I'm thrilled this year, as the president, to be able to invite Dr. Anne O'Donnell as our lecturer today. This has been a tradition since 1970, when we had the first Presidential Honor Lecture. And it's really based on giving this, not only to someone who's an expert in the field of your choosing, but also somebody who's been passionate about moving that forward, that field forward, as Dr. O'Donnell has done over the last 30-plus years. She's the Nehemia and Naomi Cohen Chair in Pulmonary Disease Research at Georgetown University Medical Center, and she's a professor of medicine and chief of the Division of Pulmonary Critical Care Sleep Medicine at MedStar Georgetown University Hospital. Prior to joining the faculty there in 1991, she served on active duty as Major, United States Air Force Medical Corps in Fort Worth, Texas. Anne herself is a graduate of Georgetown University School of Medicine, and she did her internship residency and fellowship there. She's internationally recognized for her clinical work and research in bronchiectasis and related conditions, and she has a long track record of publications and involvement in clinical trials. She recently served with me as co-chair of the Sixth World Bronchiectasis Conference in New York City this past July. And within CHESS, Anne's been very active. She's been on many committees, including our Guidelines Oversight Committee, and she was chair of the Scientific Presentation and Awards Committee in Vancouver in 2010. And in addition, she's been awarded our Distinguished CHESS Educator for many years. Anne has been an absolute dear friend of mine. We met back when I was a fellow. She was already in attending at a program director dinner, and little did I know that we both grew up on Staten Island and that we both went to the same high school together. And we were trained very well by all the nuns that taught us. We have a lot of the same values. We're passionate about family and about all the work that we do and about our patients. And over 30 years, we've grown to be great friends. So I'm thrilled today to be able to have Anne as our Presidential Honor Lecturer. Thank you, Anne. Yeah, thanks, Doreen, and thank you, everybody, for being here this morning. These are my disclosures. I do want to acknowledge and thank Doreen and CHESS, obviously, for this honor of giving this presentation. As Doreen alluded to, we went to the same grammar school and high school in Staten Island. And here's Doreen giving the commencement address with the nun checking her out. I didn't even think we were allowed to wear sunglasses at St. Joseph Hill Academy. But both of us got our start in this school and on Staten Island and from our parents. So I'm sure it's been a great pleasure. And I also want to acknowledge my friend, Alan Barker, who I really think is the master of bronchiectasis in the U.S. He's from Oregon Health Sciences University. And he's the one that helped me get started in bronchiectasis. A word of advice to any young people in the room, I got volunteered to be part of this trial in the late 90s. And it really launched me on my career in bronchiectasis. Alan was kind enough to let me be the first author on this famous paper. And so it really helps to have great colleagues and great friends. And I want to also acknowledge our U.S. bronchiectasis registry and our European colleagues. And as Doreen said, our world bronchiectasis team. And of course my friends and colleagues at Georgetown. So the goal here is to give a very brief clinical presentation about bronchiectasis, a little bit about the current epidemiology, pathophysiology. We'll go over clinical evaluation of the patient, sort of looking at the patient holistically in terms of comorbid conditions. What kind of testing is needed to evaluate the patient. And a little bit about risk stratification in patients with bronchiectasis. And then brief management part to the talk. And then I'm going to close up with some unmet needs and current clinical research going on in our field. So of course, you know, everybody in the audience knows about this, when do we suspect bronchiectasis. The unique features in the patient really are the productive cough, the sputum production. You know, a fair number of these patients have hemoptysis. It sometimes overlaps with other lung diseases, including COPD and asthma. But certainly it's a standalone disease by itself. And it may be part of a systemic disorder or it just may be a primary lung disease. So in terms of systemic causes of bronchiectasis, there's congenital reasons why people get it, autoimmune diseases, immune deficiency problems, and GI issues. So why do we have 10 sessions on bronchiectasis at this meeting? Because Doreen's the president. And she is likewise passionate about bronchiectasis and NTM. But truly it's increasing in prevalence here in the U.S. And there's probably somewhere about at least 500,000 U.S. people with bronchiectasis that's not related to cystic fibrosis. And the incidence and prevalence has been increasing. And that's a worldwide phenomenon, but there's data from NIH work that showed that it's increasing at a fairly fast pace, like 8.7 increase per year in some databases that have been examined by the epi team at the NIH. One thing I would point out, this was a recent publication in radiology from the group in New York that got the lung cancer screening programs off the ground. And if you look at your lung cancer screen, if they looked at their over 2,000 patients who were in a lung cancer screening, and about 23% of those patients had at least radiographic evidence of bronchiectasis. So I think it's both a matter of probably a true increase in incidence and prevalence and also an increased recognition, increasing CAT scans, that kind of thing, why we're seeing more patients with this. But to put it in perspective, obviously for every one patient with bronchiectasis, there's 20 patients with COPD, right? So we're not rivaling the numbers of COPD. But the flip side is, you know, cystic fibrosis, there's about 35,000 patients in the U.S. And again, there's probably at least 500,000 with non-CF in the U.S. So back to the Cole's vicious cycle, you know, the pathogenesis of non-CF and CF bronchiectasis. There's some initial insult to the lung. This causes an influx of neutrophilic inflammation. The result of that is airway damage, destruction, distortion. Those damaged airways harbor abnormal mucus and result in abnormal mucus clearance. And then you get the bacterial colonization there. So you know, it's probably more complex than this. And I'm going to touch on that in a minute. But this is sort of still the truth, if you will, about the pathogenesis of the disease. And like I said, more complicated. This is from Chalmers' group, looking at all the interactions that are going on at the level of the airway in terms of what's causing the initial insult and then the ongoing damage. We also know that although neutrophilic inflammation is the predominant inflammation in these patients, probably about 20 to 30% have an element of eosinophilic inflammation as well. So the neutrophilic inflammatory response involves neutrophilic serine proteases and all these other inflammatory things that sort of contribute to that vicious cycle, or now we call it the vicious vortex in bronchiectasis. But eosinophilic inflammation has a role, as I said, in probably 20 to 30% of patients. And of course we all know this, you know, it's the airways are damaged, the mucus is retained, the infections flourish. But you know, patients I think benefit from looking at a picture like this in order to understand in their own airways all the things that are going on. So again, the diagnosis is permanent dilatation of the airways. It has to be confirmed by imaging. Chest x-ray is not a very effective way to diagnose bronchiectasis unless it's quite severe. We need pulmonary function testing in these patients. If I leave you with one message, we need respiratory cultures, you know, as many as possible, as often as possible, in order to characterize the patients, both from a prognostic point of view, but also in planning therapies, and we'll get into that. There's some basic lab work. The European Respiratory Society guidelines recommend a CBC with differential immunoglobulin levels and assessing for other underlying diseases, including allergic bronchopulmonary aspergillosis. So you know, again, I'm preaching to the choir here. Visual radiographic findings with the enlarged airways, thickened walls, the airway diameter is larger than the adjacent blood vessel. You can see in these slices here, this kind of signet ring, and then here, just diffuse bronchiectasis in the lower lobes with cavitary formation. But there's all kinds of radiographic features that might lead you to thinking about what the etiology of the bronchiectasis is, and you know, also the phenotype, are they heavy-duty sputum producers, or are they quite dry? So in these slices, again, different causes of bronchiectasis, but you know, I think you can appreciate the mucus plugging here, the cystic bronchiectasis here, and here, this finger-in-glove type central bronchiectasis, which at least can lead you to the possible diagnosis of ABPA. The other type of bronchiectasis that of course we see a lot in the U.S. is what we would characterize as a more nodular bronchiectasis with the famous tree and bud radiographic findings that our radiologists love to call on these images. But you can see that here, it's different, right, because there's more peripheral mucus plugging and the airways have adjacent mucus plugs, basically, hence tree and bud. And this is typical of patients who are infected with nontuberculous mycobacterium, but it's not pathognomonic. And you know, again, an important message that if the radiologist says it's NTM because the CT has tree and bud, it could be some other pathogen, even pseudomonas. But you know, this is our, not going to dwell on NTM today, but this is, you know, sort of the typical phenotype with the tall, thin female with a small waist and sometimes some muscular or skeletal abnormalities. But again, not all tree and bud radiographic finding is due to NTM. So there are a lot of different reasons why people get radiographic and clinical bronchiectasis. And you know, many pathways and sometimes a combination of pathways leads to the formation of bronchiectasis. The bronchiectasis can be more focal. And if you see a focal bronchiectasis, of course, you think more about some, you know, post-pneumonic process, post-tubercular, or an airway abnormality, including airway obstruction from a tumor or foreign body. These bronchiectasis, of course, can be due to multiple different things, you know, including genetic, immunologic, and other ciliary abnormalities. So to risk stratify these patients, our colleagues in the UK developed the bronchiectasis severity index. And you can see the criteria, number of points are assigned to each of those criteria. And I just put this in here to remind everybody that severity is usually worse with age, though not always. And the other things are pretty obvious, right? The low FEV1, more radiographic involvement on the CT scan. But also patients with lower BMIs, and I know we all see these kind of patients, you know, have a worse prognosis just on the basis of that, and if they have required hospitalization. There's a similar score that's been, the FACED score that's been published by our colleagues in Spain has a similar arrangement in terms of prognosticating patients with bronchiectasis. So when we see these patients, you know, what's the proper approach to evaluating for possible etiologies? And you know, I look at it as, let's see if there's something treatable, right? Now that treatable things I think are expanding right now. So you really have to approach each patient, regardless of their age or their gender, with kind of a broad-minded thinking as to what possibly may be the cause of their bronchiectasis. I'm going to just highlight a little bit, genetic disorders, the big three, as you know, CF, PCD, and Alpha-1, immunodeficiency, autoimmune disorders I think are a little bit underappreciated, especially like by our colleagues in GI because inflammatory bowel disease can cause bronchiectasis. Certainly rheumatoid arthritis, Sjogren's, can also result in bronchiectasis. So an important group of patients not to underestimate. And finally, you know, patients with swallowing disorders, dysphagia, certainly are at risk for bronchiectasis. So I'm really getting into the idea of screening patients much more for CF because if you look for it, you may find it regardless of the age. And in the modern era of cystic fibrosis with CFTR modulator therapy available, I think it is very important to think about the possibility, even remote, that the patient could have cystic fibrosis regardless of the other findings. They don't have to have extra pulmonary involvement. You know, they don't necessarily know about their family history. So I think it's real important and I'll touch about that again in a minute. PCD, again, I think our ability to diagnose the genetic disorder of PCD is improving. And it's going to continue to improve in terms of genetic testing. It's not as good as CF, but I think we're getting there. And you should suspect, you know, it's not just the old classic, you know, PCD presentation. But if the patient is younger, has lifelong pulmonary and upper airway symptoms, if they had respiratory distress as a newborn, if they have sinus disease, right, if they're infertile, males infertile or males and females infertile with PCD. Those are things you've got to ask the patient in order to assess for that possibility. And alpha-1, a much more rare cause, but it does cause bronchiectasis, not just emphysema. So probably worth it to look for that, although it's not clear that the therapeutics really alter the prognosis in bronchiectasis right now. So when I evaluate the patient, I try to take an organized approach. But again, I stress that you have to really ask a lot of questions in the history so that you cover all the bases here. You want to know about the patient's family history, as I said. The patient's age comes into play. The imaging, you know, upper lobe bronchiectasis might lead you more towards the thought of cystic fibrosis. You know, basilar bronchiectasis more towards maybe the patient is chronically aspirating. You want to look at the other organ involvement, comorbidities. In cultures, I mean, that's a little bit surprising, I think, but there is a small amount of data saying that, say, you consistently culture staph from the patient, and that's a small percentage of patients that may be a marker for cystic fibrosis. So thinking about what you're getting out of your cultures is also somewhat helpful in evaluating the patient. I point you to the currently available clinical guidelines for the evaluation and treatment of patients with bronchiectasis. The newest ones are now four years old, the British Thoracic Society guideline. They're very complete, I would say. The BTS guideline is quite helpful. The ERS guidelines are now a little bit older, but a revision is underway. There is a chest old cough guideline for bronchiectasis. There is a chest bronchiectasis guideline in preparation right now. So looking forward to seeing that, hopefully, within a year or so. And then, of course, the NTM overlap with bronchiectasis, Dr. Daly's guideline published in 2020. So quickly, moving on to the general principles of treating bronchiectasis, again, I really can't stress enough that you need to take a broad approach to these patients. I think the number one thing is educating the patient about their disease. Because getting the patients to buy into the treatment plan, they really need to understand why it is we're asking them to do various different things like airway clearance. So educating the patient about, how to say, bronchiectasis is always a challenge. Educating them about showing them their CT, showing them whatever data, pictures, things like that, that can show the patient, just super important. Because there's a lot of shared decision-making in the evaluation and the treatment of patients with bronchiectasis. I really want to understand how symptomatic the patient is, how frequently they're having exacerbations. I want to, you know, quantitate how extensive the disease is from a radiographic imaging point of view. And then, again, my number one take-home message is to know what organisms the patient is infected with. So the goals, right, are maintenance and then treatments of exacerbation. And I'm also going to touch on the idea of eradication. So for maintenance, you know, we want to really reduce exacerbations, control the day-to-day symptoms, improve the patient's quality of life, and preserve lung function, prevent more damage. And with exacerbation, of course, we want to try to quickly improve symptoms and hopefully reduce hospitalizations. So in green there, thinking of green sputum when the patient is exacerbated, this is a definition of an exacerbation that was the result of a Delphi procedure that was conducted with experts, quote unquote, from around the world a few years ago and was published by Adam Hill in 2017. So I think it is important to give your patient insight about what constitutes an exacerbation. Now this was really derived for clinical trial work to standardize how we define an exacerbation in a clinical trial. But I think it's worth using in clinical practice as well. So, you know, increased cough, increased sputum volume or consistency, increased purulence, breathlessness, fatigue, and hemoptysis. So if you had three or more of those change in symptoms for at least 48 hours and the clinician decides the patient needs a change in therapy, that's what constitutes an exacerbation. So I mean, again, you can translate that into the day-to-day management of the patient. I think it's also really important on the right-hand side here is what that shows is how symptomatic the patient is for the days prior to the exacerbation being defined and how long the symptoms go even after you start to treat an exacerbation. So again, an important take-home message is this notion that exacerbations are bad. They're bad for the patient in terms of just their symptoms. The symptoms linger a lot longer than you might think. And we also know that the more frequent they exacerbate, the worse the prognosis is. So a big part of treating patients day-to-day is that you want to decrease the exacerbations. So you know, we've switched from the vicious cycle to the vicious vortex of flume et al. But basically, the treatment plan is to interrupt the cycle at every point on the cycle. So we want to treat the underlying disease if you can mitigate that. You want to do airway clearance to help with the mucus mobilization. You want to think about anti-inflammatory therapies, antibiotics if they needed to target the organisms, and then as I said, treat exacerbations. So the idea is to put a therapy into each part of the vicious cycle or vicious vortex in order to improve the patient's day-to-day symptoms, but also their prognosis. So we'll talk first about airway clearance. You know, I'm a big fan of this. The data really, when you delve into data on airway clearance, is a bit thin. But there is data and there is, of course, experience with this. But the short-term goals of airway clearance is to just mobilize the sputum and the secretions. But longer term, again, to interrupt the vicious cycle. And you know, we have a lot of techniques. I mean, there could be sessions on this. We probably should do some. We did at the World Bronchiectasis Conference some demos on how to do airway clearance and how to teach it. There's of course traditional chest physiotherapy. You know, that requires a second, you know, two people, the patient and an assistant. So you know, things have switched to patient-independent type airway clearance like various techniques, active cycle of breathing, autogenic drainage, et cetera, et cetera. But basically you need to get yourself familiar with this so you can do, or your team can do some instructing of the patient on how to do this. And again, there's devices, PEP devices with resistance, with flutter. There's nebulizers. There's high-frequency chest wall oscillating vest. And then there's exercise, all account for airway clearance. We also have pharmacologic agents. And you know, the one I think in most practice right now is hypertonic saline. Of course the data, as you can see, is not robust. But generally it's well tolerated and safe and, you know, may help the patient. There's some other, you know, pharmacologic agents like RHDNAs which failed in the clinical trial that I showed you right at the beginning in 1998. There's mannitol which has been looked at but was unsuccessful in non-CF patients. So some of the practical considerations about airway clearance, right, is, you know, instructing the patient, getting them to embrace this therapy, the time commitment. Getting these therapies involved. And then just other things like how to do it properly and how long to use it for. How to sequence the various therapies that we might deliver via the airway. How to maintain the device, clean the device, and prevent self-infection, if you will, from using these devices. Is there a role for bronchodilator in the sort of regular old bronchiectasis patient? I would argue it's not needed for routine use. But clearly there are patients with bronchiectasis who are more bronchospastic and do benefit from it. There was a small trial published in the European Respiratory Journal looking at teatropium, 90 patients who were in a double-blind crossover format. And they found some small FEV1 improvement, but not a reduction in exacerbation frequency. So bronchodilators, you know, yes for some patients, but not necessarily routine. Pulmonary rehab and exercise training, I think there's some fair amount of data, as best you can do studies with these modalities that do indicate that pulmonary rehab or just exercise training can be beneficial to these patients. So summarizing on airway clearance, again, I think this takes effort on our part to teach the patient, you know, and get the patient to understand the rationale for doing airway clearance. I've learned a lot from patients over the years about how to, you know, how to get them to do it and where they can learn more about it. So I would recommend to you this Bronchiectasis Toolbox website, which is an Australian-New Zealand Thoracic Society website that shows all the techniques of how to do airway clearance. And a patient told me about this autogenic drainage app that like coaches them for each session of autogenic drainage. So something to also look into as well. Moving on to anti-inflammatory therapies, you know, I grouped the macrolide into this category and then corticosteroids. So you know, I think everybody is familiar, it's now 11 years ago that these trials with using macrolide were published. And it does seem as though patients with bronchiectasis, with or without pseudomonas can benefit from the use of a chronic macrolide. I would say that inhaled corticosteroids have to be used with caution in patients with bronchiectasis. As we all know, the ICS, the double-edged sword, is clearly some patients with, you know, especially if they have eosinophilic inflammation will benefit from it. But there is the risk of increasing the infection problem both with NTM and regular infections with using corticosteroids. So this is Chalmers' summary of the macrolide studies. And the blue line is the patients who received azithromycin. The red is the placebo. So this evaluation of all of the studies combined together by Chalmers' group did show that the strategy of using a macrolide can be helpful in patients with bronchiectasis. And again, multiple caveats on who really is eligible to take a macrolide. Going on to what are the key pathogens. This is from the three macrolide studies, which showed variation in how many patients in these trials had pseudomonas. So pseudomonas, Haemophilus, Staph, Moraxella were the four big organisms in those trials. In the U.S. Registry, we see more pseudomonas. About a third of patients have chronic pseudomonas. This is recent data from the European MBARC database. And green is pseudomonas. And you can see that this is a 10,000 patient analysis, 10,000 plus of what pathogens in their database, the MBARC bronchiectasis database. So pseudomonas was the most common. And then Haemophilus in Europe. So that tracks with what we see. And you can see, interestingly, in southern European countries, there was much more pseudomonas than in the northern ones for reasons that are not entirely clear. We also know that the higher the bacterial load in these patients, the more symptomatic, the more likely they're going to exacerbate. So clearly, infection and neutrophilic inflammation related to infection really does impact the patients. The patients with the higher bacterial load in this Chalmers study from a number of years ago had the most frequent exacerbations and the most severe ones. And other data showed that the higher the bacterial load, usually it was in older patients with lower FEV1s and had a higher percentage of pseudomonas, which resulted in worse quality of life. So we used to really stress pseudomonas, pseudomonas, pseudomonas. But now, you know, we see other organisms emerging. I think the more we treat the pseudomonas, the more we wind up seeing the acromobacter and enterobacter in these patients, which becomes a big challenge. So if you decide to put your patient on macrolide because they're able to use a macrolide, that can be a helpful strategy in these patients. The big caveats with macrolides are one, the intolerance potential, right, GI intolerance. Patients with chronic macrolide therapy can also develop hearing loss. So you do have to advise the patient about that. And of course you have to make sure they don't have QT abnormalities. The other big caveat on macrolides is, you don't want to put a patient on a macrolide monotherapy strategy if they have NTM, right. So you need to screen the patient for NTM infection before you use that. If the patient is not a candidate for macrolides and they're frequently exacerbating, and by that I mean three or more exacerbations, you may want to consider targeted maintenance regular antibiotics, if you will, like an inhaled antibiotic. So the guidelines are pretty unanimous in saying three or more exacerbations buys you some sort of maintenance strategy. I mean I think that may be a little too high. Like maybe we should go for two or even one because as I already said, each exacerbation lasts longer than you think it does in the patient and also has implications for their ultimate outcome. But there's a lot of considerations with using an inhaled antibiotic, the first of which is we don't actually have an FDA approved inhaled antibiotic in the United States. But there's ways to prescribe that off-label, of course. So the sad history of inhaled antibiotic trials, which many people in this room were involved with, as Trianam unfortunately did not meet the endpoints in the trial in non-CF bronchiectasis. Variations on ciprofloxacin, both nebulized and dry powder, also failed in the trial. Tobramycin unfortunately went down. We really have never gotten beyond the tiny little trial in amikacin for pseudomonas. Genomycin actually, the one trial that was published for genomycin, which was done in Scotland, actually did work, did reduce exacerbations. It is something to consider. And then of course there has been a trial recently looking at inhaled colistin. There's been a couple of trials, but the results of that latest trial are still pending. So if I'm going to decide between a macrolide and using an inhaled antibiotic in my frequent exacerbators, I do think of macrolide first because it's just easier for the patient, right? Take a pill rather than nebulize twice a day. So if the patient can tolerate it, if there's no contraindication, then I'll use the 500 three times a week. If those things don't work out and I want to use inhaled antibiotics, I definitely want to know what the organism is that I'm targeting. Although it may not, the MICs that we get for those organisms when we're using an inhaled antibiotic may actually not really matter very much. It may not matter that you get R on your report from the micro lab because you're delivering a heavy load of antibiotic right into the airway, probably overcomes the MICs. So if I'm going to use an inhaled antibiotic, aminoglycoside first, colistin, and some patients as T and M if it's available, and then pipeline. One of the controversies, I think it's a controversy in the treatment of non-CF bronchiectasis is whether you should do what our CF colleagues call eradication therapy, right? So the idea here is if you isolate from the patient pseudomonas for the first time, you might want to consider a very intensive antibiotic regimen at that first isolation, right? And there's a couple of publications, the Dutch experience I list here is like 60 patients with quote-unquote newly isolated pseudomonas. And they use either an oral and inhaled combination or an IV and inhaled combination of anti-pseudomonal drugs with the outcome that 36 of the 60 patients remain culture negative at 12 months. So this is a little fraught though because, you know, how do you know it's really the first isolation of pseudomonas, right? You could have a patient who comes to you who's never had a culture before. It's not like in CF where they've been monitored, you know, routinely for their microbiology. But it's definitely gained traction in some parts of the world to do this. You know, but you also have to convince the patient that they need this double antibiotic coverage and we need some better trials on this. And finally, kind of N of 1 therapies individualized to the patient. Surgery for bronchiectasis, there's actually a fair amount of observational literature on the success of surgery. But it really boils down to, you know, choosing the right patient to operate. So the focal patient or the patient who might have somewhat diffused disease but has one area of essentially destroyed lung, again, observational trials, you know, experience, you need a good surgeon who knows how to do this kind of surgery. But it is a consideration for some patients. And of course, lung transplantation, you know, this is something that has been done and certainly in non-CF bronchiectasis. And the outcomes really are in line with what we see in general in lung transplantation. And finally, another surgery that does come out, another kind of surgery is patients who are chronically aspirating or have severe reflux disease. You know, is there any data that says their bronchiectasis can be helped by addressing, like doing a fundoplication or some other GI surgery? And we certainly do it in selected patients. Of course, we really don't have, you know, supportive data for that other than our observational information. So to summarize on management, I think, you know, I've hopefully convinced you that, you know, the first step is educating the patient. The other big thing is to know the culture data. You know, patients know their A1C level. They should know their pseudomonas in their sputum chronically. And you know, I start with this sort of stepwise approach, you know, beyond the shared decision making with the patient. Start with airway clearance. Think about an anti-inflammatory. Think about a maintenance macrolide with multiple caveats. And then in the more severe, frequently exacerbating patients, inhaled antibiotics. And just as a, to reemphasize the therapies that should not be routinely used are ICS therapy, obviously oral steroids, routine oral antibiotics, and macrolide monotherapy if there's NTM. So I'm going to wrap up with some unmet needs and things that we're starting to embark on more research. One of the problems in this disease is we sort of started backwards, right? I mean, all the data that we have in non-CF bronchiectasis from like the 90s until the middle of 2010s was really like treating the patients, right? We weren't looking at the pathophysiology. We weren't trying to individualize the etiologies in patients. It was like a one-size-fits-all approach to these trials that were done in non-CF patients. And now, you know, thankfully we're flipping the script a little bit, right, and looking more at the underlying pathophysiology, learning about the microbiome and the airways, learning about these like treatable traits that we can target in individual patients, and understanding more about the immunology and the genetics of bronchiectasis. So it's really, you know, it's a very heterogeneous group. It's not like CF, which, you know, the patients all have the same defect. And so it's really, we're broadening our understanding, I would say, in this disease. So some of the things that we need to understand is how can we diagnose these patients earlier? How can we understand these different phenotypes and endotypes? What is the role of the CFTR? What's the impact of the microbiome? And what about this neutrophilic versus eosinophilic inflammation? So earlier diagnosis, I know PJ McShane is here in the room, and she's a big advocate for this. I wish we knew the answers here. But there's a body of literature, mainly from Australia, about children with a chronic wet cough, and what sometimes is characterized as persistent bacterial bronchitis. So these are children, and there are adults who chronically produce sputum but have no radiographic evidence of bronchiectasis. And is there some way to detect these kind of patients and do some kind of intervention so they actually don't go on to develop bronchiectasis? So this is an area ripe for research. I think some other, like, just basic ways to find patients earlier with bronchiectasis, and I'd love to do these kind of investigations, is, like, targeting or tweaking the EMR. So if a patient gets two or more courses of some bronchitis antibiotic in a year, we should make sure they get imaging to see if they have bronchiectasis, right? We've all seen these patients who have had 10 Z-packs from urgent care for, quote-unquote, bronchitis, right? And they really never had imaging. So I think, you know, leveraging data in the EMR, leveraging radiology databases, you know, may be a way to look at this in terms of earlier diagnosis. And then using data to try to do some predictive modeling, because that's the other bugaboo here, right? I mean, we talked about how we have this BSI to prognosticate patients, but really patients are on their own journey individually with this disease. It's very hard to tell when you first meet a patient, you know, if things are going to go poorly or well in an individual patient. So we need some better modeling even beyond the BSI. Oh, one thing, I recently, there's a new paper in radiology that talked about marijuana smoking as a risk factor for bronchiectasis more than cigarette smoking, which we really don't think of as a, so keep that in mind as well, a small paper, observational paper that was just published in radiology. So again, treatable traits or phenotypes like the clinical characteristics of the patient can be helpful in deciding on the treatment. So I've already mentioned the frequent exacerbator. If the patient has zero exacerbations per year, they definitely have a better prognosis than if they have five exacerbations per year. And again, from Chalmers Group published five years ago, really confirmed that. So finding that phenotype is very important when you're planning your therapy. Understanding endotypes, which are the mechanistic targets. So there's a world of work to be done here still on potential therapeutic targets, like cilia motility, because even though we think of, you know, PCD as the cilia disease, I mean, that mucus that coats these airways in some of these patients really impacts ciliary functions. So that's potentially a target that is being looked at, even beyond patients with primary cilia dyskinesia. Some kind of immune modification targeting connective tissue abnormalities that might result in bronchiectasis. The CFTR, I'll say another word about that. And also the microbiome, you know, understanding that as a potential target for interventions. So this diagram over there, for ciliary variants, we would hope to find a motility enhancer. There's a little bit of data, but I'm not aware of any real clinical trials in using sildenafil as a ciliary enhancer. Doing GMCSF, that's been looked at in NTM infections. You know, maybe there's a role for that to enhance the immune response at the level of the airway. Looking at connective tissue variants that might have something to do with the development of bronchiectasis and then looking for CFTR abnormalities. And you know, 10 million people in the U.S. have at least, you know, have one CF mutation. And we know from data that NTM and bronchiectasis patients have a higher incidence of this, but we really don't know yet, you know, whether we could treat them. And of course, right now, we don't have FDA approval or even clinical trials to look at this. But I really think this is like an area ripe for both, you know, the more translational research, but also for clinical trials. And you know, I think more to come on this, but again, I'm sort of harping on this. I'm interested in this, and hopefully we'll see some learning lessons that have just completely transformed the treatment of patients with cystic fibrosis. Understanding the microbiome, you know, Doreen's colleague at NYU and others around the country are really into this area of investigation. We know that if the diversity of the microbiome in the lower airway, the less diverse, the more disease severity. So there appears to be an ecology that should be present in the lower airway that keeps the bad actors in check. And again, we're just really starting to understand this and whether the gut microbiome might have any role in patients with bronchiectasis as well. Back to this crazy slide, you know, that there's a lot of targets we haven't really yet gotten to that, you know, might potentially impact the treatment of these patients. And so again, I think a lot more to come in terms of targeting specific abnormalities and further being able to potentially personalize the treatment of the disease in an individual patient. Targeting the neutrophilic inflammation, I mean, this area is advancing. We want to understand which patients are truly neutrophilic, neutrophilically inflamed. And you know, the phase two trial of the drug called brentsicatib has been completed and it was published in 2020. The phase three trial of this neutrophil elastase inhibitor just completed enrollment and there's another phase two by a different sponsor that has just been completed as well. So this is the brentsicatib phase two publication that came out in 2020 that did show a reduction in increased time to first exacerbation in patients treated with this brentsicatib. And you know, again, it's probably be a year till we get the results of the phase three trial but the safety profile is good for this drug. And again, the golden egg of reducing exacerbations or increasing time to next exacerbation is what's being looked at in this trial. And then this whole issue of eosinophilic inflammation, I mean, people are really getting on the bandwagon of this. And I think if you look at your individual patients, there clearly are some that we could identify somewhat easily that may be more eosinophilic than neutrophilic. So in this cohort that was published by Schumark et al., about 22% of the patients in the MBARC had greater than 300 eosinophils. So those are being labeled as eosinophilic inflammation. You know, whether that's really true at the airway level, more to come on that. And just published last month by Martinez-Garcia from Spain, an observational prospective study, 920 patients. And what they found was about 16% had more than 300 eosinophils at enrollment in this study. And they found that the only group that had benefit from inhaled corticosteroids were that high eosinophil group. So there's just more to come on this issue. And again, back to that, we started by treating patients and putting them in treatment trials. But now we're really looking at it from a more mechanistic point of view. So to summarize, hopefully I've given you the quick overview of how to evaluate and consider treatment for your patient. I think we've learned a lot in the last 20 to 30 years. But we haven't made the impact that's happened in cystic fibrosis, bronchiectasis, right? Because of the heterogeneity of our disease, the age difference, the fact that we don't diagnose it early, the fact that it goes unrecognized in many patients. So there's just so much more to do and it is an exciting time. And again, Chest has really highlighted bronchiectasis and NTM in this meeting, a lot more sessions that can be attended. Because again, there's just so many unknowns still about dealing with these patients. And one thing, you know, again, back to that issue, lots of pseudomonas, lots of NTM, but now we're seeing the emergence of these other bacterial pathogens that become more challenging. And you know, this is one of my patients that I think illustrates just the whole spectrum of disease. You know, she's a younger patient. She has diffused bronchiectasis, though it's mainly in the right lung. She's been evaluated at three different, four different centers now for an underlying etiology. Nothing has been found. And that's probably true in about 30% of patients that are really, truly idiopathic bronchiectasis. You know, she's been, she's had pseudomonas for 10, 15 years. She's had MAC. She's been treated for MAC. She seemingly has cleared the MAC infection. And now she's somewhat ravaged by having chronic pseudomonas infection. She's using all the therapies, but you know, it's just, these are the patients that are very challenging. And hopefully, you know, not only can we learn more about the pathophysiology, but also to formulate our treatment plans more precisely. These are some of the clinical trials underway right now. There is a novel airway clearance and hail therapy. The trial is called ARENA1 that is currently enrolling. There's a phage trial on pseudomonas, the neutrophil inflammation trials. There was a trial that was stopped for reasons that are not clear, not because of any adverse problem targeting eosinophilic inflammation with biologic. So again, lots more trials are in the offing, different sponsors involved. And we have our U.S. registry to get a better handle on natural history. So it is a reemerging disease. It's heterogeneous. We need to recognize it earlier. It's easy to diagnose, right? I mean, you just do a CT scan, but you have to correlate it with the clinical findings. The treatment, the diagnosis and the treatment should be guideline-based right now. And we're working to make the patients better. So more to come on that. So thanks, everybody, for your attention.

bronchiectasis

diagnosis

management

early diagnosis

treatment strategies

education

underlying causes

airway clearance techniques

anti-inflammatory therapies