Okay, so now I get to talk about my favorite topic ever. And I will keep to time, but they did, as Dr. Tierney said, there's a generous amount of time dedicated to this topic. How Dr. Falk and I have split this up is I'm going to review with you the epidemiology definition and clinical presentation of EOE. What I'm trying to do with my time is to review the definition and history of EOE, how it's really evolved over the years, we'll highlight epidemiology. I'll do pathophysiology in very broad strokes as you're going to get a deep dive into this with Dr. Falk. I'll highlight clinical presentation of the type of patients that we see and review with you natural history of the disease. I have this picture up here because this is a little trivia question, but the eosinophil was actually named after Eos, the god of dawn, because those granules in the eosinophil stain very bright pink. So that is not a trivia question that you're going to get, but just so you know the background of the eosinophil and where it got its name. So let's get started. What is the definition of EOE? It's a chronic immune mediated food antigen driven disease. Patients need to have symptoms related to esophageal dysfunction and pathologically one or more biopsy specimens must show eosinophil predominant inflammation. And when you look at that biopsy slide, you'll see more than 15 eosinophils per high power field which will be considered the minimum threshold for a diagnosis. Disease needs to be isolated to the esophagus and this definition used to include that you have to have this inflammation after PPI therapy. It no longer includes that, meaning you don't need a PPI for diagnosis of this condition. PPIs have moved into therapy. And then we need to rule out other causes of eosinophilia such as reflux disease. Many people think of EOE as being a very new disease, but it's actually been around for a while. So the first two case reports were back in the late 70s. They were in two patients who had concomitant achalasia. In about the early 80s, there was a lot of research in the pathology field that equated eosinophils in the tissue with reflux. So that's why when people got biopsies back and they looked at eosinophils, it was read out as reflux esophagitis. And I think that led to some delay of diagnosis in many of these patients. It wasn't until the early 90s where three separate case theories in adults really highlighted this condition in adult males with difficulty swallowing. In the early 90s also, EOE was defined as a food allergy in children who responded to an amino acid-based formula. The first consensus guidelines defining eosinophilic esophagitis came out in 2007 with the Tigers group. The second consensus guidelines in 2011, EOE was defined as a food allergy by our group and others in adults. The third consensus guidelines came out in 2013. Biologic trials hit the stage in 2015. The Seeger Consortium through the NIH came out in 2019. The AGREE guidelines that took away that PPI as part of the diagnosis in 2018. And the recent AGA joined task force guidelines in 2020. And as you all know, we have an FDA-approved medication for EOE, which just hit reports and I won't tell you what that is because I think you know. But it's really been quite wonderful and fascinating to see this evolution. And I've been a part of this kind of landscape for the last 20 years. So it's been really fantastic for me to get into this on the ground floor and really see it evolve as it has. So epidemiology. We think about these disorders as being quite rare. How rare are they? So EOE prevalence we think is 45 per 100,000 in adults and 104 per 100,000 in pediatrics. How does that compare to non-EOE ages? Well, it's 6.3 per 100,000 in eosinophilic gastritis, 8.4 per 100,000 in eosinophilic gastroenteritis, and 3.3 per 100,000 in eosinophilic colitis. So obviously the non-EOE ages are really quite rare. And taken out of context, you may not know kind of how prevalent the EOE is. These numbers are approximating that of IBD. Now let's put it in context with other atopic conditions. So let's look at the prevalence of eosinophilic disorders compared to other diseases of ATP. So EOE, I just showed you, is about 0.034%, eosinophilic gastroenteritis, about 0.005%, so really quite rare. Now compare that to asthma, which is 7% to 8% of the US population, or seasonal allergies, which is 40% of the US population. And interestingly, 78% of patients with EOE have over one atopic disease. So this is an allergic population. More recent data, looking at health insurance databases, show the prevalence being 51 to 57 per 100,000. And you can see here, they broke down the prevalence by age, and they broke it into males and females. And you can see across the board, this is a male-predominant disease. Males are affected at least three times more commonly than females. EOE definitely has a global presence. This is prevalence data that I've shown you in North America, in Europe, over in Asia, Australia. Really, we've had reports from every single continent other than Africa. Incidence and prevalence trends from those studies will show you incidence across all studies is slowly rising, as you can see here, prevalence increasing as well. And that really mirrors the rise of other atopic conditions, such as asthma, allergic rhinitis, and seasonal allergies. Now let's break that epidemiology down a bit further. And these are pooled studies that looked at patients undergoing endoscopy for any reason, patients undergoing endoscopy for dysphagia, and patients undergoing endoscopy for food bolus impaction. Now EOE was found in 2% to 7% of patients undergoing endoscopy for any reason. It was found in 12% to 23% of patients undergoing endoscopy for dysphagia. And if you look here at the patients who come in with food impactions in the ER, it's about 50%. And EOE is the most common cause of food impaction in our ER. So that brings us back to the question, EOE. Is it common, or is it really uncommon? So if we look at various different studies, there are some data that says it's 1 in 4,400. And that's some global information there. 1 in 2,000 in the US, 1 in 1,500, so getting more and more common. And then there's a Swedish study down here. And in this study, they took 1,000 of their population, offered them endoscopies and a free T-shirt. That is actually true. They found that eosinophils that met that criteria were found in about 1% of their population. They didn't really dive into that symptoms. But where is the true number? How frequent is EOE? It's probably really somewhere in here. It's still under-recognized in this eosinophilic iceberg, if you will. And why is that? Because patients with EOE have adaptive behaviors that mask symptoms and contribute to that delay of diagnosis. And we define this by impact. So patients will imbibe fluids to facilitate the passage of solid food. They modify their foods. They cut their meats into very small pieces or even puree their foods. They'll prolong their mealtimes. Many of our patients will say that they were the last person to leave the table growing up. They avoid harder textured foods. They just won't eat steak anymore because it gets stuck. They'll chew excessively. And they'll turn away from pills and tablets because they get stuck. So it's likely still under-recognized because many of these patients have dealt with these symptoms for so many years. They've adapted to these behaviors. And many of them don't think that it's really a big deal until they bring it up to their clinicians, which then alert them to this diagnosis. What about early life factors? Can anything point in the direction of why we're seeing this? So this was a study done by Drs. Dellen and Jansen looking at early life factors and showing that they are associated with the risk of development of EOE in adulthood. And those life factors that were associated were any antibiotics in infancy, cesarean delivery, preterm delivery, and NICU admission. And you may comment that there's a similar theme across here as antibiotics. But these are the things that are shown to have increased risk of development of EOE. Now we looked at rates of EOE in twin cohort and nuclear family cohort sibling non-probands. This was a study done out of Cincinnati Children's. And what they found was EOE frequency was 41% in monozygotic twins, so identical twins, 22% in dizygotic twins or fraternal twins, 2.4% risk if you had a sibling with EOE. But the general population, just 5.5 per 10,000. So you can see here, you know, increased risk across these categories. Now some of the things that were brought up earlier, EOE being associated with other disorders, I've pulled all the data from these studies for you. So what about aeroallergens, like seasonal allergies? So the comment is that it might cause EOE or increase disease activity. It's likely not the main driver of EOE, but it can lead to people not getting under good control with standard therapy. Now seasonal allergens or aeroallergens can cross-react with food allergens. And that's what leads to some people having what we call oral pollen syndrome or oral allergy syndrome, where they might say they have an itchy mouth. But this may explain seasonal variation with their diagnosis. Food allergens we know directly trigger EOE. And elimination can lead to disease remission. What about H. pylori? You may have heard about some of these studies with H. pylori. It's inversely associated with EOE, which suggests that the decrease in H. pylori prevalence has accompanied an increase in EOE prevalence over the last 20 years. Although the mechanistic data is a little bit lacking. That lends itself a little bit to the hygiene hypothesis that some people will say, is that we've become too clean of a society. So our bodies are wanting to react to more things as opposed to being more tolerant. Infections such as HSV and mycoplasma, they have been associated with EOE. But there's no mechanistic data that says it's directly linked. Oral or sublingual immunotherapy, you might have heard about this from some of the allergists that you call upon. It causes or induces EOE in certain patients. However, they never did a baseline endoscopy on those patients that went through oral or sublingual immunotherapy. So we don't know that underlying prevalence, if it was really the immunotherapy that brought this out, or these were patients that had EOE at baseline. Okay. PPIs are reported to induce IgE antibodies to certain foods. The data really hasn't panned out on that. Other risk factors, cold or arid climates increase odds of EOE in these climate zones, but not in temperate or tropical zones. Population density was looked at. And this was really interesting. The odds of EOE increase as population density decreases. So an increased incidence in rural populations, which is not what we would have thought. Early life factors, we chatted about already. Connective tissue disorders have been associated with EOE, particularly Ehlers-Danlos, Marfan syndrome, Loyes-Dietz syndrome. Celiac disease has been associated with EOE. It's more common in patients with celiac than we would have expected. And those autoimmune conditions that you heard earlier from Dr. Tassif, IBD, rheumatoid arthritis, multiple sclerosis, all of these have been associated with EOE. So moving on to pathophysiology, Dr. Falk is really going to do a deep dive into this. I'm just going to show you a very broad overview of what we think is happening. So in patients who are atopic, who get exposed to food allergens and air allergens, their body starts reacting to these food allergens. It triggers off an incredible Th2 cytokine cascade, leads to inflammatory cells, including the eosinophil, going to the tissue, and ultimately leads to esophageal inflammation, lamina propria fibrosis, esophageal dysmotility, and epithelial permeability, all of which lead to that esophageal dysfunction, strictures, and difficulty swallowing. And Dr. Falk will break this down into more detail. Moving on to the fun part for me, clinical presentation. What are the types of patients that we think about this? So this is a clinical case of a patient that I saw. He's 36. He presented with persistent dysphagia for about six years, so really a long time. He's had five emergency room visits for food impactions. He's had ongoing symptoms, despite chewing carefully and drinking water and avoiding his trigger foods. And he often avoids eating at business lunches and dinners because he doesn't want to have food impactions. And he does have a history of ATP. This was his endoscopy here. And you can see here his esophagus. And you may make note that this looks narrow. This is a really profound stricture in the top part of his esophagus. Here's his barium esophagram. Very narrow esophagus, and you can see here the stricture right at the top. His esophagus, a normal esophagus, is about 2 centimeters across, just to give you a reference. This is only about a centimeter across. And this stricture is only about 3 millimeters across. So if you can imagine how small that esophagus is and the fact that he's still eating. So what do we see in terms of adults? This is a male predominant disease in about 3 to 1. It typically presents in the third or fourth decade. 70 to 80% of our patients do have other atopic conditions like asthma, allergic rhinitis, or atopic dermatitis. The reports say that 71% of patients are white, but they can affect any race. If you ask your patients, they may tell you about a family history of EOE or a family history of allergic disorders. And dysphagia can be in 70% to 80% of people. And I have an asterisk here because patients won't often tell you they have difficulty swallowing because they're so used to adapting for their symptoms. You really have to do a deeper dive into asking how they eat and what kind of mechanisms they use. A third to a half may be seen in the emergency room for food impactions. And heartburn and chest pain are less common but can be seen. Now symptoms of EOE really do vary by age. So younger infants and toddlers can present with vomiting, refusing foods, feeding aversion or intolerance, and failure to thrive. Older children can have choking and gagging with coarse textures. They can have abdominal pain and chest pain. They can also have regurgitation, nausea. It's not until they're older adolescents that they start getting that adult phenotype with dysphagia and food impactions. And in adults, dysphagia and food impactions are by far the most common presenting symptoms that we're going to see in addition to heartburn, regurgitation, and chest pain. What do we see on the endoscopy as endoscopists? So these are very classic findings here. So you have circular rings in the esophagus. Your esophagus actually looks like the trachea, and you can imagine these being a whole bunch of speed bumps down the esophagus. When we refer to furrowing, these are these railroad tracks here in the upper right. White exudates, these white speckles all the way through the esophagus, which correspond to eosinophilic microabscesses. And of course, the dreaded food impaction. So this is a patient of mine that came in, of course, I think was mentioned earlier by Dr. Carpenter, in the middle of the night, about 3 o'clock in the morning, and had a piece of chicken stuck in their esophagus. And had to fish that out, but then realized that this patient had these concentric rings, a lot of inflammation there. We have developed, through Dr. Horano and the Northwestern Group, a grading scheme for those endoscopic features. And so most endoscopic reports you may see for patients will have this grading scheme. And these are the common features on that grading scheme. So the furrows are these linear creases here. They can be pretty subtle, or they can be pretty significant, really deep. The edema. So this is normal, meaning in the esophagus, you'll see these blood vessels, which we call vascular pattern. It's a normal vascular pattern. But then you start losing it when there's mild edema, and it's completely red when there's a lot of edema or swelling present. These are those white speckles here, which you can see, very mild, less than 10% of the circumference versus here, over 10%. Rings can be very subtle ridges here, more prominent, and then very distinct down here, almost looking like a slinky. Strictures can be a little bit more, whoops, let me see, having a hard time with this pointer, a little bit more subtle on the left, and very profound here on the right. That's probably about a 2-millimeter esophagus over in that picture. So those are the things that alert us as endoscopists that this patient has EOE and should prompt us to take those biopsies. So what do we see on the biopsies? You're going to get an excellent lecture later looking at the pathology. I just want to highlight a couple of things. So these are histologic features of EOE, and I think it's important to know that there's more than the eosinophil. This is the top part of the biopsy specimen, so the luminal surface, so the inside surface of that donut, as you heard earlier, and this is the deeper surface. These pretty pink cells here are all those eosinophils, they're bilobe nuclei, and they're clusters here of greater than four microabscesses. So this is superficial layering. You see clusters that are microabscesses, spongiosis are all these white spaces around the cells, that is intercellular edema or swelling, epithelial hyperplasia, degranulation, or those eosinophils breaking apart, and lamina propria fibrosis. And when you look at a specific high-powered field under the microscope and you count more than 15 eosinophils, then you know you've made that diagnosis. It's important to know that EOE is a patchy disease with biopsy variability, and you get an increasing diagnostic yield with increasing the number of biopsies. So studies have shown that multiple biopsies need to be taken along the length of the esophagus to diagnose this condition, and at least five to six biopsies are needed for 100% sensitivity in pediatric and adult studies. So this is a study I did as a fellow showing that if you just take one biopsy, the sensitivity is only about 55%. If you take five biopsies, the sensitivity is 100% for getting this diagnosis. So that's another reason why some of these patients may have been misdiagnosed for a while. So because of some of these studies showing the patchy disease, the ASGE has recently made some recommendations that we should be taking at least two to four biopsies in both the proximal and distal esophagus to help maximize sensitivity. And also, biopsies should be obtained from the antrum and duodenum of all children and adults with gastric symptoms and endoscopic abnormalities to rule out concomitant eosinophilic gastritis or duodenitis. Moving on to my last section here in terms of natural history, this really comes into play because it tells us why it's important to treat these conditions. And what we know about natural history comes from studies that show us that diagnostic delay leads to fibrous stenosis. And this is very consistent results in four different studies. The first one I'll show you is by Dr. Schupfer and colleagues, showing you that the prevalence of fibrotic features increases from 47% with a diagnostic delay of just two years to over 88% at a diagnostic delay over 20 years. Data from Dr. Dellin shows that every 10-year increase in age, the odds of the fibrous stenotic phenotype more than doubled. Studies by Dr. Lipka also show that the longer the diagnostic delay here, the increased prevalence of stricture and the fewer patients present with a normal esophagus. And over here by Dr. Warners, with each year of undiagnosed EOE, the risk of stricture increased by 9%. So it really just shows you the longer period of time that you have this disease, the higher likelihood you're going to have fibrosis, scarring, narrowing. We think of this happening as a continuum over time. And I really like this schematic because it puts it into a picture format in terms of things I was mentioning. So patients start off with a normal appearing esophagus. Due to some unknown trigger, foods are going to traffic to that esophagus, cause that Th2 inflammation, and start to get eosinophils in that tissue. Your esophagus starts to get inflamed, irritated. As time goes on even further, there's a lot of fibrosis or collagen and scarring. Your esophagus starts to get stiff, and it starts to get narrow, and you see these rings. As time goes on even further, more and more scar tissue, narrowing, and stiffness of that esophagus. We think of this happening as a continuum over time with kids starting off over here, which is maybe why they have those nonspecific symptoms. And as they progress on into years, coming on over to this adult phenotype where they start to have more difficulty swallowing and food impactions. This diagnostic delay can lead to greater rates of that stricturing, as we just talked about. And it may necessitate using anti-inflammatory treatment, as well as dilution therapy in some patients. And you'll hear more about that from Dr. Falk. So in conclusion for my section of this talk, EOE is a chronic immune-mediated inflammatory condition of the esophagus, and it is rising in incidence and prevalence. Males are affected more commonly than females, and it typically affects the third to fourth decade in adults. Allergy is related to genetics, allergies, and other environmental factors. Clinical presentation can vary by age, with adults having dysphagia and food impactions, children with reflux, vomiting, abdominal pain, and failure to thrive. And progressive fibrosis can occur with longer duration of disease, so earlier diagnosis and treatment is important. So with that, we actually have quite a bit of time for questions.

eosinophilic esophagitis

EOE

chronic immune-mediated

food antigen-driven disease

esophageal dysfunction

eosinophil-predominant inflammation