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Innovations in NCFBE Podcast 2
Innovations in NCFBE: Latest Advances and Personalization of Treatment

Released: June 20, 2025

Anne E. O'Donnell
Anne E. O'Donnell, MD
Activity Information

Activity

In this podcast, Anne E. O’Donnell, MD, discusses the latest advances and treatment strategies for patients with non–cystic fibrosis bronchiectasis (NCFBE), including:

  • Airway clearance as a foundation of NCFBE management
  • Strategies to address inflammation and exacerbations
  • Emerging therapies in clinical development
  • How to individualize treatment to NCFBE phenotypes and endotypes

Endothelial and Mucociliary Dysfunction

First off, I want to talk about the issue of endothelial and mucociliary dysfunction in this disease. You know, this is a very heterogeneous disease, bronchiectasis, so patients have it for various reasons. However, it is almost universal that patients have ciliary dysfunction, impaired mucosal defense at the airway level, and abnormal mucus production for the vast majority of these patients.

So, and again, hearkening back to the vicious cycle, vicious vortex, the more mucus, the more impairment of the ciliary function, the more chronic infections. It just goes around and around in this cycle or vortex. And so with that, you get more inflammation, more secretions, and then airway dehydration.

Therapeutic Strategies for Mucociliary Dysfunction

And so a big part and one of the foundational treatments for bronchiectasis is tailoring an airway clearance program for the patients. And, you know, these airway clearance things can be as simple as just walking, doing routine exercise, deep breathing, yoga for some patients. However, then we also have devices like positive expiratory pressure devices with oscillation. We can teach patients various airway clearance techniques like autogenic therapy. We can teach them huff coughing. We can move up to things like hypertonic saline, nebulization, and high-frequency chest wall oscillating vests to move the mucus.

This really requires, you know, collaborating with your team, but also with the patient, because the best airway clearance is really the one that the patient has the time and the ability and the willingness to do. So daily airway clearance really is a core feature of treating our patients with bronchiectasis. Like I said, it goes from simple to more complex.

In patients that do not necessarily respond or still have retained secretions, just by using things like oscillatory PEP devices, then we generally move up to 7% saline nebulized. Sometimes that is too irritating for patients, and so we will step it down to 3%; physical therapy. However, most important when it comes to airway clearance, and also just in general in treating patients, is really disease education and support for adherence to treatments.

Chronic Airway Infections: P. aeruginosa

Dr. O'Donnell: After you have educated patients about the importance of airway clearance, and if patients are still having problems, symptoms, and exacerbations, we want to really start to delve into the infections in the airways. And we know probably about a third of patients, at least in the United States, are chronically infected with Pseudomonas. However, two-thirds have other organisms.

We know already how many patients have non-tuberculous mycobacterial infections, but also haemophilus, staph, you know, both sensitive and resistant staph, things like moraxella, other gram-negatives are what is in the airway. So, again, an important take-home message when you are stepping up to thinking about treating the infection is that it is very important to get sputum cultures on a regular basis so that you know, and the patient knows what organism if they are chronically infected. However, Pseudomonas is a bad actor. It causes biofilms. It has been associated with more frequent and longer exacerbations, with more rapid decline in lung function, and more frequent need for advanced therapies like IV antibiotics or hospitalizations.

Therapeutic Approaches for P. aeruginosa

There are different strategies that we take to deal with Pseudomonas. There is the issue of whether early eradication, meaning that when you first identify Pseudomonas in your patient, you might consider this approach very aggressive, wipe-out strategy using double gram-negative coverage, either oral ciprofloxacin plus an inhaled antibiotic versus using an IV antibiotic in order to try to "eradicate Pseudomonas" when you first isolate it. There is some controversy about this. Of course, you know, when you first meet the patient, that may be the first time they are getting a sputum, so you do not know if that is really their first isolation of Pseudomonas. However, it is very important to approach Pseudomonas and all of the other bacteria in a very systematic management.

Chronic Inflammation in NCFBE

For chronic management of patients with Pseudomonas, although this is not FDA-approved in the United States, we often do reach to using inhaled aminoglycoside antibiotic like tobramycin.

Sometimes we will go to the formulating inhaled colistin. And we are surveilling these patients' cultures routinely, whether or not they are on inhaled antibiotics, to assess how they are responding. One question that often comes up is when you are on an inhaled antibiotic, does the resistance pattern really matter when you are delivering a high dose of inhaled antibiotic right to the airway? And that is really an area still of controversy, whether that actually makes any difference for the patient.

Anti-inflammatory Therapies

Besides infection, obviously inflammation goes hand-in-hand with the presence of chronic infecting organisms. Dr. Griffith already touched on this. Probably, about 75% to 80% of patients with bronchiectasis really are neutrophilically inflamed. And they have a lot of neutrophil elastase in their airways, which really leads to progressive tissue damage. One thing we try to avoid in patients with neutrophilic inflammation in bronchiectasis is the routine use of corticosteroids, because it is actually not very effective for the neutrophilic phenotype, and it also can exacerbate the infections.

So you want to stay away from inhaled corticosteroids as an anti-inflammatory measure in most patients with bronchiectasis. Although the caveat is there is probably about 20% of these patients that actually have eosinophilic inflammation in a more asthmatic-y pattern.

So what anti-inflammatory therapies do we go to? We use macrolides in bronchiectasis more for their anti-inflammatory and immunomodulatory effects than for their antibiotic effect. So we know that a macrolide strategy can be effective in patients with frequent exacerbations of their bronchiectasis. Emerging therapies to treat inflammation, brensocatib, the DPP1 inhibitor, with recent Phase III data that shows reduction in exacerbations in patients treated in the Phase III and Phase II trial.

There are several other agents being looked at, BI-1291583, another DPP1 inhibitor, is about to start a Phase III trial. However, we also are examining the role of the asthma biologics IL-33 antibody in patients with eosinophilic inflammation, and then other elastase inhibitors, and there actually is some interest in phage therapy as well.

Strategies to Prevent Bronchiectasis Exacerbations

So really, again, another important take-home message today is the importance of, number one, recognizing bronchiectasis exacerbations, educating patients about when to call you when they are in an exacerbation, which is generally characterized by increased number of symptoms like cough, sputum production, change in their sputum, hemoptysis, increase in breathlessness.

We really, really, really want to focus on reducing or eliminating exacerbations. We know that patients who have three or more exacerbations a year have a worse prognosis, but really, probably one or two are still significantly bad as well. However, really, from our guidelines, three or more exacerbations, those patients need to optimize their airway clearance.

If they are chronically infected with Pseudomonas, we want to start them on long-term inhaled antibiotic therapy, although macrolide therapy is still an option in those patients. If they have non-Pseudomonas chronic infection, long-term macrolide is definitely an option. And then an inadequate response, you really have to up the game in terms of all of these therapies.

So a few caveats, right? Long-term macrolides cannot be used in patients who are co-infected with non-tuberculous mycobacterium because you could breed resistant NTM organisms. There are also cardiac and hearing issues potentially with macrolides that you have to take into consideration.

So this treatment strategy really does need to be molded to the specific patient.

Phase II WILLOW Trial: Impact of DPP1 Inhibition on Exacerbation Timing

Now, we are excited about the possibility of these new therapeutics. This is the Phase II data from the WILLOW trial, which is the brensocatib Phase II study.

And what this showed here was that the 10 mg and 25 mg dose of brensocatib increased the proportion of patients who had no exacerbations over the length of this trial.

Brensocatib in NCFBE: ASPEN Study Design and Baseline Characteristics

And then the next study, the Phase III trial, the ASPEN study. This again looked at two different doses of brensocatib versus placebo.

And what it showed was in patients who were having two or more exacerbations prior to enrollment in the trial, that there was about a 20% reduction in exacerbations in this very large trial. And the effectiveness held up across various subgroups, including patients from different geographic areas, who were chronically infected with Pseudomonas. So we conclude that brensocatib, which will be evaluated by the FDA later this year, really does seem to have a significant effect in reducing exacerbations.

So more to come on this drug in the near future.

Strategies to Prevent or Slow Structural Damage

Strategies to prevent or slow structural damage. Obviously, a CT scan does not prevent it, but monitoring the CT, and I know this question comes up, how often should you get a CT in these patients? The low-dose radiation scans nowadays make these scans much more safe.

Really doing routine scanning 1-2 years in your stable patients and possibly more frequently in your exacerbators is definitely a strategy. We want to be very aggressive about airway clearance, treating infection and inflammation aggressively. Definite reassessment. I always tell my patients once I meet them, you are my patient for life because bronchiectasis is not going away, and we really need to monitor you closely.

Another important take-home message I already mentioned is avoiding steroids whenever possible.

Individualizing Treatment: Phenotypes and Endotypes

We want to individualize the treatment based on their underlying disease cause, their endotype, and then on their phenotype, and really aggressively go against particularly the Pseudomonas-infected patients, the frequent exacerbator, and look for eosinophilic phenotype in your patients.

Eosinophilic Inflammation in T2-High Airways Disease

This shows some data, there is some observational data. I already mentioned about 20-30% of patients with bronchiectasis have eosinophils, and there is observational studies that show benefit to the asthma biologics, but more placebo-controlled studies are needed in this area to understand this better.

Emerging Therapeutic Options in Clinical Development

We have, fortunately, a whole host of drugs in development. You can see the list here, including the drug ensifentrine, which this study is currently underway in bronchiectasis to look at new options, new therapeutics, and, again, approaching the vicious cycle and the vicious vortex at each point in the cycle to break the cycle and improve the patient's condition.

Key Clinical Takeaways

To sum up, again, make the diagnosis as early as possible. Educate your patient. Assess them for their phenotype. Start them on the foundational therapies, like airway clearance, and then advance therapies as needed based on their phenotypical presentation.

Patient Case 1: 50-Yr-Old Female

Here is a patient case 50-year-old female.

Chronic productive cough, mucus plugs that she coughs up. She is unintentionally lost 50 pounds. You can see her pulmonary function testing shows an obstructive pattern with a moderately reduced FEV1.

We send the patient for a CT. And on the CT what Dr. Brett Elicker showed us before, the mucus plugging that is more central bronchiectasis with the inhomogeneity of the mucus. And this case really makes you want to check the patient's IgE and aspergillus-specific tests.

And as shown previously by Dr. Elicker, really the imaging clinches this, that this is ABPA. Any comments, Dr. Elicker or Dr. Griffith, about this case?

Dr. Elicker: No, just the CTs, as you said, is pretty typical. The high attenuation mucus in the partly collapsed lung there, so very, very classic. And always remember that bronchiectasis can cause significant bronchiectasis, often causes collapse of lungs.

In the middle lobe there is some partial collapse there, but yes, pretty typical.

Dr. O'Donnell: And this is one kind of patient that sometimes really the bronchiectasis can be almost reversed with appropriate treatment of the ABPA. So really important to recognize this.

So the bottom line, again, is the cycle of infection, inflammation, lung damage, and we really want to use all of our armamentarium that we have discussed to deal with all aspects of this disease to help our patients.

Endothelial and Mucociliary Dysfunction

First off, I want to talk about the issue of endothelial and mucociliary dysfunction in this disease. You know, this is a very heterogeneous disease, bronchiectasis, so patients have it for various reasons. However, it is almost universal that patients have ciliary dysfunction, impaired mucosal defense at the airway level, and abnormal mucus production for the vast majority of these patients.

So, and again, hearkening back to the vicious cycle, vicious vortex, the more mucus, the more impairment of the ciliary function, the more chronic infections. It just goes around and around in this cycle or vortex. And so with that, you get more inflammation, more secretions, and then airway dehydration.

Therapeutic Strategies for Mucociliary Dysfunction

And so a big part and one of the foundational treatments for bronchiectasis is tailoring an airway clearance program for the patients. And, you know, these airway clearance things can be as simple as just walking, doing routine exercise, deep breathing, yoga for some patients. However, then we also have devices like positive expiratory pressure devices with oscillation. We can teach patients various airway clearance techniques like autogenic therapy. We can teach them huff coughing. We can move up to things like hypertonic saline, nebulization, and high-frequency chest wall oscillating vests to move the mucus.

This really requires, you know, collaborating with your team, but also with the patient, because the best airway clearance is really the one that the patient has the time and the ability and the willingness to do. So daily airway clearance really is a core feature of treating our patients with bronchiectasis. Like I said, it goes from simple to more complex.

In patients that do not necessarily respond or still have retained secretions, just by using things like oscillatory PEP devices, then we generally move up to 7% saline nebulized. Sometimes that is too irritating for patients, and so we will step it down to 3%; physical therapy. However, most important when it comes to airway clearance, and also just in general in treating patients, is really disease education and support for adherence to treatments.

Chronic Airway Infections: P. aeruginosa

Dr. O'Donnell: After you have educated patients about the importance of airway clearance, and if patients are still having problems, symptoms, and exacerbations, we want to really start to delve into the infections in the airways. And we know probably about a third of patients, at least in the United States, are chronically infected with Pseudomonas. However, two-thirds have other organisms.

We know already how many patients have non-tuberculous mycobacterial infections, but also haemophilus, staph, you know, both sensitive and resistant staph, things like moraxella, other gram-negatives are what is in the airway. So, again, an important take-home message when you are stepping up to thinking about treating the infection is that it is very important to get sputum cultures on a regular basis so that you know, and the patient knows what organism if they are chronically infected. However, Pseudomonas is a bad actor. It causes biofilms. It has been associated with more frequent and longer exacerbations, with more rapid decline in lung function, and more frequent need for advanced therapies like IV antibiotics or hospitalizations.

Therapeutic Approaches for P. aeruginosa

There are different strategies that we take to deal with Pseudomonas. There is the issue of whether early eradication, meaning that when you first identify Pseudomonas in your patient, you might consider this approach very aggressive, wipe-out strategy using double gram-negative coverage, either oral ciprofloxacin plus an inhaled antibiotic versus using an IV antibiotic in order to try to "eradicate Pseudomonas" when you first isolate it. There is some controversy about this. Of course, you know, when you first meet the patient, that may be the first time they are getting a sputum, so you do not know if that is really their first isolation of Pseudomonas. However, it is very important to approach Pseudomonas and all of the other bacteria in a very systematic management.

Chronic Inflammation in NCFBE

For chronic management of patients with Pseudomonas, although this is not FDA-approved in the United States, we often do reach to using inhaled aminoglycoside antibiotic like tobramycin.

Sometimes we will go to the formulating inhaled colistin. And we are surveilling these patients' cultures routinely, whether or not they are on inhaled antibiotics, to assess how they are responding. One question that often comes up is when you are on an inhaled antibiotic, does the resistance pattern really matter when you are delivering a high dose of inhaled antibiotic right to the airway? And that is really an area still of controversy, whether that actually makes any difference for the patient.

Anti-inflammatory Therapies

Besides infection, obviously inflammation goes hand-in-hand with the presence of chronic infecting organisms. Dr. Griffith already touched on this. Probably, about 75% to 80% of patients with bronchiectasis really are neutrophilically inflamed. And they have a lot of neutrophil elastase in their airways, which really leads to progressive tissue damage. One thing we try to avoid in patients with neutrophilic inflammation in bronchiectasis is the routine use of corticosteroids, because it is actually not very effective for the neutrophilic phenotype, and it also can exacerbate the infections.

So you want to stay away from inhaled corticosteroids as an anti-inflammatory measure in most patients with bronchiectasis. Although the caveat is there is probably about 20% of these patients that actually have eosinophilic inflammation in a more asthmatic-y pattern.

So what anti-inflammatory therapies do we go to? We use macrolides in bronchiectasis more for their anti-inflammatory and immunomodulatory effects than for their antibiotic effect. So we know that a macrolide strategy can be effective in patients with frequent exacerbations of their bronchiectasis. Emerging therapies to treat inflammation, brensocatib, the DPP1 inhibitor, with recent Phase III data that shows reduction in exacerbations in patients treated in the Phase III and Phase II trial.

There are several other agents being looked at, BI-1291583, another DPP1 inhibitor, is about to start a Phase III trial. However, we also are examining the role of the asthma biologics IL-33 antibody in patients with eosinophilic inflammation, and then other elastase inhibitors, and there actually is some interest in phage therapy as well.

Strategies to Prevent Bronchiectasis Exacerbations

So really, again, another important take-home message today is the importance of, number one, recognizing bronchiectasis exacerbations, educating patients about when to call you when they are in an exacerbation, which is generally characterized by increased number of symptoms like cough, sputum production, change in their sputum, hemoptysis, increase in breathlessness.

We really, really, really want to focus on reducing or eliminating exacerbations. We know that patients who have three or more exacerbations a year have a worse prognosis, but really, probably one or two are still significantly bad as well. However, really, from our guidelines, three or more exacerbations, those patients need to optimize their airway clearance.

If they are chronically infected with Pseudomonas, we want to start them on long-term inhaled antibiotic therapy, although macrolide therapy is still an option in those patients. If they have non-Pseudomonas chronic infection, long-term macrolide is definitely an option. And then an inadequate response, you really have to up the game in terms of all of these therapies.

So a few caveats, right? Long-term macrolides cannot be used in patients who are co-infected with non-tuberculous mycobacterium because you could breed resistant NTM organisms. There are also cardiac and hearing issues potentially with macrolides that you have to take into consideration.

So this treatment strategy really does need to be molded to the specific patient.

Phase II WILLOW Trial: Impact of DPP1 Inhibition on Exacerbation Timing

Now, we are excited about the possibility of these new therapeutics. This is the Phase II data from the WILLOW trial, which is the brensocatib Phase II study.

And what this showed here was that the 10 mg and 25 mg dose of brensocatib increased the proportion of patients who had no exacerbations over the length of this trial.

Brensocatib in NCFBE: ASPEN Study Design and Baseline Characteristics

And then the next study, the Phase III trial, the ASPEN study. This again looked at two different doses of brensocatib versus placebo.

And what it showed was in patients who were having two or more exacerbations prior to enrollment in the trial, that there was about a 20% reduction in exacerbations in this very large trial. And the effectiveness held up across various subgroups, including patients from different geographic areas, who were chronically infected with Pseudomonas. So we conclude that brensocatib, which will be evaluated by the FDA later this year, really does seem to have a significant effect in reducing exacerbations.

So more to come on this drug in the near future.

Strategies to Prevent or Slow Structural Damage

Strategies to prevent or slow structural damage. Obviously, a CT scan does not prevent it, but monitoring the CT, and I know this question comes up, how often should you get a CT in these patients? The low-dose radiation scans nowadays make these scans much more safe.

Really doing routine scanning 1-2 years in your stable patients and possibly more frequently in your exacerbators is definitely a strategy. We want to be very aggressive about airway clearance, treating infection and inflammation aggressively. Definite reassessment. I always tell my patients once I meet them, you are my patient for life because bronchiectasis is not going away, and we really need to monitor you closely.

Another important take-home message I already mentioned is avoiding steroids whenever possible.

Individualizing Treatment: Phenotypes and Endotypes

We want to individualize the treatment based on their underlying disease cause, their endotype, and then on their phenotype, and really aggressively go against particularly the Pseudomonas-infected patients, the frequent exacerbator, and look for eosinophilic phenotype in your patients.

Eosinophilic Inflammation in T2-High Airways Disease

This shows some data, there is some observational data. I already mentioned about 20-30% of patients with bronchiectasis have eosinophils, and there is observational studies that show benefit to the asthma biologics, but more placebo-controlled studies are needed in this area to understand this better.

Emerging Therapeutic Options in Clinical Development

We have, fortunately, a whole host of drugs in development. You can see the list here, including the drug ensifentrine, which this study is currently underway in bronchiectasis to look at new options, new therapeutics, and, again, approaching the vicious cycle and the vicious vortex at each point in the cycle to break the cycle and improve the patient's condition.

Key Clinical Takeaways

To sum up, again, make the diagnosis as early as possible. Educate your patient. Assess them for their phenotype. Start them on the foundational therapies, like airway clearance, and then advance therapies as needed based on their phenotypical presentation.

Patient Case 1: 50-Yr-Old Female

Here is a patient case 50-year-old female.

Chronic productive cough, mucus plugs that she coughs up. She is unintentionally lost 50 pounds. You can see her pulmonary function testing shows an obstructive pattern with a moderately reduced FEV1.

We send the patient for a CT. And on the CT what Dr. Brett Elicker showed us before, the mucus plugging that is more central bronchiectasis with the inhomogeneity of the mucus. And this case really makes you want to check the patient's IgE and aspergillus-specific tests.

And as shown previously by Dr. Elicker, really the imaging clinches this, that this is ABPA. Any comments, Dr. Elicker or Dr. Griffith, about this case?

Dr. Elicker: No, just the CTs, as you said, is pretty typical. The high attenuation mucus in the partly collapsed lung there, so very, very classic. And always remember that bronchiectasis can cause significant bronchiectasis, often causes collapse of lungs.

In the middle lobe there is some partial collapse there, but yes, pretty typical.

Dr. O'Donnell: And this is one kind of patient that sometimes really the bronchiectasis can be almost reversed with appropriate treatment of the ABPA. So really important to recognize this.

So the bottom line, again, is the cycle of infection, inflammation, lung damage, and we really want to use all of our armamentarium that we have discussed to deal with all aspects of this disease to help our patients.