Highlights from the 2023 American Thoracic Society Conference (ATS)

Podcast Transcript

Raed Dweik, MD:

Hello and welcome to the Respiratory Exchange Podcast. I'm Raed Dweik, Chairman of the Respiratory Institute at Cleveland Clinic. This podcast series of short, digestible episodes is intended for healthcare providers and covers topics related to respiratory health and disease. My colleagues and I will be interviewing experts about timely and timeless topics in the areas of pulmonary, critical care, sleep, infectious disease, and related disciplines. We will share information that will help you take better care of your patients today as well as the patients of tomorrow. I hope you enjoy today's episode.

Daniel Culver, DO:

Hello, everybody. My name is Daniel Culver. I'm the chair of the Department of Pulmonary Medicine at Cleveland Clinic. Welcome to another episode of Respiratory Exchange, the podcast for people interested in respiratory diseases. In this podcast we focus on pulmonary disease, critical care medicine, infectious disease, allergy and immunology. And we cover a broad range of issues from clinical to therapeutic to leadership to professional development. With me today I have Drs. Rachel Scheraga and Brian Southern. Dr. Scheraga is primarily appointed in the Department of Critical Care Medicine, and Dr. Southern is primarily appointed in the Department of Pulmonary Medicine. Today we're going to talk about the American Thoracic Society meeting that just finished up last week. Rachel, welcome.

Rachel Scheraga, MD:

Thank you, Dan. I'm happy to be here.

Daniel Culver, DO:

Brian, welcome.

Brian Southern, MD:

Thanks, Dan. Thanks for asking me to be here.

Daniel Culver, DO:

So, the American Thoracic Society meeting was in Washington DC. It really felt like the first time for me that we were back in a normal meeting. And it was great to see everybody, and I noticed a lot of connections, and of course the attendance was great. I wonder a little bit about whether you had the same experience. What was your overall impression of the conference?

Rachel Scheraga, MD:

Yeah, I agree with you, Dan. I thought that there was overall better attendance. There were more folks that were excited about coming back post-pandemic. And I also noticed that there were more international folks that came to the meeting. And that was really great because that brought a lot of research from international space that we haven't seen over the last couple years. People were more willing to discuss science and go out after the conference and just interact with each other like it used to be before COVID.

Daniel Culver, DO:

Very refreshing. Same thing for you, Brian?

Brian Southern, MD:

Yeah, I totally agree with that. I was just blown away by the enthusiasm people seemed to have about being at the conference and networking. Clearly, the attendance was way back up like it was before, pre-COVID. And then everybody was interested, like Rachel said, in networking and talking about collaborations. And there were a whole number of events that we didn't have last year during the COVID pandemic. Such as the assembly meetings and get togethers that we usually have. And so, it was nice to see everybody and see everybody so enthusiastic about their field of interest and their work.

Daniel Culver, DO:

Almost like there was pent-up demand.

Brian Southern, MD:

Yup.

Daniel Culver, DO:

So, if you look back on this for a decade, what was the one thing that you think will stick with you? A theme, or a thought, or an idea, or a moment, something you heard?

Brian Southern, MD:

Well, one of the big things that stuck with me was that I went to several sessions, and my area of interest is interstitial lung disease, and specifically IPF. And there were several trials reported at this conference with positive results with therapeutics in IPF. And, we just haven't seen that in years past. You know, year after year, I'm used to going to conferences and hearing about negative trials in IPF and so there were several, not just symposium but poster presentations, and poster discussions that showed very promising results for patients with IPF. And so, I was very, very excited about that.

Daniel Culver, DO:

Were you surprised to see all of those at the same conference, and especially since many of those had to be conducted during the COVID era?

Brian Southern, MD:

Yeah, and there were some that were stopped prematurely, and their data was negative. Or their data was inconclusive because they had to stop and because of the COVID pandemic. But you know, there were a couple that were published just this last year as we were coming out of the COVID pandemic where they were able to get adequate numbers of patients. And they did show very promising and robust results.

Daniel Culver, DO:

Yeah. Very, very optimistic and positive. What about you, Rachel? Anything that's going to stick with you as a lasting memory from this one?

Rachel Scheraga, MD:

Yeah, I want to piggyback on what Brian said, because I felt like the rigor of, I'm more interested in basic science, and I thought, looking at drug targets was a lot more of the theme for the basic research topics, and using more rigorous scientific methods. And really talking about animal models of both lung injury and sepsis and how we use individual models to test drug targets. I thought that was much more rigorous than in prior years. And maybe that lends to Brian's comment on more clinical trials and more targets for our patients.

Daniel Culver, DO:

That's really good to hear. Was there something within your particular field, within your area of expertise, and maybe tell us, just maybe for a minute or two what that is that really stuck with you? Some really big advance or salient thing that you heard?

Rachel Scheraga, MD:

Yeah. Thanks, Dan. So, I'm interested in mechanical signals that the lung sends to other cells, and how the cells interact with the lung to fight injury and repair. And so, there were a lot of talks in this space, not so much the matrix, but in mechanisms of lung injury. And a lot of talks using sort of exploratory, you know, single-cell omics on patient samples. So going from the patient, getting samples, and then testing it out in mouse models. And so, I found that extremely interesting and I think they were able to obtain more patient-related data over the last, probably, the last year than they have in the past because of COVID. And also, we're able to get lung samples now that COVID is sort of relaxing. So that was good as we went into trying to treat these terrible diseases.

Daniel Culver, DO:

So, you mentioned that word that's on people's tongues all the time, omics and what that all means. So maybe I can ask you a little bit, either of you, what is new and phenotyping, and do you think omics really is arriving at a place where we can integrate different omic platforms with enough systems biology to really get some novel insights on pathophysiology, or even to translate a little but into clinical use. Did you see something new in terms of omics here at the conference that's noteworthy?

Rachel Scheraga, MD:

Yeah. So, I think I'll take that from the critical care perspective. So, there's definitely increasing evidence that our patients that come with common syndromes such as ARDS and sepsis have certain phenotypes. Meaning, they respond to treatments differently. That is really where we're at in the field. But now overlaying the phenotypes with actual mechanisms of diseases is probably the next step. In order to do so, omics seems to be a reasonable platform to do this. Now, it's going to be, Next step is difficult, is integrating the data you get on omics and making it more of a causal relationship than just associative. I think that is the next difficult step. I didn't necessarily see that that's been done yet, but I think we all think that that would really help our patients the most.

Daniel Culver, DO:

Yeah, that seems like the bridge that's very difficult to cross from observational into something that really demonstrates a mechanistic understanding. And you sometimes see people doing a lot of omics works and then moving onto the next omic work without really modeling how to understand the results that they see. So, I hope that we see in the field that we're starting to make those connections better.

Rachel Scheraga, MD:

Yeah. I think that we should do the omics and find special cellular clusters, and then do functional studies on those cells to then know how they're functionally affecting the patient at hand, would maybe be the only way to connect the two.

Brian Southern, MD:

One of the most exciting omics talks I saw, and there were several of them, is this newer technique, spatial transcriptomics. Where you can look at actually different parts of the lung and see that genes are unregulated and down-regulated spatially within the lung rather than taking cells out of the lung and then looking at them in a test tube. And some of the studies were able to show that there are very specific ranges that occur in areas such as the upper airways in IPF. And we've never known things like that before. We just look at the areas where there's an obvious change. And I think techniques like spatial transcriptomics are going to be able to help us to understand more about the overall pathogenesis of these types of any kind of lung disease. And so those are really exciting for me.

Daniel Culver, DO:

So, people may not be so familiar with spatial transcriptomics. They probably know transcriptomics, and they may have heard of single cell seq, for example, but can you tell them a little bit more about how those techniques work?

Brian Southern, MD:

Well, from my rudimentary understanding of how it works, they basically are able to barcode and label the cells within a specific anatomic region on a slice of lung tissue, and then they do the normal procedures too, to get to the transcription levels. And that gives you areas where certain genes are up-regulated and down-regulated. Rather than regular transcriptomics is when you kind of take all the cells, you digest them, and then you put them into a sorter that sorts them one by one and looks at the up gene, up-regulation and down-regulation of each individual cell.

Daniel Culver, DO:

So, this gets us closer to the importance of cell-cell interactions, and it probably doesn't quite get us to the point of understanding those on the same level as a model would, for example?

Brian Southern, MD:

That's correct, yeah.

Daniel Culver, DO:

And you mentioned a little bit about how we use these things to identify targets. And how they're being leveraged in ILD and IPF, specifically. And that makes me think a little bit about some of the work that's happened for molecular characterization of ILDs and some of the drive for that has been to identify better endpoints for clinical trials. So, was that something where you saw the needle moving at all at the conference?

Brian Southern, MD:

I did see a lot of talks trying to use different clinical endpoints. I don't know that any of them really jumped out or stood out as ones that are going to be, you know, the sole endpoints used in upcoming clinical trials, but for instance, Jeff Swigris gave a great talk on patient-reported outcomes and using those as endpoints, and we're doing a lot more of that, including those in clinical trials. There were talks on using supplemental oxygen needs. There was one talk by the group from Chicago on using home spirometry, and I think that's an up-and-coming thing that you'll see in clinical trials. And there was a lot of talk about data from wearables, like Apple Watches and Fitbits and being able to incorporate that into clinical trials and use some of the data from that. Because the patient's wearing it 24 hours a day and giving you a good objective quantitative measurement of some readout. And so, I think a lot of these things are going to start making their way into clinical trials.

One of the most exciting things that I saw in ILD was that, and there were several sessions on this, was that there was a question: can three-month FVC be used as clinical endpoints in our trials? And, you know, IPF clinical trials have suffered for a long time because we need long trials, a large number of patients, and they take forever to get through these trials and get through all the way to Phase 3 and then FDA clearance. And that's why we only have two approved treatments.

But there especially was one, a trial by Boehringer Ingelheim this past year where they looked at a phosphodiesterase-4B inhibitor in IPF. And the trial was done over a period of 12 weeks. And their primary endpoint was FVC decline at 12 weeks. And we've typically looked at FVC decline at 52 weeks. And they were able to show that there was a significant difference just over that 12-week period. And what was exciting about it was that the patients that received the drug, the phosphodiesterase-4 inhibitor, actually had an improvement in their FVC over the 12 weeks. And we just don't typically see that in IPF clinical trials.

And then, for instance, another trial by Dr. Steve Nathan, the INCREASE trial where they looked at inhaled Treprostinil in patients with IPF or ILD and pulmonary hypertension. That was a 16-week trial and we presented at ATS some of the open-label extension data, which was really exciting. It showed that people that were not on the drug had a decline during the trial. And then when they went to the open label extension after a two-week washout and they gave the patients the drug, inhaled Treprostinil, their FVC actually improved by as much as 133 milliliters over the course of a year.

And then there was a pro/con debate as well that featured, you know, pro, is three months a good time point for clinical trials in IPF? And, you know, they made a convincing argument. If you look at all of the past clinical trials, such as INPULSIS and ASCEND, and all of the ones that we've done in the recent past, there's a clear separation of the curves at three months that goes out to 52 weeks. And so, this is exciting because this means that we can shorten our clinical trials, and really have an impactful endpoint within three months. And that would translate more rapidly to bringing drugs to the patients. That was really exciting for me.

Daniel Culver, DO:

Yeah, clinical trials, shorter and with more accurate endpoints, I think is a real theme that we heard in a variety of diseases during the conference. A lot of disease states also, including interstitial lung disease, are really looking at quantitative imaging. And of course, that requires a lot of sophisticated, computational techniques. And it brings up the question of whether or not we're starting to see an impact either on a scientific side or on a clinical side from machine learning or even impacts from the use of AI. And I thought that was one of the themes that I heard at the conference. Did either of you hear the same thing?

Rachel Scheraga, MD:

I didn't really attend that many of the talks that specifically talked about AI or machine learning. I'm wondering if Brian heard some.

Brian Southern, MD:

I didn't attend them either, but I agree that that was definitely a theme. You know, looking over the program there were a number of sessions on machine learning and AI. And I think this is the next big thing in medicine is AI machine learning.

Daniel Culver, DO:

We can only hope that some of the abstracts weren't created by ChatGPT, right?

Brian Southern, MD:

That's right.

Rachel Scheraga, MD:

I do think we have to be a little bit careful about the place for machine learning and AI in some grant reviews that I've been doing. So, we have to use it in the right place, I think. Just using those words to say that we're going to be able to move medicine forward, I think they have unique areas that they could help us with.

Brian Southern, MD:

And limitations.

Rachel Scheraga, MD:

And limitations.

Daniel Culver, DO:

Yeah, it sounds like you're a little bit skeptical, Rachel. Tell me more.

Rachel Scheraga, MD:

No, I think, you know, any new technology, new topics, it's always wanting to fit your current data to use the new technology. But the new technology isn't always going to help facilitate what you're trying, the question you're trying to ask. So, I think it's important to know what machine learning and AI can do for you, and then see if that will help answer your question or not before you try to plug a round peg in a square hole.

Daniel Culver, DO:

Study sections like the newest technology, don't they?

Rachel Scheraga, MD:

They do, but if there's experts on the panel that do these technologies, and they can more readily know if it fits or not. So, I think that is something to know as well.

Daniel Culver, DO:

Sure. Well, I think there will be more to come on that. We're just entering that era for sure. Another thing that seems to be pretty common on the program at the conference is the issue of COVID. And we're moving now out of COVID, at least in the early days of it. Now we're learning to live with COVID, but we're also starting to really focus on Long COVID or sequality of COVID. And there are in fact several funding mechanisms that are available now or that are already in the works. Do you have a highlight or some of the work that you saw at ATS on sequality of COVID and whether or not there are new ways of understanding it or new technologies we can use to understand it better?

Rachel Scheraga, MD:

Yeah, Dan, I can take that one. So, I had the pleasure to moderate a poster discussion on Long COVID. And so there were three themes that really came out of that session, one of which was a new physiologic measurement of patients, like pulmonary function tests over time. And they also looked at new radiographic methods such as Xenon MRI, and how that can show early signs or lung dysfunction from Long COVID. And the final theme was more mechanisms.

But the general take home, I think that came out of that session was that these patients have lots of symptoms post-COVID. And lung function and Xenon MRI actually start to normalize; however, these patients still have symptoms. So, the thought is that there's maybe extra pulmonary manifestations of COVID that last longer, even though COVID initially affected the respiratory systems. So, I thought that was an interesting take home from that. But in terms of specific therapies, we're not really, it's just sort of supportive care at this point, and sort of understanding how long COVID really is.

Daniel Culver, DO:

Yeah, that's a tough question and I don't think that we understand that in the end how long this is going to go on. Do you have a sense that we're going to find more similarities with the sequality of COVID and other autoimmune diseases, so-called chemo brain, cognitive difficulties that happen in autoimmune diseases like multiple sclerosis and rheumatoid arthritis? Or do you think that somehow these are all going to end up being part of the same thing?

Rachel Scheraga, MD:

Well, I think a lot of the things we're seeing with Long COVID we've seen with other viral illnesses. It just seems to be more exaggerated, and now more studied, and there's more interest. So, I think that there is a possible autoimmune component that wasn't really the theme of this talk. Or nobody was really looking at autoantibodies in these talks that I went to. But I think a lot of these diseases have, you know, syndromic symptoms post, and so I think we'll just have to wait to see if any of them can resolve, or there's any other therapies for these patients.

Daniel Culver, DO:

More to come on that, I think.

Rachel Scheraga, MD:

Yeah, agreed.

Daniel Culver, DO:

One other big area that I thought received a good bit of well-merited attention at the conference, and it impacts all of our areas, is really the effect of the environment and climate change on the risk of lung diseases, and on the behavior of lung diseases once it's established. Did you hear anything interesting or new that changed how you think about it? And I wonder, where does the field go from here? We know it's a problem, but what does that mean?

Rachel Scheraga, MD:

Well, the interesting thing that I saw, Dan, was that I saw that air pollution was linked with tuberculosis risk. And my interest in lung infections I thought that that was pretty interesting. There was a whole session just based on that. So, I thought that the environment, I mean, we've all known that the environment affects lung function. But for it to affect, or have, be more susceptible to specific infections, I thought was really interesting. Because we don't know how some folks get certain lung infections and others don't. So, if it's an environmental or area-specific effect, that might help a lot of us with, we're in, with bacteria. We know with some, with some specific organisms, but not, but TB is not one that I usually think of to be area specific.

Brian Southern, MD:

Yeah, and I didn't attend any specific of these talks, but I saw there were a number of talks across disease states on how climate change is affecting asthma, COPD, pulmonary fibrosis, any number of lung diseases you can think of. Climate change is definitely affecting this. Pollution, particulate matter, like Rachel mentioned, is known to be linked to fibrosis and other lung disorders. And so, I think that that was another big theme of these ATS was how climate change is impacting the lung, and I think we're going to see a lot of that in the next few years.

Daniel Culver, DO:

Yeah. I hope we do. And I feel like, as lung doctors, we need to advocate for the importance of substantial policy changes and regulatory changes that improve the health of our patients and people who don't even have lung disease, for both our generation and for future generations. That's very important.

Brian Southern, MD:

Agree.

Daniel Culver, DO:

So, the Cleveland Clinic group had a lot of great presentations at the conference. Some plenary talks, a number of excellent scientific presentations. If you had to pick out just one, what work, that you saw from the Cleveland Clinic group got you the most excited? I'll start with you, Brian.

Brian Southern, MD:

Well, I'll start with the person here in the room with me, Rachel Scheraga, MD's group showed some really exciting data regarding a calcium channel called TRPV4 and macrophages, and how its activity affects fibroblast and fibrosis. And they did this really cool experiment where they took media from macrophages that were growing in culture, with and without this TRPVS channel, and then they transferred them to fibroblasts that were growing in culture. And showed the activated TGF-Beta which is a growth factor that's known to be involved in fibrosis, activated the fibroblasts, and made then profibrotic. And this kind of built on the work that Dr. Mitch Ulman's group is showing in this lab, and the importance of the TRPV4 channel and fibroblasts as well, and I think that this is really exciting work that is leading the way for potential new therapeutics that target this channel and other similar channels like this in lung fibrosis.

Related to that, one of our 232 fellas, Dr. Eric Orsini, presented some exciting work looking at another one of these mechanosensitive channels called Piezo1, also in macrophages, and showed that it was important in cleanups of bacteria in pneumonia when the lung becomes stiffer. So as the lung becomes stiffer in either pneumonia or in fibrosis, the macrophages are able to sense those changes in stiffness through these different channels, and that's how the signaling pathways occur. And, if we can start to find ways to target that interaction, then I think this will provide some really cool ways to treat everything from acute lung injury to pneumonia, to pulmonary fibrosis. So, I was really excited to see that.

Daniel Culver, DO:

And these are druggable targets as I understand? You alluded to that, right?

Brian Southern, MD:

Yeah. Like, in fact, TRPV4, the calcium channel already has there’s clinical trials that are ongoing in heart failure. So, there are drugs that are being made looking at this and other areas and can easily be repurposed for some of these lung diseases.

Daniel Culver, DO:

How about you, Rachel? What particular thing that you saw stood out other than the work that he just described?

Rachel Scheraga, MD:

Thanks, Dan. So, I think I was really enamored by Peter Mazzone's work on looking at novel biomarkers in lung cancer. Because, you know, with increasing data on specific genetic pathways on biopsy, but you have to get tissue, but if there’s a blood test that you can then know or measure or know what cancer you have in the lung without any invasive sampling, I think would really move the field forward. So, I thought that that was very exciting work that came out of Cleveland Clinic.

Daniel Culver, DO:

So that’s not good news for bronchoscopists, I guess, right?

Rachel Scheraga, MD:

They can work in tandem. I think if you can have early detection and then do the sampling, especially of their smaller lesions that you cannot get to, if you have bronchoscopy, this could be a way to either know to just do screening, or to go ahead and get tissue.

Brian Southern, MD:

Dan, I'd be remiss if I didn't mention Dr. Gustavo Heresi's talk. He gave a very high-profile talk in the Clinical Year in Review on pulmonary hypertension. And he did a fabulous job on a number of topics. It's one of the best talks I've heard not just at ATS, but anywhere. His presentation was incredible. He talked about the updated pulmonary hypertension guidelines, and how it expands the risk assessment scheme to intermediate low and intermediate high. And now we're treating intermediate-high patients as being similar to high-risk patients, so it's changing the way that you're escalating drug therapy or referring for transplantation.

He talked about the pulmonary vascular disease phenomics study, or PVDOMICS study, which is a huge study that the Cleveland Clinic is a site for, looking at all kinds of omics in patients with pulmonary hypertension. And he just presented some baseline characteristics of those patients and presented some very interesting data there. And then the last thing he presented was a Phase 3 trial called STELLAR that looked at Sotatercept, which is a fusion protein that traps activins. And these are proteins that result in proliferation of pulmonary vascular cells. And they found that the patients that we have taking the Sotatercept, even on background therapy, had a median change in six-minute walk distance that was 34.4 meters, whereas it was only 1 meter in the placebo group.

And so, this is a brand-new class of molecule, brand new target in pulmonary hypertension that didn't exist before. And a very positive study that looks like this is going to be a promising drug for the treatment of pulmonary hypertension. So, I was very impressed with Dr. Gustavo Heresi's presentation.

Daniel Culver, DO:

Yeah, I think that was a big talk and a great honor for him, and he knocked it out of the park. And I think Sotatercept is something that everybody in that field is quite excited about. And, in that vein, I'd also like to recognize that one of our own, our Chief Academic Officer, Dr. Serpil Erzurum received a big award from the circulation assembly, the Grover Award, for her lifetime achievements as a scientist working in that area. And in the same conference, our Institute Chair, Dr. Raed Dweik, was installed as the Secretary of the American Thoracic Society. So overall, a pretty big meeting for our Cleveland Clinic crew.

Brian Southern, MD:

Very exciting.

Rachel Scheraga, MD:

Yes, I'm very excited.

Daniel Culver, DO:

Just to wrap up, if you had any take-home theme, from the conference that you wanted to leave the audience with in eight words or less, what would it be? Rachel, I'll start with you.

Rachel Scheraga, MD:

So, this is a very exciting conference and with novel therapies, and a review of the current literature, and I think all should attend next year, in 2024.

Brian Southern, MD:

I would say, ATS is back, baby! And things are looking great! The future is bright.

Daniel Culver, DO:

Well, how can we end any better than that? I want to thank you all for tuning into another episode of Respiratory Exchange. On behalf of Dr. Brian Southern and Dr. Rachel Scheraga, I'm Dan Culver from the Pulmonary Department at the Respiratory Institute at Cleveland Clinic. Thank you.

Raed Dweik, MD:

Thank you for listening to this episode of Respiratory Exchange Podcast. For more stories and information from the Cleveland Clinic Respiratory Institute, you can follow me on Twitter at Raed Dweik, MD.