Transcription
Hi everyone, welcome. We'll get started in just a minute. People are still filing into the webinar room. Thank you for joining us. We'll start in just a minute.
All righty, well, why don't we get started? Hello everyone, thank you for joining us here today. I'm Linda Mitchell, CEO of Allergy and Asthma Network. Welcome to this afternoon's webinar. We're in for a real interesting session today on type two inflammation with Dr. Warner Carr.
We have a few housekeeping items to go over before we start. First, all participants will be on mute for this webinar, and we will be recording it. We will post it on our website within a few days. You can always find all of our recorded webinars at allergyasma.network.org. If you scroll down to the bottom of the homepage, you'll find the webinars and the recordings that we've recently had. This webinar will be 1 hour in length and does include time for questions. We will take those questions after Dr. Carr is finished his presentation. Um, we will be monitoring the chat and the Q&A, so if you have any questions during the session, please enter them in the Q&A, and then we will um go over them with Dr. Carr after he's done speaking. We will not be offering continuing education credits for this webinar, but we do have a certificate of attendance if you need one for your records. And, at a few days after the webinar, you'll receive an email from us with a list of resources related to type two inflammation, along with a link to download or re or view the recorded session. Um, and we also try to uh link to the certificate of attendance in the chat; sometimes it works with Zoom, and sometimes it doesn't. So let's get started.
Um, today's topic is the role of type two inflammation in asthma, allergy, and immunological diseases. Type 2 inflammation is a systemic allergic response, um, that is known to play a role in moderate to severe asthma, atopic dermatitis, and nasal allergies and other conditions. In this webinar, we will learn what type two inflammation is, how it affects certain conditions, and how it's treated.
It's my pleasure to introduce our speaker, Dr. Warner Carr. Dr. Carr is board certified in allergy and clinical immunology, as well as internal medicine. He is a busy clinical practice at Allergy and Asthma Associates of Southern California and has been the principal investigator for numerous clinical trials. He has served on several boards, including the American College of Allergy, Asthma and Immunology, the college, a national organization of over 6,000 allergists. He has served 17 years in the United States Army. Thank you for your service, and has served as a medical officer at the Food and Drug Administration. Dr. Carr has authored several scientific articles and a book on lung function testing. Dr. Carr has also been invited to present scientific lectures around the world.
I want to give a special thanks to Sanofi Regeneron, who's who has provided the funding support to make this webinar possible today. So thank you for being here, Dr. Carr. I'll hand it over to you.
Uh, Linda, thank you so much. It really is my pleasure to be able to present today. And while you were speaking, I I brought up the mission statement of uh The Allergy and Asthma Network, and I think it's important we just touch on that for one second. You know, this organization and the tireless work uh that you all have done to advocate for our patients, I think is is very important. I just want to make sure that we recognize that today. I'm going to give a talk um on uh type two inflammation, and I I gave this talk uh at the college meeting, um, and for those of you that uh were not able to make it, hopefully I can uh share some very valuable information with you here. And for those of you that were there, this would be a good refresher. I do want to also uh extend um uh thanks and gratitude to Sanofi and Regeneron for uh sponsoring today and with the preparation of these slides, um, and uh their tireless, their tireless uh endeavor in helping advance learning about these disease states. So these are my learning objectives today. First off, number one, we're going to review the the roles of just the epithelium itself and how it can serve not only as a barrier, but also that it's biologically active, and and it's important to consider it as more than just a barrier. We're going to talk a little bit about eosinophilic inflammation, allergic inflammation, how the immune and neurological system, this neuroimmune disregulation uh plays in amplifying and perpetuating diseases like eczema with itching and so forth. Second thing, we're going to discuss the contribution of type two inflammation to specific diseases like asthma and chronic rhinosinusitis with nasal polyposis and NSAID, or historically we call it aspirin-exacerbated respiratory disease, atopic dermatitis, EOE, even COPD with a type 2 inflammatory signature. And then finally, we're going to discuss the frequency of how these things coexist, just by the nature of the disease. These are these are systemic issues; type two inflammation, uh, and we treat patients that have more than one of these simultaneously, and it's important when we think about this. So type two inflammation may involve an interplay between a variety of different things: between triggers, the epithelium, both innate immune system uh components and adaptive immune components. And you see in this diagram here, you know, historically people used to say is it nature or is it nurture? And the answer is yes, it's both. There are critical environmental factors, and then there are genetic factors, and then how your genes interact with your environmental uh factors, that so-called epigenetics. These are the key components that play into the development of type two inflammation and then drives it. So type two inflammation, you have this classic allergic inflammation with with B cells uh making IgE, loading on the mast cells and having the typical mast cell degranulation and all of those chemical mediators. You see this epithelial or epidermal, this quote-unquote barrier dysfunction, whether it's in the nose, whether it's in the lungs, whether it's on the skin, um, and this this can lead to irreversible tissue damage or remodeling. We like to use with with fibronectin deposition or effectively scar tissue formation as part of this. And separate and distinct, one of the key white blood cells that's involved in type two inflammation is the eosinophil and how the eosinophil will get activated and and produced in the bone marrow and then go to the target tissue and become active and live longer and survive there under influences from type two inflammation. And then there is this neuroimmune dysfunction, and itching is a great example; paroxysmal itching is a great example. This is a non-histaminergic; it's not exhaustive, but these are some key components of type two inflammation.
Unfortunately, a little bit of this slide got cut off a little bit, but the point of this is that type two inflammation, it really is systemic, and it can drive multiple things simultaneously. And in other words, many of these diseases coexist within a patient. You can have a patient that has asthma, atopic dermatitis, allergic rhinitis, even nasal polyposis; all of this so could be one or many of them. And what this is showing is it's it's kind of a grid of how frequently these coexist together in these different disease states, but the key factor here is type two inflammation. And I and I I hope by the end of this presentation everybody understands the systemic component of this as well as the local component of this, and I'll show you that later on on what I mean. But you see the primary diagnosis and how frequently it coexists with secondary diagnosis, all driven by type two inflammation.
Long-term effects of type two inflammation not only affects affects immune cells but structural cells as well, and these structural cells really contribute to this tissue remodeling and and there's kind of just a general cartoon here. And if you're looking at tissue remodeling, you you see it in in asthma patients by a reduction in lung function; you see it with in the sinuses and in the nasal passageway with polyposis, polyp formation; you see it in the skin of patients, this thickening, lyinification, itch, dryness and atopic dermatitis; and then in the esophagus of patients that have eosinophilic um esophagitis, you see these structural changes. So it's not just immune cells, uh it's structural cells as well. And you can see how it's complex in this cartoon. You get loss of this epithelial uh morphology; this barrier is disrupted. In the skin in particular, there are these tight junctions that hold the skin cells together, and one of the key proteins in there is called filaggrin. We know that filaggrin deficiency and other genetic mutations kind of increases the permeability; you lose that tight junction that can play into this, letting allergens, microbes, other irritants, even dryness take in, and then you get this synthesis of these ECM proteins, which ultimately leads uh to this tissue remodeling. And when this happens at the level of the epithelium, what happens is it sends a signal downstream to everything that's underneath that epithelium that there's a problem. We call these alarmins, and there's three alarmins here: IL-33, IL-25, and TSLP. TSLP is thymic stromal lymphopoietin. So these, this epithelial barrier gets disrupted, and it sends an alarm downstream, and then that's what drives and triggers that type two inflammation, and that can actually go back up onto the epithelium and cause progressive inflammation, kind of this cycle.
Uh, so some of the key cytokines, I'm going to go over these cytokines uh throughout the the course of the the presentation today. I just mentioned a couple of them, IL-33 and and IL-25. These are some of the alarmins. What I'm going to do now is downstream, after activation of of those alarmins and you get generation of this type two inflammation, there are some signature cytokines like interleukin 4 and interleukin 13 that are part of this cascade. And what we know is when these levels go high, when interleukin 4 and interleukin 13 goes high, you get a decrease in the integrity of those junctions between cells, and with this you see uh more permeability. And you know, we look at this a clinical application of this would be in little babies that have eczema, and we think that in certain cases kids can get food allergy through their eczema skin, and it's because of this type two inflammation that's going on and it creates um an avenue for those allergens to get into the cell. So on the left side we're looking at the lower airway of a biopsy, and you can see where interleukin 4 has disrupted this bronchial epithelial uh junctions and and structures. Uh, when they do this in test tubes, you can see the control on the top is intact, and then down on the bottom where you see the effects of interleukin 4, you've kind of lost that. And the surrogate would be things like uh house dust mite; you know, we can inhale those things, and then it's easier to to to get into the respiratory epithelium, activate those alarmins, and cause that downstream inflammation, and then it just keeps going on. If you look up in the uh upper airway, you'll see the effects of uh both interleukin 4 as well as interleukin uh 13, where you're getting this disruption of the airway as well, and then again it feeds back and and it starts this whole cycle. Interleukin 13, especially when it feeds back on the respiratory epithelium, it can cause fibrosis or or thickening. The other thing it does is drives inflammation there through the induction of nitric oxide synthetase, and there's a test that we do called the exhaled nitric oxide, and that goes up because of the effects of interleukin 13. So again, damage to to the epithelium, alarmins, type two inflammation, and then it feeds back and you see this on the left, the effects of IL-13 on human fibroblasts. Down at the bottom left you'll see uh down here a lot more deposition; this pink stuff is is effectively scar tissue; it's fibroblast activity, and they will lay down and this will in in the airway it cause thickening of the basement membrane. On the right side of this screen you see the same process going on uh in the esophagus, um, and this is actually uh in an animal model, a mouse model that has eosinophilic esophagitis, um, but essentially the same process would go on in humans here as well under the influence of interleukin 13.
One of the key cytokines in this type two inflammation, tissue remodeling is also very, very important in atopic dermatitis or or or eczema. I really want what I want you to look at is the right side of this slide, and you'll see it says an H&E stained human skin. You'll see at the very top, nonatopic normal skin; that means somebody who does not have eczema, okay? This is from a person who does not have eczema, um, and uh you see normal characteristics there. When you go to the second, the middle image here where it says non-lesional atopic skin, this isn't a patient that has eczema, but where they did the biopsy there's no rash. And then at the bottom you see lesional eczema skin or atopic skin; that's a biopsy of the rash in an eczema patient. And what I want you to notice is even in non-rashed up skin, non-lesional atopic skin, you'll see disruption of the epithelium and all this all this tissue remodeling that's occurring downstream. So those alarmins causing that downstream inflammation. So it's very important that we understand that, very important that we understand that, um, and if you look at the left side of this panel, you'll see what's driving it, right? You're going to see the classic lesions, interleukin 4, interleukin 13; I've already discussed those. You'll see interleukin 5, and then you'll see interleukin 31. Interleukin 31 is a key one that drives itching of the skin, okay.
Type two inflammation and asthma. I think we should break it down here a little bit and talk specifically about some of the disease states and how it applies specifically to each one of these type two-driven diseases. We'll start with asthma. So the type two high profile includes allergic as well as eosinophilic, and I and I want to make sure you understand those are two different phenotypes; one is allergic, one is eosinophilic. You can be eosinophilic with no allergy; you can be allergic with no eosinophils; but you can also have both; you can be allergic and eosinophilic. When you look at the immune pathways that occurs here, um, you you see high expression of these key type two cytokines: IL-4, IL-5, IL-13. You see eosinophilia; you see tissue remodeling. Patients that are more allergic tend to have an earlier onset; these are the patients that have childhood asthma. It's more allergen-specific; we go to Grandma's house and we get an asthma attack, or or you know the pollen count is high, we get an asthma attack, and they can have a lot more comorbidities with things like eczema and allergic rhinitis. Allergic rhinitis makes sense, right? It's affecting the respiratory, upper respiratory, and where asthma is affecting the lower. If you go over to the eosinophilic phenotype, um, this is more so in adulthood; it's usually non-specific with regards to the IgE; could be high, low, or indifferent, um, and you see a little bit more of the chronic rhinosinusitis with nasal polyps, and those that are purely driven by eosinophilic. But realize the allergic and eosinophil can also coexist together in the same patient. Interleukin 4 and interleukin 13 really drive that IgE production. IL-5, by the way, to some degree is eosinophil infiltration. IL-5 is a key cytokine that is what is causing differentiation in the bone marrow and driving that eosinophil out of the bone marrow out into the periphery. Ultimately, when it hits the target tissue, in this case the lungs, it promotes its survival. So when you look at allergic inflammation on here, this is the classic um B cell creating specific IgEs, loading off mostly onto mast cells, but don't forget the contribution that basophils have in amplifying and perpetuating these immune responses. When you get exposure to what you're allergic to, then it activates that mast cell, basophil, and it releases all those chemicals that causes the symptoms downstream. With eosinophilic infiltration again, uh IL-4 and IL-13 play a role; that this is primarily driven by IL-5 when we're talking about the differentiation of the eosinophil and the survival of that eosinophil once it gets into the target tissue, um, but eosinophils amplify and kind of perpetuate these responses that are being provided by IL-4 being made locally. So you can see how these are two separate things that interact, and you can be allergic, you could be eosinophilic, or both can happen in the same patient.
Type two inflammation is really reflected and defined by different types of biomarkers, um, so on the left, on the left is what is called the fractional exhalation or fraction of exhalation of nitric oxide; it's a biomarker of inflammation in the airway, and you see that people that are allergic tend to have more more of the phenotype. Blood eosinophils is another biomarker, and then finally serum IgE is another biomarker. These things right here, these three things plus um an the asthma control test plus a spirometry and FEV1, that's what I like to call the asthma vital signs, and I get these in every one of my patients, and it helps me to phenotype my patient and ultimately helps me to direct my therapy in in in my patient. So these are some kind of key common markers, biomarkers of, if you will, of type two inflammation.
When you look at the GINA guidelines, there's really a couple of guidelines that we use; there's the NA guidelines, these are the American-driven guidelines, and then there's the GINA guidelines, which is the Global Initiative for Asthma, um, I'm focusing today more so on the GINA guidelines, but when you look at the GINA guidelines and type two inflammation, we should be thinking about this very, very much every patient. So type two inflammation should be considered if any of the following are found while a patient is taking a high-dose ICS or a daily um or or I should say even recurrent doses; a blood eosinophil of greater than 150; if you do an induced sputum and you have eosinophils greater than 2%; if you have an exhaled nitric oxide of 20 or greater; uh or asthma that really clinically is driven by allergies. And this is a very important and patients requiring maintenance or really frequent oral corticosteroids also may have underlying type two inflammation, okay, especially if they respond to the steroid. Lots of cumulative exposure of steroids; we know that there are problems with it; you can get significant adverse effects. I just, you know, I saw patients all morning here in my clinic and multiple times I tried to talk to them about how the fact we can use therapies to decrease exacerbations, and by decreasing the exacerbations we are decreasing the need for these steroids. Patients will ask me, Dr. Carr, I'm afraid to take my asthma inhaler because that's a steroid, and I'll point out to them, you know, you've been to urgent care, you've been to your primary care twice, you got three rounds of oral steroids; that is a big dose; it's a big, big footprint of steroid. By taking an inhaler, it's a much smaller dose. So by using the inhaler, you can have much less exposure to steroids. We know cumulatively over over a lifetime you're seeing increased risk of osteoporosis, fractures, pneumonias, type 2 diabetes, other metabolic disturbances as well as cardiovascular and cerebrovascular disease, um, even with these bursts that we see cumulatively. So it doesn't just have to be the patient that takes a low dose daily; it could be a patient who's had a couple of doses per year for several years. It's important; we need to be better with our steroid stewardship. Uh, type two inflammation can really contribute and then self-perpetuate the cycle of exacerbation, impaired lung function, exacerbation, more inflammation, and this is exemplified, I think, in this diagram on the left where we're talking about recurrent needed uh oral corticosteroids or systemic corticosteroids and hospital care and then ongoing inflammation and remodeling. We really need to attack the source of the inflammation. If you look at on the right side, if you look at changes in your FEV1, your airflow and your air capacity and you look at patients that um have uh their FEV1 correlated with the rate of a severe exacerbation, in the light blue, this kind of almost turquoise uh color down here at the bottom, the triangles, you'll see how they have an accelerated loss; the more exacerbations they're having, the more remodeling they're having, the more impairment that they have in their lung function. And so it's important for us to identify this inflammation and then ultimately to target this inflammation. Why am I saying that? Because we know that if you can improve the lung function, function, it decreases the exacerbations; it decreases the need for steroids; we can have better steroid stewardship, but it also correlates with improved health-related quality of life. I don't think I've ever had a patient come in and say, hey, Dr. Carr, can you increase my FEV1, you know? They come in and they say, hey, can you make me feel better? I feel bad; I feel sick. I don't know how many times the patient comes in and says, I feel sick, and I have to stop them and I say
Can you explain that to me? What do you mean by sick? Like, how are you feeling? Anyhow, if you look at this on the left, you can see that changes in F1 as F1 goes up, you see improvements in their overall quality of life, and so it's very important that we don't forget this. This is critical in all of our patients, and there's a correlation.
On the right, you look at this Venn diagram; there's a correlation between lung function, symptoms, and these healthcare-related quality of life issues, and they all overlap. It's important that we address each one of them. All right, now let's talk a little bit about the upper airway. There's this United Airway hypothesis, and I 100% subscribe to it. How many times have you guys out there been sick? Something happens in the nose and sinuses, in the upper airway, and then it settles into the chest, in the lower airway. We know that there's a correlation between the upper and the lower airway; there's interactions that occur. So when you look, there's pathological and epidemiological evidence that supports this United Airway. We can look at sputum counts; we can look at bronchial inflammatory responses with allergic rhinitis and asthma, and it kind of makes sense.
When you look epidemiologically, we see this coexistence of all of these type two driven diseases, uh, with chronic rhinosinusitis, either with or without naso polyposis, um, asthma, and then NSAID-exacerbated uh respiratory disease. And I know that in this diagram, they have the chronic rhinosinusitis without polyps kind of as an outsider, but I I think there should be a tiny overlap because there are some patients that have comorbid type two diseases, even though that's not what perhaps would be driving their CRS. All right, so when you look at patients that get their care primarily from ENT to start with, right, you'll see a need for repeated surgery in these chronic rhinosinusitis patients, um, especially with nasal polyposis. And when that happens, you're going to start seeing an increase in coexisting type 2 diseases, so you see, um, chronic rhinosinusitis with or without asthma, and how that correlates to needing more surgery. You see that, um, also in those patients that have chronic rhinosinusitis with NSAID-exacerbated respiratory disease. I kind of almost look at that as a separate syndrome, especially when they have asthma. This kind of like three little things where they have asthma, and and they have chronic uh rhinosinusitis with nasal polyposis, and a lot of these people can have aspirin or NSAID allergy. In the old days, we called that Samter's Triad. Um, anyhow, so in those patients, they have a higher coexistence of type two disease with these patients that have uh chronic sinus disease, chronic rhinosinusitis in particular with nasal polyposis. You see all these other comorbidity comorbidities, and when you see this, they're more likely to end up having more oral corticosteroid use. So it's the same story I just gave you for asthma; you see it with chronic sinus disease.
I don't know how many times I've had these patients come in, and they told me they've gone to the Urgent Care and they got oral steroids there; they went to the ENT, they got oral steroids there, and they've they've had multiple courses of oral steroids. And we have to think again with these patients in upper airways disease about the risk of long-term oral corticosteroid use or even systemic corticosteroid use. There is a a special thing that we need to consider in these patients with nasal polyps, okay, and that is these aggregates of the eosinophils. Remember, remember what I talked about the eosinophils um being one of the key factors for these type two inflammatory syndromes? Nasal polyps are almost little bags of of eosinophil aggregates, and you see that these are associated with recurrent um chronic rhinosinusitis with nasal polyps, and these eosinophils are exquisitely sensitive to prednisone. And so what ends up happening is these patients start seeking, and and the doctors notice the patient gets better, but it's short-term when they give them multiple courses of these oral steroids. And it ultimately, this type of patient is the one that ends up having to have more surgery.
In the big scheme of things, in the big scheme of things, when you look at patients that have chronic rhinosinusitis with nasal polyposis, if all you do is this cycle of prednisone and surgery, you see about an 85% recurrence rate, 85% recurrence rate within a 5-year time interval in these patients. So we need to be better at controlling the type two inflammation versus constantly dealing with the consequences of the type two inflammation, and and and and that's kind of the key thing for us to to think about. You know, when you look at these key cytokines, and I'm going to focus on this slide on interleukin 4 and interleukin 13, these two cytokines, they are driving, driving, and driving this type two inflammation. You start seeing thickening, thickening of the nasal um uh epithelium, and then at some point, a section of it kind of just plops up, and now you have that polyp. You see matrix activity; you see crosslinking of this fiber; we call it a matrix; you get almost a biofilm with this fibrin matrix being uh uh um generated, and you get this chronic non-immune cell-mediated inflammatory changes to the nasal epithelium, all driven by those type two um uh cytokines. And when you're looking at the fibrin degradation, fibrin is what helps it, you know, prevents it. When that is degraded, then it's you have less protection, and so you see that that is that is being degraded, and it's giving you less protection in these patients that have a chronic rhinosinusitis with nasal polyps, and the higher the IL-4 and IL-13, the more that you see that. So back in your mind's eye, you can see it: the epithelium, alarmin, type two inflammation, IL-4, IL-13 feeding back onto the epithelium, inflammation, polyp, um, and then it just is self-perpetuating, and then that that then they do surgery on that, and it starts all over. So we need to be better at targeting the type two inflammation. Let's move on now to another syndrome.
In the old days, we called this aspirin-exacerbated respiratory disease, but we know it can be with more than just aspirin, so now we call it NSAID-exacerbated respiratory disease, and it really is characterized by a burden, if you will, and I use that with a capital B, a burden of nasal polyposis and comorbid asthma, and it is a a it is almost a subset disease. When you look at the prevalence of hypersensitivity to selective COX-1 inhibitors, um, and these are in patients that you cannot give an NSAID to that is non-specific COX-1 or COX-2, like aspirin, um, there is a prevalence of COX-1 uh uh allergy at about 8 or 9% of these patients, and if you throw in asthma, it goes up to 30% of these patients. You can't just give them a, you know, a COX-1 um uh inhibitor, and if this is probably um probably underdiagnosed uh in the US, it's probably one that is not really recognized, and and patients don't really um, or I should say doctors don't really, you know, funnel these patients to specialists so we can make the appropriate diagnosis. But this subgroup of patients really contributes a lot to the cost of health care in this disease state, as well as quality of life is significantly impaired, and there's a lot higher morbidity. They get more frequent exacerbations; these exacerbations tend to be more severe; they end up in the emergency room more often; they end up uh being hospitalized from the emergency more often; they end up in the Intensive Care Unit more often; and then they end up being intubated more often, and it's those patients that tend to have a higher death rate too, worsening lung function and quality of life, um, you know, compared to just aspirin-intolerant. High-dose corticosteroids uh are often required, um, and and we can desensitize some of these patients, but it's complex, and this needs to be done uh with a specialist who understands how to do it, and it's often uh associated with a higher revision rate for surgery. Okay, now let's move from the airway to the skin.
Atopic dermatitis. Atopic dermatitis is characterized by the same general process, if you can think about it globally, about immune mechanisms in the epidermis, um, and we see a lot of abnormalities here. Here, so you got your immune abnormalities, okay? They're six times the number of cutaneous T cells. T cells are like the main orchestrators of the immune response; they're the ones that are telling the B cells what to do, um, and other cells as well, um, so a lot more T cells in there causing inflammation. 86% increase in the dermal T cells of non-lesional skin. Remember, we talked about that before on a biopsy; you'll still see abnormality even when there's not a rash, compared to normal skin. You'll see epidermal thickness in non-lesional skin increased um versus normal healthy patients. You see a significant decrease in barrier proteins in non-lesional skin um versus lesional skin versus normal skin, right? So it's defective uh in the barrier uh function, as well as some of the protective proteins that are that are there are decreased. Big, big problem with sleep disturbance, right? Aside from itch, it's like sleep is the biggest problem, and the reason they can't sleep is because of the itch. So this is an interesting uh survey of almost 300, 287 adults with moderate to very severe, somewhere between 80% reported difficulty in falling asleep, and 93 reported restless um sleep to some extent. So what's happening is even if they do sleep, they are not getting restorative sleep, and this compounds on it; that's a stressor, and that and that triggers their eczema even more. And this is a this itch is a big problem. 91% of patients experience daily itching. You'll see it in babies; sometimes you take their clothes off, and they just go straight right to itching. So this is a proposed model, um, which I subscribe to, of the interaction between type 2 inflammation and sensory neurons that are contributing non-histamine contribution to itching, um, and you'll see this on uh the the left. So this itch, this pruritus, you get stimulation by these type two cytokines, IL-4, IL-13, IL-31, PSLP; you get all these type two cytokines that are pushing um itch and inflammation at the same time. As a consequence of this, in sometimes genetic mutations, you get a decrease in filaggrin, so you have loss of the barrier; you have more itching; and this starts this type two inflammatory process, and it involves multiple cell types: T cells, B cells, mast cells, eosinophils; you see the innate lymphoid cells, and then you see interleukin, I'm sorry, the innate lymphoid cells, and then you see interleukin IL-4 and IL-13 activated monocytes and and and uh macrophages, these these effector cells, if you will, and then the issues with the the keratinocytes, the skin cells themselves that I've already discussed. All right, how about eosinophilic esophagitis? Let's move the skin and let's move to the esophagus.
Another mucosa, EOE or eosinophilic esophagitis, is a chronic relapsing uh disease driven really by type two inflammation. We see on the left side; we see this allergic sensitization, and it it tends to be in young ones, in the little kids; they're tends to be more food. In the older uh patient population, there tends to be more environmental, but environmental can drive this just like a food can drive this, so we always check for food allergy; we always check for environmental allergy, and we treat it when we see it. Obviously, it's in the name eosinophilic, so the eosinophil becomes activated, um, infiltrates the tissue, and um increases secretion of some of the chemicals when it's activated that it secretes, like axon. On the right side of this panel, I'm just reinforcing this point about the frequency of these type two diseases when they occur together. So if you look at EOE and then you look at the number of patients that have all these other allergic diseases or or type two diseases, asthma, allergic rhinitis, atopic dermatitis, even food allergy, right, um, especially in the younger age group, you see that frequency. This is really a systemic process that we're seeing, um, okay. Tissue remodeling and fibrosis really is one of the hallmark features, and some of the uh inflammation is eosinophilic, right? It's in the name, so the gastroenterologist will do a biopsy, and they'll see greater than 15 eosinophils per high-power field. Sometimes they even see eosinophilic micro abscesses, but you'll see disruption of the epithelium, and you'll just see the epithelium infiltrated with the eosinophils, and you see a significant thickening of um of that basal layer. Okay, so that's again immune cells and non-immune cells, just like we see in the lungs, just like we see in nasal polyps, just like we see in the skin, all being activated; it's just in a different tissue now; it's the esophagus. This is all driven by type two inflammation. Finally, let's talk a little bit about COPD.
So when we te when we think about COPD, um, we think about it more as something that's driven by neutrophils, not eosinophils, neutrophils, long-term smoker, uh, you know, low levels of type two inflammation. Well, there is a subset of COPD uh patients who actually have COPD, but it's as a consequence of type 2 inflammation, and this is what we see when you look on the left panel here. You will see that blood eosinophils do correlate with severe COPD exacerbations. When you look on this panel on the left, this is a study that looked at patients with COPD over a little over uh 3 years, and you'll see the mean annual exacerbation rate, and then the blood eosinophils, and you'll see the higher the blood eosinophils in these COPD patients, the higher um the exacerbation rate is, so risk for severe exacerbation um uh goes up, and you see that on the right panel. So you're looking at this eosinophilic phenotype; this subtype of COPD patients can help us because in those patients, those are the ones that are going to be at higher risk um for exacerbating, and it predicts those future exacerbations, so you treat them a little bit differently than you would perhaps one who has no signs of type two inflammation. So even in COPD, there's a subset with type two inflammation. Now it makes sense, right? It makes sense that if you have an elevated eosinophil count, you're more likely to exacerbate, and makes sense that you're probably probably going to be utilizing healthcare, and this is what we see: those patients that have higher um type two inflammation, right, uh with more uh exacerbations, you're going to see um uh more exacerbations, more utilization of healthcare, and a shorter time until they exacerbate, so they exacerbate sooner, and they exacerbate more frequently. So there is a distinct subset of looking at eosinophilic COPD versus non-eosinophilic COPD, and not only does the exacerbation have a cost, but when they get hospitalized and recurrent hospitalization, that just kind of compounds um the risk in these uh patients, and it adds to the cost. So elevated blood eosinophils, more exacerbations, they exacerbate more frequently; they end up getting hospitalized more and and sooner and more frequently; higher healthcare utilization. Not only is there a decreased quality of life, but they're being hospitalized, and and when you look at the global burden, it's much more expensive as well, economically.
Focusing in now on one of the key type 2 cytokines, interleukin 13. Remember when I said interleukin 13, it feeds back; it feeds back onto the respiratory epithelium. The respiratory epithelium actually has seven, seven different cell types; this is a very complex epithelium, and there's a group of uh almost stem cell-like cells, and these can can turn into a goblet cell that secretes mucus; it can be a normal respiratory epithelial cell; it can it can be a neuroendocrine cell; these are much rarer, but the point is under high IL-13, you get much more shift to the mucus-secreting cell. This is a key feature in COPD; there's a shift um where those those those, if you will, those stem cell-like respiratory epithelial cells in the basal layer, they then um grow into a mucus cell, and this is through this expression of of of MUC5AC. So high IL-13, more MUC5AC messenger RNA, more goblet cells, more mucus secretion in COPD versus non-COPD, and when you look at this in a mouse model, it kind of uh mirrors it, right? We see overexpression of IL-13 in these biopsies, um, and and you see the overexpression and um much higher uh mucus production in this animal model as well, so it kind of correlates with what we've seen clinically in humans. So this was my learning uh objectives today, talking about the epithelial barrier, kind of transitioning into multiple different disease states, and how it's very important for us to have early identification, and then if we can treat type two inflammation. We have a few minutes left, and I'd like to open it up now for any questions that we may have out there.
Well, thank you, Dr. Carr, um, really wonderful presentation, really appreciate your time here today. So um it's a complex topic; that usually means we don't get as much questions as as usual, um, but one of the questions that um I'm just going to is just a comment. So you said in the old days, we used to call it AER. So when when was the old days? 2023, because I'm just learning this today that it's changed to NSAID.
Yeah, no, we we changed that terminology several years ago. It's essentially the same thing, right? I mean, AER is an NSAID. We've always called it, you know, we first we called it Samter's Triad, then we changed the name several years ago to aspirin-exacerbated respiratory disease, and then we realized, you know, it can occur with Advil, ibuprofen, um, naproxen. So we now we call it NSAID-exacerbated respiratory disease; it's all the same disease, just with different nomenclature.
Yeah, now I appreciate you explaining that because um I want to go and check our website to make sure we have the current terminology and explain this too so that people can learn about that, so I appreciate that. So um regarding NSAID-ERD, um, so why are the patients hospitalized more? Is because they've got really severe asthma that's prompting those hospitalizations and intubations, or is it something else going on?
Well, it's it's it's mostly related to asthma, yes, um, and when when patients have this this this triad of having hypersensitivity to aspirin, and they have this really robust airway inflammation, and that's manifested in the nose and sinuses by the polyps; the same process is going in the lungs. Kind of like at the end of a spectrum, if you can imagine type two inflammation like a a forest fire, this forest fire is raging in these patients, and just a little bit of extra fuel on the fire just sets these people off; they don't have as much reserve, and when they exacerbate, they have so much inflammation, they tend to just really rapidly decompensate, and it so it's kind of a spectrum of disease, and the answer is yes; it's be it's because of how severe the airway disease is um when they get their accidental exposure to aspirin, Advil, one of the NSAIDs.
Okay, so the next question really isn't about type two, but I'll ask it because it's about AER. If a patient has and allergies to environmental, seasonal, and other types of allergens like dust mites and animals, is it beneficial to treat with allergen immunotherapy, or is there some other way to treat those?
Okay, the answer, I'm going to answer the the specific question, yes, and the answer is yes. And you may say why? How does that help? Well, here's how: when you have environmental allergies and the pollen counts are high, what happens is you start getting immunologic priming; your IgE starts going up, and you become more sensitive, so less of what you're allergic to needs to be exposed to you to cause the same reaction, but you're not getting less; you're actually getting more and more and more, so you start getting worse; you're primed. If you look at it like an allergy bucket, when you're being primed, your allergy bucket is full, so then when you get your exposure, your reaction is going to be worse; there is no reserve. If you can do allergy-specific immunotherapy, you remove that as a component. The other thing to um extrapolate on uh that question is there are cases, and you should only do this if if you understand how to do it and you're an expert in doing this; there are cases where we can actually desensitize these people, and so that they're taking an aspirin a day, uh, and there are other medications that we can use, and and doing that really really uh significantly uh decreases the risk in these patients.
Okay, so back to type two asthma, um, can people with this type of asthma get help that will help put their airways back to how they should be?
I wish I could give you, whoever asked that question, I wish I could give you my business card. Yes, that's what we do as allergists and clinical immunologists; that's what we do is we treat; we are experts in type two inflammation, and it just depends. In this in this particular case, the question was asthma, and yeah, there's there are much better therapies today than there were 20, 30 years ago, uh, and each day we get better and better at understanding the disease.
And, doing treatment, so my recommendation—I'm not sure who asked the question—my recommendation would be to find a board-certified allergist and clinical immunologist. Find a board-certified allergist and clinical immunologist in your community, and that's who you should be seeing. Um, and we can help you. If you go to the American College's website, you can see a registry there. You can look up a local allergist in your community, and only people who are board-certified are on that little registry, and that's acaai.org. Um, you can search for a doctor there for anybody who would to know.
So this is a question about, um, oral steroids. Does a low dose of oral steroids cause significant side effects if used over long-term use? I know that you were talking about the long-term side effects and the complications or comorbid conditions that can arise from that. Can you comment on that?
Yes. Um, the answer is yes. Low-dose cortical steroids do cause a problem over long term. Let me explain myself. Your body makes a steroid; it's called cortisol. The biological equivalent is about 5 milligrams of Prednisone. So any Prednisone that you take tells your body to stop making cortisol. When you take anything in excess of that, you've shut down your—not only have you shut down your body's ability to make the stress hormone cortisol, you start making it in excess. You increase your risk of cataracts, glaucoma, uh, decreased bone mineral density, diabetes, heart attack, stroke, immune deficiency. Um, even small amounts over a long period of time can have those effects. Remember what I said? If you do the math, if you look at it, if if you look at an asthma inhaler and if you look at just kind of just generally speaking, you look at an asthma inhaler, you take once or twice a day, and you do that every day, it will take three to five years of a daily dose of an asthma inhaler with a steroid to equal one 5-day course of Prednisone. One 5-day course of Prednisone equals years of taking an inhaler. So we always want to use inhaled therapy, topical targeted therapy if we can, and then look for steroid-sparing alternatives if you can. Hopefully that answers the question. Okay.
Um, so, uh, do pulmonologists treat type two inflammation? I know that allergists are immunologists, but what about pulmonologists?
Yes. Um, there is a very, very good study that uh I have been a pleasure of being a part of since its inception. It's called Chronicle, and the Chronicle study is a study sponsored by a pharmaceutical company, and it's looking at severe asthma patients and different therapies that they've been on. And as part of the study, we looked at who do these patients see, and we're talking several thousand patients, uh, in Chronicle. Um, you can just look it up and see all the publications that we've looked at. And yes, pulmonologists, allergists, even primary care, uh, treat type, uh, treat type two inflammation, um, and, uh, it it's regional. You'll see it within your communities, uh, and, um, the use of steroids also, believe it or not, is regional, and it's different based on different specialties. But to answer the question, yes, pulmonologists do to do treat type two inflammation, um, and if somebody is out there seeing a pulmonologist for asthma, they should ask them about it. In my community, most of the pulmonologists in my community, if the question is, hey, we need a specific therapy for for treating the type two inflammation, in my community, most of the pulmonologists here refer to me, and I partner with them, and I manage that that aspect of their care. But there are a lot of communities where the pulmonologists do it all on their own, or, um, where the allergist refers to the pulmonologist, and then there's a lot of systems out there where the pulmonologist and the allergist are working together in the same clinic.
Thank you. Well, with that, that's going to be the last question that we have for today. We're at 4:57, so we're going to end on time. I want to thank you so much for making this very complicated topic easier to understand. Um, so I want to just thank you again for being here today, and, um, we have several webinars coming up in the upcoming months. First is food allergy: current approaches towards individualized management. Um, that's Dr. Katarina Agasu; she's an expert in food allergy, so I hope you join us for that. And then we'll have another one. Dr. Lus Fosier, she's um an expert in atopic dermatitis, and and and she will be here talking about the complex relationship between atopic dermatitis and allergies. As I mentioned before, you'll receive an email from Zoom in a few days with a link to this recording as well as some additional resources. And with that, I'm going to say thank you very, very much, Dr. Carr again, and for all of you who have, um, remained with us until the end, um, I think it's been a wonderful presentation. I know I've learned a lot. And so with that, I'm going to say have a good night, um, and take care, and we'll see you next time. Bye. Thank you everyone. Goodbye. Thank you, Dr. Carr.