Activity Transcript

Caralee J. Forseen, MD: Hello. I'm Caralee Forseen. I am the adult program director at the Medical College of Georgia in Augusta, Georgia. Welcome to this program titled "Clearing the Air on Cystic Fibrosis: Airway Clearance Approaches for Patients." Joining me today is Elliott Dasenbrook, who is the director of the Adult Cystic Fibrosis Program and the Bronchiectasis Center at the Cleveland Clinic Respiratory Institute in Cleveland, Ohio. Welcome.

Elliott Dasenbrook, MD, MHS: Hi, Caralee. Looking forward to the program today.

Dr Forseen: Today, we are going to have a discussion about the role of mucociliary clearance agents for airway clearance in patients with cystic fibrosis. To begin, let's spend a few minutes taking a look at the overall treatment of cystic fibrosis. Elliott, could you take us through how patients with CF are currently treated?

Dr Dasenbrook: Absolutely. So, Caralee, as you know, we have had a dramatic change in how our CF patients are cared for with the introduction of CFTR modulators, most recently, and a large proportion of our patients having access to highly effective modulators. We are focusing today on the pulmonary aspects of CF treatment and the changes that have resulted from the modulators. Decreased pulmonary exacerbations, increases in lung function, and really significant improvement in symptoms have changed how we approach our treatment. We are using science and research studies to try and understand the role for all of our medications that we have available for our patients. I think a lot of us are still using bronchodilators quite frequently to help open up the lungs. About a quarter of our patients will have an asthmatic component along with their cystic fibrosis.

Today, we are going to spend a lot of time talking about airway clearance techniques, so we will review those a little bit later. But dornase alfa, hypertonic saline, in the past have been vital to the treatment of our patients, and we are now trying to figure out the role for our patients that have access to these modulator therapies and how they fit in. In our patients with chronic Pseudomonas and other gram-negative infections, inhaled antibiotics have been a big part of what we do. Finally, anti-inflammatories—CF is a very bronchiectasis, neutrophilic inflammatory disease—and so daily azithromycin and other medications that are currently under study to see if those will be helpful for our patients. So, we are very fortunate in CF we have a large number of therapeutics available to us to help treat our patients.

As a result of these large numbers of treatments, unfortunately there is a burden that goes along with this. And so, just the cognitive burden of having to take so many medications. Often we think of taking pills, well, that's pretty easy, but remembering to take them every single day, having to get the refills, a lot of these medications are very expensive, working with multiple pharmacies. So it is not just how the medication is delivered, but also just trying to keep up, even if it is something that seems simple, like taking a pill. But of course, with all of those medications that we just reviewed, many of them are delivered directly to the airway, and so that requires different devices, significant amounts of time, and does not even include the other things our patients do in terms if they happen to have diabetes and the time that it takes to treat that, the exercise that they are doing. But having said all of that, I think certainly in the last 2-and-a-half, 3 years here in cystic fibrosis, we have seen a decrease in the treatment burden.

Overall, I would argue it is still pretty significant, but our patients recognize this. They are feeling better. Their pulmonary function tests are better. The pulmonary exacerbations are less. So, they are really working with us, hopefully, sometimes doing it on their own, to modify their treatments to decrease the overall burden. On the clinical side, this is where I think we really kind of push back and try and work with them on how important it is to take your medications. You and I both take care of adults, and so a lot of my patients, the vast majority, already have established lung disease. They have bronchiectasis on their CT scans, and so their symptoms may have improved, but as a pulmonologist, I believe that continuing to help that mucus move and augmenting mucociliary clearance, even in the face of modulators, is important and believe that, long term, that is important for our patients, as well.

As we know, adherence is a big challenge. I think we see it in different types of patients. Do they have advanced stage lung disease or do they have very early stages of lung disease? Sometimes in those patients that are sicker, the adherence, they get that feedback right away. "If I do this treatment, I notice that it's easier for me to kind of clear things. My chest feels better. I have less shortness of breath." And they kind of get that feedback. Whereas in contrast, our patients with earlier stages of lung disease, it is a little bit harder to make that argument just based on an immediate change in symptoms and trying to say, "Hey, we're looking for benefits 10, 15 years down the road maybe." Certainly the different types of administration like nebulized medication versus a pill, something like that. Quick nebulizers, powder, dry powder, and the pros and cons of those individual treatments. And then, our patients' ages and their socioeconomic status as well are all kind of important variables as we think about adherence with our patients.

As we have alluded to though with the CFTR modulator era, there are definitely changes that are occurring in our clinical practice, and so we have seen this shift. As patients feel better, and they are healthier, they are really wanting to cut back on their chronic routine. As we look throughout the world, there is still about, depending on where you look, 10% to 20% of patients that do not have access to CFTR modulators for varying different reasons. I think we think about these patients differently, those that do and do not have access to the modulators. But the good news is survival is improving. It is approaching 50 years for our patients, and that does not really even take into account yet the long-term impact of these highly effective modulators for the vast majority of the population. As we continue to see more and more adults in CF, which is fantastic, this really gives new opportunities and challenges to treat these patients in this current era.

Understanding more about airway clearance, again, as a pulmonologist, I believe that this will be vital to the long-term health of our patients. How can we decrease the treatment burden but still meet their needs of being able to have them get some of that mucociliary clearance done? As we all know, the purpose of airway clearance, even in the face of modulators, is that we know that mucociliary clearance is still abnormal. Even if patients are not getting to the point where they are physically coughing up mucus, we know that in the small airways, that mucus is not moving the way it should. It is not ideal. We have these different tools to be able to loosen and help move the mucus out of the airway. Ultimately, that is going to help prevent bacteria from getting trapped in the airways and building up and leading to chronic colonization of patients who are already colonized. We do have guidelines for airway clearance. And admittedly, the overall level of evidence is fair for these different recommendations, and the grades on the different scales will usually be along the B level.

I think it is important here we work very closely. CF is a team sport. We work closely with our respiratory therapists in clinic, especially when talking about airway clearance therapy. It is about finding what works best for the patient. No individual technique has been demonstrated to be superior to the others. I think studying airway clearance in general is just really difficult to do. It is one of those things where it makes sense that people have established lung disease, they have abnormalities and mucociliary clearance augmenting that should definitely provide benefit to the patients.

The different types of techniques. Certainly our respiratory therapists will talk with our patients about effective coughs, huff coughing, and kind of going through some of those techniques. Some of our patients find benefit from that, especially in the postmodulator patients who maybe now are not expectorating sputum on a regular basis, but will still have some of that chest congestion. Sometimes they can get at some repetitive, violent coughs because they cannot clear something and sometimes the huffing can be effective in that particular patient population. Very common, the oscillating positive expiratory pressure devices. It is part of the treatment burden, but we definitely talk about those with our patients in-clinic. Chest PT is much less common. We used to even do this inpatient, and even that has kind of fallen away. But we really rely on the high-frequency chest wall oscillation devices and spend a lot of time talking to our patients about those and the different benefits with those. Again, another way to help augment their airway clearance. So, with all of these different devices, what are the changes in our patients' symptoms? Caralee, I'm kind of curious. You also take care of adults. When do you think of airway clearance being initiated in your patients or talking to them about that?

Dr Forseen: For us, and I think for most CF providers, whether it is pediatrics or adults, airway clearance is vital. So it is one of the first discussions I have with my patients. Those medications that we deliver, if we are not combining that with some form of airway clearance, they are just not as effective.

Dr Dasenbrook: Absolutely. And when you think about airway clearance techniques in the current treatment era, are you finding that you're individualizing your care for these patients? Or how is it different compared to 2018 or 2017 for the majority of your patients?

Dr Forseen: Yes, absolutely. Especially since none of the airway clearance techniques are necessarily superior, I think it is really important that we just have to partner with our patients to find out what they are willing to do. We as physicians and providers can prescribe something, but if they are not willing to do it, then it's really a very ineffective treatment.

Dr Dasenbrook: Well, Caralee, do you mind telling us a little bit about the specific agents that facilitate or augment airway clearance in some of the treatments?

Dr Forseen: So, bronchodilators are the first thing we will talk about, and as people know, they dilate the airways by relaxing smooth muscles. As a result, they increase air movement through the airways, which can help the medications work more effectively. These usually are taken before other treatments, or along with airway clearance techniques, but certainly before the mucus thinners and the antibiotics. Long-acting bronchodilators and inhaled corticosteroids are used for some individuals with CF if they have asthma. Asthma certainly occurs at increased frequency in individuals with CF, but not all individuals with CF have asthma. Some of the examples of these bronchodilators are albuterol and levalbuterol. They can be administered with metered-dose inhalers, dry-powder inhalers, or nebulizers. The important thing is to find which mode of delivering that medication is best for that particular patient.

Looking at the different mucus thinners, the oldest medication is dornase alfa, which reduces the viscosity by cleaving the extracellular DNA. This breaks up that sticky mucus, makes its thinner, and makes it easier for the individual to cough up. It is typically nebulized once a day, but sometimes twice a day. Looking at the data from the original trials back in 1998, it did reduce the rates of exacerbations and improve lung function. Moving on to hypertonic saline, which has also been around for decades, it is a key agent for airway clearance because it increases the amount salt in the airway and improves the periciliary fluid layer by thinning the mucus. It is relatively inexpensive, but it does have a time burden because it is nebulized, so it takes longer. And some individuals are not able to tolerate it because of cough or hemoptysis.

The most recent medication in the mucus thinner category is mannitol, and that is a mucoactive, hyperosmotic agent. It hydrates the airway, increasing or improving mucociliary clearance, and cough as well, to help get that mucus up and out of the lungs. It is administered twice a day. It is a small portable breath-actuated, dry-powder inhaler, and it is relatively quick. It's 10 capsules. It takes about 5 minutes to deliver versus a nebulizer therapy, which takes much longer.

We do have some recent clinical trial data in adults. This was a multicenter, double-blind, randomized, parallel-group study in adults. As part of the screening, patients did have to undergo a mannitol tolerance test. The reason for this is about 8% of individuals can have bronchospasm associated with mannitol. Individuals received inhaled mannitol from 40 mg up to a cumulative dose of 400 mg, and if there was a greater than 10% drop in oxygen saturation or 20% drop in FEV₁, those individuals were excluded from this clinical trial.

Individuals who passed the mannitol tolerance test were randomized one-to-one, and they either got inhaled mannitol 400 mg twice daily, or the control, which was inhaled mannitol 50 mg twice daily. This subtherapeutic dose was selected because blinding using any other compound would be complicated by differences in taste and appearance. The treatment was continued for 26 weeks. The patients were adults, 18 years of age or older. Their FEV₁ was 40% to 90% predicted. The exclusion criteria area include failed or incomplete mannitol tolerance test. They could not use maintenance hypertonic saline in the 2 weeks prior to the randomization, and they were not allowed to continue hypertonic saline during the study either. If they had a significant episode of hemoptysis of greater than 60 mL in the last 3 months prior to screening, they were also excluded from this clinical trial. The primary objective was the mean change from baseline in FEV₁ over the 26-week treatment period.

As you can see, there was a significant improvement in FEV₁ starting at week 6, which is when we typically saw the response, and it was maintained over the course of the 26 weeks of the trial. The proportion of subjects with an improvement from baseline and FEV₁ of greater than 100 mL at week 26 was 34.4%, which was a significant improvement compared to the control group. The proportion of subjects with adverse events was similar with the 2 treatments: cough, which is certainly something which we expect, which is actually beneficial to help expectorate the sputum. There was no significant difference in hemoptysis between the groups. And importantly, the side effects were relatively mild or moderate.

So, Elliott, when looking at inhaled mannitol, where do you see this fitting in your overall management plan?

Dr Dasenbrook: It is fantastic in CF to be lucky to have another treatment option for our patients, and especially focused on airway clearance. It will be interesting to see where this ends up fitting in. I think we should talk about the mannitol test that is required prior to that. But I think in general, initially, I think that as we see patients that are kind of pulling back on some of their nebulized therapies, so for example, hypertonic saline, a common thing I hear in the clinic is that, "I don't want to spend 10 to 15 minutes now nebulizing this twice a day. I have to be hooked in with my nebulizer."

I think for that subgroup of patients that we say, "Hey, look, we think this is important for you. We have this other option that's a dry-powder formulation, and it takes about 5 minutes once you figure out how to use it.” It is portable, and more and more of our adult patients are going back to work now who maybe were not able to work. So, portability is a big factor as well. I think those types of patients are who I think about first as definitely discussing this treatment with. The nice thing is when something is approved, we can kind of use it how we want. We don't have to follow the clinical trial inclusion and exclusion criteria precisely. I have a significant number of patients maybe on modulators, or not on modulators, that despite a very aggressive airway clearance regimen still tell me they are bringing up sputum. It is thick. It is copious. They need additional mucociliary clearance help. I think as an add-on therapy to people that are already kind of maxed out, I can see that being another potential as part of a treatment option for these patients. There was this talk about the association with hemoptysis and I am glad to see that in the setting of this clinical trial that there was not a significant signal there. It was similar between the control and the intervention groups. That was reassuring, as well, especially as we think about introducing this into patients with more advanced stages of lung disease, where they are at higher risk of having episodes of hemoptysis. What do you think about some of the different advantages and disadvantages of the inhaled mannitol?

Dr Forseen: I certainly think the portability is a big benefit for adults, and for kids, too, as they are going to school and going to work, and being able to carry it with them. Not having to worry about sterilizing it. Not having to worry about refrigeration. It is ultimately a disposable device. So those are advantages. I think the biggest disadvantage right now in the setting of COVID has been the mannitol tolerance test, which has limited being able to prescribe it maybe to more patients.

Dr Dasenbrook: Yes. For nonpulmonologists or others, this tolerance test is similar to a methacholine challenge test in terms of what is being done. Certainly at our pulmonary function lab during COVID, people were not wild about doing methacholine challenge tests. We had to have negative COVID tests done prior to that, so there were barriers to even getting methacholine challenge tests. We would do them, but it was difficult. Compared to 2019, if you wanted a methacholine challenge test, you would just do it. Now there is kind of this little extra level of thought that goes into it. We work closely with our respiratory therapists and of course do not want to potentially expose them to anything. I think the mannitol test has had the same issues with barriers, but as we are coming out of COVID, those will be removed. I think, again, being able to have this as an option for our patients will be helpful.

So, talking about COVID-19 and the impact that it has had on our patients with CF, everyone in the world in 2020 had this impact in their life and in any chronic disease that they had just from COVID itself. With CF, we had the impact of COVID and the modulators going on at the same time. We were fortunate that the CFTR modulators really reduced pulmonary exacerbations. In the US, the vast majority of our patients were eligible for these therapies. At the beginning of the pandemic, like we always have, but our goal was really to try and keep our patients out of the hospital, have them at home as much as possible. At the beginning, we did not know when our patients, if they came in, would they get it from other patients? They had to do nebulized therapies. Were we going to be able to give nebulized therapies?

There were all these concerns. Certainly what we did, and lots of CF centers did, we were really doubling down with our patients at home. "Let's hit the airway clearance hard. Let's reinforce that. Let's try and do anything. If you do get a viral illness started, let's make sure that we're helping you augment your airway clearance to see if we can clear it out that way." I think some of that airway clearance has carried over now as we are coming out of COVID-19. Of course, then there is the impact on mental health from COVID-19: the isolation, the social distancing, the fear of getting COVID-19. We are very thankful to the CF Foundation that was almost on a daily, weekly, basis updating us on what was happening real-time in the United States with the impact of COVID-19 on our patients.

Fortunately, for the vast majority of CF patients, it was not as severe as we thought it was going to be. Being able to share that with patients certainly helped alleviate some of their fears, as well. Really, COVID-19 impacted how we interact with our patients. We had patients that did not want to come in to the CF clinics, and a lot of our outpatient clinics, and for periods of time we were almost purely virtual. Then, over time, we kind of had a balance, 50/50. People would come in. Now we are still seeing a significant number of patients virtually. But when we were not seeing people in person, we had to be creative on how we got throat cultures and sputum specimens in our patients, and working with them to have them get access to other resources. The CF Foundation Compass Program was very helpful, as well.

Telemedicine I think is here to stay. This has been a dramatic shift in how we deliver healthcare to our patients. Not just CF, but all the way around. I think that it is really going to overall improve the care of our patients compared to the in-person visits that we used to do. Because of COVID-19, there was a program, as everyone knows, every CF patient in the US had access to a home spirometer if they wanted to get one so to be able to do those measurements at home. A lot of centers have come up with creative ways to be able to get throat cultures or sputum samples from their patients in the context of a virtual visit. Third, I think ultimately it will allow us to do more visits with our patients and touch base to be able to say, "Hey, I don't need you to drive 2 hours."

A lot of our CF centers are in larger cities, and parking is an issue, and it takes 15 minutes just to walk to the clinic from where you parked. It is a whole day to come to a clinic visit, so to be able to say, "Hey, we can just check-in." I know you have done the same. "Do a virtual visit." I see patients that are at work. I see patients that are at home. They click on, we talk for 30 minutes, I can bring in other members of the team, and then they are done and they can go on with their day. This is definitely going to have a huge impact in the future. We are going to involve the whole team. One of my favorite things about CF is that, I call it a team sport. Unlike some other areas of medicine where it is the physician and the patient and that's it, we have a whole group of people that are helping support our patients.

Patients at the center, and we have pulmonologists and internal medicine physicians and endocrinologists and ear, nose, and throat [specialists] (ENTs), but we also have key members of our team: respiratory therapists, dieticians, nutritionists, the nurses, the clinical coordinators, nurse practitioners, advanced practice providers (APPs). We are getting more and more pharmacists into clinic, which is huge. Mental health coordinators. What we have really been working on also is trying to get primary care physicians involved on the outpatient side. Not to do the CF care, but because our patients are living longer, they are having other issues that they are experts in to help with their care. This makes it a whole team supporting our CF patients. Caralee, during the COVID-19 pandemic, what strategies did you use in clinic to help care for your patients?

Dr Forseen: We really transitioned to telemedicine almost immediately, and that was our sole communication unless people had needed to be seen for sick visits. And it was vital. Really, like you had mentioned, telemedicine I am hoping is here to stay because it is very beneficial as an adjunct, but also for those individuals who are traveling 5+ hours one way to come see us. If they are healthy and they are doing well, being able to do telemedicine visits, alternating with in-person visits, as long as things are going well, is very helpful.

Like most places, the pulmonary function test (PFT) lab became less available because of the concern of COVID-19 and transmission. So we were very fortunate that the CF Foundation provided home spirometers for patients. We have utilized that very frequently. I think our patients have really embraced it, and now we use it to help us guide potentially onset of exacerbations [inaudible 00:29:47]. While it has been a very awful 2 years in many ways for individuals around the country and for CF patients, too, it has brought out some positive things.

Dr Dasenbrook: Yes, absolutely. I think one of the other challenges of telehealth is getting the whole team involved. When someone comes into the clinic, the patient goes into the room and then respiratory therapy goes into the room, the nurse, the social worker, whatever the patient kind of needs that particular day, or if it is their annual visit. How have you worked the whole team into the virtual visits as well, if they are, like you said, doing that? You have patients coming from 5 hours away and still being able to access other members of the team.

Dr Forseen: Right. Especially for those individuals who maybe have a respiratory therapy need or a mental health need, we have just gotten individuals on the call or we tag team. You can get creative. Sometimes we have to do a series of calls. But I think overall it has worked pretty well. It still has its challenges. Sometimes things just are more effective face-to-face. But I think all in all, I think all of us have adapted: the patients and the providers and the care team.

Dr Dasenbrook: Yes. It has definitely an exciting time to be in cystic fibrosis, with a lot of changes, good changes, for our patients helping them along their journey. Do you want to go over some of the key takeaways with us?

Dr Forseen: Sure. I think one of the big things is that today, fortunately, individuals with CF are healthier because of better therapies, especially the CFTR modulators. But unfortunately, not all patients qualify for these modulators, so there is still work to be done. The CF Foundation and researchers are very committed to finding a cure for CF, which is what all of us hope for. Airway clearance also remains a very important component of CF care. No airway clearance therapy has really been found to be superior, so it is really important that we partner with our patients, and for those who have kids with CF, partnering with the parents to come up with the best approach for each individual.

Telemedicine, as we talked about, has allowed centers to continue to provide high-quality care at the height of the pandemic, and I am hopeful that it is going continue to be a very valuable option for the care for our patients. Finally, with the improved health of individuals with CF, the treatment burden will be a significant concern for patients. Again, we are going to have to partner with our patients and put our heads together to find out what treatments will work best for each individual.

Elliott, I'd certainly like to thank you for this great discussion today, covering many aspects of CF care and airway clearance. And I'd like to thank you for participating in this activity, and please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.