Good morning, everyone. Welcome to the Canadian Thoracic Society's 2023 Scientific Program. My name is Chris Hergott, and I'm the Chair of the CTS Education and CPD Committee, as well as the CTS Scientific Program here at CHEST. I'm an Interventional Respirologist and Clinical Associate Professor at the University of Calgary. The CTS Scientific Program is an annual CME event held every year in conjunction with the CHEST Annual Meeting. The program features lectures and debates delivered by leading Canadian experts in respiratory medicine and research, as well as highlights up-and-coming faculty. Thanks to our faculty and members of the CTS Education and CPD Committee, we are again delivering what I think is an outstanding educational program that is well-recognized and anticipated as part of the broader CHEST Meeting. It's great to be back again in person in beautiful Hawaii. I would also like to take this opportunity to thank the leadership of CHEST for their ongoing partnership and collaboration, and in particular for facilitating the delivery of the CTS Scientific Program as part of their annual conference. We always appreciate our collaboration with CHEST, and this is a great example of that. It's always an honour for us to partner with CHEST in this great conference. Before we start the presentations, I would like to remind you to complete the CTS session evaluations, which can be accessed immediately on the CHEST Events app. I was going to get into trouble if I didn't say that, so I've said that now, and I think we're good. So we're going to get started with our first talk. It's my pleasure to introduce Dr. Brianne Filippenko. Dr. Filippenko is an Assistant Professor in the Division of Respirology at the University of Saskatchewan, and she's talking today about physical activity in asthma. Brianne. Awesome. Thanks, everyone, for coming. Today I'm going to be talking on physical activity in asthma, and we'll review the effect of aerobic training as a non-pharmacologic intervention in our asthma population. We're living in a very exciting time and working in a very exciting time in asthma with the advent of biologics. We're talking about remissions, super responders, but today I wanted to switch things up and review a part of our comprehensive management that we give our asthma patients and why it's important for us to think about in clinic. A few disclosures, none of which are relevant to this talk. That's me. Okay, so my goal for you is to be able to identify the mechanisms of exercise limitation in asthma by the end of this talk and to be able to summarize the effect of aerobic training as a non-pharmacologic intervention in asthma patients. And finally, we'll review the effects biologic therapy can have on exercise capacity in the severe asthma population. But I want to start off by talking to you and convincing you about why this is an important thing to discuss. Both in our GINA and CTS guidelines when we review patients in clinic every day, we want to establish whether a patient is controlled or not from an asthma standpoint. And when we ask patients about any activity limitation due to asthma, part of the GINA control criteria, and CTS, we ask about physical activity. If patients describe it as normal, we consider them to be controlled. But if they say that they have an impact on their physical activity, what does that mean? Does that mean that they have active airway inflammation and we need to escalate their therapy? As you can imagine, it's much more complex than that. Further, it should be important to us because it's important to our patients. When severe asthma patients are asked about what's important to them as an outcome measure out of 17 hypothetical outcomes, patients with severe asthma rank being able to participate in physical activity as the third most prioritized outcome after improved quality of life and reducing number of asthma attacks. They rank it above fewer hospital admissions, which we find very important as clinicians, as well as taking less steroids. So it's important to our patients, so it's something we should think about. Patients with asthma across all severities do not meet the recommended 10,000 steps per day. They're less physically active than they should be. But what is particularly interesting is we think about COPD patients and inactivity a lot. COPD patients with an FEV1 less than 50% takes an average of 4,500 steps per day. But a severe asthma patient is actually in a similar ballpark of 5,800 steps per day. And yet we discuss physical inactivity a lot less in this population. In addition to severity of asthma, those asthma patients who are older in age as well as women seem to be particularly impacted. We see patients with severe asthma participate in fewer minutes of moderate to vigorous physical activity per day, approximately 20 minutes fewer per day than healthy controls. And we see them take fewer steps per day, 2,400 on average fewer steps per day than healthy controls. And not surprisingly, there is a linear relationship between physical activity on a daily basis measured by step count or moderate to vigorous physical activity measured by accelerometry and performance on functional exercise capacity testing by six-minute walk distance. The more active patients are, the better they perform in that test. We see that higher levels of physical activity are associated with better asthma control, exacerbation rates, and improved exercise capacity. Patients who participate in 30 minutes of moderate exercise per day are 2.5 times more likely to have good control. Those that jog 20 minutes three times per week have been shown to have a 19% lower exacerbation rate compared to those with no physical activity. And those that increase their physical activity by 1,000 steps per day increase their six-minute walk distance when tested on functional exercise capacity testing by six-minute walk test by an average of 20 meters, which is quite impressive. If you remember nothing else from my talk, remember this slide, that not all physical activity limitation in asthma is due to a pulmonary cause. When we objectively assess these patients on cardiopulmonary exercise testing, we see that a lot of patients do have exercise-induced bronchoconstriction. Especially in the severe asthma population, we see up to 80 to 90% experience this. We see patients demonstrate dynamic hyperinflation, dysfunctional breathing, but we also see several other non pulmonary causes of exercise limitation when we test people on CPET. We see patients become deconditioned after years of inactivity and being afraid to exercise due to provoking their symptoms. We see patients develop corticosteroid-induced myopathy after all their courses of steroids, especially in the severe asthma population. And some patients that feel that their exercise capacity reduced actually end up having a normal cardiopulmonary exercise test. I know in our center we probably underutilize CPET in the severe asthma population, but it can be really helpful. There's an interesting study out of Northern Ireland that looked at patients who were referred with difficult-to-treat asthma with described reduced exercise capacity by the patients. They underwent a cardiopulmonary exercise test and only 28% had a pulmonary cause of exercise limitation on their CPET. They looked at medications six months before cardiopulmonary exercise testing and six months post, and patients with non-pulmonary causes and pulmonary causes all had a similar amount of inhaled steroid and oral steroid courses before the CPET. After CPET showing no pulmonary cause of exercise limitation, reduction in inhaled steroid did not lead to a loss of control in those patients. So it's possible we're inappropriately prescribing higher doses of inhaled steroids to these patients when maybe they need a different targeted intervention such as pulmonary rehab or an exercise prescription. I wanted to talk briefly about exercise-induced bronchoconstriction, which is a topic unto itself, but really just to highlight one key point here, that there are specific measures that can be implemented that can be helpful if a patient does demonstrate EIB or have symptoms of EIB to make you suspicious that it's present. A good warm-up is important. In Saskatoon, where we live, it's very frigid and cold and dry, so wearing a mask that humidifies and warms cold air during exercise outdoors is important. Short-acting beta-agonist 15 minutes prior to exercise can help prevent exercise-induced bronchoconstriction. And what I wanted to highlight here is for those patients on SMART therapy on ICS for moderal, as needed ICS for moderal, 15 minutes prior to exercise is not inferior to short-acting beta-agonist 15 minutes prior to exercise. So for those patients on ICS for moderal therapy, they can use it before exercise with good effect. Now what happens when we use aerobic training as an intervention in the asthma population overall across all severities? There's a good systematic review on this topic, but I will say having read the individual articles that the aerobic training intervention varied a lot between studies, so that probably explains the variety of results that you'll see, but overall we see aerobic training interventions in the range of 8 to 12 weeks in duration improve asthma control. Effect size on FEV1 is less pronounced but still favors exercise. And there does not appear to be a significant impact on airway inflammation. Most of these studies measured pheno, only one looked at sputum eosinophils, but there does not seem to be a significant impact with an exercise intervention. This naturally leads to the question of who stands to benefit the most. Perhaps looking at asthma patients overall is too broad and we should look at patients that we think would benefit the most to target our exercise interventions, particularly if we're going to refer patients to pulmonary rehab in limited capacity that we have. So we'll look at obese and moderate to severe asthma populations. In a study of overweight and obese asthma patients examining the effect of weight loss with diet restriction, exercise, or both, we see that those that reach the targeted 5 to 10% body weight loss with a combination of exercise and diet had a clinically significant improvement in their asthma control as well as quality of life, which is pretty important to keep in mind when we're seeing these patients in clinic. The weight loss component though seems to be important because the exercise intervention alone did not result in the same change in asthma control. Now let's look at moderate to severe asthma patients. In a pulmonary rehab program that include asthma patients across all genus severities, we see that all patients did improve a significant amount on six-minute walk distance with a pulmonary rehab intervention. Those that improved the most, however, were those with reduced exercise capacity at baseline, and the only patients that had that were those on Gena Step 5 therapy. So the most severe patients had the reduced exercise capacity at baseline and had the most to gain. In a meta-analysis of aerobic training programs in moderate to severe asthma looking at four RCTs, we see an improvement in step count of over 1,500 steps per day. And we see again an improvement in quality of life, asthma control, as well as VO2 max measured objectively on cardiopulmonary exercise test. What I will say is important to keep in mind when looking at these studies is they have very varying interventions. Some had supervised aerobic and resistance training as their primary intervention. Some got a Fitbit and told to try to increase their step count. So it was very different and probably why you see the different results. And the one that improved the most was the study that looked at supervised aerobic and resistance training, very akin to what we do in our pulmonary rehab programs. And finally, do biologic therapies improve exercise capacity? I'll say up front that we don't have enough information to say definitively, but I'll show you what we do know. There's a very small study looking at omalizumab with cardiopulmonary exercise testing 16 weeks after initiation of therapy and prior to the initiation of therapy with a control group not on omalizumab, but with severe asthma. And we see a significant improvement in VO2 max on omalizumab from 63% predicted to 70% predicted and no significant improvement in the placebo group. There have been two small studies that look at this question with regards to anti-IL-5 therapy. The first one looking at both mepolizumab and benrolizumab and showed no significant change in VO2 max after three months of therapy, which arguably may be too short of an interval to assess a change. Seven patients, however, did show an improvement in ventilatory limitation and dynamic hyperinflation. So there might be a signal that it does improve exercise capacity. We just needed to wait a little bit longer. The second study, which the graphs on the slide are from, look at accelerometer data and patients started on mepolizumab and showed an increase in daily step count of over 600 steps per day after 12 months of therapy and did also show an improvement in minutes of moderate to vigorous physical activity per day in the range of 20 minutes. It looks very blurry, but that big blurry blob, my goal is to bring this all together and we should really be including assessment of physical inactivity and obesity when reviewing our airways disease patients, both of which are important and recognized extra pulmonary treatable traits. We talk about treatable traits a lot with regards to eosinophilic inflammation, airway hyperreactivity, but if we can find somebody that's physically inactive and target that with an exercise intervention and improve their outcomes, we should really be doing that. It's inexpensive and really gives some power back to our patients. My final points today are that participating in physical activity is an important outcome measure to our patients with asthma and so it should be an important outcome measure for us to consider. There are many possible causes of exercise limitation in asthma, many of which are non-pulmonary in origin and we probably should be utilizing cardiopulmonary exercise testing more than we are in the severe asthma population. Aerobic training may have a positive effect on asthma control, quality of life, and exercise tolerance, though it's really difficult in terms of what to recommend to patients given that all the studies had very different interventions and so just in general recommending to your patients to be active is all we can really do for now. And finally, the effect of biologic therapy on exercise capacity is largely unknown and an important one that we should be looking at, particularly in those with an incomplete response, we should be looking at cardiopulmonary exercise testing and if they have a non-pulmonary cause considering addition of something like pulmonary rehab in this population. Thank you. And next we have Dr. Brian Ross. Dr. Ross is a respirologist at the McGill University Health Centre and assistant professor as well as a clinician scientist. Dr. Ross is going to speak to us about remote monitoring platforms, wearable technologies, and exacerbations of COPD. Okay, thank you to everybody for coming in this early. My name is Brian Ross and I'll be talking today about remote monitoring platforms, wearable technologies, and exacerbations of COPD. That's home base for us in beautiful Montreal, Canada, and that's me. My disclosures are at the bottom. They relate to who funds my research as a PI as well as who's asked me to deliver COPD speakerships for educational content. So these are my lesson objectives, but I've sort of distilled that into a more bare-bones outline given the time constraints. So I'll be starting by talking about COPD and acute exacerbations and why they're important. I'll then be moving on to this concept of what is remote patient monitoring, specifically in the realm of COPD. And then we'll be looking under the hood of my own research program, looking at some active research we're doing, looking at RPM applications in COPD and where that could lead us to. So what is COPD? So I would point you to the very first paragraph of the recently released guidelines, CTS COPD guidelines, about a month ago. But basically COPD is a chronic obstructive disease. It's characterized by fixed air flow obstruction. The natural history is that of chronic progressive dyspnea that slowly gets worse over time. But then you also have these sort of discrete sudden periodic episodes, lung attacks, that are called COPD exacerbations. And these exacerbations are quite important. And I've been very deliberate about putting those two in red because those treatable traits or those targets are really the backbone of both CTS and GOLD in terms of how we approach managing COPD. So it's a leading cause of morbidity, mortality, and it's very prevalent. And it's only getting more and more prevalent. So why do we care so much about COPD exacerbations? Well, I'll point you to the very second paragraph of the CTS COPD guidelines, which says it all. So exacerbations lead to a faster lung function decline, worsening health status, increased hospitalizations. They are a main driver of health care costs. They are a large economic burden. They're associated with increased all-cause mortality. So that's why they're so important. That's why there's specifically two treatable traits in GOLD, that of dyspnea and that of exacerbations. And that's why in the CTS guidelines, we talk about PICO, say, two and three, the exacerbations, and for the first term, mortality, which are very closely tied together. So we really care about exacerbations. We care about treating them properly, and we actually care about preventing them too. There's a real interesting paradigm shift in COPD exacerbations. What are they? How do we diagnose them? And how do we classify them? This is important for clinicians and for researchers alike, because previously it was rather subjective. We would have patients on a patient-individual level who would be able to detect their own symptom profile or not, would go to seek their physician for treatment or not, and then we would classify it retrospectively based on how we decided to treat them. Did we admit them to hospital or not? Did we treat them with antibiotics, corticosteroids, or both? So there's been a hunger for objectivity, and this has really manifested in the recently proposed Rome proposal, which was published at the end of 2021 and has been incorporated into the latest GOLD guidelines in terms of how we might classify the severity of an exacerbation using objective markers such as changes in respiratory rate and heart rate and SBO2. So with that in mind, we recently published a paper just talking about what exists in the literature in terms of patient monitoring and COPD. What have been the influencing forces? Well, I'll tell you COVID-19 was a huge one. Everyone who had their PFT lab shut down and everyone who had their in-person clinic shut down realized how do we deliver excellent chronic care to these patients with COPD? We also have this massive tidal wave of COPD prevalence that continues to increase. We're getting better and better at treating them, and so they live longer, and so they're more and more complex, and that's an issue for our healthcare system. And then at the same time with all this, we have big data, machine learning, rapid advances in technology in terms of the software and the hardware that's available to us. What are the benefits here? Well, if we can do this right, we can make a pandemic-resistant monitoring platform. It doesn't matter if there's a lockdown. It doesn't matter if you don't see them in person. Geography resistance. So we're in beautiful Hawaii, but back in Canada, we have a geography problem where there's a lot of distance to travel for many of our patients between urban rural areas and so on. Another benefit would be the infrastructure. So you would need less brick and mortar infrastructure if you have this sort of virtual remote monitoring platform. And really interestingly and importantly, and it's sort of akin to blood pressure measurement, you're really measuring the patient's physiology in their natural ambulatory home environment, not in a clinic room. There's no white coat. There's nothing like that. So you're really maybe getting a better sense of their true physiology or pathophysiology. So overall, those could all lead to better chronic disease management. Of course, there's a lot of obstacles that we still have to face. There's the feasibility of giving a bunch of technology to our average patient with COPD and saying, you know, adhere to this very complex thing. The practicality goes along with that. How long can we do that for indefinitely or not? There's privacy and regulation issues. And I would argue that we're all building the plane as we're flying it. That includes the scientists, the clinicians, but also our regulatory bodies, including REB and even the government. And then of course, lastly, the evidence isn't there yet, especially prospective evidence, and especially with really clinically important outcomes. So we have to take a stepwise approach here. So this to me was kind of the recent birthplace of remote patient monitoring and COPD. These are two really interesting studies in 2012 and 2015. Both studies, all patients were on long-term oxygen therapy. And on the study on the right, they were on LTOT as well as NIV. So these were patients, kind of a subset of all of the patients with COPD that we see, and they were kind of tethered to something. So not really the ambulatory environment that I was sort of referring to a couple of seconds ago. But both studies found that the change in respiratory rate actually subtly increased in the days leading up to an exacerbation, specifically in both studies in the five days leading up to an exacerbation. So that's quite important that as a proof of concept from the home environment, you could detect subtle changes in respiratory physiology, and perhaps detect and diagnose the exacerbation early. And why is that important? Well, we've known for about 20 years now that if you delay the onset of the treatment of the exacerbation, they have worse outcomes. They come to hospital more often, the emergency department, they go to the ward, perhaps even the ICU. Whereas if you treat very early in the inflammatory cascade that the Rome proposal talks about, perhaps you can really change the trajectory of the pathway of the patient. Maybe they can stay home with an outpatient action plan alone. So it's really, really important. If you manage COPD, you should care about this. If you're a taxpayer, you should care about this. So what is the schema or the framework? Well, in theory, this is kind of what we're talking about. We're talking on the left side, whether it's a CPAT lab or an ICU, a patient who's tethered, who has a bunch of different gadgets on them, measuring continuous heart rate, respiratory oxygen sat, et cetera. Well, if we can, through the advances in technology, equip them with a very comfortable, wearable biometric device, we get those same physiologic markers near continuously from the comfort of their own home. And on the right side is from a New England Journal of Medicine paper talking about how we can leverage that data to perhaps develop a remote patient monitoring platform. So with the last half of the talk, we'll be looking under the hood of my own research program. I'm really excited to share some results of a study we've been working on. So a very long worthy objective, but this was the objective of the study to prospectively determine during an acute exacerbation of COPD, the association between near continuously moderate outpatient daytime and nighttime physiologic parameters, talking about cardiac, respiratory, activity-related and sleep-related using two biometric wearable devices with a daily validated patient reported symptom score. So the symptom score served as the gold standard against which we were trying to characterize and understand the natural history of a COPD exacerbation in terms of its pathophysiology. As a secondary and quite important outcome, we wanted to know what the wear time would be in these patients who are quite sick, the participant usability experience using validated scores, and the overall feasibility, keeping in mind that this was a several week observation period. So they were supposed to wear it for weeks at a time. This is in a COPD patient population where if you've done COPD clinic, you know that there may be age-related or generation-related issues saying what is Wi-Fi, what is a tablet, that kind of thing, technology literacy. And then of course, because of the way the study was designed, everyone in the study was acutely unwell. So was any of this even feasible to start out with? So we actually did a phased approach where we did a pilot and feasibility, small pilot and feasibility study before we moved on to the larger study. This is straight from the recruitment posters. So who was eligible and not eligible? Well, we took patients with COPD regardless of the severity of airflow obstruction. They needed to be currently experiencing exacerbation, receiving treatment for it from a physician. And we just basically excluded patients with cardiac arrhythmia because we wanted to see if the heart rate would go down, for example, heart rate, one of many variables, if it would slowly go down over time, we didn't want that to be affected by sudden arrhythmias and things like that. We also, I'll just point to the last exclusion criterion because we wanted to catch these patients quite early. We wanted to characterize the pathophysiology of an exacerbation. So we didn't want to wait too long into the days of treatment before we were able to recruit them. So the study and design and equipment, this was a convenience sampling. So we, there was a day hospital in the emergency department and all sorts of places where patients, participants, eligible participants would actually come to you and you would recruit them at that one single study visit. It was a single visit study because at the time I wrote the protocol, we were, I think, between waves of a COVID pandemic and I didn't want many study visits. And so I wanted to be as reasonable and as streamlined as possible. All we needed to do was meet them at the visit. They were recruited, enrolled. They were trained on their wearable devices after being fitted. And then all data for the rest of the study was remotely captured during an exacerbation. The study equipment, well, I have it highlighted in red here. We have a biometric ring, biometric wristband, and a study tablet. It didn't matter if the patients had a smartphone or not. We equipped them with what they needed for the study. The tablet served as a way to not only transmit the wearable data, but it also allowed us to get the validated daily symptom questionnaire. And they were encouraged to wear the devices pretty much at all times over a 21-day period. And that's pretty much other than recharging the device or re-syncing data or while showering or washing the dishes or whatever. So data collection and analysis. So they, at certain intervals when the battery would get low, they would recharge the device. And at the same time, they could sync to their tablet and sort of send the data to our research lab. And the XactPro was the questionnaire that we used. They filled it out every single day after 4 p.m. as it is validated. We used the system usability score on the very last day of the study for both the ring and the wristband to understand what the patient experience was with wearable technology, well, these specific wearable devices. Statistical analysis. Well, we captured all the data from day one until the minimum observed day over the 21 period of the exact score of each participant and all of that data was included in the analyses. We decided to use analyses of all data as well as just inactive data, keeping in mind that perhaps during an exacerbation if you're largely bedbound or more sedentary and then as you recover and you say are more active for a patient with COPD, that might mean getting dressed, doing groceries, going upstairs, you actually might see physiologic increases in their heart rate and respite and things like that. So we actually chopped all data with a step count of zero at one minute intervals to only look at the inactive data as well as all data as well, just to adjust for that. We used linear mixed effects regression models because these were clusters of participants that were contributing observations to the overall data that accounted for repeated measures. Each physiologic parameter served as the independent variable in separate models and then the daily exapro was the dependent variable. We ran both unadjusted and adjusted models. So some results, just having a quick look at the watch. Some results, so despite being open to all patients with COPD regardless of airflow obstruction, we tended to recruit the severe and very severe patients with COPD, which actually lends credibility, I think, to the study results. Age 66.6, 40% female. I was surprised and impressed with the wear time. So 87% and 88% of all study time over the three week period. So they were very diligently wearing their biometric wearable devices. The usability scores were 82 out of 189 out of 100 for the wristband in the ring. There were some issues with the wristband in terms of loading data and large, large, large amounts of data were being collected from the wristband that led to some IT issues. Daily symptom score and remotely obtained physiologic measurements. So this is my sort of table two here. I'll just point out that the median time to the minimum XactPro score was about 14 days. And that, to sort of justify why we did what we did in terms of the inactivities sub-analysis and sort of dovetailing with the first talk, actually, we saw a marked increase, four time increase in the daily step count from day one to the day of their minimum XactPro score. So that's why we did the all data analysis and the subset of data analysis. So this is what it looks like graphically. The each point, data point are raw participant data and I just sort of made a smoothing line for visual effect, for simplicity of interpretation. But this is the XactPro score over the three week study period. A slow decline as patients improved. And so now I'm just gonna move rather quickly through the sort of categories of parameters that we were able to capture near continuously daytime and nighttime. So we have heart rate, so on the left side for all the rest of these slides, the left side's gonna be the wristband, the right side's gonna be the ring. I put both all data as well as only inactive data on the right side, very similar profiles. What I, to my eye at least, what I see is a slow progressive decrease in the heart rate and then it sort of rebounds at some point back to some baseline. Same thing, similar with the respiratory parameters in terms of all data and only inactive data. Nighttime data's quite interesting because you kind of see this slow decrease and paradoxically, not what I was expecting to see, nighttime oxygen saturation actually, to my eye again, sort of slowly goes down. Now we didn't adjust for what supplemental oxygen therapy or what liter of oxygen patients were getting over the study period. And then we had cardiorespiratory variability and EDA. So autonomic function in a way, sympathetic activity, variability in the heart rate and the respiratory rate. And I think these might be the key moving forward. So we have respiratory rate variability, we have heart rate variability, we have EDA, which is a marker of sympathetic dysfunction. And they all sort of slowly change over time. And then lastly, temperature. This is at the skin temperature, of course. Importantly, with the first talk, daily step count. So again, one of the most impressive results is how much that sort of rebounds and increases following an exacerbation. And then sleep scores, which is something that we don't really think about that much in COPD exacerbations, but it's a lot of physiology that we might be ignoring that might be quite important. So I hope, I'm not sure if that transmits very well, but these are basically the study results. So the parameters, all of the parameters here reach statistical significance for an association with the XACTS ProScore. What we found was respiratory rate, and this I guess would make sense because it's a COPD exacerbation, it's a respiratory event, even though it's quite systemic. Respiratory rate, nighttime, and respiratory variation during the nighttime were both significantly associated with the daily XACTS ProScore. The daily step count, so physical activity in its own right, not only using it to adjust for other sub-analyses, but in its own right is a very important outcome, it seems. And then, of course, sleep efficiency and the minutes per night that you're spent in deep sleep were also, surprised me as really important markers. So I just leave the point estimates and the 95% confidence intervals. They all reached a p-value of less than 0.05 here. So I think with that, I will summarize. So COPD is a leading cause of morbidity and mortality. It's very important. And within COPD, exacerbations are a major driving force of this, so we should really care about this. Remote patient monitoring in COPD is a very active field. It's a very early field, but it holds great promise. There's a potential to address many persisting barriers to deliver excellent care for our patients, inside or outside of pandemic situations. It does require further development, and I think we need a phased approach before we get to the holy grail of prospective, randomized controlled trials looking at clinical efficacy. So I think I summarized with today's talk what we're trying to do currently, in the current sort of stepwise approach, is to understand and characterize the pathophysiology of COPD. And I haven't seen this published in such detail before, so we're really excited about these results. But I'll tell you, sort of looking to the future, we just got a nice grant to look at predicting future exacerbations of COPD using big data, artificial intelligence, machine learning. So I'll leave you with a rather chilling quote. Machines will not replace physicians, but physicians using AI will soon replace those not using it. So learn AI, and if not, buddy up with those who know how to do it. And with that, I'll end my presentation. Thank you so much for the invitation. All right, it's my distinct pleasure to introduce Dr. Christina Thornton. Dr. Thornton works at my institution, so Division of Respiratory Medicine, Microbiology, Immunology, and Infectious Disease at the University of Calgary. She's a clinician scientist, MD, PhD, and she's going to talk today on the overview of the current landscape of non-CF bronchiectasis. Great, thank you so much, and thanks very much for having me and the organizers for coming and letting me present about NCFB, which is my distinct pleasure, or otherwise, what to expect when you're expectorating. I cannot take credit for that. It's the best title. My supervisor came up with that in grad school. So, thank you. It's, he is a brilliant, brilliant individual, yes. So, just to jump ahead. So, that's me. I didn't put a picture. I'm right here, but. So, in terms of our objectives, you know, with bronchiectasis, I think when some of us were in training, it was sort of this no man's land, and it's a really exciting time in it. The session next door has some of the world leaders in bronchiectasis right now. So, really, what we're gonna be discussing today is summarizing the initial presentation and how to work it up, because it is a very heterogeneic disease, present some of the longstanding pharmacological and non-pharmacological therapies. But what I wanna really emphasize is some of the novel therapeutics, and then take it home with what we're doing from a Canadian landscape. So, I have a couple questions here. Don't worry, it's not shame-based learning. You don't have to give your answer, but maybe you can dwell and think about it as we go through the talk. But, you know, the first question is, well, how common is bronchiectasis? So, there's a couple options there. It's probably not a rare disease, because we are speaking about it, and there are many sessions at this conference on it. But just take a gander as to what you think might be on that list. So, bronchiectasis, as we all know, it's a chronic respiratory disease characterized by cough, sputum production, and recurrent pulmonary exacerbations. It's another form of separative lung disease, and its sequelae is very similar to CF. So, those of us that work in bronchiectasis often overlap between the two. There is clear radiographic abnormalities, as are indicated there, and often these patients produce cups and cups of sputum a day. I have patients that some of them produce up to 500 mils a day. So, it is quite problematic. In terms of pathophysiology, it's sort of the classic paradigm where there's some insult with many etiologies that have been described. So, in the literature, about 50 different diseases have been associated with bronchiectasis. But what's fascinating is different diseases present differently, and likewise, some of those with very different etiologies all manifest in a similar disease presentation. Classically, it's been associated as a neutrophilic condition, although recent studies have shown about 20% have an eosinophilic subtype, so it's mirroring some of our other chronic lung diseases. And it's often associated with current mucus production and then associated microbiologic infections, which we'll go into. So, over the last decade, prevalence has highly, highly increased, about 40%, and it's estimated to be up to 566 per 100,000 people. It's significantly associated with healthcare costs. The recent estimates suggest about 650 million US dollars per year. So, for those of us who know from our Canadian dollar, that's a lot of money, especially from our perspective. And while we don't have any Canadian prevalence data whatsoever, and that's something we're hoping to address with some of our research, doing some basic math, it's about over 200,000 individuals that can be affected. So, we're really just seeing the tip of the iceberg, and the answer is it is the third most common airways disease, after asthma and COPD, but quite a bit higher than CF, which, again, is a separative disease with very similar sequelae. And James Chalmers, who's published a lot in this field, has a beautiful quote I love from the clinics in chest medicine last year, where it's referred to as the most neglected disease in all of respiratory medicine, given how little we know compared to the prevalence. So, jumping ahead, in terms of what is the most common cause of bronchiectasis? I just said there's a laundry list that you can pick from, but if you had to take a gander, do you think it's one of the following? And we'll go through what that is. So, this is a study that was just published in the summer in Lancet Respiratory Medicine by the Chalmers Group that really described their MBARC registry data. So, for those that don't know, MBARC is a huge registry cohort in Europe. About 27 different countries, including Israel, were included, with 17,000 people over a seven-year period. And this is, by far and away, the richest data set we have in bronchiectasis research. And what they found is that 38% had no identified etiology. Now, is it truly idiopathic? Tough to say, depending on the workup that was done. But nonetheless, a large proportion, as you can see, indicated by the pie chart. And amongst those identified, about 21% were post-infectious. This will become relevant for a few reasons. Number one, if you look on the graph there by country, you can see there's a huge geographical distribution based on where post-infectious comes into play. And secondly, we know from the changing epidemiology of childhood infections, this is on the decline. So as our population is getting older, this may shift in the years to come. Moreover, this is a very nice sort of Venn diagram figure showing that these are not distinct etiologies, and there is often overlap. So we're all familiar with ACOS, for example. There's now BCOS that's been described with bronchiectasis, COPD overlap syndrome. The alphabet soup continues. So the point being, these are not distinct entities. Moreover, this is a systematic review that was published in 2018. We know there's a huge geographical distribution in terms of etiologies. So I'll point you here to the American data by McShane's group. You can see the vast majority in that cohort was immune-related, which is vastly different than the European group. Notably absent, however, is Canadian data, and we will come to that later on in our talk. But thus far, we don't have any Canadian data in terms of prevalence and etiology. So at this point, we've deduced that there's a very heterogeneic distribution in terms of underlying causes. So how does one begin to work it up? Because it can be quite overwhelming how far down you go. And to answer that question, I think we have to first understand what are our goals of treatment. They're really designed to reduce symptom burden, frequency, and severity of exacerbation, which are events that we know clearly are associated with adverse events, improve the quality of life of our patients, and halt or stop disease progression. And part of the importance of understanding the underlying etiology is that we know from literature and other data, treatment change can occur in about a fifth of patients. So you're going from a disease that you may not have a lot of options to one such as ABPA, in which may be readily treated. And so there's a large, large forks in roads you can go down, but it's very important to kind of have a systematic approach to it. So with that, next question to think about, in a newcomer or all-comer for NCFB, what would be part of your initial workup? Because you could go nuts, clearly, and that's not choosing wisely. So take a look at this list here and think about which options you would do for the new or all-comer that's coming to your clinic. So there is actually no consensus for this. And again, we don't have Canadian data. We don't even have North American guidelines, actually, around bronchiectasis. So all of our data is extrapolated from European through the ERS or SPEIM guidelines. So this here is a summary that was published in the Clinical Chest Medicine. They had a very beautiful issue all dedicated to bronchiectasis, summarizing the different guidelines. But the take-home point is in all comers, a minimum set includes CBCF differential, serum immunoglobulins, and workup for ABPA, simply because while ABPA may not be that much common, it is something that we can actually go after. Other considerations, sputum should really be obtained for everyone, and please do the expanded sputum culturing, the CF protocol, such that those pathogens are very similar. AFB is controversial, but I think most practitioners in our field would suggest doing it. And then while not listed here, spirometry to get a sense as to the underlying severity. Of course, other things like PCD, CF testing depends on the clinical circumstance. So next question, which of the following is a licensed therapy for bronchiectasis? So there's a lot of options there, but I'll point you to option G that says there are no licensed treatments for bronchiectasis, and shockingly, that is the answer even today. There's absolutely nothing. Everything we do is off-label and extrapolated. And for those of us that work in NCFB, you've probably filled out a lot of forms to get nebulized antibiotics, and unfortunately, that's the reality of it. So I just wanted to take a few minutes and go over sort of the pillars of management. And I think airway clearance therapy is by far and away the most important therapeutic avenue we have for NCFB. Time and time again, all guidelines recommend some form of airway clearance. It can be used with mucolytics or mucoactive agents, which we'll talk about. And really, thus far, even in CF, where a lot of our literature is obtained, there's really been very little evidence around head-to-head comparisons of different therapeutics. So it really comes down to patient preference. Because even though it's the most important, the adherence is often quite low. So about 40% of patients do their therapeutics as prescribed. And to give a bit of kind of how long it takes, there's no studies in bronchiectasis, but in CF, we know the average patient spends about 110 minutes per day on their therapy. So you're asking a lot of your patients. So you really want to have an informed decision-based modality. And there's many options. We clearly do not have time to go over them all. But this was a nice review done by O'Donnell. And then this is, while in CF, an editorial we just published in the ERJ, just going through many options. So don't give up on one. Talk to your patients and talk to your chest physiotherapist who will become your best friends. So moving on from chest physio, the next pillar is mucoactive agents. And I think this is where a lot of people sort of know that they have to inhale something and what does what. And again, no great evidence in bronchiectasis. Majority is taken from CF. But probably the main pillar is hypertonic saline. And really what this does is that expectoration will improve in conjunction with your active chest physio. It'll reduce sputum viscosity and does clearly have been shown to reduce frequency of exacerbations. There's no known salt content. So maybe people living by the oceans will do better. But generally in Calgary, which is also very dry, like Saskatoon, we try and go as high as we can, 7%. But you have to make sure they're not gonna bronchoconstrict. And we usually do a test dose in clinic. Other options here, including NAC, the carbocysteines, which had some promise with reactive oxygen species, attenuation and anti-inflammatories. They're small studies. But really what we do know is what doesn't work. And that's palmazime or DNAs, as this has clearly been associated with adverse events. So the next part when looking at the microbiology is what pathogens are the ones at play in bronchiectasis? And Embark really nicely outlined this. But you can see these are kind of the common bad guys involved. So you can kind of think about what priority order and what prevalence these come about. So antibiotics is a tricky one in bronchiectasis. I'm sure many of you have seen your patients and cultures and it's just a list of R's next to it and you don't know what to do about that. But there's really three main goals here. It's to reduce treatment or treatment of acute exacerbation, perform eradication, and continue maintenance therapy. And the key I really want to emphasize here is around eradication. Where clearly the guidelines suggest only eradication attempts against Pseudomonas aeruginosa. So not even all Pseudomonas is, Pseudomonas, like fluorescents, but simply just aeruginosa. And this is a critical aspect because we know sustained Pseudomonas cultures are associated with mortality. And you really want to attempt it at first culture acquisition because after that it does go into a biofilm or a mucoid phenotype and you're really not going to be achieving successful eradication. So from MBARC, how prevalent is this? We know Pseudomonas is just in over 25% of our patients, but you can clearly see a distribution of other pathogenic organisms that have not been well studied. And clearly have no identification in the guidelines in terms of eradication attempts. Moreover, again distributed by country, you can see clear geographical predispositions by organisms and we have no Canadian data to go with that, so it's all extrapolated. So just briefly, I won't spend too much time on this, but these are straight from the ERS guidelines. We know that eradication attempts pick your poison, but it should be done with Pseudomonas. And other antimicrobials such as macrolides should also be done as part of long-term targeted oral therapy as an anti-inflammatory, mostly around anti-isolate attenuation. Maeve Smith out of Edmonton has a really beautiful summary in CMHA that was published a couple years ago that nicely summarized macrolide therapies, which I won't go into for time, but really azithromycin or erythromycin tends to be the option. So what I want to spend just the last couple minutes on is the exciting developments where bronchiectasis is going. And the latest drug on the spectrum is brenzocatib. So this drug is a DPP-1 inhibitor, it's an oral agent. It works against neutrophils in the context that the DPP-1 is the agent that releases serine proteases from the bone marrow of neutrophils. So the thought process is it will attenuate protease production and then reduce that inflammatory cascade. So this study by the Chalmers Group published in the New England Journal 2020 was a phase two, 24-week study, just over 250 patients. And what they found was when they randomized to placebo or different doses of drug, there was clear reduction in both time to first exacerbation and risk of exacerbation, as well as reduction in neutrophil elastase. In fact, the study was very interesting. They actually could not calculate time to first exacerbation in the treatment arm because there were so few exacerbations, so they had to do some different statistical analysis. But you can clearly see here the Kaplan-Meier splits, attenuation of exacerbations, and a secondary analysis just published by James Chalmers in the ERJ Open showed that the number needed to treat to prevent an exacerbation was six. So it is a pretty exciting drug. Right now, it's in phase three trial through the Aspen Group. I believe they're just at the point where they finished enrollment. It's about 1,600 patients, and we're all eagerly excited to look at that. Some other therapeutics that have been kind of up and coming with bronchiectasis, so for those in the CF world, Trikafta or ETI therapy, there is a study going on right now looking at this in non-CF bronchiectasis, given that there are high rates of CFTR dysfunction. So I think there will be some things coming up. So lastly, just in the last minute, treatable traits seems to be the theme of this morning. We've heard that discussed time and time again, and bronchiectasis is no different. So part of the issues with this disease and why many trials don't meet end goals is it's a very heterogeneic pool. So we don't have a good way of deducing which patients will benefit from which therapies as compared to our asthma colleagues or our COPD colleagues. And so this study just came out two weeks ago in the Blue Journal, it's hot off the press, looking at inflammatory endotyping. And to jump right into the results, what they found in a large cohort of bronchiectasis is they could clearly distinguish endotypes or palmitypes based on inflammatory markers as well as microbiome features that are clearly associated with exacerbation risks. And as I mentioned earlier, there is a cohort that is a non-type two or neutrophilic component, which is not typically described in bronchiectasis. And their earlier Blue Journal paper did show that that 20% with high peripheral eosinophil counts were higher risk of exacerbation. So it's a potential therapeutic target such as biologics, which is not typically thought of in bronchiectasis alone. Lastly, what about NCFB in Canada? So as I've probably alluded to, we have no data, which is not great. A lot of it is extrapolated from other countries. And as a result, we don't have good prevalence and our patients are missing out from clinical trials. So myself and a colleague, we are doing a bronchiectasis and NTM registry that's hopefully gonna be launched across Canada in years to come. We have about 110 patients enrolled in Calgary. We'll be going to Edmonton next. And the stars there indicate the clinics that have agreed to participate. So if it is something of interest, please come and chat with me. To go along with this, we also have about a 40-year biobank of close to 10,000 sputum samples, all with metadata that we're gonna be interrogating to get a better sense what's happening longitudinally with these patients. So to summarize, I hope I've shown you bronchiectasis is common, heterogeneic, and it's a very exciting discipline where basic science and clinical practice meet together. I think as clinicians, we should be aware that bronchiectasis treatment is up and coming and there's a lot more we can be doing and expecting in the years to come. And as scientists, I think we should consider a very exciting area for discovery-based research. And so I think there'll be a lot more to come. And clearly at this conference, there's many, many talks about it. So with that, thank you very much for your attention and I'd be happy to take any questions.

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