Well, in the interest of time, I'm going to introduce the session. I'm Andy Limper, and this is a session on pneumotoxicity, what you need to know about medications and lung injury. I'm gonna start out by giving an overview talk. I may do that sitting down, I got a bad back, and after I stand in one place for about 10 to 15 minutes, I start to have conniption, so I won't do that. I'll probably sit down. And then we're going to go to the last talk, which is Dr. Peter Leary on medication-induced pulmonary vascular disease, and we'll wind up on how you balance the risks and benefits of medication that have potential toxicity, how and why by Dr. Nabeeta Sood. So I'd like you to welcome. This is gonna be a little bit of a whirlwind, but hopefully there'll be some points that you can learn. Now I'm gonna see if I can get this up. I'm going to see if I can sit down. And you can still hear me, good, that's good. And I'm gonna see if I can advance the slides. Good, so I'm Andy Limper from Mayo Clinic. I've done a lot of writing on drug-induced lung disease for the last 30 years, and we'll share some of that. The objectives are really, and I have nothing to disclose, the objectives are to discuss the variety of drug-induced lung diseases that present in manners that can mimic idiopathic lung disease and it can be a challenge to the clinician. Bottom line is think, think, think, think, think about drugs no matter what you're dealing with until you have a definite diagnosis of what's causing your disease. We'll talk about the differential, how you make the diagnosis, how you manage, and it's case-based format. So there are tons of this. Reported to the FDA, we only have about a million and a half reports a year, because how often do you all report every drug-induced lung disease you see? Out of 30 years, I've done it like three to four times. They were all new toxicities or emerging toxicities. So if you get one of those, please report them. And also you might wanna talk to Philippe Camus for his data set as well, and we'll talk about that at the end. It costs tons of money, over $15 billion a year in lost work, time, or bidding to mortality. There's now over 500 drugs that have lung toxicities. So way back in 2003, the ATS asked Philippe Camus, Ed Rosen, and myself to do a session and to come up with what we thought were the best criterias. The symptom complex is consistent with drug-induced lung disease. The time course is also compatible. And it could be acute, subacute, or chronic. You have to reasonably get rid of the competing diagnoses because there's no blood test, no tissue test, no bowel test that's absolutely specific for any of these things. Yep, if you get a bowel, you got a lot of eosinophils, rotundal lymphocytes, that's pretty good ground, but that doesn't always happen. Most of the time, it doesn't. You usually do the bowel to exclude infections or the underlying malignancy. It can be compatible. And then in the old literature, they said to re-challenge. Don't do it, just don't do it, unless you want to have quality time with your attorney because people do die from re-challenge. Now there are some examples and some exceptions, and we'll talk about this. In checkpoint inhibitor grade one toxicity, oftentimes those people can go back on grade one, grade two. Higher grade checkpoint, no. And sometimes with the calcineurins and sometimes the methotrexate. But the other 500 minus those three or four, you shouldn't re-challenge. Now, there are 500. We're not gonna talk about 500, but hang on, because here we're gonna go. So this is my mentor, Ed Rosenow, passed away about a year and a half, two years ago. Ed taught me everything he knew about drug-induced lung disease. And he said, Andy, it can look like anything. And it is. Anything we see as pulmonologists, drug-induced lung disease, have examples of all of these things. You know, it can look like absolutely anything. So I think about it in several categories. Ed was smarter than me. I think about things that occur very rapidly. They could look like acute interstitial pneumonitis, idiopathic or DAD, you know, like ARDS, like we're seeing in the ICU. Then these more subacute, like cryptogenic organizing, pneumonia-like, or some eosinophilic infiltrates, or even granulomatous process. And then finally, more of the chronic fibrotic types of patterns. So cases, 70-year-old woman, 60-pack-year smoking history. She had combined pulmonary fibrosis and emphysema. She had progressive growth. I kept watching this area that got bigger and bigger in one of her subplural scars. All of a sudden, it looked like cancer. Yes, it was. People with fibrosis have 200-fold increased risk of cancer. We think about COPD with cancer, but fibrosis also causes cancer. And so we found that that was actually an advanced non-small smell that had PD-1 positivity. She was put on Pembrolizabab, and about three weeks later, got short of breath. High oxygen needs. And then we went on. You can see she has infiltrations bilaterally as well. This could be an acute exacerbation. It could be a lung infection, or it could be checkpoint inhibitor pneumonitis. And indeed, we excluded infection with nasal film array and Bell. And the Bell excluded infection real well. We put her on high doses of prednisone with one of my favorites, Bactrim prophylaxis. And within a few weeks, she got back to her normal basal state. She did well for several years before her fibrotic lung disease got her, and her cancer never really came back. It stayed off, and she stayed off of checkpoint inhibitors from that initial treatment. So there's a lot of referencing on this. It could be either focal, it could be diffuse. It usually occurs about three months after therapy, but it can occur earlier. Wide ranges of symptoms. As you know, checkpoint toxicity, brain, liver, skin, lung, heart, muscles, nerves, you name it, it affects it. There's not any definite pathologic or radiographic finding. You have to think about it. You have to exclude infections, exclude your underlying malignancy getting worse, and then look at the temporal relationship. And then if you've excluded an infection, treat it. And most of the time, it gets better. It is rarely fatal. And as I said, you can retry gingerly with the low-grade toxicities if they go away. If there's a high-grade toxicity that this lady was on high-flow oxygen before she finally got turned around, you don't want to give it again. Another case, 32-year-old man with a leukemia on cytoxan, cyclophosphamide, methotrexate, and BLEO. He had his spleen taken out because he had massive splenomegaly. He got respiratory failure. Why did he deteriorate the day after surgery? The anesthesiologist gave him high oxygen. This happens two to three times a year coming in referred into our practice. People don't think about it. Talk to your anesthesia colleagues. And this is an old syndrome, 1978, British Medical Journal. You know, you need to try to keep the oxygen as close to FiO2 as normal. It occurs within the first few days post-op. It's often fatal or bad. We've seen it unilateral. And everybody said, was it a pressure effect? Nope, because our anesthesiologists use, you know, lung-defending ventilation pressures. It was the oxygen all went to the one lung. Unfortunately, I've seen it amnestic. It occurred three, five, seven in the literature up to a decade or more later because the BLEO gets into the tissues, decorates the tissues, you have high FiO2, it redoxes with your iron, and reactive oxidants take the toxicity forward. You could get also a non-cardiogenic pulmonary edema, bilateral infiltrates. Now, classically, we know about this with narcotics, right? But of course, it also is similar on the airway side on things like vaping or EVALI, electric vaping lung injury, on the epithelial side, narcotics on the endothelial side, and actually, usually with IV drugs, but it can be with orals. That case I showed you actually was an old case of Darvon overdose, propoxyphene. So it can occur with orals as well as IV. Endothelial toxicity, some CNS effects as well. You, of course, treat them with Narcan, oxygen support. Steroids really aren't very helpful. I gotta tell you, we give a lot of steroids in drug-induced lung disease. There's not a lot of literature that supports them with a few examples. Usually, with things like nitrofrantoin, it helps a lot. Sometimes in BLEO, it will help, but not in the BLEO oxygen toxicity. Another drug that has an oxygen toxicity in the cardiovascular post-op, loading with amiodarone. The same thing can happen with low-dose loading amiodarone in the cardiac ICU. How about chemotherapies? They're big for causing diffuse lung injury. This is high-dose ARAC, cytosine arabinicide. I don't know if you can see my pointer because it's weak and wimpy like me, but you can see that there's some hyaline membranes scattered throughout, and indeed, this is just acute lung injury, diffuse alveolar damage. A number of years back, Ogi Gajic, Dokar, myself, looked at all of our cases, and the thing is, is you're all ICU docs. I'm past that point in my life, thank you, but up to about 10% may be drug-associated, so think about that. Now, this is one of those oh-God lists in drug-induced lung disease, right? That's what this is, right? Drug-induced lung disease is memorized list. No, you don't have to. We'll talk about that, but you know, chemotherapeutic agents are the number one things we think of, of course. You know, Bleo and Cytoxan, cyclophosphamide, cytosine arabinicide, all of these, methotrexate can do it, too, and fliximab, but also a variety of other agents. Nitroferantoin could be an acute failure right away. Amiodarone, even with the loading doses and oxygen in the cardiac ICU, contrast, and then a whole host of other things, including the narcotics we talked about. Oh! Am I backing up or not? I'm sorry for that. I must have had a seizure or something. There we go. Okay, lady with rheumatoid, pleuritic chest pain, no fever, hemoptysis, or cough, wheezes. We did a CT negative for PE. She had been taking methotrexate. She had some wedge-shaped infiltrates. Boy, they looked like Hampton's Hump. Went in there, we wedged one of them out. God bless. This thing is not good. There we go, because I want to show you. We got these nice little granuloma. I'm not touching this. You can see a granuloma with the arrows there, and methotrexate is one of the things that'll cause a granulomatous reaction. Keep thumb to side, Andy. Okay, methotrexate pneumonitis, it could be subacute, it could be acute. Oftentimes, there's fever. Peripheral eosinophil might be present, might not be. You can have a variety of histologies. Yeah, granulomatous is classic for boards. Some of you out there are gonna take that, or the research, or whatever, but it could also be organizing pneumonia. UIP-like, MSIP-like, or just the diffuse alveolar damage. Now, I get this consult, run over to the hospital. This is seven, eight years ago. The rheumatology fellow says, "'I have a methotrexate lung.'" Well, patient had been on methotrexate and a little low-dose prednisone, as you can see, for rheumatoid arthritis, and about a week of cough, dyspnea, and fever. And there were lots and lots of infiltrates. And, of course, what do we always do? Exclude other things. And this was not methotrexate lung. Methotrexate, chronic fibrosis, actually is a lot more rare than we get consulted for. It's not a real common entity, but it does occur. But pneumocystis jiraveci sure does. Both the steroids and the methotrexate can set you up for a pneumocystis, no prophylaxis. The patient did respond to therapy. Cyclophosphamide. I have one of these right now that is pulling what little hair I have left out of my head. Because we do use cyclophosphamide, the rheumatologists use for muscle-associated myositis and such, it has lung toxicity, too. You can see this pleural pulmonary fibrosis, kind of upper lobes on the right, and there's some things on the left near the base. And, indeed, it's not common. Ulrich Specks, Dick DeRamey, Saeed Malik looked over 22 years, and they found about six cases at Mayo. There's an acute type that gets better fast, and then there is a slow type that doesn't get better hardly at all, ever. If you get the slow type, which I'm dealing with now, it really has progressive fibrosis, and you really can get rid of the drug. You can give them steroids. I got news for you, it won't help. And I usually treat those few patients that I've seen with antifibrotic therapies for progressive fibrosis. What about drugs for chronic ulcerative colitis, sulfazalazine and such? And here's a case of a guy that had long-standing CUC, and he was dyspneic on exertion. He had these fine little nodules. The respiratory secretions in the bowel were negative, and he had shadows on his chest ray and his CT scan, and when biopsied, he has little organizing pneumonia pattern. Now, the problem is, as we all know, we know that sulfazalazine, 5-Asa, and other related drugs can cause lung reaction like organizing pneumonia or eosinophilic infiltrates, but ulcerative colitis by itself can do a lot of the same thing. It can cause organized pneumonia, interstitial infiltrates, eosinophilia, plus bronchiectasis, bronchiostenosis. Differentiating is hard. Stop the drugs, try to maybe increase the steroids if suitable, and see how the patient does, and then you have to wade through whether it was indeed the 5-Asa or the sulfazalazine or not. Other drug organizing pneumonia, bleo in this young guy that had a seminoma, nodular cough, infiltrate. What do you think the cause of his lung lesion? Well, this guy has had a seminoma, and you see that, the first 18 things on the differential of yours and your fellow is that that's metastasis, right? Well, fortunately, he had that thing that was right there by the wall. We were able to, you know, transthoracic needle it under CT guidance, and indeed, once again, organizing pneumonia with bleo responded well to corticosteroids. There's a growing list, this is a small list, but bleo, amiodarone, sulfazalazine radiation outside the radiation ports can cause organizing pneumonia, mitomycin, methotrexate, cyclophosphamide, coke, cocaine, d-penicillamine, temozalamide, and oxaloplatin. Now, progressive fibrosis over time. This happens three times a year in my ILD practice, and that's all I do anymore is outpatient ILD, and indeed, pulmonologists referred, we see this, 68-year-old woman that had a history of UTIs and is referred for IPF, and you ask her, you don't just look at the drug list, you ask them what they're taking, and what was she taking that she had in her cabinet from Dr. X 30 years ago kept getting renewed? Nitroferantoin, right. Look at that CAT scan from J. Rue's paper. That does not look like honeycombing or UIP, but it does look like nitroferantoin, and that's good for her, because she's gonna do better. You'll stop the drug, you may give her corticosteroids, they may improve, or they may stabilize, but if they stabilize, the ones that I've been following, some now for a decade plus, do a lot better than UIP, so get them off of that nitroferantoin, and please think about it, right? We're all pulmonologists, think about that. That's gotta be in your history workup when you're running through IPF, is drugs as well as birds, bats, all the other stuff we always ask about. Okay, chronic progressive dyspnea in a patient that has non-Hodgkin's lymphoma, got bleomycin, this is the other face of bleomycin. I've shown you bleomycin acute, I've shown it with oxygen, I've shown it as organizing pneumonia, and now you're seeing chronic fibrosis, right? And indeed, it looks pretty bland like chronic fibrosis. It could look a lot like UIP under a microscope. Amiodarone could do this too. I told you amiodarone with oxygen in the post-cardiac ICU can cause an acute lung injury, yes, but it also can cause chronic fibrosis. Now, 20 years ago, everybody was really excited about the bowel. Guess what? All the bowel shows is exposure. That's not pathognomonic for nothing, okay? There were some old board questions, I hope they throw them out because they're wrong, I hope they throw them out because they're wrong. If you take people that are getting amiodarone with no lung pattern at all, they've been taking it for years, particularly at a higher dose, they will have those lipid-laden macrophages. That's where the amiodarone goes. They're not pathognomonic. It does show exposure, so if you've had somebody that's on it, you don't see those things, that's pretty good news, unless it's in the post-cardiac ICU. So it's more of an exclusionary than a diagnostic type of test. Boy, I'm ending up on time, I'm good. So there's a whole list of things that cause chronic fibrosis. The chemotherapeutic agents can cause chronic fibrosis. Some of the TNF-alpha inhibitors, amiodarone, AZA can cause chronic fibrosis. Rarely, I've seen it twice, ever. But the nitrosoureas, BLEO, all the alkylating agents, fludarabine, high incidence of fibrosis as well, infliximab, minamicin C, nitroferantoin. The last thing you wanna do is keep letting that little lady have her nitroferantoin that she takes five times a year, it doesn't tell anybody in her medicine cabinet. And Taxol and a variety of other agents that are there. Now, we've hung on to that 500 drugs that I didn't even talk about, a tenth of them. This is the drug-induced overlap, drug-induced information overload syndrome. So you are like me, and the jackass is over his head, right, with all this info. Hey, I gotta laugh, I gotta laugh. So my good friend, Philippe Camus, has a world's resource in pneumatox.com. Go there, it's organized a little wonky, but you can find anything you want by the drug name, they're alphabetically ordered, you can see what's there. If it's not in there, you're not home free. That's why you have Dr. Google in the internet, because Philippe does this out of the goodness of his heart, nobody pays him or gives him money, and he updates a few times a year. And I certainly have found cases of things that have been described elsewhere that are not pneumatox. I'm not banging Philippe, because what I do is I take those articles and I email them to Philippe, who's a good buddy of mine, and bless him. I don't know what's gonna happen to this when Philippe retires, because nobody is paying for this. So it's a resource that we all need. And we'll talk about management, I think, at the end. So, you know, stop the drug, you could judicially use steroids, and support them the way we do. And so with that, I'm gonna stop, we're gonna hold questions till the end. And Dr. Leary, are you gonna come up next? Thank you, thank you. And Dr. Leary's gonna talk about vascular, and all you have to do is click on your, perfect. Thank you. Well, thank you very much for having me. It's a pleasure to chat with everyone. So we're gonna get rolling with medication-induced pulmonary vascular disease. I figured this was a fall-themed conference, and so I took a picture of the gutter outside my house in Seattle, which pulmonary vascular disease kind of sweeps up and catches a lot of things, a lot of drugs kind of get swept up in it. It's a real stretch, and that really may be emblematic of my entire talk. So, but just stick with me. So this is me, those are my disclosures, most of which is related to grant-funded research. So really at the end of this, what I wanna do is come away with an idea that we're gonna explore a framework to consider medication contributions to acute and reversible pulmonary vasoconstriction, and then the contribution to chronic remodeling in pulmonary vascular disease. And I'm gonna give you a little bit of the reason for the rationale as we go forward in just a couple of minutes, because it may not have been totally the brief you were expecting. So I wanna start out with my biggest disclosure, which is this is my sole published work on drug-induced pulmonary vascular disease, which I published with my wife. And the real beauty of this is that we were very, very, very not right. So we started out and we said, this was around the time that they were doing a long-term cancer survivor study out of St. Jude, which is where she had done her fellowship in oncology. And they had a sweeping indictment of chemotherapeutics causing pulmonary vascular disease. And we said, whoa, pump the brakes. There's not enough data here. Let's research this before we start bringing it into practice. And it was really just like a week before the French experience published a very convincing series of desatinib-induced pulmonary arterial hypertension. So we'll start with that as my biggest disclosure. So what is the framework for this talk? I said that it was gonna be acute changes in the pulmonary vasculature and chronic changes in the pulmonary vasculature. And I think it's fair to get out of the way right in the beginning that there are things that overlap. So chronic pulmonary vasoconstriction can lead to pathways that lead to pulmonary vascular remodeling and ultimately a disease like pulmonary arterial hypertension. And so I've conceptually separated them while we're talking but there is some overlap as we move forward. And I think that that's important to remember. So acute changes leading to pulmonary hypertension. I figured we were in Hawaii. We would start with some palm trees. These are things that hopefully are gonna reverse but maybe like this palm tree right here don't always reverse. So that's the little bit that kind of sticks around. So why are we talking about pulmonary vasoconstriction in a session on drug induced pulmonary vascular disease? And I think there's a couple of reasons. One, everyone should be aware that if they're dealing with somebody who already has some right heart failure, there's a number of things that can make that worse that are not disease progression. And the second is, is everyone is probably aware we've lowered our thresholds for what we're calling pulmonary hypertension. The most recent guidelines dropped it to a mean PA of 20, dropped the PVR down to two. And so we are really living in a realm where a lot of the medicines that we use can give you the hemodynamic picture of PAH. And if you're not aware of what you're doing with that, you could inadvertently diagnose PAH when you're really just talking about pulmonary vasoconstriction. And so that's really the rationale. The wolf in sheep's clothing that's sitting right here, which it's hard to actually find an image for a wolf in sheep's clothing on Google that is not terrifying. I would encourage you not to look. So this is what I'm gonna talk about in terms of the acute pulmonary vasoconstriction, just gonna touch on hypoxia, hypercarbia, acidemia, and then a fitting other category. So hypoventilation, we're all pulmonologists, we're all closet physiologists. And so we love thinking about hypoventilation and what it does in the body. And this is just a study here on the left right here that was changes in the PVR with hypoxia. And just again, to really highlight that we give lots of things that induce hypoventilation all the time in the ICU, within about 90 minutes, you've got a PVR that is over two and is into that range where we would be calling this pulmonary hypertension. And so just recognizing that that's gonna be there. I will make the side caveat as somebody who continuously tries to rescue people from high flow oxygen, that when you're thinking about hypoxic pulmonary vasoconstriction, most of that is being driven by the alveolar oxygen tension and very little of it is being driven by the systemic saturation. So you don't need to put them on gobs of oxygen to get their systemic saturation up above 88% because you're saving them from right heart failure. You just need to put them on a little bit of oxygen to wash out their alveolar space. And that's gonna get you most of the way to the goalpost. Almost everybody with pulmonary hypertension will desaturate and it's a quick way to end up on 100% high flow and never leave the hospital. The second is that hypoxia is not alone. So hypoxia is a strong contributor of pulmonary vasoconstriction and hypoventilation, but so is hypercapnia. And this is hypercapnia in the absence of hypoxia. So if you have somebody who you have sedated, they are hypoventilating, you put them on oxygen, you fix their oxygen, they're still hypoventilating and their pressures are still going up from their hypoventilation. And so I think this is particularly relevant. We just came from another talk directly behind those walls over there that said that about half of people doing right heart caths are sedating their patients for their right heart caths. The other half are just using lidocaine alone. And so this is just a reminder that if you are really sedating your patient for a right heart cath, you may be getting into a range where you're confusing yourself. The final thing is things that cause acidemia. So either diseases or conditions, metformin. This was a pig model that was infused with acid. And you can see that inducing metabolic acidosis can increase your pulmonary vascular resistance by nearly double. And so if you're in a space where that's the case, these things are all going to cause pulmonary vascular changes. So finally, we have a bunch of kind of drug-mediated increases in PVR. Many of these are receptor-mediated. Pressers being probably the most common one. There are a lot of casts of convenience where somebody comes in for another reason. They get an echo because they're sick. They then have pulmonary hypertension and then they decide to work up their pulmonary hypertension. If they're on pressers, those are very hard to interpret. Blood products, platelets are really the big offender here. Lots of thromboxane A2, which is gonna increase your pulmonary vascular resistance and can increase right heart afterload. Tryptans aren't as often encountered, but you certainly are gonna see them in your migraineurs where they're still pretty used as are prostaglandins in delivery. And then really, I think amphetamine-like drugs is a big one. When I agreed to this talk, I thought I would be talking about methamphetamine where I felt like I was a real ace. But then I realized there's a whole nother session on that. So a plug to go to the session on meth-induced pulmonary hypertension because it is sweeping the nation. But here you can also look at things like fen-phen and things like that, that are all kind of within a couple side chains of methamphetamine. All right, big deep breath and a shift to a new part of the talk. So now we're gonna go and think about chronic changes leading to pulmonary hypertension. I chose again, another fitting beach theme. This is not something that is gonna go away when the storm passes. Obviously, these changes are there to stay. Again, I really like to explain my pictures in a way that is probably unnecessary. So there's lots of roads to pulmonary hypertension, right? So I'm not going to talk about all of them. We could talk about pulmonary hypertension and rope in all of the ILD. We could rope in really just a montage of different topics. I'm really just focusing on those drugs that kind of lead to a progressive pulmonary vascular narrowing, leading to right heart failure and potentially death. So pulmonary arterial hypertension, that rarer of the subsets. And because it is ski season, we're gonna kind of have a roadmap in terms of levels of complexity of where we're thinking about it. I'm gonna start with the pathognomonic features of drug-induced pulmonary arterial hypertension. Those things that you can look at and say, this is 100% drug-induced pulmonary hypertension when you're working somebody up. I'm gonna move to alternatives to the diagnosis of drug-induced pulmonary hypertension. That's gonna make more sense in a second. And then a little bit that's gonna be kind of moved forward by Namita about whether or not to stop a drug and re-challenge. So here are the five pathognomonic clinical features of drug-induced pulmonary hypertension. Voila, there are none. So there is nothing you can do on a workup for drug-induced pulmonary hypertension that is gonna say, this is drug-induced pulmonary vascular disease. How do you know? When do you think of drug-induced pulmonary vascular disease? You really, it's just careful descriptions. And so this is more than just a medication history. This is really kind of a careful kind of layering of the medication history related to symptoms. Everyone knows this, but I think it's worth saying it out loud. You wanna make sure that you have good reason to suspect that the pH was not present before the drug in question. We have a lot of people who come in on their chemotherapeutics with drug-induced pulmonary hypertension who very clearly had the same symptoms before the drug was there. And these drugs are being given for a reason. And if we stop them for no reason, then we probably haven't done anyone a favor. Then you wanna take the time to really say, is it there once the drug is there? And then finally, that final step, which is really the most bedeviling one is the reason to believe that it may be causally related to PAH. And I'd say this is a information light space. And so a lot of this is gonna be judgment calls with some exceptions. So when I first agreed to do this talk, I really got stuck on just putting this slide up here and being done dropping the mic and walking away and figured I had to fill another 19 minutes beyond that. But these are the medications that are known or suspected to be associated with pulmonary vascular disease. And I really love the pneumotox slide in Dr. Limper's talk. These are changing, these are evolving. Just memorizing this slide of kind of drugs and toxins is really not going to get you very far. It'll get you a little far, but it's not gonna get you incredibly far. And so this was in the last ERS guidelines that were put up there. Hands up for anybody who has ever seen toxic rapeseed oil-induced pulmonary arterial hypertension. Nope. Neither have I. My hand stayed down. So they fall conceptually into a couple of big groups. Again, amphetamine-like drugs, tyrosine kinase inhibitors, antivirals, alkylating agents, antineoplastic, immunosuppressants, and then kind of a hodgepodge. So why is it that just memorizing that list is not enough? It's because this is a constantly evolving space. And so when we have something where it seems to fit that category, the pH wasn't there, they started the drug, the symptoms came on, and then we have to decide whether or not it's related. The pulmonary hypertension is there. There's a bunch of different ways that we're finding this. A big one is case reports. So you just go in, you either go to PubMed or you go to Google, and you see whether anyone else has talked about it before. And I would say for any kind of newer drug on the market, I do this in clinic in front of the patient. And so, and if you find it, report it. A second big one is disproportionality assessments. So this is kind of at the population level. This was a disproportionality assessment of pulmonary vascular disease suspected drugs. Essentially, this is a fancy observed versus expected analysis, where you look to see whether there's more pulmonary hypertension than you would expect in a given population. I'm gonna pause here and just say, both of these are gonna have a hard time separating out whether it is a drug that is causing the pulmonary hypertension or the underlying condition that is causing the pulmonary hypertension. And I think that that is important because there was some data presented at a conference earlier this year on drug-induced pulmonary vascular disease, linking Adderall to pulmonary arterial hypertension. It was a very weak association. It wasn't very strong. And I think it has the potential to terrify a lot of people in the country. I think it's important when you think about that to know that the rate of methamphetamine abuse in patients with ADHD is about five to six times higher than the rest of the population. And so those types of signals could be from the underlying disease or associations with the underlying disease and not the drug itself, as we kind of think about these associations with pulmonary vascular disease. And that should be published soon. So we'll see whether they incorporate that in their thought process. The other way to think about, find new and worrisome associations is to think about the biology. So tyrosine kinase inhibitors are really the ones that we're thinking about with PAH right now. These are phylogenetic maps that are really mapping out what's being hit by your tyrosine kinase inhibitor. If there are really any ambitious fellows in the room, you can take these maps and get back to kind of basic levels of biology to figure it out. The simplest way is to just look and say, all right, Dasaponib is hitting Able, which is named after an oncologist from Seattle, I just like to give a tie in back home. What are the other ones that target Able and do they cause pulmonary arterial hypertension? That would be the most simplistic way, but then you can also really flesh it out and try and get down to kind of overlaps in some of these dirtier antagonists. So we're coming into the home stretch here. And I would say, one thing is you've done your careful history, you're really proud of yourself for anchoring it to a drug, try to really avoid premature closure and avoid satisfaction of search. The reason why I say this is, oh yeah, I found out it was Dasaponib. I know Dasaponib causes pulmonary vascular disease, I'm done. Nope, remember to do the good workup you know to really round it out for pulmonary vascular disease. A lot of these things are chemotherapeutics and for cancer patients. If you skip the rest and say it's the Dasaponib, you may miss out on things like chronic thromboembolic pulmonary hypertension, which is going to take you in a totally different direction. And I would say it is very common that people say, ah, figured it out. They used meth, they're on Dasaponib. And that is often the smoking gun, but it is not always the smoking gun. And it is easy to do even by people who are really, really good. So this is just really mostly to introduce Namita as I don't want to steal all of her thunder, but when you're thinking about stopping and re-challenging in pulmonary vascular disease, which I think is a different space than ILD in some ways, the question is, is are there good alternatives to the medicine you're stopping? How strongly do you believe that that drug actually is causing PAH? And in most cases, we don't have a strong belief, we may have a suggestion and then kind of fold all of those decision-making pieces in in tyrosine kinase inhibitors specifically, about two thirds of the PAH resolves with just stopping and no PAH specific therapies. Re-challenge even with a different tyrosine kinase inhibitor can lead to a recurrence of the disease. But I will say it is still often tried because there are not always great alternatives for the underlying disease that's being treated. And that's it. Thank you. And our last speaker will be Dr. Sood. You're going to talk about balancing the risks and the benefits and the times when you're stuck against the wall and you don't have a lot of alternatives. So I'm looking forward to this. Well, thank you, Dr. Limper, for including me in this very interesting session. And okay, we got the slides right. So I was given the task of how to balance, which is always a challenge. These are my disclosures. So the first thing is we need to identify, I think moving sort of proactively identify what the risk factors for the patient is. So we can be aware of it and also counsel the patient before they start therapies that they might get into trouble. And they can also help us by looking out for the symptoms. So the risk factors that are kind of commonly identified are patients with non-COPD, male, gender, men don't do well in anything. Tobacco use, when it comes to disease state, they always have the worst outcome. Tobacco use, ongoing tobacco use, we have to counsel them to quit smoking. Previous ILD and previous radiation therapy or previous chemotherapy that they might have received. And then there is no shortcuts to detailed history. I see some of my fellows current and previous in the audience, and they know that when they're working up a patient, they're frequently sent back to get more data. And we, because we want to differentiate whether this could be an infection, progression of disease, could it be vascular spread of the underlying malignancy, we know thromboembolism, and then of course we think about drug toxicity. And why is that history so important? Because we want to assess the temporal relationship of the initiation of therapy with the onset of symptoms. And I have to be honest, some of the drugs I'm going to be talking about, I don't even know sometimes which category they belong in and how to say their names. But I can point out the association. They were started on this and the patient started having symptoms now. That much I can do with confidence. So here's the current sort of recommendations as to how to proceed. The patient has new respiratory symptoms. You want to get a CT scan. If they have persistent lesions, then you might do a little bit more invasive diagnostic testing to rule out the infection, get an echocardiogram to sort of make sure there's nothing else causing the symptoms of dyspnea, and then go on and grade the degree of toxicity. So the current guidelines for the checkpoint inhibitors is that you grade the degree of pneumonitis. Grade one is asymptomatic with ground glass infiltrates on the CT chest. Grade two is symptoms affecting activities of daily life. Grade three is severe symptoms affecting self-care and needing oxygen. And grade four is life-threatening respiratory compromise. And when a patient is sent to my clinic because there's concern that they might have cytotoxicity, I really have to consider several things. Do we need to treat the malignancy, right? There's changes within the world of oncology, and it is more about controlling the disease than affecting cure, right? So they've also approaching it differently. We want to take into account the patient's age and how effective is this treatment going to be. When they tell me, well, we're giving this chemotherapy, and the chances of benefit is like 10%, 20%, that's a different number, as opposed to that likelihood the patient's going to go into remission is 90%, right? So that's sort of something that we have to consider and discuss. Has there been response to the current therapies? Are there alternative options? And what is the patient's quality of life? This cytotoxicity that the patient has developed, how much is it impacting their overall quality of life? So we have to find that balance. And in finding that balance, we have to engage in a team approach. First, of course, the most important person is oncology. I have all my oncologists' cell phone numbers on my phone, and they're used to me calling them at odd hours, and pulmonary, because I'm going to tell them how serious and bad this is, and the patient, which is the patient's expectation, and what are they willing to tolerate? What is the acceptable quality of life? And we, again, go through those same questions, assess response to therapy, explore alternative therapies, overall long-term outcome, degree of toxicity, other organ involvement, right? And patient quality of life and their expectations. All that has to be taken into account. So I'm going to sort of change gears and kind of go into some clinical scenarios just to highlight these points. So the first one is 71-year-old lady with multiple myeloma. She was treated with four cycles of RVD. Those are the drugs that come in that protocol. Stem cell, then underwent a stem cell transplant in 2018. In 2022, she had relapse of a multiple myeloma. I'm sorry, that's a typo. There's nothing known as MMM. And then she was started on denosumab and the other two. Somebody read them for me. And in February of 2022, she reported some numbness, fatigue, and diarrhea. So that's the clue. Something's not going right. And then in June, she has shortness of breath. And then between June and August, August was when I first met her, she had three admissions to the hospital with acute respiratory failure requiring high dose of oxygen. Once it was treated as an asthma exacerbation, she didn't really feel that much better. The other time she received a little bit of diuretic, was sent home again with supplemental oxygen, and now she was back. So I met her on her third admission. And she's on high flow oxygen. This is a CT chest. And if you can see, we don't see any drip-roaring interstitial infiltrates here. And then she had an echocardiogram, but the LVEF was 60%. There was no pericardial effusion. The RV was read as low systolic function and the right atrium and the left atrium looked essentially normal. The RVSP was increased and then she had a positive bubble study, right? So we diuresed her and then sent her for a right heart catheterization. And here is her hemodynamics. The RA pressure is slightly high. The PA pressure is borderline-ish, 22, which meets the criteria by current definition. Wedge is eight, cardiac output is four liters, and the PVR is 3.5 volts unit. And a VQ scan to rule out chronic thromboembolic disease is negative. So we did a little. We went to the pneumotox because that's the only place we know to go. And we found that there were case reports of Denisovab causing pulmonary hypertension and her symptoms appear to coincide with the initiation of therapy. But having said that, multiple myeloma in itself can cause pulmonary hypertension. So of course, that leads to a phone call with the oncologist to see, okay, what's going to be the best way to proceed? He tells me that the multiple myeloma is actually well-controlled. All her markers are negative. So we made a diagnosis of just a new NAB-related pulmonary hypertension. Now, the next question was what to do next. Should we continue to treat? Should we stop? Are there other alternatives? Well, you know, remember this patient had relapsed and she was now responding well to treatment and there were really no other good therapies for her for various reasons. Do not ask me why. So we decided to continue with close monitoring. We started treatment for pulmonary hypertension, put her on diuretics, and she had significant improvement and currently just needs supplemental oxygen with exertion at high altitude and in Sacramento, she does well. So this is someplace where we can manage. The patient is under close follow-up. And if she were to get worse, then maybe the discussion would be different. All right, case number two. 80-year-old gentleman, very active. He was cutting trees before I met him. Diagnosed with uroepithelial carcinoma, was treated with gemcitabine and carboplatin for three months. He had partial response and then he was put on these fancy agents. And then he reported worsening shortness of breath, cough, and productive sputum. The PEMBRO, however you say it, is a checkpoint inhibitor. Yes, thank you. I don't know who comes up with these names. So this was his baseline CT scan when he was receiving conventional chemotherapy. And this is when I met him. And you can definitely see here that there is a little bit of worsening in filtrates, right? So risk factor, older gentleman, previous some interstitial lung process maybe, and now he is worse. So now he's symptomatic. So if we were to look at the grading, then grade two is worsening in filtrates with symptoms affecting activities of daily life. So we called him a grade two toxicity. And here's the current recommendations, that if it is grade one, then you may use corticosteroids or just do close monitoring. Grade two, you can consider stopping the therapy and corticosteroids, and then you can go ahead, re-challenge the patient. And grade three, you got to stop the therapy, higher dose corticosteroids, and perhaps no re-challenge. And similarly for grade four, grade four is very scary. So we diagnosed him with grade two. And because he was in the clinical trial, where they decided to just continue with high dose corticosteroids, and he remained on therapy with close monitoring. And this is what he looks like right now. That was his initial CT on the top. And then you can see that there is some clearing of those infiltrates with the high dose corticosteroids, but he remains on the checkpoint inhibitor under very, very close monitoring. So it's all about balance. It's about patient's expectations and also close sort of assessment, continuous assessment. All right, so the current guidelines, like I said, if it's grade one, close observation, perhaps corticosteroids, if you do do that low dose. Grade two, close observation, stop the drug for a little bit, corticosteroids, and you could consider re-challenging. And so this is my guy here. Now, this is another gentleman, 55-year-old non-smoker, gets diagnosed with metastatic adenocarcinoma, which is pretty widespread by the time he's diagnosed. This is his expressions for those who are interested. Gets treated with carboplatin and P-metrexate with progression after five cycles. So then he is enrolled in the DASH trial and it's started on Brigtabinib, which is a tyrokinase inhibitor, EGFR, and versus all three. And literally within a week of enrolling in the clinical trial, he reports cough, shortness of breath, and tachycardia. And this is what his CT looks like. So the one on the left is his pre-treatment CT scan. He has that mass there, but if you look on the left side, you can see some early sort of fibrotic changes that he probably had before. He's a healthy 55-year-old guy, used to bike regularly, and this is what his CT looks like, literally after a couple of weeks of treatment. And you can see that he's, not only is there enough ground glass, but there's also fibrotic changes that are happening. So we diagnosed him with grade three, initiated him corticosteroids, the drug was stopped. He now has a new oxygen requirement and his subsequent CT showed worsening fibrotic changes and worsening lung cancer. So path forward can be re-challenged in small, as I mentioned earlier, several small series of set that you can, in grade one and grade two, consider re-challenging the patients, but even then, 30% of them will have recurrence. So really it has to be a discussion with the patients with very, very close monitoring. And then there's some more aggressive sort of interventions that have been considered in checkpoint toxicity with using agents like infliximab, cyclophosphamide, or IVIG, and the role of antifibrotics in the patient, like the one I just presented, is being explored. And what do we know about these agents? So not a lot, but this was a small series that came out of John Hopkins just recently. They had 12 out of their 65 patients who they determined were steroid-resistant pneumonitis. That means either they'd received 48 hours of very high dose corticosteroids without improvement or a pretty good dose of at least two milligrams per kg for some days without any improvement in their infiltrates. And they were either treated with infliximab or IVIG or combination. And this is what we get. You can see that the patients who received that combination therapy seem to have a pretty decent response in clearing their infiltrates. So little gutsy, a little, you know, creative, but that's what oncology literature is all about. They always push the limits of what we are comfortable with. But you can see here that there is, these are steroid-resistant patients who continue to show some improvement. All right, so to summarize, we basically have to assess each patient the way they are. So I'm going to wrap it up with another case. So 52-year-old, and I apologize, this is a little old case, but I've had three or four more patients like this with other agents. So 52-year-old lady diagnosed with AML was treated with citerabine and donorubicin, underwent bone marrow transplant. This is an old one, so received ablation with BCNU. We don't use that anymore. And her post-transplant course was unremarkable. She engraft well, no graft versus host or anything like that. And then she started to develop dyspnea. Chest CT did not show any infiltrates. And the PFTs showed mild restriction with a DLC of 38%. Echocardiogram showed mildly dilated RV. VQ scan was essentially unremarkable. And this is her CT scan. And you can see here, we don't have any interstitial infiltrates, but nor is it normal. You have these little sort of vascular process going on here. We do a right heart catheterization. She's got a PA pressure of 30. Her cardiac output is still preserved. And because of the clinical setting and sort of our pre-test probability of her having a veno-occlusive disease, we went ahead and get a biopsy. And this is her pulmonary veins are completely occluded. So this is PVOD related to BCNU. And this has been associated with several other chemotherapeutic agents. And sometimes it can of course be idiopathic and in the setting of connective tissue disorder. So what do we do? There's no good therapies for this. We put her on PD5. Diuretics are usually not very effective in these patients because the veins are kind of occluded. She remained limited with supplemental oxygen and her CT continued to get worse, but this is where she is. So she's not a candidate for any good therapies other than if she survives long enough, maybe she gets to lung transplant or something like that. All right. So in conclusion, cytotoxicity should be considered in all patients. We need to proactively identify and think about a high risk patients. Always consider alternative etiologies, infection, thromboembolism. I've had patients come in with pulmonary hypertension who had vascular spread in the vessels and so forth. And then risk benefits should be ascertained with the oncologist and the patient absolutely needs to be in that discussion. And with that, I thank you for your attention and I will take any questions. Thank you.

pneumotoxicity

medications

lung injury

risk factors

patient history

case examples

alternative therapies

multidisciplinary approach

follow-up