Identifying and Managing Respiratory Diseases and Symptoms after Transplant

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Identifying and Managing Respiratory Diseases and Symptoms after Transplant

Tuesday, May 2, 2023

Presenter: Kyle Brownback MD, FCCP, University of Kansas Medical Center

Presentation is 38 minutes long with 22minutes of Q & A

Summary:  Stem cell transplant recipients may develop pulmonary complications after transplant. Some, like bronchiolitis obliterans syndrome (BOS) can severely restrict breathing. This presentation describes the symptoms and treatments for these complications with particular attention to bronchiolitis obliterans syndrome.

Highlights:

• Four major pulmonary issues can arise for transplant patients: pre-existing pulmonary conditions that compromise lung function, infections arising after transplant, drug toxicity and side effects, and GVHD that affect the lungs.
• Bronchiolitis obliterans syndrome is a type of graft-versus-host-disease (GVHD) in which the bronchioles of the lung become narrowed and compromise breathing. Treatment for bronchiolitis obliterans syndrome includes systemic and inhaled steroids. They can be essential to treatment but have serious side effects.
• Transplant patients can reduce the risk of developing serious lung and breathing problems by getting treated for asthma or COPD, quitting smoking, avoiding vaping, and using air purifiers. Wearing masks, maintaining hand hygiene and other precautions to avoid infection, along with physical activity can minimize the effects of post-transplant pulmonary issues and GVHD.

Key Points:

(00:02:00): The lungs are an ingenious system by which we're able to bring oxygen from our environment into our body so it can be used by our cells, and also expel our waste gas, which is carbon dioxide.

(00:05:32): A variety of tests are used to test patients for bronchiolitis obliterans including spirometry, tests for lung volume and diffusion capacity, and tests forforced vital capacity compared to actual lung function.

(00:12:53): Prior to transplant, patients are typically tested for pre-existing lung conditions such as asthma, COPD, interstitial lung disease, and long COVID.

(00:14:24): Pulmonary infections from various sources including bacterial, fungal, viral, pneumocystis, cytomegalovirus, aspergillus and respiratory syncytial virus (RSV) can pose pulmonary risks for transplant patients.

(00:16:40): The conditioning regimen given prior to transplant as well as some medications, like checkpoint inhibitors, can create pulmonary problems for transplant patients. Typically, these patients present with symptoms similar to a lot of other infections.

(00:18:19): There are three major forms of GVHD that affect the lungs:  idiopathic pneumonia syndrome, organizing pneumonia and is bronchiolitis obliterans syndrome (BOS)

(00:18:40): Idiopathic pneumonia syndrome may or may not be an actual manifestation graft-versus-host disease.

(00:19:38): Organizing pneumonia is a pneumonia that can occur in patients and is not infectious. This is a pneumonia that is not treated with antibiotics. It was very common with COVID and is treated with steroids.

(00:24:03): Bronchiolitis obliterans syndrome is diagnosed by the presence of other forms of GVHD and signs of airflow obstruction.

(00:29:34): Pulmonary rehabilitation is a supervised exercise regimen that can be crucial in restoring lung infection.

Transcript of Presentation

(00:00:07): [Michala O’Brien]:   Introduction. Welcome to the workshop Identifying and Managing Respiratory Disease and Symptoms after Transplant. I'd like to introduce our speaker today, Dr. Kyle Brownback. Dr. Brownback is an Associate Professor of Medicine in the Division of Pulmonary, Critical Care and Sleep Medicine at the University of Kansas School of Medicine. He is also the Medical Director of Pulmonary Rehabilitation at the University of Kansas Health System.

(00:00:34): Dr. Brownback has been active in managing pulmonary complications of stem cell transplantation for nearly a decade, including those in patients with graft-versus-host disease (GVHD) and chronic lung infections. His research focuses on the management of bronchiolitis obliterans syndrome after transplant and the effects of systemic GVHD therapies on lung function. Please join me in welcoming Dr. Brownback.

(00:01:04): [Dr. Kyle Brownback]: Overview of Talk. Thank you very much. I really appreciate that introduction and I'm very pleased to be with you today. I'm going to spend some time on this talk starting off with just the basics of how lungs work, and how we measure lung function and determine how the lungs are doing throughout the post-transplant journey.

(00:01:29): We'll discuss some of the specific pulmonary conditions that can occur after transplant and how we manage those conditions. Finally, we'll close with discussion of things that you can do to be your own advocate and provide yourself with the best overall lung health, as you go forth with your post-transplant life.

(00:02:00): The lungs and respiratory system sustain life by bringing oxygen into our body and expelling carbon dioxide.  To begin, we'll talk about the respiratory system in general. The lungs are a really ingenious system by which we're able to bring oxygen from our environment into our body so it can be used by our cells, and also expel our waste gas, which is carbon dioxide.

(00:02:17): Our lungs act as a vacuum. So, when we take in a breath, our chest wall expands, our diaphragm decreases, it lowers itself, and this causes a decrease in intrathoracic pressure. As some people with any type of engineering background might know, gases travel from areas of higher pressure to lesser pressure. So, by having a larger space, we are able to decrease our intrathoracic pressure, and air, gas, is sucked into our chest.

(00:02:53): It's done through either our nose or through our mouth. Our nose and mouth are approaching to heat and humidify the oxygen that we breathe in. The nose and the nostrils will help to filter out particles going into the lungs as well.

(00:03:07): Once the air that we breathe in arrives in our lungs, it will travel throughout the lungs into the alveoli, which are some of the distal air sacs that go terminally at the end of the main bronchus into the distal lung units. At their place there's an alveolar capillary unit, and at that point is where oxygen is absorbed from the alveoli, from the air sacs, into the blood vessels. Carbon dioxide is transferred in the opposite direction.

(00:03:40): Once that gas exchange occurs, we exhale and our diaphragm raises, our chest wall collapses and gets restricted.. We create increased pressure inside of our chest and that expels air from our area of higher pressure, now in our thorax, to our environment. These are the main areas as far as where oxygenation comes into the lungs.

(00:04:11): Bronchiolitis obliterans syndrome is a type of graft-versus-host-disease (GVHD) in which the bronchioles of the lung become narrowed and compromise breathing. One thing that you may hear a lot of us discussing is bronchiolitis or bronchioles, because those end up being a very important part of the development of graft-versus-host disease (GVHD). Graft-versus-host disease affects the bronchioles for majority of patients and that's what's termed bronchiolitis obliterans syndrome.

(00:04:33): I mentioned that air travels from our mouth and our lungs past our vocal cords into the trachea, which is our windpipe, and into the bronchi. The airways that are in between the bronchi and the alveoli, which is where gas exchange occurs, are called the bronchioles. This is a representation of what a bronchial look like. These are essentially the side streets of our lungs, how air gets from the major highways into the small cul-de-sacs where gas exchange occurs.

(00:05:08): These bronchioles are what end up being affected, predominantly, in the most common forms of graft-versus-host disease, which is bronchiolitis obliterans syndrome. These bronchioles can become narrowed in this spot, which makes it harder for air to get from the major airways, the trachea, the bronchi, into the alveoli where the oxygen needs to get to.

(00:05:32): Spirometry is a forced exhalation maneuver that can identify the presence and seriousness of compromised breathing due to bronchiolitis obliterans syndrome. How do we monitor for bronchiolitis obliterans following transplantation? The most important part becomes something called spirometry, that I'm sure many of you guys have done several times before. Spirometry is a forced exhalation maneuver where we ask you to breathe in as deep as you can and then exhale as forcefully and completely as possible. Based on this performance, we're able to calculate your forced vital capacity, which is the amount of air that you are able to inhale and forcibly exhale in one breath.

(00:06:08): Also, with that we're able to calculate our FEV1 or force expiratory volume in one second. That's the amount of air that's able to be exhaled completely from your lungs in the first one second of exhalation. This is important because diseases like bronchiolitis obliterans are diseases that are obstructive. That means this makes it harder for the air to escape from your lungs and to be exhaled and such. This number, FEV1, will be significantly less than the forced vital capacity in patients who have the most common forms of graft-versus-host disease involving the lungs.

(00:06:44): Other assessments of bronchiolitis obliterans syndrome can be done with lung volume testing and assessing diffusion capacity. Additionally, some of you have probably undergone the lung volume testing and this is how we calculate what your total lung capacity is along with your residual volume and your diffusion capacity. This is called body plethysmography, which is essentially a technique that many of you done where you are panting into a shutter valve, and it allows us to make small calculations involving the pressure changes in the lungs. Based on these calculations, we can assess the residual volume, which is how much air is left over in your chest after a complete exhalation. This is a number that can become elevated in bronchiolitis obliterans syndrome that we try to monitor for.

(00:07:27): We also will assess your diffusion capacity. This is a measurement of how well oxygen transmits from your lungs into the blood vessels. When we do our pulmonary function testing at the University of Kansas, we will get a report that looks similar to this. Many of you may see your pulmonary function testing on your patient portals and this is the way it's presented to us as providers, and also the way our patients see them.

(00:07:59): You'll see a spirometry section which talks about the force vital capacity in FEV1. You'll see lung volumes, which measure our residual volume, our total lung capacity, and then our diffusion capacity. That's called the DLCO. That's how well oxygen goes from the alveoli into the blood vessels.

(00:08:19): What most of you will end up seeing in the number that your physicians and providers will talk about is your percentage of predicted. As humans, every one of us are built a little bit differently. We have different volumes of lungs, we have different amount of air that we can get inside our lungs with one deep breath, and there's quite a bit of variability from person to person. We are able to calculate what would be a predicted amount of your force vital capacity based on your age and height. Taller patients typically have larger lungs than shorter people, and as we age, we do lose lung function over time.

(00:09:06): Measures of forced vital capacity compare predicted with actual lung function to assess damage to the lungs. When we are calculating your lung function, we will obtain the forced vital capacity, which will be written here as actual, but we will also have a predicted amount. This is based on the database of a large number of patients of what would be your expected forced vital capacity based on your age and your height. That will give us a percentage of predicted and that's just basically of what you are able to do, divided by your predicted amount.

(00:09:34): So, when patients ask, "What is my lung function?", these are the percentages that we would tell you about what your lung function measures. These are good for baseline measurement.

(00:09:45): Ultimately, over time, during the monitoring process, we measure how you're doing compared to your previous testing to assess how your lung function is doing. But at onset this gives us an idea about whether your lung function is abnormal. We'll compare you to what would be predicted based on those factors.

(00:10:03): Imaging can also monitor and measure lung function. Other ways that we're able to monitor and measure lungs is by imaging. Chest x-rays and CAT scans are very important in this process. CAT scans are very important to look for evidence of infection. They can also show changes of graft-versus-host disease when they display things like air trapping. They provide a very sensitive measure, and they can help to distinguish graft-versus-host disease from a non-graft-versus-host disease process.

(00:10:40): Bronchoscopy can be used to distinguish infection from GVHD. Another thing that is utilized commonly in the post-transplant practice is bronchoscopy. This is a procedure that's typically done with anesthesia where a small fiber optic scope is introduced into the lungs. It allows us to look for infection. And in the majority of our patients with GVHD, that's what we're looking for to distinguish infection from GVHD. This allows us to get samples of the lungs to run cultures and to look for any type of infectious pathogens that could be present. We utilize this in several other conditions in pulmonary medicine, the diagnosis of lung cancer and for other types of treatments that we're able to do for patients with a variety of lung conditions. But when it's utilized in our bone marrow transplant population, typically it's to determine whether there's an infection in the lungs.

(00:11:35): Four major pulmonary issues can arise for transplant patients: pre-existing conditions, infections, drug toxicity, and GVHD. After transplants I generally think about there being four major categories of pulmonary conditions that can arise. Number one is that patients can sometimes go into their diagnosis with some sort of lung condition. It's not uncommon for patients, maybe older patients who come in with significant COPD or patients who have severe asthma, to get a condition that requires a bone marrow transplant. Those things can still occur after transplants and need to be managed.

(00:12:12):  Infections are relatively common, especially in the early time frame, either during the peri transplant period or immediately afterwards.

(00:12:22): Drug toxicity, complications that can happen to the lungs related to the conditioning regimen as part of the transplant, also can be seen commonly in patients who require treatment with checkpoint inhibitors, which are the immunotherapy type of medications.

(00:12:42): Then finally, graft-versus-host disease. These are the conditions that we are very commonly looking for in the post-transplant patient population.

(00:12:53): Pre-existing lung conditions for transplant patients include asthma, COPD, interstitial lung disease, and long COVID. When it comes to preexisting lung conditions, the most common things that we assess for are asthma and COPD. Before you have a transplant, in the majority of centers, they will do a pre-transplant pulmonary function test That serves as a baseline so that we can monitor how you're doing post-transplant. It also allows us to assess conditions like asthma or COPD. This is how we can determine if those conditions were present, and if not diagnosed beforehand, we can start you on the appropriate treatments before your transplant to try to prevent any complications afterwards.

(00:13:38): Another common thing that can be evaluated is interstitial lung disease, which can be scarring related lung diseases. Blood clots or pulmonary embolisms are also common in the peri transplant period of time and are typically assessed for with a CAT scan with contrast.

(00:13:57): Then finally long-COVID. I feel this is something that has really become a major challenge to us, as pulmonologists, knowing what this condition is, which is rather nebulous right now, and how to monitor or treat it. There are still a lot more questions than there are answers as far as the long-COVID goes, but certainly it can be a detriment to patient's lung health if they need to go through this type of process.

(00:14:24): Pulmonary infections from various sources can also be problems for transplant patients. As many of you know, during the first 90 days, then 365 days you'll be on prophylactic medications to prevent infections after transplant. This is a list of some of the infections that we end up looking for. Bacterial, fungal, viral, pneumocystis, cytomegalovirus, these are all very common ones that we try to prevent but we also test for. A lot of these require testing, such as a bronchoscopy, to look for these types of specific infections if they occur in the first three to 12 months after transplantation. These are all things that we assess for and are why we like to have our patients monitored very closely for fevers, coughs and sputum production that happen in that timeframe after transplant.

(00:15:17): This is just another graph showing the infections that occur and the time frame when they typically occur.

(00:15:28): Aspergillus and respiratory viruses like RSV pose additional pulmonary risks to transplant patients. Things that we particularly worry about, aspergillus, which is a fungal infection. Depending on what region of the country you are in, you may have high incidences of other types of fungal infections. In Kansas City we have a mold here called histoplasmosis that's not common at all on either coast. But there are different types of molds that need to be tested for, depending on what region of the world that you are in.

(00:16:02): Also, it's not included on this chart, but respiratory viruses are common after transplant, and can make people very sick. RSV (respiratory syncytial virus) is a real problem currently. Also, COVID. It seems like our patients can shed COVID for a very, very, very long time and that's something that we assess for quite frequently when patients develop new respiratory symptoms. It has certainly made us change our management style in the last three years. These are the infections that we specifically look for.

(00:16:40): Some medications can also create pulmonary problems for transplant patients. Specific toxicities can occur with some medications that are used to treat these malignancies, either the conditioning regimens or checkpoint inhibitors. Typically, these patients present with symptoms similar to a lot of other infections. They may be coughing, having shortness of breath, or having chest pain. It requires a thoughtful assessment. It requires, in many situations, a bronchoscopy to assess whether there are any infections involving the lungs. It requires people with expertise in the field to help determine if one of those toxicities could be occurring.

(00:17:28): This is a list from our pulmonary medicine textbook that a lot of us follow about different medications that are known to potentially cause drug toxicities in our patients. I think the one that most people know a lot about is bleomycin, which is part of the ABVD regimen of chemotherapy. These are typically things that cause toxicities in the short-term, not necessarily in the long-term but things that, when we get a history from our patients who have respiratory conditions, we ask about to see if you can remember being on any of these medications, or if they might have been part of your prior treatments.

(00:18:19): There are three major forms of GVHD that affect the lungs. A lot of you are interested in is graft-versus-host disease involving the lungs. There are three major manifestations of graft-versus-host disease. One is the idiopathic pneumonia syndrome. The second is organizing pneumonia. The third, which is the most common one that most of you should be familiar with, is bronchiolitis obliterans syndrome (BOS).

(00:18:40): Idiopathic pneumonia syndrome may or may not be an actual manifestation graft-versus-host disease. It's still unknown what causes it. This is something that causes our patients to become very ill in the first 20 to 90 days following transplantation. Often these patients can end up in our intensive care units and require ventilatory support. It is distinguished as being a disease where patients have significant lung inflammation that's not infectious. It is something that we generally assess for and one of the reasons that we monitor patients in that first three months after transplant very, very closely. The majority of cases that I see in this situation are patients during the first 30 days after transplant. This is something that we assess for in these patients and, fortunately, is not very common.

(00:19:38): Organizing pneumonia is a pneumonia that can occur in patients and is not infectious. This is a pneumonia that is not treated with antibiotics. It was very common with COVID and is treated with steroids. We typically will look for patterns on CT scan that are similar to what I'm showing you on the screen. It typically requires bronchoscopy to exclude infection and is treated with a prednisone for somewhere between two and four months. It generally responds very well without a long-term complication.

(00:20:21): It can occur in patients who also have bronchiolitis obliterans syndrome but not necessarily, and it sometimes follows a viral illness. It was a very common finding in COVID. It was one manifestation of long COVID that we were seeing very commonly. This can occur in the first year after transplant, typically in that three-to-18-month period after transplant. I have seen it sporadically at different times. It occurs in the non-transplant community as well. It was most known, in the last three years, as a long COVID manifestation, but was something that we saw following other viral illnesses in the past.

(00:21:10): Typically, it takes a month or two to diagnose this because we are treating it as an infection and it requires someone to say, "Oh, this is not behaving like a typical pneumonia. Are we sure it's not a non-infectious organizing pneumonia?" I've been in practice for about 10 years now at the University of Kansas. I've probably diagnosed this in the post-transplant community in probably 20 to 30 patients in that period of time. So it is not very common.

(00:21:38): Bronchiolitis obliterans syndrome is significantly more common and a condition that most of us consider to be the major manifestation of lung GVHD. It’s the most common manifestation and the one that we have a lot of concerns with.

(00:21:54): In bronchiolitis obliterans syndrome, transplanted cells attack the bronchi which become narrowed due to inflammation. These cases often follow a viral illness. This condition occurs in the bronchioles, which, as I showed you earlier, are the airways that connect the large airways, the bronchi to the alveoli, which is where oxygen gets from the lungs into the blood vessels. They become narrowed. It initially is due to inflammation and that inflammation is triggered by some sort of factor. We think about it as being graft-versus-host disease where the transplanted cells attack in that area, cause significant inflammation.

(00:22:29): A good chunk of these cases follow a viral illness. They start with a parainfluenza virus or a influenza or respiratory syncytial virus (RSV). That inflammation is propagated and if unrecognized and untreated can lead to scarring in those areas, making those airways very narrow.

(00:22:52): Patients may have symptoms or be asymptomatic with bronchiolitis obliterans syndrome. Some patients present with cough, some patients present with shortness of breath, a lot of patients are completely asymptomatic. We're built with a lot of extra lung function that we may never ever need, so you can lose 30% of your lung function and may not have a lot of symptoms, especially if you're not very active. It's very easy to become very sedentary in that post-transplant period and without a lot of activity or pushing yourself to exercise aggressively, you can sometimes develop a significant deficit that may not be recognized. That's why we have our patients get routine pulmonary function testing following transplantation to screen for this condition.

(00:23:32): Risk factors for bronchiolitis obliterans syndrome are a history of viral infections and airflow obstruction prior to transplant. These are some risk factors that have been identified for developing bronchiolitis obliterans. The two I think of the most are, one, a history of viral respiratory tract infections, and two, the presence of airflow obstruction prior to transplant. If you go into transplant with COPD or asthma, you are more likely to develop bronchiolitis obliterans syndrome afterwards, so those are patients that we typically monitor very closely for that period of time.

(00:24:03): Bronchiolitis obliterans syndrome is diagnosed by the presence of other forms of GVHD and signs of airflow obstruction. So how do we diagnose bronchiolitis obliterans syndrome? This is a diagnostic criterion that has been proposed. The overwhelming majority of patients who have a history of transplant will have some other manifestation of chronic GVHD at the same time. I always ask my patients, "Do you have a skin rash? Are you having any eye or mouth dryness? Muscle or joint pains? Gastrointestinal symptoms?" What other type of chronic GVHD is manifesting?" Typically, these things occur together, not always.

(00:24:35): We look for signs of airflow obstruction, so where it's harder to exhale where your FEV1 is less than your FVC. A lot of times we'll get CT scans of the chest to help to make sure there's no signs of infection that might be causing a similar drop in lung function. We also look for air trapping on our CAT scans which can be consistent with graft-versus-host disease. These patients should not have an infection present. If there is any areas of abnormalities of CT scans that are not typical, we often do a bronchoscopy just to exclude infections that could be causing some more symptoms.

(00:25:20): Treatment for bronchiolitis obliterans syndrome uses steroids to manage systemic GVHD. They can be essential to treatment but have serious side effects. How do we treat this? First off, you have to manage the systemic graft-versus-host disease. This is where steroids become important. Steroids are ultimately the best drug to manage these patients, and they also are the worst drug to manage these patients. They are unquestionably the most efficacious, as far as providing a prompt anti-inflammatory effect, but they unquestionably have a terrible side effect profile. It pains me to start these drugs, but there really is no substitute for first line therapy for graft-versus-host disease when it affects the lungs. Prompt initiation is generally very important. That's why we do screening PFTs, that's why we ask patients to monitor very, very closely.

(00:26:04): A number of other drugs can be used as second line therapies to treat bronchiolitis obliterans syndrome. We use second line therapies for patients who are either steroid intolerant, (you can't be on steroids because of the side effect profile) or are steroid-refractory (you're on steroids but things are getting worse, or the steroids are effective but you need to wean off of them). We need to put you on something else, and that's where these other drugs are utilized such as ruxolitinib, which is Jakafi®; belumosudil, which is Rezurock®; ibrutinib or Imbruvica®; extracorporeal photopheresis, which is a procedure that's done to try to reduce the function of circulating lymphocytes; and rituximab, which is a anti CD20 antibody that is used to block antibodies that may play a role in systemic GVHD.

(00:26:49): Part of my research has been to look at these drugs' overall efficacy in management of the lung function in GVHD treatment. Both ruxolitinib and belumosudil and ibrutinib all have FDA approvals for treatment of graft-versus-host disease, and they are drugs that are utilized throughout the country for this type of condition. At our own individual center, we commonly use both ruxolitinib and belumosudil, and we're glad to have those medications. I think it definitely requires a lot of individual expertise from your providers as far as what are the appropriate systemic GVHD treatments at this time.

(00:27:42): Inhaled steroids can also be used to treat bronchiolitis obliterans syndrome. How do I treat? So specifically, when it comes to the lungs, we use inhaled steroids, in addition to systemic steroids. These steroids are inhaled into the lungs by some sort of inhaler. They help to reduce inflammation at the site of deposition, which is hopefully the bronchioles. These are inhalers that are utilized to treat asthma and COPD as well. They're very commonly used in the United States. The main one is called fluticasone, Flovent. I use a lot of medication called Symbicort®, which is a combination of a steroid budesonide and a long-acting version of albuterol called Formoterol. This helps to relax the airways and also provides an anti-inflammatory effect. Both these medications have been studied in the transplant space with good results and help to stabilize lung function and potentially improve it.

(00:28:48): Additionally, we use leukotriene modifier medication called montelukast, Singulair® is the trade name. It helps block the allergic pathways in patients with constriction of their airways. It is a generic pill that's commonly utilized in combination with both inhaled corticosteroids and Symbicort.

(00:29:19): Finally, short-acting bronchodilators like albuterol can provide immediate relief. They're not studied in pulmonary GVHD particularly, but they're utilized very commonly if patients have congestion, or feel like they have tightness in their chest.

(00:29:34): Pulmonary rehabilitation is a supervised exercise regimen that can be crucial in restoring lung infection. Other things that are important, assess if patients need oxygen. Pulmonary rehabilitation is something that's very, very important to me. It's a supervised exercise regimen that's been utilized for many, many years for conditions like COPD, but it probably has a significant role for our patients with lung GVHD. It's an exercise program that's typically done in an outpatient setting where patients work on both strengthening of the respiratory muscles and also improving conditioning under the supervision of an exercise physiologist. It can help to improve patients' exercise capacity and to improve their quality of life and their symptoms, especially if they've been very ill. I find its most effective in those patients who've had severe pneumonias and are very debilitated. It can be really helpful to help to get them back on their feet again.

(00:30:31): We also assess for other conditions. One is infection and also sleep apnea. If you have any sleep apnea symptoms, a sleep study can help distinguish if you have sleep apnea and improve some of your symptoms.

(00:30:43): Patients can do self-care by getting treated for asthma or COPD, quitting smoking, avoiding vaping, and using air purifiers. So, now to the part about what you can do. What could really help patients improve their symptoms? First off, if you have asthma or COPD, we need to have you on treatment for that. This can be inhaled corticosteroids or another type of bronchodilator regimen that can help to control their underlying lung disease, help to get the patient's lung health as good as possible.

(00:31:11): Smoking cessation. There is nothing more important that I can do for my patients than to help them to quit smoking. Smoking after transplant increases your risk of lung complications, both infectious and non-infectious. If you are still smoking, or have people smoking around you, it's really, really important to do everything possible not to do that anymore.

(00:31:37): I get asked about vaping a lot and the honest, the truth there's not a lot of data on what the risks are from vaping long-term. I think you should always err on this side of not vaping. I get asked a lot " is vaping safer than smoking?" The answer is I'm not sure. My sense is that it probably is, but that's not based on much scientific evidence.

(00:32:02): Air pollution, air purifiers, I get asked about those a lot. Certainly, in your first 90 to 365 days after transplant, avoiding molds, reducing air pollution exposures, that's important. That's not necessarily something a lot of our patients can do, though.

(00:32:19): Air purifiers are not well studied. I do say that it's useful if you have a heavy mold burden, especially if you've had any type of fungal infections, to consider an air purifier, but there's really not a lot of data to support that one way or the other.

(00:32:37): Preventing infections is important for maintaining pulmonary health with masks, hand hygiene, and other precautions. Infection avoidance becomes very important, so following the vaccination protocols that your transplant center establishes, avoiding viral illness as much as possible. That involves masks. It's a lot harder now that the world is masking less, but an ounce of prevention is worth a ton of cure here. So, good hand hygiene, avoiding sick people, wearing masks are important because a lot of these conditions typically occur following viral lung illnesses, these contagious illnesses that we talked about earlier.

(00:33:12): Physical activity can minimize the effects of pulmonary GVHD after transplant. Physical activity, maintaining a good functional status is so important. If you are developing lung GVHD and you are exercising, you're going to be more sensitive to changes in your lung capacity. I think from that perspective, it's important. But it also helps to prevent some of the debilitation that can occur after transplant that's heavily linked to improved quality of life and improves mental health. I can't recommend enough that my patients be as active as possible after transplant. Easier said than done. I know that doing exercise and being physically active is very challenging, but it is truly, truly worth it. A good walk a day can really help to improve symptoms and to prevent other types of complications.

(00:34:10): Notifying transplant teams of early symptoms of lung problems can lead to more effective and aggressive treatment. Symptoms detection, so when to notify your transplant team. Transplant teams generally have a good protocol in place, but for cough, fevers, new respiratory symptoms, generally we want to promptly get pulmonary function testing and a CT scan done to determine if one of these conditions is occurring. A lot of time, detecting these things early allows for more effective and aggressive treatment.

(00:34:33): I often get asked about home spirometry. There are a few trials that will be up and running in the near future doing home FEC and FEV1 testing to monitor, very closely, how your lung function is doing on a day-to-day basis. It's something that's been utilized for some time in our post lung transplant patients to monitor for lung transplant rejection more closely. There have been some efforts to consider doing that in patients who've had transplants for early assessment of lung GVHD. It's too early to know, yet, if that will be effective or not. But my sense is that if you've been diagnosed with lung GVHD, home spirometry could potentially be an effective way to monitor how you're doing so we can assess how things are going. I think it's a little early to know if that's something I would blindly recommend to all patients, but I am hopeful that we will have some clarification based on some studies and the upcoming years.

(00:35:57): In conclusion, the lungs are susceptible to several different conditions that can occur after transplant including other common lung conditions, infections, toxicities of treatment or graft-versus-host disease.

(00:36:14): Standard of care is to monitor pulmonary function tests after your transplant to assess for any decline that could be suspicious for lung GVHD. If you are having a new symptom that's occurring after transplant, especially early after transplant, these typically need to be assessed with pulmonary function testing and a CT scan. Do as much exercise as you can, avoid infection and avoid things that could be causing harm to your lungs. I think, overall, that will help reduce these risks, help improve your overall lung health and help you get through these illnesses, if you are unfortunate enough to get them.

(00:36:58): So quick thank you to the transplant team here at the University of Kansas that I've been working with for a while. Dr. Abhyankar and McGuirk have been really instrumental in my work in this field. I partner with Dr. Shune and Dr. Singh in patient care and also with some of our research projects, and then also with the Lung GVHD Consortium Group. That's a group of other pulmonologists, like myself, who manage patients with this condition across the country both in adults and pediatrics and we discuss what we think are the areas that need to be improved upon with better research, as well as establishing what the standard treatment should be for these patients going forward. So with that, I thank you for your time and I am open to any questions you might have.

Question and Answer Session

(00:37:55): [Michala O’Brien]: Thank you, Dr. Brownback, for this excellent presentation. We'll now begin the question and the answer session. First question is what are your thoughts on long-term use of azithromycin?

(00:38:10): [Dr. Kyle Brownback]: Azithromycin has been utilized for quite a long time for the treatment of bronchiolitis obliterans syndrome after lung transplantation. This would've been for chronic lung transplant rejection. It was found to slow the rate of decline in patients who'd had a lung transplant and who had a similar condition that happens in our post-stem cell transplant patients.

(00:38:41): We adopted the use of azithromycin early in my career as part of our regimen. Some of you may remember a regimen called FAM, which was fluticasone azithromycin montelukast, that we utilized several years ago. A study was done by Dr. Bergeron in France where she looked to see if azithromycin taken after transplant could reduce the risk of developing lung GVHD. In this study, which is called the ALLOZITHRO trial, she found that it didn't help in that situation, and there was also an increased risk of relapse of leukemia in patients treated with azithromycin.

(00:39:29): After that study was published, it was decided that there probably wasn't a good reason to use azithromycin for treatment of bronchiolitis obliterans syndrome after stem cell transplant. We felt that the overall benefits probably did not warrant that particular risk.

(00:39:49): I currently do not utilize azithromycin chronically in the management of my patients with bronchiolitis obliterans syndrome due to graft-versus-host disease. I don't believe anyone else in my center does. I'm not sure if it's utilized in other centers, but I know at least at our center we do not have it as part our algorithm for bronchiolitis obliterans syndrome after stem cell transplant.

(00:40:20): [Michala O’Brien]:  Speaking of that, this patient has GVHD manifested as bronchiolitis obliterans. They want to know if there's a pattern or staging of what it looks like and has research demonstrated a possible plateau in symptoms?

(00:40:37): [Dr. Kyle Brownback]:  A lot of heterogeneity in this field. There are some patients where there is certainly a plateau that happens early on and a lot of times that can be just related to the patient themselves or it can be a marker of an effective treatment with steroids or other types of GVHD treatments. There's not any accepted grading that I'm aware of as far as a grade one, two or three, unlike in other types of manifestation of GVHD. I generally talk about presence or absence of it, whether its active, and if it something that requires systemic treatment to keep it from worsening or is it something that is quiescent. There' are certainly a number of patients who have an acute area of inflammation and thin scars, and it's no longer active whatsoever. In a number of those patients, once they're stable for several years, it no longer requires treatment. It is simply a scar that will slowly improve over time but doesn't require ongoing treatment.

(00:41:44): [Michala O’Brien]:  Does pleurisy leave lung scarring?

(00:41:48): [Dr. Kyle Brownback]: Pleurisy typically does not. Pleurisy's symptom of a sharp pain in the thorax that is associated with inflammation of the pleura, which is the lining of the lungs. Pleurisy can be a symptom of pneumonia, of fluid around the lungs or a pleural effusion. It can sometimes be a symptom of blood clots. It is typically not something that can cause scarring and is more of a symptom than an actual disease itself.

(00:42:20): [Michala O’Brien]:  How do you usually wean off prednisone when Rezurock® and Jakafi® are introduced?

(00:42:27): [Dr. Kyle Brownback]: Good question and this is something that I partner very closely with our transplant team to do. The way I typically do it is that I communicate with that patient's primary transplant attending physician and their pharmacist to say that I think this patient has a significant lung GHDT, or that they're having a lot of complications from the prednisone, and we should probably introduce a steroid-sparing regimen. Our pharmacist will provide a patient with a calendar to wean that dose down. I generally follow the national guidelines that I believe the NIH published and I really follow what our BMT team does as far as their algorithm, too.

(00:43:24): As far as a specific timing for integration of Jakafi® or Rezurock®, I think a lot of that's dependent on the underlying severity of the initial presentation, how significant the lung GVHD is and what we think that patient's tolerance of steroids will be. I think you have to be very individualized. But if a patient presents with a severe drop in their lung function, I generally will ask them to get approval for Jakafi®  or Rezurock® right off the bat and start them on the one mg per gig prednisone at that same time We will typically begin the weening of the prednisone within around a month, or so, after it was started and hopefully leave them on Jakafi®  or Rezurock® that we started in that timeframe. If we're weaning off the prednisone and we need to do it faster because of a lot of myopathy or side effects due to prednisone, then that's certainly the time to use it. If we're weaning it and we find that, "Oh, the lung function issue got a little bit worse as we went from 20 milligrams prednisone a day to five milligrams a day", then we need to integrate Jakafi® or Rezurock®.

(00:44:40): I wish I could give you a standard rule, but this is something where there's a lot of nuances and it just requires providers who have experience in this space to have thoughtful discussions with each other about what their right overall treatment plan would be.

(00:44:58): [Michala O’Brien]:  If a patient has bronchiolitis obliterans, is there any value in home incentive spirometry?

(00:45:09): [Dr. Kyle Brownback]: I would say that if a patient can't walk, can't exercise, then yes, that absolutely is better than nothing. If a patient is asking me, "I have 30 minutes today that I can do exercise, should I spend that 30 minutes doing incentive spirometry or should I spend that 30 minutes on a bike or a treadmill or an elliptical machine?", I will tell them. 10 times out 10, do that whole body exercise, do what makes you take in deep breaths more. It's better than nothing but I would still choose a more robust form of exercise over incentive spirometry.

(00:45:52): [Michala O’Brien]:  This patient wants to know what components of pulmonary rehab would you identify as essential?

(00:46:00): [Dr. Kyle Brownback]: The process of pulmonary rehab is first, education about lungs and how the medications work, particularly inhalers, and second, focusing on strength training. This typically can be upper body training with lightweights, Then the third is endurance training.

(00:46:22): We utilize, in our own center, stationary bikes, elliptical machines, treadmills and cycle odometers. Our program is usually done two half days a week for an hour to an hour and a half per session and lasts for around 12 weeks. That's a standard type of program seen throughout the country. I think that those are all important. I think that the endurance capacity probably ends up being the most important component because we get people trained to do things that are important for their quality of life. It can be really beneficial.

(00:47:11): One patient comes to mind; it was a great situation. He was a young patient who was 22 and had a horrible case of idiopathic pneumonia syndrome. He was in our ICU for two and a half months and left the hospital frail, debilitated and needing eight liters of oxygen just to walk. He completed three months of pulmonary rehab and a month after that he was completely off oxygen. He was able to get his strength back, and it gave him confidence to exercise even though he is short of breath. It really improved his quality of life and really improved his exercise capacity.

(00:47:51): Not everyone needs that degree of rehab, but when you can provide it, it can be an exceptional benefit for patients. I mention this for our patients who are really limited by breathlessness. The sicker you are, the more likely you are to benefit from pulmonary rehab. It's certainly something to inquire about with your transplant center.

(00:48:17): The major downside is the risk of infection. During the heart of the pandemic, our rehab program shifted to all masking. That's not something that is being done at my center anymore, or at most centers throughout the country.

(00:48:37): There are some companies that are evaluating virtual pulmonary rehab. That's not something that's readily available currently, but it may be something in the future that would be a good treatment option for patients who need rehab but are fearful of being around a lot of unmasked people who are exercising. I am hopeful that will be an option in the upcoming years. I'm in Kansas and there's one company we've been partnering with in some of our research to potentially offer that not just to patients with graft-versus-host disease, but patients in rural Kansas who need pulmonary rehab, who have other conditions and who can't get to a rehab center. I'm very hopeful that virtual pulmonary rehab will be something that's adapted and paid for by Medicare going forward that we can offer to our patients.

(00:49:39): [Michala O’Brien]:  I'm post eight years BMT and post CAR T treatment. I was diagnosed with small airway disease. Is there a treatment you would suggest for this?

(00:49:52): [Dr. Kyle Brownback]: I think, first and foremost, being evaluated by a pulmonologist who is knowledgeable and has expertise in this field is important. Typically, small airways disease can be a GVHD manifestation, but it could also just be something that's completely unrelated, may just be a manifestation of asthma that can develop later in life. Typically, these are treated with some form of an inhaled steroid, so either inhaled steroid alone or a combination of inhaled steroid and long-acting version of albuterol. Medications like Advair® or Dulera® or Symbicort® or Breo® can be utilized to treat these areas. But first and foremost, it's just to make sure that you are being managed by a provider who's knowledgeable of these conditions and that it's treated in conjunction with your transplant team to ensure that this is purely a small airway disease and not necessarily a manifestation of lung GVHD that requires other treatments.

(00:51:01): [Michala O’Brien]:  I am now 20 years out from a transplant, but I've noticed every year I get more breathless with exertion. Is this normal? I now find I cannot talk and walk at the same time.

(00:51:16): [Dr. Kyle Brownback]: I'm sorry, not knowing all the history there, it's hard for me to know a lot, but I would suspect that with that type of symptom, you would benefit from having further evaluation. Having a pulmonary function testing done, having a CAT scan done to look and see what the lung function looks like now, compared to the last time it was checked. Is it getting significantly worse? That could be a manifestation of lung GVHD and would require an evaluation and potentially starting treatment. If it is something where the lung function looks stable but you're that much more breathless, you might be in a situation where a rehab program could be helpful to improve your symptoms shortness of breath.

(00:52:12): With those type of symptoms, I would definitely want to have further workup looking at the lung function. Also, cardiac disease can also manifest in a similar manner. If you're having those type of symptoms that are changing and getting worse, it's worthwhile to have both a lung checkup, and if nothing's identified there, then a cardiac checkup, too, to make sure that there's nothing that's being missed. But I wouldn't just chalk up those symptoms are a normal process of aging, so you exclude other conditions.

(00:52:43): [Michala O’Brien]:  Once diagnosed with lung GVHD and having a significant decline in FEV1, what's the current frequency recommended for pulmonary function testing if there are no new symptoms?

(00:52:57): [Dr. Kyle Brownback]: If you're stable without any new symptoms, I would say in the first two years it would be every three months. In years two through four, probably every six months, and then years five going forward, probably yearly, but that would be a little bit dependent on the severity of the underlying GVHD and the presence or absence of systemic GVHD. But all things being equal, that would be the frequency that I would suspect that you'd want to check your lung function.

(00:53:29): [Michala O’Brien]:  This patient is trying to taper off steroids. How often should they check PFTs?

(00:53:37): [Dr. Kyle Brownback]: So, depending on the underlying, it would be a little bit variable based on how severe the lung GVHD is. I would say that if it's more of a mild reduction, then I would suspect probably every six months. If it's more of a moderate severe, then probably every one to two or three months, just depending on symptoms and the speed of decline and what the other systemic GVHD symptoms are.

(00:54:22): [Michala O’Brien]:  Are there any parameters of lung function not included in the standard PFT that could account for symptomatic shortness of breath worse than the baseline?

(00:54:36): [Dr. Kyle Brownback]: There certainly are some limitations that we're seeing in pulmonary function testing. There's a lot of variability from test to test, about a 5% or 6% difference in spirometry is noted. If I have a patient do the point functioning testing today, tomorrow, the next day, it'll be about a 5% margin of error with each testing due to barometric pressure and the effort of the patient.

(00:55:05): I don't necessarily think that point functioning testing always provides the full picture. A lot of times a CAT scan is necessary, too, to get a picture of the lungs. Are there patients who have shortness of breath, but their pulmonary function testing and their CAT scans are normal? Yes, that certainly can occur. Sometimes that can be from cardiovascular disease. Sometimes it can be from deconditioning.

(00:55:36): There are new studies ongoing about the use of MRI imaging of the lungs to look for small airway disease, especially in long COVID syndromes where the pulmonary function testing might be normal. It's something that some of my partners are looking into. Sometimes we will utilize cardiopulmonary exercise testing, which is where we place our patients on a stationary bike. We increase the resistance until they're unable to go any further and the whole time we're monitoring their carbon dioxide levels, their oxygen levels, their heart rate, and their blood pressure, and we can determine what it is that happens to make our patients have to stop exercising. I think there are a lot of other things that can be done for symptoms, even if the lung function is normal, to assess and give us a better idea about what the overall cause of their breathlessness is.

(00:56:40): [Michala O’Brien]:  There are two questions about COVID. If ground glass opacities found during a baseline CT remain unchanged since treatment, are they likely to continue to be stable or can something like long COVID affect them?

(00:56:57): [Dr. Kyle Brownback]: Ground glass opacities can occur for a number of reasons on CT checks. They can be a sign of infection. It can also be a sign of scarring. There are sometimes situations where very, very early indolent lung cancers can present like those, and so we generally repeat our CAT scans after you developed a ground glass opacity to make sure that they either go away or resolve on their own, or are not growing, going forward. They generally always require further workup.

(00:57:37): COVID can cause ground glass opacities. You would expect those to go away with time after the COVID has resolved. If they don't, they typically will require some sort of further workup, either with visit to a pulmonologist, lung function testing or a bronchoscopy to exclude other types of infections.

(00:58:01): [Michala O’Brien]:  Does chronic GVHD sometimes affect diffusion in the lungs instead of worsening obstructive disease?

(00:58:09): [Dr. Kyle Brownback]: Sometimes it can. It can be an early manifestation of bronchiolitis obliterans. If there's heavy inflammation, if there are a lot of inflammatory cells that are being produced that plug the alveoli, sometimes that can cause a diffusion impairment. Most patients with bronchiolitis obliterans syndrome maintain a normal DLCO. So whenever a patient has a DLCO impairment that is only present, then we almost always need to do a CT scan to assess and make sure that there is not a second process going on.

(00:58:55): [Michala O’Brien]:  This will have to be our last question. I have scleroderma around my ribcage and across my abdomen. Would it make sense that I would have a decline in lung function due to the restriction of diaphragm expansion?

(00:59:09): [Dr. Kyle Brownback]: Yes, 100%. It's a very, very common finding in scleroderma lung disease that it will reduce the findings of our lung function testing. It does not mean that you have lung GVHD. It essentially means that your lungs are unable to expand related to the skin findings there. Most of my patients who have that condition all do a CT scan to make sure there's no air trapping present. I typically do not utilize inhaled steroids in that situation just because they aren't very helpful with symptoms. It does not make the lungs easier to expand and so we try to focus more of a treatment on manifestations of skin GVHD rather than giving steroids to the lungs. But it requires a case-by-case evaluation.

(00:59:59): [Michala O’Brien]:  Closing. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Brownback for his very helpful remarks and thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way and enjoy the rest of the symposium.