Pulmonary Problems after Transplant

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Pulmonary Problems after Transplant

Friday, April 23, 2021

Presenter: Joe Hsu MD, MPH, Assistant Professor of Medicine, Stanford Health Care, and Director of Stanford's Lung Graft-Versus-Host Disease Clinic.

Presentation is 39 minutes long with 16 minutes of Q & A.

Summary: Some transplant recipients experience breathing difficulties months or years after transplant. Patients may not have symptoms until lung damage is significant. Frequent monitoring for lung problems and early treatment is critical to prevent the damage from getting worse.

Highlights:

• Pulmonary problems can be generally divided in two main categories. There are restrictive problems where the lung is too small. This type leads to pneumonia, truncal sclerosis, serositis. There are obstructive problems, mainly bronchiolitis obliterans syndrome (BOS) which is often caused by graft-versus-host disease (GVHD).
• There are often no symptoms of lung problems after transplant until the problem is severe.
• Early detection of pulmonary problems is critical to successful treatment. Pulmonary function tests should be done every three months for patients with chronic GVHD.

Key Points:

(03:32) Healthy lungs function like a bellows that draws in oxygen and removes CO 2.

(05:35) Treating lung issues means improving the whole cardiopulmonary system. A strong heart, adequate blood, and efficient muscles all contribute to pulmonary health.

(06:30) Graft-versus-host disease (GVHD) can cause truncal sclerosis – a tightening of the skin around the trunk and abdomen – which makes breathing difficult. It can lead to a condition called serositis, which is a build-up of fluid in the lungs, or cause pneumonia.

(07:33) The lung problem most often associated with  graft-versus-host disease is bronchiolitis obliterans syndrome (BOS).

(08:52) Organized pneumonia can be caused by GVHD but also by medications used during transplant.

(20:37) The initial treatment for BOS is FAM: fluticasone, an inhaled corticosteroid; azithromycin, an antibiotic and anti-inflammatory medication; and montelukast, anti-inflammatory and anti-allergy medication.

(21:37) Prednisone helps 20-50% of patients who do not respond to FAM, but it has significant side effects.  Extracorporeal photopheresis (ECP), imatinib and etanercept may also help.

(25:24) A recent study tested pirfenidone as a treatment for BOS. It improved lung function and appeared to help with GVHD of the skin and mouth as well.

(29:24) Aerobic exercise activity is key to improving lung function.

(35:58) Lung transplants for bone marrow and stem cell transplant patients pose complicated issues and do not have promising survival rates.

Transcript of Presentation:

Note: In this presentation the speaker(s) sometimes uses the terms “BMT” or” bone marrow transplant”. For purposes of this presentation, both of those terms also apply to patients who have been through a stem cell transplant.

(00:00) [Sue Stewart]  Introduction. Hello. My name is Sue Stewart, and I will be your moderator for today's workshop. Today, we are talking about pulmonary problems after transplant, and it's my pleasure to introduce to you Dr. Joseph Hsu, who will be our speaker. Dr. Hsu is an assistant professor of medicine, specializing in pulmonary and critical care at Stanford University Medical Center. He has over 10 years experience caring for patients with pulmonary problems, including chronic graft-versus-host disease. Dr. Hsu is the director of Stanford's Lung Graft-Versus-Host Disease clinic, which, among other things is developing methods for earlier diagnosis of lung GVHD, and new therapies to treat bronchiolitis obliterans syndrome, or BOS, after transplant. Please join me in welcoming Dr. Hsu.

(00:57) [Joe Hsu]  Thank you, Sue. I wanted to thank the organizers for inviting me to this wonderful conference. By way of introduction, my name is Joe Hsu. I'm a pulmonologist at Stanford Hospital and director of the Lung GVHD clinic, where we are dedicated to treating persons with pulmonary complications after stem cell transplant. I'm thrilled to be able to talk to you and share the stories of my patients from the clinic.

(01:23)  In the lower right hand panel is a graduate from the clinic. His name is Jason Tirado. ANW here stands for American Ninja Warrior. Jason went from not being able to walk a few feet without shortness of breath to being on the finals of American Ninja Warrior, and we're going to have the pleasure of watching his run at the end of the presentation.

(01:47) I thought I would start the talk with a quite from Miguel de Cervantes, the author of Don Quixote. For those of you unfamiliar with the story, Don Quixote is the story of a man who becomes a self-proclaimed knight on a quest to fight the injustice of all the world.

(02:01)  About five years ago, I had my Don Quixote moment. I had a clinic of amazing, inspirational people who were living a life with a debilitating condition known as bronchiolitis obliterans syndrome, otherwise known as BOS, and there was no treatment for the progressive decline. Refusing to accept the status quo, I self-sponsored the STOP-BOS trial to use a medication called pirfenidone to treat bronchiolitis obliterans syndrome, and am excited to share the preliminary results of that trial with you later in today's talk.

(02:34) Overview of talk. Today, we're going to start by talking about the breath, and this is more than just the exchange of oxygen and carbon dioxide. This is actually a mechanical system, and there's also opportunities to improve shortness of breath by improving your cardiopulmonary status, and this is really the philosophy of the clinic.

Then I'm going to try to explain to you the problems that can happen after transplant. Unfortunately, those can be quite common.

I'm going to talk about some current treatments, and future treatments. I think that this is a really exciting time for lung GVHD because there are so many future treatments in the pipeline, including preventative.

So I'm going to talk with you about living with lung GVHD and how you can try to get past the pulmonary impairment, some frequently asked questions usually in regards to COVID and lung transplantation, and then we're going to see Jason run his American Ninja Warrior attempt.

(03:32) Healthy lungs function like a bellows. So, the lungs in the simple form are a variety of small balloons, and in those small balloons, you are taking in oxygen and you are removing CO 2. But the lungs are much more complicated than that.

(03:51) So here, you can see that the lungs are acting like a bellows, so the diaphragm descends, and the lungs draw in air. And as the diaphragm rises, then actually the CO 2 is removed. And seeing the way the lungs function, you can actually begin to understand why problems can get created.

(04:17) Lung problems arise from obstructions or restrictions in this “bellows.” For example, if you have an obstruction where the lungs cannot empty air, then it's like a balloon that you fill up and yet never deflate, and that filling of the balloon and not deflating is known as air trapping, which is one of the cardinal symptoms of BOS.

(04:33) You can also imagine that if you have any kind of restriction that prevents the diaphragm from actually descending, then that can actually make the lungs smaller, and that is known as restrictive lung disease, and the most common one is pneumonia or truncal sclerosis.

(04:48) Breathing is a complicated process. But the breath is much more complicated than this. I like to draw cartoons in my clinic, and this is one of the cartoons that I drew. So what I do is I compare breathing to trying to transport persons from one station, i.e. the lungs, to the city. And therefore, you can see that even if your lungs are debilitated, there are multiple opportunities to to make things better.

(05:17) So here, the persons that are getting onto the train is the analogy for the oxygen, the blood is the analogy for the passenger cars. The train itself is actually the heart, and the offloading station where people need to go to is the muscles, or the city.

(05:35) Treating lung issues means improving the whole cardiopulmonary system. And what we really try to focus on is improving the whole cardiopulmonary system. In other words, you need a strong heart, you need adequate blood, you need a very efficient set of muscles to actually offload so that the train can get back and bring the CO 2 back to the lungs so that it can be removed. And we'll talk more about this as we talk about living with GVHD.

(05:58) Lung issues can involve obstructions or restrictions. As I mentioned before, there are many problems that can happen after transplant, and those problems can be broadly divided into those that are obstructive and those that are restrictive.

(06:08) Obstructions mean not being able to empty the lungs so they become hyper-inflated. Thinking back to the slide where you imagine the lungs as a bellow, you can start to see that the mechanical problems can result in obstruction, that you can't actually empty the lungs out, and because of that, they become quite hyper-inflated. Unfortunately, in BOS, this obstruction is not happening in the main airways, it's happening in these small airways, and we'll look actually what that looks like under the slide.

(06:30) Truncal sclerosis - tightening of the skin around the trunk and abdomen caused by skin graft-versus-host disease - can make  breathing difficult. You also have a variety of conditions that can cause restriction, and these are basically resulting in smaller lungs, and there is less place to change gas.

You can have restriction of the chest abdominal wall after transplant. This is known as truncal sclerosis, and this is that tight skin that you can get along the trunk and the abdomen, and this basically causes the diaphragm to not be able to fully go down or the lungs to fully expand, so the lungs become trapped in a box.

(06:59) This can lead to serositis or several types of pneumonia. You can get fluid that builds up inside the lungs that essentially takes up space, and it doesn't allow you to exchange gas, and this is the condition known as serositis.

 (07:09) You can also get pneumonia. Pneumonia can be infectious, which can be the result of viral, bacterial, or fungal organisms, and you can also get inflammatory pneumonia, and a condition known as organizing pneumonia. This is also known as cryptogenic organizing pneumonia, or COP, or bronchiolitis obliterans organizing pneumonia, or BOOP, but we'll refer to this as organizing pneumonia.

(07:33) Chronic graft-versus-host disease can cause numerous problems but bronchiolitis obliterans syndrome is its clearest manifestation. So, here essentially is the landscape of the pulmonary problems that you can have after transplant, and here the solid line represents those that are, for example, clearly associated with chronic GVHD, and the dotted line represents conditions that for which chronic GVHD is a risk factor. Among the restrictive conditions, you can have infectious pneumonia, you can have organized pneumonia. You can have fluid around the lung, or you can have skin-related GVHD that causes truncal sclerosis. And then the only real manifestation of chronic GVHD in the lung that is clearly defined is bronchiolitis obliterans syndrome.

(08:19) My sense is that the epidemiology of the other conditions will eventually change. For example, organized pneumonia is very strongly related to chronic GVHD. Skin GVHD causing truncal sclerosis obviously is also very strongly related, so in the future, this definition may begin to change. For now, we're going to focus first on pneumonias. Because I know Dr. Brown gave a talk, and I imagine that she talked about infections pneumonia, I'm not going to go into that too in-depth, but rather I'm going to focus on organized pneumonia.

(08:52) Organized pneumonia and its symptoms can be caused by GVHD but also by medications used with transplant. Organized pneumonia. The risk factors are chronic GVHD, viral infections, but the reason that this is not clearly associated with chronic GVHD is because this can actually also be caused by a variety of medications, particularly those that are used in and around the time of transplant. The diagnosis becomes very difficult because it will actually present exactly like an infectious pneumonia. Fifty percent will present with flu-like illness. Shortness of breath is common. Fevers can be low-grade or higher, such as you might get with the flu, and you get a cough.

(09:24) One of the symptoms that I've found particularly telling for this condition is this notion of chest pain when you take a deep breath. And people will also sometimes say that they have a catch at the top of their breath that limits them from taking a deeper breath.

(09:39) Corticosteroids are an effective treatment but relapses are common. The treatment for this condition is corticosteroids, and people really respond very quickly to corticosteroids, and you can have a dramatic recovery. Here, we have a gentleman in my clinic who I met in the ICU on the verge of intubation. We treated him with corticosteroids, and literally within days he was out of the ICU, and here he's showing us his medal that he won from getting third place in a 5K run. Unfortunately, relapses can be very common.

(10:12) What I'm showing you here is a CT scan, so this is cutting down the lungs like you're cutting down a slice of bread, and you're seeing a cross-section of the lungs. The white that you see within the red circles, this is actually the organizing pneumonia where you have inflammatory cells, not infections cells, that essentially start to take up those alveoli or those balloons that comprise the lungs.

(10:39) You'll notice that unlike you might see in a pneumonia where there'll be a completely white out, you have these areas that are spared. And we in pulmonology like to label things in geographic ways, so this is actually known as the atoll sign, which is a reasonably good sign for diagnosing organized pneumonia.

(10:57) Oftentimes, the diagnosis is very difficult and we actually see patients that have been treated with multiple rounds of antibiotics and have not gotten any better. And typically, without any discovery of any organism, this turns out to be an inflammatory pneumonia.

(11:12) As I said before, it is very amenable to treatment, and in fact, he went from nearly being intubated to six weeks follow-up where you can see the lungs have basically completely cleared up.

(11:27) Restrictive conditions involve serositis or truncal sclerosis which is fluid in the lungs. The next set of conditions are also restrictive, and these involve serositis or truncal sclerosis. Serositis essentially is fluid that has built up around the lung lining. It can also present with fluid around the heart in the space known as the pericardial space.

(11:47) Now, typically when you see these effusions, so you can see that this is a gentleman that has serositis, and you can compare his lung size on the left to the lung size on the right where the fluid is completely drained. You can imagine how much volume he's actually lost in his lungs.

(12:04) Corticosteroids can be an effective treatment. This is also treated by corticosteroids, and sometimes you actually need to use these catheters. So you can see that on the right, you have this curly Q catheter, which we call a pigtail, that gets placed to drain the fluid. Now, the use of these catheters is very institutional-dependent, so some institutions would place them, others would not. In my experience, when you have someone that's unable to resolve it by say removing more fluid, then you need to place these catheters and then start the corticosteroids to help hold the fluid at bay.

(12:43) Restrictive lung disease also comes from tightening of the chest or abdominal wall. You can also get restrictive lung disease from a tightening of the chest wall and abdominal wall, and going back to the video, you can imagine that the diaphragm can't distend into the abdomen, then you can derive quite a bit of shortness of breath just from this restriction. And this is a bit like taking an ace wrap and wrapping it around your whole torso. The typical symptom is that people start to get shorter breath when laying flat.

(13:07) It can be treated with several medications. The treatment for this condition, it can be somewhat difficult to treat. Typical treatments are extracorporeal photopheresis, otherwise known as ECP or immune suppression. There are some specific medications that can be used for this condition. In my experience, ruxolitinib has some effect, vismodegib has some effect, and there is a new drug called KD-025, which also actually has some effect at softening the skin.

(13:35) And the nice thing about this condition is that the lungs underneath the skin are actually normal, so if you can soften the skin, then you can really improve your shortness of breath. And I have one patient who, when her skin began to soften, she went from not being able to walk a few feet, now able to start to job. So it can really be a dramatic difference, but unfortunately that difference happens over the span of weeks and months, as opposed to days. There is also some potential future of anti-fibrotic medications, including medications that I will mention later, like pirfenidone.

(14:13) The most obvious manifestation of chronic GVHD is bronchiolitis obliterans syndrome (BOS) which is a mechanical obstruction in the airways of the lungs. So then we get to the condition that is truly associated with chronic GVHD, and that's bronchiolitis obliterans syndrome, or BOS. As I showed you before, bronchiolitis obliterans syndrome is a mechanical obstruction that happens in the distal airways of the lungs.

(14:31) What we are seeing here on the right is actually a technology that we're pioneering with a company known as enBio. This allows us to colorize the lungs into areas that are green or normal, purple or squashed lung, yellow represents the actual trapped air behind, and red here is known as epididymis, or extremely trapped lung, so a hyperinflated lung. And you can see that the condition could be very patchy, so there could be areas of normal lung and there can be areas that are air trapped.

(15:07) As the lung enlarges with BOS, restrictive problems also arise. And what happens to the lung is that basically it becomes larger and larger, and as it becomes larger and larger, the diaphragm is able to go down less, and then you have that combined obstructive and a little bit restrictive problem that develops.

(15:24):What this looks like under the microscope, so as you can see on the left is the normal lung. In the very center, that represents that airway that is cut in cross-section, and on the right, also in the center, should be an open space but what has happened is that there is this fibrotic scar that happens on the airway that essentially closes down that central airway.

(15:51) Pulmonary tests should be done every three months for patients with chronic GVHD. From work that has come out of a colleague of mine, Guang-Shing Cheng, we begin to understand the epidemiology of bronchiolitis obliterans syndrome, and just to point out that the amazing thing about people that we treat in clinic is that they all generally start with normal lung function. In fact, you have to have normal lung function to get to the transplant. And unfortunately what happens is that bronchiolitis obliterans syndrome comes on fairly quickly, and you're seeing the blue line which represents the cumulative data here, and what we're seeing basically is that drop can happen within the span of four months. And for this reason, we really have been pushing to get national guidelines to really focus on getting pulmonary function tests in a very frequent way, say every three months, when you get diagnosed with chronic GVHD.

(16:41) But lastly, what also you can see is that the blue line will stabilize out, and I think that this is part of treatment, but certainly also potentially part of the natural progression of the disease. And this is the place that I really focus on in trying to fix when I'm using pirfenidone.

(17:01) Pulmonary function tests help diagnose BOS. This is the patient of mine that I'm going to introduce to you later. We'll call her 003. She is the third to be enrolled in the pirfenidone trial, but you can see that her lung function dropped quite precipitously. How we gauge lung function in bronchiolitis obliterans syndrome is by pulmonary function tests, or PFTs. And what we're looking at is the FEV1, and that stands for the force expiratory volume in the first second. In other words, how much air can you actually blow out in that first second?

 (17:33) And you can imagine that with all the tiny obstruction that you have in the distal part of the lungs, this is the area that becomes most affected by BOS, and this is the area that we're going to be looking at consistently. And her FEV1 dropped from 120%, which is 120% predicted for a person of her age, height, and ethnicity, all the way down to 60%, and basically kind of stabilized out at that point.

(18:02) Early detection and treatment can prevent progressive lung decline from BOS. So one of the major focuses that we have in the lung GVHD community is to really try to find the people that drop just slightly off their top normal, and really try to hold them into this higher range. And one of the ways that we're trying to do this is by using something known as home spirometry. Home spirometry has really been pioneered in our field by work from Ajay Sheshadri and Guang-Shing Cheng at MD Anderson and Fred Hutchinson, and what this is, is you can think of this as a home breathing test. So you have a device that will connect to your iPhone or your smartphone, and then load your data up into the cloud. And essentially, we can track your pulmonary function test as it starts to decline, and if you were to see a decline of more than 10%, then we bring you into the clinic and we verify that, and hopefully we can start treatments earlier and prevent the progressive lung decline that happens within bronchiolitis obliterans syndrome.

(19:12) In our clinic, we have pioneered new artificial intelligence models. This is in conjunction with that same company, enBio, and as you can see moving left to right what the various conditions look like. So to orient you to the slide, green is normal lung. Yellow is air trapped lung, so lung that cannot release the air. Purple is squashed lung, so as you might see in a pneumonia. Red here is so-called emphysema, but it's not truly emphysema as we would typically think about it. You could think of this as severely air trapped lung.

(19:53) In BOS, the lungs get larger and compress the diaphragm. One thing you might notice is that the size of the lungs are different. The normal lung as compared to the bronchiolitis obliterans lung, the BOS lung is clearly larger. This is related to that inflation, that balloon that cannot completely empty, and therefore it gets bigger and bigger and bigger, and you can imagine what this is going to do to the diaphragm.

(20:11) You can see what happens in organized pneumonia. The lung actually gets smaller, and you begin to take up space. And then you can really see what happens in truncal sclerosis, where the lungs actually are very, very small, but notice that the majority of the lung is actually green. So once again, if you can release that restriction, then you can actually get the lungs to be healthy again.

(20:37) Treatments include corticosteroids, anti-inflammatory and anti-allergy medications. Treatment really falls into three main categories. The first category is to use a regimen known as FAM. FAM stands for fluticasone, which is an inhaled corticosteroid, azithromycin, which is an antibiotic and also an anti-inflammatory, and montelukast, which works on the allergic side of the immune system.

(21:01) You'll also notice that I have fluticasone slash L-A-B-A, LABA. LABA stands for long-acting bronchodilator, and what we've seen in clinical trials is that FAM actually was able to decrease the amount of corticosteroid that was needed. It didn't, unfortunately, significantly improve the lung function, but fluticasone and LABA together, if used early, actually was shown to actually improve lung function in some cases back to normal baseline.

(21:37) Prednisone is the typical treatment for clearly defined BOS but it does not work for everyone and has multiple adverse side effects. For those that FAM does not work, or for those that present with significant symptoms that clearly meet the definition of BOS, most institutions will start some type of immune suppression, and the typical immune suppression that they'll start is prednisone. Prednisone is a very controversial medication because there are a certain proportion of patients, about 20 to 50% of patients will respond to prednisone, and there are those that do not.

(22:11) In those that do not respond to prednisone, it can be a very difficult drug to take because it is associated with multiple adverse effects, including osteoporosis, including weight gain, diabetes, and as well as infections. And infections are one of the most serious complications that patients get after bronchiolitis obliterans syndrome. It is recommended that if there is no response to prednisone, that it be tapered, and certainly prednisone doses greater than 30 milligrams can probably cause more harm than they can do good.

(22:44) If patients do not respond to prednisone, immune suppression with extracorporeal photopheresis can be effective. For patients that are so-called steroid refractory or not responding to prednisone, then one of the main treatments is ECP. And this has been studied in multiple clinical trials, including randomized control trials and looking at a group of trials, and this actually has been shown to be quite effective in improving lung function after the diagnosis of BOS.

(23:12) Other medications are also available. There are a variety of other medications that can be used for treating progressive disease. Ibrutinib is a medication that we studied extensively at Stanford. It has been shown and is FDA approved for chronic GVHD. However, there is not a lot of literature out there for it to specifically treat BOS, and that's one of the studies that we're actually currently running.

(23:39) There's Imatinib, there's mycophenolate, and then there's entanercept. These are all medications that have been used, and generally in trials that are somewhat difficult to group together because of different methodologies. But you can kind of anticipate they're effective around 50%.

(23:58) Other drugs in clinical trials are also showing promising results for the treatment of BOS. As I mentioned, we are in an exciting time for the condition of BOS. There are multiple clinical trials that are being currently run. The ROCK Star study looked at KD-025, and that has concluded and now I believe they're looking for FDA approval. Ruxolitinib is also a very interesting medication that is being used. There is actually a clinical trial specifically looking at BOS right now. Nintenadib is a medication that is similar to the medication that I studied, pirfenidone, is an anti-fibrotic that initially was FDA approved for interstitial pulmonary fibrosis, and then I want to focus on the medication that I looked at, which is pirfenidone, in the STOP-BOS trial.

(24:50) Even when patients have improved lung function, fibrosis of the lungs may persist. So as I mentioned, this was my Don Quixote moment. I had a variety of clinic patients that I've followed for many years, and those patients had some significant improvement in their exercise capacity with the improvement in their cardiopulmonary status. But they were always left with this obstructive lung disease, and this obstructive lung disease typically in the medical literature is known as fibrosis, which is thought to be an irreversible condition.

(25:24) A recent study tested pirfenidone as a treatment for BOS. And at that point, not trying to accept the status quo, I actually approached Genentech and offered to try to study this in my patient population, and Genentech was nice enough to allow me to use their medication, and from that we started the safety and tolerability of pirfenidone for bronchiolitis obliterans syndrome, otherwise known as the STOP-BOS trial.

(25:46) We recently concluded enrollment in the STOP-BOS trial, so we enrolled 30 patients, and what I'm going to do next is show you the results of the interim analysis of 22 patients that have completed the trial.

(26:05) So, we looked at a variety of outcome measures. Generally, the medication was well-tolerated. We saw about 60% of patients could tolerate the recommended dose, and to be clear, the recommended dose of pirfenidone is to take a lot of pills. It's three capsules three times daily, so you're taking nine pills daily of this medication, and this is the recommended dose that is seen when Genentech studied it in the pulmonary fibrosis patient population.

(26:35) Pirfenidone appeared to help with GVHD of the skin and mouth. But one of the outcome measures that we looked at was the Lee's GVHD scale, and this is a patient reported outcome measure that looks at various organs that can be affected by GVHD. And what we found in our small group of patients was that there was a significant improvement in how the patients perceived their sclerotic skin disease, and the nice thing about this finding is that it also correlates well with what has been seen initially in animal studies. In other words, in an animal study of skin GVHD, pirfenidone also seemed to have effect, so I think there are some biologic plausabilities to this as well.

(27:17) We saw improvements from the beginning of trial, which is represented here in the white, to the end of trial in gray in the eye, and we also saw improvements in patients with outcomes with the mouth score from the middle of the trial to the end of the trial, as well. So for this, this is actually quite encouraging, and begins to suggest that perhaps pirfenidone can not only work on lungs, but also work on the fibrosis that is seen throughout the condition of chronic GVHD.

(27:53) Pirfenidone also appeared to improve lung function as measured by pulmonary function tests. Looking specifically at the lungs, to orient you to the slide, we are looking once again at the FEV1, so that's how much you blow out in the first second. And the red here represents the patients that were before trial, so 18 months before, and the blue represents that patients that are on trial. And what we found was that 40% of the patients in the trial actually had a significant response to the treatment with pirfenidone. Overall, we found that there was a significant difference comparing pretrial values to post-trial value in the FEV1, and overall it looked like there was a general stabilization of disease. Now, this trial was not designed to look and find specifically a signal on efficacy. So we're very, very encouraged by these results, and we are in the process of developing a manuscript to begin to explain our full results.

(28:57) Living with lung GVHD and the philosophy of minimal gains. So next I'm going to shift gears, and I want to talk about living with lung GVHD. At our clinic, we have a philosophy of what I call minimal gains. And in this philosophy, what we try to do is we try to maximize the supporting systems, recognizing that the lungs have this persistent obstruction.

(29:24) Aerobic exercise activity is key to improving lung function. So as I mentioned before in my analogy of trying to transport persons from one station to the city, which is the offloading station here described as tissue demand, the important components are to have a strong heart. All of my patients are exercising. We have patients, essentially they exercise to the capacity that they can do, and they measure that capacity in terms of limitations, and they try to exceed those limitations.

(29:52) And this is exactly what Jason Tirado did. He first got into cycling, then became interested in rock climbing, eventually got into crossfit, and before you know it he calls me up and he tells me that he's going to appear on American Ninja Warrior.

(30:07) Obviously, you need boxcars to carry the oxygen, and you have to have a normal hemoglobin. And then finally, you have to have muscles that are very efficient in that endurance way, so what we really focus on is aerobic activity in our patients.

(30:32) A case study shows how exercise and medications helped a patient improve lung function through multiple infections over several years. This is a sample curve of patient 003, which is a woman that I've followed for more than 10 years in clinic, and what you're looking at here is the blue line, the forced vital capacity. That's how much you can blow out completely, and the orange line, you're looking at the FEV1. And what you're going to notice is that there's a severe drop from baseline, which is happening on the far left, which is the 2010 value, to November 2011. At that point, she is diagnosed. She is short of breath at rest. She is treated with prednisone and has a dramatic response to prednisone, with increase in both the FVC and the FEV1, more so the FVC.

(31:23) And then you'll notice that in November 2013, she falls down again. This is actually related to an infection with a microbacterium known as MAC. She is treated and her pulmonary function tests improve, and then she has another dip in November 2014. This is actually related to an infection with a fungus known as aspergillus. She is then treated for that infection, and has a significant improvement that comes back up. And then you notice that she has another fall in November 2017, and this is actually after an influenza infection. And viral infections can be some of the most problematic infections that people can get.

(32:17) What I'm showing you here now is another pulmonary function test parameter known as the DLCO. The DLCO is, I think, the most holistic parameter because it involves the transfer of oxygen to the blood stream, and the removal, the pushing of that blood forward, so really this is an example of that same train analogy that I described to you before. In other words, strong heart, efficient muscles to try to get past the obstruction. And you'll notice that even before transplant, she was only at 80% of predicted, and actually through her dedication, she is able to exercise.

(33:02) She exercised to the point that she begins to exceed her baseline levels, and this is really the cornerstone of how she was able to continue to live an active life. And you're looking at the difference between being short of breath at rest to being able to hike four miles in the hills.

(33:19) However, in the time period that I'm outlining here in the red, she begins to fall down again. And as I mentioned previously, this was due to an influenza infection. Looking more closely at this time period, what we then did is I enrolled her into the STOP-BOS trial, and this represents the time of enrollment. And as you can see, she has an improvement in her FVC and FEV1.

(33:54) Transplant recipients’ response to COVID-19 depends on their level of immunosuppression. So now we're going to switch gears. I'd like to address some common questions that come up in the clinic as related to COVID. The first question, how do BMT patients do after infection with COVID-19? I think that this is up for study. Initially, it was thought that there was no evidence that transplant patients do more poorly with COVID. There was a recent study that came out in the journal of the Lancet that suggested perhaps that patients do more poorly, but I think that in my experience in clinic, I don't necessarily see that patients that have had COVID-19 do necessarily more poorly, and I think that it really depends on the level of immune suppression that you are on when you get this condition.

(34:40) Vaccines against COVID 19 are generally recommended though their effectiveness may depends on the patient’s level and type of immunosuppression. The second question that comes up, should I get a vaccine? I would say that you should talk to your physician, but it is generally recommended that transplant patients should get vaccinated.

(34:53) The next question is will the vaccine work? I think that this really depends on the level and type of immune suppression that you received, and it is currently being studied, so hopefully in the next few months we'll have some clear answers about this question. Other considerations, as I mentioned before, level of immune suppression, type of immune suppression. So for example, patients that have specific immune suppression to knock down B cells, they are going to have a hard time developing antibodies that actually are going to respond to COVID.

(35:29) Recent GVHD flares. We have had patients in the clinic that have ongoing flares get the vaccine, and it seems to extend the flare.

(35:39) Intravenous immunoglobulin, which is a common treatment. Generally it is thought that you should wait several weeks after your IVIG treatment before you get the vaccine, and several weeks until you get the next IVIG treatment, as it may affect how you will respond to the vaccine.

(35:58) Lung transplants for bone marrow and stem cell transplant patients pose complicated issues and do not have promising survival rates. The other frequently asked question that I get in clinic is about lung transplant. In terms of who can get lung transplant, you have to be cancer-free for five years and have no serious infection

(36:11) What is the survival after lung transplant? Unfortunately, the survival after lung transplant is not great. The median survival is about five to seven years for all lung transplants, and the median survival for those that have had bone marrow transplants and lung transplants is shorter, about 49 months. And for me, this really sets the timeframe in terms of when you actually want to give the transplant.

(36:38) How do you know when you need a lung transplant? This really is a multidisciplinary decision. I think that it comes from your bone marrow transplant physician, the lung transplant physician, and your pulmonologist, and you really want to hit that sweet spot in terms of improving the quality of your life and maintaining yourself so you can take maximum advantage of the transplant itself. Once again, getting back to exercise.

(37:04) Won't the GVHD come back in the transplanted lung? This is certainly a possibility. The common thinking is that the level of baseline immune suppression that is needed for the lung transplant is generally higher than that which is occurring in the bone marrow transplant, so hopefully that will keep GVHD at bay.

(37:24) There are also novel transplants being developed, something known as a tandem transplant, where you get a combined bone marrow and lung transplant, but this has actually not been done, and is mainly theoretical.

(37:40) Summary of presentation. So in conclusion, surveillance is critical for maintaining lung function. We saw that with our patient 003, that she had these infections, we were able to improve the infections and therefore maintain lung function.

(37:53) There are new diagnostic techniques that are coming out, home spirometry as well as machine learning techniques that were developed at Stanford.

(38:02) Pulmonary problems can be generally divided in two main categories. There are restrictive problems where the lung is too small. This type leads to pneumonia, truncal sclerosis, serositis. There are obstructive problems, mainly this represents BOS. BOS can be very difficult to diagnose and treat, but there are many, many new treatments on the horizon.

(38:24) And finally, living with BOS, it takes a village. It takes inspirational caregivers, doctors that are all in, transplant doctors, and those around you, as well as a certain amount of willpower to get past the lung disease that gets created.

(38:44) And in terms of acknowledgements, I just want to acknowledge my clinic staff in the picture on the left. This is a Christmas party before COVID, but in the front is Dr. Julie Lai. In the back is Dr. Husham Sharifi, who along with two other physicians work in my clinic. In the very front is Theresa Brondstetter, who is our nurse, and on the right is my family and my research team that have helped me with the STOP-BOS trial. Great. And with that, I'd be happy to take any questions from the audience.

Question & Answer Session

(39:22) [Sue Stewart]  Thank you so much, Dr. Hsu. That was really a very good presentation. One of the better I've seen on the lung complications that you can develop after transplant.

(39:30) We have a lot of questions, and I'm going to try to get through them as quickly as possible. The first one is from a woman who has seven years after transplant, was diagnosed with BOS, bronchiolitis obliterans syndrome, six years ago, and she's been on just about every type of treatment. She's had imatinib, Jakafi, ibrutinib, [inaudible], KD025, three or four extra corporeal photopheresis sessions. She's currently on prednisone, Spiriva, and Advair inhalers, and uses Life2000 daily. Currently, her FEV1 is 31%, declined from a year ago, and she's heard that there's a possibility of inserting endobronchial valves into the lung to make it possible to empty itself and/or the one-way lung valve Zephyr, which blocks air from invading the damaged part of the lungs, and which air can get trapped and hinder breathing. She wants to know whether you think either of these is worth trying, and if not, if you have any other suggestions.

(40:44) [Joe Hsu]      Great. Thank you, Susan. The endobronchial valves is a complicated question. Even in its indicated use, which is COPD, there is some controversy as to how effective they are at so-called lung bond reduction. The part of the complications that happen with the endobronchial valves is that there are passageways in the lungs that sit in the very far periphery of the lungs that can still exchange gas, even if the main airway is plugged up. So really there are certain specific scans that are obtained to try to determine whether or not a person is a candidate for endobronchial valves.

(41:42) And I would recommend that if that's being considered, that she has a very careful study because oftentimes what can happen is that you plug one pathway, and then the other pathway opens up and it essentially makes the valve not useful. So it takes a careful amount of study with your interventional pulmonologist to determine whether or not that's going to be a good situation.

(42:10) It also depends on how heterogeneous or how patchy the disease is. In other words, if it's happening all throughout the whole lung, then blocking one part of the lung is not necessarily going to make anything else any better. However, if it's happening in only say the lower part of the lung, then maybe reducing the size of that lung can actually make things better.

(42:35) And this gets to what I hinted at in the presentation, where when the lung gets too big, then it begins to create a mechanical disadvantage for the lung, and that results in that combined restrictive and obstructive effect, and that's why it can be so severe. I guess my recommendation at this point, she's obviously seen a lot of medications, but I'm noticing that there's a switch out of many different types of medications, and sometimes it takes a little bit more patience on one medication to see the effect. So it may be that, at least when we were studying pirfenidone, really within the first three months there was no major impact, but then you start to see some effect toward the tail end of the trial.

(43:35) So the imatinib that she had been on, which is an anti-fibrotic as well, which is also very interesting to us, that's going to work over a span of months. So I would wonder about using one of these things as a baseline in addition to other things.

(43:55) Something that I didn't mention is that these anti-fibrotics, they work on the very tail end of what happens with BOS, so the combination of some of these medications sometimes can be helpful. In other words, to control the inflammation say with ruxolitinib and an anti-fibrotic can be an additive effect, as opposed to one versus the other.

(44:23) [Sue Stewart]      All right, thank you. That was helpful. Next question is bronchiectasis on the spectrum of GVHD?

(44:31) [Joe Hsu]      That's a great question. Bronchiectasis is a condition that can be created by many different things. Certainly patients with BOS get bronchiectasis, which is an enlargement of the airways, but also having low immunoglobulin levels can create bronchiectasis, having frequent infections can create bronchiectasis, so it is something that's associated with but not necessarily caused by chronic GVHD, aside from its association with BOS. Now, I have many patients with bronchiectasis, and the real focus there is actually airway clearance. Oftentimes, with good airway clearance working with your pulmonologist, that can prevent a lot of the negative side effects, mainly the current infections that can occur with that condition.

(45:29) [Sue Stewart]     All right. The next question is from a person who wants to better understand how you determine how immunocompromised you are. He's on two grams a day of mycophenolate, and wonders whether this is considered an immune system that's very compromised or not.

(45:49 [Joe Hsu]      Yeah. Two grams of mycophenolate, it really depends on size, but that is a moderate to higher level of immune suppression. We are not very good at knowing how immune suppressed patients are, and assaying that aspect of our treatment, but I think that's a point for future study. But generally, to be on that level of medication, I would consider it to be at least moderately immune suppressed.

(46:29) [Sue Stewart]      All right. The next question is from someone who has BOS. It's stable. She's using prednisone and sirolimis and extra corporeal photopheresis, and she wants to know how long she should stay on ECP. Forever?

(46:47) [Joe Hsu]       That really depends on how well her GVHD is controlled. I think that the advantage of ECP is it's not immune suppressant, and if they're requiring higher and higher levels of doses of prednisone, then certainly ECP has been clearly shown to help reduce that. If the GVHD is, as many times happens, quiescent and it burns itself out, then an attempt can be made to try and reduce the frequency of the ECP.

(47:20) [Sue Stewart]      All right. Next question is about cramps in the throat and throughout the body. She wants to know whether that might be related to truncal sclerosis.

(47:34) [Joe Hsu]      That's a great question as well. Cramps I see as a GVHD symptom in general. It doesn't necessarily have to be related to truncal sclerosis. There are patients of mine actually when the truncal sclerosis begins to soften, they begin to develop more cramps, so the two I think are potentially associated, but they can also happen independent of each other.

(48:09) [Sue Stewart]      All right. Next person is 15 months out of transplant. She was diagnosed with. I can't pronounce this, bronchiectasis before transplant, and is wondering if there's a difference between the disease and BOS, and if she should be taking more frequent pulmonary function tests.

(48:30) [Joe Hsu]      I would say absolutely. I would say to go into the transplant with some degree of lung impairment is a risk factor for the development of BOS. And recall the Guang-Shing Cheng graphic that I showed, where BOS can happen very quickly, so I would recommend that pulmonary function test be at least checked on at least a three month basis, and in our clinic we would probably check it on a monthly basis to make sure that things were stable.

(49:10) [Sue Stewart]      All right. The next question is from somebody who actually had an autologous transplant using their own stem cells instead of donor cells, and what he said is, "I experienced symptoms like what you showed with truncal sclerosis. Difficult breathing while lying down or chest submerged in water, and feeling unable to use my diaphragm to take a deep breath. I had no skin issues, and I believe GVHD doesn't occur in autologous transplants. It resolved slowly without treatment after six months. Could this have been a form of truncal sclerosis, or have you see these symptoms with another diagnosis?"

(49:47) [Joe Hsu]      So, with the autologous transplant, right, there is no GVHD. But with the medications that are used in and around the time of autologous transplant, there can be inflammation that gets created from the medications themselves. There can be situations where the medications can affect the heart function, and affecting the heart function can create a symptom that is very much like a patient would get with truncal sclerosis, which is an inability to lie flat. So I would wonder if the patient has had an echocardiogram to evaluate their heart function, and/or a study to see if maybe is there some type of inflammation that's happening in the lungs after the transplant.

(50:37) [Sue Stewart]      All right. The next question is what factors do doctors consider when they choose a medication? For example, Jakafi versus ECP, or vice versa? Can you elaborate on the ECP process and how it improves BOS?

(50:52) [Joe Hsu]       Right. The ECP process is interesting. Essentially, it has multiple immunologic effects, so to explain ECP, essentially you're taking the lymphocytes or the immune cells out. You expose them to a light-sensitive agent, and then you expose them to a UV light, and what that does is a few things. One is it begins to eliminate those lymphocytes that are very active, and those are considered to be the alloreactive lymphocytes. In other words, those that are reactive to your body. In doing that, it's also thought to shift the immune response toward a more controlling response as opposed to a more active response, so those are the effects that ECP renders that are helpful for GVHD.

(51:51) ECP is probably best studied for skin-related GVHD. It is thought to be adjunctive as opposed to just used alone, and the main risk that people have for ECP is to have to have the [inaudible] line, which presents a risk for infection, but it itself is not considered immunosuppressive. For that reason, it's oftentimes backed up with another type of immune suppressing medication.

(52:23) In terms of how these medications are used, there's a very specific pathogenesis or order of which GVHD happens in the lungs and in general. And it really depends on where people are in those phases. There are three phases.

(52:41) The first phase is to create an awareness to the bone marrow that "self" is not good, and oftentimes that's due to an infection, say a viral infection, that causes our lungs to become exposed, and potentially the immune cells begin to recognize the lung itself as foreign. There's a propagation of that immune response, and then there's the end result, which is the fibrosis, which is kind of a third phase. So really, a lot of the medications that are being used right now are trying to target one of those three phases.

(53:16) Nicely, ECP sits across and actually not only blunts the reaction of the immune system to itself, but also it pushes the immune system toward more of a regulatory, controlling phase, so it works on multiple areas. Ruxolitinib has also multiple effects to it, so this is kind of how the medications are chosen. Essentially, it's prednisone first, and those that can't come off prednisone try to pick a steroid sparing agent like ruxolitinib. And then if fibrosis is the primary thing, then that's perhaps where medications like what I study can come into play.

(54:03) [Sue Stewart]      All right. And I think this is going to have to be our last question, unfortunately. We have so many questions here, but so little time, as they say. When you said you should separate your COVID shot and IVIG by several weeks, what do you mean by several? Two, three, four, more weeks?

(54:21) [Joe Hsu]      Right. The general recommendation is about two weeks, but I think that can vary in that example. Say if you are very immune suppressed, like high doses of prednisone, we'll say over 30, then that already is mitigating your possibility for a response to the vaccination, and then you throw on IVIG in there and you may further mitigate your response. So what's currently understood or what's currently reported by the various societies is at least two weeks, but it's not exactly known how long you should wait, and I think how long you should wait is a decision that your transplant doctor and yourself can come to some conclusion for, and that is going to be dictated by what other factors may be at play.

(55:11) [Sue Stewart]     Closing. All right. Thank you so much, Dr. Hsu. That was really an excellent presentation, and I want to thank everyone who submitted questions. Those were great questions, and we learned a lot from each other as well as from Dr. Hsu. Thank you.