Breath of Life: Your Lungs after Transplant

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Breath of Life: Your Lungs after Transplant

July 14, 2020 Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020

Presenter: Jane Turner MD, Assistant Professor, Division of Respirology, Hamilton Health Sciences/McMaster University

Presentation is 38 minutes with 21 minutes of Q&A.     

Summary:  20% of patients experience breathing problems 100+ days after transplant. Pulmonary function tests can help determine the cause of the problem and define treatment options.

Highlights:

• Breathing problems during the first 100 days after transplant are usually caused by infection.

• Graft-versus-host disease (GVHD) in the lungs can cause bronchiolitis obliterans syndrome (BOS) which makes it difficult to breathe.

• Patients are at higher risk of developing lung GVHD if they have a pre-existing lung condition, radiation was part of their treatment and or experienced viral infections after transplant.

Key Points:

05:34     Bronchiolitis obliterans syndrome (BOS) destroys airway passages and makes it difficult to exhale

08:26     Prednisone can weaken muscles around the lungs which can cause breathing difficulties.

09:06     Skin GVHD can tighten skin around the chest can cause breathing problems.

13:52     The biggest risk factor for developing BOS in the lungs after transplant is having GVHD in other parts of your body

16:21     Pulmonary function tests which measure how well you breathe in and out are one of the tools used to diagnose BOS and lung GVHD

24:18     A temporary decline in lung function after a stem cell transplant is common and can be caused by a variety of factors.

26:57     Although lung GVHD can lead to death in some patients, many patients are able to stabilize the disease and live a long time with lung GVHD.

28:45     FAM+LABA is the usual treatment for patients with BOS after a stem cell transplant.

34:29     Second line treatments for lung GVHD include extracorporeal photopheresis (ECP), ruxolitinib and ibrutinib. Supplemental oxygen and pulmonary rehab can provide effective supportive care.

35:35     A lung transplant is a potential treatment option for some patients with advanced lung disease. However, BOS is a also common complication after a lung transplant

Transcript of Presentation

00:00     [Moderator] Welcome to the workshop, Breath of Life: Your Lungs after Transplant. My name is Sue Stewart, and I'll be your moderator today. It's my pleasure to introduce to you today's speaker, Dr. Jane Turner.

Dr. Turner is an Assistant Professor in the Division of Respirology at McMaster University in Canada, and a pulmonologist at Juravinski Cancer Center. She studied with leading experts on pulmonary problems after transplant at the Fred Hutchinson Cancer Research Center. She recently founded a specialized clinic within the Juravinski Cancer Center to provide accessible and specialized care to stem cell transplant patients with respiratory concerns. Please join me in welcoming Dr. Turner.

00:49     [Dr. Turner] Thank you so much for having me, everyone. It's a pleasure to be here. I'm calling in from Hamilton, Ontario, as Sue mentioned, from McMaster University. I don't have any conflicts of interest to declare. I have a little bit of research on the go which is supported by my academic center. That is my email on the slide there. If you have any questions after the presentation, then please feel free to reach out.

I would like to review some of the respiratory or pulmonary issues that we run into after the stem cell transplant process. I was going to start with some basic respiratory anatomy function and review, mostly because I know we're all coming into this talk today with different backgrounds and different knowledge bases. I think understanding some of that function can put things into context.

 From there, we'll talk about some of the different types of pulmonary dysfunction after transplant, who might be at risk and how we're currently approaching management.

Explanation of the anatomy and function of the respiratory system

01:44     The components of the respiratory system, how do we breathe? The most important... Well, one of the most important components are the airways. If you feel right between your two heads of your clavicle, and you poke, and you feel a bit of discomfort in your neck, that's your windpipe or your trachea, and that's our biggest area that leads down into our chest. From there, it divides into smaller and smaller branches like a tree. As those airways get smaller, they take on different terminologies or names. The very smallest airways we have are called bronchioles. They're about a millimeter in diameter.

Those bronchioles then turn into these air sacs, which is they're almost like a sponge. Those are the gas exchanging units of the lungs. The air travels all the way down your airways into those smaller and smaller airways until it hits those little air sacs. Each of those air sacs is surrounded by a very small blood vessel or a network of blood vessels. Those blood vessels pick up the oxygen from the air, and then eventually lead it back into your heart. After we get past the airways, the lung tissue is that network of spongy airways and blood vessels.

Other components which are very important are the muscles. The major musculature system of our respiratory anatomy is the diaphragm. It's a big dome-shaped muscle that lies right underneath our lungs. As it contracts, it allows our lungs to expand and to breathe in air. Other muscles include muscles in between our ribs as well as those in our neck, which we use more so when we're in distress, and we need extra help with exertional breathing. These are all very important components. They all work together to enable us to breathe and to exchange oxygen within our body.

Potential Pulmonary Complications After Stem Cell Transplant

03:32     In terms of what can be affected in the post stem cell transplant population, any of these segments of our pulmonary system can be affected post-transplant, so your airways, your blood vessels, your lung tissue itself, that spongy tissue that mixes in with the blood vessels, the muscles, as well as whatever is surrounding the lungs. The lungs sit in our chest, and they're surrounded by some soft tissue and by our chest wall. Anything that tightens up that tissue or that chest wall will also impede how our lungs work and their ability to inhale and to exhale.

In terms of the spectrum of these complications, so as I mentioned, they can affect almost any part of our breathing system or a pulmonary system. When you group them all together, the incidence is about 20% of post stem cell transplant. Now, this is post 100 days.

In the first 100 days after your transplant, the majority of pulmonary complications we see are infectious, so while those cells are engrafting, while their immune system gets back up to speed, although, admittedly, it takes much longer than 100 days for that to happen.

But after that 100-day mark, we see a shift in that pulmonary problems that can be less infectious and more non-infectious in nature. The 100-day mark is called the late onset, non-infectious pulmonary complication. We see some kind of lung problem about in about 20% of patients, which we fit in this category. It's important because breathing is life. Any problem with your breathing not only impedes how you live your life, but it also leads to many hospitalizations. Unfortunately, it's also a leading cause of death in the non-relapse category of a stem cell transplant.

Lung diseases associated with graft-versus-host disease (GVHD)

05:34     In terms of lung disease, the most common thing you'll hear about, especially in this group today, is GVHD-associated lung disease. The only entity that's defined as GVHD at current is something called BOS, which is bronchiolitis obliterans syndrome. We will talk more about that shortly. That's an airway problem. As I mentioned, the pulmonary system, the first thing to think about is the airways. The bronchioles are the smallest airway in that system. With bronchiolitis obliterans syndrome or BOS, those airways become destroyed. They become obliterated. It's called an obstructive process. That is simply a term we use when looking at pulmonary function tests or the breathing test that you will receive as part of your screening after your transplant.

 If you imagine breathing through a straw, a straw is your airway. Imagine what happens if that straw's diameter gets cut by half or if someone stands on that straw and occludes it partly, it's much more difficult to breathe out. That's what happens when your airways start becoming destroyed. That ability to take that nice, forceful breath out is much more difficult.

 BOS is the only pathology that's definitively part of the GVHD definition. There are other things that we think of probably related to GVHD. We think the pathology of GVHD probably trigger the process which leads to pulmonary problems, but they haven't actually been included in the definition.

Cryptogenic organizing pneumonia (COP) can cause breathing problems after a stem cell transplant

07:13     There's several of these entities, but the one that you're most likely to have heard about or to come across is something called cryptogenic organizing pneumonia. The short form for that is COP. The reason I bring that up specifically is because it often gets confused with BOS, because of their three letter acronyms. They're quite different in terms of diagnosis and pathology. COP or interstitial lung disease is when that actual air sac or that spongy lung tissue, that gets filled with inflammatory, fibrous material. It should be filled with air. Things like COP, it becomes filled with a substance that's not air, and that limits our lungs to moving.

Not only is there no gas exchange in that area, but your lungs actually become a little bit smaller looking because it's no longer filled with air. It's filled with something else. We call that a restrictive pattern. That's one of the first differences in terms of categories we place lung problems into, whether it's an airway problem like BOS, which is obstructive, or a lung tissue problem like COP, which is restricted.

Prednisone can weaken muscles around lungs and cause breathing difficulties.

08:26     Then we come to what I call collateral damage. After transplant, as many of you will know, you're very de-conditioned. You're often on prednisone or other immunosuppressants, and it can affect everything that supports your lungs. When I say support, I mostly mean the muscles. Being on prednisone can cause you to be quite weak, being in hospital for prolonged periods of time, but any transplant complications can make you to be quite weak. All of those muscles supporting the lungs need strength to help you breathe properly. As soon as you start losing your conditioning and your strength, your lungs will be affected.

Skin GVHD can tighten the skin around the chest and cause breathing problems.

09:06     Similarly, in terms of things that surround the lungs, if your chest wall is affected in any way, your lungs sit inside your chest, and you need that nice flexible skin and nice flexible thoracic cage for your lungs to breathe in and out, almost like an accordion effectively. One of the more common GVHD manifestations, which is skin GVHD, if you have that sclerotic phenotype or that tightening of the skin that can sometimes come with skin GVHD, that limits how much your lungs can move inside your chest. It's like having a tight rubber band around your chest. That can also lead to pulmonary problems that aren't specifically involving the lung tissue, but these things are supporting or outside of the lungs.

What is bronchiolitis?

09:55     I wanted to talk a little bit more about bronchiolitis, because I think that's one of the more common things that we see. Bronchiolitis is simply a defining term. As I mentioned, the smallest areas that we have are called the bronchioles. -itis, so I-T-I-S, means inflammation or something. The bronchiolitis is an inflammation of those very small airways.

 It's not specific to the stem cell transplant group. A lot of different things could cause bronchiolitis. Though rheumatoid arthritis or certain toxic gases or chemicals can lead to a similar pathology or similar disease, we call it or we label it something else when we see it the transplant population.

This is just a closer look. Again, our airways branch into smaller and smaller branches. At the very end, a very terminal branch. You see there, it's respiratory bronchioles. There's no cartilage in their airway as opposed to some of the bigger ones. They're mostly supported by smooth muscle. They tend to be about one millimeter or less in diameter.

This is a graphic to show what happens in the obliterative bronchiolitis process. On the left, you have a normal bronchiole. You see a nice painted lumen similar to a straw. On the right, you can see that these inflammatory cells and smooth muscle is hypertrophying or increasing in size. It's truly obliterating or destroying that lumen. That nice patent straw that we like to breathe through, it's all of a sudden occluded by inflammatory cells and smooth muscle.

This is how it looks under a microscope. On the left, again, you have that nice clear lumen. On the right, you can see that the lumen has become thickened. It now followed that pink material which represents airway wall, inflammatory cells and smooth muscle. The clinical correlate or what happens to you as a human being when this starts happening is that you get progressive airflow obstruction, meaning that it's much harder to breathe out. Over time, that leads to breathlessness. Sometimes a dry cough can be the first symptom. Ultimately, it affects how air can get into your lungs and your ability to effectively breathe and exchange oxygen.

In terms of how this might happen specifically BOS and the GVHD spectrum, it's still being defined. There are various hypotheses out there. It's thought that some initial inflammatory insult probably sets off a cascade, whether it be a viral infection, which has been linked to a higher incidence of BOS, whether it be a toxin... In the stem cell transplant group, it's usually a conditioning regimen or possibly radiation that's thought to just initiate an inflammatory injury.

Sometimes too, it can be something as simple as reflux or heartburn, which we don't even realize that some of those micro droplets of acidic fluid end up in our lung if we have bad reflux or bad heartburn. That acute inflammation can subsequently and ultimately lead to chronic inflammation, which then sets off the cascade of chemical signaling molecules in the body called cytokines, and leads to this dysregulated process, which eventually leads to fibrosis. This is, again, just to remind us that BOS is an airway issue.

Through this graphic, you can see an airway coursing through spongy tissue. It's the very smallest bit of an airway that's getting obliterated, and it doesn't actually affect the lung tissue or the gas exchange in bubbles themselves.

The biggest risk factor for developing BOS in the lungs is graft-versus-host disease (GVHD) in other organs.

13:52     Just a little bit of background on BOS. The most definitive risk factor we know is GVHD in other organs. That's why it came to our attention this is probably part of the GVHD spectrum, and that most of the time, we see it in people who have already established extra-pulmonary or non-lung GVHD.

In that higher risk population, the incidence is about 14%. You can see it in isolation, it's not always the GVHD, and the incidence or the chance of it happening over a population level in that group is more along the lines of 5%.

We tend to see it diagnosed within the first six months, sorry, within six months to about two years after transplant. Sometimes, it can be as early as three months. Very rarely is it ever before three months. A lot of the literature suggests about two years out is when we started to see it a bit less, but it really can... The more we learn about it, the more we realize we're actually seeing this entity up to five years, sometimes even 10 years post-transplant. It is something that can creep up even in the late post-transplant years.

In terms of how we diagnose it, we rely on pulmonary function tests. Those are those big breathing tests that we use to screen post-transplant. A CT scan is often used to look for specific things, which I'll go into briefly. Sometimes just to exclude other things such as infection or making sure that nothing else is confounding our diagnosis, things like a bronchoscopy or a biopsy is required.

Other risk factors for developing BOS after a stem cell transplant include lung problems prior to transplant, high-dose chemotherapy and/or radiation prior to transplant, and viral infections after transplant.

15:36     As I mentioned, the biggest risk factor, the most defined risk factor to know is GVHD in other organs. There are certain things that we think may contribute. If you had pre-transplant lung problems or if you had COPD or frequent pneumonias or some kind of lung issue, you may be at a higher risk.

 Myeloablative conditioning regimens are thought to be a higher inflammatory insult, so it's probably a risk factor for BOS. Your radiation for previous cancer treatments, especially the chest, and the viral infections are a big one, so there is more and more evidence to suggest that after transplant, viral infections may set you up for that inflammatory cascade, which can eventually be BOS.

What do pulmonary function tests measure?

16:21     Just in case anyone is not familiar, this is a PFT. You sit in a body box, and it measures how easily you can breathe in and breathe out air. What do we measure? I think this is important to run through because often, we talk about these numbers and don't really explain what they mean.

16:41     Actually, FEV1 is one of the biggest markers or most important markers that we use to actually track your lung function. What we're actually measuring here is the amount of air you can breathe out in the first second or fourth exhalation, so a deep breath in and then you have a big blow out. In that first second, there's a volume of air that exhales. That's what we call the FEV1. It's a measure of airflow, so the less resistance to airflow you have in your lungs, the more air you'll be able to get out.

Similar to that straw analogy, if you blow out of a straw that's nice and big, you can blow a lot out. If it's very small, it's harder to blow out a meaningful amount of air to that straw. As the airways are obliterated or destroyed, even the very small airways at the great end of our airway highway, that airflow becomes more difficult to blow out, and you FEV1 will decline or drop with time.

17:37     FVC is another measurement that we follow over time. It's called the forced vital capacity. Then you take that nice deep breath in, and that forced exhale out. The first second of the exhale is the FEC1. Then the volume of the entire exhale is the FVC. It's how much air you can breathe out from start to finish or that nice, big forced exhalation. That's an important measurement, because it helps us know how much air you can actually hold in your lungs, and that you actually expire out.

So, something like a restrictive process, like COP, which I mentioned earlier, which takes up airspace by inflammatory goop, you can no longer have air in that space. When you try to fill up your lungs with air, you'll have that much less air to blow out. When we start seeing a drop in FVC, we call it a restrictive pattern, and we start thinking about lung tissue problems or something that's restricting our lung tissue.

18:42     Then finally, the DLCO, so this is a measure of gas diffusion. When we take a deep breath in, the air comes through our airways, and ends up in those small air sacs or that spongy tissue that I mentioned, which is surrounded by capillaries, which are small blood vessels. The oxygen has to be able to diffuse from your air sac into that blood vessel. If it can't diffuse into the blood vessel, then our body has no way of picking up that oxygen from the air that we're breathing in. The DLCO measures how well our body is picking up that oxygen into our blood from the air.

How efficient is that interface? If you start having a byproduct process, if you start having scarring of your lung tissue or that spongy tissue, then it's more difficult for the gas to get through. I's more difficult for a body to pick up the oxygen that we need from the air into our blood and then to send it around to our body. This is the value that we most often see a change in post-transplant. A lot of the times, we'll get referrals just because what we call a nonspecific decline in DLCO, so this number drops in that first year of post-transplant, and it often drops and then stabilizes.

It often... We do a CAT scan and we look for pathology, and we can't find anything. Some studies show that up to about five years’ time, some of those numbers will start normalizing again. It's not clear why this efficiency of gas transfer can drop in the transplant setting, but it's thought to be probably that some of the conditioning regimens and the radiation and the cytotoxic treatment that people receive causes a microscopic damage to those tiny little air sacs and those tiny little vessels, and impedes that ability of gas exchange, even though we can't see it on a CAT scan.

How is BOS diagnosed?

20:45     This is an example of a graph that we might see when we're looking at your lung function tests. This red line here with that scooping, that's what we see when it's graphed out in terms of an obstructive pattern. That's typical for BOS.

In terms of how we diagnose BOS, so technically, you actually need a good chunk of lung which requires surgery and often ICU stay. It's not practical to obtain in most patients, so we rely on other criteria, softer markers to signal to us maybe there's airway pathology happening in the lungs.

The most commonly used system we use is that of screening pulmonary function tests as well as CT scan findings. To avoid having to do lung biopsies in any patient that we suspect may have some airway problems or BOS, the National Institutes of Health created what's called consensus criteria. This is criteria based on a bunch of people who are sitting in a room and decide that this topology tends to present like this in this way with obstructive airways disease, so we're going to provide these criteria to diagnose it, even though technically, you still do need the biopsy.

You need airflow obstruction so that FEV1 value that I mentioned will drop, and needs to have dropped over the last two years in some measurable way. You have to rule out other confounding things, which is where things like bronchoscopy come in to make sure there's no infection. We also look for supporting features, so something else that signal that yes, this is a small airway process and not something else that drops the FEV1, because a variety of problems can actually affect your FEV1.

CAT scan of a person with BOS

22:41     Some of you may be familiar with these steps. In terms of the the CAT scan that we look at, this is a CAT scan of the chest. As you can see, there's little white spots speckled throughout. That's normal. Those are just blood vessels, and normal airways or normal lung tissue on a CAT scan looks black. You will see around the periphery, it's more black than it is around the center. That inconsistency in blackness or in grayness is actually abnormal. You should just see it all one color.

The reason that it's patchy like this is because as those small airways get destroyed, you can't take a nice, good deep breath out. Some of that air gets trapped, because those small airways are being destroyed, so you can't blow out all of your air, and because some of the airways are okay and some of them aren't, it leaves us with this patchy appearance on CAT scan. That's what we're looking for in terms of supporting criteria when we start seeing one function changes.

You may also see some dilated airways, so essentially, although it starts in your small airway, the pathology can creep up the airway and start affecting your larger airways. On the right-hand side, you might see some cystic nodular lucencies or holes in this CAT scan. Those are just dilated airways. As the pathology is progressing up, the airways become more proximal.

A temporary decline in lung function, caused by a variety of factors, is common after a stem cell transplant.

24:18     In terms of monitoring your lung function post-transplant, it's actually very common to have a little bit of lung function substitution after your transplant. Anne Bergeron in Paris has [done] a lot of work with BOS and pulmonary GVHD. She demonstrated prospectively that up to 80% of people after their transplant will have some dip in FEV1. Now, most of the time, they aren't sustained. Meaning, some of the time it's just because you're feeling a bit weak from your hospital admission. You don't blow it hard that day. It's only a sustained decrease that makes us worry.

It's often alarming for people to have that drop into FEV1, but it's not always BOS. It's just a signal for us to watch you a little bit closer. As I mentioned, there's many events following a transplant that can lead your lung function to dip a little bit. If you have an infection, if you're de-conditioned, sometimes the conditioning regimen can be very toxic, and it can affect your lungs in ways that takes a few years to recover from. Then as I mentioned, any other GVHD that's around your lungs, so skin GVHD, or muscle weakness from parts of your treatment, that can also affect how your lung functions and how your lungs look on that pulmonary function test.

How often should patients have pulmonary functions tests after a stem cell transplant?

25:40     In terms of how often we like to monitor lungs for GVHD, we tend to recommend every three month screening for at least the first one year. If you've had a very easy or uneventful post-transplant course, and by that, I mean no acute GVHD, no chronic GVHD, everything, you come off of all your immunosuppressants, you might be able to do a little bit less than that in the high risk population. So, anyone who has bad GVHD elsewhere, so you think, "If I got risk, then we would likely opt to extend that pulmonary screening at least to two years and sometimes longer." Not only do we have to do screening, which basically means performing lung function tests when you're well, but we also tend to repeat them if there's any sign of inflammatory bursts elsewhere. If you're having a GVHD flare, if you're having a respiratory tract infection, then we'll probably get an intercurrent or a breakthrough screen just to make sure your lung function is holding steady and it's not getting caught up in that inflammatory process.

This is a graphic demonstrating the same thing, just in terms of how often we like to keep an eye on your lung function.

What is the prognosis for patients with lung GVHD after a stem cell transplant?

26:57     One of the most common things we get asked in the office is what's the prognosis of lung GVHD? A lot of the literature suggests that your risk of death is almost doubled by diagnosis of GVHD at the lung. Some of that data is a little bit older.

What we're seeing now is a bit more optimistic in terms of a lot of patients actually get lung GVHD, which stabilizes with time and doesn't progress any further. You can actually live a long time with GVHD of the lung, and it doesn't progress any further.

What Dr. Cheng found in Seattle, with her population that she studied, is that there seems to be a somewhat predictable pattern in terms of... The red line there is the point at which BOS is diagnosed. It's preceded by a drop in lung function. The blue line is your FEV1. There seems to be this sudden drop of lung function, and then it stabilizes. We don't know if that's a treatment effect. We don't know if that's just the natural history of BOS, and that's just how it behaves. But it does suggest, especially with these really sharp declines in lung function, that in those patients in that population that perhaps there was an inciting event, whether it be a GVHD flare, whether it be a respiratory virus. When we see that really quick drop before a BOS diagnosis is made, then we start thinking, "Was there something else contributing to this onset of airway topology?"

FAM+LABA is the usual treatment for patients with bronchiolitis obliterans syndrome (BOS) after a stem cell transplant

28:45     In terms of how we manage BOS, maybe you're familiar with FAM. It's actually FAM + LABA. This is a treatment regimen based on trials performed over the last decade or so, as well as an experience we have with bronchiolitis in other populations. Standard of management tends to be a puffer or inhaler, which has a steroid in it. That's fluticasone or budesonide, the different names for steroids, a long acting beta agonist. So what that is it's a bronchodilator, meaning it's a presser that you inhale, and it activates receptors on your smooth muscles to keep that smooth muscle open, so it helps open up those airways and relieve some of that obstruction that's causing you to be short of breath.

Azithromycin, which is an antibiotic, which is thought to have anti-inflammatory effects, and then Montelukast, which is technically an allergy medication, but again, it's thought to have some anti-inflammatory and immune modulating effects.

In terms of what we hope to gain from starting this regimen, there's possible stabilization of FEV1. Again, it's not clear whether some of that stabilization is simply the way that BOS behaves naturally, is simply the natural history of the disease itself. What we do know with a bit more certainty is that in studies that has demonstrated it allows us to reduce the amount of prednisone you're taking. It means that we can overtime over a population level, with FAM therapy, we saw a reduction in how much chronic prednisone and cumulative prednisone people were receiving.

And cutting out prednisone is always a good thing. You may have seen various inhaled corticosteroids or inhaler combinations prescribed. The most common ones you'll probably see are Symbicort, Advair, Breo. Dulera, I don't use but you may be familiar with it, and then some of the long-acting puffers you might see are these names on the right here.

Lung GVHD does not respond to treatment with systemic steroids.

31:01     In terms of systemic corticosteroids, so as many of you will know, this is a mainstay for other forms of GVHD, so skin GVHD, gut GVHD. For lung GVHD, it's actually thought to be a little bit different, and that it's not terribly responsive to oral steroids. There's no compelling evidence to suggest that a long course of oral steroids really changes the disease at all. While we do usually give a short burst, usually around 50 milligrams for two weeks at the onset of FEV1 change or BOS's onset, there's no evidence that suggest that a prolonged, long tapered prednisone is beneficial for a BOS diagnosis.

We always try to reduce any exacerbating inflammatory insults, so things like infections. In the time of COVID, everyone's very familiar with hand washing and being careful of your mouth covering. That's standard course at the stem cell transplant group, in terms of just being very clean and careful, and making sure that any sinus disease, any reflux, any environmental exposures that might be dangerous. Occupational exposures to work are all controlled, just to minimize that inflammatory insult to the lung which could possibly cause a cascade which ultimately leads to that pathology of BOS.

Is azithromycin safe for stem cell transplant patients?

32:27     There's been a lot of talk lately about Azithromycin. As some of you may be aware, there's a study published out of Paris in 2017 for using azithromycin as prophylaxis. Prophylaxis means you take it to avoid getting BOS. Right after their transplant was completed, a group of patients took azithromycin to see if maybe BOS would be prevented through this medication. An unexpected outcome was that there was a signal that there was an increase risk of relapse with azithromycin. That was not expected at the time of the study creation. It resulted in early termination of the study.

It also led us to think a bit more carefully in terms of when we prescribe azithromycin. I think it's important to know that this trial was looking at azithromycin prophylactically, so very early after transplant, and how we tend to use it as pulmonologists is once that BOS diagnosis has been made.

There's a fair bit of difference between a prophylactic treatment versus a treatment that you start once a diagnosis has been made just in terms of timing. We tend to not use azithromycin until at least six months to a year post-transplant, just by the nature of when BOS presents itself. It's still concerning. These certainly involve the hematologist and the patients and the families in terms of deciding when to start azithromycin if we feel it's indicated.

In terms of what to do if things get worse when you're already on therapy, we always, like I said, try to control background factors. You'll probably receive a CT scan. Make sure that there's nothing else going on, no secondary process. We'll often recommend bronchoscopy. People will be susceptible to infections in general post stem cell transplants to make sure there's no additional treatable issue at play.

Second line treatments for lung GVHD

34:29     Then in terms of second line treatments, extracorporeal photopheresis has been met with a moderate amount of success as has ruxolitinib and ibrutinib. Those are all now being approved for lung GVHD. This is just a list of ongoing studies in case you have interest.

34:53     Supportive care, so if there is significant lung function decline, you may find that home oxygen is needed in order to improve your quality of life and improve function. Once airways start becoming very inflamed, they can secrete mucus and phlegm, and so people might start to find they have the worst cough with production or with phlegm, so some airway clearance mechanisms, so devices that help you clear out that phlegm can be very helpful. Pulmonary rehab, which basically means strengthening of your muscles and strengthening of your system through exercise, and then, again, staying mindful of staying safe to infections.

Is a lung transplant a treatment option for patients who develop BOS after a stem cell transplant?

35:35     At the end of the road, if BOS is progressive and we get to end stage lung decline, then lung transplant is a possibility. In terms of who is eligible, it depends on the center. It depends on your country. I'm Canadian based, so my restrictions are a little bit different from American restrictions. But in general, it's very important to pick the patient population carefully. By that, I mean it's ideal if it's been at least two years since your transplant, because then your risk of relapse becomes that much lower. It's ideal if you don't have any other significant GVHD that's causing you a lot of problems, because that will weaken your whole body and make you a more high risk candidate for surgery, meaning, a lung transplant is a big undertaking, so if you don't have that strength going into the surgery, it's very unlikely you'll have a good quality of life coming out of the surgery.

36:36     I think what's important to know is that BOS also exists post lung transplant, so it's actually one of the highest incidences of complications that we see post lung transplant is another form of BOS. You're condemned to always be afraid of this BOS entity, even if you go on to get lung transplant. We do find that when transplants fail, the vast majority of patients who get a transplant, it will be from BOS or [inaudible 00:37:07] functions. I mean, it's certainly an option, but it does have to be carefully weighed in terms of its pros and cons, in terms of, "Is it a good option for you as a person?"

As always, living with... Going through your transplant and things that happen after your transplant is a team effort between yourself and your care providers, so working with the hematologist and the pulmonologist and other sub specialists just to optimize your health in all other ways, and then to treat these problems as they come up is integral to good post-transplant care.

Thank you so much for your attention. It was a pleasure being able to provide this talk today. I'd be happy to answer any questions you might have.

Question and Answer Session

38:02     [Moderator] Thank you very much, Dr. Turner. That was an excellent and very comprehensive presentation, which I'm sure we all learned a lot from. We'll now take some questions. Again, if you have a question, type it into the chat box, and we'll try to get to as many as possible. We do have quite a few, so we'll try to get through them as quickly as we can.

The first question is a new finding, a PET scan, CT scan showed mild pulmonary hypertension. This was never noted in prior scans. I'm pretty active. I walk three to four miles daily and do aerobics and strength training. I have no symptoms. I read that pulmonary hypertension is associated with hematopoietic stem cell transplants. I was assured this was nothing, but can you discuss how this occurs after transplant? Is it from GVHD? I'm on tacrolimus for mild GVHD, oral and ocular. Should I keep exercising?

39:01     [Dr. Turner] Thank you for the question, excellent question. A lot of things in the GVHD world, especially when it comes to lungs and vessels, aren't well understood. It's not thought to be a definitive... It's not part of a GVHD diagnosis, so we don't call post-transplant PH GVHD, but it probably involved the pathology somewhere, and that the cytokines that are released or the molecular markers that signal in our body cause what we call endothelial dysfunction, so the inner lining of our blood vessels, it's called the endothelium. If that gets remodeled, it's basically a similar thing that can happen to the airways. It can remodel, and it becomes thick and it becomes tight. As soon as you close the lumen of that blood vessel, the pressure goes up. That's why it's called hypertension because that pressure in that blood vessel goes up. So it's not GVHD. It's not thought to be GVHD, but that immune dysfunction, that dysregulation of your immune system that comes along with GVHD may well have something to do with it in terms of how that blood vessel remodels itself and ultimately leads to higher blood pressures inside the lungs.

40:17     [Moderator] All right, next question. I'm two years post allo transplant. I've had near pneumonia episodes since my transplant, one at 12 months and one at 18 months. Will I be more prone in the future?

40:33     [Dr. Turner] It is thought that past episodes of pneumonia can lead to future episodes in pneumonia, mostly because those airways get a little bit scarred. Once airways get scarred, it's more difficult for them to clear out properly. If you get a little bit of mucus and phlegm in there, it's just a sitting duck to generate infection, but it's not always the case. If they were small pneumonias that you recovered from, especially post-transplant when your immune system's still getting back on its feet, I wouldn't say it sets you up definitively for more pneumonias, but it could be considered a risk factor.

41:06     [Moderator] All right, and this question comes from a myeloma survivor. "I find that about two to three days following my treatment infusions that I feel breathless, poorly supported breathing and speaking. Is this a common event? Currently, I received dara and dex in the infusion and oral pomalyst. This also occurred with previous treatment modalities."

41:31     [Dr. Turner] Drug reactions post chemo are, as you know, very common. Pneumonitis or lung inflammation from chemo is certainly possible. If they're resolving on their own, and you don't have any changes on x-ray, and you're not hypoxic and your oxygen levels are okay, then it's less likely, but I would certainly let your cancer provider know, and perhaps you can get some lung testing done to make sure there's no lung involvement.

42:02     [Moderator] Next question, are pulmonary function tests routine after you discontinue immunosuppressants after transplant? When should pulmonary function tests be monitored after transplant? If you wait for symptoms to appear, is it sometimes too late?

42:19     [Dr. Turner] Also, excellent question in three parts. Off the bat, anyone who's getting a transplant should have some degree of pulmonary function test monitoring. It will vary from center to center in terms of how often it's done. Personally, in someone who has known GVHD and they're coming off their immunosuppressants, I will increase the frequency of monitoring to make sure I don't miss a drop on FEV1. If you're coming off of your immunosuppressants routinely post-transplant, if you haven't had any GVHD, and you're just coming off your routine post-transplant immunosuppressants, then I wouldn't necessarily increase your screening frequency. If you already have GVHD and you're coming off your immunosuppressants, then that's considered a higher risk timeframe for involvement of other organs.

43:13     [Moderator] Next question, is there any treatment for chest flow restriction from sclerotic GVHD? Is this reversible?

43:24     [Dr. Turner] What I found in my practice is that the two modalities which seem to have the most help with sclerotic skin changes leading to breathlessness are photopheresis as well as ruxolitinib. Those will be our go-to agents. In terms of reversible, I have seen some mild improvements in FEV1 or lung function with improvements following GVHD specific therapies, but it's not definitively irreversible. There may be some room for improvement in terms of your lung function though.

43:59     [Moderator] Next question, is bronchiectasis post allo transplant a kind of lung GVHD and or related to BOS and have the same possible causes and treatment?

44:10     [Dr. Turner] Sorry, was that bronchiectasis?

44:12     [Moderator] Yes.

44:14     [Dr. Turner] Yes. Bronchiectasis is an airway problem. It's dilatation of more proximal or slightly bigger airways. It can be a result of BOS, so if we see bronchiectasis on a CAT scan, it does raise our radar for BOS or airway involvement of GVHD of some kind. It can also be from other things. Bronchiectasis, again, is not a specific entity. For instance, if you've had bad infections, either as a child or post-transplant, then that can lead to some airway scarring. Bronchiectasis just basically means scarring and enlargement of the airway, but it can be part of the BOS spectrum. It's just not specific to the BOS spectrum.

45:01     [Moderator] How do you find the balance between immunosuppressive meds and living with some GVHD cough? Does the GVHD cause permanent damage?

45:10     [Dr. Turner] Sorry, was that cough or COP?

45:14     [Moderator] Cough, C-O-U-G-H.

45:18     [Dr. Turner] Okay. I'm so sorry. Can you repeat the question again?

45:22     [Moderator] How do you find the balance between immunosuppressive meds and living with some GVHD cough? Does the GVHD cause permanent damage?

45:34     [Dr. Turner] It depends on the kind of... If it's lung GVHD you're referring to, it can cause permanent damage, in that the airway form, so BOS, is irreversible. Once those areas are destroyed, they're gone. In terms of other etiologies for coughs related to GVHD, the list is pretty long. For lung specific GVHD, though, immunosuppressants in and of themselves, especially prednisone over the long term, aren't particularly helpful at controlling that disease.

46:16     [Moderator] All right, if a lung transplant is being considered, is it better to do it somewhat earlier while the patient is relatively healthier, or is it better to wait until the patient is more compromised?

46:28     [Dr. Turner] It's better to wait until that lung function drops. At least usually below 20% is when we start thinking about it, mostly because even though it sounds so tempting to have new lungs, it is a very difficult procedure to live through, and it's very complicated. We try to get as much life as we can, or good quality of life as we can by optimizing your function before transplant. Then once you get to a point where your quality of life is so limited, then we start thinking about transplant only because, like I said, it's a very difficult process and comes with its own problems.

47:12     [Moderator] All right, can you compare the difference between autologous and allogeneic transplant in terms of how much sustained lung damage they cause long term?

47:23     [Dr. Turner] Definitely. I general, allogeneic are much higher risk from a lung transplant perspective, mostly because when you're accepting someone else's immune cells into your system, you're setting yourself up for possible GVHD or an immune-related dysfunction. Whereas when you're receiving your own cells, which is autologous, back into your system, pulmonary GVHD in that context is almost non-existent. You're still at risk for some of the earlier complications, so engraftment syndrome in the engraftment period and some first 100 days inflammatory type reactions as your body gets those stem cells. But in terms of long term, not infectious complications, the rate is much lower in the autologous group.

48:09     [Moderator] All right, I'm two years post allogeneic transplant and in the hospital, or actually in the hospital, I developed pleural effusion of one liter of fluid that was drained off. My breathing is normal. I use CPAP at night for apnea since transplant. I have two questions. Why might that have happened? The pleural effusion, she's referring to. Am I more at risk for lung GVHD as a result of that.

48:37     [Dr. Turner] Pleural effusions are very nonspecific. They require their own workup to determine why they're there. Sometimes it can be a heart problem. Sometimes, it can be a medication problem. There is a subset of effusion that's thought to possibly be related to GVHD. It's called serositis, which is when your membranes get inflamed and secrete fluid. That's a very specific diagnosis that requires exclusion of other things. If there was an answer for why you had the pleural effusion, then that's great news. If there was never an answer, but it never came back, that in and of itself is quite reassuring. If it puts you at risk to BOS down the road, I wouldn't expect, so no, not unless it was thought to be a GVHD issue to begin with.

49:36     [Moderator] Next question, is Rituxan effective for BOS?

49:40     [Dr. Turner] Is... Sorry? Rituximab?

49:43     [Moderator] Rituximab, yeah.

49:45     [Dr. Turner] There are studies of rituximab in BOS. I think it was actually one of my slides here. Not in this one. There are some studies in process for rituximab, more so in the earlier complications, so something called idiopathic pneumonia syndrome and alveolar hemorrhage. In BOS, specifically, there's no evidence as of yet, but I believe there are some studies looking at rituximab.

50:15     [Moderator] All right, Marla, can you take over with the questions, please?

50:21     [Moderator] Yes, I'm here. When exercising, is there a limitation in how intensely one should push themselves? Is it risky to get very breathless?

50:34     [Dr. Turner] Exercise is always good, so it really comes down... Exercise as you would if you hadn't had a transplant. Don't push yourself until your limit. Be moderate. Be kind to yourself, but getting out of breath and feeling sweaty and tired, I mean, that's never a bad thing. I'm sorry, I think I missed that component in the first question in the pulmonary hypertension. Should you keep exercising? Yes. Stay strong, keep exercising, keep moving those lungs. It's the best thing you can really do for your lung health in the long term.

51:08     [Moderator] Could the total body radiation I received during my transplant have had a detrimental effect on my lung functioning?

51:17     [Dr. Turner] It's possible. A lot of these risk factors haven't been definitively proven, but there's an association, meaning there's probably some link between inflammatory factors, so total body irradiation would be a fair amount of inflammation that your body works through in receiving that cytotoxic damage. It is thought that it may put you at increased risk of lung pathology down the road, because of that baseline inflammation that your body works through. It may set you up for some cascades of inflammatory dysregulation and then subsequent airway, fibrosis down the road, it's possible.

52:03     [Moderator] Thank you. Is post lung transplant BOS treated the same way as post stem cell transplant BOS?

52:13     [Dr. Turner] Excellent question because that is why that exists in my clinical trial. Well, that's part of what it was grounded on, and that, yes, azithromycin is used to treat post lung transplant BOS. The inhalers and the montelukast do not as much in terms of routine therapy as one might get an inhaler because of airflow obstruction, but the azithromycin, certainly.

52:42     [Moderator] How would COVID-19 affect someone with lung GVHD?

52:48     [Dr. Turner] Very common question in clinics. I would treat yourself as anyone else with pulmonary dysfunction, and that you would be an at risk population. If you do have compromised lung function from whatever source, then you should certainly be taking extra measures to keep yourself safe from COVID, because you would be at risk of having a worse outcome from the infection.

53:16     [Moderator] What are your thoughts on hyper oxygenated bottled water? I think it's geared towards elite athletes, but could it help BMT patients that have reduced lung function?

53:28     [Dr. Turner] To be honest, I can't really comment on that. There's been no studies of hyper oxygenated bottled water. A lot of that is marketing. I wouldn't expect it to be a robust response to GVHD.

53:48     [Moderator] How do lungs post BMT and steroids compared to smoker's lungs long term?

53:59     [Dr. Turner] They're the same, and that it's both an obstructive process. Smoker's lung will also get that airway inflammation and that airway closure or narrowing, which leads to airflow obstruction. They're both obstructive processes. It's just that the way that you get there, and the immune cells involved are different. They both end up in the same stage and in the same place, and that you have a low FEV1 and the airflow obstruction, but they're very different pathologies.

54:34     [Moderator] Next question, at what point is FEV1 and or clinical symptoms would you suggest a lung transplant? Do you know the mortality rates for folks with CGVHD who have had lung transplants?

54:48     [Dr. Turner] As I mentioned before, we do try to hold off on lung transplant until FEV1 is below the 20% range for the most part. In terms of outcomes for the BOS population, it's quite a small population that we can study because it's a rare disease, and then a lung transplant is not something we can offer to everybody. What we do know is that many people who receive a lung transplant for BOS will die or develop BOS within four years, and very few remain alive and free from BOS at 10-year post lung transplant. It can be a very effective method to improve survival. It includes the number of years that you have. But again, it has to be in a specific patient population with promising factors. Are you two years out from your transplant? Do you have other GVHD that's limiting your function? Are you on a lot of immunosuppressants or prednisone? All of these things will contribute and influence how well you do post lung transplant.

56:01     [Moderator] All right, next question, can cardio exercise help with BOS and overall lung functioning?

56:07     [Dr. Turner] Absolutely. Anything that you do... Think of your lungs and your heart as biceps that you're training, so they're all muscles. Your lungs are supported by your muscles. Your heart is a muscle, so anytime you train, especially with cardio training, you're improving the function and efficiency of those muscles, and they support your lungs. Although your lung isn't a muscle, it's supported by the muscles that surround it. Your heart with time and exercise will become more efficient and stronger as well. Conditioning exercise is good for both lung and heart problems within reason.

56:47     [Moderator] If ibrutinib, Myfortic, sirolimus and Jakafi have been used, but had to be stopped due to serious side effects, what would be your next choice apart from prednisone for advancing BOS?

57:07     [Dr. Turner] Let me just get to the right slide here. Extracorporeal photopheresis, you could inquire about. It doesn't actually require you starting a new medication, but it's a processing of your blood that some centers offer. We have seen some good outcomes from the lung perspective with that treatment.

57:31     [Moderator] Can you use budesonide in a nebulizer instead of an inhaler? Would that be best once or twice a day?

57:39     [Dr. Turner] Yes, you can use budesonide in a nebulizer. You have to get the nebulous from your pharmacist. I would say it's usually prescribed twice a day.

57:51     [Moderator] I think this needs to be our last question. We're getting close to the end. Can you explain what pulse oximetry readings demonstrate, and why can you PO2 but low FEV1?

58:04     [Dr. Turner] Pulse oximetry, basically, what that's reading is it uses light to determine how... When your red blood cells hold oxygen, they take on a different shape, and so it determines how much oxygen your blood is carrying. That number, we'd like to see above usually 94%-ish. In terms of why you can have a normal FEV1, sorry, a normal oxygen as low as FEV1, is because that exchange of gas and your lung tissue is okay. You can still breathe in oxygen and transport the oxygen to your blood and at rest, your blood is still carrying that oxygen if it is your airways that are affected. As soon as you start trying to move and exhale, and you can't get that air to move through your lungs properly, that's when you start getting breathless, but you don't have any problems picking up that oxygen from the air because your DLCO or that gas transfer number is still okay.

59:01     [Moderator] Thank you. With that, I think we will need to close the question and answer period.