Good morning and welcome to the CHESS United Therapeutics PH ILD immersion course. My name is Debbie Levine and I'll be talking to you mainly about pulmonary hypertension associated with ILD and kind of giving an introduction on the evaluation. Pulmonary hypertension itself is not one disease state. It's really just an observation of increased pulmonary pressures either in the arterial or venous side. The complexity of these diseases really centers on the heterogeneity of these conditions and trying to evaluate and classify each one. You know, pulmonary hypertension you always hear is a very rare disease, but when you look at the umbrella term of pulmonary hypertension, the prevalence is actually very high, up to 1% of the whole global population with about 10% of individuals older than 65 being afflicted. The difference between all these patients with pulmonary hypertension is everyone doesn't have just one type. As we've seen in many, many, many different classifications sequentially, both the categorization and the classification of pulmonary hypertension is split into five different groups. Remember, group one is pulmonary arterial hypertension. Group two is pulmonary hypertension associated with left heart disease. Group three, PH associated with lung disease. Group four, PH associated with pulmonary artery obstruction or CTEF. And group five is kind of PH with a multitude of mechanisms. The reason it's so important to classify patients and classify them correctly into the right diagnostic group is because basically this is how we decide to treat patients. So if we classify a patient incorrectly, we could be classifying them into a group that if they got or received treatment, it would be detrimental. Today, we're going to be talking mainly about group three, or PH with lung disease and hypoxemia. Again, this is a separate classification that we'll be talking about most and we'll really be talking about it in a multitude of ways. When you think about pulmonary hypertension associated with lung disease, you look at the spectrum and it is more common than those patients with PAH, more common with those with CTEF and even those with group five etiologies. However, it's not as common as PH associated with left heart disease, as that is probably the highest group associated with pulmonary hypertension. But even though it's quote unquote common, it's very difficult to find. It's not easy to evaluate. It's not easy to elucidate or to diagnose. And so we'll go through a very intense evaluation to make sure we can find these patients in those patients who have PH along with their interstitial lung disease. When you look at group three, it's not just patients who have restrictive lung disease or ILDPH. Group three is associated with any lung disease or hypoxemia, whether it be obstructive lung disease, restrictive lung disease, those with the mixed restrictive obstructive pattern like CPFE, those patients with hypoventilation syndromes, those without lung disease but are just hypoxic, for example, in high altitude, and those with some developmental lung disorders. Today, we're going to be talking mostly about those with restrictive lung disease and mostly with patients with ILD. Again, interstitial lung disease and CPFE are the most common lung diseases associated with PH. So when you talk about PH in general, let's talk about how we diagnose patients just with that umbrella term of pulmonary hypertension. We know from two recent guidelines that reflect evolving definition and classifications that the hemodynamic definition or the gold standard definition and classification of PH is based on accurate findings on the right heart cath. So you may get a right ventricular systolic pressure or a pulmonary arterial systolic pressure on an echo, but absolutely for any type of pulmonary hypertension, you need to make the diagnosis with a right heart cath. This definition hemodynamically was based on the definition by the World Symposium on PH in 2018, and that definition by right heart cath is those patients with a mean pulmonary artery pressure greater than 20 millimeters of mercury. As we discussed, there are just two recent guidelines reflecting these definitions, and one was that 2018 World Symposium definition, but then there's an updated 2022 European Society of Cardiology and European Respiratory Society definition that are very similar but have some differences. Most people are now looking at the 2022 ESC-ERS as the definition and hemodynamic characteristics that we look at, and so that's what we're going to use today. Again, for all patients with pulmonary hypertension, the mean pulmonary artery pressure greater than 20 millimeters of mercury is key to making that first diagnosis of generally pulmonary hypertension. Then the hemodynamics get a little bit more complicated, kind of spreading patients out and classifying them into pre-capillary pulmonary hypertension, post-capillary pulmonary hypertension, and those with combined pulmonary capillary pulmonary hypertension. Today we're going to be really focusing on those patients with pre-capillary pulmonary hypertension. These are patients in group one, PAH, group three, PH associated with lung disease, group four, PH associated with the pulmonary artery obstructions or CTEF, and some of group five. The hemodynamic definition includes, of course, the mean pulmonary artery pressure greater than 20, but it also includes a wedge pressure or filling pressure of less than or equal to 15 millimeters of mercury and a pulmonary vascular resistance greater than two Woods units. Now I just want you to compare this definition to the World Symposium definition where the PVR back in 2018 was greater than three Wood units, greater or equal to three Wood units. And again, this is now a change in that definition. But we'll be focusing on the pre-capillary pulmonary hypertension definition for our patients with PH associated with ILD. The European Society of Cardiology and the European Respiratory Journal guidelines have then taken it a step further. They look at these patients with PH associated lung disease or group three PH and split them into non-severe PH and those patients with severe PH. The definition includes those patients with non-CF PH having a pulmonary vascular resistance less than or equal to five Wood units and those with severe PH greater than five units. Now you can see that both negatively impact survival and symptoms but non-severe PH is quite common whereas severe PH is not. The other comparison is that when patients have severe PH their outcomes are much worse than when patients have non-severe PH or less than five Wood units on their pulmonary vascular resistance. I don't want you to think that just because it says non-severe that mild PH is not important in the mortality or survival of ILD patients. Quite the opposite. Even very mild patients with PH have associated declines in their survival as compared to those patients who have no PH. And you can see not very easily, I'm sorry this did not come out on the slide right, but as you can see this very light gray line where my cursor is is where it says no PH and then you look at the patients with those patients who have a lower and higher pulmonary vascular resistance and you can see that even though it might be a little bit better than those with severe PH, those patients with mild PH still have a much different survival curve than those with no PH. So when you look at that distinction it's important to look at the trajectory and the prognosis of patients but you still have a high risk when patients have any PH associated with their ILD. When you look at the pathology and the vasculopathy of these patients the lesion in a patient with pulmonary hypertension associated with ILD is similar but not exactly equal to those with PAH. There's still the intimal proliferation of fibrosis and vascular remodeling, there's still the medial hypertrophy and the pulmonary artery radius is still decreasing over time causing this vascular obstruction. It still leads to patients having right ventricular dysfunction, remodeling, and heart failure. There are a few different changes however in the true pathology. Those patients with PH secondary to ILD have a proliferative arteriopathy with intimal fibrosis, hypertrophy, and obliteration just as those with PAH do, but in these patients there's also often introduction of the pulmonary veins having disease with intimal fibrosis as well as obliteration leading to questions of whether pulmonary abdominal occlusive disease is also involved. So there are a few differences. However, when you look at patients' trajectory symptomatically, hemodynamically, and pathologically, it's very similar to those in group one. Patients have an increasing pulmonary vascular resistance leading to those patients having worsening symptoms over time until the patient has a decline in their cardiac output or cardiac index leading to a decline in decompensation of their right heart and leading to right heart dysfunction and right heart failure. One caveat to that is this. As you see in this first column, it says these patients are not symptomatic and they don't have compensation. That may be true in patients with group one PAH because that's the only disease we're talking about. However, when you have a patient with ILD and PH on top of it, these patients may already be symptomatic from their ILD and this, my friends, is where the difficulty comes in trying to identify it, PH ILD, and identify it early. We'll talk a little bit about that in a minute. In 2022, the ATS, ERS, and ALAT put together and published the reiteration of ILD classification and diagnosis. You can see that it's based on the CAT scan or CT scan pattern. It's along with the pattern of histopathologic changes that occur in these patients. Based on that, these patients are split up into their own classifications of five different classifications with each having a higher risk in terms of PH ILD. But no matter which type of ILD patients have, we know that the development of PH and ILD is not a new finding. We've known it for years. We've just never really been so intent on finding it early. We know that ILDs are characterized by both interstitial and pulmonary vascular components and are variable in the way they're expressed in individual patients. For example, I can have a patient with interstitial lung disease or even IPF, patients with any type of ILD that may have, patients may have the same type of ILD, the same type of process. One patient may have progressive PH and the other may not. So even when you have the same type of ILD and there is a higher risk in some than others, each patient will express PH differently. And so it makes it very difficult to number one, diagnose and number two, even harder to treat. When you look at the literature, you're going to see there's a huge spectrum in every article you see about the commonness or the frequency or prevalence of ILD in, PH in ILD. Really the numbers go from 15% all the way to 90% based on the study, based on the type of ILD and based on how they were calling patients PH ILD. Some of these studies were probably based on echo findings rather than right heart cats. And some maybe have missed them early on in their diagnosis. But no matter the variability in diagnosing, the sequelae are well-established. Patients who do have PH ILD have worsening functional status. They have increased oxygen requirements. They have increased healthcare utilization, and they have a higher mortality rate than those patients without PH. The other thing is PH progresses over time. I'll show you a slide about that in a few minutes. So it's really important to identify it early so that we can treat it early and hopefully reverse some of the changes. The other thing is I want to point out early that even though PH does progress over time, it is definitely unpredictable in how it will progress. And some patients will progress very quickly, and some patients will progress over years. How important is PH in ILD? Let's look at a few different studies. What about decreased mobility? We know that the six-minute walk test is something that we use all the time in pulmonary hypertension as well as in IPF. We know that six-minute walk distance has been associated to survival in both diseases. So when you look at patients who have pulmonary hypertension associated with ILD, we see that their six-minute walk distance is much less, their oxygen saturations are much less, and their mortality rate are much higher. Now, this is an older study. It's from 2006. And so you see that the definition of PH back then was a mean pulmonary artery pressure greater than 25. But that would even mean now that with an earlier diagnosis of PH that there may be even more patients diagnosed with a worsened survival. So this has been shown in multiple studies, and six-minute walk has been able to be parallel to both morbidity and mortality. How important is PH ILD? Well, PH is associated with increased exacerbations in IPF. We know that from multiple studies and from 2012, which just shows us that the development of acute exacerbations in IPF is worsened in patients with PH. What's more important is that you can see that the number of exacerbations associated with IPF decreases survival. So this has nothing to do with PH. If a patient has higher amounts of exacerbations, they're going to do worse if they have IPF. So PH increases the amount of exacerbations in IPF, and the amount of exacerbations in IPF increases the mortality of patients with IPF. So yes, PH in ILD is very important, both in exacerbations and in survival of patients. Another slide and study that, again, is a few years old but very important is, we've all been very focused on how the survival in group 1 and group 4 of PH is so horrific. But if you look at this study, and some like it, you can see that the survival by PH group really points out that group 3 has some of the worst survivals of any group, including group 1 and group 4. So again, something to look out for. When you look at survival in PH ILD, not just group 3 in general, we see that it is worse than patients' survival in IPAH. You can see in red patients with idiopathic pulmonary arterial hypertension or group 1, and you can see in the blue line or the lower line, patients with PH ILD have a much lower survival. So this is kind of the survival at 1, 3, and 5 years, and you can see at all time points, the patients with PH ILD have a much worse survival than those with patients with IPAH. So what do we do? We need to consider the diagnosis early. We need to consider it early and we need to know when to start evaluating it early. The reason it's so hard is something I alluded to a few slides ago, is that there's many overlapping symptoms of ILD in PH. Oftentimes, you may think, oh, the patient's ILD is just worsening. Their fatigue is worse. Their shortness of breath is worse. They need more oxygen. Their exercise tolerance is worse. Both of these are considerations in the progression of PH and in ILD. And so you have to just think in the back of your mind and consider it, hey, could this worsening in ILD really be PH? If you all were here in person, I would make you fill out this chart that I made for each of us to go through individually. And this is the assessment for diagnosis of PH ILD. I would ask you what the history would be with PH ILD. I would ask you the physical exam and pulmonary function test and ask you what the echocardiographic findings were. But since you're not there, we'll go through it together. Let's go through the history. Again, these patients are already often short of breath. They're already having a cough. They're already having some problems with exercise intolerance. So I think one of the things is, is on top of the shortness of breath, are they having a disproportionate amount of shortness of breath based on their CAT scan and their pulmonary function test? A patient comes in to see you and says, hey, I have some shortness of breath on top of my ILD. What's going on? Of course, you'll probably get a CT. You'll probably get a group of PFTs. And they're exactly the same. And you may be thinking, what could it be? Well, it could be a PE and it could be general PH ILD. Another thing that may help you in the history is maybe this patient has signs of right heart failure. We're going to talk about that in the physical exam. But the patient may say, I've had some weight gain. I've had some lower extremity swelling. Maybe these can be harbingers of looking for PH ILD. What about the physical exam? With a patient with just plain old ILD, you should have a normal heart exam. But as patients develop PH ILD just with any other PH, you can get allowed PDU and assign signs of right heart failure as it progresses. So that would be weight gain, lower extremity edema, right-sided ischemia, meaning chest pain. These types of things may not occur in a patient with ILD without PH. Pulmonary function tests. Obviously, patients with ILD have a low FVC and a low TLC. But patients with pulmonary vascular disease, whether it be a PE or a patient with PH ILD, have lower DLCOs and an FVC-DLCO ratio greater than 1.5. So look into that. Again, on six-minute walk, remember that patients may have a lower six-minute walk. They may have worsening exertional desaturation on top of their baseline poor exercise tolerance from their ILD. Serum biomarkers. ILD on its own likely won't cause an elevated BNP, but we all know it's a wonderful marker for patients who have progressive pulmonary hypertension. The CAT scan or the CT chest may show changes in the vessels. You can't see it very well on this CT, but this pulmonary artery can be much bigger than the aorta, leading to questions of whether there's some increased pulmonary pressures. On the CT, you can also see an enlarged right ventricle. The morphology is different than it used to be. This will show up much better in the echocardiogram, where you may see an elevated rate ventricular systolic pressure greater than 45 or 50 millimeters. Again, that doesn't tell you we have it, but it kind of gives you the hint that we may need to find it. You may see the morphology of the right ventricle and right atrium being more dilated or more hypertrophied. There is a reduced right ventricular ejection fraction, and so you may have hypofunctioning of the right ventricle as well. So how do we confirm pulmonary hypertension? Obviously, we want to write hard cath. We need to confirm pH. We need to evaluate pre- versus post-capillary pulmonary hypertension by ruling in or out other pH groups. Remember, other types of pH can coexist in pH ILD. Once we determine that there is pH, we want to determine the severity and consider what therapy we can use. Of course, I'm a transplant physician as well. Early referral to transplantation for these patients will be discussed more in the treatment group. I love this slide because it talks about connective tissue disease. ILD is connected very highly with connective tissue disease or autoimmune diseases, and that's evident in this schematic. Pulmonary hypertension can also be highly connected to connective tissue disease, whether it be group I pH in pulmonary veno-occlusive disease, myocardial involvement with group II, some type of clotting disorder giving you CTEF in group IV, and interstitial lung disease group III. So pH can be so—in patients with connective tissue disease, all bets are off. You may have more than just group III pH, so make sure you do an intense evaluation. This is a slide from the 2018-2019 WSPH guidelines looking at how do we decide if a patient with ILD has ILD and is in group I, has what group I pH and just has a little ILD, or they're group III disease and they have really just a little bit of pH. Well, what we need to do is weigh group I and group III characteristics, both clinically, radiographically, and hemodynamically. If there's more characteristics that need you to believe it's group I pH with a little bit of ILD, that would be possibly how you would treat these patients, and you would treat them in an expert center. If there's more characteristics or factors that lead you to group III, then patients should be referred both to a pH center to be treated as well as evaluated for lung transplant right away. The management of pH ILD includes both general management as well as disease-specific therapies like inhaled triplostanol, and you're going to be talking a lot about this. I'm not going to go into detail. What I wanted to show you was there's a lot of things to do for these patients, and so before you start thinking about management of pH ILD, I urge you to make sure you made the correct diagnosis and make sure your evaluation that we just went through is complete from history and physical all the way through to right heart count. The diagnosis, I want to leave you with two points. The diagnosis of pH ILD is unpredictable. The course can be any which way, and it can change on a dime, so diagnosing this early is important in everything. You want to get these patients the right therapy quickly, and you want them to be evaluated by lung transplant centers very early on, so diagnosis is key. Early diagnosis is key, and again, I think I talked about this early on is that it is a progressive disease. Here's a great study that from a long time ago, many years ago, but showed these patients had a right heart cath pre-transplant, and their mean PAP wasn't that bad, but at transplant, at the time of transplant, you can see that those pressures had already gone up significantly at different rates, so know that it's progressive and know that it's not common to have a patient who has pH ILD that just kind of stays where it is. So pH ILD, in summary, we really need to identify if a patient has pH ILD based on symptoms, and that can be challenging, but it's our one spark to let us know when we can move forward. A thorough evaluation is imperative, and checking echoes frequently to look at screening is important. The diagnosis, again, as we discussed, must be made early to make sure we get the correct therapy so that patients can be referred for both management and early referral to lung transplant. I thank you so much. I'm sorry we weren't in person, but if you have any questions, here is my email, and I hope you have a great time listening to the rest of the course on the recordings and hope to meet you in person soon. Thank you very much.

pulmonary hypertension

interstitial lung disease

evaluation

classification

diagnosis

management

PH