in them, we kind of grade them differently between mild to severe. And then you see these rings as well, which is probably the most typical of what we see with EOE patients. You see these concentric rings from mild to more severe rings. And that's actually a very typical finding of EOE that make you think about EOE. What about when we get biopsy? We talked a little bit earlier about getting biopsy. That's one of the definitions of EOE. There are a number of different findings that we see. You can see layering of the eosinophils. You can see eosinophilic microabscesses, basically concentrated pockets of these eosinophils on the biopsy. You can see spongiosis, some hyperplasia, which is basically just the layers of the esophagus basically trying to regenerate itself as it gets inflamed and damaged. Some degranulation, some fibrosis as well. The lamina, lamina-appropriate fibrosis is basically these scar tissue that develop over time with a lot of inflammation. That's actually important, which we'll talk a little bit about later in terms of natural history of EOE. But these are a lot of the typical features that you might see in addition to just counting the number of eosinophils you can see there. I think one of the earlier questions this morning is the getting biopsy and how do we increase the diagnostic yield. As we talked about, EOE is a very patchy disease. So it might not involve the entire esophagus in a uniform manner. There might be more eosinophils in different parts. So if you're just taking random biopsies and you're not taking a lot of them, if you happen just to take a few from areas that are not a lot of eosinophils, you might actually miss the diagnosis. And there have been studies that have shown that multiple biopsy needs to be taken along the length of the esophagus to make the diagnosis. The study have shown that when you take six biopsies, you have a near 100% sensitivity of diagnosing EOE. Anything less than that, you'll be somewhere about four, we take four biopsies in the low 90s in terms of sensitivity. So when you get to six biopsies, you get to close to 100. Importantly, when you take more than six, you take seven, eight, nine, or 10, the study have actually shown that it doesn't really increase your yield much more. So that's why six is really the optimal number that's been suggested to take. Where do you take it is important. You don't want to just take them all in the distal esophagus. You kind of want to get them throughout the esophagus to make sure that you get a good distribution. In the past, we often would take biopsies from different levels. For example, the distal esophagus, maybe the mid or the proximal esophagus and put them in different jars. In the past, people would think that you need to have a high eosinophils in all the different segments to make the diagnosis. Now we know that all you need is any one samples to have at least 15 eosinophils per power field. That's all you need. You don't need multiple segments. I still do separate them in separate jars, but really per current diagnostic criteria, you don't really have to. You can just take them all and put them into one place. You don't really have to separate them. I like to know where a lot of these eosinophils are, especially when patients come in after treatment, if they're still refractory, to see where the refractory area is. They might help guide me, especially with the current treatment. But for making a diagnosis, that's not necessary. So the last thing I want to talk about is the natural history, which is actually important to understand in terms of understanding when and how we should treat these patients. And one thing to note is that diagnostic delay is actually very common. We talked about how a lot of patients might not even realize that they're having symptoms because that's how they used to swallow. Or patients who may have symptoms, they just don't feel like that's an important thing and resist or just never went to the doctors about it and ask about it. The issue with that is that the natural history of EOE is that with inflammation that's untreated for a long time, you're very likely to start developing fibrosis or scarring. And as it goes along, you leave that untreated for a long time, then more scarring is gonna happen. And that's when you develop those stenosis, those strictures and fibrosis and narrowing of the esophagus. And there've been studies I've actually done looking at this, looking at the diagnostic delay and the chances of developing these fibrosis. And what was found is that the later, the more of a diagnostic delay you have, the more likely you're gonna start having these fibrotic features from endoscopy. So one of the risk factors for having later stage EOE, of having these scarred down esophagus is if you don't get your diagnosis and start treatment early. So this is one important part. We always tell our patients, once we get diagnosis, there's no reason to wait. We want to get this disease under control and under remission. And not just symptom remission, but histologic remission. We want inflammation to be controlled to prevent them from developing this stenosis, not just to control their current symptoms. And these are a number of other studies that basically show the same thing. The longer you wait to make the diagnosis, the longer the delay there is, the more likely you're gonna start having strictures. And this will become important. And I'm not sure Rishi will talk about it a little later, in terms of treatment, because once you progress to that fibrostenotic stage, the responses to medical therapy of any type becomes lower. A lot of these patients then have to rely on just dilation to help control their symptoms. So you really want to help, want to prevent patients from progressing to that part. And this is actually the thought, the current thought of the natural history of EOE, and how it is a continuum from going from early stage, which is mainly inflammation, to the later stage on the right-hand side, which is mainly fibrosis-based. And as you can see here, in the early stage, which a lot of the patients we see now, we see a lot of those inflammation, now we see a lot of those inflammatory changes on the esophagus. We see a high eosinophil count. And then as they progress along, they start having scarring, some fibrosis, and at the very late stage, all you see is these fibrotic changes. And not surprisingly, adult patients have a lot more patients that are in the fibrotic stage, probably because they hadn't been diagnosed earlier on, compared to children, which are mostly in the inflammatory stage when you diagnose them, because it's early on in life. But this is the part at the bottom, is what I was referring to in terms of therapy, is what type of therapy you need in the early inflammatory stage. Diet, medical therapy oftentimes work, because you control the inflammation, you control their symptoms. When you're fibrotic, those treatment, this targeted inflammation, can still decrease the inflammation, but that's not gonna change the fibrotic part very much. And that is when you need dilation to basically open the esophagus up. That's what you want to prevent. So just a few key points from this. First of all, we know that EOE is a chronic immediate inflammatory condition of the esophagus. Again, male are affected more commonly than females, typically in the third decade. We know that the pathophysiology of EOE has several different factors, genetics, allergies, and even other environmental factors, whether it's food or environmental allergens. The common clinical presentation include dysphagia, and very commonly food impaction. A lot of times food impaction is the first time the patients might come in and get diagnosed with EOE. And in adults, there are some, and in children, there are actually other symptoms that they might present with as well, especially in the younger kids, when it's harder to know, it's harder for them to describe actually dysphagia. Sometimes they actually come in with symptoms like reflux, vomiting, pain, or because they have a hard time tolerating food, their failure to thrive. Progressive fibrosis can occur if, with longer duration of disease, they're uncontrolled. So early diagnosis, early treatment is important to prevent progression to this fibrosis stage. I think that's it for all the slides. I think we're... Thank you.

eosinophilic esophagitis

chronic immune-mediated disease

clinical symptoms

histology

fibrosis

diagnosis

prevalence