So without further ado, I'll start my talk. The way we have set the agenda is I'll start to explore whether really eosinophilic COPD is a distinct entity or is there anything distinguishing about it. And then we'll kind of go into biomarkers and then look at therapeutics from the standpoint of corticosteroid use and of course biologics. So before we launch into whether eosinophilic COPD is a distinct entity or can be defined, it's good to first understand whether COPD itself is a distinct entity and do we have a really good handle on how do we define COPD? And the answer is that it's still evolving. I mean the diagnosis of COPD is still changing and there's little tweaks being made by Gold in their annual reports. And the very first word in the definition is heterogeneous, right? So it is a heterogeneous lung condition and there is a lot of variance in terms of clinical presentations, outcomes, and even pathophysiology that is still being debated and discovered. The idea that there are phenotypes in COPD is not new, right? For the last 70 years, ever since in the 1950s when they first started talking about these two, you know, the blue bloater and the pink puffer with the blue bloaters being the ones who had more of a hypercapnic response, more pulmonary hypertension, more weight gain, and actually obesity and a lot of chronic bronchitis, meaning lots of cough, mucus, phlegm, and sort of the pink puffers being the ones who had more emphysema, the barrel chest on physical exam, more dyspnea, less cough, very little pulmonary hypertension and really not much of a hypercapnic response. I mean, obviously these terms have long been abandoned, but the fact is that it has long been recognized that the heterogeneity in COPD lends itself to multiple and varied clinical presentations. And then as we start looking at things like treatable traits, endotypes, biomarkers, and phenotypes, it's good to sort of get an idea about what exactly do we mean by all of these things. So a treatable trait is something that is a therapeutic target that can be identified by either an endotype or a phenotype, usually through either validated biomarkers or through some kind of symptom profile recognition, whereas a phenotype is tied into disease attributes that describe differences which relate to clinically meaningful outcomes, and endotypes, again, are subtypes of disease that are defined functionally or pathologically, typically by a molecular mechanism or by a treatment response. So now sometimes these aren't used in a very exact sense of the word, and so some people may throw out, throw the term phenotype or throw the term endotype, but that's sort of at least a working understanding of what these terms mean. We talked about chronic bronchitis as a phenotype, and so chronic bronchitis is strictly defined as at least three months of sputum production, two years in a row with no other identifiable causes to explain the symptoms, roughly occurs in about a third of all patients with COPD, usually associated with poorer lung, you know, more severe lung function, greater smoking history, male gender, and somewhat of a younger age. Interestingly, up to 22% can be found in nonsmokers as well, and so that is sort of the one type of the heterogeneity you see in COPD, in about a third of patients having this chronic bronchitis, meaning cough, phlegm, and so forth. And then there is the other type, which is sort of the other end of the spectrum, is the emphysema, which is typically characterized by CT, by radiography, by CAT scans, and depending on the severity there, you can look at the prevalence of emphysema. So if you look all the way to the right at the severe cases of COPD, the prevalence of emphysema is about 90%, and that, but if you scroll, you know, to the left into the mild category, that is no more than about 40%. So there's still about 60% of patients, at least in, again, this is one study, but roughly only about 50% of patients or so overall with COPD will end up with CT, evidence of emphysema. So about a third of patients will have, like, more of a chronic bronchitis and cough and those types of things, and about half of them will have CT, evidence of emphysema. So before I sort of delve into the talk, I think it'll be good to present a few clinical cases. These are all patients from my own clinic that I thought I would sort of introduce here because it would help us contextualize the discussion that is to come, particularly with regards to the biomarkers and much more so with regards to, you know, the therapeutics that Dr. Kraft will be exploring. So real quickly, case one, 64, 65-year-old male with severe COPD, steroid-dependent, chronic oral prednisone, 80-pack-a-year smoker, also has had occupational exposure to paint sprays and fumes, non-allergic, no history of prior allergies. Eosinophils were 200. Interestingly, CT scan showed no evidence of any emphysema. So, you know, no emphysema, no parenchymal lung disease even. And you can see that reversibility there on his PFT is about 44%. So, you know, marginal eosinophils, huge reversibility, CT scan looks pretty pristine for someone with oxygen-dependent severe COPD and extensive smoking. Case two, on the other hand, 67-year-old Caucasian female, mainly has dyspnea as well as chronic bronchitis, chronic cough, lots of phlegm, 46-pack-a-year smoker, again on oxygen, so sort of a common theme there. Eosinophils here are 700. Extensive emphysema on the CAT scan. So lots more eosinophils, but also lots more lung destruction and parenchymal lung disease and reversibility. Case three is a 45-pack-a-year smoker, quit six months ago. This guy has a lot of, this female has a lot of allergies and also obesity, sleep apnea. So, you know, pretty, lots of comorbidities and you can see that 21% eosinophilia that is, you know, right there, very, very striking. Allergy panel, as you would expect, with a strong clinical history of allergies, you know, strongly positive. And interestingly, reversibility was absent. So somebody like this, you would expect, you know, lots of eosinophilia, lots of allergies, and yet PFTs didn't show any kind of reversibility and CT scan didn't really show any evidence of emphysema or parenchymal lung disease, nor evidence of any kind of bronchiectasis. And finally, closing off with a 64-year-old Caucasian female, 25-pack-a-year smoking, quit about three years ago. Exertional dyspnea, very little cough, so not at all that chronic bronchitis kind of phenotype. Never had any kind of allergies. Comorbidities were mainly just high blood pressure. Eosinophil count of about 500 and extensive emphysema on CAT scan and pretty strong reversibility. So you can see here in these four cases, I've just kind of given you a flavor for how all these things can be very different in one individual patient. Very hard to compartmentalize and box these into, well, this is like you're allergic, bronchitic, reversible, with good-looking, you know, parenchyma on the CT. They're just all over the place. Sometimes you get patients who are reversible with extensive emphysema. You get patients with very little eosinophilia but robust levels of PFT reversibility. So really, do any or all these patients of asthma COPD, certainly by the numbers, they all have eosinophils over a certain 2% threshold. But do they truly have eosinophilic COPDs? Is there such an entity like that? What about asthma COPD overlap? Would you say all these patients, I mean, certainly almost all of them had reversibility. Do they have asthma COPD overlap? How do you really define that? And then, most importantly, which would be a topic for Dr. Kraft's presentation is, you know, which of these patients is likely related, is going to be put on eosinophilic-targeted therapy or perhaps is going to respond? If you look at the classic papers on pathogenesis of COPD, even up until recently, you, of course, have a very heavy focus on the neutrophils. You have a focus on macrophages. And then, everything down the line in terms of, you know, ICAM, you have PDE4 there, you have PI3K, adhesion molecules, all of those stuff. And then, if you look at the targeted therapies, they're also sort of covering most of these target areas, right? You have the EGFR inhibitors, cytokine inhibitors, primarily targeting IL-6, TNF-alpha, protease inhibitors, PDE4, adenosine receptor antagonist, adhesion molecule inhibitors. So, certainly a lot of molecular target in terms of targeted therapy. And what is really missing in this is really anything about eosinophils, right? So, for a very long time, we were, when we were sort of, you know, either teaching about the pathophysiology of COPD, pathogenesis of COPD, the eosinophils were never really, you know, central to that kind of a dialogue and discussion, nor was there so much of a focus in target therapies. And yet, here we are, really having a lot of now focus that is shifting to eosinophils. So, in terms of prevalence, you know, we looked at what is the prevalence of clinical phenotypes, like chronic bronchitis, or radiographic phenotypes, like, you know, the emphysema. Well, what about eosinophils themselves? What is really the prevalence of eosinophilic COPD? Or eosinophilia in COPD, to be more precise. So, at least in this one study that was from, that looked at Eclipse, at the Eclipse cohort, about 37.4% of these patients had eosinophil counts, persistently more than 2%. Interestingly, about 50%, it was variable. Could be about the 2%, below the 2%. But what, at least to me, was very interesting was the control group, the healthy controls, had almost an identical level of distribution. That is, you know, about 37% or 36% of that also had eosinophils more than 2%. So, really, was this just part of the normal distribution amongst healthy people, or was there something specific about those individuals, remains to be seen. Interestingly, when they took that threshold up to 300, only about 10% ended up being, or actually about 19% ended up being always above the threshold with COPD. Again, a different study, this one is from the UK Clinical Practice Research Datalink, and about half of these patients with all comers, all COPD patients, about half of them had bloody eosinophils, but they used a threshold of 150. So, you can already see, you know, early on in this deck that there is all sorts of definitions about where that threshold needs to be. 150, 2%, 200, 300, sort of a little bit all over the place. And again, an interesting comment that was made in this particular study was that patients with COPD and asthma had significantly higher bloody eosinophil counts. So, really, when we are looking at a lot of patients with COPD and eosinophilia, are we really looking at patients who have that overlap? Eosinophils and exacerbation, so this is really where the story starts to gain more strength in terms of, you know, why are we really even focusing? If it's not such a central part of the pathogenesis or the pathophysiology, if the prevalence seems to be a little bit all over the place, only about a third have persistent eosinophils, and even that isn't too different than the normal population, then why are we even really spending time talking about it and really laboring about this issue? And so, there is certainly emerging data that seems to suggest that exacerbations in COPD seem to be more tied into the presence of eosinophils in COPD. So, the COPD gene study was analyzed for discovery and the ECLIPSE study for validation, and they looked at, in this particular paper, the COPD exacerbation risk, and they found that the higher the eosinophil counts, the greater the exacerbation risk, and the adjusted incidence rate ratios, both when they looked at COPD gene and then in a validation group in the ECLIPSE, was in about 1.22 to 1.32, suggesting that, you know, there does seem to be a signal somewhere there. In a different study, this one was from Copenhagen, and not in the moderate group at the top panel, but certainly in the severe, there's my cursor, so, yeah, in the severe group, there does seem to be this almost dose-dependent relationship between exacerbations and eosinophil levels, and when they actually measured it, there was a increased blood eosinophil levels were associated with a 1.76-fold increased risk of severe exacerbations. A different study, and this one was, again, from the United Kingdom, and they looked at 145 patients with 182 exacerbations, and they were able to sort of see four distinct clusters, a bacterial etiology, a viral, and an eosinophilic predominant, and then something they labeled as a posainflammatory, and the eosinophilic component was seen in roughly about 29, 28% of these exacerbators, so a little bit of a different approach, and then finally, this was a paper that really showed a fairly linear correlation where they were able to show blood eosinophil levels and odds ratios of an exacerbation, and in this study, they did it both by including as well as excluding patients with an asthma phenotype and still found a substantial level of correlation, suggesting that there really seems to be a signal that more eosinophils you have if you have COPD that there is a likelihood that you might exacerbate more. However, like with everything else in medicine, and particularly in pulmonary medicine, things don't always seem to be very straightforward, just as we are able to tell a really good tale for this, come some studies that sort of really put a damper on this, so this was one study where they really showed a lack of noticeable difference in prognosis, outcomes, clinical features, or pulmonary features in patients at all levels of eos tested, 2%, 3%, 4%, didn't seem to matter. Exacerbation, no exacerbation. Barcelli and his group, really, this was another study that really make us pause for whether this truly is a signal or not, so they had two large cohorts of COPD patients, found a lot of variability in serum eos over a two-year period, and only 15%, and again, their threshold for eosinophils was 300, a lot higher than the 200 or the 150 we were seeing earlier, and only 15% of their patients had persistently high blood eosinophil counts, and then when they sort of dialed into these 15 patients and said, well, they surely got to have more exacerbations and things like that, turns out all-cause mortality was actually lower in patients with high eosinophils, and blood eosinophils did not seem to be a risk factor for COPD exacerbations, in fact, high eosinophil count was associated with better survival, so three for, two against, there's definitely maybe a signal there, but then that doesn't seem to be consistently the case. And then we move on to something, this is gonna overlap a little bit with what Dr. Monica Kraft is gonna talk about, which is the steroid response, but just to, again, complete that story of how this evolution happens in terms of why we are really looking at eosinophilic COPD is that there did seem to be, in quite a few studies, a suggestion that if you have serum eosinophilia and you have COPD, that you have a good response to steroids, and that is a biomarker-driven approach to COPD. So this was one study by Neil Barnes and his group out of the UK that showed that once, if you use the blood eosinophil as a biomarker, you can distinctly see two groups of COPD patients, ones that don't respond at all to fluticasone and the other ones that do in a very significant manner. You can see the FEV1 changes is pretty significant over there. This was another study, and what this did was it was a randomized placebo control trial that prospectively used biomarker-driven approach to direct steroid treatment. So what they, they defined a threshold of 2%, again, a little bit different than the previous studies we were seeing, and if they didn't have the eosinophils, those patients did not get steroids. So in the biomarker-directed group, 49% of exacerbations were not treated with steroids. The respiratory improvement, the CRQ improvement in both groups was similar. So by withholding the steroids in the negative group didn't seem to really lead to poorer outcomes. And there was a greater improvement in the biomarker-negative exacerbations were given placebo versus steroids, suggesting that the steroids really didn't play any role, provided you were able to exclude out those who had serum eosinophils. And in the biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone, suggesting that the steroids were really not doing anything. Again, strong evidence to suggest that using, or at least detecting this entity called eosinophilic COPD or finding eosinophilia in patients with COPD is clinically relevant. Once again, I'm probably sounding like a pro-con debate rolled into one talk, but this is the FLAME trial, and when they looked at looking at whether blood eosinophils in response to, and the response to maintenance treatment, they really couldn't find anything there. They couldn't find that there really made a difference that if you identified eosinophilia, and you kind of, that there was any kind of correlation between steroid responsiveness and not. So sort of putting it all together, what Gold's, in their 2023 iteration of their guidelines said is that, at present, blood eosinophil counts of more than 300 provide guidance to identify COPD patients who are at higher risk of exacerbations, and more likely to benefit from preventative treatment with a nail steroid. So they are sort of giving two things. One is that getting that biomarker, getting that eosinophil measure at least tells you who is at risk for higher risk exacerbations, and two, more importantly, guides you on how to manage your patients with COPD, and again, we'll get more on this in the subsequent talks. So just a brief word. This will be covered a lot better and more elegantly by Dr. Monica Craft, but just to continue on this theme of eosinophilic COPD from the standpoint of why this continues to remain relevant is that in targeted anti-eosinophil therapies, such as with IL-5, we are, most of us are probably familiar with Metrix and Metrio, which were the phase three trials evaluating mepolizumab in COPD, and again, I won't go into the details here. That'll come in the subsequent talk, but clearly you can see here the rate ratio in terms of stratified by the eosinophil counts, and you see here in terms of the mepolizumab arm doing better, either with historical values over 300 or with current values of either 300 or 500, and clearly the trend is unmistakable in terms of which direction that rate ratio is trending. Again, weeks into randomization and cumulative exacerbation rate, you can see the curves separating out from placebo and metolizumab at both arms, both studies. This was sort of more of a combined analysis of all the studies done for both Bendra and Mepo, and then much more recently, you have dupilumab, although this one isn't strictly an IL-5 and has much more of a dual mechanism of action, clearly had very robust phase three results with that separation from placebo and dupilumab, both in terms of exacerbations as well as in terms of lung function with FEV1. And finally, which kind of gets us to this word salad type of thing, which is asthma COPD, started off with ACOS, asthma COPD overlap syndrome, and then the S got knocked out and became ACO, and then Gold said, well, we don't like the CO part, so let's just retain the A, so now it's COPD with asthma or COPD-A, so it's a little bit all over the place. What Goal 2023 says is that we no longer refer to asthma-COPD overlap, instead we emphasize that asthma and COPD are different disorders, although they may coexist in any individual patient. Again, the topic of today's talk, the today's topic is not relevant, is not exactly an asthma-COPD, but I think it is relevant from the standpoint that perhaps a lot of patients with eosinophils and COPD may indeed be having an asthmatic phenotype, and certainly in the clinical cases that I highlighted, perhaps a lot of them have, exactly as Gold is suggesting, that they have asthma and they have COPD. Interestingly, all the four cases that I presented today, they were all treated by me with biologics with excellent outcomes. One of the patients came off oxygen, excellent improvements in six-minute walk test, even spirometry, and so forth, suggesting that they were patients who had eosinophils and COPD. They were patients who got put on biologics and they were patients who got a lot better. Now, whether that is necessarily evidence or hard evidence of a cause-effect relationship, it's still to be determined. We just don't know enough. The ATS and NHLBI workshop, Dr. Monica Kraft, was part of this, sort of came up with a way of saying, ACO can be used to describe two types of patients. So if you have patients who have asthma and you see that they are not reversible, then they could have ACO. And if you see patients who have COPD, but they show evidence of bronchial responsiveness, meaning they're reversible, so they could have ACO. So depending on what you're starting off with and what your initial diagnosis of the patient is, a patient comes to you with cough, dyspnea, wheezing, you do PFTs, they are obstructed. Depending on whether you feel they have asthma based on the clinical context, the lack of reversibility might actually lead you to believe that they may have ACO. On the other hand, same kind of clinical presentation, but depending on the clinical context, you feel this person has COPD, the presence of PFT reversibility or bronchodilator responsiveness might lead you along to the same path. So it's a somewhat counterintuitive, it's somewhat a little bit paradoxical, but it does make sense if you sort of think about it because everything depends on what your starting ground is. In terms of what the global prevalence is, I don't think you could get, I mean they might as well have put this as zero to 100%. Right, I mean like four to 66, like why even bother? So and the reason is that we don't have a diagnosis. So we are, you know, if I told you like what is the prevalence of bubbla boo, and you'll be like, well what is it? I'm like, I don't know, you just tell me what the prevalence is. And so you'll be like, yeah, maybe it's 50%. I'll be like, yeah, sure, why not? So that's sort of what ACO has unfortunately become. It's just, we don't know what it is. We kind of think we know it when we see it, but do we have a test to prove what it is? Well, it would be helpful to know what it is before we figure out a test to prove it. And so the estimated prevalence, you know, in both in asthma and COPD could be as high as 60, 65%. Depending on, I mean my own clinical approach to it as a simple country doc, I do feel a lot of my patients with COPD do have asthmatic features. And whether I call it COPD-A or ACO or ACOS, it really doesn't matter. I give them treatment as if I'm treating an asthmatic, and many of them do get better. So take that, I mean, again, not a very scientific approach, but certainly a lot of us, that is how we come down to it in terms of how we approach therapeutics and clinical decision making with our patients. Certainly there is a, you know, if you define ACO using whatever criteria of definition you want to, there will be a trend to see higher eosinophil counts in these patients. So usually I end my talks with some take home points. I'm ending my talk here with more some take home questions. So are eosinophil levels in COPD reliable over time? Very first question probably is my answer. Is eosinophilic COPD a distinct entity to be determined? What really is the correlation or degree of overlap between eosinophil levels, CT findings, radiographic findings of emphysema, presence of some sort of a chronic bronchitis phenotype, which really presents a lot like asthma with a lot of coughs, sputum, and so forth. And then what about this ACO, A, ACOS kind of thing? A very interesting approach would be to say, you know, do we move away from these distinct names and instead start thinking about it as clusters? Hasn't happened yet. It has kind of been thrown about as saying, you know, why don't we start identifying them as clusters where CT plus biomarkers in blood plus clinical features plus PFT data and then start segregating those in some kind of a cluster-based hierarchy? Certainly attractive, hasn't really, we just don't have the data yet. And then finally, you know, in terms of going back to the definition and what is really the correlation? Is it a very linear, does everyone with ACO have eosinophilic COPD and vice versa and so forth? And then, you know, just pointing out a recent paper by Ravi Kalhan which came in the Blue Journal which is sort of using omics to present COPD exacerbations and really introducing this concept of an immunome which is using radiomics and, you know, kind of an immune cell biomarker assay along with serum biomarkers. And coming to a much more nuanced level of COPD endotyping and particularly in this era of CHAT-GPT whether artificial intelligence can really help us identify when we, you know, use that with large data sets of COPD patients and feed in a lot of this sort of radiomics and immunological and biomarker-driven information, whether that can help us really identify some of these clusters which will in turn help us do a better job of doing what we think would be helpful for the patients. So with that, I'll stop. We have a great set of panels coming after me so really eager to learn from them along with all of you. So I'm Stephanie Christensen from UCSF, so close by. So I'm Stephanie Christensen from UCSF, so close by. And my specialty's in airway immunology and biomarker science, also in bioinformatics but I'm not really gonna discuss that today. And so I'm gonna kind of, I feel like we might have some overlapping data in all of our talks but I'm going to at least talk about it a little bit more through the lens of, through the lens of kind of how to think about the biomarker because really what we wanna know is should we measure any of these biomarkers and why and who in? So I think that's particularly important. All right, so these are my disclosures. All right, so the first thing I'm gonna talk about and I will be very brief because I know that nobody really likes looking at our pictures of what the overall immune response is. But I'm gonna just show a little bit on type 2 inflammation and why we actually measure eosinophils versus some of the other biomarkers. We're gonna talk a little bit about blood eosinophils and I think we've already fortunately had actually quite a bit. So I think I can be, I'll try to be brief and just go through the key points so we stay on time. We'll go a little bit through sputum eosinophils and I'm also gonna talk a little bit about exhaled nitric oxide. Just kind of as a, these are the three biomarkers really that are out there right now. There's certainly a bunch more that we could talk about but I just, I mean, that's for another time. That's a little bit broad. Okay, so like I said, I'm going to try to be brief so that I'm not totally inundating you with a pathology lecture here. But if we think about type 2 inflammation in the airway and why we care about eosinophils, certain other biomarkers, and where we can possibly target along the pathway, what we might want to think about first is, okay, so what is, so type 2 inflammation or allergic or atopic inflammation, what we usually typically think about in our asthmatics but as we know now, we can sometimes see in our COPD patients. So we start with activation by like a stimulus. So maybe an allergen, although maybe a virus, maybe smoking, maybe something else. And we're going to hit the epithelium to start making alarmins like IL-33 or TSLP which may strike your memory because we can target those. And they are going to activate our antigen presenting cells to really kind of start working with our T-cells. And our T-cells are going to become IL-4 competent. So one of our cytokines, IL-4, and that can work in a few different ways. First of all, it's going to work with our B-cells to do class switching. So we're going to start making IgE and that's going to go and start working with our mast cells. So we're going to start having mast cell production, which is one of the things we think about with allergic inflammation. They can also go into the epithelium itself or into this subepithelium mucosa, both places actually, and start also, so you get now IL-4 production, IL-5 production, IL-13 production. And then that's going to really go to stimulate some of our really end downstream effector cells. So the eosinophil. So usually we get IL-4 and IL-13. They're going to start activating IL-5, which is what activates eosinophils. So that's why we think of IL-5 and eosinophils together. But we also get goblet cells being, so we get our basal cells reprogramming to make more goblet cells. So you get a lot more mucus. You can get airway fibrosis. You have all these mast cells. So if you think about it, the eosinophils here, it's just one little part of this very large program. And so we're really looking at kind of one biomarker of a lot that's going on in our airways. So this is why sometimes we're thinking about targeting other things and looking at other biomarkers. And we actually, I've kind of circled here that there's a lot here that we can potentially target with therapeutics. So stay tuned for that. I don't need to go into that. Okay, so let's start talking though about, so now we're, so we have biomarkers particularly for the eosinophil, but potentially for some of these other points along the cascade. But certainly what are we using now? We're using the eosinophil. And how are we using it? Well, I can at least tell you how the GOLD report recommends that we use it. And that is that in our, the places we particularly want to think about changing therapy is, okay, let's say for an initial pharmacologic therapy that if your group E, so meaning are exacerbation prone, doesn't really matter if you have symptoms or not, they mostly all have symptoms, but that we want to look at, if you have a blood eos greater than or equal to 300, that those are the people that you might put on triple therapy. And I feel like Monica is gonna talk about this. Sorry, Monica. But so that's kind of one point. And then we have the blood eos lower than 100 to maybe take you, if you're like further down the pathway, like most of our patients coming to pulmonary, right? They all come to us, they all come to us on advert, frankly, we all know that. But as to what we're actually gonna do with them, here they're suggesting that if eos are greater than 300, we may have them on triple. If eos are less than 100, we may think about taking them off of medication. So, okay, so what is the evidence for blood eos? And we kind of heard some of this evidence already. So I'm not gonna like go through each study, but I think no matter what, a lot of the studies have actually shown like the post hoc analyses of a lot of our inhaled, our ICS trials have shown that we get improved exacerbation prevention in patients who have high blood eos. So it could be useful because man, I really want to prevent exacerbations, right? We know they're highly morbid. If you've got severe ones, they can actually be highly associated with mortality. So I really think of them as kind of, you know, my heart attack of the lung. And so I really do want to prevent them. So if I can measure this, if I can measure something that tells me when I'm gonna have a good response, that's what I care about. So we do see in a lot of these post hoc analyses that we have better improvement with our inhaled therapies. Now you will see a lot of these are not done from the triple therapy, the triple therapy trials. A lot of these studies here, none of these studies here. So we do have some equipoise there, which is kind of interesting, right? So FLAME, which we already talked about, that if you're looking at Labalama versus ICS-LABA, that that was, that the Labalama is better than ICS-LABA regardless of eosinophil levels. In fact, that is one of the reasons we have it in the guidelines, right? That we use Labalama first, not ICS-LABA on these patients. And, you know, our triple therapy studies like IMPACT really show that ICS-LABALAMA decreased exacerbations more than our dual therapies, kind of regardless of eosinophil levels. So, you know, this is an area for thinking about what do we do with these? So certainly we have people who have high blood eos that I really care about treating. And then we have a lot more equipoise in the levels of low blood eos. I will say, certainly, like if I have really low blood eos, I may start thinking about taking them off, particularly if we've got a really frail patient. This is some of that data for that from Mona Baffadel and colleagues, kind of showing that if you are, where they looked at kind of, and this again is dual therapy, not triple therapy, but if you have low blood eos, let's see if I can, I don't know if I can do, if I can show this. But basically you can kind of see how these two lines cross, that they looked at, oh, and I'm showing SGRQ, I'm sorry guys, but I meant to, we also have it for exacerbation, exacerbations, similar data, that basically if you, as you increase your eosinophil counts, that your level, on for motorol alone, so on just not, where you're not giving them ICS, that they have increases in symptoms, they have increases in exacerbations, once you start kind of getting in the higher than 100 to 200 range, whereas kind of ICS containing somewhat remains flat, and we see that kind of cross in the 100 to 200 range. So basically that if you're really low, you're probably not gonna really benefit. So that's where some of that data comes from. And I'm just showing a little bit of this, not to, again, we don't need to, I don't need to present everything Monica's about to present, but I did wanna show kind of that there's mixed results, so like I was saying, IL-5 is what targets the eosinophil. So if we think about, is it just a biomarker? When we're thinking of it as a biomarker versus as a target for something, those two things can be very different, but somewhat overlapping. So something can be a biomarker for type two inflammation, but not be, not actually be the thing that you need to target. However, I think there's mixed results for anti-IL-5 treatments and some of that may be based on these bloody eosinophil levels of what they targeted. So the mepulizumab and the benrelizumab studies where they showed kind of, there's mixed exacerbation features, and really they're looking at targeting 150 and above, like what we do in asthma, or 220 and above for the benrelizumab studies. And I think they were mixed results, so this is why you're certainly not seeing them yet, but I think as we already saw this kind of picture that as your eosinophils go up, that we may wanna start thinking, then we're seeing better response, so that that may be, that as you get into the higher ranges, into those like 300s and more, that we may actually have a response. So it may not just be a biomarker, it may be part of the biologic pathway. That said, so BORUS, which is the dupilumab study, and again, we'll talk about this more later, so there they used blood eos greater than 300, and had a greater response. Now some of that could be because we're targeting higher levels of blood eos, where we think it actually, where we think a blood eosinophil as a biomarker is actually helpful for us in COPD. Or it could be that we're actually targeting different places along that T2 pathway, where we're looking at IL-4, IL-13, which are upstream of IL-5, and maybe dealing with other parts of the pathway. And I think we'll learn a lot more about that as the clinical trials come out, which there are many of. Okay, so that's kind of like blood eosinophils. So I think we've got data here on the less than 100, greater than 300, but still a lot of, a little bit of wiggle room in between. So now what about other biomarkers? Now, so if you think about blood eosinophils, okay, we're talking about a systemic response. And where is a lot of the biology, the pathology focused on? It's really in the airways, right? So I really care about what's happening in the airways themselves. And I will say, a lot of my research, we'd go down and do research broncs, and we'd get in there and get epithelial cells and sequence them and do all this other stuff. But really, are there ways that we can easily measure what's happening in the airway? And I will say that it does seem like in COPD that may be somewhat important. So, you know, as we move forward and as we start thinking about who beyond maybe the 300 and greater that needs to be looked at and how do we look at them, maybe we really do need to be looking in their airways. So this is just a couple of studies kind of showing, first of all, that sputum and blood eos really don't correlate as well in COPD as they do in asthma. So in asthma, you know, we look at a blood eosinophil and we have actually pretty decent correlations between the blood eosinophil and the sputum eosinophil. And so we can kind of see that this is one kind of smaller study here. On the left, that, you know, we really see, okay, in asthma, there's a lot higher correlations both with blood eos counts and blood eosinophil percentages, where in COPD, we don't have quite as much of a correlation. And some of that can be actually because we've got lower levels in most people. So, you know, if you're actually looking when you actually go higher, so at eos greater than 300 in the blood that you've got some better correlation. But if you're looking at everybody, there's a lot more, a lot of people are lower. And same in spromyx, which is a multicenter study that I participate in, where we really did not see that, you know, the correlation, there's a correlation, but it's a little bit more like a, I don't know, it's more like a Rorschach test. You're just like, what am I looking at here? So it's, you know, there is a correlation, but it's not great, it's a little bit all over the board. Now, I will say, when you look at this, so I'm actually cutting it here at 5% blood eos or 300 eosinophil count, and we can kind of see that, okay, that's where we start to get people who maybe have these sputum eos that are much, much higher. Like you've got a couple of these outliers here that have sputum eos in the like 10, sputum eos percent range in the 10, 20, 30%. So it may be that you've just finally like got people who are really, really high. Okay, but I will say, so at least in this spromyx study and in a few other studies, it does look like sputum eosinophils are a better biomarker of disease than blood eosinophils. And I will say, what they found in some of this is actually that, you know, the sputum eosinophils, the group that had high sputum eosinophils here was actually quite a bit smaller than the group that had high blood eosinophils, but we did measure blood eos in a lot more patients. So, but either way, it was really marking, sputum eosinophils was better at marking a group, a subgroup of patients that looked different and looked like a group that you should be taking more seriously as a type two group. So they had more radiographic features of type two-ness. They both had higher airway wall thickness, although we see that actually with blood EOs as well. But they also had measures, total lung, the TLC was higher by radi, by imaging than we saw in the sputum EOs low group. And I will say that potentially a measures of air trapping, which is kind of a bigger thing in asthma, or in COPD than sometimes in asthma, although maybe we just don't always measure it enough in asthma, but if you're thinking about small airway disease and something that we can reverse in a COPD patient, that small airway disease and air trapping, we do see that a lot more in these high sputum eosinophil groups. We see a little bit more in the way of symptoms, although there are some symptom increases in the blood eosinophil high group as well. But this group is particularly the people with high sputum eosinophils seem to be the people who exacerbated more, there was at least an association there, whereas we didn't see that in the, with the blood eosinophil group. Okay, now, I just am bringing this back up, not to go through it again, but to suggest, hey, okay, what about other things beyond the eosinophil? So like I said, the eosinophil is one of the end stage, or the end of the line effector cells. One of the other things we can measure, and there are certainly many others, but one that is measured clinically is the exhaled nitric oxide, or pheno. And we tend not to measure that in our COPD patients. In fact, I can't even measure it in my asthma patients in our clinic, they stop doing it. We're trying to get them to bring it back. But in COPD, we tend not to measure it because one thing, smoking can decrease the levels. So it's still kind of hard to know if, you know, what to even make of pheno in COPD. But I think we're starting to at least learn more about what to do with this biomarker. And one of the important parts of it is that pheno really is potentially measuring more of this kind of upstream, so the more IL-4, IL-13 inflammation, although it can be measuring other pro-inflammatory signals. So I will just give you like a couple little tiny pieces on T2 inflammation, and that's, this was a meta-analysis. Oh, and I'm sorry, I didn't give the reference here, but I will give it to anybody who wants it. So this is from, this was a meta-analysis of pheno and looking at pheno in COPD. And they did see that, looking across all these very small studies, that in general, pheno is higher, and COPD, of course, is lower if you are a current smoker than a former smoker, so that's always gonna need to be adjusted for. But we do see some association here. And this is just measures from, this is just a snippet from the Boreas study where they looked at, where we looked at the effect of dupilumab in COPD. And one of the biomarkers, they measured pheno amongst multiple biomarkers, and what's particularly interesting here is so their blood eos actually didn't really go down very much over time with dupilumab, but pheno did. So really kind of suggesting that they are really, that they are really blocking that type two response, and so you can kind of see that here. And I'm just, I'm showing the table here where we've got blood eos percent change, fibrinogen, which didn't change appropriately, it shouldn't change, and pheno, which really does decrease quite a bit with dupilumab as compared to placebo. And again, we see that in the graph over here. All right, so these are my few little snippets, takeaway points. Blood eos are particularly useful, maybe at greater than 300 and less than 100, but I really do measure them in all of my COPD patients because I'm really trying to, I really would like to prevent exacerbation, so I am measuring them a lot more than we used to. Sputum eos are probably more, are more useful than blood, and pheno may also have a role, but I think it's still really being studied, and I think particularly when we're talking about this kind of gray zone of 300 to 100, like what do we do with those patients? So I think hopefully we'll have more data soon with all the clinical trials coming out, and with that, I'm going to give it to Monica. All right, looks like I have about 10 minutes, so I'm gonna talk fast. And you've heard a little bit already, but I figure repetition's good. It only makes us remember things, right? So that's what we're gonna do. So my charge is to talk about steroids and biologics and COPD. These are some of my disclosures, which really actually don't, aren't really relevant to COPD. This is mostly focused on asthma. So what I hope to do in the time I have with you is talk about the evolution of nomenclature briefly from asthma-COPD overlap to eosinophilic-COPD, knowing that some of that's already been covered, to talk about the association of eosinophils with steroid responsiveness and outcomes in COPD, and then talk about the biologics in a bit more detail, maybe a little differently than you've heard, to sort of try to put it all together. Where are we today in 2023? So asthma-COPD overlap is something that many of us got very comfortable with. It was a term, first it was ACOS, ACOS, then it was ACO, really because a lot of the patients who had these overlap symptoms really weren't included in trials, and that's sort of how it sort of bubbled up organically. COPD patients with asthma and allergies, asthma patients who smoke, COPD patients with allergies who had not smoked, asthma patients without bronchodilator response, COPD patients who had a bronchodilator response, and asthma patients with non-reversible PFTs. So a lot of these different buckets, if you will, and not always sure what to do, and one of the challenges, I think, of this whole area is exactly what you see. There are many different kinds of asthma-COPD overlap, and I think that's probably why it didn't really get off the ground. It's not the easiest to study, and I can tell you that from personal experience, having tried to design a trial to study this, we had multiple groups like this, and how were we gonna find these patients and really characterize them carefully and look at precision-based approaches to therapy? It was a daunting task, and we started looking at this in the American Lung Association network I'm part of, but also very costly, and that's where we ran into trouble. It was gonna be a very expensive trial, so it didn't happen, and then I think eventually, as you heard, both Gold decided to make those really, really get rid of this entity entirely and talk about COPD with asthma or asthma with COPD, but still, we know that there is this overlap, and we know that lung function declines, especially in those asthmatic patients who smoke, and that's the, I'm gonna see if I can do this here. Let's see, I'm gonna, actually, you know what? I'm gonna do this. There we go. You can see this line up here. Those are the normals, but the asthmatics who smoke have the most rapid decline in their lung function, and as Stephanie has already told you, she's been doing work in the area of biomarkers in COPD for a long time and actually showed us a few years ago that COPD patients who had high T2 score based on the score that Prescott Woodruff and her group really put together had lower lung function, more eosinophils, more bronchodilator reversibility, and improved air trapping after steroids, and speaking of steroids, sputum eosinophilia has been shown to be higher in ACO and predicts ICS response, so this was sort of the first really, well, one of the papers that really suggested that eosinophils in an entity like COPD could actually change the response to treatment, so over the, now we're here in 2023 and we're calling it eosinophilic COPD, and I would say the definition has also evolved. It really started out as mild was anywhere from 500 to 999 eosinophils per microliter, and this is in blood. Moderate was 1,000 to almost, to 1,499, and severe greater than 1,500 eos per microliter. Then mild then reduced, more to 350 to 500, or 2% of total cells, total cells in the blood, which is what you'll see if you look at some of the studies, and then it even became a little more permissive, showing that with several studies requiring at least 300 per microliter, and then over the course of the trial, and with 150 per microliter required at minimum, and so the cutoff for eos has changed, and that sort of, I think, made the landscape a little murkier, and so the question is, do peripheral eosinophils predict response to inhaled steroids? I think we've seen a little bit of that data already, and does the presence of peripheral eosinophils predict COPD exacerbations? So I will just spend a little bit of time sort of summarizing the data, and you've gotten to see some already, so I guess, like I said, repetition is key. So using a permissive definition of eos greater than 200 per microliter, or 2% of total cells, there was a study of about 479 patients with COPD. 36% met that definition, so pretty decent proportion. These patients had more hospitalizations and readmission after their first hospitalization, so that's relevant. In a different study of about 2,600 Danish patients with COPD who had blood eos a little higher, 343 per microliter, so that's getting a little bit more substantial. They had more exacerbations than those who had less, so in this study, there was sort of a cutoff of almost 350 per microliter, and then lastly, a cohort of 2,400 current and former smokers from the spiromics cohort demonstrated a correlation with blood eo count, this time 200 per microliter, and exacerbations. This was the HASTY trial, I believe, we've taken a look at. So that then begs the question, what is the relationship of blood eosinophils and COPD and response to inhaled corticosteroids? And as you have seen from our speakers, the data are conflicting. Some show that it's beneficial, but where the cutoff is and how much of an improvement is actually a little bit all over the map, and data are conflicting across individual studies, some post hoc analyses, but overall results suggest with variability, if you look at the literature as a whole, that ICS can impact exacerbations in lung function really 200 per microliter or above. That's when you start to see a signal. It obviously gets stronger as the count increases. There were two meta-analyses that showed that ICS did not confer benefit when the peripheral EOs were low, so less than 150. So that's actually helpful, it's quite definitive. And the presence of elevated blood eosinophils does not increase risk for pneumonia, and I think that's also important. Doesn't mean that ICS doesn't, but EOs themselves do not increase risk for pneumonia, and I think that's an important take home message as well. And so we've seen a couple of these slides already from the GOLD 2023, really looking at non, well, I always like to mention this first, non-pharmacologic therapy for COPD. Not spending a lot of time on this, but just to kind of remind us, we need to talk about physical activity, smoking cessation, vaccinations, all those things first. And then we can think about pharmacologic treatment. And we can see in anti-inflammatory COPD, certainly an ICS component with a LABA is actually very helpful, especially in those patients who have higher eosinophil counts, and that's in the GOLD guidelines. And in fact, regular treatment with inhaled corticosteroids does increase the risk of pneumonia, especially in those with severe disease. So we have to really balance the adverse effects of ICS, especially in severe disease, versus the benefit in the setting of eosinophilia, and I think that's where, especially in more severe disease, it can be a little bit gray. As I mentioned, lower sputum, blood and sputum eosinophils are associated with greater presence of proteobacter and haemophilus. And then, and I'm not gonna read all of this, but the bottom line is, the importance is really to look at the level of blood eos, look at the exacerbations that your patient is having, and that helps in the decision-making process around the use of ICS. And I think this slide actually says it very nicely. If there's a history of any hospitalizations or exacerbations of COPD, especially two or more, with blood eos greater than 300, and if there's any history of concomitant asthma, I think that really strongly favors ICS use. Then there's the middle ground, where the eos can be between one and 200 and perhaps one exacerbation in the last year, and then against it would be certainly repeated pneumonia events, blood eos less than 100, and then history of mycobacterial infection. So I think this slide is actually quite helpful to sort of decide when do you really think about it strongly versus absolutely not, and then there's a little bit of that gray zone when the eos are between 100 and 300. So the key points for anti-inflammatory therapy is long-term monotherapy with ICS is not recommended, and certainly you don't wanna use LABA-ICS and COPD if there's an indication for triple therapy, for sure. And then in patients with very severe airflow limitation, chronic bronchitis and exacerbations, think of other treatments, such as the addition of PDE4 inhibitor, long-acting bronchodilators without corticosteroids can be considered. And then certainly preferentially, but not only in former smokers with exacerbations, despite appropriate therapy, macrolides might be something to think about as well. So we have other alternatives besides ICS. And I think Stephanie showed this slide, really with the focus on this group E, these are the frequent exacerbators, and again, really 300 is the level of eos that the goal guidelines have really sort of settled on, and that's a pretty robust eosinophil count. This is what we think about in asthma as well in terms of response to, especially the IL-5 inhibitors in particular, and so we see a robust response, and I think that's why that and some data that we'll talk about in a minute really is a good place to land. And then of course, the management cycles, of course first you want to look at symptoms, dyspnea and exacerbations, you use the inhalers, you assess, and then you adjust. And this is obvious, but I always like to sort of remind myself that it's really a continuous level or a plan of assessment and reassessment to make sure your patient still needs the medications that you've prescribed and not to leave them on something for long term. And I think we've already seen this slide, but really focusing more on the idea that if eos are high, that you would consider an ICS, and again, 300 seems to be the level that the goal guidelines have settled on. And then the ultimate goal for treatment-stable COPD is of course review symptoms and reduce exacerbations, of course being the main goals. So let's talk a little bit about biologics, and I know we've talked, you've heard a bit about the IL-5 inhibitors, and I wanted to just talk about this Cochrane analysis that I think was actually quite instructive, and this is looking at anti-IL-5 therapies in COPD. And so of course we know monoclonal antibodies targeting IL-5 are used for the care of patients with severe eosinophilic asthma and have been for a while now. And that there's a nice safety signal actually in asthma, which is good. And in this study, the authors looked at six randomized controlled trials studying about 5,500, a little over 5,500 participants with COPD who received anti-IL-5 therapy or placebo. And the results were this. So mepolizumab, 100 milligrams, reduced moderate or severe exacerbations by about 19% in patients with high EO counts, and in this case it was only 150 per microliter, and 8% in those with lower eosinophil counts. Mepolizumab 300 likely reduces the rate of exacerbations by 14%. So 100 and 300, the authors kind of hedged and said, likely reduce exacerbations, moderate and severe, in participants with eosinophilic COPD. Benrolizumab at 100 reduced the rate of severe exacerbations, but those who had EOs greater than 220. And then 100 probably reduces the rate of severe exacerbations requiring hospitalizations, again 220 being the cutoff. Benrolizumab 30, which is something we use in asthma, didn't have much of an effect at all. So the conclusions were that treatment with mepolizumab and benrolizumab appeared to be safe, there was little or no impact on these products on quality of life measures, and both products likely reduced the rate of moderate and severe exacerbations in patients with COPD with high levels of eosinophils. But the cutoff was not clear, is what the authors concluded. And I just wanted to show you a little bit of the actual data, and I'll go through this relatively quickly. So this is mepolizumab 200, and these are the folks with eosinophils, elevated eosinophils, and this is the metrex and metreo studies. And you can see just barely on the side of the line that favors the biologic. And this is for rate of moderate to severe exacerbations. And this is time to first exacerbation. You can see that one of the two studies, really stratifying by eosinophils, showed an effect, the other one didn't. And this is looking at rate of severe requiring hospitalizations, just barely one of the studies showed that. So I think this, a little bit of inconsistency across the two studies is probably one of the reasons that this ultimately wasn't approved by the FDA for treatment of COPD. There seems to be a signal, but it just wasn't consistent across multiple endpoints. And here we're looking at serious adverse events with mepolizumab, of which there's no change. And here's quality of life, which there's no change. And just to round this out, we're also looking at outcomes, COPD assessment tests. The CAT score, no big changes there. And this is looking at benrolizumab, 100. Again, this is looking at the rate of severe exacerbations. And you can see that there might be a little signal here, in the, here in particular, in this eosinophilic phenotype there. You can see that. But when it comes to rate of exacerbation that doesn't require hospitalization, just barely right here. But there's a very, they're not huge signals, I think is the take-home message. And then the study was done, as you probably, if you attended ATS, you probably saw the presentation. And this is looking at dupilumab. So instead of an IL-5 inhibitor, looking at four and 13. And these were patients with COPD who had elevated eosinophil counts of 300. And so, again, a little higher than the IL-5 studies. And we know that dupilumab targets the IL-4 receptor alpha, so inhibits both IL-4 and 13. And so, this is table one, looking at the different, the demographics of the patients. And I think the only thing to point out here is that the number of black patients or participants was quite underrepresented in the study. Otherwise, and then there also, the study was not stratified for former and current smokers, which is interesting. But otherwise, you can see that they had evidence, certainly of, I'll go to the next slide to show you. They had eosinophils that were elevated, and a good proportion had elevated pheno as well. And so, I think the bottom line is treatment with dupilumab resulted in lower annualized rate of exacerbations. And it went, it actually decreased, and you can see here. And the safety also, with the percentages of adverse events, were similar in the two groups. So, with all comers, again, making sure those eos were 300, you saw a change in the exacerbation rate, which you see here. It wasn't a huge change. It was 1.1 per year to 0.78. So, you have to decide amongst yourselves if you think that's a big change as a group. But these are the, more of that data, looking at the cumulative number of events, and then looking at lung function. There was about 160 mil improvement in the dupilumab group versus 71 mils in placebo. The difference was statistically significant. It's a, you know, it's, you have to decide, is it clinically significant? That, I think, is actually, it's reasonable for COPD, because these were folks who did not have reversibility. And then a couple of key points, just to show you. Here, a lot of these secondary endpoints, which were change in bronchodilator FAV1, also improved significantly, along with the exacerbation rate. And then there was also some nice changes in quality of life, which the IL-5 inhibitor studies did not show. So, overall, there were some limitations in that the trial was conducted during the COVID-19 pandemic, which may have affected patient behaviors, exposures, frequency, and exacerbations of COPD. Those patients who identified as black were underrepresented and randomization was not stratified according to smoking status, which can affect exhaled nitric oxide. But overall, amongst patients with COPD who had type 2 inflammation, as indicated by these elevated EO counts, 300, who received dupilumab had fewer exacerbations, better lung function, better quality of life, and less severe respiratory symptoms compared to those who received placebo. So this was a much more, I think, definitive study. I think it would be nice to see a second one, just as we saw in the IL-5 situation. There were two different studies really looking at IL-5 inhibition. I think that my understanding is plans are underway to actually repeat this. And so it would be nice to see if this is a consistent finding, again, in a broader patient, or in another population of patients with COPD who also have eosinophilia. And so that remains to be seen. So in conclusion, I think I would say an eosinophilic phenotype does exist in COPD. I think focusing on IL-5 showed some benefit in selected patients with elevated blood EOs, but it just wasn't something that was really consistent across the board. I think inhibition of 4 and 13 may have more widespread effects, and I'm going to just hypothesize about what's relevant to the COPD airway. Inhibiting 4 and 13 may have effects on mucus secretion, collagen depositions, muscle contraction, all of which could benefit the airway in COPD. And perhaps that's one reason why we saw more of a benefit with dupilumab compared to IL-5 inhibition. But that really deserves more study. So with that, I'll stop, and thank you for your attention. Thank you.

eosinophilic COPD

asthma COPD overlap syndrome

heterogeneity in COPD

evolving COPD

eosinophils as biomarker in COPD

treatment decisions in COPD

corticosteroids in COPD

biologics in COPD

individualized treatment in COPD

research on eosinophilic COPD