»» Good morning, everyone. We're going to get started. Thank you for joining us this morning. This is a CHEST ATS session that we are putting together. We did the first part of this session at ATS this year in Washington, D.C. and we're very happy to be doing the Part 2 here in Hawaii. I know on your program we were supposed to have four speakers today, but Dr. James Chalmers who was going to be talking a little bit about phenotyping was unable to get here from Scotland. So we will have some time for question and answer at the end and certainly you can feel free to ask our panelists questions on that area and we can perhaps give a quick update. I wanted to thank our faculty. I'm one of the co-chairs. I'm Doreena Drizzo-Harris and happy to be president of this meeting. And Dr. Shannon Kasperbauer from National Jewish Health is on her way from another session that she was chairing. So she will be joining us shortly. Our first speaker today is Dr. Pamela or P.J. McChain. And P.J. is a professor of medicine at the University of Texas in Tyler. And she will be talking to us today about the evaluation of bronchiectasis. Thank you, P.J. Thank you so much. It's really a pleasure to be part of this. I'm always honored to be included with all of you. So I'm P.J. McChain from the University of Texas and I get to talk about one of my favorite things here is working up the etiology of bronchiectasis. The heterogeneity of this disease is always sort of referred to as a challenge and it certainly is a challenge with regard to clinical trials and finding the right treatments for all these people. But on the other hand it's what makes it fun because we don't do the same thing all day. And if you look at these four axial cuts representative images of each one of my patients here, you can kind of look to see the nuances within this bronchiectasis manifestation that these are all different causes. The very dramatic finger in glove pattern in the upper left hand corner, if there are any fellows in here, that's a pattern that you'll know to recognize through your fellowship. We think of that as ABPA right off the bat and it kind of zones you into the right workup, hopefully. The pattern on the lower right, you can see there's some scoliosis present and significant bronchiectasis in the right middle lobe. So I start thinking about a woman who has non-tuberculous mycobacteria. My patient in the left lower lobe, I'm sorry, in the left lower corner has lower lobe bronchiectasis and really prominent, prominent sinus symptoms. And so that's a PCD guy. So I don't know, I think it's such fun to have these very diverse manifestations of bronchiectasis because then we're not doing the same thing all day long and we're thinking about different things, even though it's within the same disease. Oh, I'm sorry, these are my disclosure slides. I got so excited, I got ahead of myself on my disclosures. Such an exciting time in bronchiectasis. I'm grateful to the industry who has recognized that bronchiectasis patients need a treatment. Lots of clinical trials going on right now. So if you have gone to any of the other bronchiectasis sessions, you've seen this slide before. This is a global disease, bronchiectasis is, and this slide demonstrates the various etiologies that have been identified through study in each of the geographic locations. And the blue, sort of the royal blue piece of the pie is the idiopathic. And so, you know, certainly we do think of bronchiectasis as the final common pathway to many different diseases, but there is, in fact, a true idiopathic bronchiectasis that happens with no associated etiologies that I hope that before I retire we'll be able to say a little bit better what causes that. Okay, so with regard to etiology, so you've got your bronchiectasis patient, you feel compassion and empathy for their clinical symptoms, and you want to tell them why they have this. There are guidelines to guide you, and there are many of them. So there's the Australian guideline, which will be updated this year. The Spanish guideline, bronchiectasis, or sorry, the Brazilian guideline. There's a Saudi guideline. The European guidelines, again, that's going to update as pending. And then the sort of motherlode is this UK-British guideline that is many pages, very thorough, and if I'm honest, it's, I bound it, and it's sitting on my workstation. Okay, this is the summary of those references on the left-hand side. And then on the right-hand side, most of these guidelines recommend a minimum bundle. And the minimum bundle is shown in bold. This, certainly no one is advocating that you stop there. And I've listed a non-bold type below there is what some of the guidelines endorse as you should probably include as standard workup for all people. You can see that for sure there's a CBC, serum immunoglobulins, the aspergillus serology may be more unique to where you are in location and the manifestations that your patients describe, but airway sputum cultures are a must. And then by no means saying that don't get the things in non-bolded text, but I'm just referring to what these guidelines sort of mention as the minimum out-of-the-gate what you should get. So what I thought I would do is go through some clinical examples to sort of make it more interactive so that it's not just type on the slides. This is my patient. He's a 74-year-old restaurant owner from Louisiana, so I don't know what it is that they feed them down there, but they're the nicest people ever. He's smoked for 70 years, and he was a big cyclist, so he gets to 74 with pretty severe bronchiectasis, but yet he's fairly functional still running a restaurant. He's got a right tympanostomy tube in place when you examine him. His FEV1 is down to 40%. He's got a normal CBC. His IgG is elevated. The A and the M are normal, and the E is low. I do the sweat chloride standard in most people, and especially if it's an idiopathic case, I just keep going and try to find something. And his alpha-1 antitrypsin was normal. Note his lower lobe bronchiectasis. So I suspect, does any fellow want to call out what they think they might have? That fellow in the room? Anyway, so one thing I didn't mention was his cilia workup. So I'm happy to have a nasal nitric oxide analyzer in my clinic. And so I did his nasal nitric oxide, and as you know, below the high 70s is really indicative of primary ciliary dyskinesia. That doesn't mean that you stop there if they've got a normal nitric oxide level, for sure. But if you've got one somewhere in the 70s and below, you probably have either a cystic fibrosis patient or a primary ciliary dyskinesia patient. And then I sent the genes, and he does, in fact, have two genes suggestive of primary ciliary dyskinesia. So because this is such an important issue, I want to drill down on this genetic workup. Because I think, as bronchiectasis-interested people, you've heard a little bit about etiology so far at other sessions. So I want to tell you, when you suspect a patient who's got PCD, and I wonder if more and more and more of our patients actually have PCD that we're maybe not finding. And it's harder to find it in an adult, because they don't have the classic signs that the kids have. And a lot of them don't remember their childhood, or they just figured they were sick. Or if you're practicing in a rural setting, I mean, their parents just said, if you're sick, you still go out and work on the farm, or you still go to school. Anyway, so what do you do when you want to think about PCD? So I regret that this is a very active algorithm, and it's hard to see. But you can see the reference. And what this is, is it guides you on who you want to do genetic workup and who you do nitric oxide. And essentially, where we are as adult pulmonologists is you don't have a laterality defect. You probably have a patient with sinusitis, maybe some history of ear infections and bronchiectasis. And you may not even have nitric oxide nearby. So that's OK. And you want to send off the genes. So then what do you do? You're busy in clinic. You're running 20 minutes behind at best, right? And so you want to send off the genes on this person. I have no relationship with any of these companies. All I know is that they help me. You know, on my free time, I log on, and I get an account so that they can send me the kits. And so these are three examples of companies that you can have gene kits sent to you. Now, recently, I have learned, by keeping in touch with the PCD people, that this particular blueprint genetics in the right lower corner has a gene test for the Hyden gene. And they now know that the Hyden gene is about 10% of PCD. So we don't want to miss that. And the Invitae kit that I had been using before doesn't check for the Hyden gene. So basically, this is one example. Again, I have no relationship with this company. I'm just a customer. And if you say, OK, well, the patient has some other things that are suggestive of immune deficiency. They have a comprehensive immune cytopenia panel. But what you do is just go to their website, create an account, and then you have a link that you can order kits. And so I do that on my enjoyable Sunday afternoon. And then they mail the kits to me, and then I've got them sitting there You just have to be careful that they do expire. So you want to make sure you, every six months or so, make sure you've got enough kits in your clinic room. So that's the PCD. And I think I would encourage all of us, I try to make sure I'm really looking for that. PCD is a work in progress, as you know. The cilia protein, what builds that thing is like 250 proteins. And so there's 40-ish genes that have been identified. There's a lot more work to figure out primary ciliary dyskinesia, or just ciliary dyskinesia in general. So I think we all need to work together to identify that a little bit better. So my next case is a little more common, especially at University of Texas, where we do a lot of NTM. This is a 64-year-old lifelong non-smoker and she has MAC that's been treated three times. Just can't get enough azithromycin, this gal can. And then she also has staph aureus in her sputum. Her FEV1 is down to 36%, although the rest of the workup is normal. She's got this classic upper lobe upper lobe bronchiectasis. And these ladies always have a lot of trouble and these ladies always seem to have it more on the right side than the left. It's always right upper, right middle, and some on the lower. I don't know that that's really established. So anyway, what's left over? Upper lobe bronchiectasis. She's a MAC lady. I did the sweat chloride and the genetics are suggestive of cystic fibrosis. So with, I mean, this lady was 64 when we tested her. So, and you saw my other guy, the ciliary dyskinesia guy is 74. I mean, it just speaks to how age is not an exclusion for any of these childhood genetic disorders. Just go looking for it and we'll learn more from doing so. So clues to cystic fibrosis, upper lobe bronchiectasis, difficult to treat NTM. And basically that's where I kind of stop as an adult bronchiectasis patient with an NTM clinic. They don't always have the GI symptoms, the diabetes, the history of infertility. They just don't have all that other stuff if they've made it to the older age. And the main point I want to make here is a little bit different from primary ciliary dyskinesia where you just have to, because there's more genes that need to be identified for ciliary dyskinesia. In CF, it's a little bit more advanced. And so if you get an intermediate sweat chloride, then the genetic panels are a little bit more thorough. Whereas in ciliary dyskinesia, if I'm not finding a gene that's suggestive, and I think the clinical picture is really, really convincing, then I may reach out to a very center that's doing genetic research to see if they can find a gene in that patient. Case three is a 50-year-old non-smoking woman with bronchiectasis. She's a librarian, as sweet as can be. She is sick all the time. And the type of exacerbations that you can hardly get her to be well enough to enroll in a clinical trial because she's just so sick all the time. FEV1, 53%. Bronchiectasis severity index is 18. As you know, that's one of the higher numbers in the bronchiectasis severity index. And then her immunoglobulin panel is normal. Sweat chloride was low. And of course, she is an alpha-1 antitrypsin. This lower lobe bronchiectasis, very severe disease, sort of lights up my fire that I need to go looking for alpha-1 antitrypsin if the other CF and PCD stuff looks normal. So a lot of these patients, I notice if you really dig into their family history, they've got someone who's got liver disease, someone who has lung disease without a big smoking history. This is my 19-year-old who I think she didn't show up for her last appointment. She's in big trouble. She partakes in marijuana recreational use. She has asthma and sinus infections. Another one who, before I met her, was getting antibiotic course after antibiotic course, seven courses over the last two years. And she's been in a lot of pain. Over the last two years, FEV1 already 53%, which is really concerning for a 19-year-old. Her immune globulins were the G, A, M, and E. The G, A, and M were all normal, and the sweat chloride was low. And not surprisingly, with this, her aspergillus antigens were high. This finger and glove, I think Dr. O'Donnell presented an even better finger and glove pattern on the bronchiectasis yesterday. This one's pretty good, but sometimes it gets really remarkable with the big fat fingers extending out to the periphery with these impacted airways, large central bronchiectasis. So if there are residents or fellows in the room, you should zone in on the AVPA diagnosis for that patient. So in summary, I've put together sort of a collection. There's no easy way to do this. It's a bulky thought process. Generally speaking, when you look at these patients, you're thinking of, do they have a genetic disorder that is related to cystic fibrosis or primary ciliary dyskinesia? Do they have an immune globulin deficiency? Do they have an alpha-1 antitrypsin? So I've sort of tried to put together on the left-hand side symptom history of things to think about and their correlation to the disease and then what you should do to test. So that could be sort of a summary thought process. And then I've added in, time doesn't allow to go through every single scenario, so I didn't present an immune deficiency. And I do actually, going back now, I do want, I think I put primary immune deficiency at the very top. These patients have other systemic manifestations too. If they've got septic joint infections in their history, maybe they have skin cancers. They've got many other things that kind of signal an immune globulin deficiency, so be thinking of that when you see them. The upper left-hand corner here, we discussed a case with allergic bronchopulmonary aspergillosis. And then below that, the alpha-1 antitrypsin, we've discussed. GERD is another one that may be perhaps causative or at least have a role of worsening bronchiectasis. And I hope one day to have a GI group of colleagues who wanna be more engaged in how to manage this with us because so often I find that I send my patient to a GI to get evaluated and they just give them a proton pump inhibitor and then I get them back. And so I hope one day we'll get, I mean, thank God for GI physicians and we love them. I'm happy to be in this world with them, but I'm just saying, we gotta do something more than a PPI. And so we have to be always thinking about GERD. And then connective tissue disease, I didn't discuss for time, but these are, of course, your patients who manifest joint disease. If you see cysts on the CT scan, then be thinking about Sjogren's, order the work up. And then finally, inflammatory bowel disease, the colitis can be present. So bronchiectasis is the final common pathway of a lot of diverse conditions, which just makes our job kind of fun. And then start with the basic bundle for all of your patients, but by no means stop there. At our last discussion at ATS, we had a colleague stand up and discuss IG, the subclass deficiencies of IGG. By no means am I saying don't get those, but I was just sort of highlighting what the guidelines recommend. And then finally, utilize, get yourself set up with these genetic test kits so that you've got them in your clinic and get your, if you have a nurse who's helping you, get her familiar with them because they do take a little bit of time to fill out the forms when you see the patient. So it'd be helpful if you have someone set up to help you do that when you're busy in clinic. So I really thank you for your attention and I'll transition to the next speaker. Okay, everyone. It's a pleasure to be here. I was tasked with discussing therapeutics and bronchiectasis. For those of you who are at our new conferences, this will be very familiar to you. But hopefully one of the two times I will say something that you will recall. These are my disclosures. I have not changed since yesterday. Okay, so I'm gonna approach this looking first at current management approaches for the treatment of non-cystic fibrosis bronchiectasis. Then we'll look at the role of the neutrophil, the important role of the neutrophil. Also, though, also what does the eosinophil do in this setting? And what are some of the drugs coming our way? So this is our typical approach, right? We have three general areas we focus on with bronchiectasis, the airway clearance, when you say, what's the most important thing you can do for your patient? Number one is airway clearance, number two is airway clearance, and number three is airway clearance. And we do this using hypertonic saline, oscillating PEP valves, VEST, because we're trying to improve mucociliary clearance. The other big thing is the treatment and prevention of infections, which is, or exacerbations. So we use antibiotics, all kinds. And then in terms of anti-inflammatories, right now we really only have the macrolites, and we'll talk a little bit about the inflammatory condition and how we would treat that. At the end of the day, when you're doing all three of these, you're trying to achieve these objectives. Very importantly, you want to prevent exacerbations, you want to reduce the patient's symptoms, improve the quality of life, stop disease progression, and decrease mortality. And believe it or not, with what we have right now, we can do these things. It's just, we can probably do it better. So when we talk about airway clearance, one would be a more mechanical means, like oscillating PEP valves, high-frequency chest wall oscillation, of which you have desktop models as well as mobile ones, so the patient can just wear these around when they're walking around the house or at work. And none of these have really been compared to each other, so I can't tell you which one is the best one. I can just tell you that, as we often quip, the best one is the patient's willing to use. And for all of these, they may have their favorites, and we'll go with that. Now, they have been shown to have several benefits. Airway clearance, increase in sputum volume, reduce the impact of cough on the quality of life, as measured by the St. George Respiratory Questionnaire, reduce peripheral airway obstruction, less inflammatory cells in the sputum, and improved exercise capacity. Now, many of us like to pair these mechanical methods with pharmacologic methods. There are different categories that we use, like expectorants. Hypertonic saline is really the one that has the most evidence to support it. There are other things, mannitol, not currently available, mucolytics, data supporting these outside of CF are not very good, and mucokinetics, again, the data supporting those are not very good. But if you look at hypertonic saline, this is a Cochrane review of hypertonic saline in the setting of cystic fibrosis, looking at three to 7% hypertonic saline, 17 trials, almost 1,000 participants. The results of this Cochrane review show that hypertonic saline decreased exacerbations, and again, that is a major goal when we're managing patients. And there was some small improvement in quality of life. There are also studies in non-CF brachiectasis, comparing 7% versus 0.9%. 7% was shown to decrease sputum viscosity, improve quality of life as measured, again, by the St. George Respiratory Questionnaire, and very importantly, decrease exacerbations. So there are benefits that have been shown. Are the data perfect? No, but what exists looks like it's positive. And I think most people who work with brachiectasis patients every day, we see the benefit usually within days of starting airway clearance in terms of improvement in cough. So eventually, though, people will get an exacerbation, no matter how hard you work. I mean, it's just part of brachiectasis, but what we want to do is limit it. This is a definition that was designed for clinical trials, but probably does have some clinical utility. It was defined, an exacerbation is defined is when there's a deterioration in three or more of the following key symptoms for at least 48 hours. And these are kind of the things you already know. Cough, sputum volume inconsistencies, sputum purulence, breathlessness, or exercise intolerance, fatigue, malaise, hemoptysis. The patient comes in and they're sicker. And then the second part of this is that there's a determination to change the treatment. Often what that means is to add an antibiotic, but not always. Now, more severe exacerbations have been associated with poor outcomes like lower quality of life, daily symptoms, lung function decline, and increased mortality. And they're very common. In the European Embark Registry, half of their patients had two or more exacerbations a year, and about a third of them ended up in a hospital at least once a year. So this is a terrible burden on the patient and also our health systems. Now, if you have someone who's exacerbating, we often think about, are they a frequent exacerbator? In the European guidelines, three or more exacerbations per year is considered a frequent exacerbator. But, you know, not all exacerbations are the same. I think you have to use some clinical judgment. If someone has two a year, but they get hospitalized both time, that's a very significant course for that patient. And I wouldn't require three personally to begin a process like this. When any patient exacerbating, it's a great time to review, are they doing their airway clearance? Is it optimized? What other underlying conditions need to be treated like their COPD or asthma? And right now, the European guidelines recommend if the patient grows pseudomonas, that you should initiate long-term inhaled antibiotics. These are traditionally given 28 days on, 28 days off, but not necessarily. Sometimes they can be given more frequently, even sometimes less frequently. And these may not work alone, and you may have to think about other strategies like the use of long-term macrolides. But do they work? There are a number of studies out, and unfortunately, many studies have failed and have not made it to approval. But if you look at this systematic review of inhaled antibiotics, you can see 16 trials, 2,500 patients. And in terms of efficacy, they did show greater reduction in colony-forming units. That's important, but maybe not so important to the patient. It may not affect how they feel. Increased bacterial eradication, but this is important, reduced exacerbations, including severe exacerbations. Also, the time to the first exacerbations prolong, which is also a very important outcome. And the adverse events were minimal, and really no significant difference across the groups. So they do work. The problem is that in the U.S., we don't have any that are approved for non-CF bronchiectasis. We have three that are approved for CF. We have two tobramycin formulations, one a solution, one a powder, and an ACE3 and an inhaled solution. Sometimes you can get these for your non-CF patients, but sometimes insurance balks. We do have two other inhaled agents in the U.S. that we can use that are not FDA approved. These are both intravenous solutions, colistin and tobramycin, and what we've done for many, many years is we take the parenteral, dilute it with saline and have the patient inhale it and have seen clinical benefit from an experiential perspective, difficult to prove because we don't have randomized trials. We do not have the formulation of colistin available in Europe, in the U.S., so if we're using colistin, this is what we have to do. And once you begin this process of giving inhaled therapies in CF, the order is very important. The first thing would be to give a bronchodilator, but that's only if they need it. Most patients actually don't need a bronchodilator. Those who have reactive airways, history of asthma, they may benefit, but not all people benefit from this, and I've had more than one patient go into an arrhythmia when they're bronchodilators that they did not need. And then we think about eucalyptics, physiotherapy, airway clearance. We like to combine these, so we'll give a flutter in line with hypertonic saline as an example. It cuts down the time that the patient has to spend. The time can be significant because it's not just the time of doing it, but now they have to clean everything, and that's that hidden time that we often don't tell the patient. They're going to have to clean it, and it's a timely thing. But the most important thing is the inhaled antibiotics should be last. Obviously, you don't want to give them inhaled antibiotics, but you can give them hypertonic saline, dilute it, and have them cough out the antibiotics. So antibiotics are last. Now, there's also the population that doesn't grow pseudomonas. They grow some other thing, maybe Haemophilus influenzae or another gram negative. In the guidelines currently, it's recommended that this is a group that you start on long-term oral macrolides. Like before, that may not be enough, and then you may want to add inhaled antibiotics. But if you do this, please rule out NTM. And if you rule out NTM and initiate macrolides, you still need to survey for NTM periodically during the year. We do it about twice a year. And if they grow NTM, you need to stop the macrolide. All right, so these are the anti-inflammatory therapies that were reviewed in the European guidelines. The only one that is recommended to be used are the macrolides. Corticosteroids, of course, is someone who has asthma, reactive airways disease, and is treating that comorbidity, but not for the treatment of bronchiectasis. This is a meta-analysis, individual patient meta-analysis performed by James Chalmers. Basically, he took the data from the three randomized trials of macrolides, all of which were positive. He showed reduced frequencies of exacerbations, but what's different is when he combined the data, he showed that this was also relevant to those who had pseudomonas. Remember in the previous slide, if you had non-pseudomonas, it was recommended to get macrolides. If you had pseudomonas, it was inhaled antibiotics. But here in this meta-analysis, it looked to be beneficial for basically any infection, any bacterial infection. He also showed delayed time-diverse exacerbation and improved quality of life. So it was quite a benefit to the use of macrolides. So I think what that means to me is that in the update of the European guidelines and probably the U.S. guidelines, which will be coming, macrolides probably should be the first line of therapy. It's easy to do, pretty well tolerated, much cheaper than inhaled antibiotics, a lot less time, and therefore I think we'll probably have better adherence. But that remains to be seen how that will play out. So what's the role of the neutrophil? Patients who have bronchiectasis, they have frequent exacerbations as we've seen. These are usually associated with neutrophilic inflammation, and these neutrophils contain neutrophil serine proteases, or NSPs, one of which is neutrophil elastase. And Dr. Chalmers has demonstrated that that neutrophil elastase level is very important because it's associated with severity of disease, bacterial load, and clinical outcomes, exacerbations. And there's another enzyme, dipeptidyl peptidase, or DPP1, and this cleaves neutrophil elastase and other NSPs, and it actually activates them as they're maturing in the bone marrow. So one question is, you know, if you were to stop that process or inhibit that process of maturation, what would happen? And that's exactly what was done in the Willow study, which was a Phase II trial of a DPP1 inhibitor, brinzacatib. So this is an oral reversible inhibitor. And I'm sure you're all familiar with this trial, the Willow trial. Patients with bronchiectasis were randomized into one of these three groups, either 10 milligrams of brinzacatib, 25 milligrams, or placebo, treated to 169 days and then followed to 197. The primary endpoint was time to first bronchiectasis exacerbation, but there were other important secondary, most notably the rate of exacerbations. This is the primary outcome, and you can see very clearly that brinzacatib, both doses were associated with a delayed time to an exacerbation, and this was highly significant. This is the frequency of exacerbations, another outcome. This is a secondary outcome. If you look at the number without or zero exacerbations, both doses, again, significantly less exacerbations compared with placebo. In fact, the percent of patients with one or more exacerbations was lower, and the severe exacerbations were about half of placebo. And then, as you might expect, if you give this drug, the neutrophil elastase level goes down. And for both doses, it went down very quickly, stayed down during the course of therapy, but within a month of stopping it, it was back to baseline, just highlighting that this is an oral inhibitor of DPP-1. That phase two trial has resulted in the Aspen trial. This is a trial that has now completed adult enrollment. We're just waiting with bated breath for the final patient to take that final dose, which will be, I think, March or so next year. Over 1,600 people enrolled. The population were people who had it. These were the frequent exacerbator phenotype, at least two pulmonary exacerbations within the previous 12 months, and then they were randomized, just like in the phase two, to one of the three arms. The outcome's a little different. It's going to be the rate of adjudicated pulmonary exacerbations, not time to next exacerbation. You should know there's another trial that has completely enrolled called Airleaf. This is a captation C inhibitor, so similar mechanism of action. It's a phase two trial, so smaller, 240 patients, slightly different population enrolled. This is one that needed to have at least two exacerbations, but if they didn't, they could have one exacerbation and a St. George respiratory question score of greater than 40. Here they're randomized into four arms, three different doses of the compound versus placebo, and it's time to first exacerbation. That's not the whole story. Let me end with the eosinophil, because about 20% of patients with bronchiectasis have elevated serum eosinophils and sputum eosinophils. In the serum, they're usually 300 or greater. If you give an anti-IL-5 or anti-IL-5 receptor antagonist, in the setting of someone with severe eosinophilic asthma and comorbid bronchiectasis, their exacerbations drop. This is an example of just five patients from Italy that were taking these type of drugs, and you can see just an incredible drop in their exacerbation rate. This was over two years it stayed down. It suggests that targeting the eosinophil in this particular patient population can have significant results on exacerbation rates. I'll end with there are multiple trials that are enrolling. Some have enrolled. Some have completed. This is very exciting. Most all of these are targeting inflammation at some point in an inflammatory cascade, or they're trying to improve airway clearance. These are all listed on clinicaltrials.gov. If you have patients with bronchiectasis, please take a look and see what's out there so maybe you can refer your patient to a center so we can try to move these forward and get them to the bedside. With that, I'll just summarize by saying that the treatment of bronchiectasis really focuses on improving airway clearance, treating and preventing exacerbations, and reducing airway inflammation. We know that exacerbations can be prevented through the use of long-term antibiotics and macrolides, but please rule out NTM. Thankfully, there are new drugs coming, and they're going to be targeting neutrophilic and eosinophilic inflammation. I think that's the right path, and I hope that you'll be able to use them to treat your patients. Thank you. Don't forget the evaluation. Thank you very much, Dr. Rodrigo and Dr. Casper-Bauer, for this kind invitation, and aloha to all of you. By a raise of hands, how many of you have been in front of a patient with bronchiectasis that happened to have the results back from the sputum that grew seldomonas aeruginosa that happens to be resistant? Okay, so probably you know more than me on this lecture, but I have to recognize that I have no conflict of interest related to this presentation, and I only have one objective. I hope by the end of this lecture you have a much better understanding of the alternatives that we have to treat multidrug-resistant infections in the setting of bronchiectasis. By doing this, I have initially the setting of the problem, then we have what are the current recommendations, and then what are the new alternatives that we have available. So let's start with the problem. This is something that our prior speakers, Dr. Bailey, pointed out very elegantly. What is an exacerbation and why do we care? So we know that exacerbations are related with this worse quality of life, the increased daily symptoms, lung functional decline, increased mortality. And this is the frustration that many of your patients show up with to your clinic. We have two phases of the disease. The one that presents very acutely to your clinic with very, very high symptoms or to the hospital in which you have to make several decisions whether you are going to provide oxygen therapy, you are going to admit the patient to the floor, or even to any ICU setting requiring a higher level of care. In the chronic phase, this is what is the most common presentation for the clinics. It's the patients that have three or more of these presentations in a one-year period that have these multiple symptoms, and it's usually related to a series of pathogens. But the most remarkable pathogen that we have to always think about these patients is Seldomonas aeruginosa. And the reason why is because the mortality risk is three times higher. Second, hospitalization rate is seven times higher. And third, there is an additional exacerbation per patient per year. So this is a thing that will go with you forever. It's like getting married. So initially, on this cycle of events, I'm just going to focus on the one on the left, on infection. And particularly among those that have Seldomonas aeruginosa that are highly difficult to manage in the clinical setting. Here is a summary that I tried to do from all the registries that have published data on microbiology around the world. You notice that in the United States registry, Seldomonas aeruginosa that is in green is the number one. Same thing in Europe, equal with Haemophilus influenza that is in pink. You go to Korea, China, India, and Australia, and you see the same pattern. So Seldomonas aeruginosa is definitely the bug that is all over the place. When we look at data from Europe, in a very nicely done registry from EMBARQ, Dr. Chalmers' report and his group and collaborators show that Seldomonas aeruginosa is number one with Haemophilus influenza. Then when you look at the distribution, you notice that the percentage of infected patients with Seldomonas aeruginosa tend to be on the southern part of Europe. You see all these countries in red, they have the highest rate of Seldomonas aeruginosa. But on the bottom, what I wanted you to see is all these lines that means we live in a heterogeneous world. What happens in your institution, it is not necessarily the same thing that happens on my institution and institutions in New York, in Tyler, etc. Therefore, you need to know your patients and the ecology on your specific population. So what do the guidelines say about this thing? If you really look at the series of pathogens, if you look at the series of recommendations, and the recommended first and second light agents, and you focus in this case on Seldomonas aeruginosa, you see that the initial is oral ciprofloxacin, oral ciprofloxacin, and then on the second light agents are the intravenous agents, and I mark here meropenem that will be important later on in the talk. Therefore, when we have this situation, first or new isolation of Seldomonas aeruginosa, there are three different alternatives. One is oral fluoroquinolone, intravenous antibiotic, particularly among those that are severely ill, in combination therapy with aminoglycoside, assuming that it's likely that just the beta-lactam, beta-lactamase inhibitor that you start against Seldomonas may be resistant. Therefore, you may have another agent, not because two are better than one. It's because if you do not have the second agent, it could be just completely resistant to one or both, and then you have nothing given to this patient by assuming just single monotherapy. The third alternative is the oral fluoroquinolones or the intravenous antibiotics plus the inhaled antibiotics. So basically it's kind of going to the grocery store and then say, OK, let's put the oral medication. OK, but in case this thing gets worse, let's put the IV medications. But in case this thing gets even worse, let's put on the inhaled medications in all the same baskets. So it's a growing number of antibiotics for the same patient. But I want you to focus on here, on the asterisk, that it says all these intravenous antibiotic recommendations. OK? So when to use IV antibiotics? Dr. Chuck Daly just mentioned this very nicely. He said resistant organisms or failure to oral therapy or the patients we have exacerbations that may be defined in the last 24 hours of three or more of these things or 48 hours depending on the organization that you look at. Once you start antibiotics, for how long you are going to do this thing? And the guidelines try to really define whether it's 40 to 21 days, like when many of you went to medical school, the ones with the gray hair like me, probably it's 40 to 21 days. That was the recipe, 40 to 21 days. Then a new version of antibiotic studies came up and said 10 to 14 days. OK, shorter duration of antibiotics. But the guidelines say we suggest, OK, with low certainty, that we need to treat with at least 14 days of antibiotics. The reason why I bring this study is because this recent paper published during the past year, this is a feasibility randomized controlled trial. So be careful about this. I'm not intended to really reply that this is the way to go. This was just an initial assessment of a possibility to really reducing the extra duration of antibiotics. This is a short versus long IV antibiotic therapy with the bacterial load that was inserted here, and I want you to remember this BLGG, Bacterial Load Guided Group, that is this column here. So what these people did was they studied everyone on meropenem. Remember I showed you the slide with the antibiotic therapy alternatives, and meropenem was one of them that will cover cell pneumonia appropriately. Then they did the sputum bacterial load that monitored at 0 days, 7 days, 10 days, 14 days, and 21 days. If the bacterial load in the sputum target was less than 10 to the 6th on day 7 or day 10, they say you could stop antibiotics. So, by raise of hand, how many of you have the guts to stop antibiotics at 7 days when you receive the phone call from the lab, guys, you have a patient with a bacterial load less than 10 to the 6th. Would you have stopped it? How many? No one? No one has guts in this room, or no one has the guts to stop antibiotics, okay? Therefore, on day 7, if the bacterial load was in the sputum less than 10 to the 6th, these people, 84% had this bacterial load less than that. So, what does it mean? You start antibiotics. You reduce the bacterial load, not completely eradicate the pathogen probably, but at that time, 84% of the people were eligible to be potentially removing of the whole duration of antibiotics, okay? What I think is very remarkable here is stop antibiotics at day 8. This sounds like Disneyland, no? For many of us, we never use these short courses of antibiotics in these patients, but 81% of these patients in the 14-day course were potentially eligible to be stopped antibiotics, but they did stop antibiotics by day 11 on 100% of the patients and by day 8 on 80% of the patients. It's very interesting. The clinical improvement by day 21 was exactly the same on both. In the time to nexus observation, the median interquartile range was 60 days, and much longer, something really interesting that the authors did not really truly expect to really see completely. How were you going to be able to really extend this thing? One potential answer on this is that antibiotics may cause some harm on the way to go there that does not necessarily reflect to the time to nexus observation, but it's an assessment that I don't know with confidence. My take-home for this is I don't want you to start calling the lab and asking what is the bacterial load tomorrow because they are not going to know this bacterial load, honestly. They are not going to be able to know, but many of the new platforms, the BioFire and things like that, can potentially give you this kind of information. Second, this is a feasibility randomized controlled trial, so they need to follow with another randomized controlled trial well-designed to be able to prove that these findings were correct. But what I'm trying to really see to you is that we see patients that a day after the first week they come and say, I'm feeling great, I'm doing fantastic. And you always wonder, should I really keep this antibiotic or should I really say this is okay? So in my mind, I think the most association within the bacterial load is the possibility that most likely at the end of the day we will not be able to really kill pseudomonas completely, but what we are going to keep is a patient with a lower bacterial load with the same principle that inhaled antibiotics have, is trying to really reduce this number of bacteria that increase or decreases in time that link to inflammation and exacerbations. Okay, so what do we have in the alternative regimens here? When we look at the resistance of pseudomonas aeruginosa strains from patients with bronchiectasis, you notice that in gray this is a monoresistant. So it was resistant to one class of antibiotics. In 16% of the patients, MDR, and in 5% of the patients, XDR. So pseudomonas is literally resistant to everything, just one or more. Therefore, it is the challenging part of the alternative. There are places where oral fluoroquinolones are basically like drinking water for these patients with pseudomonas aeruginosa. It had no effect because the majority of this monoresistant in gray is fluoroquinolones. Therefore, you may have this situation. But this is very interesting because they did antimicrobial-resistant susceptibilities patterns on all these patients that have this pseudomonas aeruginosa. And you notice that, for example, imipenem here is only around 66% susceptible. But you see here that the newer antibiotics have more susceptibility ranges, and we have ceftazidime and astreonam, for example, that is intermediate resistant. So astreonam, for example, in this particular population in Spain, would not have been a great choice despite that it's included in the guidelines. So this is the big complexity of pseudomonas aeruginosa, is that there are multiple patterns of antimicrobial-resistant that some of them are acquired, some of them are adaptive, and some of them are innate resistant. And this is what the biggest challenge is about. But the reason why I'm here today is because there are new alternatives for multidrug-resistant pseudomonas aeruginosa. You see here in the column, you have all these yes, yes, yes, yes, yes. So all these yeses are intravenous antibiotic alternatives that have been reported with data over the past few years. But the data is not on bronchiectasis. The data is on hospital-acquired pneumonia and ventilator-associated pneumonia. So what we're going to do right now is an extrapolation from data that is not necessarily linked to this thing, but has been generated to kill the bug. So the message here is, even with the new antibiotic, let's say a completely new antibiotic that has not met that pseudomonas aeruginosa yet, you still need to do susceptibility testing. So don't rely that no matter how new the medication is, it's going to be completely susceptible. You should do it. And look at the example here. This is a multidrug-resistant pseudomonas aeruginosa with a new antibiotic, ceftolazontazobactam. You see? The susceptibility range is 87%. For an XDR strain, it's 80%, and it goes for a betalactam, it's 72%. For meropenem, it's a washout, basically. For piptezo, it's a washout. But for ceftazimab, very similar numbers. So what I wanted to show you is, please, please, please, when you're dealing with a resistant strain in which you are going to consider the new antibiotics, do not think always that because it's a new thing, it must be with good, good, good certainty, it's going to kill the bug no matter what because it's so new that the pathogens have not been able to develop resistance. You should still send it for your susceptibility pattern in the lab. This is a summary of the majority of the randomized controlled trials in hospital-acquired and ventilator-associated pneumonia that have been published over the past almost a decade and a half. What I want you to remember is in blue is the comparator regimen, colistin, piptezo, best available therapy, meropenem, best available therapy, meropenem, meropenem, imipenem, imipenem. In gray is the new antibiotic that came to be tested on these randomized controlled trials. Remember, all these randomized controlled trials were designed as a non-inferiority trial. Therefore, nothing was designed to be better than the other. If you notice, in very few instances, the gray seems to be larger than the blue. That's number one. Number two, the clinical cure rate is how the patients feel at the end of therapy or at the end of the assessment. It is as best at 70%. The majority is between 50% to 65%. What does it mean? Just two-thirds of the people said clinical cure was achieved. I felt better. My symptoms improved. I was able to really stop the antibiotic with improvement of my symptoms. One-third never, never achieved this clinical cure rate even while they were taking the antibiotics. We do not have outstanding antibiotics here. They are okay. This is why, if we really go back to that initial study that I showed you for shorter duration, I think they have a point here, is on evaluating how much bacteria is there that we can reduce it. Because these people, even not all these patients had Pseudomonas aeruginosa, you need to remember that the clinical cure rate is exactly what we see on many of these patients that recur and have multiple episodes of the same infection. In this one, I put this mark because despite that the clinical cure rate was different and Cephyderocol is a new alternative for patients with Pseudomonas aeruginosa and Acinetobacter, it had a link towards higher mortality that was non-statistically significantly different. This is why there is not a recommendation to be used, at least in the context of HAP or BAP. To summarize this slide, we have these cases where clinical cure was similar. This is just a summary of all the antibiotics that I think had been reported recently for multidrug-resistant pathogens, whether Enterobacteriaceae, Pseudomonas, Acinetobacter, or Stenotrophomonas maltofilia. Very nice summary. You see that the alternatives for Acinetobacter are very limited to just two. So with this, I would like to conclude that multidrug-resistant pathogens continue to be an alarming problem for the management of patients with bronchiectasis around the world. The clinical practice guidelines offered an initial empiric approach to the care of these patients. However, we now have new alternatives that are systemic antibiotics that could potentially help us to treat these patients with multidrug-resistant Pseudomonas aeruginosa. With this, I would like to conclude with this quote, turn your obstacles into opportunities and your problems into possibilities. So we need more fellows and more people interested to really help us to really deal with this because you are the future of the care of these patients with bronchiectasis. Thank you so much for your attention. ♪

bronchiectasis

management

evaluation

airway clearance

infections

anti-inflammatory therapies

multidisciplinary care

research

multidrug-resistant infections