Graft -versus- Host Disease: What to Do When it Attacks the Lungs

Transcript of Presentation.

(00:04): [Jordan Sexton]: Welcome to the workshop, Graft-versus-Host Disease: What to Do When it Attacks the Lungs.

(00:09): Before we begin, I'd like to thank Incyte Corporation and Sanofi, whose support helped make this workshop possible.

(00:17): Speaker Introduction. It's my pleasure to introduce Dr. Guang-Shing Cheng. Dr. Cheng is a pulmonologist at the Fred Hutchinson Cancer Center in Seattle, Washington. She focuses on improving outcomes for cancer patients who have respiratory failure and lung complications related to their cancer treatment.  

Dr. Cheng is developing new ways to prevent lung damage and improve lung function in these patients. Her main interest is lung graft-versus-host disease (GVHD) – a serious complication of blood stem cell transplantation. Please join me in welcoming Dr. Cheng.

(00:48): [Dr. Guang-Shing Cheng]: Thank you so much, Jordan, for that introduction.  

(00:50): Overview of Talk. Today, we will discuss graft-versus-host disease (GVHD) of the lungs. I will specifically review bronchiolitis obliterans syndrome (BOS), a manifestation of graft-versus-host disease (GVHD) that affects the lungs. We'll talk about the treatment of BOS and review some other lung conditions that are also related to graft-versus-host disease.

(01:23): A transplant can affect the lungs in many ways, and bronchiolitis obliterans is a one of the non-infectious diseases that can occur. We think that bronchiolitis obliterans syndrome is a manifestation of GVHD, whereas the causes of other complications, including interstitial lung disease and organizing pneumonia, are not always entirely clear, and may be caused by GVHD or other reasons, such as drug toxicity.

(02:06): Graft-versus-host disease can cause other issues as well. It can affect the chest wall and musculature, as well as the pleura – or the lining of your lungs – and impact your breathing.  

(02:19): Late-onset non-infectious complications are pretty common after transplant; about 20% of transplant survivors will experience one of these entities in their survivorship.

(02:36): Let’s first look at the anatomy of lung tissue. This is a micrograph – or a close-up – of a piece of lung tissue. You have a small airway that leads into the lung tissue, and these small saccular structures – known as alveoli — are where your body obtains oxygen from the air and expels carbon dioxide. These tiny airways terminate in alveolar sacs, and this is where a lot of the graft-versus-host disease occurs. Other diseases, such as interstitial lung disease or organizing pneumonia, also affect the alveolar sacs, and if you get pneumonia, these alveoli become plugged up with infectious and inflammatory material.  

(04:06): Bronchiolitis obliterans syndrome (BOS) starts when the transplant donor cells attack the airways. This inflammation leads to obstruction of the airways and fibrosis – resulting in decreased airflow that makes it harder for air to be expelled, and difficulty breathing.

(04:35): The pathology is referred to as obliterative bronchiolitis. This slide shows two examples of lung biopsy specimens from a person's diseased airway. The image on the left shows an airway that has been narrowed by the presence of extra fibrotic material around it. The image on the right shows an outline of an airway that's been completely obliterated by fibrotic material. That's why it's called ‘obliterative bronchiolitis’. Bronchiolitis is a rare condition, but is also seen in other disease contexts like lung transplantation.

(05:29): While it does vary from patient to patient, BOS has a very typical clinical presentation. It often presents as cold symptoms and can even be diagnosed as pneumonia. Sometimes people receive antibiotics to treat it, and they recover. Then, a couple of weeks or months later, their lung function starts to decline. They develop a persistent cough and have shortness of breath on exertion. After BOS is diagnosed, people might improve, but the fact that they are also on immunosuppression medications, BOS can be increasingly difficult to manage.

(06:35): Treatment generally helps alleviate symptoms, but lung function typically does not fully recover. It will stabilize, but BOS is punctuated by periods of worsening symptoms, generally due to infections. Sometimes, when other infections arise, hospitalization is required to get additional treatments and support.  

(07:04): This next slide is a graph – or ‘spaghetti plot’ – of lung function and shows how people can have very different trajectories.  

(07:09): The earlier BOS is diagnosed, the better the chances at preserving lung function. Oftentimes, the only indication that BOS is occurring is the loss of lung function, with no other symptoms present. This overall lack of symptoms can make early diagnosis more difficult. After diagnosis – which is referred to as ‘day zero’ on this plot – lung function plateaus; the damage has already been done, but it has now been diagnosed, and the disease is more or less stable.

(08:04): There are some risk factors for BOS including having chronic graft-versus-host disease elsewhere, certain chemotherapy regimens such as those that include bulsulfan, prior lung disease and low immunoglobulin levels. 14% of people who have GVHD elsewhere, get diagnosed with BOS within six months of the initial GVHD diagnosis. Prior lung disease also increases the risk. Measuring lung function can potentially help predict the occurrence of BOS, but it can indicate other problems as well.

(08:51): Some conditioning chemotherapy regimens – such as those that include busulfan – also are risk factors as they are known to cause lung toxicities.

(08:59): Low immunoglobulin levels have been shown to be a risk factor, as it predisposes people to infections, and we suspect certain respiratory viruses increase one's risk for BOS as well. There are two retrospective studies, and I’m currently doing research in a study to determine if experiencing lung dysfunction after a respiratory viral infection will increase your chances of complications and poor outcomes related to BOS long-term.  

(09:50): The specific viruses that we think impact BOS include respiratory syncytial virus (RSV), parainfluenza virus, and COVID-19. So, it's important to get vaccinations after a transplant.

(10:06): The diagnosis of BOS depends on pulmonary function tests (PFTs), and is predicated on a new decline in spirometry compared to your prior PFTs. Abnormal PFTs will also generally be accompanied by other signs of graft-versus-host disease in other areas of the body as well.

(10:24): This graph shows an abnormal PFT, and shows evidence of airflow obstruction. When you blow out into the spirometer, this red line should be a smooth, convex line. This line however, is scooped and indicates that air is having a hard time being expelled from your lungs. The airflow obstruction should not be due to other lung diseases – including asthma – and you shouldn't have an active lung infection when undergoing a PFT.

(11:08): A CT scan of the chest will help confirm a diagnosis, and will sometimes show air that is not leaving the lungs properly, called ‘air trapping’. In this picture on the left, you can see this occurring where areas appear too dark. Dilated airways – called bronchiectasis – is shown in the picture on the right, and is a sign of late disease. We can utilize these scans to help provide further information and help confirm a diagnosis.  

(11:41): Usually, a bronchoscopy is also performed to rule out infection. This is important because infections can complicate lung function and also promote BOS. We can either perform a lavage – which is a minimally invasive way to sample the lung tissue with the installation of saline – or with a biopsy if necessary. Generally, this is an outpatient procedure and tolerated well.  

(12:14): Routine PFTs are performed after transplant to help catch and diagnose BOS early. Symptoms don't generally develop until a significant amount of lung function has been lost, so we try to catch changes early and suggest routine PFTs every three to six months.  

(12:38): Current recommendations for PFT monitoring post-transplant include getting a baseline prior to transplant, day +80, day +100, 6 months post-transplant, and then annually thereafter. If you have chronic GVHD, you will also have one at the time of your GVHD diagnosis, and every three months thereafter, particularly while you're on immunosuppression.

(13:30): You can do it in the PFT lab with the assistance and supervision of a technician.  We now have these handheld devices and portable devices, and even have individual Bluetooth battery-operated devices that sync to your smartphone. The measurements are then saved in a cloud that your doctor and care team can look at, and send an alert if something doesn’t look right. These options all allow people to perform these tests at home more frequently and easily.

(14:42): Let’s discuss treatment options for a diagnosis of BOS. The current backbone of treatment is this regimen that I call ‘FAM + LABA’. Fluticasone is an inhaled steroid, Azithromycin is an antibiotic, Montelukast is a daily anti-allergy pill, and a bronchodilator to help open up the airways called a long-acting beta-agonist (LABA). This regimen is based on two clinical trials published approximately 10 years ago. Most people will also get a high dose of prednisone for two to four weeks, followed by a taper.

(15:38): Sometimes the question of whether or not azithromycin is safe for BOS comes up. This is because of a clinical trial conducted in 2017 that examined azithromycin as a prophylactic agent. People were given azithromycin at the start of the transplant, with the hypothesis that this would prevent people from getting BOS or lung GVHD. The trial was stopped early because that did not happen, and the people who were taking azithromycin were dying sooner than the placebo group due to relapse. It also did not prevent the occurrence of BOS.

(16:43): The reason behind this is still being worked out. We believe that azithromycin may actually affect the cancer surveillance mechanisms; however, azithromycin is generally considered a safe drug used for various purposes.  

(17:14): Inhaled corticosteroids are probably the mainstay of what makes this LAM + FABA treatment effective, as they target the initial inflammatory aspect of lung GVHD. They are associated with a small increased risk of pneumonia and other obstructive airway diseases, so we do take that into account, but generally it’s well tolerated.

(17:48): The long-acting beta-agonist is probably not necessary after the first month, but this is really for symptomatic relief. It's not disease-modifying.

(17:56): Azithromycin itself is a very good adjunctive anti-inflammatory and is effective in alleviating other airway diseases as well. There is limited evidence regarding its effectiveness in treating BOS, however, so we measure the risk of subsequent malignancy with each person in determining whether or not they would benefit from taking it.

(18:29): Montelukast probably doesn't have a major effect, but it's very well tolerated and not harmful.

(18:37): My practical approach is to avoid azithromycin if you're less than one-year post-transplant, if you've had acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL), or have a high risk of relapse. I try to discontinue it in three to six months. Then, if people are stable, I discontinue the other medications in a stepwise manner. The inhaled corticosteroid is the last thing I’ll discontinue. People typically follow this regimen for at least 6 to 18 months, and possibly longer.

(19:15): There are now additional treatments that we can give for BOS, and that includes things we offer for GVHD as well. Extracorporeal photopheresis is certainly something that we can use as a steroid-sparing approach, but it is often not practical for people.

(19:37): The last couple of years, we've been fortunate to have new agents approved – including ruxolitinib (Jakafi), belumosudil (Rezurock), and axatilimab (Niktimvo).

(19:54): In addition, there are FDA-approved medications that are specifically meant to treat pulmonary fibrosis. These include pirfenidone and nintedanib (Ofev or Vargatef.

(20:38): We just completed a phase II clinical trial to assess the effectiveness of Jakafi as an anti-inflammatory agent. 49 patients with newly diagnosed and established BOS participated, and roughly a third of participants – particularly those with newly diagnosed BOS – showed improvement in their lung function at three months. Those who had established BOS were generally stable, and Jakafi was tolerated reasonably well. This study just came out, and while we don't see a response in everybody, at least a third of the people experienced some improvement, which is encouraging.

(21:15): I also want to mention Rezurock. This has already been FDA approved for other GVHD symptoms and is well tolerated. We think it might also provide some benefit for people with BOS and are currently running a trial. My colleague, Dr. Corey Cutler at the Dana-Farber Cancer Institute, is leading this study called the ‘BEPOP study’, and I encourage you to check it out. We're enrolling patients for BOS prevention, as well as those with new-onset BOS, here at the Hutch and at the University of Michigan, and Stanford will be opening the trial soon as well.

(21:57): Pirfenidone (Esbriet) has been tested and is well tolerated. Long-term, about 40% of patients had some improvement in their lung function.

(22:25): If your lung function continues to decline, we start to consider the exacerbating factors. This might include whether or not you have an infection, or if reflux is causing the worsening lung function. Workup generally includes a CT scan, possibly a bronchoscopy, and then we consider second-line treatment options. These include clinical trials – which I strongly suggest joining if one is available – a prednisone burst, a new GVHD agent, or a pulmonary antifibrotic.

(23:05): Oftentimes, we must rely on supportive care options to help alleviate the BOS symptoms. People will plateau, and things won't decline any further, but those symptoms are still there, so we manage them with various supportive care measures.  

(23:31): Adjunctive treatments for shortness of breath include bronchodilators – such as albuterol and formoterol, – muscarinic agonists – such as tiotropium, – and utilizing supplemental oxygen.

(23:56): We want to prevent and treat infections like sinus disease, reflux, and other allergies. Vaccinations are really important for infection prevention as well.  

(24:10): Airway clearance is important for people who have a chronic cough. Some experience a productive, chronic cough because their airways are distorted. Utilizing things like positive expiratory pressure devices – such as this capella device – can help clear secretions and improve these symptoms.

(24:36): For people who have a lot of symptoms or are on supplemental oxygen, I recommend pulmonary rehab. This helps by enhancing and strengthening all the other parts of your body that contribute to breathing. Pulmonary rehab happens differently in different places, but it generally consists of education, some fitness, and breathing exercises.

(25:11): I now want to briefly cover other lung conditions that people might get after transplant. One of them is a condition called ‘organizing pneumonia’. This condition occurs when the alveoli are attacked and filled with an inflammatory material. You can see on this CT scan. It can present like infectious pneumonia, but it can also occur after a lung infection. This factor was well described after COVID-19, but we had this even before COVID-19.  

(25:49): Patients with a history of acute and chronic graft-versus-host disease are certainly at risk. The good thing about organizing pneumonia is that it's generally responsive to treatment, and the first-line treatment is prednisone. So, I think a lot of people suffer more from prednisone’s side effects than from the disease itself.

(26:16): Unfortunately, one does need to be on a treating agent for quite a long time to avoid relapse, and treatment also depends on the disease burden. For those who can't tolerate the steroids, inhaled steroids or some of the other agents like ruxolitinib (Jakafi) or mycophenolate mofetil could be effective.

(26:39): I also want to mention that people who have sclerotic GVHD can really notice their breathing being affected, primarily through skin tightening of the abdomen and chest. GVHD can also affect your respiratory muscles in the form of myositis. Prolonged steroids for the treatment of GVHD can cause overall weakness and respiratory muscle weakness. So, the cause of people's shortness of breath and lung impairment can be very complex. These are all factors that we take into consideration when evaluating people's lung function.

(27:26): People can also get pleural disease or pleural effusions – which is inflammation of the lining of the lungs that causes fluid buildup and compression of the lungs. This can be due to graft-versus-host disease.

(27:44): For those who haven’t been able to recover their lung function and have significant lung disease, a lung transplant may be an option in specific circumstances. Lung function has to be significantly impaired – like requiring home oxygen at all times. Generally, most lung transplant centers want you to be cancer-free for at least five years without a lot of immunosuppression medications needed and no other organ problems. You need to be an adequate weight, have social support, and the motivation and ability to do pulmonary physical rehab.

(28:28): We hope that nobody has to undergo a lung transplant, but sometimes this is the only option. Many lung transplant centers are becoming more willing to accept stem cell transplant patients with lung complications.

(29:01): Conclusion. So, in summary, lung GVHD can be really challenging and can limit people's activities and quality of life. It often begins without the presence of symptoms, so routine lung function monitoring after transplant is really important.

(29:20): One is more likely to prevent the loss of lung function if it is treated early. And there are additional lung complications related to graft-versus-host disease that we are still learning about. Given that this is a family of rare diseases, we're trying to study it and understand it, and get people the right treatment to ensure they have an improved quality of life. With that, I'll open it up to questions.

Question and Answer

(30:07): [Jordan Sexton]: Thank you very much, Dr. Cheng, for an excellent presentation.

(30:25): When you consider the progression of BOS, is it accurate to consider that after the anti-inflammatory processes, then the fibrotic processes occur?

(30:46): [Dr. Guang-Shing Cheng]: Generally speaking, yes. I think what is happening in many cases is that there's probably an inflammatory process occurring concurrently with fibrosis. If it’s just inflammation, in theory, it should stop with treatment like prednisone or ruxolitinib. If people continue to progress, then yes, a fibrotic process is occurring. It's really difficult when that occurs in the lungs, because the lung itself does not regenerate. So, once fibrosis happens, and the fibrosis blocks the small airways, it's really, really hard to get it back. So that's why this is so challenging to treat.

(32:01): [Jordan Sexton]: Do medications like second-line treatments and FAM support ensure that there is no worsening or progression of the disease? You discussed the opportunity to consider weaning off of FAM meds. What factors do you consider to initiate weaning?

(32:21): [Dr. Guang-Shing Cheng]: We think that – while they might not work right away – longer-term agents like pirfenidone as an anti-inflammatory and belumosudil are likely to prevent further fibrosis. At some point, the GVHD process stops, and when that happens, we can start weaning off the FAM meds. Lung function has to be pretty stable for at least six months, and we need to feel like other GVHD occurring is controlled for me to consider weaning.

 (33:29): The reason why I don't want to keep people on FAM forever is first, azithromycin’s association with relapse and subsequent malignancy, and second, the long-term exposure to inhaled corticosteroids more than likely slightly increases the risk of infection.

(34:01): [Jordan Sexton]: What is the best approach to dealing with a cold? This person feels their immune system ramps up and then their GVHD can be very bad afterwards.

(34:10): [Dr. Guang-Shing Cheng]: We do observe that happening, and if you already have BOS, then I suggest still using your inhaled agents. And if you're on azithromycin, continue with that as well.

(34:36):  For someone who doesn't yet have any diagnosed issues with their lungs, I recommend getting a lung function test after your cold has resolved. Ideally, I would like it to be standard for everyone at risk to have an at-home spirometer, so utilizing that if that is available to you as well.

(35:09): [Jordan Sexton]: Have you seen a significant change in mortality percentages associated with lung GVHD and the new systemic medications available?

(35:19): [Dr. Guang-Shing Cheng]: Not yet. It’s too early to tell right now with Jakafi and Rezurock, but I anticipate that mortality rates will be decreased. Over the last 15 to20 years, mortality from this disease has already gone down.

(35:49):  I do think this is related to earlier diagnosis. Twenty years ago, people in the FAM study at diagnosis had a median forced expiratory volume in one second (FEV1) of 46%. At that point, they’d already lost half of their lung function. Whereas in 2020, our median diagnosis FEV1 was like 68%.

(36:20): We've improved over one and a half decades in earlier recognition of this disease, and survival is now over 70%, where it used to only be 40%. So yes, mortality due to BOS has definitely gone down over the years. Also, people can have really bad lung function and survive for a long time. A lot of people just simply adjust. I know that’s very easy to say, and very hard to do, but they can still have hope. We have a lot more work to do, and I anticipate that with Jakafi, Rezurock, pirfenidone, and these other agents, it will continue to improve.

(37:21): [Jordan Sexton]: This person is 11 years post-stem cell transplant and has GVHD of the fascia and eyes. They were just diagnosed with early-stage BOS due to a chronic cough. They're on Montelukast. Are there any non-pharmacological recommendations you may have or things they could do?

(37:47): [Dr. Guang-Shing Cheng]: I think simply staying active and avoiding infection are the primary things. If that person is only on Montelukast, then my guess is it's probably pretty mild.

(38:24): [Jordan Sexton]: Would you be able to recommend a prednisone pulse schedule?

(38:30): [Dr. Guang-Shing Cheng]: Okay, I'm assuming this is possibly somebody who's just been diagnosed with BOS. I generally don't give more than one milligram per kilogram for say two to four weeks. I would taper it after that, because if it's going to work, it generally does so within the first couple of weeks. I would then get a spirometry test to confirm the results.

(38:57): At four to six weeks, we don’t often see people getting worse or improving, so at that point you want to begin a prednisone taper to get back down to your original dose and prevent the risk for side effects.  I don’t think long-term prednisone does anything for the lungs. Instead, people often develop side effects and contract lung infections.

(39:27): [Jordan Sexton]: This person is curious about the plateau of pulmonary function. Have you seen that plateau regardless of continued medications?

(39:36): [Dr. Guang-Shing Cheng]: Yes, a plateau is generally the norm. I think we're understanding that there are probably different types of BOS. Maybe 10% - 20% will experience significant improvement, and most will have a very stable plateau.

(40:06): If they're going to plateau, they plateau either immediately or a portion of people – maybe 30% – continue declining for about three to six months after their diagnosis. And that is hard and perplexing to us pulmonologists.  So that's where the clinical trials come in, to study how we can effectively stop this decline.

(40:46): [Jordan Sexton]: Is an increased occurrence of viruses or the flu associated with worsening of BOS? Do you recommend continuing to mask?

(40:59): [Dr. Guang-Shing Cheng]: We hypothesize that viruses and flu exacerbate BOS. It doesn't happen in everybody, but we're accumulating evidence to suggest this. It’s also seen in people post-lung transplant who also get BOS.

(41:24): In regards to masking, my recommendation is to use your judgment. There are specific situations in which you may want to keep masking – like in very crowded situations – but I don't recommend masking all the time. Use your judgment, and utilize good hand hygiene.

(42:03): [Jordan Sexton]:  You showed the device that helps with bronchiectasis. What are the symptoms that this device can address?

(42:11): [Dr. Guang-Shing Cheng]: I showed a positive expiratory device. And it's an airway clearance device, where you exhale into it and it creates little vibrations. This is helpful for people who have a chronic, productive cough, and have difficulty clearing their secretions. It's not necessarily for everyone, but it's very harmless and actually feels good.

(42:47): The other way to do it is with chest percussion, which is having somebody pound on your chest to create those vibrations. The idea is that you're helping move these secretions so they don't build up in your lower lung and cause more problems. If your airways aren't cleared, then that can promote inflammation, and possibly worsen the disease. The device is for those people who have a chronic cough and experience recurrent infections and pulmonary secretions.

(43:23): [Jordan Sexton]: Are there any recommendations you have to help get lung GVHD back under control after having a cold?

(43:38): [Dr. Guang-Shing Cheng]: Well, I think inhaled steroids can probably help. I don't have a lot of systematic evidence to prove that, but I think that it will hopefully prevent symptoms from worsening further.

(44:01): [Jordan Sexton]: What is the standard of care for monitoring lung function after allogeneic stem cell transplant?

(44:11): [Dr. Guang-Shing Cheng]: I'm really glad somebody asked this question because the standard of care is currently different at different institutions. In my opinion, everybody needs to have a pre-transplant lung function test, and at three months, six months, and one year post-transplant.

(44:44): If you develop new graft-versus-host disease – which generally occurs around six months – you should have that baseline lung function test to compare to and possibly help diagnose BOS early. If you have any GVHD or are on immunosuppression medications, continue getting lung function tests every three months thereafter.

(45:12): These recommendations are in two documents. We put this forth in 2021, as part of the NIH project on GVHD. Additionally, other international guidelines were published regarding post-transplant monitoring. Both recommended fairly close follow-up, at least every six months.

(45:43): The fact is, most centers do not follow this. I know this because I surveyed a lot of these centers participating in trials, and less than 50% of transplant centers actually comply with these PFT recommendations. Part of my role is to educate transplant providers, and encourage more frequent lung function testing.  I wish the standard of care was truly a standard of care at all centers. I think that overall, centers are improving, but this is definitely not uniform across the country.

(46:47): [Jordan Sexton]: Could you talk about what pulmonary rehab is and when it can help?

(46:58): [Dr. Guang-Shing Cheng]: Yes, pulmonary rehab is done a little differently in every place, but it's a program designed for people with end-stage lung disease. The program helps teach techniques to people with airway diseases to help with breathing, as well as focusing on strength and conditioning. You may have a two-week program, or a program where you go once a week for eight weeks, and then you get exercises to do at home. It definitely helps with quality of life and exercise tolerance. The people who get the most benefit out of it are people who have relatively severe lung disease.

(47:46): Regardless of how bad their lungs are, I recommend overall rehab for my patients, which is simply making sure they are getting some sort of movement for 10 to 30 minutes a day. Start with small goals, and work up from there.

(48:11): The unfortunate thing is that pulmonary rehab programs are not widely available, and are in high demand. I wish there were more of them.

(48:38): [Jordan Sexton]: Once there is evidence of chronic GVHD causing lung problems after a stem cell transplant, can re-implementation of immunosuppressants stop the progression of lung disease?

(49:01): [Dr. Guang-Shing Cheng]: My belief is yes, that probably does happen in many instances. Generally, if there is a new diagnosis of BOS and people are symptomatic, you re-initiate prednisone as sort of upfront therapy. We are considering the possibility of giving prednisone plus another agent upfront, and that's what the BEBOP trial is about. We're going to give Rezurock upfront and not wait for things to get worse before starting that second agent.

(50:04): [Jordan Sexton]: This person is struggling with GVHD of the lungs. Are there any new drugs on the horizon that could help?

(50:12): [Dr. Guang-Shing Cheng]: Axatilimab was just FDA approved, and I’m really trying to get people into a clinical trial for that.

(50:32): Some pulmonary antifibrotics are in development right now. They are not quite yet in phase I studies, but I'm currently working with colleagues to see if we can get that one through. There are a lot of regulatory hurdles we must get through, but I’m really hoping we can get this very promising antifibrotic into clinic sooner rather than later. Unfortunately, not terribly soon, but possibly in the next two years, I think we could have a trial.

(51:22): [Jordan Sexton]: This person wakes up some mornings gasping and dizzy, and they're concerned about whether their breathing tubes may close up when they're sleeping, causing them to die.  Do you have any advice you could provide there?

(51:45): [Dr. Guang-Shing Cheng]: Breathing while you're sleeping is a very complex process. And gasping and being dizzy could mean a number of things. It depends on how severe one's intrinsic lung disease is, but it could also be an upper airway thing like sleep apnea. I think if these are your symptoms, it certainly would be worthwhile to at least get a nighttime oximetry to see if your oxygen levels are declining, because at the very least, one could use oxygen at night. Your upper airways – like your throat and oropharynx – are more likely to close up. The lower airways just participate in breathing.

(52:52): [Jordan Sexton]: This next question is from someone who is eight years post-stem cell transplant and has had chronic GVHD of the lungs for about three years now. Their pulmonary function tests occur every six weeks, and are getting worse, and their inhalers hardly work. Their oncologist says they should avoid letting them put a breathing tube down their throat as they're worried they won't survive. But they'd like to understand your opinions on how their potential next steps could look.

(53:38): [Dr. Guang-Shing Cheng]: This is a hard question. I mean, I'm reading this question as, “How am I going to die with really, really bad lung disease?” I don't know if this person is already on supplemental oxygen. Suffocation is really an unpleasant, scary feeling and sensation. So how do people with lung GVHD, how do they die?

(54:34): There are two ways really. One is that you get an infection – such as pneumonia – which is oftentimes unavoidable. I mean, it’s a risk and can happen in any person with chronic lung disease. Secondly, one can also die of primary respiratory failure, which is basically your lungs just simply stop working.

(55:01): And yes, that feeling of suffocation is really, really profound. If your carbon dioxide levels are going up, your oxygen levels are going down. and it's not reversible – meaning it's not like an infection that they can fix or something that can be helped with a mask or other non-invasive ventilation to help you breathe – then that would be the time where you might want to consider opiates for relief of this shortness of breath.

(55:52): The problem I think that a lot of doctors have is that, because this is a really rare disease, people don't have experience in prognosticating what's going to happen, so it's very hard to predict.

(56:15): I would have to see the lung function tests, but if this one measurement – called forced vital capacity –is going down, then one probably only has about two years to live.

(56:35): So at this point, I think it really is important to consider how you want the end of life to look like? Do you want to go through really aggressive treatment to see if we can possibly reverse something? For example, if you had pneumonia and had to go to the hospital, would you want a breathing tube down your throat to help you through that episode or not?

(57:04): The other thing to consider is that if your lungs are your primary problem and limiting your life, could you be a potential candidate for a lung transplant? Again, because BOS is rare, and not a lot of doctors in the community will know how to manage this, it's just really difficult to have these conversations.

(57:42): I hope that answers the question. It's a really tough question, but if one is at that point, it is really important to have a frank discussion with your doctors about how to alleviate the sensation of not being able to breathe.

(58:09): [Jordan Sexton]: Closing. Well, thank you very much, Dr. Cheng. I think you've answered a lot of amazing questions from everybody who attended, and your presentation was excellent. The work you're doing is very meaningful and helpful. On behalf of BMT InfoNet and our partners, I'd like to thank you for your incredible remarks. And thank you, the audience, for all of your amazing questions. Please contact BMT InfoNet if we can assist you in any way.