Thank you, everyone, for coming. I know the challenge for you to show up at 3 p.m. here. We actually had a bet on how many people are going to be in the room, so you guys win. Thank you. So today we're going to be talking about bronchoscopic interventions for patients with COPD. I'm glad to do this session with my colleagues and friends. Dr. Murthy, he's an assistant professor of medicine at NYU and the director of their IP fellowship program. And Dr. Holden is an associate professor of medicine at the University of Maryland. She's also the program director of their pulmonary fellowship. Last but not least, Dr. Shakdeva is an associate professor of medicine at the University of Maryland. He's also the section chief of their IP program and the program director of their fellowship. Also a great mentor, if you're looking for one. These are my objectives for the talk today. We're going to be talking about potential therapies for COPD that are under clinical trials. And then we're going to shift gear and talk more about therapies for patients with COPD focusing on how to best select candidates for bronchoscopic lung volume reduction, their outcome and durability of the procedure, and the challenges that we face during these cases. These are my disclosures for the talk. And my objectives for my part would be reviewing the potential novel treatment for patients with COPD and then summarize the prior publications on the available potential treatments and some of the possible benefits and outcomes of these procedures. So starting just to lay the talk, we're talking about the sequelae of COPD exacerbation. This is a study that was followed 2,000 patients over five years. And they found that patients who had repeated COPD exacerbation had a faster decline in their lung functions compared to patients who did not have COPD. It affected more patients with milder stages of COPD. We also know that repeated COPD exacerbation increases the risk of cardiovascular events. This is a study that followed more than 1,600 patients with more than 550 cardiovascular events, sudden cardiac deaths. Patients who had two or more COPD exacerbations were at threefold more risk of sudden cardiac deaths compared to patients with COPD that did not have repeated COPD exacerbation. From that, several treatments have emerged. The first would be that I'm going to be talking about is targeted lung denervation. That it's a minimally invasive procedure, bronchoscopic guided, with the idea of denervating the parasympathetic system around the lung, targeting the peribronchial branches of the vagus nerves around the bronchi with the aim of potentially reducing the frequencies of COPD exacerbation. The procedure is a bronchoscopic procedure delivered by a catheter, a balloon catheter, that has an electrode on the outer surface that emits radiofrequency energy. So we insert it through a bronchoscope inside the airways, and it lays on the interior surface of the airways. And once you activate the catheters, it emits the energy to ablate the nerves running parallel to the airways. Then you turn the balloon in four positions so you get circumferential treatment. You do it on both sides, and bilateral treatment is done in the same session. This is the electrode, if you don't appreciate the view on the fluoroscopy. Also to minimize any risk of injuring the nerve plexus around the esophagus, there's an esophageal balloon that is inserted in the esophagus. So you can see it and measure the distance between it and the electrode. And based on that distance, you can either decrease the energy emitted or skip treatment in that area if you're too close to the esophagus. So for targeted lung derivation, their first larger publication, Airflow-1, they treated 46 patients with COPD with FU1 30% to 60%. It was more of a feasibility study that was achieved in the majority of the patients. Some patients developed some impaired gastric emptying. So with that, they adjusted the procedure and introduced the esophageal balloon that I just mentioned. And the confirmatory group, 16 patients with 3, there was no complications. The following study, the Airflow-2, was also published in 2019, the same year. And in this one, they treated 82 patients, and it was a randomized trial, one-to-one with sham ablation procedure. In this one, the recruited patient was gold stage BRD. That means that they recruited patients that were more symptomatic. And what the goal is to determine the safety of the TLD catheter. And the primary safety endpoint was the difference between the two groups at three and six and a half months after treatment. And the rate of COPD exacerbation has decreased significantly in the TLD arm, the therapeutic arm. Also at the one-year mark, there was no difference in the rate of respiratory adverse events between the two groups. The risk, however, the risk of COPD exacerbation that required hospitalization was significantly lower in the TLD arm. And also, we have like a longer-term outcome from these studies now. So we have a three-years outcome falloff from the initial cohort. And the treatment has shown that there was stable quality of life at the three-years mark in terms of St. George's respiratory questionnaire. And there was also stability of the lung function at the three-years mark. There is also a two-years outcome for the second cohort. And in that one, the time to first COPD exacerbation was significantly lengthened in the treatment arm. And there is no data on the recent trial. This is the largest airflow three trial that just recently closed the enrollment. And 388 patients were randomized with the primary endpoint to look at the probability of moderate or severe COPD exacerbation at one-year mark. Recruitment this time included patients with Gold Stage 2 and 3, Group D patients with COPD exacerbation. And also to decrease the risk of any gastrointestinal side effects, an esophageal cooling device was introduced in the middle of the trial. And more than 160 patients were treated safely with that device. So with the idea just to minimize any risk to the esophageal plexus during the treatment. Shifting gear, talking about patients with chronic bronchitis. Chronic bronchitis has a high prevalence, up to 35% in patients with COPD. And we know that the chronic mucous hypersecretion causes a faster decline in the lung function in those patients. And this is a slide just showing the difference under the microscope, 40-fold magnification. Just on the right side, a biopsy from an airway mucosa of a patient with chronic bronchitis and showing the hyperplastic goblet cells compared to the left side, just normal patient with COPD still, but with no phenotype of chronic bronchitis. So there are two potential therapies in the pipeline for chronic bronchitis. Both of them are aiming towards destroying the hyperplastic goblet cells and allowing the body to regenerate fewer number of goblet cells. There's a third treatment that there was some publication on, but there is no any clinical trial in the pipeline, so I'm not going to talk about that one. So the two potential therapies are ongoing right now. The first is liquid nitrogen meter cryospray, and the second is the bronchial rheoplasty. So the first one was the meter cryospray. They use liquid nitrogen at a very low temperature to deliver the meter doses of cryospray. So each bronchial airway will receive a certain amount of nitrogen based on the airway size to deliver the cryo treatment at a depth of up to .5 millimeter with a width of 10 millimeter. And the same idea is just to destroy the underlying hyperplastic goblet cells. The second treatment, sorry, these are the published data on that treatment. These are the initial clinical trials on animals and humans who are undergoing lobectomy and pneumonectomy, and just the device have shown to be safe. There was no complication from the device. They have one larger publication. It's still a sample size, a small 35 patient. It's a prospective cohort that was treated. The enrolled patient was COPD, was chronic bronchitis phenotype, and they delivered three treatments with four to six weeks apart. Efficacy was the primary outcome that they were looking at, and they found that the St. George's pressure questionnaire has meaningfully decreased by six points at three months, and the effect was durable up to nine months. And the same for the CAS score that has decreased significantly, was durable effect up to six months. Also, the cough questionnaire score has decreased as well, and the changes was durable up to nine months with that treatment. Safety-wise, at 12 months mark, 14, there was 14 serious adverse events in 11 patients, so that's one-third of their cohort. But most of the adverse events were, as expected, were COPD exacerbation, pneumonia, and one case of worsening cough of all these patients have recovered. They have right now an ongoing trial, and it's a two-to-one randomized trial with crossover at 12 months. Sham control trial, they're looking to randomize 210 patients. It's going to be done, there will be two treatments instead of three in this trial, and each lung will be treated 30 to 60 days apart. And the primary outcome would be acute COPD exacerbation at 12 months, as well in changing the St. George respiratory questionnaire at 12 months period. The other treatment, which is the bronchioreoplasty, same idea but different mechanism. The catheter would deliver a non-thermal pulse electric energy with the same intention as to ablate the goblet cells in the airways and promote the generation of healthy underlying epithelium. And it uses a monopolar electrode. That means that there are some patients that are going to be excluded or there will be some contraindication. Anyone who has an implantable device, that's going to be a contraindication for these patients. They have one publication. It's more of a pooled analysis of 30 patients. They looked at the safety and feasibility mainly of the catheter. There was only four procedure-related significant adverse effect at six months. There was no catheter-related adverse effect. And they found that there was a significant improvement in the quality of life at 6 and 12 months in terms of CAT score and St. George respiratory questionnaire. They do a mucosal bronchoscopic biopsy before and after the treatment. And they found that there was a mean goblet cell hyperplasia score significantly reduced after the treatment. That's a good sign. They also, the same as the cryospray, they have an ongoing trial that is recruiting right now with the aim to randomize 270 patients. It's a prospective multicenter randomized trial with double-blind sham control trial. And the randomization is two to one. So this was just a summary of what's in the pipeline for management of COPD. All these therapies are under clinical trials. This is a possible like treatment pathway for these patients in the future if these potential therapies were proven beneficial. So if a patient will have COPD with significant airway obstruction and frequent relapses and exacerbation, then targeted lung denervation can be a potential treatment for them. On the other hand, if they have a chronic bronchitis phenotype, then cryoablation or uroplasty can be a potential treatment for them. If the patient has severe emphysema, hyperinflation, and dyspnea, then lung volume reduction would be the path that they would follow. And they can go either to surgical lung volume reduction or bronchoscopic lung volume reduction. And this is like our internal referral. It's the same slide, but it's internal. So it's more fun. This is how the path that we follow in clinic. If someone has COPD, if they have more airway obstruction and relapses, they go in one pathway. If they have more emphysema and hyperinflation, they go into the BLVR pathway, just something to stick in the mind of our fellows. With that, I'm going to wrap up here, and I'm going to ask Dr. Sakliva to follow, I'm sorry, Dr. Murthy to follow me. Thank you for joining us on a beautiful Monday afternoon. While this is loading, I'm just curious, if you don't mind raising your hand, who here is a trainee, a resident, or a fellow? All right, really thrilled that you guys are with us. And then who here amongst the faculty perform bronchoscopic lung volume reduction routinely? Wonderful. I know most of you. If there's any heckling, we will call security, just so you know. All right. All right, so I'll be discussing predictors for best outcome of bronchoscopic lung volume reduction and the patient selection factors. My name is Vivek Murthy. I'm an interventional pulmonologist at NYU, and I have nothing to disclose. So over the next couple minutes, I'd like to talk a little bit about how we think about patients when we evaluate them in the clinic, when we're trying to predict which outcomes, which factors are likely to result in good outcomes from lung volume reduction by endobronchial valve therapy. So I'll talk a little bit about collateral ventilation, how we assess for that, radiographic considerations when planning, whether patients are good candidates for BLVR. And then I'll talk a little bit about some absolute and relative contraindications for pursuing BLVR. So as Dr. Gattas mentioned, you know, hyperinflation, as we all know, is a major contributor to symptoms and to morbidity for patients with COPD. With that in mind, the National Emphysema Treatment Trial was designed and published in 2003 to evaluate the efficacy of a surgical approach to lung volume reduction. And in many ways, the NET trial not only has provided a huge amount of information on the phenotype of these patients and outcomes from surgery, but also has informed minimally invasive approaches that we're taking today. So I think it's an important place to start when we're thinking about patient selection. So this is a multicenter trial conducted at 17 sites, a randomized trial comparing optimal medical therapy, including pulmonary rehab, to bilateral lung volume reduction with the goal of reduction of 25 to 30 percent of the most destroyed part of an individual's lung. They enrolled 1,200 patients, and they were randomized to either of these two groups with the primary outcome of all-cause mortality or improvement in exercise capacity. And they followed patients for an average of two and a half years. There was a subsequent analysis later on that we'll talk about. Really importantly, their exclusion criteria really mirror some of the exclusion criteria we think about even today, because every subsequent trial of minimally invasive approaches has had a similar approach, almost every one. So very low FEV1, less than 20 percent. This was added at some point in the trial, actually. Homogenous emphysema, prior major lung surgery, a non-COPD major pulmonary issue, or a bullae occupying more than a third of a hemithorax. All these were felt to be exclusion criteria for the study. So there wasn't really any major difference in overall mortality. However, in subgroup analysis, it was demonstrated that specific phenotype of patients seemed to benefit most from surgery from a survival standpoint. These were patients with upper-low predominant heterogeneous emphysema who had a low baseline exercise tolerance. The study wasn't really designed to evaluate this difference in a significant way, but it was compelling enough that, you know, these patients were followed for several years. And that survival benefit appeared to persist six to eight years after their randomization. There was some crossover, it's worth noting, after the two-year NET protocol completed. So some patients who were randomized to medical therapy did have LVRS subsequently. But even so, this raised the question about whether there might be a way to capture the potential benefit for this subtype of patients without the morbidity of surgery. It's worth noting that mortality aside, about 20 to 30% of patients had some cardiopulmonary issue post-operatively, whether it's arrhythmia, pneumonia, respiratory failure, with a higher 30 and 90-day mortality rate for surgery versus medical therapy. So this resulted in a number of trials of valves and other approaches to lung volume reduction, leading to the point of where we are today, which is that we have two FDA-approved valve therapies for bronchoscopic lung volume reduction, with slight differences in patient selection criteria and considerations for the two currently available approaches. So when I'm seeing a patient in the clinic, there's a couple of things that I first think about when I'm evaluating someone for endoscopic lung volume reduction. First is, how does the patient look? Second is, what do their PFTs look like? And third, what does their imaging look like? And there are other considerations. But those are the three big things that come to my mind first when I'm considering candidacy. And I think it's really important to have a thorough evaluation, but also to be honest with patients. Because these are usually people who have not really had a lot of other options. They may or may not be transplant candidates. They've usually been maximized on medical therapy. And so it's really important, I think, to be very upfront with them when we have these conversations. So these are some examples of the kind of imaging we might see for a patient who's referred for consideration for valve therapy, who may or may not be appropriate might require some scrutiny before we consider this as an option. So in A, we see a patient who has a really large apical bullae. It's about a fourth to a third of that hemithorax. So this might be a patient we'd have to think really carefully about whether they're really a candidate for valves versus perhaps a surgical or other approach. B, it's kind of hard to appreciate. It's easier to see when you're scrolling through a high-res CT. But that's an example of an incomplete major fissure. And we'll talk about that a little more. C is an example of paraceptal emphysema with really, really large bullae. Not any one large one, but many that might be worth noting when we're thinking about planning. D is a patient who has not only emphysema, but we see some peripheral fibrotic changes, which might be relevant. Great that we can induce atelectasis. But if they have combined pulmonary fibrosis and emphysema, they might have issues down the line after the procedure. It has to be considered. E is a patient with severe bronchiectasis, probably has a high mucus burden and probably is not a great candidate for valves. And F is a patient with a lung nodule that, if it's proven to be benign by one means or another, could still be considered for valves. But that would have to be established before proceeding with the workup. So one of the key considerations when we're thinking about the likely efficacy of lung volume reduction is the presence or absence of collateral ventilation. So collateral ventilation, we know, occurs due to microscopic connections between alveoli or terminal bronchioles for a number of reasons. We'll talk about that. This was first studied on a physiologic level in 1978, when this group passed a swan-gans catheter through a bronchoscope and generated the first flow decay curve, showing that with complete lobar occlusion and simultaneous measurement of flow and pressure, they could demonstrate the presence or absence of collateral ventilation in a target lobe. So the COPD gene study, you're probably all familiar, was a large observational study looking at the genetic epidemiology of COPD. But one of the nice things about it was they also collected high-risk CT data on many, if not all, of the patients that were enrolled. So looking retrospectively at that data of almost 10,000 patients, there was actually no association identified between the presence of collateral ventilation and environmental or clinical factors like smoke exposure or severity of COPD, but there was a genetic association identified, not yet well-characterized or understood. But there was a three-fold higher likelihood of intact fissure integrity amongst black participants in the study versus non-Hispanic white participants, suggesting that while clinical factors probably do play some role in this large study, that really wasn't demonstrated to correlate directly with or without smoking. It's kind of interesting. So when we're thinking about how we assess for this, you can't just look at someone's CT and definitively necessarily know that they do or do not have intact intralobar fissures. So there are non-invasive ways of evaluating using software guided by a radiologist. There's a couple of platforms that are available. One very popular commercially available platform looked at patients with, sorry, undergoing evaluation for lung volume reduction. They all had COPD. They included 25 patients and they looked at 91 fissures. And they compared the findings of this software analysis, which took a detailed look at fissure integrity, and compared that to physiologic findings at the time of bronchoscopy. So what this small study found, and this has been borne out, I think, in subsequent real-world practice, is that when the estimate based on the software's assessment was that fissure completeness was under 80%, there was a high likelihood that there would be clinically significant collateral ventilation, 100% in the small studies, 25 patients. And also when there was high likelihood of, when fissure completeness was estimated over 95%, there's a high likelihood that you had intact lobar fissures. You could believe the high and the low, but the intermediate range of 80 to 95, some physiologic assessment was needed because only 40% of those patients actually had collateral ventilation. So there's a subset of patients for whom additional data might be helpful when they're deciding whether to commit to bronchoscopic lung volume reduction. One of the putative advantages of VLVR over surgical lung volume reduction is that it's reversible. But the reality for anyone who does the procedure is that, yes, you can remove the valves, but that doesn't mean that the effects are completely reversible. There is morbidity related to the procedure that has to be considered. And so when you have patients who fall into this middle range, I think it's really, really important that we counsel patients that we might need more data before we can commit to a treatment plan. So this is an example of a, I'm working really hard, you may notice, not to mention any brand names, by the way. So this is an example of a software platform that generates flow and pressure curves with low bar occlusion. I'm just acknowledging it because, yeah. But here we see at the top, this is an example of, just for example, this is a case where you might have a bronchoscope lodged in the right main stem bronchus with a balloon inflated in the right upper lobe, and you have complete occlusion of the right upper lobe. If you did that and you had no collateral ventilation between the right upper lobe and other lobes, what you would expect to see is a progressive decrease in flow. You don't really see a decrease in pressure because you're still getting some pressure and the measurement is not up against a wall so you can believe the value that you're getting, but the flow is eventually gonna reduce to zero or close to that. Contrast that to B, where we see that despite low bar occlusion, we have a continuous flow pattern. It's low, but it's there. This indicates the likelihood of collateral ventilation. So, I'm gonna move forward. So presence or absence of collateral ventilation is obviously critical to deciding whether someone is a candidate for lung volume reduction. And the other criterion that is, I think that there may be more nuance in the application of that is in quantitative assessment of emphysema. So the vast majority of studies that have been done of bronchoscopic lung volume reduction have focused on patients with heterogeneous emphysema, though there are some data suggesting that there may be some benefits for select patients with homogenous emphysema. And so, how is that quantitated? Well, the software that I mentioned, there's a couple of platforms, they all use Hounsfield units as their way of quantifying tissue destruction. With lower Hounsfield units correlating with greater tissue destruction and most likely local hyperinflation. This is an example of two different patients where we're considering treatment of the left lung. And this is the kind of report you would get from one of these third-party platforms. So what we're getting in this report is the estimated degree of fissure completeness, voxel density, a voxel is a 3D pixel, and an estimate of the volume, of course. And what we're looking for really is, is there a difference of greater than 15% between two lobes in an ipsilateral lung? What we see on the left in A is that this is probably someone with more homogenous manifestations of emphysema in the left lung, because it's a relatively small difference between the left upper and left lower lobe with an intact lobar fissure. In contrast to the right where it's more kind of a heterogeneous pattern where there's a clear difference in destruction with more on the left upper lobe than the left lower. So this is actually from a paper published by Dr. Holden. It's a single patient who had their data uploaded to two different platforms where we see very similar findings overall, but selection criteria for different platforms differs for a variety of reasons. So in A, we see a tissue destruction score of greater than 40% with fissure completeness of over 90% on the left. Similar finding on the right. And in the same patient for whom balloon occlusion was performed, we see a signal of absent collateral ventilation. So this is someone who would be a good candidate potentially if they meet other criteria for consideration of bronchoscopic lung volume reduction. So perfusion is obviously a major factor when we're thinking about the overall expected response to bronchoscopic lung volume reduction. And that's especially true in patients with homogenous emphysema where additional data on the potential effects of atelectasis can be very helpful. So there's a difference between single photon emission computed tomography SPECT and a conventional ventilation perfusion or perfusion scan done by nuclear medicine in that there's more precise low bar perfusion data provided by SPECT than is generally available even with quantitative perfusion where perfusion is usually defined as upper, mid and lower lung fields versus right upper, right middle, right lower lobe. So the added value I think is either for cases where the data from software assessment is a little bit unclear or in patients with homogenous emphysema who you think might be otherwise good candidates based on their visual integrity for at least at our center, perfusion imaging has become pretty routine for evaluation of patients. And when SPECT is done pre and post bronchoscopic lung volume reduction, we see that there's in successful cases, there's greater homogeneity of ventilation and perfusion three months after BLVR, which suggests that this impact is not just related to atelectasis but also changes in blood flow post procedure. So thinking about all of that, if I'm approaching a patient, it's nice to have kind of a set of guidelines for things that are likely to be helpful in selecting patients for BLVR. So when it comes to absolute contraindications, I think these are pretty consistent amongst different centers. So someone with an ongoing infection, someone who's actively smoking, an allergy to a component of the valve, so nitinol, silicone, polyurethane, probably shouldn't get one. A bullae larger than one third of the hemithorax, this has been an exclusion criteria in basically every study and it's something that I think we all pretty much follow given the high risk of pneumothorax with this procedure at baseline. And then incomplete lobar fissures. Though even that, there are some centers that are kind of pushing the boundary on what constitutes an incomplete lobar fissure where there might be some partial atelectasis. But at this point, I would say it's still probably an absolute contraindication. Relative contraindications, I think you have to take with a huge grain of salt because this is still a relatively new procedure. Highly experienced centers are really pushing the boundary of what can and should be done with bronchoscopic approaches to lung volume reduction, sometimes with interesting and novel results. So I would take all of this with a grain of salt and this might change in a year for all we know. But for now, some things that are pretty obvious, if you have a high sputum burden, a lot of mucus impaction probably should be treated before considering valves. Frequent exacerbations are definitely a relative contraindication. Major cardiac issues are a consideration as is chronic hypercapnia or pulmonary hypertension. And then an indeterminate pulmonary nodule, I would say that if it remains indeterminate, I would call that an absolute contraindication because of the potential risks of managing something that could be growing in an atelectatic lobe. And the inability to stop anticoagulation, of course, is a major consideration. So just to kind of summarize a best case scenario, I wanted to show you a case that we did earlier this year, which I thought kind of really checked all the boxes really nicely and it was just a really good example. So this was a 70-year-old woman. I changed some of the details here, so this is not 100% the person, but a 70-year-old woman, she has a 50-pack year smoking history, quit many years ago on triple therapy, on two liter supplemental O2 with persistent exertional dyspnea. She did complete pulmonary rehab, which she said helped a bit, but really she was still pretty symptomatic, not able to complete her ADLs as much as she wanted. So her pre-lung volume reduction PFTs are seen here. IVV1 of 0.91, 57% predicted. You see her RV and TLC are both elevated, DLCO is reduced, and she's on oxygen. And here's an example, just showing the heterogeneity of her emphysema. We can already get a sense of what we might be treating if all the workup is favorable. So this was her software analysis. What we see is a really high tissue destruction score in the right upper lobe. Perfect fissures, at least as predicted by the software. So this was just a great candidate for right upper lobe treatment. And in fact, that's what we did. Oh, wait, I skipped ahead, sorry. We did get perfusion imaging on her as well. And so this is not a SPECT. So in contrast to that, we see only upper middle and lower lung zones. It's nice because this is readily available. Most centers, getting a SPECT might be a little more difficult. The disadvantages, particularly when you're trying to treat a lower lobe, so the superior segment of the lower lobes can often show up in the mid-lung zone and differentiating that from the middle lobe on the right can be tough. And so there are real limitations to just using regular perfusion scanning. But what we really cared about was the right upper lobe. And there was very little perfusion to the right upper lobe. And this was the patient's physiologic assessment at the time of bronchoscopy. So what you see is the balloon is inflated. We see initial flow. We see a drop. At the bottom, this VT60, that's the average volume over the prior 20 seconds. And once that drops to six, that's usually our cutoff to say that there's absent collateral ventilation. That happened. And that happened at about four and a half minutes. And then we placed three endobronchial valves. Patient stayed for three days, no pneumothorax, went home. And this is her post-CT and spirometry where we see atelectasis of the right upper lobe. We see a little bit of increase in size of the left lung, which is expected, and probably some hyperinflation in the right lower and right middle as well relative to previous. But overall, her spirometric values were much better with improvement in FEV1, a better RV and TLC. And while her DLCO was lower, actually her O2 requirement was less. She was only using oxygen with significant exertion. So overall, it was a very successful case. And we hope that all of them are like that or close to that. So summary for inclusion would be patients who have emphysema, who have spirometric values that suggest hyperinflation, but that are not so severe that they're outside the bounds of available research, and who haven't had frequent exacerbations of COPD or major contraindications to valve insertion. Many of our patients are on prednisone, but as long as it's a low level, that's usually manageable and tolerable. And in fact, we as protocol put our patients on prednisone at the time of the procedure anyway. And then meeting criteria for non-invasive assessment for tissue destruction and fissure integrity. I always say the procedure is the easy part. Everything else, I mean, we actually end up putting valves as most centers do in about 15 to 18% of patients that are screened. So there's a lot of work that goes into screening these patients. But the more time you spend doing that, the better the outcomes are likely to be. Thank you so much. Okay, good afternoon, everybody. Okay, good afternoon, everybody. Today, I'll be discussing the outcome and durability of bronchoscopic lung volume reduction. So the objectives of my talk will be to describe both the short-term clinical outcomes as well as the durability of patients undergoing bronchoscopic lung volume reduction. So why are we discussing this today? What is the impact on the patient, both immediately after the procedure and years afterwards? For the purposes of my talk, I will be focusing on the use of one-way valves in patients that have heterogeneous emphysema and no clitoral ventilation. So in terms of post-bronchoscopic lung volume reduction clinical follow-up, typically the clinical follow-up is first done one to two weeks after the procedure to evaluate for patient tolerance and any potential complications. Subsequent clinical evaluations occur at one, three, six, and 12 months, and then yearly. In most of the clinical trials that have been published, they assessed treatment response at three, six, and 12 months using both subjective and objective parameters. It's important to continue assessing these parameters on a yearly basis to determine the long-term outcome and the efficacy of the treatment over time. Pulmonary rehabilitation can generally be recommended after the first month, once the risk of pneumothorax is lower. So we're going to review just what are the available data in these patients in the short term. So there has been a meta-analysis evaluating studies of patients who've undergone bronchoscopic lung volume reduction. The meta-analysis that was published included the following studies that were listed. It's important to note that these studies had various outcomes measured at three, six, and 12 months. So the longest study, the LIBERATE trial, included outcomes at 12 months. So in this meta-analysis, it showed that there was an improvement in the use of both of the commercially available valves, one-way valves. There was improvement in FAV1 of .11 to .14 liters per minute. There was an improvement in the six-minute walk distance only in one type of the valves, and that improvement was in 52 meters. And in the St. George respiratory questionnaire, there was improvement in both types of valves in lowering the score there. And looking at these outcomes in the patient-oriented outcomes is going to be the quality of life. They may not necessarily care what their FAV1 is, but they're going to care about what is their impact and their ability to do more and their quality of life. So specifically focusing on the one-year outcome of quality of life, they did look at a post-hoc analysis of patients who were in the LIBERATE study. So just as a reminder, the LIBERATE study was patients that had heterogeneous emphysema and little to no claral ventilation, randomized to a valve or a standard of care. And up to one year out, they looked more specifically about, besides the St. George respiratory questionnaire, what were the components of that questionnaire and other improvements in dyspnea and breathlessness score as well as activity scores. So they found that bronchoscopic lung volume reduction showed improvements in the impact in patients' lives, their activity domains, patients were able to do more. They had an improvement in breathlessness, improvement in energy level. And this is, I found very important, was an increased confidence in leaving home. So that's very meaningful and impactful for patients, that they can leave their house. And then TDI is a transitional dyspnea index, and it shows that they also had improved measures of effort, task, and functional impairment. Looking at post-BLVR three-year clinical outcomes, there's very few studies that have looked at clinical outcomes past one to two years. This was a single-center retrospective study of 280 patients who underwent BLVR. And looking at the six-month versus 12-month follow-up, there was still a statistically clinically improvement in all of the parameters listed, and then up to two years and three years summarily. The only caveat was that looking at the six-minute walk distance and the CAT score, it showed that there was no improvement at the three-year mark. But there was improvement at the two-year mark. Everything else, including the FEV1 residual volume, St. George respiratory questionnaire, and MMRC were all improved. So this shows that there has been clinical improvement subjectively and objectively out to three years in this single-center study. However, what was interesting is that the magnitude of the improvements did decrease over time. So the magnitude of improvements in FEV1, residual volume, six-minute walk distance, and the St. George respiratory questionnaire decreased over the course of those three years. And the authors postulate that EBV treatment does not stop the natural progression of COPD disease. So there's still going to be an overall slight decline in FEV1 over time. And the benefit that, even on the magnitude of benefit decreases over time, it's still better than the standard of care group. In terms of longer-term clinical outcomes at five years, patients here in the LIBERATE study are currently undergoing data collection. This year is actually their five-year mark. So we're going to be excited to see what the results of the five-year clinical outcomes will show. In terms of other clinical outcomes, there have been several studies showing that doing BLVR has resulted in prolonged survival. So in this study, patients who are selected for BLVR live significantly longer than patients who are not selected, median of 3,000 days versus around 2,000 days. This study also highlights, though, what Dr. Murthy mentioned is a challenge in evaluating patients and selecting patients to undergo BLVR. So in this study, they had 1,500 patients who were referred. And automatically, 19% of the patients referred did not meet criteria. And ultimately, only 12% of patients underwent BLVR. So it's a very select group of patients who are able to undergo the procedure and have this benefit. It also highlights the challenges of the intake and the referral process as well as education of referring physicians and which patients would be eligible. And the other challenge is also setting expectations with patients up front. Patients may have seen advertisements for valves and may have this expectation that all of a sudden, they're going to feel better and be able to do more and they're automatically a candidate. So a lot of it has to do with patient education as well. This was another study that showed they had 33% of patients that were referred underwent BLVR. And those that underwent it also had prolonged survival of a difference of 1.7 years. And there's been very few interventions that have been shown to prolong survival in patients with COPD. The results of these studies have then led to bronchoscopic lung volume reduction being included in the GOLD guidelines. Most recently in the last few months, there's been several studies have also published on other outcomes of patients who have undergone BLVR. In this first study here, they showed that the St. George Respiratory Questionnaire and the six-minute walk distance were independent predictors for improved survival. So the question is, why did these patients survive longer? And they postulated that they survived longer because they had improved exercise capacity and quality of life. In another study that was just recently published, it also showed that there was a decreased risk in moderate and severe acute exacerbations of COPD. And this was even more impactful, decreased from 2.5 to 1.4 exacerbations per year in patients that had complete low-bar atelectasis. Finally, there are physiologic benefits of patients who undergo bronchoscopic lung volume reduction. So if you have a decrease in the residual volume, which decreases intrathoracic pressure. You can increase the preload, which increases contractility and cardiac output to the heart. So in this small study of 24 patients that underwent BLVR that had cardiac MRI one week before and eight weeks afterwards, and it shows that there's a reduction in hyperinflation, improved preload, myocardial contractility and cardiac output. Also recently, there's been one very small study of less than 30 patients that showed improvement in their mean pulmonary artery pressure. So in conclusion, both physiologic and quality of life indicators can remain improved out to three years. A follow-up, however, the magnitude of the benefit may diminish over time. Additional studies of long-term clinical follow-up are needed, and the clinical outcomes can include improvement in survival. Thank you. I want to thank the organizers for having me here and thank the chairperson and the committee for putting up this session. And I'm honored that there are a lot of people in the audience I respect, and I've learned a lot from you guys. My topic is very simple. There's not a lot of literature. No. There's good literature, and I'll share some of that literature tying it to my patient's own journey. I think what Dr. Gattas talked about is this is a very exciting time of realistic optimism for our patients who have severe lung disease. Many of us have been going through this journey with a lot of vendors who are focused towards optimizing the treatment for COPD. So that's a lot of work that's in progress. You know, Vivek talked about lung volume reduction surgery, and I think that should be a part of discussion of every patient who comes for a lung volume reduction, and it should be a programmatic approach. What Dr. Holden talked about was there is clear benefit in outcomes. The question I'm trying to answer today for you all is how do we maintain that benefit and how strugglesome it is to do so? This is the so my objectives are very, very simple. The question is can revision bronchoscopy help or hurt the patient? Does it need it, and how often? What are the findings that you're likely to encounter in patient who has undergone BLVR, and how do you manage those? And describe the outcomes that are tied to these revision bronchoscopies. The main goal for what we want to accomplish is to sustain the effectiveness of the procedure that you have spent so much time and energy screening the patients, getting them through the pipeline, rehab, optimization of medications, offering them clinical studies that are available, and then how can these patients have minimal long-term complications? What I'm talking about is in the context of a patient. That is not what you're seeing over here. I hope you can read it. This is a patient who has very classic severe COPD with FEV1 around .51 liters. You have hyperinflation. You have reduced DLCO, but still very preserved. It's not less than 20%. Patients who had less than 20% DLCO and less than 20% FEV1 were excluded from the NET trial. You do a quantitative ventilation analysis and PCOS scoring, and you find that there is a good bit of integrity of the fissure and lack of contralateral severity. In this particular case, the right side has a little higher severity, and we were a little nervous, and this was one of my first cases. You do the valves, and you are seeing a good response in a few hours, as you can see on the left side of the diaphragm is coming up. But the next day, the patient walks to the bathroom, and you have a pneumothorax, and you place a chest tube, and you have a persistent air leak. We all know in the protocol when we were part of the earlier studies that we had to go back and look at taking out a valve in day five. That's not the typical scenario that we followed in this situation. The patient had a lung expansion, and we maintained the tube, and we had a persistent air leak that slowly resolved over a period of 10 to 12 days. This was a tough decision at that time when we had just come off the study and trying to get the patient on a clinical pathway. That is not the focus of my talk, but I'll share some recent very nice publication from Bobby Mahajan talking about how can we manage these patients with persistent air leaks at home. What typically we are going to see is a patient like this who has severe COPD, very motivated, wants to talk about lung volume reduction, has hyperinflation to a reasonable degree, has somewhat lower reduction in DLCO, and when you do the quant analysis, it's not the classic case that Vivek shared where you have heterogeneous emphysema. You get a classic right upper lobe. You're all very happy. So what do we do with this patient who has significant emphysema on the left side, some heterogeneity. On the right side, the heterogeneity index is very low. So would you do something about this patient who is motivated and does not have a lot of options? Based on the data that we have, I think offering them endobronchial valve is reasonable, and likewise this patient with hyperinflation underwent right lower lobe valve placement, a total of six valves were placed, and you can see minimal change in the right hemidiaphragm day after the procedure. There is lack of response, and sometimes we anticipate this to happen, and we are excited that a slow atelectasis is probably good. The patient went home, felt a little bit better. The mucus was suctioned, but there is not inadequate response. How do you handle that? You see the valves in these locations. The anterior segment, lateral, and posterior, and there were six valves placed. So how do you manage those? Do you do a post-CT scan assessment, and then go forward with a bronchoscopy? And I'll share what the post-CT scan assessment looked like, which is a quantitative assessment offered by the third party through the vendor. But bronchoscopically, we assess these valves, and they seem to be quite functional. These are in the anterior segment, lateral, and posterior, and these are, I believe, in the lateral. There were two lateral segments. But when we looked at the superior segment, there seemed to be an airway that this valve had slided down and migrated a little bit, and there was an open airway. So how do we manage these situations? Coming back to my first patient, where the patient went home with a chest tube, this is a recent publication from Bobby Mahajan, which talks about safety of home discharge. There were 24 discharge events, where about 100 patients underwent endobronchial valve placement, rung volume reduction, and only two of these patients who went home after 24, they were in PIMA. That's probably the function of how long the chest tube has stayed in. Again, there was no mortality, and the average length of chest tube was about 16.9 days, somewhat different than what we did actually in the study, which was typically five to seven days, and we would go in and remove one of the valves. Again, that constitutes a revision bronchoscopy. So typically, the situations that require revision bronchoscopy are patients who haven't achieved the expected rung volume reduction, or they have minimal response in terms of their symptoms, or they had an initial response. They felt good. They were walking more. They went back to their rehab, and now they are receding back on their response. They have persistent cough, hemoptysis, or sudden change or acute change in symptoms. We were just sharing a case where the patient had acute change and ended up having a kinking and almost a torsion of the right middle lobe. That was the anticipation, though. Or have post-obstructive pneumonia. If you look at the two major publications from, again, the European group, Dirk Janswebers and the Heidelberg, this summarizes the indications for revision bronchoscopy, and most common are in the blue on the right side, that's 44%, which is lack of therapy benefit. And then patients who underwent revision bronchoscopy for removing the valve for granulation tissue, which is a bit of pain, and then had a reimplantation. And then you have the gamut of patients who undergo other things. What were the interventions performed? Again, you can see the majority of the patients who had interventions done was a valve replacement. And then there were about 17% to 18%, or about 20%, if you look through across the literature, ended up removing the valve. That number varies across the center. If you talk to a high-volume center that pre-selects their patient very heavily, that number may be around 10%. If you have a center that is high-volume, but they are pushing the envelope and trying to beat the odds, the number may be higher. Again, that doesn't mean it's good or bad. It's just the nature of how you're doing the patient selection. What is the time that these patients end up with a revision bronchoscopy? If you look at this large study from Dirk Janswebers, where the curve is basically the numbers at risk of patients who underwent bronchoscopy, they were actually subtracted. And approximately 40% of the patients that by the end of a year and a half had gone some type of bronchoscopy. And if you underwent revision bronchoscopy and had to have granulation tissue treated or valve removed, you automatically buy in another bronchoscopy because you're going to go back and implant, give them a chance to do better, especially if they respond. So typically, the endoscopic findings are you're seeing a granulation tissue and you have loss of initial effectiveness. You could have clinically significant secretions, then you have colonization, whether it's post-obstructive bronchitis, pneumonia, or valves not working and you have loss of function because of that. We have even seen valve migration, and we had to put some instilled saline both to assess if there's a area around the valve or the valves have completely migrated. We lost a valve in one of the patients where it was so taut that we could not get enough landing zone and that was a significant challenge. In this particular situation, we tried to replace the valve and it migrated distally into the subsegment of the superior and we had to just leave it alone. And lastly, but not the least, you can have airway kinking. This is from Suevo's paper where they had a left lower lobe that was kinked and they had to put a biodegradable stent. And that resulted in improvement of lung function as well as clinical meaningful impact. What is the real-world scenario of a long-term post-BLVI? Not a lot of literature exists on this. There are two large publications, again, from the European group, and I'm hoping some will come from the group in the U.S. So there were about 256 patients, 66 patients for a three-year period timeline. So, you know, compared to a clinical study, a real-world, you're seeing patients are, there is attrition of patient population that is not being able to forward up for various reasons, the death being one of the major reasons in this severely ill patients. And in about 23% or almost quarter of these patients, the valves had to be removed because of lack of clinical benefit in more than 50% after a revision bronchoscopy. Pneumothorax, which, again, constitutes the first few weeks of that acute phase or subacute phase, and then decision for definite LVRS. So most programs who say, okay, you have an initial benefit and you lose the benefit, maybe LVRS needs to be reconsidered. But I want to point out that these are really sick patients. You need to pay attention to every aspect of their disease, including cardiac dysfunction. They may not die of COPD. They may die of coronary artery disease. So be mindful. The most common finding in patients who undergo revision bronchoscopy and have lost the initial benefit, granulation tissue is the number one pain point for the physicians and the patients. So this requires revision bronchoscopy to take the valves out and then bring back the patient in a few weeks to re-implant once the granulation tissue is improved. Now, everybody who does interventional bronchoscopy, we have seen impact of cryotherapy in setting of lung transplant patients or patients who have airway stenosis that, when you have granulation tissue, they respond nicely. But unfortunately, in this situation, you're going to implant another foreign body. And to size that airway, it's necessary to actually take this out and re-implant. One of the technical challenges one may anticipate is that this is a case shared by Christian. You can see there is a valve that was left open because no particular valve could be easily implanted. And the idea was that the patient probably will do well, meaning it's a very small airway. As the atelectasis happens, this airway will collapse. And I believe that did not happen. We had a similar case where we had to implant a different valve. And I'll share that with you. In the post-treatment report that you get after you do a CT scan from one of the third-party vendors, looks like something like this. And in particular, over here, you can see it gives you a good indication of how much total robar volume reduction has happened. It is not the total lung volume reduction. It's the total robar, which is 514 ml in this case, about 20% reduced. So it is certainly more than the MCID that we see in the clinical trials. And the patient had loss of benefit and initial improvement. So we wanted to offer this patient a revision bronchoscopy and pay attention to this RB6, where the radiologist identified that it's not treated. But we did treat that. And there was a change or migration of the valve. If you look at the total volume reduction, and I think that's important to pay attention, that's only 455 ml because there is compensating increase in the right upper lobe, the ipsilateral lobe. What the software doesn't do is give you the understanding of what's happening on the contralateral lobe. And Vivek's case was a beautiful case where there is a contralateral hyperinflation happening simultaneously. And we know from our lung transplant patients that single lung hyperinflation or post-transplant hyperinflation over a period of time is a very significant problem. That sometime in the same thoracic cavity space does not help with the dynamic movement of the diaphragm. And that's why we offer lung volume reduction to those patients. So this is what we were able to identify. And then this is how close of a look they give. And they look at the column of air or fluid around the valve on the airway wall. And that's you can tell if there is a leakage around it or not. In our particular patient, we looked at each of the valves. You can actually see some of the granulation tissue. But it's not impinging on the duct build mechanism. And this duct build is clean. And there is some secretions which might be impeding. Again, as we keep looking at these airways, we tend to identify what might be the issue that we can fix. So this is where we are putting a saline to capture if we can see the valve. Is there an air leak around it or not? In this particular case, we found a small airway that was not captured. And then we had to put a different type of valve which was housing nicely. At the time we placed it, there was a concern that this could achieve distal migration. And I'll share with you what happened later. Now if you look at the post post-treatment report, this was done again as the patient did well for a few months. But then had a lack of response or the response faded away. And in this particular case, you can see that robot volume reduction is still pretty robust. But the patient is feeling worse. And what do we do? And we looked at the same things again. Look at the valves. There was not a particular airway that we could identify. But because there was a different type of valve placed, the vendor will not comment on whether that valve is in good location or not. But if you look at the total lung volume reduction, this is certainly more than what the patient had achieved on the right side in the initial treatment phase. So it's a very difficult situation. The patient is feeling worse. You have looked at their other organs and there is no organ failure. They have been getting deconditioned. How do you manage this situation? I'm not talking this in the negative or nihilistic viewpoint. But I think I'm more realistic, optimistic sense that these are the challenges that you have to be prepared for. When you look at the literature, almost 70% of the patients who undergo revision bronchoscopy feel better after the revision is done and appropriate treatment is offered to these patients. If it's a granulation tissue, about 20% of these patients will have complete removal of valves. How do you, I think the question is, is there any therapy that will help us decrease the inflammation in this airway, which is a very active epithelium along with the goblet cells, could that potentially decrease the option of these inflammatory response? I think that answer has to yet come. So in this particular patient, we had a total of seven bronchoscopies over a period of time from July 21 to as early as July 23. And because the patient, even though they had improved TLVR, we had significant granulation tissue issue right here. This is a valve. This is a valve, supposed to be there was a valve and there's full of granulation tissue. Even though this patient did not have hemoptysis, there was significant secretions issues that were a constant challenge. And we had to remove the valves for this particular patient. So can you remove the valves? It is not 18 days, about 180 days since implantation. The valves can be removed easily. The most common reason in Dr. Suebo's paper was about 40% of the patients got removed due to granulation tissue, significant secretions. And in their group, 5% of the valves could not be removed. So I think the focus of our research, and it will be valuable to other areas in interventional pulmonary, is how do we manage these challenges of granulation tissue? And it doesn't matter which valve we use. It's a foreign body. So we have to summarize things simply. If you have a patient who undergoes BLVR, if you have a complete robot at electasis, the only time they would need revision bronchoscopy, and that's going less and less is if they have a pneumothorax and they need a valve removal or they have a tear that requires valve removal to have good apposition of the visceral and the parietal prura. If they don't have a pneumothorax, you're reasonably good, and then you have to watch these patients. The proportion of the patients who lose that type of response is variable. But if you have an incomplete response, the most common thing is granulation tissue. You can have valve malposition, and that can be easily fixed, and that's why you do a repeat analysis. And then airway kinking is rare, but you need to pay attention to the CT scan because there is usually acute change in patient symptoms including cough, hemoptysis, and dyspnea. So I will conclude my talk that I think there is a lot of excitement happening in the area of COPD, chronic bronchitis. We need to have a programmatic approach, not a procedural approach. I say this again and again to our trainees. It's not a procedure. It's a program, and you need to bring in all stakeholders to make sure you can deliver the best care for the best outcomes. Thank you so much. Thank you.

bronchoscopic interventions

COPD

targeted lung denervation

liquid nitrogen meter cryospray

bronchial rheoplasty

patient selection

clinical outcomes

quality of life

bronchoscopic lung volume reduction

managing complications

Chronic Obstructive Pulmonary Disease