Hi everyone, and welcome to the session. We're going to get started. We're going to be talking about the controversies in asthma COPD overlap today in a pro-con debate format. My name's Niveda Murugesan. I'm one of the pulmonary and critical care fellows at the Baylor College of Medicine, and I'll be the moderator for the session. I personally don't have any disclosures. And here are a few of the lesson objectives for the next hour we're going to talk about. I'll begin this hour with a case presentation. So this is a 61-year-old male who presents to a pulmonary clinic with nocturnal and early morning shortness of breath, cough with expiration, and wheezing episodes for the past two weeks. He was diagnosed with COPD about six years ago and has a 20-pack year smoking history, but quit over 10 years ago. And when you interview him, he states that he's noticed some seasonal variation of breathlessness and states that he also has noted that dust and cold weather can also worsen his breathing issues. On exam, he's got your classic barrel-shaped chest, clubbing of his nails, and some bilateral bronchi with decreased breath sounds. Some recent lab work you reviewed, and you see that hemoglobin was 12.9, but his absolute eosinophil count was pretty high at 766. And his spirometry testing is as below. You notice a 12% improvement in FEV1 after a single-dose bronchodilator and a 20% improvement in his FEV1 and FEC ratio. So what is the diagnosis for this patient? To begin our discussion, it's my absolute privilege to introduce Dr. Nicola Hanania to make his case on why asthma and COPD overlap does exist. Dr. Hanania is currently the Section Chief of the Pulmonary and Critical Care Division at Benton Hospital in Houston, Texas, and also the Director of the Airways Clinical Research Center at the Baylor College of Medicine. He completed his medical training at the University of Jordan and his residency and fellowship at the University of Toronto. He's currently Editor-in-Chief of Respiratory Medicine and has prolifically published throughout his career. Without further ado. Thank you very much for the invitation, and aloha, everyone. I'm glad to be here in Hawaii, enjoying the good weather. I'm also glad that I was given the pro part of this discussion. And I apologize, Garbo. Dr. Mack is going to be trying to show me that maybe it does not exist. The question I was given was a simple one. Does asthma-COPD overlap exist? And you heard my conflicts of interest are here, none of which I believe will influence today's discussion. These are my learning objectives in the next 12 minutes. I'll try to point out why I believe and strongly believe that asthma-COPD overlap is an entity. Why is it important? What are the challenges in diagnosing this entity? And review some of the clinical implications. And maybe if I have time, discuss some of the future needs in this area. Well, going back to the 1960s, most of you maybe were not born there, but I was. But I don't remember this, but I read about it. The Dutch hypothesis. The Dutch came up with this hypothesis that asthma-COPD is a spectrum of one disease. In fact, they came up with this chronic nonspecific lung disease, which we don't use anymore. And in this bronchitis book that Dr. Ory, Professor Ory wrote, he actually mentions that one must be impressed by the very long road medicine must travel before understanding where the disease is reached, even if clinical symptomatology is relatively simple. Well, the debate continues. The British hypothesis says absolutely not. These diseases are too different. They have different risk factors. They should not be lumped up together. And again, Fletcher and others have written on this for many years. Well, I was asked, does asthma-COPD overlap exist? So the easiest way for me, going to Mr. Google and looking at Wikipedia. Well, Wikipedia says it does. But actually, more important is Chad GPT. I asked Chad GPT, does asthma-COPD overlap exist? And he says, yes. ACOE is recognized medical condition, Dr. Mack, where individual exhibit characteristic of both asthma and COPD. But on a more serious note, there's no question that there's quite a bit of overlap between asthma and COPD. Both are genetic environmental diseases. And certainly, distinctly, asthma tends to be, although not always, an allergic-driven, is an aphilic-driven, T2-inflammatory-driven with airway hyperresponsiveness. The pure COPD are the ones that, you know, I smoked for a long time, have fixed airway obstruction, emphysema on CT, low diffusion, and the non-T2 type of inflammation. However, many, many years now, now for the last at least 10 years, we have to recognize that these two can overlap. In fact, many COPD patients have had asthma in childhood and developed COPD later on. In fact, some epidemiologic studies suggest asthmatics are at higher risk of developing COPD if they have airway hyperresponsiveness and smoke. But at the same time, some asthmatics may grow older and have fixed airway obstruction that mimics COPD. But what's interesting is this ACOE type of definition has been linked to several outcome measures, including higher symptom burden, higher exacerbation, and potentially lower FEV1 decline. But we've debated this for a long time. There's been several consensus statements, criteria that have been published. I won't have time to go through this, where they actually talk about the COPD criteria and the asthma criteria. And there's major and minor and all this stuff. But I want to draw your attention that Gina and Gold, and I'm not a member of either one, I respect every member there, has actually shied away from using that term a few years ago. And they mentioned that there's no specific criteria for persistent obstruction. And diagnosis is based on simultaneous features of both. So this is what Gold and Gina suggest in their latest reiteration. Well, guess what? Gold 2023 was published. And here you go. They come up with another terminology, or etiopathogenesis for this COPD. And look at the COPD-E there. They call it now COPD-A, which is COPD and asthma. So even within our esteemed colleagues who write strategies and, I want to say, guidelines, there's still this asthma issue comes up whenever we talk about COPD. Well, let me review with you what we know about the prevalence of this entity, depending on which definition you use. There's been some interest in looking at, obviously, prevalence of this disease. It tends to be higher in older patients. In the asthma population, it's about 10% to 31%. In the COPD population, it's about 25%. So it's about 20% if you take the average. And in fact, a recent systematic review that looked at 27 studies published looking at prevalence, the estimate is about 25% of patients with COPD have concomitant asthma. But not only that, but most of these studies have agreed that patients with ACO, previously called ACOS, their syndrome was dropped off appropriately. Patients with ACO tend to have higher symptomatology and higher comorbidities than patients with asthma alone and even COPD alone. Now, obviously, we have to admit there's quite a bit of overlap in symptomatology. ACO patients tend to be older than asthmatics, but younger than the pure COPD. They tend to have both asthma features and COPD features. Physiologically, and this is neat work from David Kaminsky in a recent paper, a review paper I'll buy it, showing that there is some data to show that ACO tend to have more fixed auto-weight obstruction, hyperinflation. There's more data that needs to be generated regarding use of oscillometry and other physiologic tests. And pathophysiologically, this ACO tends to have evidence of inflammation of both asthma and COPD, where T2 inflammation may be present there, looking at blood eosinophils and also other T2 inflammatory cytokines. But we sort of understand, and I understand the complexity of this, that ACO does not have one face. Just like asthma and COPD, there are multiple phenotypes. And this is some work that we published with my friend Louis-Philippe Boulay at one time where we said, well, there are some sub-phenotypes of COPD that may be in this ACO category, but also there are some asthma phenotypes that may be lumped up in the ACO. So there is no question that there are multiple phenotypes for ACO. And it is not just one type, one disease. People have done other ways to propose phenotypes. These are data we published a few years ago where we looked at the different phenotypes based on their smoking status, whether they have asthma or also based on the presence of allergy or high blood eosinophilia or reversibility to bronchodilator. And there are at least four phenotypes that we described. I won't go through this in detail because of the time. But we have to admit, yes, it does exist, but it doesn't exist as a one face disease. And it does have an impact on outcomes. Now finally, what is the clinical implication of ACO? Well, obviously, the approach to ACO should be the same way we approach asthma and COPD. We're going to be talking about treatable traits in a few minutes. But it's certainly important to look at the history, the exposures, the biomarkers, and comorbidities. These patients tend to have comorbidities of both asthma and COPD. Not only the COPD comorbidities, but the asthma comorbidities are often there and should be treated and assessed. Obviously, assessing symptoms and treatable trait is very important in this type of approach because it will affect your treatment strategies. And in general, one of the biggest challenges in diagnosing ACO is the initial use of inhaled corticosteroid in these patients. Where we don't do that in COPD, pure COPD patients, we do that in all patients with persistent asthma. And in ACO, inhaled corticosteroid should be used as an initial therapy. Of course, other bronchodilators. Of course, let's not forget that there are non-pharmacologic approaches for this disease, including monitoring, adherence, approaching treatable traits, pulmonary rehab, and occasionally other intervention. There are several potential novel therapies and targets as we know more about this disease. One of the biggest challenges has been regarding therapy, and I'm a clinical trialist, is that ACO patients have notoriously been excluded in all clinical trials. In the asthma trials, we don't include smokers with fixed area obstruction. In COPD patients, we exclude asthmatics. So clinical trials on ACO population are not really abundant. There may be a few, one or two small trials. But there are potential for novel therapies, including biologics, in this type of patient population. And of course, the non-pharmacologic approaches are important, just like they are in COPD, including exercise training, smoking cessation, and vaccination. And of course, identifying and treating comorbidities. So my take-home message is that I definitely believe ACO is a distinct entity compared to asthma and COPD. It is often challenging to diagnose, but it's important as pulmonologists to understand and agree that this entity does exist. It has clinical implication and treatment implication. There may be some shared physiologic and pathologic features between both asthma, COPD, and the asthma-COPD overlap management. And I look forward to the next pro and con in this session about treatable trait. You know, I don't want to bias this, but I believe treatable trait strategies should be implemented in this disease. Managing comorbidities is important. Now what we need, and this is important, is we need larger longitudinal studies to understand the natural history of patients with ACO. We need to understand molecular mechanisms and possibly identify biomarkers. There are a few papers out there that identify biomarkers that are unique for this population, not to asthma alone or COPD alone. We also need to enroll these patients in clinical trials in the future to see how they do on the long term, especially when it comes to targeted therapy. So in essence, the question is, does asthma-COPD overlap exist? And I say absolutely yes. I am a strong believer in this. In fact, I edited the whole issue on immunology in clinical and allergy clinics. We published this in August, and I have several reputable authors who published their opinion on different aspects. I recommend this. Of course, I'm biased. But also, if you don't want me, you can ask Don Sin and his colleagues from Canada. He actually published this very nice review in just what are the important questions. And this is my email and Twitter. I look forward to your comments and questions. Thank you very much. So next, I'll introduce Dr. Mock. She is currently an assistant professor in the Division of Pulmonary Critical Care and Sleep Medicine at the University of Washington in Seattle. She graduated, actually, from Baylor College of Medicine, where she did her fellowship. And she was recognized multiple times, won awards at the Best Graduating Fellow and Award of Excellence as the Best Outpatient Clinic Fellow as well. She's active in her asthma research and quality improvement processes, especially in the outpatient setting. Now, even though Dr. Mock may have trained under Dr. Hanania, she may not share the same views as her mentor. So I look forward to the next conversation. Thank you, Niveda, for the introduction. Good morning, everybody. That is a really difficult talk to follow, so I will do my best. My topic is on why asthma and COPD are distinct diseases. And I also wanted to add why we should abandon the term asthma-COPD overlap. I have no disclosures. So it is very tempting to lump together asthma and COPD because they share common features. However, in the practice of medicine, we recognize that it is very important to recognize separate entities and separate diagnosis. The reason for this is because having a diagnosis helps guide treatment. It sets expectations about prognosis. And it also facilitates communication amongst clinicians. And so for some time now, we've known that asthma and COPD are separate conditions because they have different variable clinical features, as well as spirometric data, and also are associated with different types of conditions, as well as exposures like smoking. Asthma and COPD are also different because they have different risk factors in terms of development of the disease and expression of the disease. And so for some time now, we've recognized that asthma and COPD are distinct entities. And typically, in clinical practice, it is very easy to distinguish a patient with either asthma or COPD. The pathophysiology is also different amongst the two. Asthmatic inflammation is typically characterized by Th2 inflammation with eosinophils and mast cells and Th2 lymphocytes. There's also a role for airway hypertrophy, as well as hyperplasia. And this is in contrast to COPD, where the airway inflammation is typically Th1 mediated with neutrophils and macrophages. There is also a disruption of alveolar attachments, which results in obstruction, and also a role of inflammatory obstruction within the airways. However, it is also important to emphasize that distinguishing pathophysiology between these two is very important. This is probably most recently seen with our advancements in severe asthma. And so being able to identify a pathophysiology is really at the forefront of providing personalized, as well as precision medicine. Asthma and COPD are also recognized to be distinct diseases. In fact, we have multiple global guidelines, initiatives that really highlight the difference between the two. For example, the Global Initiative for Asthma and the Global Initiative for Chronic Obstructive Lung Disease are published yearly in order to help guide clinicians on how to best manage this disease. So again, very important to distinguish between the two. And although asthma and COPD are distinct, we do recognize that they are heterogeneous. And within asthma and COPD, there are different phenotypes, just as Dr. Hananya had highlighted. Some of the phenotypes that we commonly think of for asthma would include Th2 high inflammation or T2 low. And then in COPD, we may also have differences in airway inflammation, depending on neutrophilic or eosinophilic presence, and also some radiographic findings like emphysema. And I'm not going to say that asthma and COPD can't coexist, because I do believe that they can. But they are common diseases, and so there are going to be individuals who may have expressions of both. And it is common for, perhaps, an asthma patient to have these classic features of COPD, like fixed airway obstruction. They may be smokers. There may be neutrophilic inflammation. And in a COPD patient, for them to have asthmatic features, such as bronchodilator responsiveness or eosinophilic inflammation. And so this term, asthma-COPD overlap, coined by Dr. Gibson here in 2009, was kind of brought into the medical literature as a way to define these patients. But truly, what is asthma-COPD overlap? Well, as Dr. Hananya had already described, but I'll go through these slides anyway, is that there are multiple proposed theories of what ACO is. The first, this here, is demonstrating the British hypothesis, which shows that asthma and COPD are separate entities. They have distinct inflammation. They have distinct genotypic phenotypes. And then in this construct, ACO is a completely separate entity with its own inflammatory markers and its own genetics. There is this kind of a subtype of the British hypothesis, which, again, asthma and COPD are separate and distinct diseases, but that there is an overlap, some type of additive or synergistic interaction of pathologies. And then it is also a separate entity. And then there's the Dutch hypothesis, where asthma and COPD are on the same spectrum. And then due to a difference in exogenous and endogenous factors, the expression may be different. It can be anywhere from asthma to COPD to anything in between. But despite having all these hypotheses introduced in the 1960s, today we still do not definitively know if these actually exist, and these have not been proven or disproven. So one of the biggest drawbacks is that we don't have a definition for asthma-COPD overlap. In fact, many people have attempted to, based on expert opinion, either by different authors or by different consensus groups. And they do use a number of major and minor criteria, some of which are similar, but there are also a lot of differences between what people think is asthma and COPD overlap. Another downside to this is many of the criteria are looking at COPD patients who might have features of asthma, but there's not a lot that really look at the inverse. So it really just focuses on a very small subtype, subpopulation within this proposed condition. Probably one of those most recognized definitions was published in 2015 by Gina and Gold. And the way that they defined asthma-COPD overlap is that it's persistent airflow obstruction with several features usually associated with asthma and several features usually associated with COPD. So this really highlights how diverse of a patient population this can include and how nonspecific and how it really lacks a lot of clarity. So I wanted to bring up a few clinical scenarios where we might think of someone having asthma-COPD overlap. The first is a middle-aged asthmatic who perhaps has a 10-pack year history of smoking and then has fixed airflow obstruction. So the smoking and the fixed airflow obstruction are considered features of COPD. But smoking, as we know, doesn't always lead to COPD. In fact, some people may never have symptoms associated with it. And also fixed airflow obstruction is a feature that we've seen in several individuals with asthma, just a natural evolution of their disease. So truly, is this patient who's asthmatic, has maybe a lighter smoking history and fixed airflow obstruction, are they truly having COPD? I think another way to think about it here is that over a lifetime, years on the x-axis and symptoms on the y-axis, where there may be asthma onset in young childhood, a patient starts smoking, maybe alters the airway inflammation, causing reduced symptoms, and then they developed airflow obstruction later in life, that we should really call it what it is. This is an asthmatic who has fixed airflow obstruction but doesn't necessarily have COPD. Another clinical scenario, and this is actually very similar to the patient that you presented in the beta, is a older person who has a history of heavy smoking but also has bronchodilator responsiveness and eosinophilia, features that we more commonly think of as being asthma. However, we do know that patients with COPD can have bronchodilator responsiveness. It's not just classically associated with asthma. And eosinophilia, similar in a normal population, there's going to be a distribution. So why is a cutoff of 300, which, by the way, is a normal value on many reference labs, why is that diagnostic of asthma? And we actually don't use it as a diagnosis for asthma. So let's say that, however, this patient does have clinical features of asthma and COPD. Perhaps a better way to describe and to think about it is that after onset of smoking later in life, they can develop airflow limitation. And then because of the smoking, they are then sensitized to an airborne allergen, which then becomes a risk factor for their asthma development. And then they can develop some different and overlapping features of bronchodilator responsiveness and eosinophilia. I also want to emphasize the importance of a diagnosis, kind of going back to the fact that when we have a diagnosis, a very specific term, we want to be able to set expectations about a patient's prognosis and also be able to communicate as either subspecialists or to primary care doctors as well. And so when we use a term like asthma-COPD overlap, it is very confusing because it really implies that this is a homogenous entity when, in fact, it really isn't. And so this oversimplification makes it really challenging to determine the most effective therapy for an individual person. And in fact, there is a risk if we label any patient who has COPD who has bronchodilator responsiveness as asthma, then we risk overtreating them with inhaled corticosteroids, which we also know are associated with comorbidities like increased risk for pneumonia. So I really propose moving away from asthma-COPD overlap as a term. And in fact, in 2020, GOLD has stopped referring to asthma-COPD overlap. And taken directly from their initiatives, they say we emphasize that asthma and COPD are different disorders and that an individual can have coexistence of asthma and COPD. There can be overlapping traits, but they really are separate. And as Dr. Hanania had outlined as well in this most recent publication, GOLD has a newly proposed taxonomy or classification of COPD for patients who develop COPD without that significant tobacco smoking. And so please note that they call it COPD and asthma. They don't call it COPD, asthma-COPD overlap. So in conclusion, I think that asthma-COPD are distinct diseases. They may coexist in an individual, and there may be some shared clinical features as well. However, we should call a condition by what it is, asthma and COPD, with specific features or specific traits. And we should also be using the guidelines that we have for both of these conditions in order to help guide treatment. Thank you. Thank you. I don't know, Dr. Hanania. I think she did a pretty darn good job there. OK. So let's now shift our focus to talking about the treatment strategies for these patients. The next speaker is here from Australia, and it's my privilege to introduce Dr. Peter Gibson, who serves as the lead for the Severe Asthma Service at John Hunter Hospital in New South Wales, Australia. He's also the chief investigator for the Australian National Health and Medical Research Council Centre of Excellence in Asthma Treatable Traits. Thank you. It's great to be in this session. What we've heard in the first two talks really challenged us about how to label these very common airway diseases of asthma and COPD. And I've lost my slides. Here we go. So the first two talks talked about labelling. And wherever you fall on the outcome of that, whether you believe asthma-COPD overlap should be separate, or as a separate condition, or whether you just should follow asthma and COPD, you're still left with the problem of how do you treat the patient? And that's the issue that I want to address in my talk. So my disclosures are that this concept of treatable traits, I've received research funding from our government, conducted investigator-initiated trials funded by some pharmaceutical companies, and present this work at educational meetings sponsored by pharmaceutical companies. The objectives are what's the treatable traits approach? What's the evidence that supports it in asthma and COPD? And how do I go about implementing it in my practice? So as we've heard, we start medicine by learning about diagnosis. And that's a really exciting phase of your career when you start to recognise these problems and can pick them out from patients and apply the labels asthma, COPD, bronchiectasis. But once you start in practice, you have to go beyond diagnosis. Diagnosis is not enough. And you move away from the disease to managing the patient in front of you. And increasingly, that management is about what are the individual problems in this person that I can address that will improve the health of this person? And that's where treatable traits comes in. So although these groups of people might have asthma or COPD, they don't have the same individual treatment problems. One person might have asthma with severe eosinophilic inflammation, whereas another might not have any of that at all. They might be troubled by obesity or reflux or smoking. And similarly, I think we're reaching a really good position in COPD now. We're recognising eosinophilic inflammation as a separate trait of COPD, and that's allowing us to move forward with treatment. So what treatable traits is seeking to do is identify the relevant individual problems within each person and offer a treatment approach to that. This area received a really strong boost with the results of this trial. And it's an unexpected way that the area might get a boost, because the trial was negative. But in the early 2000s, a highly effective drug for removing eosinophils, mepolizumab, was developed. It was tested in the asthma paradigm, which is a step-up treatment paradigm, applied to the people with the more severe end of the disease, persistent symptoms on ICS larvae. What was the results? No difference in exacerbations. And the authors concluded that mepolizumab is not useful for all patients with persistent asthma on ICS. That could have been the end of the story. But Freddie Hargreave and Ian Payboard, Param Nair, designed investigator-initiated studies which looked closer at this population of asthmatics. So these are the people on maximum inhale therapy, persistent disease, not responding. And they pulled out a subgroup with persistent eosinophilia. Usually recognized at that time by sputum, and you can see the sputum eosinophils in this slide. And when they did that and did two randomized trials, you saw this dramatic reduction in exacerbations, 50% reduction. So we go from a drug being non-effective to 50% effective. They are worlds apart. How could that be reconciled? The reconciliation is the patient selection or identifying the treatable trait of eosinophilic inflammation. So that really spurred on this concept. Okay, can we apply this in other parts of airway disease? So treatable traits is at its heart a model of care. It's a way you go about managing your patients in your practice. There are many traits, over 20. For convenience, we break them into three domains, pulmonary, extra pulmonary, which is comorbidities, risk factor behavioral, smoking, inhaler technique, adherence. To be a trait, something has to be clinically relevant, identifiable, and treatable. What's the evidence supporting treatable traits? So here we have a table of all the traits, and Catherine Dusik has searched the literature to grade the evidence that supports the treatment of each individual trait. And that's graded one to four using a grading system. One and two are randomized trials, systematic reviews of randomized trials. So you can see that for each individual trait, there's an evidence base that's high level and says, if you give this treatment for this trait, the patient will get better. And there's no surprises there. These are clinically recognizable traits, and we're familiar with many of the treatments. What about applying this concept in practice? So in this systematic review, SAWA pulled out clinical trials that use the treatable traits approach in asthma and COPD, but they had to use approaches which treated traits in every domain. So the pulmonary domain and the extra pulmonary domain and the risk factor behavior domain. So what they found was there were a small number of randomized trials that did this. They were mostly in COPD, but when they did it, on average, there was a clinically significant improvement in quality of life. So here we have the St. George's respiratory questionnaire. The improvement is a reduction of a score of 6.9, and four is the minimum clinically important clinical difference. So on average, treatable traits applied to asthma and COPD improves quality of life, and it also reduced hospitalizations. So this approach is effective for the patient and the health care system. But one thing you will notice is that there's mainly trials in COPD, and the positive trials are all in tertiary care. So a challenge we have is translating this into primary care. Now I also want to draw your attention to this trial. So this trial tried to treat as many traits as possible in the setting of a severe asthma clinic. And it's a good trial to sort of think about. It reflects the type of clinics we might be. We do run in CF, multidisciplinary clinics. We're starting to run in severe asthma, and it might be a way forward for complex airway disease, COPD, bronchiectasis, and severe asthma. So in this study, Vanessa McDonald recruited adults with severe asthma, randomized them to usual care or a treatable traits approach, and then assessed quality of life at the end of 16 weeks. This was a very intensive intervention. These are all the traits that she identified, and if they were present, offered treatment. So patients were having between five and eight visits to receive these treatments. They're all evidence-based treatments in themselves, and she looked at the combination. The challenge was how do you actually implement this? And the way she did this was with a case manager, usually a specialist nurse that organized the patient and the doctor and the investigations so that they could be delivered in a systematic fashion. What were the results? So quality of life showed a 22% of people in the usual care group had a clinically significant improvement in quality of life compared to 55% in the treatable traits group. So over and above pharmacotherapy, which people got in usual care, once you add on treatments for these other traits, you start to get further increments in quality of life. How do you actually do this in practice? This is an ongoing question. This study has been helpful. This is the novelty study where over 11,000 adults with asthma and COPD across the world were evaluated in usual clinical practice for treatable traits. So it shows that you can do it in practice. The graph on your right shows that on average, patients have five traits, whether you label them as asthma, COPD, or asthma and COPD. And the bar graph, the importance here is not so much the labels, but just look at the spectrum of traits. It's highly variable. So although people have five traits, the prevalent traits are quite different. But you will see that there's a handful of traits that are present in at least one in three of patients with adults with asthma and COPD. So they're probably the traits to go after firstly. Another way to approach this question of what traits to target is this issue is looking at these features of the traits. Is the trait prevalent in my practice? The novelty study can help answer that for you. Is it treatable? How treatable? What's the impact and risk of the trait? What's it associated with? If you treat this trait, will you get any other add-on benefits? That's the concept of connected comorbidity. And is the trait a priority for the patient and or the clinician? In Newcastle in Australia, when we ask that question in our practice, and we just look at the pulmonary traits, we think these are the important pulmonary traits, which have clear treatment implications. Air flow obstruction, treated with larval lama. Emphysema, treated with smoking cessation and other interventions. Eosinophilic bronchitis, treated with in-house steroids or monoclonals. And then this last complex group of mucus bacterial colonization, which we tend to use macrolide antibiotics for. Another approach is to say, what are the super traits? What are the traits that are so important that I must look at in every setting? And we would say that these are the ones I've mentioned. Obstruction, eosinophilic bronchitis, mucus hypersecretion, together with smoking cessation. And just to highlight here, each trait has its own objective marker, a trait identification marker. So you can work those out for the ones on the left. For smoking, it will be self-report or could be exhaled carbon monoxide. The next super trait is self-management skills, which is inhaler technique and adherence. And then lastly, I've put physical inactivity, but it could be a comorbidity that's prevalent and important in your practice. Another one that's relevant in severe asthma, for example, is vocal cord dysfunction. So if we take that as how we might go about putting treatable traits into practice, let's look at T2 inflammation as a super trait. And I want to draw your attention to this recent publication. So this is the Boreas study using dupilumab and anti-IL-413 monoclonal for patients with eosinophilic COPD. There's a few points to make here. Look at the title, COPD with type 2 inflammation. That shows you how far we've come. We're not saying asthma COPD. We're not saying COPD with asthma. In the early part of this century, I don't believe this trial could have been done because our concepts would have prevented this sort of trial being done. If you agree with that, you have to ask the question, would we have this drug for these people if we didn't change our thinking about what asthma and COPD has and the importance of identifying traits? So I think we've really matured our concepts and COPD with type 2 inflammation has shown to be a useful way to get a new drug. And does it work? Yes. So here we see a 30% reduction in exacerbations, not as big as in severe asthma, interestingly. But we also see a clinically significant improvement in lung function. So is T2 inflammation a super trait in asthma and COPD? Well, yes, it's prevalent. It's highly treatable. We know a lot about its impact on exacerbations and even death. It's connected to other comorbidities such as polyps and rhinosinusitis. It's becoming a priority for clinicians. Is it a priority for patients? I think most patients don't know about it, whereas allergic inflammation, for example, is a priority for patients. There's a number of examples of how you go about treatable traits in practice, and these are referenced using checklists, multidisciplinary teams, or setting up a service. And so I would conclude by saying that treatable traits is a model of care to manage complex and severe airway disease. It's more effective than step care, and it's now the standard of care for severe asthma in the GINA document, and it's referred to as a mode of practice in gold. So I've tried to present you some evidence that describes treatable traits, supports its use, and describes how to use it in practice. There's one thing I've missed, and that's the patient voice. What do our patients say to us? This woman, an older woman with severe asthma, highlights the importance of her individual type of asthma, and patients are recognizing the need for personalized medicine. Treatable traits is one response to that. And I'll leave you with this poem, which is a palindrome. You read it from the top, and then you read it from the bottom. And it might be how someone might respond to treatable traits. It's too hard, so don't tell us that treatable traits is a new paradigm, because the reality is that regulators won't support it, and don't trust anyone who says we need to demand better outcomes, because I am living my life with breathlessness. Now read it from the bottom. Because I'm living my life with breathlessness, we need to demand better outcomes, and don't trust anyone who says the regulators won't support it, because the reality is treatable traits is a new paradigm. So don't tell us that it's too hard. Thank you. Thank you so much, Dr. Gibson. So finally, last but not least, is Dr. Arjun Mohan, who serves as the associate professor at the University of Michigan. After completing his fellowship at the University of Buffalo, he focused his attention on severe asthma, and founded several programs at East Carolina University and Virginia Commonwealth University before moving to the University of Michigan. He actively leads several clinical trials, and is active in development of guidelines for the disease. So Arjun, Dr. Mohan. Thank you for that kind introduction. Now, I truly have an uphill task, right? Not only am I a fan of Peter Gibson's work, not only do I believe in treatable traits, but he also softened you up with that patient voice right at the end, which I don't have in my talk. So talk about starting from a losing place, but let me do my best. I have no disclosures, except deep, deep, deep in my heart, I agree with the treatable traits approach. And the only other disclosure is, I'm going to use some strong language as a way to do some voodoo magic and convince you of why I don't think we're ready for the treatable trait approach. So the key here is approach, okay? So I'm going to keep using that word. I'm going to briefly go over some of the stuff Peter has already spoken about, to understand and contextualize the treatable trait approach as a con for my conversation, review treatable traits as advertised, i.e. an alternative to the stepped approach, which I kind of disagree with, really highlight the shortcomings of this approach, and give you some time to think about where it may fit into where we're going with asthma care and COPD care. I feel we just started getting the messaging right about endotypes and phenotypes. I feel like I've just started to grasp these concepts and apply it to patient care, and now we have to think about it in a very different way. And that's fine. I mean, treatable traits are attractive, right? They're traits which have specific, offers specific therapeutic targets for individualized patients based on their endotypes and phenotypes. Another way of thinking about it would be they are observable and treatable features of disease that describe differences between individuals of the same disease as they relate to meaningful outcomes. Again, the approach fails because we're going to start talking about meaningful outcomes. If you read the literature, if you hear from advocates of treatable traits, the biggest reason they advocate for treatable traits is because it offers an alternative approach to the one-size-fits-all stepped approach that's currently in many guidelines and reports. And in some ways, treatable traits is the natural evolution in an approach for the management of asthma because it paddles our understanding of asthma. We like to get all the basic science and pathophysiological advances we made in literature to our patients as soon as possible. Hence, when we moved away from thinking of asthma as a cluster of features and moved towards endotypes and phenotypes, it makes sense that the next step would be to break it down more in a way that we can improve clinical care. And the other part of the reason why we want treatable traits to exist and have that approach in our armamentarium is because biologics are not taking us all the way. Anywhere between 30% to 50% of our patients are partial responders to biologics and concerningly, 10% are non-responders. So maybe the solution or the maybe reason we all want to believe deep in our hearts that treatable traits is the answer is because we know even these highly expensive and highly effective targeted therapies don't always work. I like how treatable traits is packaged. It's packaged by saying, hey, we can simplify this in a way that's palatable. We can call them traits which affect the pulmonary domain, traits which are behavioral or lifestyle-related, and those which affect the non-pulmonary domain. And again, in jest, it's kind of important to point out that a vast number of these traits are actually non-pulmonary or behavioral in nature. So that's kind of an interesting observation right there. I also do want to kind of go over some of the great work that's been done with treatable traits at Newcastle with Peter and Vanessa. This highly cited randomized controlled trial is a testimonial to why we should at least consider treatable traits. They had 55 patients in a single center study and they put 27 patients in the treatable traits approach and 28 in the treatable traits and 27 in the usual care. Had a case manager do some absolutely fantastic work with them for 16 weeks and then showed that that approach did improve quality of life as measured by the AQLQ score and the difference was significant both from the patient's own baseline as well as opposed to usual care. I will pick on this study a lot to prove my points, so you must forgive me if you have been part of the study or authored it. This study and others like it, again, came up with a systematic review that Peter presented, essentially suggesting strong trends towards why this approach exists. But I feel we need to reassess and pause before we take this approach in a grand scale. A few reasons why. I don't believe it's necessarily different from what we know or what we do right now. I feel if you break the traits down and look at them individually, there is an absence of evidence for most of them except for three. I feel we miss a lot if we treat single traits, focus on single traits, and lose out on treating the whole disease, which does exist in a continuum of spectrum. Overall, I don't believe the evidence is there to advocate strongly for a large scale uptake of treatable traits as an approach. And finally, as Peter has already alluded to, I do question how pragmatic this approach is. And of course, of course, we're talking about a disease state that we already spend $82 billion on per year, so what are the expenses of the price tax that come with this approach? So let's go through that a little more and see if I can continue to convince you. So there's obviously the stepwise approach. It's been there. It's been tweaked around for donkey's years. It exists in pretty much every major publication that's out there. I'm going to use Gina for my example. And I like Gina because it's a clinical report that goes out of its way to market itself as not being a guideline. I think even NAEPP, when they launched, they said, yes, we know Gina's not a guideline because Gina told us it's not a guideline. So Gina does a very good job about that, by which I'm saying the individual decision for treatment, even if you're using Gina, lies upon the provider with the patient in front of them, not on the guideline itself. The next point I want to make is Gina and other stepwise approach have been criticized because there is a belief that using this approach will lead to either overtreatment of some patients with toxic agents, such as oral corticosteroids, or undertreatment of some patients, because Gina is this one-size-fits-all approach. But again, there is an abject lack of evidence to support that statement, even though it's been cited again and again and again. So we don't know if Gina really fails our patients in that regard or not. And then you look at what is being offered as an alternative. And in this review, again, I feel bad picking on people like this, but c'est la vie. In this review, they've used this example of how you can break people down based on their biomarker signature and whether they have airflow obstruction or not. And then you can use, which actually in theory is still a stepwise approach, of how to manage them and then maybe spare them certain therapies and maybe get them to the best therapies available. To me, this approach is intuitive, but again, doesn't really take me that far away from undertreating or overtreating patients by mistake. So that's my grief. I mean, that's my grievance with using treatable traits approach to say that it's going to get us away from the stepped approach. The other part of it is, they say, well, the treatable traits approach allows this novel method for treating patients who are not controlled with current therapies. And if you look at the reasons people are not controlled with therapies, all these reasons have already been addressed in existing guidelines and bodies. So the treatable traits approach doesn't necessarily replace the stepwise approach. At best, it fits into the stepwise approach. So again, it's not this solution that publications would make you think that it is. Fortunately, this is where Peter's slide failed, so I'm able to cite this instead of him. Let's talk about these three critical criteria for being treatable traits. One, a treatable trait should predict clinically relevant outcomes, prognosis, or mortality. Two, should be quantifiable with validated or objective or semi-objective subjective tools, and should be related to specific treatment responses, ideally confirmed in a randomized controlled trial. If I add another criteria, that it should be pragmatic and relatively inexpensive, I can tell you the three that I flagged here would probably not even make the cut. Of all the traits listed here, these are probably the only three that we can truly apply these criteria to, to be called treatable traits, with the evidence that we have at hand. And those would be airflow obstruction, eosinophilic inflammation, and smoking. Here are some examples where I kind of individually assessed and kind of graded these evidence, I mean, these traits. So you see my columns. They're essentially the importance that I feel they have in obstructive lung disease, the presence of any recognition tools that allows us to quantify them at the beginning and then after treatments, and what the impact of those treatments are, and then my own little notes that I put in there. So T2 inflammation, yes, we know this is important. Yes, we have tools that helps us recognize it. That should actually be a double plus, given the fallacies of biomarkers and the shortcomings, but I'll give it a three plus right there. We have effective therapies, which are biologics and corticosteroids. But I do want to mention that studies using treatable traits have heavily relied on corticosteroid titrations, and I wonder if that has allowed us to get away from overusing corticosteroids or not. Then you have airflow obstruction, another trait that's important, easy to identify. Yes, we have add-ons, dual, triple bronchodilators, but the effects of bronchodilators are somewhat overstated in asthma. So for example, adding on a long-acting muscarinic antagonist gets you an FEB1 increase of about 160 ml. So I wonder how much bang for our buck we're getting with that as a treatable trait. But beyond that, if you go down this list, you'll start seeing a number of one plus, two plus kind of situations, and that's more reflective of our current understanding. If I go to my next slide and talk about extra pulmonary traits, well, that holds less water than the previous slide. These are all traits which are associated with illness, but I wonder if today we have the tools to assess them. I wonder if we have adequate treatment options to assess them. And moreover, I wonder specifically in the context of obstructive airway disease, do we have literature to support their use? This should be behavioral traits, but I'm sorry about the typo. If you look beyond smoking, again, these are things which we find in existing stepped approach and guidelines. So I wonder what else the treatable traits approach is offering beyond what's existing right now. The evidence just doesn't match the enthusiasm for the approach itself. It matches it in the sense we now know better about the prevalence of treatable traits, but the evidence for the approach itself doesn't exist. Sample sizes are small. Interventions are not practical, usually involve a case manager or something like that. A lot of the evidence comes from the pre-biologic era. So in the 2020 Newcastle publications, for example, being on Omalizumab excluded you from being part of the study. And then the outcomes that were studied were not what we think of as hard outcomes. We didn't see the robust exacerbation of mortality data. We saw quality of life, which is obviously important, but can be influenced by a number of factors. To point out other shortcomings, again, this is the eosinophilic signature was high in the one randomized controlled trial, and the baseline medications did not include biologics. The next thing I want to offer to you is this broken down approach of treatable traits. Are we losing disease traits itself? So for example, if you break down a patient's disease burden based on which airway compartment is driving symptoms, we may lose on some of these unified airway benefits that we've been noticing from our biologics. So we know that patients who have uncontrolled upper airway disease can be treated effectively with asthma medications that helps in control of both disease states. And I wonder if these nuances are lost in the treatable traits approach. The other concern I have is by lumping all obstructive airway diseases into one bucket. Clearly our existing tools don't perform the same for all airway diseases. And eosinophils would be a good example of that, how our understanding of eosinophils and COPD is way behind what our understanding is in asthma. So the next issue I have, and I'll be brief because I'm out of time, is the biomarkers we have, for example, for eosinophilic inflammation are not stable. Using sputum eosinophils is not really practical. And I also present a case, a cautionary tale rather, about how these traits are constantly evolving as well as our approach to them is constantly evolving. The classical example is the one with omalizumab, where we felt having high T2 markers was predictive of response, but then found out five years later in subsequent trial that that wasn't the case. Lastly, my last point, and then I promise I'm done, treatable traits is just not practical. In the one randomized controlled trial, this was the role of the case manager, and I could never make a case in my practice to have such support. Also, some of the more validated facts that drove the results may have been not practical. For example, using sputum-based eosinophilic counts to drive corticosteroid therapy. All right, so what am I concluding here? I feel the treatable traits approach, the approach itself is not ready. I think it's a novel, exciting concept, but it's pretty much impossible to bring it to clinical care. I don't think it's a viable alternative to stepped approach. I think it fits into stepped approach, but not there yet. And I think more research is needed. I hope that future randomized controlled trials pretty much blow my whole slide deck out of the water, but I don't think we're there yet. So, thank you.

asthma COPD overlap

ACO controversy

distinct entity debate

spectrum of one disease

overlap between asthma and COPD

symptom burden in ACO

comorbidities in ACO

treatable traits approach

personalized treatment for ACO

insufficient evidence for ACO existence