Critical Observations in Pulmonary Medicine, Ep. 4

Bronchial Thermoplasty in Severe Persistent Asthma

Albert A. Rizzo, MD

This podcast series aims to highlight clinical advancements in pulmonology, sleep medicine, and critical care medicine. Moderator, Albert Rizzo, MD, interviews prominent health professionals to help our community gain insight on leadership lessons learned.


In this episode, Dr Rizzo interviews Geoffrey Chupp, MD, on his team’s research titled "Bronchial Thermoplasty in Patients with Severe Asthma at 5 years: Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma Study." Dr Chupp speaks about the efficacy, safety results, challenges, and controversies of the therapy.

Additional Resource:

  • Chupp G, Kline JN, Khatri SB, et al. Bronchial thermoplasty in patients with severe asthma at 5 years: the Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty In Severe Persistent Asthma study. Chest. 2022;161(3):614-628. doi:10.1016/j.chest.2021.10.044​​​​​​

Geoffrey Chupp, MD

Geoffrey Chupp, MD, is a pulmonary, critical care, and sleep physician, a professor of medicine, the director of the Yale Center for Asthma and Airways Disease, and the director of the Pulmonary Function Laboratory, at Yale School of Medicine (New Haven, CT).

Albert Rizzo, MD

Albert A. Rizzo, MD, is the chief medical officer of the American Lung Association and a member of ChristianaCare Pulmonary Associates in Newark, Delaware.



Moderator: Hello, and welcome to Critical Observations in Pulmonary Medicine led by Chief Medical Officer of the American Lung Association, Dr Albert Rizzo. The views of the speakers are their own and do not reflect the views of their respective institutions.

Dr Albert Rizzo: So I want to thank Dr Geoffrey Chupp, a well-regarded expert in the treatment of asthma from Yale University School of Medicine, and who is the lead author of the recent article in the journal Chest; Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma study, to be with us today.

Dr Geoffrey Chupp: Great to be here, Albert.

Dr Albert Rizzo: Thank you. Before we begin discussing the recent article in Chest, can you please set the stage for many of our listeners regarding the background on the proposed mechanism as to how bronchial thermoplasty came about and why it may be effective in patients with severe refractory asthma. This may be a good time to also just review what's actually involved for patients when they get to that point.

Dr Geoffrey Chupp: Sure. Bronchial thermoplasty was developed about two decades ago. And they recognized that if you applied heat to the airway, that you could reduce smooth muscle. And this was first done in animal models, of course, including pigs. And there was very nice data showing that when you applied this radio frequency energy, so this is radio frequency energy going through a catheter that is in contact with the airway wall. That when you did that, and you went back in and biopsied the animal's airways, that a few weeks later, a few months later there was a reduction in the mass of the smooth muscle. And there was a reduced amount of airway hyperreactivity in these animals. And so studies were eventually moved into man.

And the technology that was developed was, again, this catheter that has a basket on the end of it with four different wires that can expand like a standard foreign body retrieval basket. Looks about like that. And energy goes through these, radio frequency energy. And so the wires get hot. They don't burn the airway, but they heat it up. And what happens is that you apply this energy for a few seconds to the airway wall. And again, the amount of smooth muscle mass is reduced. Now, this wasn't shown in the pivotal trials, but it was shown in follow up studies that have been published by other groups, prospectively in patients being treated.

So, what happens when a patient has a procedure is that they have a bronchoscopy. And in order to do this safely, so that you're not treating the whole lung, you do it in three different procedures each about a month apart. So you do the right lower lobe first. And what you do is you do the bronchoscopy and you treat the airways where you can contact the airway wall with the probe. And these are generally about three millimeters in diameter to one centimeter in diameter. And you treat as many airways as you can, and you move the catheter a few millimeters each time, so that you go from, for example, one airway from three millimeters to one centimeter contacting the whole airway and actuating the probe, passing energy through it for a few seconds each time.

So a typical procedure, a patient will have 50 to 100 actuations treating all the airways that can be reached in that portion of the lung. So with the first procedure, you do the right lower lobe. Three weeks later, you come in and you do the left lower lobe. And then in the third procedure, you do both upper lobes. And this is so that any inflammation or injury that is caused by heating up the airway during the procedure is only affecting that portion of the lung and reduces the side effect profile.

The right middle lobe is not treated because that has a very small airway generally. And so there's always some concern about airway obstruction. So generally the right middle lobe is not treated. And patients take prednisone periprocedure. And the side effect profile has proven to be very good periprocedure. Maybe in the 10% range of patients who have some kind of asthma exacerbation, sometimes rare hemoptysis, occasional hospitalizations.

Dr Albert Rizzo: So fairly well tolerated from a side effect standpoint. And the procedure itself sounds a little labor intensive for the patient. How long does this usually take the whole procedure?

Dr Geoffrey Chupp: Well, usually about an hour. The pre and post bronchoscopy takes a bit of time, but the procedure itself is an hour or less. It's always much more mundane than you might think, because there's no actual biopsying or generally injury to the airway. So the procedures really go very smoothly for the most part.

Dr Albert Rizzo: And is it usually done under conscious sedation, or do they require more anesthesia?

Dr Geoffrey Chupp: Yeah. I think most centers do this under conscious sedation, sometimes with an oral airway in place. I think there may be a few centers that do this in the operating room, but it's really not the norm.

Dr Albert Rizzo: And like so many procedures in medicine, is it... I'm assuming this is relatively done at centers where large referrals occur and individuals who do this procedure are doing a lot of them and are more and more interventional pulmonologists being trained in this procedure.

Dr Geoffrey Chupp: Yes. I think there's definitely centers... In my most states I think, there's centers where there's somebody who has become experienced with this. You have to track the actuations when you do the procedure for each patient. And that does require some staff and infrastructure, because you ideally check their lung function before and after the procedure to make sure it hasn't dropped too much. In our center, we do the evaluation of the patient and the care of the patient before and after the procedure. But our interventional bronchoscopy team actually does the procedure. And we find that that really gives the best results and experience for the patient, because we have the bronchoscopist and the expert asthma team managing the patient and applying their expertise at the appropriate time in the process.

Dr Albert Rizzo: I know when I referred some patients, one of the hurdles is often the case that this is sometimes considered still experimental by some third party payers. That it's been a struggle to get some covered. Is that still the case? Do you run into that fairly often?

Dr Geoffrey Chupp: Absolutely. This is our biggest barrier actually to getting it for patients. It's frequently denied by insurance companies and it's very laborious to appeal these denials. And now with biologics available, there's a straightforward alternative to getting severe patients therapy. The downside of this of course, is that bronchial thermoplasty, it is three procedures, but its cost is about the cost of biologics for one year. So there is, I think definitely an opportunity to improve some patients and reduce their need for biologic therapy. I think that's part of what the PAS2 trial shows, and allows us to improve patients without requiring long term injection therapy.

Dr Albert Rizzo: You mentioned that bronchial thermoplasty has been around for two decades in the making. But I know there's been a series of articles, some of which have led to a little bit of controversy over the effectiveness or the efficaciousness of the thermoplasty and the interpretation of these studies. I think with previous studies and now with your most recent post-FDA trial, can you talk about how things have changed and what your particular article has added to the literature?

Dr Geoffrey Chupp: Well, when the therapy was approved, there was a requirement to FDA and the company decided to do a long term observational study to examine safety and durability of response. And this was, I think in part, because there were question marks about whether or not applying heat, this energy to the airway might have longer term effects on the lung; risk of bronchiectasis or injury. And so I think the first thing that the PAS2 trial showed is that after five years, there was really no evidence that the patients incurred any long term untoward effects or injury to the lungs scarring to the airways.

The second thing was obviously durability of response, and who are the patients being treated in the real world. It wasn't strictly speaking a real world study, but the patients who were enrolled, the criteria for inclusion were more flexible than the phase three trial. And so ultimately the patients being enrolled in PAS2 were more severe than were enrolled in the AIR2 trial. So it did show that patients had more severe disease, could be treated safely with bronchial thermoplasty.

The third thing it showed is that the therapy works and that the response is durable over five years. And a large proportion of the patients came off of systemic steroids. And while some of these patients did end up on biologic therapies, ultimately their trends over five years were very consistent in terms of reductions in exacerbations and healthcare utilization. So I think it's important because I think bronchial thermoplasty should be available to patients, and physicians should have this as an option. And insurance companies should really start to recognize that this is an efficacious therapy and they should approve it.

Dr Albert Rizzo: Are there particular criteria that you go through when you're evaluating somebody? Have they failed steroids? Have they failed biologics? They can't tolerate biologics. What makes the ideal candidate for our listeners who may be thinking about referring patients for such a procedure?

Dr Geoffrey Chupp: Well, generally speaking, we're looking for patients that are severe and uncontrolled. And that is a patient who is on high doses of inhaled steroids. And additional control are usually a long-acting beta-agonist, and they still have a lot of disease activity. Now that doesn't have to be exacerbations requiring systemic steroids. But if they're having a lot of symptoms, for example, trouble exercising or their asthma control score is below... ACT score, for example is below 20. These are patients who need additional therapy. And so bronchial thermoplasty is an option for those individuals.

From a physiology standpoint, most of the patients who were treated in the trials had FEV1s above 60% of predicted. And so I think a lot of us try to adhere to the trial criteria and treat those kinds of patients. Ones who have lower lung function, which can be treated as well and gain some benefit. But I think it's a little less predictable because those patients... There was one trial, the RISA trial that looked at patients with lower lung function. But our understanding of the outcomes in those individuals is a little less clear. So that's one of the criteria we adhere to. Prednisone dependence is okay, but at least in the PAS2 is 10 milligrams or less to be enrolled. So people who are requiring high doses of systemic steroids would need to be tapered in order to be treated.

Dr Albert Rizzo: So what I'm hearing is not necessarily an allergic or high eosinophilic asthma patient who would or would not be a candidate for this. It's both eosinophilic and non-eosinophilic asthma. As long as it involves-

Dr Geoffrey Chupp: Right. So that was an interesting result in the study, which is that we tried to do a responder analysis to see if we could identify features that were associated with response. And so, one of the things of course that has emerged since the development of bronchial thermoplasty and its approval has been the emergence of blood eosinophils as an important biomarker of T2 asthma. And so when this was looked at, both neutrophils in the blood as well as the eosinophils separating by standard criteria 300 or higher, versus 300 or lower, I really thought we might see a difference in response to the therapy with patients who are lower T2 or with lower eosinophils, have a stronger response. But that actually wasn't the case.

So, this worked in both high T2, as well as low T2 patients. It was the same for neutrophils. So there wasn't an obvious factor, clinical or biologic or in the blood parameters that actually identified that a certain patient type would be more likely to respond. I think this was interesting and important because again, I think it supports the use of bronchial thermoplasty potentially in conjunction with biologic therapies. And that we shouldn't think of it as necessarily an either or, but as an option that could be included together. And that maybe there's a chance to remodel the lung and alter disease progression if we use both therapies.

Dr Albert Rizzo: I read, I believe an editorial or two looking at the actual science behind the smooth muscle. And some reports saying that some patients even got better when the smooth muscle did not seem to be decreased with the bronchial thermoplasty. So the mass of the bronchial smooth muscle didn't seem to be a good corollary to efficaciousness. Is that true?

Dr Geoffrey Chupp: Well, the studies that I've seen, I think the best were from France, from Marina Pretolani, where there was a very nice decrease in smooth muscle mass and that correlated well with clinical response. Biopsy studies can be challenging because you're only biopsying a few areas of the lung, but you're treating a lot of areas. And so you might have some sampling error there, but I believe there could be effects also related to reduction in cytokine expression where you don't necessarily see a change in mass. And then there was also some evidence that you are affecting the neural innovation of the smooth muscle through the parasympathetic nervous system that's also being affected, runs along the airway wall as well. And so I think it is possible that you're seeing some changes in smooth muscle function or reactivity where you're not necessarily seeing a change in mass.

Dr Albert Rizzo: So again, based on your most recent article, where do you think things are moving to next, as far as this possibly becoming a little more available to centers and more acknowledged by a third party payer as an option?

Dr Geoffrey Chupp: Well, I think first of all, there is work still being done on how to optimize bronchial thermoplasty and what is the best way to use it in a given patient. And this work comes from Mario Castro's group, where he's been looking at Xenon enhanced MRIs to map ventilation in the lung and actually apply bronchial thermoplasty through a single procedure to the airways that are most affected by ventilation. And looking to see if this is a way to make this procedure more efficient and more targeted. So I think that's a useful thing that'll actually bring down the cost and the side effect profile if it's effective.

I think that, again, the biggest barrier we have now is insurance companies. And I think that until we have a more flexible or a more reasonable response regarding the patients that we want to treat, this is going to remain as a secondary or tertiary approach to treating these patients with severe uncontrolled disease. I think biologic therapies have really moved into the third option for patients; step four or five in GINA guidelines once patients are failing inhaled steroids and additional controller medications. And so that's going to continue. And until we really, I think have more of a, probably a guideline or expert based effort to replace or remove bronchial thermoplasty into the treatment algorithm at a higher place.

Dr Albert Rizzo: And I think you did mention there are some patients who are on biologics, even with the bronchial thermoplasty. And are there obviously patients who may be able to come off of that biologic after thermoplasty is performed? Or is that not [crosstalk 00:18:14].

Dr Geoffrey Chupp: So that's a great question. We don't have data on that. I think that's an attractive, obviously a very interesting hypothesis that we should certainly consider, but it needs to be studied.

Dr Albert Rizzo: So it sounds like there is more work to be done. Anything else you want to mention about either your study or just the field itself with regard to thermoplasty?

Dr Geoffrey Chupp: No, I think that's really it. I think this has been a great discussion and really appreciate your interest in the PAS2 trial and giving me the opportunity to talk about it.

Dr Albert Rizzo: Well, I appreciate your time. And for those who want to go into it further, again, this is a recent article in Chest, the Post-FDA Approval Clinical Trial Evaluation Bronchial Thermoplasty in Severe Persistent Asthma study. And Dr Chupp was the lead author. So again, I thank you for your time today, and good luck in the future.

Dr Geoffrey Chupp: Thank you. Thanks for having me

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