Interconnected Pathophysiology and Impact of NCFBE

[00:15:04]

Dr David Griffith (National Jewish Health): So now we will start with the didactic portion of the presentation. And I am going to talk about the interconnected pathophysiology and impact of non-cystic fibrosis bronchiectasis.

[00:15:30]

Challenges and Unmet Needs in NCFBE  

Non-cystic fibrosis bronchiectasis is a relatively newly described process but has been around for centuries. It is only that it took the introduction of chest CT scanning to allow more frequent and early diagnosis of the disease. We believe there is a rising disease burden, perhaps over 500,000 U.S. adults and 70,000 newly diagnosed cases per year. The prevalence increases with age to about 70 cases per 100,000 population in adults older than 65 years of age. I would add that if you have particularly a female with the characteristic morphotype for patients with bronchiectasis and a chronic cough, that that prevalence probably goes very much higher.

[00:16:38]

Bronchiectasis Diagnosis  

The diagnosis is made almost always with high-resolution chest CT scanning. However, there is a considerable delay in the time from when a patient develops symptoms to when bronchiectasis is diagnosed. And as you can see, it can be as high as 12 years. And unfortunately, there are fragmented care pathways between specialties. Some patients going to pulmonary, some to infectious disease. And at least until recently, therapeutic options have been limited.

So, in terms of diagnosing bronchiectasis, obviously, like any other disease, there has to be some diagnostic suspicion. And there are a number of tests that can be done, but the ones that are most important are the ones that include chest radiography. Usually, first, a simple or plain chest radiograph, followed by a chest CT scan. And then underneath the diagnostic tools are how you might evaluate the cause of bronchiectasis in your patients.

And not all patients require all of these tests. However, this is a pretty good general guide. I would only say part of the reason that the delay in diagnosis is as long as it is, is because patients with chronic cough do not get radiographic evaluation in a timely fashion.

[00:18:24]

The Vicious Vortex Pathophysiology  

This is a schematic of a model of the pathophysiology of bronchiectasis. It was first introduced a few years ago with the vicious cycle of inflammation in the lung. And now it has become a vicious vortex.

However, the reason that occurs is that each 1 of these factors, airway dysfunction, the inflammatory response, infection, and structural disease, has a feedback to each of the other aspects of the vicious vortex. So everything serves to perpetuate a self-perpetuating cycle of airway inflammation. And interrupting that is actually rather complicated.

[00:19:20]

Functional Endotypes and Clinical Phenotypes  

There are now phenotypes and endotypes of bronchiectasis, where even 5 years ago, those concepts were not widely appreciated. In terms of the functional endotypes, you are looking at underlying inflammatory and immunologic mechanisms. And probably the most important of those is a subgroup of bronchiectasis patients with eosinophilic inflammation.

Those patients respond better to bronchodilator medications than the neutrophilic inflammation, predominant inflammation. And then you have phenotypes I am sure you are all familiar with, daily sputum production, infection by Pseudomonas mycobacterial lung disease, and some patients who cough up very little sputum.

[00:20:22]

Neutrophilic Inflammation: A Central Driver  

However, neutrophilic inflammation appears to be the central driver for the majority of patients with non-CF bronchiectasis. And 1 pathway for that inflammation, that self-perpetuating inflammation, is release of serine proteases by neutrophils. And a substance called DPP1 activates those neutrophil serum proteases.

This type of inflammation is associated with frequent exacerbations and decline in pulmonary function. This is actually a rather potent stimulus for a self-perpetuating cycle of inflammation in the airways of patients with bronchiectasis.

[00:21:16]

Patient-Reported Burden  

Symptomatically, patients almost universally have cough. This figure of 73% seems a little low to me, but it is by far the most important or the most frequent symptom. Dyspnea is very common. Sputum production does not occur in all patients, but it does occur in the majority. And 1 that is not on here is fatigue. Patients, again, almost universally feel fatigued. They also have quality of life and socio-emotional distress.

It is very taxing for a woman in her 70s to have chronic cough. That is anathema to many women in that age group and very distressing when it occurs in public. And you can see there is both a high hospitalization rate and a high economic burden.

Survey and Online Focus Group [00:22:20]

So now we will play a patient video.

Speaker: It was a slow recovery, and I was told if I caught a cold, it could easily lead to pneumonia. Since I had been quite ill, I surely did not want to catch anything. He told me if I caught something, do not walk, to see him, but run.

Family and friends were very respectful about staying away if they had a respiratory infection. However, I found myself becoming fearful of catching something. I am sure people thought I was paranoid.

I stopped going around the crowds during January and February when colds and flu were prevalent. I especially felt disappointed because I had planned to keep our first grandchild while our daughter worked part-time. The other grandparents became the babysitters, and I felt left out.

I wanted to be more active in our church. I wanted to have lunch with friends. I wanted to visit our grandchildren out of state, but began to realize these things were not going to happen with the frequency I had hoped.

There is the expense of replacing vaporizers, which run continuously in different parts of our home. And I am thankful my husband cleans them. The expense of switching to a Mediterranean diet. Food is more expensive. Lots of over-the-counter drugs. One ongoing expense is Navage with salt pods, distilled water batteries, especially since I use them 3 times a day.

[00:23:52]

Highlighted Survey Data  

Dr Griffith: I would like to look at the results of a survey and a focus group related to non-cystic fibrosis bronchiectasis. It was 18 patients in the survey, and 10 patients shared their experiences in a moderated online focus group. Just to highlight a few things, we have already mentioned that most patients are diagnosed after a significant period of time, but this is very important. 55% rated their understanding of bronchiectasis as either fair or poor, and only 6% felt it was excellent, and only 12% said treatments were working very well.

Just to pause 1 second, what I am struck with most from patients referred to National Jewish Health is the lack of understanding of what is bronchiectasis. What does it mean?

I am always surprised many of the patients have the belief that bronchiectasis is a terminal diagnosis, and are very relieved to learn that it actually, particularly in people with mild disease, does not affect life expectancy. However, having said that, I think it is extraordinarily important for the diagnosing physician to spend a little time explaining what bronchiectasis is, perhaps showing an example of it on a chest CT scan, and then working through the management of bronchiectasis.

[00:25:46]

Smart Patients: Actual Quotes for Better NCFBE Care  

These are a few comments by patients.

Another 1 that is frequently asked is, why did I get this? Most of these patients have never smoked, and they cannot understand why they are burdened with this incredibly inconvenient chronic disease.

[00:26:10]

Key Takeaways for Providers  

A few takeaways.

Patients with bronchiectasis have to understand that this is a chronic disease. It is not going to go away, and that they are going to have to deal with it in a long-term basis, and understand the financial and social burdens it places on them. Those sorts of things are actually underappreciated during brief clinic visits.

One other thing that, I think, is just as important as explaining the disease is discussing airway clearance techniques. The majority of people who come to National Jewish with a diagnosis of bronchiectasis have not been taught airway clearance techniques. Frequently, they are advised simply to go to YouTube and see what is available there.

I understand respiratory therapy is very difficult to come by, even in some urban areas. However, for bronchiectasis, there just is no replacement for adequate respiratory therapy and airway clearance technique teaching.

[00:27:22]

Risk Factors and Delayed Diagnosis  

So, why is the diagnosis delayed? Patients are frequently diagnosed with obstructive lung disease, either reversible or non-reversible. Frankly, it is often misdiagnosed as 1 of these obstructive lung disease phenotypes. As we have talked, you have to have radiographic imaging to make a diagnosis.

[00:27:52]

Current Management of NCFBE  

In terms of management, 1 other aspect of management that we frequently see is the use of inhaled corticosteroids. Usually, because patients are misdiagnosed as having asthma or some other bronchospastic disease. However, there is pretty good information that the inhaled corticosteroids potentiate the progression of mycobacterial disease. There is also underuse of inhaled antibiotics for Pseudomonas.

[00:28:30]

Stepwise Management Algorithm  

This is a proposed stepwise management algorithm for bronchiectasis patients. It was published a few years ago.

However, just a couple of important points is that anybody with bronchiectasis should be taught airway clearance. Now, it may prove to be ineffective. However, for the majority of patients, this is the foundation of management.

And then use of long-term anti-inflammatory medications like macrolides. And then with more advanced disease, treatment of Pseudomonas, treatment of non-tuberculous mycobacteria. However, this is essential. And unfortunately, as we have just discussed, it is unavailable to many physicians and their patients because of a lack of respiratory therapy.

[00:29:32]

Tailor Management to Phenotype/Endotype  

So, this is a nice summary of problems associated with bronchiectasis. And how you meet those problems with currently available treatment strategies.

I will point out that, as we talked about, those patients with eosinophilic inflammation may do well with some biologics. You have to be a little bit careful with those in patients with mycobacterial disease.

And with that, I want to close that portion of our talk and turn things over to my colleague, Dr Brett Elicker.

Radiologist Perspective: Imaging in NCFBE Diagnosis and Management

[00:30:17]

Dr Brett Elicker (University of California, San Francisco): Well, thanks so much. And it is great to be with you all today. I am a simple country radiologist from San Francisco.

And so, I am going to talk about and try to give you an approach to the imaging of bronchiectasis and the considerations when you see that on imaging. Let us just get into it.

[00:30:38]

Imaging Bronchiectasis: Classic and Inflammatory Finding  

As Dr Griffith mentioned, CT is very sensitive and specific for bronchiectasis. And the things that we are looking for are enlarged airways. And we are going to talk about the criteria for calling an airway enlarged. And of course, these are often associated with other signs of inflammation, which may be thickening of the wall, mucus plugging.

If you have involvement of the distal airways, you can see clustered central lobular nodules in tree-in-bud. And we will talk more about the sort of criteria for calling bronchiectasis on a chest CT in just a minute.

[00:31:14]

Chest Radiography: Low Sensitivity for Bronchiectasis  

And of course, chest X-rays are often obtained and are often the first test that is obtained. However, CT, the sensitivity of CT is way better than chest X-ray. And this is a patient with really a severe childhood viral infection that resulted 50 years later in very advanced bronchiectasis. You can see these kind of circular opacities with air fluid levels in them.

However, you are not going to see detect bronchiectasis on a chest X-ray until it is quite advanced. And after, you know, down the road when potentially treatment might have been effective early on in slowing the progression of disease. So, as Dr Griffith mentioned, have a low threshold for obtaining chest CTs.

[00:32:01]

Do You See a Difference?  

Now, of course, there are different diseases that affect different levels of the airways. And certain diseases tend to affect more of the large airways and other diseases tend to affect more of the small airways. And you are going to think about a different spectrum of disease depending upon which 1 is most affected.

And, of course, there is overlap. However, usually, certain diseases affect predominantly one or the other.

Large airways are what we are talking about today. Bronchiectasis, airways inflammation, mucous impaction. The findings of small airways disease are more clustered central labrinodules, tree-in-bud opacities, and bronchiolectasis where the airways are dilated very distally in the lung. And, again, there is overlap between the different causes of predominantly large airways vs predominantly small airways disease.

However, here is a list for your reference. So, for instance, this case on the right side of the screen with these small clustered central labrinodules is a case of advanced panbrochiolitis, which tends to be a disease that predominates in the distal airways. Whereas the disease on the other side, I think, as I recall correctly, is an immunodeficiency patient, which tends to be a large airways process.

Again, certain diseases tend to affect more of the large airways or more of the small airways. So the first question when you are seeing this is, what is the predominant size of the airway that is involved by the disease? And that helps you with your differential diagnosis.

[00:33:25]

High-Resolution CT and Role in Detecting Progression  

CT, very sensitive and specific. It is really a great test for detecting and characterizing bronchiectasis and the diseases that cause bronchiectasis. It is also, you know, obviously we get this often at the beginning, but we also do serial CTs over time to monitor changes.

What is happening? What is the direction of changes? Are the airways getting more dilated, or are we actually showing improvement in the degree of inflammation? Do we have worsening findings of inflammation or improvement? And then are there any other superimposed findings in patients with acute or more worsening symptoms? So a really good test to detect the initial bronchiectasis and then follow it over time and detect those changes over time.

[00:34:17]

Understanding the Different Types of Bronchiectasis  

So here is the deeper dive into what we call bronchiectasis on CT scan. The simplest is the bronch-arterio ratio. And that is just measuring the internal lumen of the bronchus, the airway, compared to the adjacent artery, which is right next to it.

And that bronch-arterio ratio classically in normal is less than 1. Definitively abnormal is greater than 1.5. And then there is this sort of gray area in between of 1 to 1.5. There are a couple of papers that actually show that normal people who are older, over the age of 60 or 70, and people who live at elevation, where Dr Griffith is in Denver, might have a bronch-arterio ratio normally between 1 and 1.5. In that gray area, you look for other findings to help you. Is there airways inflammation? Is there mucous impaction? Is there tree-in-bud?

So that is the simplest way. Now, obviously, some other features that we look at are this lack of tapering shown by the yellow arrows. You can see that airway as it is going out is actually where the yellow arrows are pointing. That is not tapering. It is staying the same size as it radiates out from the hilum. And that is abnormal.

And then the green arrows show very distal airways. And you can see that you should not really see airways that last 1 to 2 cm of a lung. If you do, there is probably some problem with the airways.

And this patient has bronchiolectasis and a lot of airways inflammation, that distal 1 to 2 cm of a lung. So these are the findings you are looking for on CT to find bronchiectasis.

Now, we want to distinguish, there are different types of bronchiectasis.

There is inflammatory bronchiectasis, which is the topic of today. And then there is traction bronchiectasis, which is merely a manifestation of lung fibrosis. That is not what we are talking about.

And traction bronchiectasis is seen in things like idiopathic pulmonary fibrosis or fibrotic hypersensitivity pneumonitis. So the goal today is to talk about inflammatory bronchiectasis. The airways are dilated, but they are also inflamed with a lot of mucous impaction, airway wall thickening.

Whereas traction, the airways are dry. There is nothing inside of them. They tend to be dilated, corkscrew-shaped. And you will see other findings of lung fibrosis, such as reticulation and honeycombing. So that is a very important decision point in terms of differential diagnosis.

[00:36:36]

Classifying Inflammatory Bronchiectasis Subtypes  

Now, there are also different subtypes of inflammatory bronchiectasis.

And the classic imaging descriptions of the airways that are dilated due to inflammatory bronchiectasis are cylindrical, varicose, and cystic. And that is in order of severity and chronicity. And the differential diagnosis for cylindrical bronchiectasis is really broad. You can just see that with acute viral infections occasionally.

The differential of varicose and cystic becomes more and more narrow because there is a limited number of diseases that produce both severe airways inflammation that lasts for years. And that is what it takes to get cystic bronchiectasis.

Again, the differential goes from being very broad for cylindrical and being much more focused for varicose and cystic bronchiectasis. Because the cystic in particular implies severe airway inflammation that lasts for many, many, many, usually years. And so once we have those more severe forms of bronchiectasis, we look at the distribution and associated findings in terms of thinking about the diseases that cause them.

[00:37:46]

Radiologic Distribution of Bronchiectasis by Underlying Cause  

Classic, we are not focusing on cystic fibrosis. However, the classic, we need to know what it looks like. The classic cystic fibrosis is symmetric and upper lobe.

The other big 1 that we deal with regularly is nontuberculous mycobacterial infection. That classically has a middle lobe lingular predominance. There are different subtypes or different manifestations of NTM, but this is the most common.

What we often see, collapse, partial collapse of the middle lobe and lingula. There is lots of airways inflammation, but there is very little disease outside the airways. So consolidation, typical findings of pneumonia, like a bacterial pneumonia, are not usually seen in these patients. And there is really very little else that does this. We have varicose and cystic bronchiectasis predominant in the middle lobe and lingula. It is almost always NTM, very specific.

And then there is a group of diseases that often manifests with symmetric lower lobe predominant bronchiectasis, including immunodeficiency, recurrent aspiration, primary cilia dyskinesia, which, I think, is underrecognized. And then we will talk more about in a second, longstanding constrictive bronchiolitis. So that is helpful.

Again, distribution can be very helpful in differential diagnosis.

[00:38:56]

Differentiating Various Causes of Bronchiectasis  

A couple other diseases to think about. Allergic bronchopulmonary aspergillosis tends to produce really dilated airways that are involved, that are right around the hilum. And they tend to be kind of not very extensive and diffuse, unless the disease is very severe. However, you see 1 airway over here, 1 airway over there, 1 airway over here, right around the hilum, really dilated and mucus impacted. We also tend to see high attenuation mucus.

The mucus is actually much denser than typical mucus because of, I think, it is something to do with how the calcium ions are accumulated in the aspergillus itself. And you can see when you treat this, often the airways inflammation gets a lot better, but the bronchiectasis may persist.

The other disease that you may see occasionally is cartilage disorders, particularly Williams-Campbell and tracheobronchomegaly. And while those are rare diseases, you want to find them and detect them. And they typically, they have a sort of characteristic appearance of the airways are very dilated and irregular, but they are pretty thin walled. And there is not a lot of mucus impaction. And that tends to imply some problem with the cartilage itself.

We see this also in patients with other inflammatory diseases that produce bronchiectasis that have been effectively treated. I think probably the most common we see this these days are cystic fibrosis patients with these targeted therapies. And once they go on the therapies, the mucus and airways inflammation gets a lot better. So it may look like this. However, if you are seeing some patient from the beginning who has significant bronchiectasis, but the airways are, there is a real paucity of inflammation, think about 1 of those cartilage disorders.

The last disease or pattern of injury I want to talk about, which I think is really under-recognized is constrictive bronchiolitis. And this is a great example of Cole's vicious cycle or vicious vortex.

My son's name is Cole. The other panels have heard this joke already, but my son's name is Cole. And for me, Cole's vicious cycle is he asked me for money and I give it to him, and he spends it. And then he has no money. And then he asked me for more money. So that is the cycle that I think about.

However, anyway, so Cole's vicious cycle in constrictive bronchiolitis, you have scarring. Constrictive bronchiolitis is scarring around your distal airways. Occurs in a variety of different causes, but 1 of the more common ones is childhood viral infection and frequently adenovirus.

That scarring prevents you from ventilating well. And it takes a lot of pressure to ventilate. And I think the theory is you are trying to ventilate through the obstruction of your distal airways, and then that starts to affect the large airways, actually. So that large airways disease becomes worse. Those large airways start to balloon out and get more and more inflamed. And you enter that vicious cycle. So this is an example of rheumatoid arthritis with constrictive bronchiolitis. And you can see baseline, the lung density just looks sort of heterogeneous. However, over time, you start to get bronchiectasis. And that may become quite severe over usually decades. And so this is 1 potential cause of bronchiectasis, and 1 to think about, particularly in patients when they have this sort of evolution on CT over time, and with a history of childhood viral infection, rheumatoid arthritis, Sjögren's disease, things like that.

And then, of course, I think it is really important to get expiratory CT at least on the first CT scan you get in suspected bronchiectasis. Because this can really improve your sensitivity for diseases or patterns like constrictive bronchiolitis. And so we have found that adding expiratory CT increases your sort of yield for finding airways disease by about 10-20% in that range. So it really does improve your detection of airway obstruction.

And obviously, air trapping is often a finding of small airways disease. However, you can sometimes see it with large airways disease as well. And here is a sort of table of the different causes of airways disease, and some of the most common findings that we are going to look for, and some of the characteristic appearances of those causes of bronchiectasis. We have gone over all of these basically already.

However, this is just here for your reference.

[00:43:30]

Importance of Early Imaging Diagnosis, Correct Method, and Follow-up

And again, so I think CT is really sensitive for detecting airways disease, both small and large airways disease. And also really narrowing your differential diagnosis using a combination of the findings of the airways disease themselves and the pattern of those findings within the lungs.

And as Dr Griffith said, have a low threshold for getting a CT with suspected airways disease. It allows you for earlier detection and intervention, which actually really the trajectory of these patients changes significantly once you have found it or are able to treat it. I think in terms of protocols for high-resolution chest CT, we want thin sections, at least 1.5 mm or smaller. We do usually 2 series, 1 with full inspiration, 1 with those expiratory images. And I would say these days the majority of our chest CTs are at this slice thickness of 1.5 mm or less. So a standard non-contrast chest CT in most places is just as good as a high-resolution chest CT. The only thing high-resolution adds is the addition of the expiratory images.

[00:44:19]

Collaborative Imaging Approach  

So radiologists are important, hopefully, in detecting this and in being a part of this really multidisciplinary approach to these patients with suspected airways disease.

With that, I think I am going to turn it over to Dr Anne O'Donnell, who is going to finish off. So thank you very much.

NCFBE Treatment Strategies: Latest Advances and Personalized Management

[00:44:40]

Dr Anne O'Donnell (Georgetown University Medical Center): Great. Thank you, Brett, Dr Elicker, Dr Griffith for leading us off here and for the organizers and for everybody attending. So I am going to cover treatment strategies, the latest advances, and some personalized management of bronchiectasis.

[00:45:02]

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.

[00:45:53]

Therapeutic Strategies for Mucociliary Dysfunction  

And so a big part and 1 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 1 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 like Acapella or Aerobika, 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.

[00:47:42]

[VIDEO]  

Speaker: After my diagnosis with bronchiectasis, I was put on antibiotics and an albuterol inhaler. I could not get the phlegm up when I coughed, so I would lie across the bed leaning over the edge and my husband would pound on my back. It was a bit frightening because I could not get my breath.

And later the pulmonologist told me if phlegm was choking me, I could come into the office, and they had a machine that would help loosen and remove mucus buildup. Also, I am thankful to see my doctor routinely. If I have a flare-up, he sees me the same day.

And if I have a problem over the weekend, they have a pulmonologist on call. I do not have to go to the ER.

[00:48:28]

Chronic Airway Infections: P. aeruginosa  

Dr O'Donnell: After you have, you know, I am not going to say indoctrinated, but 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.

[00:49:54]

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 vs 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.

[00:50:47]

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.

[00:51:46]

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.

[00:54:00]

Strategies to Prevent Bronchiectasis Exacerbations  

So really, again, another important take-home message today is the importance of, number 1, 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 3 or more exacerbations a year have a worse prognosis, but really, probably 1 or 2 are still significantly bad as well. However, really, from our guidelines, 3 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.

[00:55:45]

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.

[00:56:12]

Brensocatib in NCFBE: ASPEN Study Design and Baseline Characteristics  

And then the next study, the Phase III trial, which was just published April 24th of this year in the New England Journal, the ASPEN study. This again looked at 2 different doses of brensocatib vs placebo.

And what it showed was in patients who were having 2 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.

[00:57:13]

[VIDEO]

Speaker: Inflammation has never been raised by my pulmonologist. I did not even know bronchiectasis was rare until the Smart Patients focus group. I was simply treated with meds and continued to be monitored regularly in X-ray.

And even though the link between Sjögren's and bronchiectasis was made in 2010, I do not think my older pulmonologist knew. It was in the Smart Patients focus group that I learned there needs to be a paradigm shift in the way bronchiectasis is treated. Of course, this will mean the development of new drugs, which means funding, and that is so often limited with rare diseases.

I told my NP about the focus group explaining the role of inflammation in bronchiectasis, and he suggested that perhaps my frequent sinus infections, currently I have had 1 for 10 months, could be treated with a steroid sinus rinse, mometasone, added to my distilled water once a day, and my Navage nose cleaner. A compounding pharmacy would make the powder with anti‑inflammatory properties. It is something worth a try, and I appreciated his thinking outside the box.

The antibiotics have not brought about any improvement, and I know it has been frustrating for him because he cares about his patients, and he wants them well. The sinus drainage has caused me to cough, and it has been painful to bring up the phlegm. It made me feel sick, so I decided to use Navage treatments 3 times a day instead of once.

[00:58:43]

Dr O'Donnell: I think that the patient obviously points out the comorbidity issue. We do not have time to discuss that extensively, but treating the associated infections and sinus drainage certainly has a role here. We really want to deal with preventing more structural lung damage in our patients by the therapeutics that we just discussed.

[00:59:07]

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.

[01:00:04]

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.

[01:00:24]

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.

[01:00:47]

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.

[01:01:12]

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.

[01:01:38]

Patient Case 1: 50-Yr-Old Female  

Okay, we are going to go back to some questions.

Here is a patient case that you are going to vote on, 50-year-old female. Actually, we are just going to discuss this case.

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 already saw that, and we send the patient for a CT. And you can see 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. And you can see 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.

You can see in the middle lobe there is some partial collapse there, but yes, pretty typical.

Dr O'Donnell: And this is 1 kind of patient that sometimes really the bronchiectasis can be almost reversed with appropriate treatment of the ABPA. So really important to recognize this. Thanks.

Okay. 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.

[01:03:45]

Posttest 1: How confident are you in your ability to educate patients about the disease process, prognosis and treatment options for non-cystic fibrosis bronchiectasis?

All right, now we are going to do the post-test. So how confident are you now in your ability to educate patients about the disease process, prognosis, and treatment options for bronchiectasis to CF?

Great. So I think we made some good headway. Thank you.

[01:04:19]

Posttest 2: 65-year-old patient with bronchiectasis and chronic Pseudomonas infection, having frequent exacerbations despite guideline-directed therapy, which includes in this patient macrolide use and airway clearance. Based on what you just heard about the ASPEN trial, which of the following answers best characterizes the effect of brensocatib in patients like this?

This is a 65-year-old patient with bronchiectasis and chronic Pseudomonas infection, having frequent exacerbations despite guideline-directed therapy, which includes in this patient macrolide use and airway clearance. So based on what you just heard about the ASPEN trial, which of the following answers best characterizes the effect of brensocatib in patients like this?

1. Brensocatib reduces exacerbations across subgroups;
2. Is only in Pseudomonas patients;
3. No change in exacerbations, but improved quality of life; and
4. Decreases the severity of exacerbations but not the frequency.

So go ahead and vote.

[01:05:18]

Great. So the majority got the correct answer that bronchiectasis consistently reduced exacerbations across subgroups, not just in Pseudomonas patients. It did have a trend towards improving quality of life, but the bottom line, most important primary endpoint was the reduction in exacerbations.

[01:05:46]

Posttest 3: A patient with bronchiectasis with greater than 3 exacerbations, chronic Pseudomonas, elevated neutrophil elastase, worsening bronchiectasis on imaging. The patient is on inhaled antibiotics and adherent to airway clearance. Eosinophils are normal. Which next step best aligns with the patient's treatable traits and disease mechanism?

And posttest 3: A patient with bronchiectasis with greater than 3 exacerbations, chronic Pseudomonas, elevated neutrophil elastase, worsening bronchiectasis on imaging. The patient is on inhaled antibiotics and adherent to airway clearance. Eosinophils are normal. And then which next step best aligns with the patient's treatable traits and disease mechanism? So for this patient, would you:

1. Add an inhaled corticosteroid;
2. Begin a long-term macrolide; or
3. Rotate empiric oral antibiotics?

[01:06:34]

All right. So the majority voted for macrolides, and that is definitely the answer. We do not want to use inhaled corticosteroids in patients routinely with bronchiectasis, and we do not want to rotate empiric oral antibiotics.

I think we are going to just get these questions done, change in practice, and we are going to, I believe, move on to the Q&A.

Q&A

Dr O'Donnell: So Dr Elicker and Dr Griffith, I know a question that came up earlier is: What dose of azithromycin do you usually use if you are going to use a macrolide strategy? Dr Griffith?

Dr Griffith: Yes, Anne, I use 500 ml 3 times a week.

Dr O'Donnell: And use azithromycin, right?

Dr Griffith: That is correct.

Dr O'Donnell: Yes. Most patients can tolerate that quite well, so that is good. Here is another question for Dr Griffith. When do you do bronchoscopies in patients with this disease?

Dr Griffith: Well, we rarely do bronchoscopies at National Jewish Health. The most common reason is when we have a diagnostic dilemma. If we think maybe it is mycobacterial disease, we are not sure if it is fungal, those are generally the conditions. Now, in terms of following patients on therapy, we rely very much on induced sputum, both when patients visit us and at home.

They are all using hypertonic saline for airway clearance, and it is unusual for someone just to be completely unable to produce a specimen. So I guess it happens occasionally, but it is not something we depend on.

Dr O'Donnell: Yes, I think, in regular pulmonary and ID practices, it is a bit more challenging, right, than the resources at National Jewish. And we do a lot of trying to get patients to do it at home, either induced with hypertonic saline. I actually was on a patient conference yesterday, showed them a huff coughing video for sputum induction. So I think there are ways to get the sputum out of the patients, as Dave says.

Just back to the macrolide thing, Dr Griffin, if you would not mind saying how long do you keep patients on? If you go the macrolide strategy, do you do it forever, or how do you decide?

Dr Griffith: Yes, as far as I know, it is open-ended now. With things like brensocatib on the horizon, it may be that something like macrolide for immune modulation could be stopped. However, no one knows.

And frankly, I do not know that anybody is interested in doing that study. However, I am trying to think of a persuasive reason to stop the macrolide other than allergy or severe side effects. However, if the patient is benefiting, I do not know of a reason to stop it.

Dr O'Donnell: Yes, I think that, of course, the studies were 1 year, but I think we all do that. If the patient benefits from it, we keep it going, as long as they do not develop a problem. I usually give patients at least 3 months on macrolides to see if it is going to help them, 3‑6 months. So that is another issue.

I think another quick question: Is there any alternative to macrolide? I know people ask about doxycycline as an alternative, but that does not have the same anti-inflammatory effect, I would say. And so we are hoping that these newer drugs that are coming down the pipe are going to have a role there.

I think we are almost out of time, but here is 1 other good question. Is there any way to prevent bronchiectasis if patients are at risk?

Dr Griffith: Yes, that is such a multilayered question because we do not know what the form frost of bronchiectasis is in most of these patients when it starts and how you detect when it starts.         I mean, it is an extremely difficult problem. You cannot go around doing high-resolution chest CT scan on every young woman with Sjögren's syndrome and doing them consecutively until they manifest themselves.

So having said that, I guess the short answer is no. I do not know of a way to prevent it unless, Ann, if you can think of a specific example or examples.

Dr O'Donnell: Yes, no, but Dr Elicker, maybe comment on this because, you know, people are getting CTs for so many reasons other than symptomatic cough, right, and lung cancer screening, cardiac CTs. We see a lot of referrals for that. We really should probably look into this a little bit more, the kind of asymptomatic radiographic bronchiectasis.

Dr Griffith: Yes, I wanted to mention that Dr Elicker was being humble. I mean, I do not know what percentage it is, but it is a very high percentage of people diagnosed now are via radiology and radiologists, just like you said, because they want a cardiac calcium score and then the bottom of their lungs get scanned, and they have bronchiectasis.

Dr Elicker: We actually got a comment from 1 of our referring providers about how we over-call NTM too often. However, I would argue that we find it in patients who have no to minimal symptoms, and then you can follow them and make sure that that does not progress. So I think it just shows you the sensitivity of CT, I think, for detecting early disease.