Video Beyond Airway Clearance — Targeting Neutrophilic Inflammation in Bronchiectasis Play Pause Volume Quality 1080P Fullscreen Captions Transcript Chapters Slides Beyond Airway Clearance — Targeting Neutrophilic Inflammation in Bronchiectasis Overview TAKE CME TEST Back to Symposium Hello, I'm Mark Matursky, professor of medicine and director of the Center for Bronchiectasis and MTM Care at the University of Connecticut School of Medicine. Welcome to this session entitled neutrophil Based Targeting and non-cystic fibrosis bronchiectasis, which is one session in a series of sessions on bronchiectasis. These are my disclosures. I've done a fair amount of work with pharmaceutical companies seeking to develop drugs for bronchiectasis. Let's start with a clinical case. This patient is not an unusual patient for those of us who see people with bronchiectasis. A 63-year-old woman presents as a new patient. She has a history of bronchiectasis diagnosed about 8 years ago. She currently has a cough productive of 2 to 3 tablespoons of yellow to green sputum daily. She has fatigue and has been slowly losing weight. She's had numerous positive cultures for pseudomonas. AFB cultures have all been negative. She's had an appropriate evaluation for potential underlying causes of her bronchiectasis, and that evaluation was negative, so she's idiopathic, and spirometry reveals moderate obstruction. She's had 2 to 3 exacerbations yearly, treated with oral levofloxacin, but now her pseudomonas is demonstrating intermediate susceptibility to Cipro. Her daily regimen for the last year and a half has been airway clearance with hypertonic saline and high frequency chest wall oscillation. She has uh been taking inhaled tobramycin twice daily, and she's on chronic low dose azithromycin, so she's pretty much maxed out for her therapy. We'll leave her for now and talk more about bronchiectasis and come back to her towards the end. But uh she provides a nice um introduction to the type of patient that we we have to deal with and for whom our treatment has been insufficient with a lot of unmet need over the years. So how do we define bronchiectasis? It's unusual in that it's essentially a radiographic definition based upon the chest CT in which we see airway diameter larger than the accompanying artery, and most experts would say the inner diameter of the airway for that measurement, lack of normal airway tapering. Or a visible airway within 1 centimeter of the periphery or the pleura, although this can give false false positives sometimes if there's atelectasis that brings a normal airway close to the pleura. So, you have to be careful with that one. Clinically significant bronchiectasis has been defined, but mostly for clinical trial use, although I think it's useful to mention it, and that's defined as at least two of the following cough most days of the week, sputum production most days of the week, and a history of exacerbations. I have some imaging here just to provide some context. This is a patient who clearly has cystic bronchiectasis, and in a distribution that suggests non-tuberculous mycobacterial infection. And as you can see, there are cavities here. There's a cavity here that's not part of the bronchiectasis. There's a large nodule, and then subsequently, about a year later, this cavity had filled in. And this one had enlarged, so this was Mac that had not been recognized or treated. Here's another patient with bronchiectasis, and you can see a lingular distribution, but I put this up to show the tree and bud here by the where the cursor is. So this is classic tree and bud nodularity. Which shows or demonstrates inflammation in the very small airways, the bronchioles, um, caught on end through the CT slice, and this is suggestive of non-tuberculosis mycobacterial infection also, especially when it's patchy and asymmetric. Let's discuss the etiologies of bronchiectasis, and it's important to know that this isn't just an academic exercise. About 20% of cases of bronchiectasis have an underlying cause that when determined is likely to result in a change in therapy. In the left panel, I have listed specific causes that often result in a change in therapy. These include allergic bronchopulmonary aspergillosis, non-tuberculous mycobacterial infections such as Mac. Immunodeficiency, the most common of which we find in adults, is common variable immunodeficiency, alpha one antitrypsin deficiency, gastroesophageal reflux, and cystic fibrosis. We often find patients with some of the milder CF mutations that present late in life and don't get diagnosed until they're in their 60s or 70s. Other common causes on the right that generally don't result in a change in therapy include post infectious such as after severe pneumonia, pertussis, or measles. We're seeing much more, um, bronchiectasis in patients who have long lasting COPD or asthma, generally in patients who have more severe underlying, um. Uh, COPD or asthma, prior tuberculosis, autoimmune disease such as Sjogren's, ulcerative colitis, rheumatoid arthritis, all can be associated with airway disease, um, including bronchiectasis, but often sometimes more subtle airway disease. Primary ciliary dyskinesia, um, and many other rare conditions, uh, can lead to bronchiectasis. The epidemiology has changed over the past decade or two, It used to be considered an orphan disease. Um, prevalence estimated about 25 years ago was about 110,000, and as you can see in the left panel, it's predominantly a disease of older people. Um, in the right panel, an updated, um, estimate. About 400,000 up to perhaps 500,000 from data from 2013. Again, mostly a disease of older people, and you can also see that. Women more frequently are diagnosed with bronchiectasis than men, and this is a constant finding in just about every cohort study, uh, population-based study across the world. And this is a different paper that used different methodology that shows the same thing significant annual increases in prevalence and more frequent diagnosis in women than men. Now, do we really think that the prevalence has actually almost tripled? Probably not. Certainly there's probably an increase in prevalence related to the increased age of the population. But we're also finding patients that previously were undiagnosed or had delayed diagnosis because of increased recognition, uh, and awareness, but also because we're doing a lot of CT scans, so coronary calcium CTs, um, CT angiograms in the emergency department, so we're finding a lot of bronchiectasis that previously would have, um, not been diagnosed or diagnosis would have been delayed. Let's move on to the pathophysiology. On the left is the vicious cycle model coined by Cole in the 1980s, um, and there's really no one starting point, um, because depending upon the etiology, you can start with abnormal mucus clearance like with PCD. You can start with bacterial infection and colonization being the primary, um, um, inciting event, so in a patient with immunodeficiency. Um, these lead to neutrophilic inflammation, release of elastases, and other inflammatory mediators that damage the airway and over time result in, uh, destruction and weakening, causing dilatation of the airways, and, and that further causes abnormal mucus clearance, which furthers this vicious cycle. On the right is the vicious vortex coined in 2018, um, which includes the same four processes, um, but what, what they've, um, Added to the concept is that each of them interact with each other. They're not independent, unrelated issues, so that's that's the vortex, but the same underlying processes are invoked. Inflammation is clearly very important in bronchiectasis. Now much of that inflammation is caused by infection, uh, but not all of it. There, there's independent inflammation that is not directly correlated with infection, at least in some patients. So on the left panel you can see that um the percent of neutrophils in BAL fluid is much higher in patients with bronchiectasis, 1% in control patients, but 37% in patients with bronchiectasis, whether it's by percent or the count. Neutrophil elastase is about 3 times higher in the patients with bronchiectasis compared to control patients. Um, and on the right you can see that, um. Exacerbations correlate with bacterial load also, not surprising, the more bacteria, um, the higher the exacerbation rate. The x axis shows the bacterial loads, as well as the symptoms such as the lesser cough questionnaire. Lower scores are worse, and again, that's worse when you have higher bacterial loads. So both infection. And neutrophilic inflammation play a role, and they're related, of course. Chronic infection leads to neutrophilic uh infiltration. Neutrophil elastase is a is a player here released by the neutrophils, obviously, but with direct direct damage as a result to the airways. Neutrophil elastase by itself can increase mucin expression and production. It directly impairs ciliary motility. It damages epithelium. It is a direct activator of inflammation and impairs innate immune function. Now, there's other type of other types of inflammation, uh, in addition to neutrophil. Uh, eosinophilic is important, and in several studies, approximately 20% of patients with bronchiectasis have, um, neutrophilia, I'm sorry, eosinophilia, as defined by greater than 300. Um, eosinophils, per microliter in the blood, and on the right you can see that the blood eosinophilia correlates with sputum eosinophilia. So it's a good marker because, um, assessing sputum eosinophilia is not something that that everyone can do. Um, So does this matter? And it does. This is a graph showing time to exacerbation in patients with varying counts, uh, eosinophil counts in their blood, and as you can see, uh, the green, which is the group of patients who have eosinophilia, um, had a much higher rate of exacerbation. So it seems to correlate with severity of disease. Just as neutrophilic inflammation does. Now, neutrophil elastase itself um correlates with markers of severity, including the bronchiectasis severity index, the uh amount of bacterial colonization, frequency of exacerbation, lung function loss. Frequency of hospitalization and mortality, so all important outcomes, um, and you can see here, um, this is a graph of exacerbations related to neutrophil elastase levels. The red is the highest neutrophil elastase level, and you can see that they remain event-free, so exacerbation-free for the shortest amount of time. So we're we're building a case here that inflammation, specifically neutrophilic inflammation, um, and elastase released by neutrophils, um, are all important markers of severity and probably pathophysiologically causative too. So which patients are at high risk, um, older patients, malnourished patients, those with impaired lung function, those with chronic pseudomonas airway infection, those with frequent exacerbations, and, uh, not surprisingly, those with worse bronchiectasis on CT scan, especially those with cystic bronchiectasis. These are all markers of patients who are going to do worse over time. There's a frequent exacerbator phenotype that's been defined in bronchiectasis, similar to what's been seen in COPD, and on the left panel, you can see patients stratified based upon their exacerbations per year when they were entered into a large database registry. And you can see that it correlates well with risk of hospitalization for bronchiectasis during the follow-up period. Those with zero exacerbations during the prior year had only about a 10% risk for hospitalization, whereas those that had more than, I'm sorry, 3 or more exacerbations during the prior year were hospitalized at up to around 40% rate. And then um overall survival on the right correlates with baseline exacerbation rates, and again you can see those with 3 or more had a significantly worse survival than those with fewer exacerbations. So let's move on to evaluation and management of these patients. Most experts would recommend these tests for initial testing of patients with newly diagnosed bronchiectasis, a pulmonary function testing with assessment of bronchodilator responsiveness, a high resolution CT of the chest, um, which in most cases will have been done, and that's what led to the diagnosis, but not always. Um, sputum for mycobacterial, bacterial and fungal culture. A CBC with differential, you're, you're looking for mostly for eosinophilia, um, quantitative immunoglobulin levels, including IgG, IgA, and IgM, looking for immunodeficiency. Again, in adults, the most common one we find is common variable immunodeficiency. And an IGE level looking for type 2 inflammation and certain underlying causes such as hyper IGE syndrome or ABPA that are associated with elevated levels of IgE. The vast majority of patients should also have testing for alpha-1 antitrypsin deficiency and cystic fibrosis. Now, there are European guidelines that recommend everybody have testing for I'm sorry, for allergic bronchopulmonary aspergillosis, and in principle, I agree with that, um, but if the patient has no history of asthma, their IgE level is normal, they have no eosinophilia, they clearly don't have ABPA, and, and that testing really doesn't need to be done in my opinion. Um. Despite all these tests, about 40% of patients will remain idiopathic, um. Many of those patients may have unrecognized prior infections that resulted in their bronchiectasis, and some of them undoubtedly have underlying specific causes, perhaps genetic, that we have not yet discovered yet. Every year there's another unknown cause, previously unknown cause, that's discovered that accounts for a small percentage of patients who were previously defined as idiopathic. Now there should be targeted testing um for some patients who have unique characteristics. So if the clinical characteristics are suggestive, as I mentioned before, uh test for allergic bronchopulmonary aspergillosis with aspergillus specific antibody levels. Primary ciliary dyskinesia, um. In general, if a patient has no symptoms, no evidence of disease until adulthood, I don't test for this, but patients who develop symptoms and disease earlier in life, uh, PCD needs to be considered. So for patients who develop earlier disease, you're going to think of a genetic cause such as primary ciliary dyskinesia. Certainly, uh, about half of those patients will have situs inversus or other abnormalities of organ location. Um, they may have a history of um. Neonatal respiratory distress and they'll have a history of chronic cough, daily cough, uh, since childhood, and nowadays we can test for PCD with uh screening with nasal nitric oxide and also there's a commercially available um PCD uh mutation screen. Frequent infections, especially infections. Outside of the respiratory tract, consider immunodeficiency and more intensive testing than just immunoglobulin levels, including IgG subclasses, vaccine response, or even potentially a referral to an allergy immunology specialist in patients who have suggestive symptoms, um, I will do an autoimmune panel. Some experts do an autoimmune panel on every patient. Uh, I generally withhold that unless they have symptoms suggesting autoimmune disease such as arthritis, rash, um, dry eyes, dry mouth, and, um, so far I have not been burned, uh, using that, um, um, trigger for autoimmune testing. And Either the development or severity of symptoms in a fair number of patients, um, GERD itself is much more frequent in patients with bronchiectasis than in the general population. Moving on to management. Um, most experts feel that airway clearance is the mainstay of bronchiectasis treatment. It should be, uh, prescribed in virtually every patient unless they basically have no symptoms and no evidence of mucus plugging on CT scan. Um, admittedly we do not have high level evidence to support this, but there are a number of studies that do provide some support for the use of airway clearance. Um, the least expensive and least burdensome devices are the handheld oscillatory positive expiratory pressure devices. Um, they have oscillating pressure as the patient breathes out through them. Um, and those, uh, oscillating pressure waves cause shear forces that help loosen the mucus. Um, they also help to stimulate cough, and, uh, the positive pressure helps keep the airways expanded. Uh, so that the patient has an easier time expelling the mucus. Some of these devices are the Aerobica, a cappella, and flutter, but there are other devices. Um, we generally recommend that they be used twice a day, uh, at least initially, uh, for at least 5 minutes, um, daily, and, um. It's important that you just don't hand the device to the patient and tell them to use it. They really need written instructions and then uh feedback on their, on their, um, technique, um, after they have the device, um. So I, I see a lot of patients where the device is sitting, sitting in the closet because they were given it but never really told how to use it. Um, we also couple it with huff coughing, so, um, not a full cough because a full cough can cause compression of the airways, so they use huff coughing followed by regular coughing to expel the mucus. We consider adding hypertonic saline nebulization. If the symptoms are not well controlled with one of these handheld devices, although the evidence is weak, a recent fairly large RCT found that the exacerbation reduction with hypertonic selenium was not statistically significant, although their statistical power was somewhat limited. But again, it's it's another. Aspect where we don't have high quality evidence. Um, there's an increased burden of treatment when you use hypertonic saline, so I don't use it with everybody, but if they're not doing well, um, with just mechanical modalities, I will often add this. And then if the patient is doing better with it, then continue it. If they find that it doesn't help or they don't tolerate it, um, then you can always stop it. And um we also escalate to a high frequency chest wall oscillation vest if the symptoms aren't controlled with with the above modalities. For patients who have chronic airway infection with a targetable bacteria, um, We often use, um, inhaled antibiotics, most commonly for pseudomonas. Um, Available antibiotics include Tobramycin, Erinam, colitin, ceftazidine. Um, none of them are FDA approved, so they're really off the shelf, uh, IV, um, preparations that are then used for, um, nebulization. A meta-analysis showed about a decrease, I'm sorry. A meta-analysis showed about a 20% decrease in exacerbation rate with inhaled antibiotics and probably a slight improvement in symptoms and quality of life, so definitely patients are on average better, but there's a significant treatment burden. And clearly unmet need for improved therapies because these are not miraculous cures. Now traditionally in the US but not elsewhere, we've used 28 days on, 28 days off regimen which doesn't make a lot of pathophysiologic sense in terms of allowing increased inflammation and symptoms when they're off. Antibiotics allowing the bacteria to replicate and potentially select for resistant strains. So more and more if patients tolerate it, if the burden isn't too much, if they feel better on continuous treatment, I will use that similar to my European colleagues who generally that's their standard. We've largely ignored the neutrophilic inflammation until recently. Um, however, uh, starting about A decade ago, um, there's been increased use of chronic low dose macrolide therapy based upon three RCTs, uh, that were well done that showed benefit. Um, in the right hand panel, you can see, um, about, um, 1 exacerbation per year decrease with the use of chronic low dose macrolide therapy, whether it be azithromycin or erythromycin in these studies. Um, macrolides, Likely have direct anti-inflammatory effects on the host, us, independent of antimicrobial activity. Um, meta-analysis, in addition to showing the lower exacerbation rate, demonstrated improved quality of life resulting from chronic low dose macrolide therapy. It cannot be overstated that the presence of non-tuberculous mycobacterial infection. Must be ruled out before commencing macrolide monotherapy. Um, macrolide resistant MAC can be created by the use of macrolide monotherapy, and macrolide resistant MC, Mycobacterium avium, is extremely difficult to treat and is often a death sentence. So this is a big mistake that can be made if you give someone low dose chronic azithromycin without making sure they do not have underlying. Uh, early subtle Mycobacterium avium complex infection. More recently, there's been a lot of interest in targeting this enzyme, dipeptidal peptidase one. In reducing neutrophilic inflammation, specifically neutrophil serine proteases, including neutrophil elastase, which we discussed earlier, is a marker for severity and correlates with increased, um, severity and poorer outcomes. This enzyme terminates an N-terminal dipeptide from neutrophil serum proteases, including neutrophil elastase, as the neutrophil is maturing in the bone marrow. So, in the presence of inhibition of DPP-1, the neutrophils release inactive neutrophil serine proteases. The first drug available for targeting DPP-1 is benzocadib, which was released about a year ago. These data show that DPP-1 inhibition reduces activation of neutrophil serum proteases. Uh, this was a 24 week designed study, um, of 256 patients with bronchiectasis. And they were treated with benzocaib, and you can see on the right that the uh placebo treated group. Their neutrophil elastase in the upper left as well as the other serum proteases, their levels stayed pretty much stable during the treatment period, whereas you can see that uh in treatment groups that had 10 mg and 25 mg of benzicib, that their neutrophil serum proteases, including neutrophil elastase, dropped to fairly low levels. Over time, um, because again, it takes time for the neutrophils that are in the bone marrow to be released into the bloodstream, and then once treatment was stopped, the levels went back up, so it's a reversible inhibition. A phase 3 study was done following up on those results, and as you can see here, in patients who received placebo, they had a higher rate of exacerbation and shorter time to exacerbation, and this was statistically significant in both the 10 mg and the 25 mg group, um, with a rate reduction of about 20%. And these were all patients with bronchiectasis who had 2 or more exacerbations during the prior year before randomization. What was really exciting to us is that the 25 mg dose also statistically significantly decreased the rate of decline in FEV1, so it appeared to be disease modifying, as you can see, the FEV1 dropped much less in the 25 mg group compared to the 20, the 10 mg group and the placebo group, so an apparent disease modifying effect. Secondary endpoints, um, we discussed the lung function with the 25 mg group, um, nominal improvement in the symptom score and quality of life with the 25 mg group. What it means is that there was a hierarchical analysis of the symptom score and because other variables didn't reach significance prior. To the analysis of the symptom score and quality of life, it couldn't be defined as statistically significant. It had to be defined as nominally significant. Brenzaccaib at both doses was generally well tolerated and had a favorable safety profile. There was concern that there would be increased risk of infections, including periodontal disease, and that was seen in one study very slightly and in the phase 3 study. Periodontal disease was, was not seen at an excess rate. Um, some patients will get a characteristic thickening and sloughing of skin. In areas such as the hands and feet and behind the knees, uh, this was seen, but was not very common and remits if the drug is stopped or the dose lowered. Interestingly and importantly, In patients who are already on chronic macrolide therapy, the effect size was similar to those who were not receiving chronic macrolide therapy, so it seems to be additive. This was not statistically significant because the, the groups, obviously the number of patients receiving chronic macrolide therapy, um, was, was not, not huge, so um the statistical power was not great, but, but the effect size seemed to be similar. And in addition, um, the patients with and without eosinophilia, uh, had similar effect sizes in the reduction of, um, um, exacerbations. So, um, it appears that even if a patient has eosinophilic inflammation, that uh targeting their coexisting neutrophilic inflammation, um, can help the patient. And finally, whether or not they had Pseudomonas aeruginosa in their sputum, uh, again, a similar effect size in um Uh, reduction of um exacerbations. So based upon this pivotal phase 3 study, forensicat was approved in both the US and in Europe in 2025. Most experts, including myself, recommend the 25 mg dose to the superior effect on quality of life and preservation of lung function compared to the 10 mg dose. You'll recall that the 10 mg dose had a similar effect with respect to frequency of exacerbation. But not these other two very important endpoints, um, so we generally start with the 25 mg dose because we didn't see an increased signal in terms of safety or side effects, um, uh, with the higher dose. And if a patient does have issues, then you can always have the option potentially to lower to 10 mg. It's important to state that there are two other DPP-1 inhibitors that are currently in phase 3, after positive phase two results, so that's exciting. We may have, um. Uh, 3 choices in several years from now, um, for DPP-1 inhibition. So it's a complex disease with a host of effects on the patient, so there, there are ancillary treatment considerations for many patients. I touched on GERD, um, which is a common comorbid condition, can contribute to the symptoms and the progression. So, um, we generally treat GERD and if despite aggressive treatment that is non-surgical, uh, even surgical modalities should be at least considered um if if the symptoms remain significant despite acid suppression and lifestyle modification. Chronic rhinositis can contribute to symptoms due to post nasal drip and cough from that reason. In addition, the sinuses can harbor bacterial pathogens that can then also, um, co-infect the airways. So, uh, an ENT consultation is often, um, one of the things we'll do with our bronchiectasis patients. Malnutrition is not unusual due to the chronic infection and inflammation, um, so dietary supplements are often prescribed, and once these patients start losing weight, it's tough to reverse that. So we'll often have them see a nutritionist. And finally, pulmonary rehabilitation. Has been shown to have similar benefits in patients with bronchiectasis than compared to COPD, so that's certainly something we consider in patients who have significant exercise limitations and not in this slide, but coexisting depression and anxiety, as you can imagine, is not unusual. So certainly be on the lookout for that and treat or refer appropriately. This is an exciting time for those of us interested in bronchiectasis, where it was truly an orphan disease before with very little pharmaceutical company interest and therefore very few treatment options. There is a lot of interest now, um, in, um, treatment of bronchiectasis. So iphentrine, which is a PDE3 PDE4 inhibitor that was recently approved for COPD, is being studied in bronchiectasis. Gelvocammi. Um, which is an anti-IL-13 IL-17 monoclonal antibody, so an anti-inflammatory agent, um, is also being studied. Atepekumab, which is an anti-IL 33 monoclonal antibody that that therefore addresses, um, epithelial based inflammation, is being looked at. Arena one is a nebulized solution of glutathione. Ascorbic acid and bicarbonate that restores the appropriate um acid base status and an antioxidant and has had promising early results. And then there's a lot of, there are a lot of antipseudomonal agents being looked at phage therapy, monoclonal antibody targeting biofilm that actually targets all bacterial biofilms, uh, monoclonal antibody targeting pseudomonas specifically, inhaled calistametate, and a novel inhaled anti-seudomonal antibiotic are some of the investigational agents that may hold promise. So, selected some selected guideline recommendations, some of which we've touched on, airway clearance for all symptomatic patients, both um the um European guidelines as well as the recently released last week, uh, chess guidelines. It says in press there, I apologize, they were just released last week. Um, chronic low dose macrolide therapy is recommended by both guidelines for patients at high risk of exacerbation despite standard care is what the Europeans said and we said for patients with 2 or more per year. Um, I certainly consider chronic low dose macrolide therapy in patients who are who have intolerable symptoms, um, even if they're not having frequent exacerbations, and some of those patients will benefit, um, but we don't have a lot of evidence in support of, of, um, patients who don't have frequent exacerbations. And then, uh, the most recent, the chest guidelines recommend DPP-1 inhibition. Currently renzacatib is our only choice, um, but as I mentioned, maybe in the future we'll have a few more. And it's recommended for patients with 2 or more exacerbations per year. So, Many treatment recommendations are based upon exacerbation frequency, and I touched on it briefly. It ignores the many patients who are what we call in chronic exacerbation, so they may not have frequent flares, but every day they are coughing up copious purulent sputum. They have fatigue. They may be losing weight, um. They have a high symptom burden, and many of these same therapies may benefit these patients, although admittedly we do not have high quality evidence for that, but certainly some of these therapies should be considered for this type of patient, which is not unusual. So back to our patient with chronic pseudomonas airway infection, uh, depending upon which study you read, uh, which cohort you're looking at, somewhere between 10 and 30 patients with bronchiectasis are chronically infected with pseudomonas, and Pseudomonas is associated with worse prognosis, including exacerbations, quality of life, and mortality. So what can we do to address the pseudomonas in our patient that I introduced uh at the beginning of the talk? Well, one option is attempted eradication, um, so aggressively trying to remove that pseudomonas for an extended period of time. There are only observational studies. Um, they suggest that prolonged eradication is possible in 40 to 50% of patients. Um, limited data on other outcomes, uh, associated with eradication, right? We want to make the patient feel better and have fewer exacerbations, have slower progression, um, which we think will happen with eradication, but we haven't proved that yet. Various regimens are used to eradicate the pseudomonas, um, but generally it's an inhaled antibiotic for 1 to 3 months. I happen to use 3 months in combination with an oral or IV systemic antibiotic for the initial 2 to 4 weeks. And I certainly have had success in patients sometimes with this type of regimen where the pseudomonas disappeared and hasn't come back for 11 or 2 years, and that's probably important. It's important to note that it's almost never effective in patients with long-term pseudomonal infections. So if a patient has had positive pseudomonas cultures, you know, every year for several years, I'm not going to try to eradicate it. Um, The guidelines are disparate on the recommendation with regard to eradication. The Europeans do recommend it for patients with a new isolation of Pseudomonas. The chest guidelines, because there wasn't strong evidence, didn't recommend either for or against. We also have long term inhaled anti pseudomonal antibiotics. Um, it's important to note that none are FDA approved for bronchiectasis as none reached their primary endpoint in. Both phase 3 studies. There are a few that had 1 positive study and 1 negative study, but nonetheless they're used, uh, using the CF model, um, where they are FDA approved. They include, as I mentioned before, tobramycin, gentamicin, estrien, ceftazidine, and colitin, um, which, um, has had one positive and one negative phase 3 study. COVID may have affected their ability to have that second phase 3 study, but it's in limbo now. We're not sure whether that's going to be submitted to the FDA or not. It's important to note there's a significant time burden, cost, potential for side effects and antibiotic resistance associated with these treatments, although the antibiotic resistant rate is fairly low and really shouldn't prevent. Um, the use of one of these agents, if it's clinically appropriate. Um, And I've shown some um data um in terms of reduction in um Frequency of exacerbation, um, about 22% reduction, bigger reduction in severe exacerbation, slight improvement in quality of life. But what I want to go over here is, not surprisingly, um, The less than stellar results are in part related to the fact that some of these patients don't have a lot of pseudomonas. So you can imagine that if there's very little pseudomonas, it may not be so important to try and control it, whereas if there's a lot of pseudomonas, um. Then it's probably more important to the pathophysiology. And as you can see from this panel on the right, the response in one study to inhale atrionam was much greater um in terms of quality of life than if for the for those that had high bacterial load. Compared to those that had moderate or low bacterial load in which there was really no improvement in quality of life, so this is pretty logical and probably explains why some patients don't have great response to inhaled antibiotics whereas others do. And the studies enrolled patients, all they had to do was have Pseudomonas, and they did not have to have a high bacterial load, and that probably explains, at least in part why some of these studies failed to show benefit. In terms of guideline recommendations, both the European and the chest guidelines recommend long term inhaled antibiotic therapy for appropriate patients. So what can we offer our patient with chronic pseudomonas? Airway infection, copious daily sputum and frequent exacerbation, probably not attempted eradication as she has chronic infection and we're not gonna be able to eradicate it. We wanna check her adherence and her technique with the airway clearance because that's a mainstay of therapy. We can augment it if she's doing it right, increase it, um, to more times per day. She is, in my opinion, a candidate for brenszacadeb at 25 mg a day. She has high symptom burden. She has frequent exacerbations, and she has impaired lung function, so. Breniccab seems to be something that would potentially um improve her exacerbation rate, her symptoms, and perhaps slow down the rate of lung function loss. She's thin, so she should have nutrition consultation and be on a dietary supplement. And if she has dyspnea that limits her physical activity, uh, we should consider referring her for pulmonary rehabilitation. So in summary, bronchiectasis is no longer an orphan disease. In a patient with newly diagnosed bronchiectasis, it's important to rule out treatable underlying causes in a systematic manner. I'm gonna start over again. In summary, bronchiectasis is no longer an orphan disease. And in a patient with newly diagnosed bronchiectasis, it's important to rule out treatable underlying causes in a systematic manner, but that does not necessarily mean doing every test on every patient. For example, testing for PCD, primary ciliary dyskinesia, is likely not going to be useful in a patient who had no respiratory symptoms until she was 70 years old. Virtually all symptomatic patients should be started on an airway clearance regimen with a device in general, but there are also, um, non-device uh modalities um. That can be used, such as active cycle of breathing or autogenic drainage, um, that some patients will prefer, but the best device or regimen is the one that the patient will use. Um, so there's some trial and error there in finding the right regimen that is acceptable and helpful for the patient. For patients who have unacceptable symptom burden and exacerbation burden despite airway clearance, we can add low dose chronic macrolide therapy, chronic inhaled antibiotics, especially in patients with pseudomonas, and DPP-1 inhibition with benzaccaib to decrease their exacerbation rate, improve quality of life, and slow the decline in FEV1. And finally, uh, there are a host of other agents investigation. So therapeutic options are likely to expand in the near future, which is very encouraging. And thank you very much for your attention. Published Created by Related Presenters Mark Metersky, M.D., F.C.C.P. Professor of MedicineChief of Service, Department of MedicineDirector, Center for Bronchiectasis CareUConn HealthFarmington, CT
