Take A Breath: Managing Lung Problems after Transplant

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Take A Breath: Managing Lung Problems after Transplant

Monday, May 2, 2022

Presenter: Ajay Sheshadri MD, The University of Texas MD Anderson Cancer Center

Presentation is 33 minutes long with 24 minutes of Q & A.

Summary: People may experience a variety of lung problems in the first several years after transplant. This presentation describes both rare and common lung problems and the available remedies to treat them.

Highlights:

• Non-infectious pulmonary complications occur in about 20% of transplant recipients. They increase the rate of death two-fold and are one of the biggest barriers to a healthy life post-transplant.
• Pulmonary complications can occur earlier or later after transplant and can be obstructive, meaning problems getting air out of the lungs, or restrictive, meaning problems getting air into the lungs. These are collectively referred to as interstitial lung diseases.
• Bronchiolitis obliterans syndrome (BOS) is GVHD of the lung; it must be detected and treated early for a favorable outcome, but early diagnosis is challenging because the symptoms of BOS are quite subtle.

Key Points:

(02:09): Here is a brief history of how breathing has been (mis-) understood from the Greeks to the present.

(09:35): Early non-infectious pulmonary complications include diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, cryptogenic organizing pneumonia and pulmonary veno-occlusive disease.

(10:54): Sclerotic skin GVHD can affect the chest wall and can make breathing difficult.

(11:35): Diffuse alveolar hemorrhage is a serious complication that involves bleeding in the lungs. It usually occurs soon after transplant and needs prompt attention.

(14:32): Idiopathic pneumonia syndrome is relatively rare and has a high mortality rate in the first-year post-transplant. It can be hard to distinguish from viral infections.

(18:35): Cryptogenic organizing pneumonia (COP) occurs in 1-2% of transplant recipients. Symptoms include shortness of breath and flu-like symptoms. It is usually responsive to steroids.

(20:14): Bronchiolitis obliterans syndrome (BOS) is GVHD of the lung. It occurs in 5% of transplant recipients and 15% of those who have GVHD in another organ. It must be detected and treated early for a favorable outcome.

(24:52): Testing for lung GVHD is important during the first year or two after transplant when the rate of lung GVHD increases.

(27:11): Pulmonary rehabilitation can help with recovery from BOS.

(28:42): Screening for BOS may be done by home spirometers.

Transcript of Presentation:

(00:02): [Becky Dame] Introduction of Speaker.  Hi, my name is Becky Dame and I'll be your moderator for this workshop. I want to welcome you to the workshop Take a Breath: Managing Lung Problems after Transplant.

Now it is my pleasure to do introduce Dr. Ajay Sheshadri. Dr. Sheshadri is the Medical Director of the Pulmonary Function Testing Laboratory at the University of Texas MD Anderson Cancer Center and is also an associate professor in the Department of Pulmonology. His research focuses on bronchiolitis obliterans disease, as well as other lung disorders after a stem cell transplant, and the novel approaches therapies to treat them. Join me in welcoming Dr. Sheshadri.

(00:49): [Dr. Ajay Sheshadri] Overview of Talk. Thank you so much. It's really my privilege to be able to speak to you today about lung problems after transplantation. And this will go over a lot of the various lung problems that we see after hematopoietic cell transplant, particularly focusing on non-infectious problems.

(01:09): First, these are my disclosures here. These are a couple of pictures of Houston. This is Buffalo Bayou Park on the top right, and then on the bottom is MD Anderson, where I really have the privilege to work. It's a well-known cancer center, and it's really my privilege to be able to work with all the folks.

(01:31): So with that, I'd like to start with learning objectives. On the right that's the Astrodome, by the way, once known as the eighth wonder of the world. It doesn't look so wondrous these days, but it is one of the notable buildings in Houston.

(01:48): Learning Objectives for the talk. So, the learning objectives for today. We will talk about the types of lung injury that can occur after transplantation. We'll talk about some of the risk factors for developing these types of pulmonary difficulties after transplant, some of the treatment strategies that we have, and then finally, how to find a specialist who can help us manage pulmonary difficulties after transplantation.

(02:09): Here is a brief history of how breathing has been (mis-) understood from the Greeks to the present. First, I want to do something a little bit fun. This is a brief history of breathing. Much of what we know about the lung in general has only been discovered in the last one to two hundred years. Early philosophers really recognized the importance of the breath. For a long time, it was thought that the soul resided in the heart, and some thought that the soul resided in the head, and then finally the Greek philosophers realized that there was a great importance to the breath.

(02:43): It seems now that the primary function of the lung, it's common knowledge that it's to deliver oxygen to the organs, to exhale carbon dioxide, but in the time of the Greeks, none of this was known. Plato, for example, realized that breathing was important, but he thought it occurred through the skin pores and not through the mouth and the trachea and the lungs. And Aristotle thought the only purpose for breathing was to cool the heart, which he thought was the seat of the soul. But even though they didn't know exactly how breathing worked and how the lungs worked, they realized that it was serving some vital purpose.

(03:20): On the right, you see a famous Greek named Galen. His full name is Aelius Galenus, and he really figured out how the diaphragm works, and he's really well known today for being an expert physiologist. And when you consider when he discovered these things, he was really way ahead of his time. Ironically, he was sort of forgotten by his immediate successors because he thought that the arteries and the veins of the body were two separate vascular systems and they were not connected. And it would be a long time before the pulmonary circulation is discovered, and they figured out how the arteries and the veins in the body were actually connected, and of course that's through the lung.

(04:06): Over a thousand years later, there was an Egyptian doctor that discovered that there was a pulmonary circulation, and it would be almost 300 years later when it was finally confirmed by an Italian named Realdo Colombo. Finally, in 1628, a gentleman named William Harvey discovered that the pulmonary circulation connected the arteries and veins of the body. Eventually with the advent of microscopy in the 1660s, another Italian scientist named Marcello Malpighi discovered that there were pulmonary capillaries and alveoli. Then finally, in 1644, it was understood that air was matter, and actually had weight and substance, and this was discovered by an Italian named Evangelista Torricelli, and then eventually confirmed by Robert Boyle, who is famous for Boyle's law.

(04:57): In the context of human physiology, John Locke reasoned that air was necessary for the proper functioning of the circulation, and in 1774, so now almost 2000 years after the Greeks were trying to figure out why breathing was important, oxygen was discovered by Joseph Priestley, and it wasn't until the early 1900s that we realized that oxygen diffused into the lungs and was necessary for that vital purpose.

(05:25): So the importance of breath has been known for a long time, but exactly how the lungs work is a much more recent phenomenon. Just to give you an idea for how much the science has changed in the last hundred years, it took a thousand years to understand that blood circulated to the lung. It took 500 years to understand that air was not just a vacuum, but actually had matter. It took another hundred and fifty years to realize that oxygen was vital for human function, and then another hundred and fifty years to figure out how oxygen got into the body through the lung.

(05:57): The lungs work through a complex breathing cycle. With that, we're going to talk a little bit about how the lung works. You can think of the breathing cycle in this way. Breath is initiated by sending a signal from the brain to the diaphragm to contract. This is an involuntary signal, but of course you can signal when you want to initiate a breath voluntarily as well. The diaphragm contracts, and then this expands through the cavity and makes it bigger. And what it does is that it creates a negative pressure, and that negative pressure causes the lung to passively expand, and then it inflates with air because the pressure now inside the lung is lower than the outside. And this continues until the lung reaches full inspiration. At that point, you can either passively exhale, or you can forcefully exhale by using some of the other muscles.

(06:41): Structures called alveoli are where the magic happens in the lung. So ambient air enters the airways, and it gets into these little sack-like structures called alveoli, and alveoli is really, this is where the magic happens in the lung. What happens here is that air gets into the alveoli, and the alveoli are very, very thin structures, they're thin sack-like structures, and oxygen can readily diffuse from the air into the blood. And carbon dioxide diffuses out of the blood into the alveoli, and then when you breathe it out, you're breathing out a slightly higher concentration of carbon dioxide than you're breathing in. Carbon dioxide is a byproduct of a normal metabolism, and it's sort of a waste product in this sense. And so it's very important both for getting oxygen to the blood, but also to make sure that you get the carbon dioxide out of the blood, because that can have some bad consequences for your health. So why is the lung so important for hematopoietic cell transplantation recipients?

(07:42): One of the things that's happened over the last 30 years, of course hematopoietic cell transplantation is not that old when you consider how much work has been done to identify why the lung is important. Well, it's really impressive to think about that in the fifties and sixties, we've been able to actually transplant someone else's stem cells into your body and cure certain cancers. And over the last 30 years, the mortality has declined quite a bit. But one of the problems that we've run into now is that pulmonary complications, and especially non-infectious pulmonary complications, are becoming first and foremost, so as we solve some problems, other problems gain greater significance.

(08:20): Non-infectious pulmonary complications occur in about 20% of transplant recipients. They double the mortality rate and are one of the biggest barriers to a healthy life post-transplant. These non-infectious pulmonary complications occur in about 20% of transplant recipients, and they increase the rate of death twofold, so it roughly doubles your mortality. So these are really significant events that we need to work harder to prevent. Other than relapse, pulmonary complications are one of the biggest barriers to a healthy post-transplant life, and this work was best shown by Anne Bergeron, who is one of my counterparts in Europe. She published this in the European Respiratory Journal in 2018.

(08:54): Pulmonary complications can occur early or late after transplant and can be obstructive (getting air out) or restrictive (getting air in). There's a simple way to conceptualize non-infectious pulmonary complications. You can think about when they occur, and so this is a little bit arbitrarily defined as early, which is in the first few months, and late, which is after the first few months. And then how, if they affect your breathing as well. Is it an obstructive disorder, so is it hard to get air out, and this is sort of like diseases like COPD or asthma? Or is it restrictive? Is it hard to get air in? These are diseases that we sometimes collectively refer to as interstitial lung diseases, and when you look at it in this context, these are some of the diseases that we'll talk about today.

(09:35): There are many types of pulmonary complications; bronchiolitis obliterans syndrome or lung graft-versus-host-disease (GVHD) is one of the most important. Early non-infectious pulmonary complications include diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, cryptogenic organizing pneumonia and pulmonary veno-occlusive disease. If we think about late complications, once again, organizing pneumonia can really occur early or late. And then one of the most important complications, which is a focus of my clinical and research interests, is bronchiolitis obliterans syndrome, or lung graft-versus-host disease.

(10:07): Bronchiolitis obliterans is the most common obstructive disorder after transplant. In terms of restrictive versus obstructive disease, bronchiolitis obliterans syndrome is the most common obstructive disorder. Most of the other disorders will not have airflow obstruction. So this is really important. Whenever we see a pulmonary function test that has airflow obstruction, that really raises the alarm to us that this could be new graft-versus-host disease. And as we will talk about, this is something that we want to catch early, and we want to treat early.

(10:34): Other non-infectious pulmonary complications are restrictive. All the other non-infectious pulmonary complications are restrictive, so this often presents with a lower lung capacity. This presents a little bit of a challenge to us too, because it's hard to distinguish these from one another sometimes. And so we have to do tests like bronchoscopy, for example, to figure out if it's an infection or to figure out the type of inflammation.

(10:54): Sclerotic GVHD affects the chest wall and can also make breathing difficult. And then finally, there's one important non-lung condition which can also restrict the breathing, and this is truncal sclerosis or sclerotic GVHD of the chest and chest wall. In this case, you can almost think of it like a tight rubber band around your chest, where you can't take a deep breath in, because the skin is basically keeping the lungs from expanding properly. This can affect the lung function, and it can often affect the lung function quite a bit, but luckily the skin has a greater regenerative capacity than the lung, and sometimes with appropriate treatment, we can get folks to breathe better even if they have significant sclerosis.

(11:35): Diffuse alveolar hemorrhage involves bleeding in the lung and can be diagnosed with a bronchoscopy. The first disease I'm going to talk about is diffuse alveolar hemorrhage. This is a disease that's characterized by bleeding in the lung, which is what the word hemorrhage means, and this usually presents with a difficulty with oxygenation. The diagnosis is made with increasingly bloody return on the bronchoalveolar lavage, and here you can see in this picture on the right, that if you look at the far-left vial, the fluid, which should be clear, has a little bit of a pink tinge to it. And then as you go from left to right, you can see that it gets bloodier and bloodier.

(12:11): This is really a hallmark test for how we diagnose hemorrhage, and so the bronchoscopy, if you're not familiar with it, is a little bit like an upper endoscopy or a colonoscopy. We use a camera that's at the end of a flexible scope. And usually we go into the nose, but some people will go into the mouth, and we just follow the airways back through the back of the throat, past the vocal cords and into the trachea and into the lungs. It's usually done with conscious sedation with agents like midazolam or fentanyl, but occasionally it can be done with general anesthesia as well. It's a relatively simple procedure. But sometimes when people have diffuse alveolar hemorrhage, they have difficulty breathing, and therefore they may not tolerate the procedure quite as well as somebody who's healthier.

(13:02): Treatment may involve steroids or anti-clotting agents. This is what a CT of someone with alveolar hemorrhage looks like. The bleeding in the lungs can really be a result of low platelets, which are relatively common in the early phase of transplantation, or radiation injury, which is commonly identified as a risk factor for alveolar hemorrhage. We usually treat this with steroids, and sometimes we'll use anti-clotting agents, but really the evidence for both of these is pretty limited.

(13:29): Just as an aside, one of the reasons that we use steroids is, we see alveolar hemorrhage outside of transplantation in folks who have autoimmune disorders. But it's really unclear as to whether inflammation is the driving force behind all causes of hemorrhage after transplantation. There may be a lot of reasons that you have this bleeding in the lung, and it may not be the type of inflammation that we see outside of transplantation. So one thing I would caution is to assume that those conditions are the same.

(13:59): Diffuse alveolar hemorrhage is a serious complication that usually occurs soon after transplant and needs prompt attention. At any rate, this is a very serious complication, and we take it very seriously. We try to diagnose it as soon as possible, and we need to address it promptly. This is something that occurs very early in transplantation, and hopefully by the time that you get to around day 100, this is not something that's a consideration anymore.

(14:23): Idiopathic pneumonia syndrome can also occur in the first few months post-transplant. The next complication is something called idiopathic pneumonia syndrome, and idiopathic pneumonia syndrome is called that because idiopathic means we don't know the cause, but it looks like a pneumonia. This is a pretty severe non-infectious pulmonary complication that occurs usually in the first few months after transplantation, typically in the first three months. It looks like a severe infectious pneumonia, but by definition, there must be no evidence of infection.

(14:50): One of the interesting things is that the word idiopathic pneumonia syndrome comes from a time before we had widespread PCR testing for viral reactions. You might be familiar with PCR testing now that, in the COVID pandemic, that's one of the ways that we confirm the diagnosis of COVID. What the PCR test does is basically look for genetic fragments and it amplify them, and it matches them to see if they fit the genetic signature of certain viruses.

(15:22): It can be difficult to distinguish idiopathic pneumonia syndrome from viral infections. We have panels that have a limited number of viruses, and as we started to use those, we realized that some of the cases that were idiopathic pneumonia were really these types of viruses. But more recently there's some evidence that it could be due to a human herpes virus. These are, of course, like herpes simplex virus, which causes cold sores, but there are several of these viruses, and one specific one is called HHP-6, which is not known to cause pneumonia in humans. But more recently, this is something that was identified in almost half of cases of idiopathic pneumonia syndrome, and it's something that we increasingly recognize as a pathogen.

(16:06): Idiopathic pneumonia syndrome has several distinct symptoms. The way we define idiopathic pneumonia syndrome is... These are the ATS criteria. You need to have alveolar injury, and the way we define this are multilobar alveolar infiltrates with symptoms and signs of pneumonia. You have to have shortness of breath or hypoxemia or something like that. And new lung restriction or hypoxemia, which means low oxygen. And you must not have any evidence of respiratory tract infection or cardiac or renal dysfunction, because if you have problems with your heart or kidneys, you can have fluid that spills into the lungs as well, which also can look like this type of idiopathic pneumonia.

(16:44): Idiopathic pneumonia syndrome is relatively rare and is associated with high-dose chemotherapy and/or radiation given before transplant; it has a high mortality rate in the first-year post-transplant. It occurs in about three to four percent of hematopoietic cell transplant recipients, so it's a relatively rare disorder, and a major risk factor is myeloablative conditioning. This is when you have a higher intensity conditioning to try to eradicate the cancers. It's associated with a very high mortality. Nearly 70% of people who develop this will die within a year of transplantation. So it's something, again, that we take very seriously, and the treatment is high dose steroids. There are some data for [the use of] agents like etanercept, which is an inhibitor of an inflammatory cytokine called tumor necrosis factor, but the truth is that this is something that we need to work harder to understand better, to be able to treat better.

(17:27): Pulmonary veno-occlusive (PVOD) involves scarring of the pulmonary venules and is very rare. The next disease I'll talk about is pulmonary veno-occlusive disease. This is a very, very rare non-infectious pulmonary complication, and the incidence is so low that I'm not sure I can quote you an accurate incidence. What happens here is that you have scarring of the pulmonary venules. Venules are small veins. The symptoms include shortness of breath and hypoxemia, and there's usually a skin rash with some weight gain or swelling that occurs around the time of PVOD. There are some limited data on drugs that have been used in hepatic veno-occlusive disease, which occurs more commonly, and this includes a drug called defibrotide, but this is another very rare condition.

(18:07): Even in PVOD that occurs in the general population, the treatment is often unknown, and in some cases those patients require lung transplantation. Luckily, this is something that occurs very, very rarely, we see it very, very uncommonly, because the mortality's very high and we don't want anybody to get this. And unfortunately, because it's so rare, we have a lot of work to do to understand what drives this and how we can prevent it.

(18:35): Cryptogenic organizing pneumonia (COP) occurs in 1-2% of transplant recipients. The next one I'm going to talk about is cryptogenic organizing pneumonia. This is something that occurs a little more commonly now. It occurs in about one to two percent of transplant recipients, and we understand a little better now that this often occurs after a viral infection. So respiratory viruses often precede this organizing pneumonia. This is something we noticed at MD Anderson as a common risk factor, and I think it's really clear now in the public eye that viruses can cause this type of reaction, because this is one of the common reactions that occurs after COVID 19 as well.

(19:11): Cryptogenic organizing pneumonia manifests as shortness of breath and flu-like symptoms but usually responds to steroids. COP manifests as a slow onset of shortness of breath, usually preceded by a flu-like prodrome. Again, that may be because of the respiratory viral infection. But unlike the other things that I presented so far, COP generally responds to steroids. Most of the cases are steroid responsive. The way we treat COP is, we start steroids and we usually treat for about eight to 12 weeks. And the reason we treat for so long is that if you taper off the steroids too soon, you might get recurrence of the organizing pneumonia. There are rare cases of severe COP, and we might have to add additional immunosuppression like mycophenolate mofetil or CellCept, but the data is very limited. Luckily, most cases are very steroid responsive, and so when we see this we can treat it promptly. We can often reverse it and minimize the amount of scarring. In a minority of cases. We do see significant scarring, and so this is, again, something that we take seriously, but luckily it's something that we can treat quite successfully.

(20:14): Bronchiolitis obliterans syndrome (BOS) is GVHD of the lung; it must be detected and treated early for a favorable outcome. The last disease I'm going to talk about is bronchiolitis obliterans syndrome. This is graft-versus-host disease of the lung. This occurs in about five percent of transplant recipients, and as many as 15% of patients who have some other form of GVHD, most commonly the skin or the gut. The prognosis of patients has drastically improved in the last couple of decades because we understand the disease better, we screen for it better. But if you diagnose this disease late, the mortality rate can be nearly as high as 80% 10 years after diagnosis. So again, this something that we take seriously, we want to catch early, and the earlier we catch it, the better patients do.

(20:54): The two major risk factors for bronchiolitis obliterans are GVHD of another organ or respiratory viral infections. One of the interesting things with the COVID pandemic is we saw fewer cases of BOS, and this is really just an anecdote, but it could be because there were fewer other respiratory viruses that were passed in the community. Why viruses trigger BOS is not entirely clear. This is something we're actively looking into, along with some colleagues of mine, to identify why viral infections seem to trigger GVHD of the lung.

(21:30): Airflow obstruction is a major symptom of bronchiolitis obliterans syndrome. This is a pretty busy slide, but this is the NIH criteria for diagnosing bronchiolitis obliterans syndrome. And I'm just going to break it down in a way that's a little more manageable. The first thing we look for is evidence of airflow obstruction. As I mentioned at the beginning of the talk, bronchiolitis obliterans syndrome is the only obstructive NIPC (non-infectious pulmonary complication), and so we look for a ratio of how much [a  patient] can blow out in one second versus how much [the patient] can blow out in total, and we try to see if that's less than 70%.

(22:00): Most of the time that number is 80% or higher. Once you get to 70%, you're often at the lower fifth percentile of the population, and if you're below that, we consider you to have airflow obstruction. We also mandate that you have a decline of at least 10%, that should read 10%, over two years. FEV1 should not correct to greater than 75%. Again, these are the NIH criteria. One of the downsides of requiring a threshold of 75% is that it potentially introduces a delay into the diagnosis. But if you move that number higher and higher, you're going to get more and more false positives. So it's a tradeoff between what we call sensitivity, which is our ability to pick up the disease, and specificity, which is our ability to rule out things that are not the disease.

(22:53): In the case of BOS, we also require that there's no active infection, and this is because certain infections, particularly viruses, can cause airflow obstruction, which is transient. This is again a challenge, because viruses are a risk factor for BOS, but they can also create a bronchiolitis, which is transient, and not the same as lung GVHD.

(23:17): Air trapping is another sign of BOS. Finally, we either look for air trapping on CT, or we look for air trapping on the pulmonary function tests. If someone has extrapulmonary chronic graft-versus-host disease, and this is a vast majority of patients, then you don't need one of those two features. But if you don't have extrapulmonary chronic graft-versus-host disease, the NIH actually recommends that you get a biopsy. I won't get into details, but a biopsy is a little bit controversial, and it can be associated with a lot of side effects.

(23:46): Early diagnosis is challenging because the symptoms of BOS are quite subtle. Diagnosing BOS early in its course is generally better. In other words, when we catch patients who are less sick, those patients often do better. Whether that's causal or just association is not entirely clear, but it seems like it's relatively reasonable to suggest that screening for this disease better could lead us to treat the disease better. But why can't we diagnose early BOS consistently? What is the problem where we're not screening as well as we could, and some patients come to us with more advanced BOS?

(24:17): One problem is that it's really hard to diagnose BOS because the symptoms are quite subtle. It can be hard to distinguish shortness of breath and fatigue from other conditions like just post-transplant fatigue, anemia, or viral infections, which are pretty common in the first year after transplantation. Pulmonary function screening, most places do it on a schedule where you get two or three tests in the first year. For example, at MD Anderson, we get tests at day 100, which is about three months after transplantation, and then at six and 12 months after transplantation.

(24:52): Testing for lung GVHD is important during the first year or two after transplant when the rate of lung GVHD increases. One of the things that we just published and showed, and I don't have the reference here because it was just accepted last month, but the rate of testing drops substantially in year two, but the rate of lung GVHD really increases at around nine to 12 months after transplantation. It's almost like we take our eyes off right as the rate of BOS is going up. And this is something that I hope we can change in one way or another, because just as we stop to test for pulmonary function testing, the rate of BOS actually rises, and we test more frequently at a time when the rate of BOS is relatively lower.

(25:30): Finally, there's no way to diagnose this with chest imaging, other than some advanced techniques, which you may read if you're familiar with the literature are called PRM or parametric response mapping. And there's some other techniques as well. These are not really ready for the clinic yet, and so this is something that if you look at a CT, it's not going to pop up at you as well. So this is something that could really fly under the radar until it becomes a big problem.

(25:54): The treatment for BOS is systemic immunosuppression and inhaled corticosteroids. The mainstay of treatment for BOS is systemic immunosuppression and inhaled corticosteroids. We used to use something called FAM, which is fluticasone, which is used as a stand-in for a general inhaled corticosteroid, azithromycin, and I'll talk a little bit more about that. And then finally montelukast, which is a drug that is often used to treat allergic types of inflammation. More recently, there's been some concerns that azithromycin might increase the rate of cancer relapse. This is based on a study by Anne Bergeron, my colleague in France, who showed that azithromycin, which was given at the time of conditioning to prevent BOS actually resulted in a higher rate of relapse, and also in, unfortunately, a higher rate of BOS as well. She's doing some work to figure out why that happened, because it's not entirely clear.

(26:43): We often consider second line therapies, so there's a couple that we often use here, like ruxolitinib and belumosudil. But one thing that's really clear is that the second line therapies that work well for non-lung GVHD typically don't work as well in the lungs. The lungs, they're a little bit rare, they're not as therapy responsive. So this is an area that I'm very interested in to figure out how to treat refractory BOS.

(27:11): Pulmonary rehabilitation can help with recovery from BOS. Finally, if you have BOS, ask your doctors about pulmonary rehabilitation. This is basically like exercise, and the way I phrase it to patients is this. What is pulmonary rehabilitation? It's a multimodal approach where we improve aerobic conditioning. So we often have folks work out on the treadmill or on a bike, and we mix it up a little bit too, so you're not getting used to the exercises. You're sort of keeping your body constantly improving. We also do stuff to improve muscle strength. For example, light weights or resistance bands. We also do things to improve balance as well, to restore some of the function of the body.

(27:52): This is almost like having a personal trainer. We teach patients based on where they are and where we think they can get and where they want to be. And then finally, we help them to cope with the symptoms of shortness of breath as well. This is pretty time intensive. It requires two to three sessions per week. Usually it's one to one and a half hours, and it may require up to six months of therapy.

The data is quite limited in hematopoietic cell transplantation, but in a small study, patients with BOS, 10 out of 11 who did lung transplant or pulmonary rehabilitation after hematopoietic cell transplantation had better physical function and less shortness of breath after this. And this should not be surprising, because even if we can't get the lungs to improve, we know that exercise improves the muscles.

(28:42): Screening for BOS may be done by home spirometers. Finally, I want to talk a little bit about screening for BOS in the digital age. I've started to use some home spirometers again, mostly in a research setting, but we would love to see this in the clinic. And we're working to see how we can get this paid for by insurance companies so we can really roll this out on a large scale. Both I and Guang-Shing Cheng, my collaborator at Fred Hutch Cancer Center, have shown that home spirometry is easy, it's reproducible. And more recently we showed that it can be cost effective when you consider the cost. This is just the economic cost, of course the economic cost is not the most important thing. The most important thing is the impact on patients' lives.

(29:19): But even if we had to just reduce it to economic cost, bronchiolitis obliterans is a very expensive disease when you consider the resources that we invest into a hematopoietic cell transplantation. Again, this is a bit of a dispassionate way to look at it. The most important thing is how patients feel and to get them to feel better. But if you had to put it into economic terms, if you develop BOS, that comes at a huge cost to payers. So if we can find ways to screen for it which cost a fraction of that, then I hope that we can show that we can really develop and use modern technologies to screen for BOS in a way that's more comprehensive.

(29:58): We can do this lung function monitoring more frequently in the home. We send folks home with spirometers that pretty much could fit in your pocket. They're tiny little devices. And usually, if we see a 10% drop, that often indicates a real drop, but we have to have people come into the clinic at that point and make sure it's not infection or weakness or some other condition. So we've gotten pretty good at teasing this out, but at the end of the day, we still have to have a face-to-face encounter to confirm it. But this is hopefully the wave of the future. And I think COVID showed, really, the benefit of doing telemonitoring and telehealth type strategies.

(30:35): So what are the costs, potentially, or what are the potential downside to home spirometry? Well, there is a cost. We have to convince payers that this is important. I hope we can convince them that it'll save them money. And I'm very convinced that it'll improve patient lives. Also, there is some burden on patients. It takes about five minutes per session, but I know that transplant recipients have a lot to worry about, and this is just one additional thing.

(31:01): We don’t want to over-diagnose BOS and cause undue stress to patients. We also don't want to over-diagnose BOS because, as I showed you, BOS is hard to diagnose. We don't have great biomarkers. This is something that I work hard on, but it's something that is not ready for primetime yet, and so until we prove that these biomarkers work, we don't want to over diagnose BOS and cause undue distress to patients. It's also hard to arrange proper follow-up. Again, these are all solvable problems, and these are problems that should not discourage anyone from doing this sort of thing, but sometimes trying to get folks to come from far away and see a pulmonologist is difficult. I would argue that all of these are solvable, and that homes spirometry is something that we should widely implement in transplant centers.

(31:40): Transplant recipients should find a good neighborhood pulmonologist for follow up treatment. Finally, I would encourage everyone to find a good neighborhood pulmonologist. If you live near a cancer center, you should see a pulmonologist that's affiliated with that cancer center, because you want to see someone who sees a lot of transplant recipients. There's a lot of unique things to consider and it takes some nuance to understand. I know when I first started here at MD Anderson, it took me probably about a year or two to really understand all the nuances. And even then it's still a continual learning process. It's something that we can always get better at.

(32:11): If you can't do that, these days we can do tele visits, and so try to see if that's a possibility as well. And then also look for somebody in the GVHD directory [offered online by BMT InfoNet] and see if we can help to coordinate you with a pulmonologist close to you or even see you in our clinic. I'm really committed to helping folks prevent and treat this condition. So with that, I'd like to open it up to questions with the help of our moderating teams.

Question and Answer Session

(32:42): [Becky Dame] Thank you, Dr Sheshadri, for the excellent presentation. We will now take questions. Our first question is, Dr. Sheshadri, what is the most important thing to do and get lung GVHD better?

(33:13): [Dr. Ajay Sheshardi] This is a great question, and I think it relates a little bit to the question below as well, can damage to the lungs be reversed and improved? These things go a little bit hand in hand.

(33:23): When we diagnose lung GVHD early, sometimes we catch the airways where potentially we can get some lung function back. But the longer it goes on, the harder that is to do. Sometimes we can get to a point where we can keep the lung from getting any worse, but we can't really get the lung any better. And I think this has to do with the fact that the lung really doesn't have a lot of airway stem cells when you compare it to other organs like the gut or the skin.

(33:52): When we think about an injury and recovery from injury, the lung and the airways really don't recover as well as the skin and other organs. Sometimes lung GVHD doesn't really get any better, unfortunately. This is something that's very vexing to patients, and a big challenge for us as well. In those cases, we try to keep it from getting worse, but is there something that we could do better? Again, I would point to pulmonary rehabilitation.

(34:20): I'll give the analogy of COPD [chronic obstructive pulmonary disease].  COPD, when folks smoke, the lung often doesn't recover to where it was before. Sometimes it doesn't recover at all. But in those cases, we have a wealth of data showing that pulmonary rehabilitation not only improves patient symptoms, but it can improve outcomes like COPD exacerbation and hospitalization. So it builds reserve. It's exercise. So even if the lungs aren't getting any better, we can improve the muscles. You could think of the muscles as the real engines of the body, and so the more efficient the engines are, the less you have to use your exhaust system, which is your lungs.

(35:02): With pulmonary rehabilitation, we can improve vascularity in the muscles, we improve blood flow to the muscles. We improve the efficiency of the muscles at a macro and all the way down to a cellular scale. And so we don't work the lungs quite as hard, So if we have a given unit of work, for example, if you wanted to take a shower or make your bed, these are things that we often take for granted until our lungs have issues. We can make that easier by improving the muscular strength, even if the lung function has not changed significantly.

(35:33): So that's what I would say, is that if you haven't tried pulmonary rehabilitation, I would strongly encourage that to you. It's like exercise, and really, when you think about side effects and risks, it's about as low risk an intervention as you can conceive.

(35:49): [Becky Dame] I believe you just answered this question, but do the specific lung exercises help more than general exercise, like walking?

(35:58): [Dr. Ajay Sheshadi] Yeah, some of the lung exercises that we do... I guess we can divide this up a little bit.

(36:04): The lung is not really a muscle, and so there's certain breathing exercises that can help calm the breath and reduce shortness of breath, but the diaphragm is working all of the time. When the diaphragm is not atrophied or strained, it's hard to really get it to be any more efficient than it is, because it's already working at full steam.

(36:27): On the other hand, the muscles are not. And so general exercises like walking or biking, these are really great exercises for someone with lung GVHD. I would say that when we talk about lung exercises, the breathing exercises have value to reduce shortness of breath and try to help when you feel like you have breathlessness. But in terms of the greatest value to prevent breathlessness, I would say that aerobic exercise like walking or biking is really great.

(37:01): [Becky Dame] Perfect, thank you so much. We have another question. I believe you've already answered this too, right at the end of your presentation. So there are some home devices available for PFT testing by the patient?

(37:15): [Dr. Ajay Sheshadri] Yes. This is something that I would really like to see where patients don't have to spend a dime to get it, and we would just take care of the cost. That's a little bit of an aspiration goal right now. It's something I'm actively working on, I've been working on it for about two years now, and I think we're making some progress. I'd really like to roll it out at MD Anderson this calendar year.

(37:43): In the meantime, we have had patients purchase their own spirometers. I review their charts. We use an electronic medical record where patients can send me those as an attachment. Sometimes they've emailed them to me. So I've monitored patients in that way. It's just not as reliable as having a central system, and so a central system, we can do things like we build in alarms so that I can review hundreds of patients potentially and do it in a way that it's not consuming a ton of time, so I could do it quite efficiently.

(38:19): That's the kind of thing that you want to see, because at the end of the day, you want it to be something that doesn't add any financial burden and as minimal a time burden as possible onto patients. That's the way that we're envisioning it, and hopefully we'll make some progress in the next couple of years. Just as an aside, this is something that the lung transplant community has been doing for 30 plus years, and so it's definitely something we can do. I think it's something that we just need to work and find a way to make it happen.

(38:58): [Becky Dame] One of the patients or caregivers with us today is asking if there are any immune suppression medications which can make pre-existing asthma or COPD worse?

(39:16): [Dr. Ajay Sheshadri] Not that I know of. Let me just make sure I'm understanding the question correctly. The question is, can some of the immunosuppressive agents make asthma or COPD worse? In general, no. And in fact, some of the agents are used to reduce the amount of inflammation in the body.

(39:42): Now, I will say, as an aside, that immunosuppressive agents can increase the risk for viral infections, and we know that viral infections are a trigger for worsening asthma and worsening COPD, so these are what we call exacerbations of those diseases. Even the common cold is well known to be a risk factor for asthma and COPD exacerbations.

(40:06): So in that sense, immunosuppressive medications can predispose you to viral infections, which even if they're relatively asymptomatic in terms of the actual upper respiratory tract infection symptoms, those can trigger exacerbations of asthma and COPD. But I don't think they can directly worsen asthma and COPD outside of that effect.

(40:32): [Becky Dame] On the same line, there's another question that if you're already taking Montelukast for asthma, does it reduce your risk for BOS?

(40:42): [Dr. Ajay Sheshadri] That's a great question. This is something that I know at least one of my colleagues is working on. The introduction of Montelukast is based on data from lung transplant that... even in lung transplant, it's not clear whether it works in all patients or how it works. It's something that I think people introduced when they introduced FAM, because at that point we didn't have a great way of treating BOS, and so it was sort of like, "Let's try to figure out how to block all the known sources of inflammation that could be happening here."

(41:21): Montelukast was used in that way. It has not been studied on its own, nor has it been studied in a way where you randomize Montelukast and placebo and you give somebody inhaled steroids and you see if there's an additional benefit with Montelukast. This is something I know one of my collaborators is looking at.

(41:38): But as far as I can tell, the main effect that we see from FAM is, with the inhaled steroids with the Montelukast, I don't think is the main effect. And I don't think there's anything to suggest that Montelukast could prevent BOS at this point. It is a possibility, but it needs to be tested more systematically for me to be able to answer that. So I would guess no, at this point, but I couldn't give a more definitive answer than that.

(42:09): [Becky Dame] One of the questions is what's best for treating the chronic cough that comes with BOS.

(42:16): [Dr. Ajay Sheshadri] That's a great question. Cough is one of the most common symptoms that occurs after BOS. And I'll say there are three sources of cough that are worth considering.

(42:33): The first is airway inflammation. This is similar to asthma. When the airways are inflamed, they're more likely to be twitchy and spasm and cause cough. And at the end of the day, cough is sort of like a spasm of the airways. With proper immune suppression, often the cough can get better, but sometimes people are still coughing, and a lot of times it's because when you have lung GVHD, you make a lot of mucus.

(42:58): One of the things that I like to do, which I will say as a caveat, there's no scientific evidence to say that this works at this point, but there's a lot of clinical evidence, and there's also evidence in other diseases like cystic fibrosis. I like to use a nebulizer with hypertonic saline. It's just salt water, seven percent salt water. It's kind of a neat story. It was discovered in cystic fibrosis because surfers who were in Australia had better clearance of their lungs, and cystic fibrosis, if you don't clear your lungs, your lungs get a lot worse.

(43:35): We use this same seven percent saline, it's almost like the sea breeze, to give the mucus a little more volume and help people cough that up. So when we clear the lung of mucus, we can sometimes reduce the feeling that you need to cough something up. I will say that hypertonic saline, seven percent saline, often with albuterol beforehand, because in some folks you can get a bit of a bronchial constriction or airway tightening effect, which can help with the cough. And again, that's something that should be proven more scientifically, I think, but I think I've used that in the clinic now for several years.

(44:13): Finally, there are some new agents for chronic cough that are being tested. They're not really ready for prime time yet, but I do think that this is something that... Chronic cough is one of the toughest problems for a pulmonologist to solve, because most of the time if it's easy, they would've already been treated by somebody else. So by the time they see a pulmonologist, you know that it's probably not your usual case of chronic cough.

(44:38): There are agents that are being tested that hopefully we'll have more information about soon. And perhaps one of those will be useful as well. So if it's not just a mucus or an inflammatory thing, maybe we can cool off the nerves a little bit and keep people from having that urge to cough. So I would just say stay tuned for that, but for now, if you're not on a nebulizer with seven percent saline, that's something that I would talk to your pulmonologist to try.

(45:02): [Becky Dame] Thank you. We have a question about one of the newer medicines. What have you seen about Rezurock that was just FDA approved, approval for BOS?

(45:16): [Dr. Ajay Sheshadri] That's a great question. It's a pretty novel method of inhibition and it inhibits something called ROCK2, and so it's got some anti-scarring effects as well, and there's a 30 to 40 percent response rate based on the phase three data with Rezurock.

(45:36): We talked a little bit about this when we wrote the NIH guidelines a couple years ago. And sometimes we talk about response or stability or getting a little bit of lung function back, but where we would like to be eventually is to have reversibility of this and try to get folks back closer to the normal range. In my experience, when I use Rezurock, a lot of times we see stability, we might even see a little bit of improvement, but we don't see a dramatic change, like the way we do in some organs. For example, in folks who have severe skin GVHD, I've seen dramatic improvements with belumosudil, but I don't see that type of dramatic improvement in the lung.

(46:16): I don't think it's necessarily the fault of Rezurock or ruxolitinib or any of these other drugs. I think it's really a fundamental issue with the lung's ability to regenerate itself. What I hope is that in the next 10 years, not only can we halt the inflammation and reduce some of the scarring, but maybe we could figure out a way to get the lung to regenerate a little bit. That's something that we have some very early phase projects looking at that. But I would say that if those were at the bedside in 10 years, we'll be doing really well. They're not really close enough to even talk about at this point, but I do think that's the way to repair the lung, is that not only do you have to stop these inflammation and scarring, but you really have to help the lung heal itself.

(47:03): [Becky Dame] Thank you. We have another patient who's asking, if you are over two years out and have chronic GVHD, do you have to worry about lung problems?

(47:19): [Dr. Ajay Sheshadri] That's a great question. If you look at when patients develop GVHD of the lungs, for the most part it is usually around year one, so right around 12 months. The median time is 12 to 18 months. If you develop it a little earlier, that often indicates a more severe lung GVHD, but there's a long tail too. And so just going back to my home spirometry program, the way we've envisioned it is that we're going to watch patients for three years.

(47:56): Now, the three years is a little bit arbitrary because most of the risk is probably in the first two years, and the risk in year three is probably lower than year two. But then there's a long tail as well. We've seen folks develop lung GVHD four or five years out. The rate, of course, gets lower and lower and lower the further you go out, but there may be no specific cutoff where we say, "Okay, you're safe forever."

(48:21): I think at three years, the risk is low enough that you can give people the peace of mind to say, "We've watched you during the highest period of risk for BOS." And then after this, it doesn't mean that there's zero risk, but the risk is much lower, and you can stop worrying about this and stop doing this weekly spirometry.

(48:42): But at two years, I would say the risk is still... The risk in year three is still high enough that I would suggest monitoring for at least three years. But again, that's more at the level of expert opinion based on when we know that BOS occurs.

(48:59): [Becky Dame] Do you feel that a patient with asymptomatic MAC, M-A-C, who also has BO, should not be on azithromycin as part of the same protocol?

(49:11): [Dr. Ajay Sheshadri] That's a great question. We've done a couple of studies to look at this, and one of the things that that FDA black box warning is that the azithromycin was done at the time of conditioning. That means that it was given at a time that we typically don't use azithromycin.

(49:27): We looked back and said, "Okay. We give azithromycin typically for lung GVHD or the treatment of infections. These occur later in the course of transplantation, when the relapse risk is much lower than at the time of conditioning, when you've freshly treated folks and induced a remission, and you feel like this is the time to start the transplantation process. The risk of relapse is much higher then. So in a period where the risk of relapse is lower, do we still see the same effective as azithromycin?"

(50:00): This is lower quality data than the original data that led to the black box warning, because these are retrospective studies. These were not randomized controlled studies. But Guang-Shing Cheng and Anne Bergeron who published the original finding showed that when you give azithromycin for BOS, there's no additional risk of relapse. There was an additional risk of mostly secondary malignancies, which, as I recall, were mostly skin malignancies, and they did not increase the risk for death.

(50:33): In our cohort, we showed that generally speaking, there's no increased risk of relapse. We did see an increased risk of relapse in patients with unrelated donors or who and who were treated with antithymocyte globulin, so maybe there's an effect with the T-cell depletion where the azithromycin, which we know has some immunomodulatory effects, reduces the graft-versus-leukemia response. And so we stopped using azithromycin altogether.

(51:01): But at the end of the day, the decision to treat MAC is something that it's a bit individualized. And one of the reasons that it's individualized is that when you use an azithromycin-based regimen to treat MAC, it takes months to eradicate MAC, and so you have to commit to that azithromycin. We often treat MAC only when we are worried that someone's lungs are getting chewed up with a disease process called bronchiectasis, where the airways are actually being damaged. And in that case, the risk of letting that go on is greater than the risks that we typically attribute to azithromycin. And this includes the pretty low risk of relapse, depending on where you are with MAC treatment.

(51:45): I guess the way I'd phrase it is that if we're worried that the MAC is so active that it's chewing up the lungs and causing problems, then we would prefer to prevent that at the cost of what's likely to be a very low, but probably not zero risk of relapse. The relapse data, again, it would be really nice if we had better data looking at the use of azithromycin when we actually prescribe it for infections and transplant. I still cite my data and Dr. Cheng's data with a little bit of a grain of salt, because these are retrospective studies and there's a lot of biases that go into them, and you can control for most of them, but probably not all of them. And so I would say that the risk of relapse is non-zero, but it's likely to be very low.

(52:42): [Becky Dame] Thank you so much. We have another question, a little bit different. This one is a 69-year-old post allogeneic transplant in 2018. They had a pulmonary effusion that needed to be drained while in-patient. They're asking what caused that, and they also are asking, they were diagnosed with sleep apnea after two years, and are the effusions and sleep apnea related now that he's on CPAP?

(53:37): [Dr. Ajay Sheshadri] One of the things with sleep apnea is that some folks may be on the borderline where if their lung function is totally normal, they may not have apneic events, but then perhaps with some loss of vital capacity, they sort of drift into the point where they're getting hypotonic episodes and apneic episodes, and they might even see their oxygen levels drop.

(54:01): The way we test for sleep apnea is we measure something called the apnea-hypopnea index. This is something that it's not a perfect tool to diagnose sleep apnea, as a caveat, but when it's combined with breathlessness, it's often a good way to determine if somebody has apnea or not. And post-hospitalization, sometimes there's a higher rate of sleep disturbances for a variety of reasons. And then when you have a total effusion, that can often tip people to where their vital capacity [inaudible 00:54:38] ability to ventilate at night is lower and they may have sleep apnea for that reason.

(54:43): So that case, the effusion may be connected to the apnea. Generally speaking, most folks with effusions don't have new-onset apnea, but in somebody who might have been on the borderline or the cusp of that, then it is possible that it might push you over the edge, I would say. That's something that potentially could be managed by a pulmonologist.

(55:08): [Becky Dame] Thank you. A patient is wanting to know, how can they distinguish between BOS and worsening asthma or COPD that was already present?

(55:20): [Dr. Ajay Sheshadri] This is a great question. And it is something that is incredibly challenging for us. When you look at some of the earlier data, when you have asthma or COPD before transplantation, that increases the risk for BOS after transplantation. When we try to look at this data retrospectively, so when we look at all our patients who develop BOS, we have to look really carefully to see if they had any evidence of asthma before. And then we have the benefit of hindsight, of course, because this happened, so we could see what happens when folks are treated. Did the lung function go up and down like in a patient with asthma? Do they have a significant history of smoking?

(56:02): Practically speaking, we look at the pre-transplant pulmonary function and we talk to patients. So if they have a substantial burden of smoking and we see pre-transplant airflow obstruction, they come to us with an exacerbation, we might treat that with the course of steroids and see if it's a COPD exacerbation and have very close follow up. But that can look exactly like new-onset BOS, too.

(56:23): So we look for some other clues, like if we see a lot of air trapping where there wasn't air trapping before, well, that points us to more of a small airflow obstruction, which could be more consistent with BOS. If we see that someone has up and down lung function over several time points, we might conclude they have asthma, particularly if they have a strong history of asthma.

(56:42): One of the saving graces is that inhaled steroids work for all of these conditions, so we often will prescribe the inhaled steroids and perhaps a course of oral steroids, and we'll just follow them up very closely in these cases that are somewhat uncertain. It is a challenge to distinguish it, because as I mentioned during the talk, there's not a specific biomarker for bronchiolitis obliterans, particularly one that can differentiate it from asthma or COPD at this point.

(57:07): So that's something that I think we as a scientific community need to work on, but at this point, I'll say that there's some clinical clues that can help us distinguish it, but they're not good enough for us to be a hundred percent certain.

(57:23): [Becky Dame] Closing.  Well, thank you so much. Thank you, Dr. Sheshadri for this excellent presentation. Unfortunately we're running out of time, so on behalf of the BMT InfoNet and our partners, I'd like to thank Dr. Sheshadri for his helpful remarks and thank you in the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way. Enjoy the rest of your symposium.