All right, thank you, Dr. Tierney, and thank you to the ASGE for welcoming me back. I had so much fun with you all last year, so it's really a wonderful opportunity to be back here. My topic, my first topic will focus on EOE epidemiology definition and clinical presentation. So what I'm going to try and do with my time is review with you definition and the history of EOE, how far we've actually come. We'll talk about the epidemiology and the association of other disorders with EOE. I'll highlight a little bit about pathophysiology because we'll be doing a deeper dive into this later, review clinical presentation and what we know about natural history of this condition. So what is the definition of EOE? It is a chronic immune-mediated food antigen-driven disease. It's a clinical pathologic disease, meaning that patients need to have symptoms related to esophageal dysfunction. And pathologically, one or more biopsy specimens must show eosinophil predominant inflammation. And that cutoff is more than 15 eosinophils per high-powered field. That's considered the threshold. So you need to have both of these things, both clinical symptoms and that histology. Disease is isolated to the esophagus. If there are eosinophils in your stomach or in your small intestine, it's called non-EOE agent. And we need to rule out other causes for eosinophilia. Now the prior definition was you needed to have failed a PPI trial. But that all changed in 2018. You don't need to have treatment with a PPI in order to make the diagnosis of EOE. If you have these two criteria, you can make the diagnosis of EOE. PPI has actually been moved more to treatment as opposed to a diagnostic tool. Now when many people think of EOE as a very new disease, it's actually been around for quite some time. And I want to walk you through that. So there are first case reports of EOE were actually back in the 70s by two adult studies in patients with concomitant achalasia. And then in the 1980s, there were two reports in the pathology literature that equated eosinophils in the esophagus with GERD. And so that was probably a little bit of misfortune. And I don't want to get Dr. Salaria mad at me here, but what was happening is all the pathology reports that were coming back with eosinophils were read out as reflux. And that probably led to a little bit of delay in diagnosis for many patients. In the late or early 1990s is when we actually started to understand a little bit more about EOE. There were three separate case series in the adult literature that defined this as a disease of dysphagia, eosinophilia in young males. EOE was then described as a food allergy in the mid-90s in pediatrics. The first consensus guidelines hit the stage in 2007. This was followed by two separate consensus guidelines in 2011 and in 2013. It was long thought that EOE was a food allergy disease just in children, but our group as well as the group in Spain in 2012 and 2013 defined it as food allergy in adults as well. Biological trials hit the stage in 2015. The agreed guidelines that I was talking about about the lack of need for PPI to make the diagnosis hit in 2018. The Seeger Consortium, the consortium for eosinophil GI researchers through the NIH, came about in 2019. In 2020, there was the last consensus guidelines. And as you know, last year in May, the first FDA approved medication for EOE. So we've really come a long way. And many people ask me, well, when did you get involved in this space? When did you start working on this? And I started working on this about 2005 when I was a third year fellow. And the reason being is that I started to see a lot of patients with food impactions. I was telling you yesterday, I was a black cloud, and we started to look into why that was. And so we did a quick little grid of all the popular steakhouses in Chicago. And right in the middle of that bullseye is Northwestern's ER. So we saw more food impactions than any other training program in the city. And it was a blessing in disguise, but it really helped kind of launch my career because I started to get really interested in this condition. So let's move on to epidemiology, the prevalence of eosinophilic disorders compared to other atopic conditions. We know that people with EOE can have ATOP. But what are the prevalence of other allergic disorders just in the general population, just for comparison? So asthma hits about 7% to 8% of the US population. Seasonal allergy is about 40% of the US population. And here we see the numbers for EOE and eosinophilic gastroenteritis, EOE being about 34 per 100,000, depending on the study you read, and eosinophilic gastroenteritis about 5% to 8% per 100,000, so really much more rare. But on the flip side of that, 78% of patients with EOE tend to have one or more atopic conditions. So ATOP is very prevalent in the EOE population. Just giving you a little bit more epidemiological data here on non-EOE agent prevalence because it's important to know. So eosinophilic gastroenteritis is 6.3 per 100,000, eosinophilic gastroenteritis 8.4 per 100,000, and eosinophilic colitis 3.3 per 100,000. And taken out of context, that might not mean much. But if we compare it to EOE prevalence, which is 45 to 104 per 100,000 in adults and peds, you can understand just how rare these non-EOE agents are. Many patients ask us, well, what happened in my life? Like, what could have caused this? And there's been some nice epidemiological studies done out of Cincinnati Children's and North Carolina looking at early life factors and their association with the risk of development of EOE in adulthood. And these are the things that came out with an increased odds ratio, meaning likely to be playing a significant role. So any antibiotics in infancy, C-section delivery, preterm delivery, and NICU admission. Now there's still a lot of question about why those things could have been predisposing factors. Many things could have played a concomitant role. For instance, all these events probably led to peri-delivery antibiotics that could have changed the microbiome. There were a lot of speculation, but these are the things that came out in that data. Patients will often ask us, well, how likely is it that I would have a sibling or a child with EOE? And this is data out of Cincinnati Children's showing the rate of EOE in twin cohort and family cohort sibling non-probands. And what you can see here is if you have an identical or monozygotic twin, that risk is pretty high, 41%, which you could imagine just having identical twins. Dizygotic twins or fraternal twins, that risk is 22%. But if you look at just siblings or first degree relatives, the risk of having a second child with EOE is really quite low, 2.4%. When you compare that to the general population of EOE, it's 5.5 per 10,000. So really pretty rare. It's not as penetrant as some other genetic disorders that we think about. This is insurance database outcomes that show you epidemiology of EOE in the U.S. And you can see here, the highlight of this slide is that EOE really does affect any age. Across these ages, you can see there's a little bit of clustering in the mid-age group, like in your mid-30s, but it really hits all age categories. There is a male predominance here, which is not surprising. Over the last many decades, the incidence and prevalence have really been rising. And you can see here, whether you're looking at Ohio, Australia, Spain, or Switzerland, across all locations, the incidence and prevalence are rising. So this is becoming more common. There's EOE affects at least three times more men than women. It's found in 2% to 7% of patients undergoing endoscopy for any reason. And it's found in 12% to 23% of patients undergoing endoscopy for dysphagia. So if you look at these specific populations now, you'll see that it's more and more common. So that's why it's really important, if someone is doing an endoscopy for dysphagia, to take biopsies of that esophagus to try and make that diagnosis. And it is now the most common cause of food bolus impaction. Over 50% of patients with food impactions have EOE. So again, another thing to advocate for at the time of food impaction, taking those biopsies. EOE definitely has a global presence. It's been reported incidence and prevalence across all continents. The only continent that hasn't reported that incidence and prevalence is in Africa. And an insurance database study that looked globally, representing 134 million individuals, estimate that prevalence of EOE to be about 8 to 10,000. So the question comes up all the time. Is this common or is this uncommon? Is this really a rare disease? And oftentimes, it depends on the study that you're looking at. So some of the data I showed you, it's up here. It's at the tip of the iceberg. The global study is down here. And then look at this one down here. This was a study done in Sweden, where they did endoscopies in 1,000 of their population. They offered people free endoscopies and a free t-shirt. No kidding, they offered them a free t-shirt. And they, I don't know, it drew people. I guess they like t-shirts. But they had biopsies of the esophagus. And in that study, they found that 1% of all that population met the histologic criteria for EOE. So if you'd look at just this study, you would think, wow, everyone has EOE. But the truth is, it's probably somewhere in the middle. And I do think it's yet to be fully recognized. And that's because patients have adaptive behaviors that mask their symptoms. And this is highlighted by the acronym IMPACT. So patients will imbibe fluids to facilitate the passage of solid food. They'll modify their foods or cut them up into really small pieces or even stick to pureed foods. They are often the last one to leave the table, so prolonged mealtimes. They will avoid certain foods. They'll avoid hard texture foods. They will chew excessively. We call them the meticulous masticators. And they'll turn away pills and tablets. And this is really important to know. Because I teach our fellows and our allergists, and I even said this last year at the course, it's not enough to just ask patients when they come to see you in clinic if they have difficulty swallowing. Because they will say no. So I actually sit down with my patients, and I give them different scenarios. And this is important even in surveillance, like after they've come back to see you after they've been treated. And I will ask them, I'll say, well, OK, you're saying you don't have any symptoms. But here, I'm going to give you a dry bagel, or I'm going to give you a chicken breast sandwich, or I'm going to give you this plate of French fries. You're not going to have any water, and let's time you and see how fast you can eat that. And they'll tell me, well, I won't eat that. And I'll say, well, why won't you eat that? They'll say, well, because it's going to get stuck, Dr. Gonsalves. I'm like, well, didn't you just tell me you were doing fine? So it's really important that we probe a little bit, because these patients really are fearful of food impactions. So they do everything they can to avoid those food impactions. There are some questions that came up I heard yesterday about EOE associated with other factors. There have been a lot of studies that have looked at this, and not many studies that have looked at these factors, but there are some trends. So in terms of error allergens, we know that it might cause EOE, or at least increased disease activity. So there is some seasonality with EOE. There was an abstract at DDW that also suggested maybe dietary therapy may not be as effective in high pollen months, because those aero allergens are kicking in. Food allergens we know directly trigger EOE. We know elimination diet leads to remission, so that's not in question. H. pylori has been shown to have an inverse association with EOE. So as there has been a decrease in H. pylori prevalence, there's been an increase in EOE prevalence. Whether or not that's because of the hygiene hypothesis, that's one speculation. Infections such as HSV virus, so herpes esophagitis and mycoplasma, has been associated with EOE, but we don't know exactly why. Oral or sublingual immunotherapy has been associated with EOE and can cause EOE. So that's something that the allergists need to look out for. Those patients where these case reports came out of, they didn't have a baseline endoscopy, so it's unclear if it just unmasked their EOE or actually caused their EOE, but it's just something to think about. PPIs, there have been few case reports talking about induction of IgE antibodies to certain foods that really hasn't panned out. Cold or arid climates has been looked at. There's an increased odds of EOE in this climate zone. Population density, the odds of EOE increase as the population density decreases. The early life factors I already showed you, there's an association with connective tissue disorders such as Ehlers-Danlos and Marfan syndrome, also mainly in the non-EOE-aged patients. Celiac disease, there's an association. EOE is more common in patients with celiac disease than would be expected. We don't know the causality. Autoimmune conditions such as inflammatory bowel disease, rheumatoid, IgA deficiency, MS, and thyroiditis have also been associated with EOE. Let's move now into pathophysiology. I'll do more extensive review a little bit later, but just to give you a quick little overview, this is what we think about happening in this cartoon of a patient. In a genetically susceptible patient, they're exposed to food and air allergens that traffic down into that esophagus. That sets off an incredible Th2 inflammatory cytokine cascade. It triggers all these inflammatory proteins, including IL-5, IL-13, IL-4. They then interact with their cellular receptors, start triggering all these inflammatory cells, eosinophils, mast cells, T cells, to go to that tissue. That leads to a lot of esophageal inflammation, lamina propria fibrosis, esophageal dysmotility, epithelial permeability, all of which lead to that esophageal dysfunction that we see in our patients. So what are the typical symptoms that we see in our patients? I'll highlight a clinical case of one of my patients. He's 36, presented with dysphagia for six years. He had five emergency room visits for food impactions. He had ongoing symptoms despite chewing carefully and drinking water. And he often avoided eating when he went out to business lunches and dinners. He would just drink. And he has a history of atopy. He had asthma. And this is what we found when I did an endoscopy on him. He had a very severe proximal esophageal stricture. So this is his stricture right here in the top part of the esophagus. And this is his barium esophagram. This is his whole esophagram. And his entire esophagus measures no greater at the widest point, 10 millimeters. This is about 7 millimeters. And up here in the point that's most narrow, it was 3 millimeters. We were talking yesterday about the diameter of the regular endoscope being about 9.8 millimeters and a pediatric scope being about 6.6. The pediatric scope wouldn't even go down his esophagus. The savory guide wire didn't go down his esophagus. That little wire that you saw, we had to dilate him under fluoroscopy. That's how significant some of these patients are, yet they're eating. So again, they accommodate for this somehow. So EOE when it presents in adults and in children, it's male predominant, about 3 to 1. In adults, it presents in the third or fourth decade. Many patients will have an atopic history, about 70% to 80%. 71% are white, but it's important to know that it can affect any race or ethnicity. It's probably just underreported in those other races. If you ask your patients, they may give you a family history of EOE or ATP. Dysphagia is the most common symptom in about 70% to 80%. And I have that asterisk there just because it's more important to ask about how they're eating than just ask about difficulty swallowing. Food impaction bringing them to the ER is really common, about 33% to 54%. And other symptoms include heartburn, reflux, and chest pain. So what do we see on endoscopy? I absolutely love pictures, and this is why I love being an endoscopist, because we get to see really cool things. But these are examples of what we see in our patients and the E-REF score, which I'll go through with you in a little bit more detail. And the E-REF score is based on edema, rings, exudate spurs, and strictures. But here are examples of some of these concentric rings. This esophagus looks like the trachea. So if you could imagine someone trying to swallow a piece of food, I mean, it's going to hit all these ridges going down. It's going to feel very funny going down. They're not going to have that smooth swallowing. The furrows are these railroad tracks here, these creases in the esophagus. That's an inflammatory change. The exudates are these white speckles down here, which correspond to eosinophilic abscess. And it looks like Canada, as Dr. Lightdale pointed out yesterday. And here's the dreaded food impaction. This is one of my patients with chicken who came in at around 2 o'clock in the morning with the rings and the demon swelling in that esophagus. And that's really what we're trying to avoid for our patients. The E-REF score, which was developed out of Northwestern, shows and breaks down these different features. So furrowing, and they're graded by the severity of the features. And you know in clinical trials, that's one of the outcomes that is looked at. So these are the creases or the furrows. Here's a lot of edema and even deeper furrows here. This patient has a stricture. Edema is basically a loss of vascular pattern. Your esophagus has a lot of blood vessels, and that's normal. So a normal esophagus can look like this with all these blood vessels. When there's edema or swelling, that goes away. And it can be pretty significant, as you can see down here. Exudates, those white speckles, can be very mild, less than 10% of the circumference. Severe all over. The rings can be very subtle ridges, so very mild here to more prominent in number two. And very severe here, like the patient I showed you earlier, where that scope just does not pass. Dr. Solari will be talking a little bit more about the histologic features of EOE. I just wanted to show you this slide, because I just think it's really pretty. I love pictures. And I love eosinophils, because they really are pretty and pink. This is why I do what I do. But anyway, here are these eosinophils. There are these bilobed eosinophils. It's at the top part of this specimen here. There are clusters of more than four, which are those eosinophilic microabscesses, spongiosis, which are the white areas around the cells, which just is a lot of intercellular edema. Sometimes you can actually see degranulation, where those cells break apart. And this is from one of our initial histology studies, where I actually got a chance to work with our pathologist and read all these slides on patients. And it was so much fun to look at. And that led to this study that's actually really important and has been incorporated into all the consensus guidelines, in that increasing diagnostic yield of EOE increases with a number of biopsies. We found that EOE was a very patchy disease with biopsy variability. And our studies have shown that multiple biopsies are needed to be taken along the length of the esophagus in order to diagnose the condition. So you need at least five to six biopsies, both in adults and children, to get 100% sensitivity in pediatric and adult studies. So our typical protocol are to take four quadrant biopsies in that distal esophagus and four quadrant biopsies in the proximal esophagus. So we typically, for clinical purposes, take at least eight to help increase that diagnostic yield. So let's move on now into natural history. What do we know about long-term outcomes of this condition? So natural history studies really show that diagnostic delay and fibrostenosis happens over time. And this is consistent results in many studies, but I'm going to highlight four. The first one is by Dr. Strepfer and colleagues in the Swiss group. And they found that the prevalence of fibrotics features increased from 47% here if someone had a diagnostic delay of only two years to up to 88% here if they had a diagnostic delay of 20 years. So it really increased fibrosis over time. Dr. Dellin and colleagues show that every 10-year increase in age, the odds of that fibrostenotic phenotype more than doubled. Dr. Olipka and colleagues also show that the longer the diagnostic delay, the increased prevalence of strictures, meaning what this is showing you is that if you had a one-year diagnostic delay, very few patients are going to have strictures. If you have a 40-year diagnostic delay, the majority of people are going to have strictures. And with each year of undiagnosed EOE, the risk of stricture increased by 9 percent. I really love this schematic because it shows EOE as a continuation, starting off from inflammation and moving on to fibrosis. So what we think about in this schematic is patients starting off with a very normal esophagus. Then genes get turned on. Error allergens and food allergens traffic to that esophagus. Eosinophils traffic to that mucosa. And you start to see a very inflamed esophagus. That's when you see the exudates, the loss of vascular pattern, and you start seeing the rings and the furrows. As time goes on, more and more eosinophils persist. You start to have collagen deposition or fibrosis or scarring. That esophagus starts to get thick and rigid and you start to get strictures. As time goes on even further, you get more and more collagen deposition, more fibrosis, a more stiff esophagus. And that's when you see that narrow-collar esophagus. We think about this happening as a continuum over time, which is why we think children start off over here and over time they end up with that adult phenotype. And diagnostic delay, I've already told you, leads to greater rates of stricture. And this really highlights that it's important to diagnose these patients early, start them on treatment early to prevent that fibrotic march. So hopefully what I've showed you with my time is that EOE is a chronic immune-mediated inflammatory condition of the esophagus. Males are affected more commonly than females and typically affects in the third decade. Pathophysiology is related to genetics, food allergies, and other environmental factors. Common clinical presentation includes dysphagia and food impaction in adults. And in children, reflux, vomiting, abdominal pain, and failure to thrive. Progressive fibrosis can occur with longer duration of disease. So earlier diagnosis and treatment is important. And I've left you a lot of time for questions. Thank you. Questions for Dr. Gonzalez? What is the history behind the 15 use measures cutoff, and how often do you know your pathologist or other pathologists actually counting beyond 15? Yeah, so very good question. That 15 came back, started from that initial consensus guideline back in 2007. And there wasn't a lot of great data at that time, but the thought leaders, we all got together in a room, and Dr. Collins was the premier pathologist at that time, and we had to land on a number. And so when she was helping to define this, she really tried to look at historical studies to say, okay, what eosinophils would be likely to be reflux? What level of eosinophils would we be very confident would be EOE, and what is that gray zone? And so that's how that 15 came about, from historical studies and conversation amongst the experts. Oftentimes, that's how consensus guidelines start to get developed, when there's not a lot of good data. And back in 2007, there wasn't. So yes, that is where that came about. I think since that time, there's a lot of interest in other histologic parameters, such as the EOE-HSS, that histologic scoring tool, and that other factors might be as or more important than that cutoff of the eosinophil number. And your second question was? How often do the pathologists? Yes. So that is a really hard ask. So I will tell you, I've read thousands of biopsies as part of that histologic variability study. I think that's why I wear glasses now. And it's really hard to count those eosinophils. It's not easy. So you have to have a really good relationship with your pathologist. And Dr. Ohana and myself at Northwestern have worked with them for the past 20 years, and thankfully, we have a really good relationship with them. So oftentimes, what I do is on my request, I will put in there, please rule out EGID. Please give me the max eosinophils per high-power field, especially for the stomach and the small intestine. And they actually do it for me, because we've had conversations about why that's important. And I say, well, it's important for diagnosing this patient, because it would mean that they can get into various clinical studies, or it would mean that they are adequately treated. But it is an ask. So that's not the case everywhere. I always tell colleagues that if you're really thinking someone has AOE, you don't have a number, go back to your pathologist and really ask them for it. So it hinges on that relationship. And I think in the pathology world, there's more and more literature coming out about how these things are very important to evaluate. Sometimes they stop at 100. Sometimes they'll just say over 100. And it's fine, because they can go up to 500. The highest number I had in that study was 546. And so if you can imagine, I had one of these old-school clickers to count that. But pathologists are really, really busy. And I'm sure Dr. Solari will speak to that. So once you get above a certain number, I think it's perfectly fine if they were to say over 50 or over 100. Oh, you can pick on who. I get often the question on the field about if you do have lucky enough to have a good pathologist, and you have initial diagnosis, and for example, they counted 100 per hypo field, patient goes on therapy, therapy, endoscopy, now the patient has 50. And the provider is considered as a success. Does it matter, the number, if it's not less than 15? Right. And so that's where the treatment talk a little bit later will kind of hit on this. But I think about this as a complete clinical picture. While histological efficacy and getting those eosinophils as low as possible is optimal, because you want to shut off that inflammatory process, you really have to look at that whole clinical picture. So I want to know what those eosinophils are at the end, but I want to know what that esophagus looks like. I want to know if those EREFs have normalized. And then I want to know if that patient really has improvement in their swallowing, or if they're still modifying that diet because of their symptoms. So that 50 really just depends. If that 50 is paired with a really inflamed esophagus, yeah, I have not met my end point. If that 50 is there and the esophagus looks beautiful, I still don't believe the 50. It's 15 to 17, and the esophagus looks beautiful. If it's up to 50, chances are there's abnormalities in that esophagus yet, and you haven't met that cutoff. Yes, you have had a response. You've had a dramatic response, but you haven't had what, in my mind, would have been optimal success for that patient. Yeah, I'm going to go way back to the incidence and prevalence slide. There was the Hamilton, I believe it was, that was really a very high line. Do you have any theories about why that one seems to be a bit of an outlier compared to the others, even though they're all trending upwards? Well, they had a very unique cohort of patients in that county that they worked with. So they had a very pure analysis. And I think that's what, and all their patients were in that sector, and they were able to follow them over time. So a lot of the early studies actually came out of Hamilton County, but that's why their number was that crisp. EOE, EGITS. So in your PEDS patients, do you write for the pathologists, rule out EOG, or if you suspect it? I'm just saying a lot of pathologists are not familiar with that. What do you do? Right, so I'm an adult gastroenterologist, but I would say for adult and PEDS, absolutely I write that down for the pathologist. So I will, if there's any EOE patient that I'm suspecting, they have concomitant EOG or EON, I will write that down. I will take the appropriate biopsies, and for the stomach, it's at least eight. For the duodenum, it's at least six. And we'll send that in a note to the pathologist. Please rule out EGIT. Please give me the max eosinophils per high-powered field. So my pathologists roll their eyes every time they see a path request coming from me, because I do 16 cases every Monday, and they're like, oh, it's a Goncalves day. But I mean, I buy them coffee, like we have a great working relationship. But it's important to have that conversation. And the problem is that where EOE was back in 2007, that's where non-EOE EGIT is right now. So we're just now getting to develop consensus guidelines for non-EOE EGIT, including the pathology piece. How many is too many in the stomach, in the duodenum, in the colon? So we're very early on, but it's very important to ask that question. Question here. So clearly, EOE is a chronic and progressive disease. What approach would you take with somebody who believes it's chronic but doesn't believe it's progressive? Yeah, I mean, that's a good question. I think what we do when we see our patients is we almost do like a little mini symposia with them in each clinical visit to try and give them a little bit of a snapshot of what we think EOE is and the long-term outcomes, because it really does frame why we're doing the different treatments for them, right? If someone doesn't believe it's progressive or if they don't do anything that they're going to progress, I mean, there are patients that say, you know what, I don't feel terrible. Yeah, you're stretching myself because I have a little pain, but I get to be loopy for a day with the endoscopy. Just I want to come back every December. And I have someone who's like that, and no matter what I tell them, no matter what kind of pictures I show them, they just don't care. So if I have someone who doesn't want to be aggressive with their treatment, and at the end of the day, it's the patient's choice, we have to be very respectful of what that patient wants, I will sit down with them and say, OK, if you don't want to do anything more, yes, there's this inflammation, please come back. Let's see each other in a year, and let's think about doing an endoscopy in a year. And if in a year, your esophagus looks relatively stable, then we can continue this course. But if you've scarred back down pretty significantly, let's have another discussion. So I always will tell them to come back so I can have another look. But that's not ideal. That's not really what I would advise anyone to do. So back to the histology, it ends up being a tense point sometimes when it comes to diagnostics, and I know that it's evolving. Two questions that come up or that I've heard before, with a biopsy, I've heard of incidences where there's only one that's over 15, let's say it's 17, and the rest of the biopsies are under. I know they take the location into consideration, could be GERD if it's distal, that kind of thing. But in addition to the ERFs, is there any other information you can provide around that? And then if I may, the other question is whether or not degranulation of those eosinophils will obscure the eosinophil count. Yeah, so the first question in terms of what happens if you get just one biopsy with that kind of threshold, and that goes back to the clinical picture, right, that whole clinical picture of that patient. And so if I have a patient who is young, atopic, has thorough rings and furrows, and I get 15, that patient's likely going to have EOE. If I have someone who has a hiatal hernia, there may have been a little erosive esophagitis, they had dysphagia, so I biopsied them, their number comes back as 15, that driver of eosinophils is probably going to be reflux. So it comes back to that clinical context, and that's what the new AGREE guidelines have done. It's left that kind of clinical context to the physician to say, okay, what do I think this patient actually has? But there are cases, to your second question, where degranulation can really affect those eosinophil numbers. When we're talking about counting eosinophils, we're talking about counting intact cells. So sometimes, you know, you may get a number of 15, you're convinced this person has EOE, and the reason why it's not higher is because those eosinophils have degranulated. So if you stain that tissue for eosinophil peroxidase, for example, one of those eosinophil byproducts in immunohistochemical staining, it will likely light up, and it will just show you that they did have degranulated eosinophils. So again, I think it all goes back to that clinical context. We don't just think about the pathology in isolation. We think about that patient and what their endoscopy looks like. We think about their symptoms. So a lot of our clinical care should be focusing on all of those things for that patient, but that's where that conversation with a pathologist comes up. If you have that kind of cutoff threshold, you're really convinced that that patient has it, you can go back and say, hey, can you look at these biopsies again? Can you see any other features? Like there are a whole bunch of additional features on the EOE-HSS, which I'm sure Dr. Solari will review in more detail, but there's a whole bunch of other features that can say, hey, you know what? This is probably EOE, even though you only have 15 eosinophils or 14 eosinophils. Look at this basal cell hyperplasia. Look at this spongiosis. My guess is your patient probably has EOE. Yeah. If you're not taking the right amount of biopsies, yes, you can absolutely miss it because of that patchy nature. You can, if you have someone with rip-roaring, like endoscopic appearance and you think they have EOE and you're just coming back with zero eosinophils, my guess is it's probably degranulated and they're missing those intact cells. The other time that that happens, we talked a little bit about this last night, is if someone truly has a burned out esophagus, you saw that continuum picture I showed you, if they're over there on the right side, they tend to have a very bland esophagus, they tend to have a very fibrotic esophagus. Biopsies, if you're not doing proper biopsy technique, are really hard to get those pieces and sometimes you don't see those eosinophils in the mucosa. What you can see, and we've had this, there are no eosinophils in the mucosa, but you're lucky enough to get that lamina propria fibrosis, but you'll see those eosinophils chock full in the lamina propria, so they're just deeper down. So that's why good biopsies and conversation with a pathologist to look in those deeper layers is also important. I just wanted to make a comment. That really gets to the quality of the endoscopy too. When you guys were in the lab yesterday, hopefully you got a chance to see the biopsy technique and trying to do that in a proper fashion to get adequate depth of your biopsies is really pretty critical. Right, and one of the things I will stress before I get to the next question is, the conversation is not just with that pathologist. The conversation is with the team that's in that endoscopy room as well. So I work very closely with my nurse, or if I'm lucky enough to have a tech in the room with my tech, and I will say with the biopsies, do I have good pieces? Once I have four good pieces in that distal, let's move on to proximal. And I mean, they're used to working with us who are dealing with this condition, and they will be very honest with me. They'll say, no, we only have three. I think you need to take another one or two. And then I think that conversation is really important because sometimes those biopsy pieces, they get lost in the biopsy channel. Sometimes it doesn't come out the forceps. And if your tech is just kind of wiggling that thing in the jar, you're not gonna end up with enough tissue. You're gonna take four passes, but you're not gonna have four good pieces. So that's where that conversation is important. Sometimes I get the comment, that's a pretty wimpy piece, doctor. Yes, exactly. Question over here. I'm sorry, I have another question from, again, the field question in the community specifically is that there's this thought process that if you have more ears distally than proximally, regardless of the number, it's usually is not the high number, it will be like 20 or something, then the physicians will still consider it reflux regardless of ERF symptoms, anything else. So is there actual importance where your ears are proximal or distal when you talk about EOE versus GERD? So there's no great cutoff to say something is EOE versus GERD, which is a challenge. The distal and proximal does become important, and I think in histology studies, including our study from 2006, does show, and most of the studies thereafter have showed a distal predominance. Like, eosinophils tend to be higher in the distal esophagus across the board. There are some patients where there's more proximal involvement. Where, I think that comes back to that clinical picture, right? Even if you have 70 in the distal and you have 40 in the proximal, it doesn't mean that it's all reflux. But that patient can have concomitant reflux. I think the one thing to remember in adults is up to 25% of patients have reflux. And so in adults especially, we're not dealing with just two isolated buckets, EOE or reflux. A lot of patients have an overlap, and that's where treatment for that reflux becomes very important. Where that proximal-distal can be very important is, for instance, you put patients on a therapy, whatever therapy that is, and you do their repeat endoscopy, and you have just a little bit of elevation in that distal esophagus, the proximal looks beautiful. And you think, why am I not, like, getting benefit in that distal esophagus? And then you go back and you ask your patient, hey, did you stop your PPI during this, like, last eight weeks? And they'll say, yeah, I did. I said, why'd you stop it? And, you know, that person's reflux is probably driving that distal eosinophilia. So I do think locations are important, but I think it all comes back to that clinical picture first. Question in the back, Matt. So when we interact with a lot of the physicians, and we talk about food impactions, and that's a big proponent of diagnosing EOE, a lot of them say, oh, it's too inflamed, or I can't do that. And I wonder if it is a training scenario where they, if they went two millimeters up or around, they could still accomplish their goal of minimizing risk, because that's what they keep saying, why they don't do that, but actually diagnosing a patient with something that can be acted on. Is that something that's evolving from a fellowship perspective? Is it something that needs to be put in the guidelines? And I'm curious as far as how you, ASGE, is addressing that particular scenario. Yeah, I mean, excellent question. I think it's imperative at the time of food impaction to take biopsies. Over 50% of these patients have EOE, and it's probably a higher number. It's just because we don't have everyone getting biopsies. There's no increased risk at the time of food impaction to take that biopsy. You will eventually disimpact that esophagus and take your biopsies. And you have done that patient such a significant service because you're not bringing them back again for another endoscopy. That is being incorporated into every training program. It was recently incorporated into the ASGE management guidelines for food impactions in EOE, and it clearly states at the time of food impaction in a patient with undiagnosed EOE, it take biopsies, take the number of biopsies that I mentioned for that diagnosis. So that's really, really important. The one caveat I will say is patient safety first, right? So let's just say you have a four to five hour food impaction, sometimes these things can take that long. And let's just say you put in an overtube, you have a big rent in the esophagus, you're really concerned that that patient might have an esophageal perforation or complication from their food impaction, then of course, do not take the time and take biopsies if there's that concern. But rarely is there that significant of a case where you'd have to worry. I will say I'm old enough to have been trained when that lore of don't do anything on the night of the food impaction, don't dilate, don't biopsy, just take care of it and get out, and that clinical practice has been in place for many decades. And of course, now we know, as Dr. Gonsalves says, that it's very safe and it probably is very important for clinical management to get those biopsies and not let that patient get out of the clinical care and the pathway for EOE. So we do have to address it. We do have to educate all of our providers, not just the ones in the training programs, but those that have been in practice as long as I have and older so that we can make sure that all patients are getting adequate care. I think it's a really great point. And there are a lot of publications and groups that are working specifically on that to try and publish about the importance of those biopsies and how few biopsies were taken at one point and how increased biopsies were taken after. We even at Northwestern weren't great. We did our analysis of our own data and found that before we instituted what we call this best practices program, we had maybe less than 40% of patients who were getting biopsy, but that has increased to over 86%, I think, after that best practices. So we're still not perfect, but I mean, it has improved. It has moved the needle. The one thing, a follow-up that Dr. Tierney said is I would not advise dilation at the time of the food impaction. That, again, is in the ASG guidelines. At that point, the esophagus really is inflamed. Dilation does come with a low, very low perforation risk, but you don't want to do it at the time of the food impaction. Food impaction inherently has risk from patients retching and being in there for so long that they can have perforations. And if someone's having a lot of chest pain after a food disimpaction, you want to know if that's because of a perforation or, and if you're dilating them, then you're clouding the picture. You don't know if it's a perforation because of the dilation. So that, in that case, no dilation, but definitely buy it safe. Okay. Thank you for those questions, and thank you, Dr. Gonzalez. Thank you. All right.

eosinophilic esophagitis

epidemiology

definition

clinical presentation

pathophysiology

natural history

chronic immune-mediated

food antigen-driven disease