AMCP Podcast Series - Listen Up: Bronchiectasis - Drs Kamelhar and Devarajan

Fred Goldstein  00:01

Hello and welcome to the AMCP Podcast Series. Listen Up as we take a deep dive into the challenges, trends and opportunities in managed care pharmacy, follow the show's social hashtag at #AMCPListenUp. And to learn more about AMCP visit amcp.org. I'm your host, Fred Goldstein. On today's episode, my guests are Dr. David L. Kamelhar, Clinical Professor of Medicine Division of pulmonary critical care and sleep medicine at the NYU Grossman School of Medicine. And Dr. Sunjay Devarajan, assistant professor of internal medicine, pulmonary critical care at the Baylor College of Medicine. Welcome doctors Kamelhar and Devarajan.

Sunjay Devarajan  00:40

Great to be with you.

David Kamelhar  00:41

Great to be with you.

Fred Goldstein  00:44

Fantastic. Why don't we begin with you Dr. Kamelhar? Can you define bronchiectasis and the difference between bronchiectasis and COPD?

David Kamelhar  00:51

Yes. So I'll give that a try. First of all, I want to thank you for inviting me to participate in this conference, especially with the you know, honored colleagues I am with.It's hard to keep a lot of these conversations brief, so we'll try to be comprehensive. The discussion today is really non cystic fibrosis bronchiectasis and that we somewhat arbitrarily separate from CF bronchiectasis, so bronchiectasis. The definition has certainly evolved since it was first described clinically by Laennec and microscopically by Lynn Reed in terms of thickness of bronchial walls and so on so forth. But more recently, by its radiographic characteristics, since the development of CT scans and of course more recently high resolution CT scans. The often cited review by Flume et al in 2018, article in Lancet, find bronchiectasis as chronic, progressive respiratory disorder characterized by irreversibly and abnormally dilated or wide airways, excessive sputum production and recurrent pulmonary infections. So this definition has anatomic features, radiographic features, clinical features and prognostic features expecting it to progress over time. We who see bronchiectasis on a regular basis, know that bronchiectasis includes a range of features, including these and in terms of radiographic specifically because radiographic CT scans are the portal to the diagnosis of bronchiectasis without which you really can't make that diagnosis. Range from mild cylindrical to varicoid to cystic. And in explaining these concepts to patients. I make the analogies to varicose veins that start off his little squiggly lines and somebody's leg and end up as big green pipes over time, because it does progress. And as it does progress, it becomes clinically relevant and shows an insufficiency in the function of what veins do in comparison with bronchial tubes do and bronchial tubes are there to conduct air and clear secretions and clear bacteria. Now, chronic obstructive pulmonary disease is defined by the gold criteria published in 2023. As a heterogeneous and this is their specific definition, a heterogeneous lung condition characterized by chronic respiratory symptoms dyspnea, cough, expectoration and or exacerbations due to abnormalities of the airways including bronchitis,  and bronchiolitis and or  of the air sacs or alveoli, including emphysema that cause persistent often progressive airflow obstruction. And what is noted is there's no mention of etiology, such as cigarette smoking or any other or any other criteria of how it got there. But these are very specific criteria. And of course, now we know we see more and more see bronchiectasis, together with chronic obstructive pulmonary disease, and if you think about the definition, including infection, airflow obstruction, exacerbations; there's a lot of overlap with bronchiectasis. So in I think it's important to mention the now increasingly recognized and emphasized notion of an overlap syndrome and in 2018, Polverino et al and the European bronchiectasis group EMBARC defined and overlap syndrome in patients who have COPD and emphasize certain criteria that they call ROSE R O S, E. So R for radiographic evidence of bronchiectasis O for obstruction on PFT s, meaning FEV one over FEC of less than point seven which are the classic COPD definition S for symptoms, and E exposure to 10 or more years of cigarette exposure. So that's how we try to separate how much of which is which. And in in the EMBARC group, they studied close to 17,000, bronchiectasis patients, and they found that well over 4,000 of them were assigned as having COPD as well. So we just want to make sure that when we have a conversation about differentiating one from the other, that always bear in mind In that there may be an overlap. And it's something that we're recognizing more and more and we're getting to even think, think of these things in terms of treatable traits, which is a term we'll come back to in our clinical management in terms of sputum production is in common and airflow obstruction is in common, and treat these entities for their commonality. And not necessarily for what makes them different. So it's not an either or, it's sometimes an and. So I hope that helps to clarify a little bit of an overlap syndrome as well. Yeah, thanks for that definition. Dr. Kamelhar. And when we look at this illness within the larger healthcare system, what's the prevalence of bronchiectasis and the associated costs? So non cystic  bronchiectasis was felt to be not all that long ago an orphan disease, which is defined as less than two in 1,000 Americans being affected by it. The NIH in 1997 to 2007 conducted a 10 year review of the prevalence of bronchiectasis; how many people in United States of America had bronchiectasis at a given time. And they looked at Medicare recipients. And the numbers that they came up with are not as important, because we have newer numbers. And I'm going to quote, Sunjay's article in a second. But what's been noticed and noticed over time, and I think there's a take home message, that we're noticing it more and more over time that every article, that's every review that's done shows that the prevalence is greater than it was in a five year or 10 year interval before and that with age, the prevalence increases as well. And one thing that hasn't gone away to my knowledge yet is that women are more than men. So, again, I will quote the article that Journal of Medical Economics led by Dr., colleague, Sunjay, that among persons, that non cystic fibrosis bronchiectasis is now recognized as the third most common respiratory disorder after asthma and chronic obstructive pulmonary disease. That's a striking statement number one, number two, among persons aged 18 to 34. Non cystic fibrosis bronchiectasis has an incidence of 4.2 per 100,000 people. And by the age of 75, it's 271.8. That's, that's logarithms greater per 100,000. And it's estimated that between 237 and 431 thousand adults in United States have non cystic fibrosis bronchiectasis. Finally, these numbers are important, in addition to being somewhat staggering, is we know that the current literature shows that patients with this bronchiectasis have an increasing risk for all cause mortality, right, not just from their lung disease. As far as the cost goes, the cost can be broken down into several groups, there's the maintenance costs, such as the sodium chloride that they use for the nebulizer, perhaps the chest PT, you may want to move that up to the cultures that they do from time to time, cost of nebulized antibiotics and formal chest therapy. And when you get past that, then you talk about intravenous medication, hospitalization, and hospitalization has been shown to be two thirds of the cost of maintenance of these patients. Last but not least, I want to be specific, it's long been said that Pseudomonas is a particularly bad prognostic factor for patients who have bronchitis. For those patients do worse than the general bronchiectasis group. And if you compare, correct me if I misquote this, please, of the author, that if you compare patients  with Pseudomonas have who are hospitalized with not pseudomonas, who are not hospitalized, the differences $179,000 per patient year is that that I say that right?

Sunjay Devarajan  09:01

Okay.

David Kamelhar  09:02

So that's, that's a staggering number also. So, you know, we can have a whole conversation about Pseudomonas and why it's that way, and so on. But this disease can become burdensome for patients clinically, burdensome in terms of their life expectancy, and burdensome for how it affects the economy and all the rest of us. And we'll talk in a minute about the importance of the important the importance of the maintenance program and prevention of these exacerbations.

Fred Goldstein  09:33

That's a fantastic overview and introduction. Thanks so much Dr. Kamelhar,  Kandahar, and you kind of lead us right into the next area, which is, you know, the experience of persons living with this disease, with bronchiectasis. So Dr. Devarajan, can can you talk about bronchiectasis and living with it? And what about this term called Vicious Vortex? What is that?

Sunjay Devarajan  09:53

Yeah, happy to discuss the symptoms. There can be like, like many other disease states, in the pulmonary sphere. There can be a lot of variability to what patients experience on a day to day basis but with clinically significant bronchiectasis. The most common symptoms you're going to see are pulmonary in nature, right? So it's going to be potentially a chronic cough that may be associated with sputum production that may be green, yellow sputum production may be clear. They may get associated wheezing, and breathlessness and then you have patients that experience only breathlessness alone, when I start to worry is when they start experiencing more systemic symptoms like weight loss, loss of appetite, night sweats, because it might indicate that there's something more serious going on besides bronchiectasis, but which may be related to the bronchiectasis that they have. So suffice it to say, the symptoms can exert quite a bit of impact on someone's quality of life. But importantly, for not only pulmonologists to know, but even primary care physicians to know is that the patient experience can be variable, but are primarily characterized by cough and sputum production. And right, who does this affect? Dr. Kamelhar already sort of alluded to this, but it's more common in women. So if you do, prevalence studies have demonstrated that maybe in the overall population, about one and a half percent of women in the United States have bronchiectasis, and that's about 1.1% in men. And it's important to know that the prevalence is rising. And part of that is just going to be better diagnostics, right. Our imaging processes have gotten better, they're more details that give us more granularity to what's going on in people's lungs, and they can rule in even mild bronchiectasis better than 20 or 30 years ago. But we also feel that there's probably more prevalence of some of the underlying disease states, like immune deficiency and autoimmune disease, for example, that might actually be contributing to increased prevalence in the population. You mentioned the Vicious Vortex. Well, it used to be called the Vicious Cycle as as coined by Cole. But I think there's two reasons why we've transitioned to Vicious Vortex. One is, human beings love alliteration. So Vicious Vortex sounds more fun. But the other bit is that I think that the Flume paper that Dr. Kamelhar had mentioned, did a really nice job of explaining why this is more complex than simply a cycle, it can actually create a milieu, which is really inflammatory and dangerous for patients that leads ultimately to the bronchiectasis, which is that remodeling and the dilation of air passages that you see. I'm happy to go into the Vicious Vortex to give you an idea of the components if that works.

Fred Goldstein  12:35

Yeah, please go ahead.

Sunjay Devarajan  12:36

Yeah, so you know, I try to tell patients, you know, they always want to know why, why me, what what exactly was it about me, that allowed this to happen. And I tried to tell them that it's, it's oftentimes a chicken and egg problem, which is to say that, you know, you can have a primary infection. So in the developing world, one of the most common causes of bronchiectasis is primary tuberculosis. So we've got great data out of India, the Indian registry, which demonstrates that, and it could be old pneumonia, even even childhood or pediatric pneumonia could sort of create scarring and bronchiectasis  that carries on into adulthood. But there are many, many other reasons, but usually need some kind of inflammatory trigger. And we're going to talk a little bit about the neutrophil involvement, but often that inflammation is a neutrophilic. inflammation, which can be a bacterial pneumonia, for example, and that pneumonia, can cause a structural damage to the lung. And you can see these air passages, which really should be as the lung sort of tapers out to the edges of the chest wall, those little air passages should get smaller and smaller in a normal situation. And that gets kind of turned on its head when somebody gets a big inflammatory injury, where these air passages get really dilated. And what happens is when you get that dilation, that net structural change, the normal cough reflex, and the clearance that we rely on starts being compromised. So you start seeing clearance problems, you see more stagnant mucus in these airways. And the lungs are very kind of heated, humidified environment, you start introducing mucus into that, and bacteria just love hanging out in there. And it could be beyond bacteria. It could be it could be fungal disease, it could be atypical bacterial infections, like mycobacterium, for example, that can sort of colonize those spaces. And then that infection in turn leads to further inflammation and you get into this Vicious Vortex cycle. So really, I think about it as inflammation and infection sort of inform each other. So because of this complexity, you can, as Dr. Kamelhar is going to talk about, you can see why it's simply throwing antibiotics, for example, is not going to necessarily solve your problem because that those antibiotics may deal with the after effects of the inflammation and the structural disease by getting at the bacteria that are in there. But it doesn't really get to the underlying problem, which in many cases is inflammatory. It's the same reason why  steroids you know which reduce inflammation, don't always, they might give you a little bit of temporary relief, but it doesn't get rid of the bacteria, for example, and it may actually increase the risk for bacterial development in a bronchiectatic lung. So those are sort of the components of the Vicious Vortex and this is why bronchiectasis , non cystic fibrosis bronchiectasis is such a complex problem to tackle.

Fred Goldstein  15:21

So moving back to you, Dr. Kamelhar, can you provide insights into these issues of exacerbations and permanent lung damage, and then perhaps get into some treatment options and other approaches.

David Kamelhar  15:31

So again, we we go back and forth and cover some of each of those topics. But I think the conversation that you just heard very carefully explain why we are concerned about lung damage that occurs from these repeated episodes of inflammation. We know that lung damage can occur certainly from any form of inflammation. And certainly as patients move on in their disease, they're more likely to be colonized by damaging organisms such as Pseudomonas and the non tuberculous mycobacteria. In the life. We certainly know very well that disease progresses there's a great bar graph from Greg Tino going all the way back to 2004, which I still like to show with with pink and blue bars, that when you get past your into your fifth and sixth decades that the slope of the curve of the line that connects those bars increases significantly. And while it's the demographics, its a prevalence chart, one can think of it as being any individual patient that moves on over time. So really, when you want to avoid exacerbations, you really want to minimize symptoms now, including cough, sputum, wheeze and full out acute exacerbations with the patient's being ill you know, as was referenced of not feeling well, fever, weight loss and the like. So you want to minimize symptoms. Now, you want to prevent exacerbations that may require antibiotics, oral, intravenous, and the like and hospitalizations, and no less important than that, so your doing it for now and you're doing it for later. Now, as was pointed out, also, understanding one of the premises of the microbiology of this entity makes us better understand why old school use of rotating antibiotics, you know, the terms of the unapproved treatments and un effective treatments. In the old days, the treatment for this was rotating antibiotics. You take one antibiotic in January one in February, you take an antibiotic the first week of every month, and so on. And we know that that does not solve the problem because you're never gonna get rid of the bacteria. Now, just a word about an important concept of the microbiome, that it's been shown that patients always want to understand, and we want to understand as well, we're finally starting to understand why is that if you do a culture, when the sputum turns more green, and they get sick, and you do a culture that comes back with normal flora, so how is that possible? It's if it's the same bacteria was have, why is it that I'm sick? And the answer is that you have a distribution as normal heterogeneity of bacteria, a distribution of bacteria, between the various bacteria and if that even distribution becomes disturbed, then all of a sudden, you're 80% haemophilus, or 80%, Streptococcus pneumoniae or 70% of Klebsiella, or anything else, instead of the normal distribution, that you will be sick, you'll have the same organisms isolated, and these organisms are always there. And it's very unlikely you're going to obliterate them. So the best you could possibly do is to try to keep the airway as clean. And as you tell patients clean, begets clean. So the cleaner you get the clean it stays. Unapproved treatments that people try and we'll come back to what I think is more effective, these rotating antibiotics. People use steroids, inhaled corticosteroids. People go to salt caves, vitamin supplements, some people are big believers in an acetylcysteine. But our approach really is that approved treatments the way we think about managing, bronchiectasis is that it's a management topic. It's a multidisciplinary disease. It's a multidisciplinary disease, and you have to involve other specialties, which we'll talk about in a minute. Number one, number two, there's no one size fits all, that works for one does not necessarily work for the other. That you try to and we're trying to do better about this, you know, different subtypes, endotypes of illnesses, bronchiectsasis. That perhaps the patient that's colonized and always carries Pseudomonas is different from the one who always has Staph is different from the one who always has Haemophilus, and we should be thinking about them differently going forward. And finally, whatever, whatever thought you have in anything you ask the patient to do is patient education and patient buy in is pivotal, because this is not take your antibiotic and feel better. It's really the patient who does the heavy lifting who has to do all the airway clearance every day and regularly. And when you stop doing it, then you stop doing well. So we think about preventative entities, such as checking your swallow, checking your esophageal function, we know that people with either of those, both of those and they often go together will alter the microbiome, the bacteria that live around their upper airway and get into their lower airway. And even if they don't frankly, aspirate meaning material going into the lung, they will get infections. So we always that's entry level evaluation of patients with that disease, chest therapy, oscillatoria devices, flutter valves, acapella valves, aerobicas nebulized hypertonic saline 7% ideally 3% If they don't tolerate it, hands on chest therapy with old school vibration, percussion vibration vest, and some combination thereof. This is just a foundation without which patients is a rule don't do well and which one works for patients something you have to work at. We strongly believe in having a nutritionist that patients who are not have adequate nutrition should be encouraged and we were lucky enough to have a full time nutritionist on the bronchiectasis, bronchiectasis MTM group with us who patients adore and really doesn't make a difference. We have routine stuff get your get your vaccinations, get the pneumococcal vaccines anti haemophilus  vaccines if you're a haemophilus person with no antibodies, you want to track them. Periodic scans, sputum cultures. AFB cultures, fungal cultures, patients can turn to, change their stripes and all of a sudden become an Aspergillus person. You want cardio type exercise, pulmonary rehab, you know there's some overlap there but even patients who don't need rehab, in addition to their chest therapy, they really do need to do some treadmill, Stairmaster and the like. Once you move past that, nebulized antibiotics and some of the more experimental or other anti inflammatories which I think we'll hear about and I don't mean to, to double dip in that and if I cover it, you know, interesting azithromycin is an anti inflammatory phage therapy for Pseudomonas, biologics for the Type 2 eosinic inflammation of bronchiectasis, all these are things which are becoming of greater and greater interest, terms of treatments for for aspects of this heterogeneous entity called non cystic fibrosis bronchiectasis, which we're learning more about almost logarithmically with time.

Fred Goldstein  22:56

Excellent, comprehensive for sure Dr Kamelhar, thank you so much. So Dr. Devarajan, can you discuss this issue of neutrophilic inflammation that was mentioned a couple times?

Sunjay Devarajan 23:07

Yeah, let me just tell Dr. Kamelhar, I thought that was a fantastic sort of explanation of how complex management of these patients can be. But yes, let's see, let's pivot to talk about neutrophilic inflammation. And this has been a real in the last 10 years has been a real focus. And there's been just a number of great studies put out in the literature that that focuses on this subject. So neutrophils, you know, for the folks who are new to this, you know, consider them as it's a really, it's a white blood cell that it's one of your earliest defenses against, usually bacterial pathogens. And in this case, it's going to be airways that we're talking about in the air passages. So, think about, if you have develop a streptococcus pneumonia, what's going to end up happening is that bacteria is going to basically enter the lung tissue. And these Neutrophils are going to be via the immune system traffic to these areas and create inflammation. And the way they do that the way these neutrophils do this is that they have these toxic granules inside and they release these in basically a matrix. It's called a neutrophil extracellular trap or a NET. And within this matrix, you get something called neutrophil elastase, which is a a protease. It's basically an enzyme that is produced by the neutrophils, to destabilize and destroy bacteria that are in the path. And so it's, it's the way our body sort of deals with firstline against bacteria. And this has been a real focus because there's been some interesting proteomic study showing that these NETs these neutrophil extracellular traps, and that associated proteins are very abundance and their, their level, their secretion level, the more they're secreted, the more strongly they are associated with severity in bronchiectasis. As a matter fact, there was a there was a study, kind of a more basic science study that was came out of Scotland, where they looked at 430 patients with bronchiectasis, and they actually measured the neutrophil elastase level in these NET complexes within the sputum. And basically, higher concentrations of those NETs, basically, conferred higher bronchiectasis severity index scores. That's a very important skill that we use in this field to determine how severe submitted bronchiectasis is, those patients with higher levels had higher dyspnea scores, they're more short of breath. They had increased lung function abnormalities and on radiologic studies like CT scan, they had worse disease. The level themselves is also associated with increased bronchiectasis exacerbations, and was also those patients were also more responsive to treatment with antibiotics. And there's also a very interesting study that Dr. Chalmers, David Chalmers is associated with, which actually looked at how these Neutrophils are behaving in patients with bronchiectasis. And this is sort of all comers with bronchiectasis that were included in the study. And they found something really interesting, which is that these neutrophils were expressing and people with bronchiectasis, were actually expressing much higher levels of neutrophil elastase. And essentially, they were more their breeding program, they were surviving longer than they were supposed to. They were hanging around longer than they were supposed to, and causing more intrinsic lung damage in, in the face of bacteria. So it could be a process that sort of begets itself, more inflammation actually leads to further and more severe inflammation in the air passages of people with bronchiectasis. And this is all neutrophil mediated. So really, really interesting topic that we've learned a lot about of the last 10 years. And it's a big focus of clinical research and bronchiectasis right now.

Fred Goldstein 26:42

You know, so given the significant involvement of neutrophilic, inflammation, creation and progression of bronchiectasis. Is there anything that targets that?

Sunjay Devarajan 26:50

Yeah, that's a great question. I think it should be it should be noted that there are actually no FDA approved treatments at all, for non cystic bronchiectasis. For non cystic fibrosis bronchiectasis rather a lot of the treatment that Dr. Kamelhar mentioned. A lot of that comes from best practices. So consensus statements, and ultimately the cystic fibrosis literature. So we're sort of borrowing from the disease, that it's not exactly the same. So unfortunately, we don't have any FDA approved treatments, but there may be some promising treatments out there that actually specifically target neutrophilic inflammation. Specifically there's a novel medicine called brensocatib, which is a, it's an oral inhibitor of Dipeptidyl Peptidase 1 or DPP-1. And this is basically an important protease that's involved in neutrophil elastase activity. And there have been a e of very interesting studies that have been completed one, which was a phase two study was published in New England Journal of medicine a few years ago. And that included patients who had two or more exacerbations in the year prior and had bronchiectasis, and it looks like they had a couple of doses that they that they tested were the time to the next bronchiectasis exacerbation was was better in the treatment group and that's led to this Phase III study called the ASPEN study, which recently closed there was a press release that came out about that a couple months ago, which states that their primary endpoints were achieved in that study using this drug, brensocatib. And the primary endpoint was reduction of exacerbations in people who have bronchiectasis. So this is something that’s not published. But it's something that I know Dr. Kamelhar and I are probably very excited to read and look through, because there are some adverse effects that that are possible with this drug because it does suppress the immune response to some degrees. So we want to make sure that there's no signal towards increased risk of infections, gingival disease, that type of thing, but at least in the press release, it didn't seem like anything concerning, no  concerning signal in that way. But I think this could be a really big advancement in bronchiectasis, given that the tools that we that we use now are not specifically approved for non cystic fibrosis bronchiectasis.

Fred Goldstein  26:42

Would you like to add anything that Dr. Kamelhar?

David Kamelhar  29:13

No, I think, you know, one of the last points that was made, really goes back to the to the long-term issue and that is preventing, you know, going forward and damage and a downward curve of the disease. So, you know, again, it's, it's keeping you good for now, and preventing exacerbations, but I think no less important. I'm not sure how well that's been studied in any of the sub studies in the brensocatib group. In terms of them, it's too early to say in terms of long term survival and if you decrease that inflammation from the neutrophils, there should be less damage to the airways and less downward trend trajectory of the disease.

Fred Goldstein  29:55

Fantastic well I'd like to thank you, Dr. Kamelhar, and Devarajan for joining us today. and discussing this important topic

David Kamelhar  30:02

was pleasure.

Sunjay Devarajan  30:03

Yeah, so nice to be with you. Thank you for inviting us.

David Kamelhar  30:05

Thank you.

Fred Goldstein  30:07

And thank you for joining us today. If you liked this show, you can find all our episodes at amcp.org/podcast on our show page at HealthcareNOWradio.com. Or on your favorite listening platform by searching Healthcare NOW Radio. You can follow our shows social hashtag at #AMCPListenUp. And don't forget to share, like and follow AMCPorg on LinkedIn, Twitter, Instagram and Facebook. I'm Fred Goldstein for AMCP. Until next time,