AAAAI Podcast: Conversations from the World of Allergy
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AAAAI Podcast: Conversations from the World of Allergy
Solving the Clinical Puzzle of Eosinophilia
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Eosinophilia has a broad differential and determining how to most effectively evaluate it can be challenging. In this episode, we’ll work through a clinical case with Paneez Khoury, MD, MHSc, FAAAAI, and discuss how understanding eosinophil biology can guide our evaluation and management.
Hello and welcome to Conversations from the World of Allergy, the podcast of the American Academy of Allergy, Asthma & Immunology. I'm your host, Dr. Rebecca Saff. Allergy and immunology is a field that's evolving at an incredible pace, and staying current isn't just important, it's essential. In this podcast, we'll talk with leading experts about the latest advances, challenge how we think about core topics, and explore how we can put what we learn into practice to provide the best care for our patients. Eosinophilia can be a clue to conditions ranging from common allergic diseases to infections, malignancy, or a rare multisystem disorder. But determining how to most effectively evaluate it can be challenging. In this episode, we'll work through a clinical case while exploring eosinophil biology, how to think through a complicated case, and understand how eosinophil pathyphysiology can guide our evaluation and management. We welcome Dr. Paneez Khoury. Dr. Khoury is a senior clinician in the NIAID. She is the head of the Eosinophil Clinical Research Unit in the human eosinophil section, where she leads up clinical trials and studies in a variety of eosinophilic disorders. She is the director of the Allergy Immunology Fellowship Training Program for the Laboratory of Allergic Diseases at the NIH. She serves on the AAAAI Board of Directors and is on the board of the International Eosinophil Society. So is the perfect guest for today's discussion about Eosinophilia. Dr. Khoury, thank you so much for taking the time to join us today and welcome to the podcast. Thank you so much. It's really fun to be here. I'd like to start by getting to know you a little better. Can you tell us something a little bit about yourself outside of all your scientific accomplishments and what made you choose allergy immunology as a field and how you became interested in eosinophils?
Paneez Khoury, MD, MHSc, FAAAAIOkay. Well, a little tidbit about me. Probably more most of my fellows know this. I'm really into coffee. So I roast coffee and source beans and make espresso and things like that. As far as why allergy immunology, it's really one of the best fields of medicine. You get a lot packaged into one specialty. You know, I really loved immunology and the applied aspects in humans when I was studying that in medical school and residency. And then once I discovered that this is actually a field that you could practice, I really went, you know, wholeheartedly into that direction. I think you get to put basic immunology directly, you know, to clinical medicine. And I think Eosinophil is a really great example of that. A funny story was, you know, nobody really knew what an Eosinophil was. I was practicing with my kids how to say the word of the thing that I study. And then one day, I think it was probably at one of these program director um assembly meetings, I was sitting in my hotel room and it was the first time that uh Biologic had gotten approved for asthma. And so, you know, I said, here's an eosinophil. And it was talking about that on TV, and I was like, we've arrived. So as far as why I picked eosinophils and eosinophilic diseases, honestly, I think a lot of what we do and choose is sometimes serendipitous. I was seeing patients in clinics at the NIH and loved seeing the difficult uh hypersonophilic syndrome patients. I have an internal medicine background. There's a lot of general medicine uh surrounding these diseases. They're very complex patients. I had no idea I would stay at the NIH, uh, but I figured that I would be able to translate eosinophil biology and knowledge into other basic allergic diseases. Of course, I ended up staying at NIH and doing that and more. And I think what I try to tell the fellows is that you can really end up becoming passionate about anything that you work hard at. Uh, I don't think they really believe me when I tell them this, but I just fell into eosinophils, and that's really true.
Rebecca Saff, MD, PhD, FAAAAISo you studied eosinophils before they were the cool kid on the block, and we had these medications that targeted them.
Paneez Khoury, MD, MHSc, FAAAAIUh-huh. That's why I know a lot about these immunosuppressive medications and how to use them too.
Rebecca Saff, MD, PhD, FAAAAIThat's fantastic. Well, we're hoping to take the kind of clinical and basic science together today so we can learn more about eosinophils in the context of kind of our clinical practice. So we have a case. I'm going to give you little snippets of the case, and then hopefully we can use that as jumping off point to talk. Um, a 48-year-old male is referred after several CBCs demonstrate an absolute eosinophil count of 3,500. The labs were checked when the patient complained of fatigue, and the PCP wanted to know if he was anemic. So that was the original reason it was checked. So nothing to do with eosinophils. It was repeated, and his absolute eosinophil count was then 5,000. He has a history of asthma on fluticosone salmuterol, 250, 500, and Montoleucast and allergic rhinitis on fluticosone nasal spray. So an atopic patient. So before we really talk about the patient's case, can you remind us what is actually an eosinophil and what role eosinophils play in both normal human immunity and the allergic disease?
Paneez Khoury, MD, MHSc, FAAAAISure. Back to the basics, huh? So an eosinophil is a myeloid cell, a granulocyte, and it's so named because its granules have a striking affinity for the acidic diet, eosin. Like neutrophils, eosinophils are packed with granules, although the contents and biology are very different. And those granules have discrete functions, but they're probably best known for containing really highly cytotoxic proteins. The classical thinking was that eosinophils dump these granules onto parasites as a form of host defense, but it's clearly more complicated than that. They can also extrude these things called eosinophil extracellular traps or Eats. This is the eosiniphyl equivalent of nets and neutrophils. In cytolytic Eats, these actually are formed from nuclear DNA. Some of those granules end up on that DNA as they get extruded. So conceptually, it's just as you imagine, it's kind of like a Spider-Man net coming out and ensnaring an extracellular pathogen. And like I mentioned, there are these extracellular granules that come from inside the eosinophils that are part of that mesh and can provide toxic things. So no one really knows exactly why we have eosinophils. You know, there are clearly examples where we've taken them away, and not a lot has happened in humans, and we'll talk about that, I'm sure. But when they're elevated in large numbers in the blood and go into the tissues under inflammatory conditions, say vasculitis or other things like eosinophilic diseases, they can clearly cause tissue damage. But I should mention that, you know, we always talk about Eosinophils being bad, but there's this thing called the liar hypothesis, which proposes that eosinophils are not merely just destructive or and stage inflammatory cells, but that they may also regulate local immunity and remodeling repair in both health and disease. And this has gotten a lot of more attention at our recent ESNFL meetings, like the International Eosinophil Society that you mentioned in the past few years, as more is being discovered about their role in different settings, for example, in malignancy or transplantation. And so I think there's a lot of excitement and interest in what happens when you take eosinophils away. Are they redundant? Are there other cells that can compensate, or will we see other untoward effects over time?
Rebecca Saff, MD, PhD, FAAAAII think a lot of these cells that are involved in the allergic response, this idea of remodeling has started to come into play. You know, type two macrophages, that there's just a lot of that we don't know about their long-term effect in disease and kind of recovering from disease, perhaps.
Paneez Khoury, MD, MHSc, FAAAAICorrect. I think that's that's definitely true. Um, and I think more and more people are studying, you know, not just one cell, but the interactions between one cell and another cells. And our techniques have gotten so much more uh advanced now that you can look at multiple things in one situation.
Rebecca Saff, MD, PhD, FAAAAIYeah. Who do eosinophils talk to the most?
Paneez Khoury, MD, MHSc, FAAAAII'm not really sure. We don't have a cell-by-cell um, you know, example, but uh there's a lot of, you know, there were a lot of discussion about eosinophils and mast cells, uh, you know, crosstalk. Clearly, they're very responsive to type two uh cytokines that are put out by other cells, um ILC2s, you know, the epithelium, and so on. So I think, you know, it's really hard to know that question that you asked, but I think that's really the holy grail of immunology and what we'll want to know in the future, you know.
Rebecca Saff, MD, PhD, FAAAAIYeah, no, absolutely. I think this crosstalk between kind of the neuroimmune system and how the different cells of the immune system interact is so interesting and what we're really looking at rather than just the individual cell and what it does.
Paneez Khoury, MD, MHSc, FAAAAIYeah, absolutely. There was a talk I saw recently, or maybe not that recently, but you know, that showed that there are receptors on neurons, even that you know might respond to similar things that are put out by by eosinophils. So certainly this neuroimmune access is a hot topic and probably a lot of the discussion at the discovery meeting.
Rebecca Saff, MD, PhD, FAAAAIAbsolutely. Well, from a biologic perspective, what causes eosinophils to be released and then to increase when there's uh something that triggers them?
Paneez Khoury, MD, MHSc, FAAAAISo in the body, eosinophils originate from hematopoietic stem cells in the bone marrow, and they proceed through this eosinophil committed progenitor stage that expresses IL-5 receptor alpha. Then they progress through this promylocyte and myelcyte stage before becoming mature eosinophils. And what causes eosinophilia depends likely on the underlying mechanism. So, what you're getting really is uh what we call these reactive states, where cytokines such as IL5, IL3, or GMCSF promote this eosinophiloplesis. IL-5 is particularly important because it, you know, I describe it as the food for eosinophils. It participates not only in the development in the marrow, but also in maturation, survival, priming, activation of eosinophils, and survival. So clinically, eosinophils, you know, eosinophilia can occur because the marrow is receiving these exaggerated cytokine signals. But the other mechanism that is possible is what we describe as a clonal process. So in clonal eosinophilia, there's more proliferation or survival signals that may be cell intrinsic, so inside the eosinophils, which cause constituably active tyrosine kinases that promotes eosinophilia. So there's many different reasons for eosinophilia or hyperosinophilia. It's not just one, um, but I kind of put them into those two buckets overall.
Rebecca Saff, MD, PhD, FAAAAISo, how would we define eosinophilia and hyper eosinophilia?
Paneez Khoury, MD, MHSc, FAAAAIOkay, so eosinophilia is basically an elevated eosinophil greater than 500 up to 1500, and hyperesinophilia is essentially an eosinophil count greater than 1500 cells per microliter or 1.5 times 10 to the ninth per liter. We define it on repeated measurements. So you said in your case that it was repeated, but how soon? When was it repeated? Those things are important. I think one of the things that is a little bit confusing for folks is that uh if you ask those who were in the room when these definitions were made, you know, 1500 is somewhat of an arbitrary threshold. It doesn't mean that if you have 1,490 isinophils that you're somehow biologically different or that you don't perhaps have a hypersinophilic syndrome. I think the main concept is that uh when it's substantial and persistent, that is what we define as hyperosinophilia. Now, I guess the next segue perhaps is you know, we don't wait an arbitrary amount of time. So the the classical thinking is that you repeat this eosinophil count, if it's you know, elevated in two or to four weeks, that that that's a persistent hyperesinophilia. Um, but we don't want to wait until someone actually develops significant organ injury. And so that gets us to hypersinophilic syndrome. The definition is really that you have hypersinophilia and eosinophil attributable organ damage or dysfunction. Um, and that's really the the definitions that we use.
Rebecca Saff, MD, PhD, FAAAAIThat can be tricky because eosinophilia can be a natural part of some allergic disease. We often see patients with asthma who have an elevated eosinophil count. In that case, is there kind of a cutoff? Is that where the 1500 comes from? Below that, it tends to be more related to allergic disease.
Paneez Khoury, MD, MHSc, FAAAAIYeah, I mean, I don't know that there's been any good studies that say what the range is for each of these atopic conditions. Certainly patients with asthma, um, eosinophilic GI disease, especially below the esophagus, atopic dermatitis, some of those patients can have really high eosinophil counts. Um, I think the number 1500 really just allows a person to you know anchor on a number above which we should pay more attention and think about this diagnosis and making sure that we're not missing something that's more systemic.
Rebecca Saff, MD, PhD, FAAAAIYeah. No, we love precise numbers, but so much of the body is not quite quite as precise as 1500 on the dot.
Paneez Khoury, MD, MHSc, FAAAAIExactly.
Rebecca Saff, MD, PhD, FAAAAIAnd we often think about IL-5, especially with now that we have these medications that can block it. Um, how central is IL-5? So without IL5, do you not have eosinophils? Are there other cytokines? You mentioned IL3, GMCSF, um, that we need to think about when we're thinking about eosinophils biology.
Paneez Khoury, MD, MHSc, FAAAAIYeah, I mean, I think the the key is that we're not usually checking these cytokines in the blood. Some people do check IL5 levels. You can have hypercinophilia without an elevated IL-5 level, as we've um we've seen when we've checked in in lots of patients. Um, but it is really the signature Eosinophil uh-related cytokine. It's not the whole story. Um, you can have non-IL5-dependent pathways. So IL-3 and GMCSF, they share the common beta receptor chain with IL-5, and they can also promote Eosinophil survival and activation. But you also have the other aspect, right? So there's a cytokine that makes the Eosinophils happy and provides the food and they come into the circulation, but there's also the trafficking side. So um eataxins like CCL11, CCL24 and 26, um, these all act through the CCR3 receptor and help eosinophils be recruited into tissues. Upstream, so in these atopic conditions, we talk about upstream type 2 cytokines. Um, things like IL-4 and IL-13 can help create that eataxin-rich environment. And epithelial alarmins like IL-33 and TSLP can help initiate and amplify these type 2 responses. So I really think of IL-5 as central to the eosinophil quantity and survival, but a lot of these other factors also play a role. So chemokines and local tissue signals help determine where those eosinophils go and what they do when they get there. So yeah, I think that's really the main thing. It's, you know, it's one part of the picture of eosinophilic conditions.
Rebecca Saff, MD, PhD, FAAAAISo when you block IL4 and IL-13, which we can do now with our biologics, um, you see this uh rise in eosinophilia, particularly initially. Um, what causes that rise?
Paneez Khoury, MD, MHSc, FAAAAIUh so the thinking is that essentially you're blocking trafficking of eosinophils out of the blood. And so you're getting a rise of eosinophils. Personally, I don't know that that's the whole story because sometimes you get this rise that's disproportionate to where somebody actually started. Um, so let's say they started an ecosophyl count of you know, um a thousand, and then all of a sudden you see eosinophils counts go up to the 20,000 range. That doesn't make a whole lot of sense that it's just a trafficking problem. But anyway, that's the conventional thinking. I'm not really sure that I fully believe that or that that's the entire story, but that's what people say.
Rebecca Saff, MD, PhD, FAAAAIAt least part of the story.
Paneez Khoury, MD, MHSc, FAAAAIYeah. Yeah.
Rebecca Saff, MD, PhD, FAAAAIAnd it does tend to go down over time, probably because it does. Yeah.
Paneez Khoury, MD, MHSc, FAAAAIIt does, but you know, is that because now you've taken away that type two um signaling? So now you're not getting further eosinophil um you know development, and it's not just a trafficking problem that you're actually reducing the triggers for um eosinophilia to occur in the first place.
Rebecca Saff, MD, PhD, FAAAAISo more to come, it sounds like multiple factors are probably involved.
Paneez Khoury, MD, MHSc, FAAAAIProbably, as is the case in immunology.
Rebecca Saff, MD, PhD, FAAAAIUm, so we have a little more of the case. So when asked about his symptoms in clinics, so this patient's now that it's a CU in allergy immunology. And when asked about his symptoms, he reports fatigue, headache, and an intermittent rash, which he describes as a bumpy red rash on his chest, arms, and back. And he does say he's mildly short of breath. He has a long-standing history of asthma, but he had been well controlled on his inhaler until recently. He does also say that he traveled internationally to Thailand and Cambodia. And when asked, he says he's been having some episodic abdominal pain, which he says really had happened since his recent travel. And he thinks it was just related to his diet. When he travels, sometimes that happens, but he definitely has had um some GI symptoms. So, in addition to the medications that we talked about, the inhalers, the Monteleucast, the fluticosone nasal spray, he also takes a multivitamin daily, which he buys online, and he does take ibuprofen for headaches and has been taking it more recently due to his headaches. So lots of factors that might be attributed or might be contributing. So when you evaluate a patient with an elevated eosinophil count, what are the key elements of the history that really start you thinking about is this someone with hyper eosinophilia, like more of a primary disorder, or it's secondary to their allergic disorders or medications or other triggers?
Paneez Khoury, MD, MHSc, FAAAAIYeah, I mean, I think there's a few large buckets that you have to think about when evaluating patients like this. I think you gave me a classical bored question with lots of distractors. But typically you, you know, you organize patients into, you know, do they have atopic disease, which this patient clearly had? Um, have they had other exposures, including medications or infections that could be precipitating? Is there an underlying autoimmune or inflammatory disease that the patient has or could be developing? And are they at risk for or could they possibly have a malignancy? And so those are really the big areas. There are more, obviously, more things in the differential, but those are the big buckets. The next thing I do is ask whether the eosinophilia fits the apparent clinical presentation. So someone with atopic dermatitis or eosinophilic GI disease or even a parasitic infection can certainly have hyperosinophilia. But as the eosinophil count starts to go up to the range of 5,000, 6,000, and there's constitutional symptoms, you just mentioned this patient had a lot of fatigue. Um, if there's evidence of organ dysfunction, that makes us think about other causes for the patient. I specifically ask about symptoms that suggest yesinophyll-mediated injury. So definitely asking about chest pain, dyspnea, neurologic symptoms, uh, if there's rash or itching and how extensive that is, obviously you're going to do an exam. But abdominal symptoms, as well as things that may be concerning for malignancy, such as weight loss or B symptoms, fevers, night sweats, things like that. And the duration matters. So again, you didn't give me the duration for this patient, but you know, we ask about whether the patient had had prior blood work. Do they have CBC diffs that you know they may not think about or remember, but nowadays everyone can pull up their portal and you can take a look. Did they have eosinophilia that predated this new lab test that was done, maybe with a different doctor, for example? And then the medications certainly matter, um, including things that were given or that they're taking now or that were given before. For example, in the case of dress or drug rash with eosinophilia and systemic symptoms, knowing that they were on a medication several weeks before, is important. So for supplements, we always worry because there's a lot out there. There, I mean, there have been historical cases of things that were in supplements like L-tryptophan that caused hypersinophilia. Granted, that's not really on the market anymore, but things that patients may not be aware of, especially if they're getting their supplements, you know, from a place that's not that reputable. Obviously, all supplements are not that um well described and we don't know what's actually in them. Um, but those that deserve attention and you can stop certain things and see whether symptoms and eosinophilia get better. As far as the travel that you mentioned, um, travel is important, but I always ask about uh endemicity too. So did they live somewhere a long time ago? Um, you know, if they just went on a cruise for uh you know a week and didn't really have any um suspected exposures, that doesn't mean that they couldn't have lived somewhere where they were exposed to a parasitic infection previously. Uh, and then of course, uh the things that you know patients are always telling us about is the things that are in their home, occupational or other exposures, that uh inhalational exposures that they might have been exposed to. So for this patient, I would say probably the NSAID use, the travel history, the rash, and the GI symptoms probably deserve a little bit more attention and consideration as far as the work up.
Rebecca Saff, MD, PhD, FAAAAIWe also we think about you know travel history overseas, for example, there's many cases that have been reported, people who've never left the U.S. And so I think sometimes I think international kind of where they've been, but we should also not forget that you can get you know parasitic diseases even here in the U.S. So something like that.
Paneez Khoury, MD, MHSc, FAAAAIYeah, that is very true. It's more rare, but yes, definitely very true. Um, there are cases like that where I've only lived in New York and then all of a sudden somehow they have strengthloides. But there's problems in terms of the testing, it was definitely false positive on certain serologies, but it's fairly innocuous to treat somebody empirically if you're gonna be, you know, giving them steroids. So something definitely to think about.
Rebecca Saff, MD, PhD, FAAAAISo, what would you ask about in terms of their GI symptoms? Um, what are the other factors that you you'd want to make sure that you kind of tease out?
Paneez Khoury, MD, MHSc, FAAAAIYeah, so from a GI perspective, definitely, you know, abdominal pain, you want to ask about diarrhea. Have any dysphagia, any other symptoms that suggest eosinophilic GI disease, nausea, food intolerance? Are they modifying the way they eat? Those sorts of things are helpful. Granted, it doesn't sound like that from this patient's history, but you certainly want to delve a little bit further. I think the asthma is actually particularly important in this patient. How long standing and stable was it really? Over what duration did it progress? Did the worsening coincide with this rise in eosinophils? Have they received steroids? Did they go to acute care, get some, you know, a meteral dose pack that they didn't think to mention? Um, how many exacerbations did they have in the past year? You know, escalating asthma can be concerning for, for example, EGPA or eosinophilic rhinulomatosis with polyangitis. Um, the other thing I'd want to know more about is the headaches. Could they be related to sinus involvement? Does the patient smell normally? Those sorts of questions are important to elicit a history of chronic rhinosinusitis with polyposis, which also again be a manifestation of EGPA. I would also deliberately ask about other organ systems that can be involved in hypersonophilia that the patient may not volunteer. For example, um, cardiac symptoms, they have chest pain or palpitations, what about neuropathic symptoms? Do they have any neuropathy, visual symptoms? Anyway, all of those things can be elicited as part of your review of systems, but specifically in the context of hypersonophilia, you want to be more complete than not. This isn't just a general allergy uh history and physical exam.
Rebecca Saff, MD, PhD, FAAAAIYeah, and the shortness of breath, you know, could that be related to cardiac involvement versus just the patient attributes it to their asthma and kind of feeling more short of breath and a respiratory illness?
Paneez Khoury, MD, MHSc, FAAAAIAbsolutely. And you know, some of the symptoms are really non-dis, you know, they're not specific. So, for example, one of the symptoms is breathlessness. It's not exactly dysony, they just feel like they can't get a lot of air. Obviously, if you do an exam, you're looking for things like hypoxemia and so on. But asking, you know, the patient to be more specific about exactly what they're experiencing. Is it exercise induced? Is it is it related to position, those sorts of things are very important. Uh the fatigue, I you know, we didn't talk about the fatigue. So fatigue is actually one of the most common symptoms that patients with hypersinophilic syndrome experience. And so we found this in many of our studies that looked at you know, questionnaires that were administered to patients. It's a very common symptom. And so it's very, again, nonspecific, but typically does go along with hypersinophilic syndrome.
Rebecca Saff, MD, PhD, FAAAAISo when so and with that fatigue, when you bring down the eosinophilic, does the fatigue get better?
Paneez Khoury, MD, MHSc, FAAAAIIt certainly can, yeah. Uh it yeah, definitely definitely can improve when you give patients eosinophil depleting agents. The other one uh thing that I mean, I always have to mention this is that you know, patients can have more than one thing. So if you're evaluating a patient for fatigue, they can certainly have a thyroid problem too. So just you know, practice your general internal medicine also, you know, look for iron deficiency as the PCP head done, think about thyroid disease, um sleep disorders or you know, obstructive sleep apnea, things like that certainly can also be uh going along with diseases too.
Rebecca Saff, MD, PhD, FAAAAIHow often will you get infectious disease involved? If it's someone, for example, who has had some overseas travel or you know, grew up in Brazil or some other country outside where there's more um exposure to other infectious diseases that you may not be as familiar with, or maybe you're more familiar with, but the average.
Paneez Khoury, MD, MHSc, FAAAAII think I think it's not fair because I work very closely with an infectious diseases doctor who's a parasitologist. So I can always curb size Amy Cleon. Um so that's not really fair. I would say that you know, when I see patients who've been referred to us from outside institutions, oftentimes they will have seen an infectious disease doctor because there's a lot of different serologies that you know have to be checked. Some of them are very specialized tests that have to be sent out. No, you know, allergists are not going to know about where to send uh you know certain serologies, some of them are only in specialized centers. And then thinking about the triggers, you can look this stuff up, obviously. There are reviews that go over different organ systems that are involved with eosinophilia, um, as well as the clinicity or how acute the eosinophilia might be and you know where to look and what what serology to test, but but I think it's a little bit out of the scope. So I would say most allergists and immunologists are sending patients to infectious diseases if they are highly suspicious that this might be a possible cause. It's pretty standard to send uh strongy serology. The other one that I you know, for those that see kids, that sometimes causes pretty significant or marked eosinophilia is toxicera. And so exposure, you know, to dogs, and that that certainly is something to think about, also.
Rebecca Saff, MD, PhD, FAAAAIYeah, absolutely. I had a patient a while back who had been eating street food throughout Southeast Asia as part of their travels. Um, and we were started to be very worried that he might have paragonomyasis. And I had knew almost nothing other than the name. And so it's been good learning opportunity for me. So it's a this can also be a good opportunity to learn about different parasites.
Paneez Khoury, MD, MHSc, FAAAAI100%, yeah.
Rebecca Saff, MD, PhD, FAAAAISo back to our patient. Um, so on exam, he had scattered erythematous papules on his trunk and upper arms, mild splenomegaly, and he did have an expiratory wheeze. Um, so are there other things that you would be looking for specifically on a physical exam in a patient with uh eosinophilia that would help you kind of start to bucket them where you want to do more evaluation?
Paneez Khoury, MD, MHSc, FAAAAII mean, what aren't you looking for on a physical exam for a patient with hypersinophilic syndrome? Um really, it's one of the times to do a very complete physical exam. Every single organ is worth looking at. Obviously, starting with the vitals. You know, you want to see if they're hypoxemic, do they have tachycardia? Is this a patient that you need to be worried about more acutely, escalating care right away? Um, and then really I just go through organ by organ, you know, skin exam, you're looking for rash, epitekia, purpura, orderia, patients can have angiodema. Obviously, they're gonna tell you they're not gonna necessarily have angiodema at that moment, but um, nodules, other lesions, those are things that you look for. Certainly a full lymph node exam is important, uh, and that can uncover lymphedinopathy that may actually be important from a malignancy standpoint. Splenomethaly would raise concern for a more um lymphoid or myeloid process. But given this patient's respiratory complaints, I'd be looking for wheezing, um, any suggestion that they have decreased breath sounds or you know um dullness, you know, looking for plural effusion or other consolidation. Obviously, you're gonna follow us up with more imaging, but certainly on exam you can look for that. For the cardiac exam, you're really looking for new murmurs if they hadn't had one before, evidence of heart failure, um, abnormal rhythm or edema. I mean, these are things that you might see. Uh, neurologically, you know, evaluating for weakness or focal isometric neuropathy would be important. Yeah, so that's really, I mean, you're gonna look at the whole person, and they're probably gonna point you to where things are wrong, but you know, you can use the history to guide. So if the patient says they can't smell, you're gonna look in their nose, see if you see polyps, things that might go along with uh history, you know, that would be suspicious for EGPA. And then, of course, as I mentioned, spotomebaly is very important. Um, you might see that on imaging, but those would um really point you towards more of a myeloid picture. The one thing that actually um has been, I think it was a couple series that showed that oral and genital mucosal ulcers went along with a myeloid condition. Um, not in every patient, but I think in like 16% of patients in some series, they they actually had um oral and genital ulcers. So if I saw that in the context of Selenomacalia, would really be, you know, have a low threshold for referral to look for a myeloid process.
Rebecca Saff, MD, PhD, FAAAAIYeah. And not something I would necessarily think to ask about. So that's a good, you know, they may not have active lesions then, but have been having them. Yeah. So where are eosinophils typically found in a healthy person? And how do Eosinophils become activated and cause tissue injury?
Paneez Khoury, MD, MHSc, FAAAAISo they're at an in a normal state, there are relatively few eosinophils that are circulating. Now, some normal people have, you know, two, three hundred Eosinophils, 400 Eosinophils without any symptoms. But most Eosinophils are tissue dulling cells. Uh, physiologically, they're found under normal states in the gastrointestinal tract, specifically in the stomach, small intestine, the colon, they um typically do not reside in the esophagus. So that's where you know having more than 15 per high power field in esophagus is diagnostic for EOE in the appropriate setting. They can also become you know activated, as we mentioned, through different combinations of cytokines and chemokines and local tissue signals. So once that's happened, um you can see them in any tissue. And so um that's one of the questions. You know, do you need to biopsy everything? If there isn't a count as five, seven thousand, you know, they could just be there under normal conditions. I mean, not normal conditions, but because of the elevated eosinophils. So, you know, that they have um been thought to be involved in, you know, remodeling and and development. And so, in some conditions, you know, under if you look at the textbook in mouse studies and so on, they're involved in they're present in the mammary glands or in the uterus and um and in some other tissues under normal states. So uh we think that they probably do play a role at some point during tissue development, but you know, they can be present in in the um in the tissues.
Rebecca Saff, MD, PhD, FAAAAIAnd what are in eosinophilic granules that make them so cytotoxic?
Paneez Khoury, MD, MHSc, FAAAAISo there are uh some specific granules. So there's major basic protein, which is actually concentrated in uh the crystalline core of the granule. It's particularly cationic and can be directly toxic. And so this is why you know people think that that's one of the reasons why they fight parasites because they're directly toxic to parasites, but obviously that toxicity can affect our cells too. So if they're um dumping those MEP granules on epithelium, that's not a great thing. There is um also eosinophil peroxidase, which generates reactive oxidin species and contributes to this oxidative tissue injury. There's also eosinophil cationic protein, which is another one of the um cationic ribonucleases uh that has um cytotoxic activity, um, and then eosinophil-derived neurotoxin or EDN, which is another ribonuclease. So these granules can contain or associate with more, you know, a broader repertoire of enzymes, um, cytokines and chemokines and mediators in the eosinophil. But I guess it's it's worth mentioning that the eosinophils don't just you know dump all of these granules all at once. Um, you know, they don't just drop this bomb of granules. They can actually tightly regulate the release of some of these granules. Not clear exactly how they do that, but there are different ways that eosinophils degranulate, and so it's worth knowing that because there's probably some biology there in terms of which granules get released and why and when.
Rebecca Saff, MD, PhD, FAAAAIYeah. Sort of like now we know mast cells can both you know degranulate kind of as a total cell or kind of do this piecemeal degranulation where they release certain granules. Eosinophils sounds like similarly can do that. Yeah.
Paneez Khoury, MD, MHSc, FAAAAIYeah, it's a lot more sophisticated than it just exploding and putting out its granules everywhere. Yeah. Um granulation is actually part of um, you know, a mode of eosinophil um secretion. Uh, they selectively mobilize certain granule contents um through their secretary vesicles or tubulovesicle carriers and release those mediators in a regulated fashion, um, kind of like the mast cells you described.
Rebecca Saff, MD, PhD, FAAAAIYeah, so very targeted to what they need to uh do to fight disease at the time.
Paneez Khoury, MD, MHSc, FAAAAIYeah.
Rebecca Saff, MD, PhD, FAAAAISo in this patient who has lots of different symptoms and different organ systems that you're worried about, you know, maybe EGPA or you're worried about hypereosinophilic syndrome, a myelid disorder, what labs and diagnostics tests would you think about kind of moving forward with?
Paneez Khoury, MD, MHSc, FAAAAIYeah, so I mean, the first thing, you know, basic things, just making sure that it's true, you know, repeating the isinophil count, establishing the trajectory with a repeat CVC differential. And then I'm kind of simultaneously doing two things. You know, I'm looking for organ injury as well as potential etiology of the isinophilia. Uh so, you know, basic things, metabolic panel, liver renal function, looking at immunoglobulins. We typically test serum tryptase and vitamin B12 as a screen for the myeloid conditions, uh, often getting a urinalysis to make sure there's no blood or protein in the in the urine or any other um cell uh aspects. A troponin or high sensitivity troponin as well as an EKG are really primary things. I think uh astrongyloidis serologies, as you mentioned, is very important and other parasitic testing as you know as indicated. If I suspect autoimmune disease, because sometimes you can have autoimmune conditions that uh go along with hypersenophilia, I would check those serologies, um, definitely checking ANCOS, PR3, MPO if EGPA or another vasculitis is considered. Um, and then for this patient specifically, I would want chest imaging, probably a high-res CT, pulmonary function testing, and an echocardiogram, just to make sure that, you know, we're not missing uh cardiac involvement. Um, you know, oftentimes we'll also check on ESR and CRP, go along with this question of, you know, could there be EGPA? Uh one thing I will mention, and someone brought it up to me when I was giving a talk, is that, you know, how come you don't ever say that you should get a sinus CT? Um, it's not something I necessarily ordered every patient, but certainly if there are symptoms and I'm concerned about EGPA, it's as if you can add it on to getting the chest CT at the same time, it certainly can help in contexts where you're worried about EGPA. One other test that I drill into the fellows is that you can, you know, if you're waiting to get heme on board or it's gonna take a long time, you can certainly order peripheral smear. It's something that can be informative for determining next steps in addition to that B12 and tryptase. And especially in a man, um, because uh this PDGFRA associated disease or FIP1L1 PDGFRA fusions are strongly concentrated in male or male predominant disease. So I'd have a low threshold for doing molecular testing in the peripheral blood even before you know getting the bone marrow biopsy. And of course, you know, if you see abnormalities, so you get a peripheral smear, you see uh abnormalities there or there on their CBC, they have cetopenia, splenomagaly, other things that would make you concerned for a malignant or clonal myeloid process. We involve uh hematology pretty early. More and more NGS in the bone marrow is being incorporated as our understanding of clonal eosinophilic disorders expands. It it, you know, there's more and more mutations and variants being reported. So basically, I would say that you target the workup to what the patient's complaining about. But there are certain tests that you might want to do in everybody if they have a significant hypersenophilia. But certainly you're not gonna wait for every test to come back necessarily if the patient needs treatment. So if there's acute ongoing evidence of organ dysfunction or damage, you know, you're gonna start treating them.
Rebecca Saff, MD, PhD, FAAAAIAnd why is that mutation more common in males? Do we understand that?
Paneez Khoury, MD, MHSc, FAAAAINo, we don't. We've certainly looked and tried to figure it out, but we still don't have that answer.
Rebecca Saff, MD, PhD, FAAAAINo, it's interesting because you wouldn't necessarily think a rearrangement would necessarily be more common in uh just bisex. Yeah.
Paneez Khoury, MD, MHSc, FAAAAIThere has been work looking into why. I mean, Amy Cleon was working with some collaborators trying to figure that out, but uh, we don't have a good answer yet. Well, we await the answer. That'll be a fascinating thing to find out. Well, so as the technology's advanced, right? You get more technology, different types of assays and and ways to look at genetics. So certainly some of those questions may be answerable in the future. Yes.
Rebecca Saff, MD, PhD, FAAAAINo, even just what we know now versus you know 10 years ago. So just to give you some, you know, re back on your testings. You sent some testing. Um, the repeat ESNFO count is 5,800. So a little bit more elevated, but certainly not going down. Um, tryptase is mildly elevated at 12 and IgE is 800. Triponin is mildly elevated, but EKG is normal and similar. Luckily, he had had one um in the past, looks the same. He had a CT of his chest and abdomen, which demonstrated splenomegaly and patchy pulmonary infiltrates, had a stool OMP, which was negative, and had strongy testing sent, but it can take quite a while to come back. So maybe just treat him in just in case. Um, ENCA is negative, and he's ordered for echocardiogram, he's ordered for pulmonary function testing. These haven't been done yet. And so we have this elevated troponin, but in normal EKG. How worried are we? And how do ESINivals cause cardiac damage? Why cardiac damage?
Paneez Khoury, MD, MHSc, FAAAAIWell, that's the age-old question of why certain organs over others, and we don't have answers as to why there's a tissue tropism in different conditions. You know, it's a fascinating question. But we are concerned. So the patient's troponin is elevated, right? So when there are abnormalities on the echocardiogram and elevated troponin, you know, I would be pushing for more testing um up front. So, you know, this delayed echocardiogram, not acceptable. Personally, I have a low threshold for cardiac MRI because sometimes you can miss things. Um, I've been burned a few times where you know had a normal EKG and normal troponin that, you know, we use use those as screening tests. But if the index of suspicion is high, patients having symptoms that might suggest cardiac involvement, we do have a low threshold for cardiac MRI and cardiology involvement too, to guide that. You know, we worry about the heart the most because of, you know, if there's rapidly progressive or progressive involvement of eosinophils in the heart, you can get irreversible complications or thrombosis. I don't think the mechanism is really different or fundamentally different than when eosinophils cause injury in other tissues, except for the risk inherent in the target organ itself. So what eosinophils do is they infiltrate into the myocardium, they release their cytotoxic granules, proteins, they promote myocardial injury, sometimes necrosis, um, and essentially you get eosinophilic myocarditis. Um, when you have damage of the endocardial surface, that can become thrombogenic, which then results in this mural thrombi that can be present in the apices. Um, it can be both apices or left. And when you know, when you have that, then sometimes that's part of the reason why uh patients with HES historically had um you know embolic strokes. So then what happens is you get remodeling, healing, if you get rid of that eosinophilia, um, sometimes that then develops into endomyocardial fibrosis. If the valves were involved just a little bit, you can get some valvular dysfunction. If they were involved a lot, sometimes those valves actually get affixed to the heart. Um, you know, particularly the posterior leaflet of the mitral valve and might require replacement. Um, you know, you can get restrictive physiology, um, cardiomyopathy. So, you know, the complications are pretty significant. Um, in some conditions, you get you can get eosinphyllic pericarditis. So, for example, EGPA, that's more of a classic presentation, you get um you know, fluid and pericardial uh effusions. And in those cases, you can also have vascular injury. So the other way that the heart can be involved is you actually get coronary vasculitis. Um, so it's not one single cardiac pathology. It depends on what part of the heart is is affected. Um, so in this patient, a troponin elevation is not something I would brush aside or call demand elevation with an acental count of 5,800 pulmonary infiltrates, as you mentioned, spinomegaly. Um, these are potentially you know warning signs of active target organ involvement and until proven of otherwise you can't really just ignore those things.
Rebecca Saff, MD, PhD, FAAAAIYeah, and it sounds like a cardiac MRI kind of moving to that more quickly in someone like this with an elevated troponin and kind of other worrisome symptoms, would provide more sensitivity even than an echocardiogram?
Paneez Khoury, MD, MHSc, FAAAAIIs that yeah, I mean, I don't think we work out sensitivity. I think it's it, you know, if you have a high suspicion and there's some abnormalities, but not classical eosinophilic involvement of the echo, then you know, we tend to go to cardia MRI. But I would probably just in this patient push to get an echo faster.
Rebecca Saff, MD, PhD, FAAAAIAnd maybe involve cardiology quickly if there's any concern.
Paneez Khoury, MD, MHSc, FAAAAIAbsolutely, yeah.
Rebecca Saff, MD, PhD, FAAAAIYeah. And so it seems like we're maybe pushing more towards a primary or clonal eosinophilic disorder. What kind of makes you kind of think more about that versus kind of other causes?
Paneez Khoury, MD, MHSc, FAAAAIYeah, I mean, you're really looking at things in parallel. There's parts of the case that might suggest more of a hypersenophilic syndrome or EGPA type presentation, and there's Parts of the case, like the you know, question for anemia, fatigue, um, the um heart involvement can I mean it can be both, right? You can have heart involvement both in idiopathic HES or in a uh clonomyeloid uh condition. But the things that would make you concerned are the splenomegaly, any other abnormalities on the blood counts that would push you in that direction. So, you know, I think we also have low threshold to get hematology involved and get a bone marrow biopsy.
Rebecca Saff, MD, PhD, FAAAAIAnd then tell us about myeloid versus lymphoid variants of HES and kind of what you'd be thinking about and looking at.
Paneez Khoury, MD, MHSc, FAAAAIYeah, so this is gets a little bit confusing because of the terminology. The group that the World Health Organization calls myeloid lymphoid neoplasms with eosinophilia and tyrosin kinase gene infusions or uh MLN-TK. It's very long. They need a better acronym to pronounce or what we've classically called myelid HES, right? It's a little bit easier, but they don't, I mean, I think that the terminology essentially has changed because there are particular tyrosine kinase gene fusions that are important to know about because the treatment is targeted, and so you know, this is not so not all clonal HES is or what we used to call lymphocytic variant or still call lymphocytic variant HES is not an MLNTK, right? So these are more genetically defined categories. Those, I think, are what the the terminology about primary, that's kind of what we're talking about. There's more of a hematopoietic problem in us in particular cells, in fact, including the eosinophil, that are a primary problem that's cell intrinsic in the eosinophil, as opposed to what some people call secondary, which essentially means that it's a reactive cause. Um, and so again, terminology is confusing because you might call lymphocytic variant HES reactive eosinophils also. Um, we sometimes use the term associated because you know it's a condition that results in associated eosinophilia. So, for example, parasitic diseases causes an associated eosinophilia. It's it's a little bit controversial and confusing, this terminology, because different groups define them differently, and you put, you know, five different eosinophil experts in a room, they'll have different ways of describing these. Um, but I think more broadly, you know, this concept of is it primary, meaning is there something that's cell intrinsic in the acinophil is important? Um, and then there's everything else, which can include reactive forms as well as clonal T cell lymphocytes that are driving the asinophilia. Sorry if that's confusing, but it it is a little bit confusing even for people who actually treat these patients.
Rebecca Saff, MD, PhD, FAAAAINo, fair enough. And it is hard, you know, that we I like the term associated versus necessarily secondary. Um, that makes a lot of sense.
Paneez Khoury, MD, MHSc, FAAAAIYeah. So it's really not a role of, you know, if this then do a bow marrow biopsy, right? So you're kind of following crumbs along a path, right? If the clinical laboratory and um morphologic clues lead you, uh, you know, the crumbs are splinter in a certain direction. So you told me about splenomegaly and potential cardiac involvement, you're gonna follow that path aggressively to exclude uh, you know, a clonal disorder. And you have tests cooking, hopefully, to figure that out. You know, you have B12 and tryptase that can come back sooner than perhaps you're gonna get hematology involved. But depending on where the patient is, if they're inpatient, it shouldn't be that hard to get the right um specialists in the room.
Rebecca Saff, MD, PhD, FAAAAIYeah. And following up the these labs at the kind of in parallel tracks, as you said. And so in someone like this, probably getting hematology involved with his tryptase mildly elevated, you know, and then with this conserved for splenomegly and cardiac involvement.
Paneez Khoury, MD, MHSc, FAAAAIExactly.
Rebecca Saff, MD, PhD, FAAAAIYeah. So in this patient, he went for bone marrow biopsy, it was done and had a bunch of molecular um testing sent and flow cytometry. How do the bone marrow findings, the molecular testing, the cytogenics, and the flow cytometry, what do we, what do we now, what do we have available? What are we looking for? And how do they tell us about the different HES phenotypes versus a more of a clonality?
Paneez Khoury, MD, MHSc, FAAAAIYeah. So, you know, what we uh traditionally called myeloid HES, really we're talking about the uh classical fusions or or variants that are associated with uh hypersynaphilic syndrome and um certain presentations. So that would be PDGFRA, PDGFRB, FGFR1, um, and JAC2. The problem is that this list is expanding. And so this is where I mentioned that you know more and more people are doing next gen sequencing in the bone marrow to look for other variants. The other thing that is often done both in the blood and uh in the marrow when it's performed is phloo cytometry. And there we're looking for um classical aberrant T cell phenotypes that define what is called lymphocytic variant HES. And so the the most common of which is C D3 dim or C D3 negative, C D4 positive T cells. These are actual T cells. The CD3 is not on the surface, but when you stain intercellularly, they're there. And these abnormal aberrant populations can range in terms of quantity. They could be, you know, a couple percent in the blood, up to 50, 60 percent in the blood. And then you're you know really thinking hard about whether this patient might have some other malignancy like a lymphoma. Now, though the reason why lymphocytic variant HES was called this is because when you look inside those cells by uh flow cytometry, by intracellular staining, you can see elevation in those type 2 cytokines. So you see elevated IL5, um, IL-13, and things like that. And so the thought process is that these T cell clones are releasing uh these cytokines, which then promotes a reactive eosinophilia. So that's really the major distinction, you know, thinking about patients with um myeloid disease, you know, the proliferative abnormality is really in the hematopoietic or myeloid compartment. Um, whereas in lymphocytic variant HES, this abnormal T cell population is upstream and drives this otherwise um reactive eosinophil expansion to cytokines.
Rebecca Saff, MD, PhD, FAAAAIAnd now it sounds like we have a lot of more targeted therapies. So if they do have a rearrangement in one of these genes, there's multiple medications we have available that can really be targeted exactly to their mutation.
Paneez Khoury, MD, MHSc, FAAAAI100%. So before we had a MATNIB, these patients had poor outcomes. They mortality at 30% in three years. Now, uh, if it's detected early before development of organ damage, we have patients who have been treated for five years with a MATNIB and are now coming off and, you know, off therapy and remaining in molecular remission. So certainly uh it's completely changed the paradigm for this population where they had the worst outcomes for hypersinophilic syndrome. And now some of these patients actually perhaps have the best outcomes and uh potential for a cure. So uh it's really important to detect this early and have a high index of suspicion. The patients don't always present with cardiac involvement and these really dramatic features. We've had patients who uh presented with what seemed like Aegid. They had ECNophylluc GI involvement, and this was actually uh published by Dr. Constantine, and the patient was not responding to typical Aegid therapies and was ended up having uh PDGFRA disease. I think, I think he might have been one of those patients where a fish test was negative because fish is not so sensitive. So when you do the PCR, in some cases you detect the clone. More and more, you know, people are doing things like uh more genetic sequencing, you know, finding this in in other ways than just fish testing. Um, so if you find that, it completely changes how you would treat a patient. And so, you know, that patient got treated with a mad nib and is completely fine on all counts, you know, terms of the disease process, risk for future progression, and also the GI symptoms completely um got better. So important to think about it, um, especially as in men, low index of suspicion for testing if things are not making sense. And and I think that lack of, you know, the treatment refractoriness uh of these patients is is notable. So patients don't always respond to a prednisone or other treatments as you would expect. And so having a patient whose treatment refractory should raise alarm bells for considering a molecular diagnosis.
Rebecca Saff, MD, PhD, FAAAAISo if this patient has a bone marrow biopsy and really there's no, you know, there's nothing really that's detected that's abnormal, is this someone you would put on more of an IL-5 inhibitor and follow them forward? Would you just monitor them? You know, what what would be your next steps, assuming you didn't find something to target exactly?
Paneez Khoury, MD, MHSc, FAAAAIYeah, so like you you said his uh tryptase was a little bit elevated, but you know, maybe just barely the B12 was fine, the patient got a bone marrow, there's no abnormal cell populations in the bone marrow, so um no atypia or dysplastic ESNFILs, no mast cell increase. Those are things that you know would make you think of more of a myeloid condition. Um, if there is nothing, cytogenetics are are fine, the molecular testing is all negative, including you know PCR, not just fish, then really your next step is treatment. And I think picking amongst one of the um anti-L5 receptor or L5 blocking monoclonals is probably important. But first, you know, it's hard to get those immediately, right? So they're not really studied in the acute setting. First things you would be doing is putting this patient on prednisone and following the ACFL counts, you know, to normalization and making sure that you know the patient is doing better from an organ standpoint. So you'd follow that troponin, make sure it's coming down, and you know, completing any other workup that wasn't done. As we mentioned, we probably would be putting that patient on treatment for strongyloides empirically, um, as the serology will take some time before we start the prednisone. Um, but that's really the next step is getting that ESMF account down, especially if you think that the troponin is a result of cardiac involvement.
Rebecca Saff, MD, PhD, FAAAAIYeah. And have you had patients that have like this that have stayed on IL-5 treatment and done well? Yeah. Do you worry about them evolving into something?
Paneez Khoury, MD, MHSc, FAAAAINo, absolutely. I mean, we've had patients present exactly like this and do really, really well. You know, we follow patients. I think it's a it's not a one-and-done situation. You know, you're gonna see the patients back, you're gonna check um their eosinophil accounts, you know, at least quarterly, for example, to start. You do a lot of anti-anticipatory counseling about what to watch for if they have redevelopment of some of those symptoms that they had, if they develop lymph nodes or something like that, that they should contact you. And you probably are repeating some of the organ-specific testing um at least once, you know, after you've um seen them just to look at resolution or progression, perhaps. Uh, so you know, we see patients at least annually. Um, sometimes if it's an evolving situation, they're not fully controlled, you see them more frequently until you get them under control. But you know, you're gonna follow a patient like this over time and make sure that nothing else happens.
Rebecca Saff, MD, PhD, FAAAAISo, what just to finish up, what is the the biggest unanswered question in e-incident file biology that you think should be studied?
Paneez Khoury, MD, MHSc, FAAAAIOh well. There are quite a few. Uh, I think, you know, one you mentioned is why they go to certain tissues, right? So we don't have the answer for that. Um, the other thing that's kind of a hot topic right now, one of the biggest basic science questions, is are there differences in eosinophils and heterogeneity of eosinophil subsets? Some mouse work shows uh striking tissue-dependent specialization, including this idea of long-lived intestinal eosinophil populations. And uh, you know, we have things like single-cell RNA sequencing, which suggests that there may be plasticity rather than this clean canonical subsets of eosinophils. And so I think the human system is still evolving in terms of understanding whether there are things like resident eosinophils or homeostatic eosinophils versus inflammatory eosinophils and you know, whether these are really stable lineages or different maturation states. So I don't think we know yet, but that's really a hot topic and something that's always being presented at our eosinophil meetings. And you know, you you mentioned the tissue tropism. That's one of my favorite questions, is you know, why does one patient get heart involvement, another person get liver involvement, another person get neuropathy? Are there tissue-specific factors that drive that? And and why, you know, when you have hypersonophilic syndrome, why is some area, you know, more damaged than another? Are there are these related to you know adhesion molecules or things that are tissue specific, which also gets us to biomarkers? And I think that's another really emerging area. The eosinophil count is kind of the tip of the iceberg, right? Like it doesn't tell us whether these eosinophils are activated, you know, whether they're gonna cause havoc, or if they're just simply elevated without any apparent problems. Like there's this um condition called hypersinophilia of undetermined significance, where patients can have high eosinophil accounts in the 5000, 300 to 5,000 range over decades with no symptoms, no symptoms, no organ involvement, and so on. So, you know, how do we find those patients? You know, we've kind of they they kind of came to attention. Sometimes they'd had lots of counts before they got to us, and we've managed to follow them without treatment because they were completely fine. So those are rare, but you know, how come those patients, eosinophils are, you know, why are they not causing problems in the blood? So there's a lot of unanswered questions, and I probably could go on and on, but we probably don't have time to talk about more eosinophils on your podcast. I think I could I could mention a lot of different uh areas of research that are needed.
Rebecca Saff, MD, PhD, FAAAAIUm and the more we learn, the more we learn that we have to to learn. And so it's not you know more about eosinophils, but now we have all these different subtypes of eosinophils possibly that then we need to figure out how they work. And so the science marches on.
Paneez Khoury, MD, MHSc, FAAAAIRight.
Rebecca Saff, MD, PhD, FAAAAIGreat. Well, thank you so much. I think this was fantastic. And we all get these patients with elevated eosinophil counts and how to think through them methodically and make sure we're not missing anything and get them to the right people to treat them. So that's perfect.
Paneez Khoury, MD, MHSc, FAAAAISo much. Thanks for having me. I always enjoy the opportunity to talk about the eosinophils. I'm probably getting asked to talk more about artificial intelligence these days, but there's still a lot to learn about eosinophils. Um, you know, hopefully I gave your listeners a useful framework for approaching eosinophilia and more importantly, recognizing when the count is something that needs urgent attention and specifically in patients that, you know, finding a cause or molecular cause can have a huge impact and potentially be life-saving. So thanks for giving me the platform to talk about that.
Rebecca Saff, MD, PhD, FAAAAIWe hope you enjoyed listening to today's episode. Please visit aaaai.org for show notes and any pertinent links from today's conversation. If you like the show, please take a moment to rate and subscribe through wherever you download your podcasts. As a reminder, this podcast is not intended to provide any individual medical advice to our listeners. We do hope that our conversations provide evidence-based information. Any questions pertaining to one's own health should always be discussed with their personal physician. The Find an Allergist search engine on the Academy website is a useful tool to locate a listing of board certified allergies in your use of this audio program is subject to the American Academy of Allergy, Asthma & Immunology Terms of Use Group, which you can find at aaaai.org. Thank you again for listening.