Good afternoon. I think we're good to get started. Hi. I'm Debbie Levine. I'm from Stanford Lung Transplant, and my co-chair here, Eric Elise, is from University of Washington, and we'd like to welcome you to the very last session of CHEST Hawaii 2023. So good job, guys, being here. So when we have a booth, yeah, we need the wine, and we probably need the cheese. But anyways, thank you for coming to the last session. I think we're so lucky to have it. Sameep put this project together, and he wasn't able to come because he's having a new baby. So we are doing this all in his honor. So I'd like to first introduce you to my co-chair, Dr. Eric Elise, who's going to give us an update on donor lung allocation in the U.S. And Dr. Elise is very qualified to do this, as being the chair of the Thoracic Council, who really developed the newer lung allocation system in the last few years. So a round of applause. Thank you. Thanks. Thank you. All right. Well, thank you. I will try to keep this interesting for folks, since it is the very last session. As mentioned, my name is Eric Elise. I'm a transplant pulmonologist at the University of Washington in Seattle, and I'm currently the past chair of the OPTN Lung Transplantation Committee that worked on this new allocation system. I do not have any disclosures. So since I know there's kind of a mix of transplant and non-transplant people in here, so I wanted to do just a very brief historical donor lung allocation review. I think it can be helpful sometimes to talk about where we've been to better understand where we are currently. And then I'll talk about the components of the new allocation, the lung composite allocation score, and talk a little bit about some of the early post-implementation data and some of the subsequent things that have happened with that. So the very first donor lung allocation policy was actually adopted in 1990, and at that time allocation was completely based off of time spent on the waiting list. And as you can imagine, this was not adequate for people with different types of lung diseases, and specifically those with more progressive or more rapidly progressive lung diseases. And so the only change that was made during that period was to provide those with IPF 90 days of additional waiting time when they were listed. But as you can imagine, what ended up happening was that people would, that programs would list patients much earlier than when they actually needed a transplant, with the idea being that because they had to wait so long that hopefully by the time they would, you know, need a transplant that they would actually be near the top of the transplant list. And so just really not an adequate system overall. So after a couple of years of development, the lung allocation score, LAS, was implemented in May of 2005. And this comprised two main components, a wait list mortality component, so how likely was somebody to, or how urgent were they, how likely were they to die in the next year without a transplant? And then also a post-transplant survival component, how likely were they to live for a year post-transplant? So the idea being wanting to focus primarily on people who were medically urgent, but also wanting to avoid futile transplants if at all possible. And so this is what remained in place, with actually very few changes, until more recently that the lung composite allocation score system was implemented on March 9th of this year. So part of the reason that the new allocation system came into play was because of the huge component that geography played in the previous allocation system. So a number of, initially, the first unit of allocation was based off of geography and it was based off of these donor service areas. And these donor service areas were developed historically because before, in the very early days of transplant, the organizations before they became the organ procurement organizations had developed all of these relationships with local hospitals. And so then when this system was formalized into the organ procurement organizations, they took with them those relationships that they had developed and it ended up being relatively arbitrary, as you can see. So I'm in the Seattle area and you can see that my local organ procurement organization has most of Washington, but there's a couple of southern counties that are not included in our OPO. And then you can look at other places like Texas, which are quite arbitrary, and you have counties that are next to each other that are included into different organ procurement organizations. And so when a donor would become available, all programs within an organ donor service area would be offered the organ first and then it would have to be declined by that entire donor service area before it then could be opened up to the next donor service area. And so you can imagine, you know, this one little yellow spot in Texas, the surrounding counties would not have access to an organ in that county until it had been turned down by everybody else in all of the other yellow counties. And so it really, really didn't, wasn't fair. And so what that led to was a lawsuit that argued that geography played too much of a role, that allocation was really based off of geography, which was true. And so the OPTN board of directors convened an ad hoc geography committee to establish a framework by which geography was not the primary decider for organ allocation, but could somehow still be incorporated. And what they came up with was this idea that organ distribution without geographic border boundaries, but it would be as broad as possible in any geographic considerations would have to be rationally determined. So have some sort of medical reasoning and consistently applied. And so the idea being is, is that, you know, the farther someone is away, that there would still be potentially points given for geography, but that there could be other things these deliver examples, but could be reasonings behind why an organ might be, might travel further than had previously been done. And so ultimately the lung group was the first group to go forward with this allocation system called continuous distribution. The other organs are in the process of transitioning to this currently actually. And so this is what the current lung composite allocation score is and the components that are included into it. And again, this is what went into effect on March 9th of this year. So I'll walk through the components. The two different components of the lung allocation score, the LAS, that weightless mortality in the post-transplant survival were maintained, but they were separated into their two individual components instead of being one big equation. And in addition, the post-transplant survival was extended from a one-year post-transplant survival to a five-year post-transplant survival. The idea being is that the community had been arguing for a long time that, you know, we should be focusing on longer-term survival if we actually ever want to improve our long-term survival. A lot of people will argue that we aren't very good at predicting post-transplant survival, which is fair, but we are just as good or bad, however you want to think about it, at predicting one-year survival as we are at predicting five-year survival. And so for that reason, the community moved ahead with the five-year post-transplant survival. So those are those two components, and they are now weighted equally, as previously the weightless mortality was weighted twice that of the post-transplant survival. There's also a category called candidate biology, and so this incorporates a few things that had previously been included and some things that were not. So blood type previously used to be categorical. So when an O organ became available, it would be offered to all O candidates before it then could potentially be considered by a non-O candidate. Understanding, though, that there may be somebody with a blood type of, say, blood type B, who's very medically urgent, doesn't have a lot of time, and needs more opportunities for donor organs. And so instead of being categorical, points are allotted based off of what the proportional number of donors somebody might have access to. CPRA, or sensitization, was not something that was previously incorporated into the lung allocation. It's something that's very heavily incorporated into kidney allocation, but not lung. And so it's something that definitely wanted to be included here. And so the more sensitized somebody is, the more points they may get to add to their composite allocation score. And then similarly, height is something that had been noted to be a disadvantage. Shorter stature was a disadvantage in the lung allocation system. For whatever reason that we don't completely understand, donors tend to be taller than candidates. And so those curves are offset from each other. And then especially if you look at somebody who's of shorter stature and has a restrictive lung disease, so therefore needs lungs that are from a donor who are even shorter than they are, those candidates were even particularly disadvantaged. So we wanted to be able to incorporate that into the new allocation system. With a differing rating scale based off of whether or not somebody has a restrictive lung disease, therefore needs smaller lungs versus somebody who has an obstructive disease and can get away with slightly larger lungs. And then lastly, patient access includes primarily pediatric status. So this was something that was a different system under the lung allocation score system. And we knew that we wanted to incorporate it all into one system. So that not only are all candidates under the same system, but all donors are in the same system. So there was this whole complex way that donors who were 0 to 11 were allocated versus donors who were 12 to 17, who they were allocated to first. And then also understanding that while the 12 to 17 year old candidates had a lung allocation score, they only had prioritization for donors who were 12 to 17. So a donor who was 18, they fell into the same adult pool as everybody else and didn't have any additional access. And so wanted to, again, incorporate them into the entire system, but understanding that wanting to give them priority overall. So all of those components that I just listed out are the lung composite allocation subscore. So that's what we see when we list somebody onto the waiting list. And I'll say that while a lot of the points allotted for some of these attributes are based off of data, how we weighted all of them is not something that you can use data for. It's really a values decision, if you will. And there was an exercise before we started this process asking the community, which included transplant professionals and patients, donor families, anybody who was invited to participate, asking what are the priorities? Who do we want to focus giving these organs to if we have options? And I would say that the breakdown is actually pretty similar to what we heard from the community, where there being an equal weighting of weightless mortality in post-transplant survival, a very high priority for pediatric candidates, and then similarly with the candidate biology. So that's how people are listed. And then when a donor actually becomes available, depending on the distance between the transplant hospital and the donor hospital, that's where points are then given based off of geography and the distance. And there's two parts of it, but it's under this idea of placement efficiency. So understanding that distance matters. We don't want really long ischemic times if we can avoid it, although there might be times when a long ischemic time is okay, say, again, for somebody who's very medically urgent or very difficult to match, say, high sensitization or something along those lines. And so those points are allotted then once a donor is actually available. And then that is how the rankings on the actual match run occur. This is points based off of geography. And while I've picked certain numbers, it is a continuous rating scale. But this just gives you a sense of how many points are allotted at different distances overall. So you can see that really after about 1,000 nautical miles, the number of points that a candidate gets based off of distance really falls off. So most organs are staying still within 1,000 nautical miles, certainly, and a lot of them still staying relatively locally except for the circumstances where there might be points given for medical urgency or some other factor. And this is just a visual representation of how this all comes together. So you can see how all the points add up for the different attributes and then how those candidates are therefore ranked on the match run overall. And I think that what highlights this partly to me also is that each of these are separate categories. And so as opposed to, again, the lung allocation score, which was one big equation, these can be individualized and changed as separate categories if needed. So what did we hear about the first three months? And so, again, this went into effect on March 9th. And so the first three months were on June 9th, and then it took a little bit of time to get the data cleaned up and reviewed. But what we found was is that, again, it's early, so there's small numbers, and you have to take that into consideration. But there was some promising evidence of increased numbers of lung transplants in general. But most importantly, I think, and excitingly, was that there were much fewer deaths or waiting list removals because of somebody being too sick. And this was a strong enough signal that I think it's actually going to be real. And we'll obviously see as we continue to go forward. But you can see that in the three months prior to implementation, there were 52 either deaths or removals for being too sick. And in the three months after, there were only 30. So pretty significant. And again, I think pretty exciting and a main part of what we were trying to look at. And then, importantly, of course, utilization of the organs remained the same. So we weren't seeing an increase in the non-use of organs or anything along those lines. But one of the things that we saw was that blood type O recipients decreased from 308 to 276 in that three-month period. And, you know, it's, again, early data. It's hard to know. It's not actually real. But the thing that was important was that modeling that we did prior to implementation showed that O candidates would actually do better under the new system. So that was quite different and was a little bit of a flag to say, hey, what's going on with that? Other things that we noticed, there was initially an increase in the number of exception requests. So programs asking for additional points for their candidates. That has since slowed down and is actually back to what we saw previously with LAS. And then there was an increase in median distance traveled, which is, again, not surprising given that the intention of this was overall broader sharing. But to get back to the blood type, so you can see here, again, that there was that decrease in the number of transplants happening for O candidates in that three-month period with a significant increase in the number of transplants happening for A candidates. And when we look at that difference, while I don't have it here, a lot of that difference for the A candidates was made up of O donors. And so O donors were being pulled to the A blood type candidates. And so, again, wanting to dig into that further and try to understand that. This was the original rating scale, and it was based off of the proportion of donors to whom a particular blood type candidate had access to. So about half-ish of the population is blood type O. So blood type O candidates have access to about half of the donors. Blood type B is not a common blood type, but they can access both blood type B as well as blood type O, or they can take blood type B or blood type O donors. And so they have access to about 65% of the population, and therefore, and moving down. Blood type AB obviously can take any organ, any blood type. And so they, in the initial rating scale, received zero points. But what you can see is that the points were overall still pretty low. And while the new rating scale, the composite allocation sub-score goes out to four decimal points, this was a pretty small number of points. And I think what we were seeing was that there was not quite an adequate number of points being given for blood type, which is what was siphoning off the O donors to candidates with other blood types. And so the committee looked at this and looked at a number of different solutions, trying to figure out how to best find this balance, where again, not wanting to have that categorical blood type where O donors can only go to O candidates, and all of those have to be declined before it could potentially be offered to a candidate with another blood type. But also wanting to make sure that O donors weren't going unnecessarily, if you will, to candidates with other blood types. And so what the committee ultimately decided was to take the same rating scale, but to move it up, and to take the O all the way up to five points, and then each of the blood types down from there. And so you can see that blood type O gets all five points, blood type B gets 2.2 points, and then A, because they can access a large proportion of the donor pool, gets very few points, and AB still gets zero. So this just went into effect on March 27th, or sorry, September 27th, and so is the newest change, if you will, since the original implementation on March 9th. So this is what we, this is available on the UNOS website, and it gives you a sense of the median distribution for the points of not only all candidates, but we thought it was also helpful to programs to look and see what the distribution is for the different blood types. Because again, five points is a lot in this system, but I think it's helpful for programs to kind of get a sense of where does my candidate fall, particularly where does my candidate with a particular blood type fall in the range, and it kind of gives you a sense of, again, kind of what is the prioritization of your individual candidate as it compares to the all patients listed nationally. So the next monitoring report is the six-month monitoring report. That will be, well, it has been six months on March, or on September 9th. The data is currently being cleaned up and evaluated, and hopefully the report will be out shortly. It will be reviewed by the Lung Committee before it will then become available publicly, but it will be available on the OPTN website, and so folks are certainly encouraged to look at that. Because it ended at March 9th, it won't include the new blood type change. Again, that went into effect on September 27th, but the blood type change will be reviewed at about three months, which will then correspond to about a nine-month post-CAS implementation, and then there will be a one-year implementation review as well, and then the plan is for annually thereafter. But I think similar to what, you know, what happened with the three-month report, if there are anything that, any signals that appear concerning in any sort of way, hopefully the committee will be able to respond pretty quickly and make any changes as needed. So the new allocation system of continuous distribution is really part of this larger effort to align all organs into what we feel is a smarter and more flexible allocation system. As I mentioned, the other organs are currently in the process of coming up with their change to continuous distribution, which will be implemented over the next number of years. And I think importantly with this was that it was really about aligning organ allocation with community, ethical, and regulatory goals, which, you know, we want to make sure that those correspond as best as possible, but sometimes can, you know, sometimes there can be differences amongst those. And then I think most excitingly, the early monitoring suggests that this lower weightless mortality, which was a huge goal of the program, of the new allocation system, is really exciting and hopefully something that we'll continue to see going forward. So with that, I'll turn it to you. Great talk, Dr. Leis. That change has been one of the most, you know, influential changes that has occurred in transplant. And some of this factors into that as well in terms of geography and in donor utilization and stuff. So I think this will be relevant to that talk. It segues nice. This is a little bit of a potpourri session, so just exposing you to the brightest and the biggest changes in the last probably three years or so in lung transplantation. So I think it's a great session for this. So I'm talking about donor management with a focus on ex vivo lung perfusion, because that's really been where a lot of cutting-edge donor management has occurred. My disclosures are shown here. Everyone knows here in this room that over 7 million people die every year worldwide from advanced lung disease. And obviously, a very large subgroup of these patients have irreversible lung disease that can only be cured with lung transplantation. Lung transplantation is an excellent option for many patients. Many patients live a completely normal life afterwards. They certainly have constant surveillance and medical conditions that have to be looked out for. But when you go from not being able to breathe one day and potentially being dead in a year to suddenly having many more years left with your family, it's an incredible opportunity to deliver this therapy to patients. The challenge, of course, in transplant, among other challenges, one of them is that you need to find the right donor. We're still not in a position to just get donor lungs off the shelf, although there are people actually working on that. So with donor lung retrieval, the rates have been increasing a lot in the U.S., and that's a big token to our OPOs and a very active promotion of being an organ donor. So I bet you probably everyone in this room is. So I think in the U.S., we're very privileged to have that. Yet despite that, we still have a consistent, pretty large, relatively speaking, large number of patients who are dying on the wait list. As Dr. Leis mentioned, thankfully, these new allocation systems are helping to address that to help it come down from this 30 percent down to as low as 15 percent. But still, the people who have the highest acuity, especially the higher scores, are at a tremendous threat and risk of dying on the wait list. And they may get access to a donor pretty quickly. They may get offers, a lot of offers, but it's also about making sure it's the right offer. Sometimes the sickest patients on the list are the least likely to handle an extended criteria organ or something that is not perfect for them. So it's something that we have to consider in ensuring that they have a good outcome. Their fundamentals of donor management, just to touch on, are basically diuresis, drying the lungs out, recruiting the alveoli to make sure we have good ventilation, perfusion, matching. Prone positioning has been very commonly employed in donor hospitals to help achieve this. The SALT protocol, which Dr. Levine designed from her days in San Antonio, that has been probably the biggest change and the only thing that everyone uses for the past decade. Suctioning, keeping the airways clear of any pneumonias or pockets of secretions. And then during in-between intervals of recruiting the lung, probably just resting the lung with conservative ARDS-type protocols, six cc's per kilo. Those are kind of the fundamentals of donor lung management. In terms of selection, we have what we consider our ideal donor here, and probably everybody recognizes this as the younger donor, with good gases, with clear x-ray, you know, absence of chest trauma, very minimal smoking history. It's what we would ideally like to get. But unfortunately, 80% of donor lungs are still being wasted. And donor utilization rates still haven't been dramatically impacted either, even by changes in allocation yet, although probably they will. And we're really only accessing about 20% of all donor offers. So there's been a lot of evolution, even without, like, you know, fancy technology, just trying to stretch the envelope with our standard procurement methods, looking at, hey, is it safe to transplant older age donors? More or less it is. How about clear x-rays versus not clear, and et cetera, et cetera, going down this list. And we've been gradually pushing the envelope in all of these elements. So we still would certainly prefer a standard donor if we have access to it. But there's a lot of evidence, even just with standard ice preservation, standard preservation methods, that you can go fairly longer distances than we thought before. I will say, though, that this is still a very minority of transplants, or people going beyond six or eight hours to get an organ and bring them on ice. That's a pretty selected group of centers or patients that are having that done. Older age donors above the age of 55, we've been stretching that even to 65, even to 70, showing that it's safe. Again, whenever we read these series, we have to realize that it's extremely selected, and it certainly reflects less than 10%, if not even less than that, in terms of donor practices. So we can't just say that we should all be using 75-year-old donors. But there's definitely evidence suggesting that it is doable. And then DCD, there's a huge interest in using more and more DCD donors. These are donors that are not brain dead, but they withdraw support at the donor hospital. And if the patient expires, then the team can have access to those organs. So there's been a lot of data across the board showing that you can get good outcomes with all of these different types of groups that were once considered to be extended or not usable. And we've looked at donor age, no real difference except for increased utilization of the vent and some more resource utilization. I do think that's a common theme whenever we're increasing, kind of pushing the realm of donors, is that you can get them through, but there is a little bit more resource utilization, a little bit longer times on the vents, and maybe a little bit more care that has to be given to that donor lung after you transplant them. We did develop a donor quality index score to try to put together this broad variety of elements that go into deciding on a donor into a simple app that helps give you a score. And it turns out that if scores are above 40, that if you turn down that offer, probably someone else in the sequence will accept it. So it was actually kind of interesting in predicting behavior. We looked at how using some sort of a scoring method may help increase transplant numbers. And in fact, it did increase our transplant numbers and decreased our underutilization rates. So a lot of what I'm kind of focusing on here in this talk and have been looking at over the past decade is as we traverse this divide from a standard criteria donor to an extended criteria donor, how can we do it safely? And how can we get more access to these extended criteria donors to almost make them standard criteria donors instead of having to find out every time once you transplant how they're going to do on the recipient? Is there some middle ground that we can use? And I think this is where ex vivo technologies are a wonderful thing for us to start to look at and harness its potential. This concept was first developed in 2001 by Steen, and it was published in the Lancet. He was looking at a DCD donor that died of an MI, and he said, you know, if somebody dies of myocardial infarction and you're going to use that lung, we probably should test it before we transplant it into the recipient. And so this is where this concept came about, that we can use a chamber to place the lung in, perfuse it with cannula that goes into the pulmonary artery and then have it drain from the left atrium and then pump it through almost like a little ECMO circuit. We can oxygenate this blood so that we can keep the lung, even if the lung is not oxygenating great on its own, we can support it like you would a patient on ECMO. And you can ventilate to help recruit the lung, you can do bronchoscopies. There's a lot of potential for you to look at and evaluate this donor organ outside of the body before you transplant it into the recipient. The alternative to that, just so that I don't take anything for granted, because sometimes people say, well, how are you doing it otherwise? The alternative is this, is an ice cooler. And we've been doing this since the beginning of transplant. Most of the outcomes that we see published for ISHLT or UNOS really have relied on standardized preservation. And this is basically, we flush the recipient, pulmonary circulation with a low potassium dextran-based solution. It clears it of any clots, a little bit of protection to the endothelial layer and a little bit of anti-inflammatory. And then our biggest principle is keeping it cold, chilling it, and putting it in an ice cooler, and traveling with it cold. It usually still has some oxygen in it. It has like 40% oxygen is typically what people will do. They'll clamp the trachea and keep 40% oxygen. Whether or not that oxygen stays in the alveoli throughout six hours of transportation, I think is difficult to know. I mean, a lot of people swear that it does, but it's hard to really know how oxygenated this organ is. Normothermic ex vivo perfusion started gaining traction in around 2011 when it was used to a large degree in a single center in Toronto. They have kind of their own protocol and their own system that they utilize for using this. And they studied it 20 patients that were extended criteria donors. And they noticed that if they used EVLP for these donors and compared the outcomes to patients with standard eyes that were standard donors, they had similar outcomes in terms of graft dysfunction. So this was the first publication that led the community to say, wow, maybe we should be using EVLP for a lot of these extended criteria donors. But then we saw an observational study come up from the UK that used not the exact same model that was used, but 50% of the patients did use that model. Another 50% used another system called the VivaLine system with a blood-based perfusion. Bottom line is they looked at it in a multi-center fashion. So it's not just one center. Let's take all the centers in the UK that are doing EVLP and see what the outcomes were. And unfortunately, this trial was actually stopped prematurely because there was an increased hazard ratio, increased mortality with using these systems for ex vivo preservation of extended criteria donors. So this kind of gave us some pause. We said, all right, well, when we're looking at EVLP in our centers, we need to make sure we're adopting protocols that everyone can adopt and it can be standardized and you can count on the results. So where are we now? So now we have two FDA approved platforms. The one on the screen left is the static EVLP platform. So lungs are delivered to the center and placed on this system. And they use the Toronto-based protocol in terms of not having blood cells and just kind of cool solution going through it and ventilating the organ. So this is the static EVLP platform and the device has been standardized for use in any center. And the other one is the portable EVLP platform, which is called Organ Care System. And this one travels with the team to the donor hospital, the lung is placed in it, and it comes back with the organ. So let's look a little bit about the data because I just suggested that it's important whenever we're using these devices to analyze some of the multicenter data that's available. With our static EVLP platform right now in terms of multicenter data, there is a prime study that is currently ongoing. It's been ongoing for a while actually. It's called the NOVEL trial. And this is the one that we all have to keep our eyes open for to see the conclusions of it. We don't have it yet. We don't have it in a publication yet. It's been peer reviewed, but it's been going. So we have to see where the final analysis will lie. The preliminary analysis was pretty encouraging though. At the ISHLT last year, 216 EVLP cases compared to 116 standard. And the three-year outcomes in terms of survival were very similar. And the EVLP group had pretty extended criteria, including DCDs, older age, and all of those different. So I think it's gonna pan out just great, but I do think it's important for us to see the final data. When we go into the normal thermic platform, it's definitely a bit ahead in terms of published data. And so I'll show you some of this right now. So this system is different in that it uses blood-based perfusion, and it travels with you so that you have access to variables, you can change the perfusion rates, you can change the ventilatory requirements, recruitment strategies throughout transportation from point A to point B. So this was analyzed a long time ago in the INSPIRE trial, randomized control trial. This was in 2018, taking multiple centers around the world using the standardized OCS protocol. And there were about 182 in the control group, 188 in the OCS group. Probably one of the most difficult logistical randomized controls trials to do and to finish. But it did show that there was less early primary graft dysfunction in standard donors. This was not extended criteria. This was standard donors that were perfused on a box versus transferred on a standard ice. Now, interestingly, when we look five years later, we start to see maybe a signal, a trend towards better long-term graft survival on the OCS cases, but this was not statistically significant. What was important, though, was to know that it wasn't worse. So if you're using a device, a technology to carry organs across the world or across the country, wanna make sure it's not worse. And so this definitely gave us convincing data that it's not. And patient survival also was not worse at five years. Now, when we switch to the extended criteria, there was another trial that was conducted and completed multi-center, multiple centers in the U.S. and in Europe involved using that standardized protocol. Ended up with 79 organs that were perfused on the system. This were the criteria that were used. Very little turndown rate. Excellent one-year survival. And then the long-term outcomes, you can see that the BOSS rates of chronic dysfunction were lower than we saw even for standard donors. So that told us, this gives us a little bit of confidence in the use of this technology for extended criteria donors, knowing that the survival is excellent and knowing that the long-term graft function is still good, even in comparison to standard donor lungs. I will say that the primary graft dysfunction rates and the time on the vent in the ICU length of stay was longer, though, for these extended criteria donors, and it continues to be that way, at least in our center. So I think this is something that we have to look at carefully. When we look at long-term patient survival, standard donors in the blue, extended criteria in the red, perfused on OCS, and we see very similar outcomes five years out. So this is very encouraging data. This is published, and this is something, actually, the long-term has not yet been published, but the one-year has. So I think it gives us some confidence that we're heading in the right direction. So where are we going with these national systems now, national perfusion programs? They're setting up hubs all around the US, probably to address some of the issues with reducing geographic boundaries. So nowadays, you can pretty much call for your donor organ and it gets delivered to you. And this is not just with the portable system. The static system also was actually doing it first with the perfusics model. So you would send your donor lung to Baltimore, they will do something with it and send it back to you, and then you'll transplant it. So there are these kind of paradigms going on, and I think that we're gonna see more and more of this happening. We don't have a lot of great data on the results of these third-party networks, so we have to be careful about it. Wow. Budweiser. The beer is here. So we've got a long way from the way that we were and the way that great technology is going now. We're using broader a lot for farther travel using these OCS platforms. Very long out-of-body times. The results are still very good. This is a single-center analysis in our program. We're looking at biomarkers and seeing if we can try to detect more molecular data from the organ now that we have an EVLP system that we trust and see if we can try to find better biomarkers for telling us whether we have wedge tissue samples telling a single-cell RNA activity, whether we know whether an organ is gonna do better than another. We're doing a variety of different environmental changes. But there are other technologies that you should keep on your radar, and I'm just gonna end it with this. Now we're going back also to ice again and looking, well, how can we do ice better too? So there's a cooling system called the Lungard system, which we've also been using for the middle category. So really long, we tend to go with the OCS. Really short, we tend to go with ice. But somewhere in the middle, Lungard ends up being a pretty affordable option that has been looked at. This is an abstract of the JHLT. We don't have much more than that. But the results look pretty decent. And then overnight coolers are also being promoted. And again, we have to look at what our long-term comparative data is gonna be like this whenever we look at any of this technology. So in conclusion, EVLP is definitely making an impact. We have to keep an eye on how this is going to progress. We really do need to keep an eye on the data though and look at multi-center data. Make sure that you can replicate it at different programs. And thank you. Thank you. Yeah. Basically, I'm gonna go kind of a whirlwind because we are kind of running out of time. And really, we're talking about monitoring for chronic lung allograft dysfunction. And we've talked a lot about CLAD in the last few sessions. And this is, I have no disclosures, but if you find yourself on the windward side of the island this week, you gotta check out Kailua Beach. This is the biggest kite surfing beach in the world. So how far have we come? We've done very well in terms of numbers, in terms of successfully increasing our numbers internationally. And I think we should all be congratulated to that from all of our centers. But we still have a lot of work to do. As we know, our outcomes just aren't as good as other organs with a median survival still between six and seven years. And we know the reason is at least because of chronic lung allograft dysfunction. And we know that most patients going to transplant are going to progress to CLAD. But what if this was not the case? What if CLAD was not inevitable? What if we were able to identify and prevent progression of risks early? Early enough to delay the activation and progression of the immune system? Well, that's challenging with CLAD, right? Because of both the chronicity and the heterogeneity of the disease or the disease state or the syndrome. And so that's when you start looking at things like biomarkers. Things that may help to, can you grab my glasses, I'm so sorry. I can't see anything. Without, you know, these are markers that are objective. They're measured in an indication of either normal processes or changes. And they really can be used to monitor and predict. And they're usually provided, derived from some type of physiologic characteristic. And so are there biomarkers for CLAD? Well, there's a lot coming up the board. And I thought maybe if we had time, we would go through all 34 of these together and go through them in detail and go through the papers. Should we do that? I don't think Harmeet's gonna have time for his talk and he's looking a little stressed out down there that he's not gonna have time. So maybe since it is also the last session of CHEST in 2023 and I only was supposed to have 12 minutes, I think maybe we won't be able to. Because if I tried that, half of you people would think I was a fish because you'd be running to swim in the sea. And half of you would be thinking, oh my gosh, I wanna be back where that fish is on the beach. So instead of doing this, I'm looking at, hey, really, are any of these ready to use right now today, ready for prime time? I think there's a few that can be. I think there's some like donor-derived self-reducing, some of the molecular mechanisms of both T cell activation and immune response. I think those are coming up sooner than some of the others. But for what we can do right now and right here, we don't have anything right here. So like Arthur Ashe said, start where you are, use what you can, I mean, use what you have and do what you can. And right now, what we have are risk factors for CLAD. We have immune and non-immune risk factors that we know have been adjudicated to lead to CLAD. And what if we look towards identifying these risks early and those risk factors can work as our current tools? We have to focus on what we control and what we can do is hopefully identify and manage these risk factors early. If we identify these risk factors early, maybe we can slow the progression to CLAD. I know I'm speaking fast, sorry, but trying to catch up. So, you know, if we look at these risk factors, we can then identify where we need to go. I think the thing is with some of the risk factors you've seen, mainly the non-immune risk factors that we're all aware of, GERD, PGD, and even infection, they're easily identifiable, right? We can see them, we can treat them, we can control them in most cases. Prophylaxing for infection, controlling GERD with either friend application or different maneuvers, and then really hoping to avoid some of the risk factors for PGD. So some of these are easy for us to do. But what about those more challenging risk factors that are not easily amenable to early and accurate recognition? And those are more the immune risk factors like ACR, AMR, and DSA. So what we have to do is focus on how to identify these kind of mysterious and not easily accessible risk factors. And I think the challenges of doing that are many. And let's just go through a few. So the challenges are acute, really acute lung injury, or acute ALAD, or acute lung allograft dysfunction. What is the first identifying factor of that? And that's really lung dysfunction, right? And we already know, if you went to the last CLAD sessions, that this is a very difficult heterogeneous disease to identify. The baseline and kind of the trajectory is so heterogeneous and we are not always easily identifiable when this is occurring. And it can overlap in many, many cases. So that's really lung dysfunction. What about challenges in histology? We know from ACR, AMR, viral inclusions, all different types of lesions we see in histology, they are all nonspecific and they can all overlap with other diagnoses. Not only, oops, sorry, not only that, they're very discordant in terms of being able to identify and report out different lesions. So I may see, my pathologist may read something out as an A2, whereas another may read out as an A1. Or maybe someone says they don't have ACR at all. And then you look at the AMR histologic changes and we know that that's just all over the board. So histology, which is supposed to be our gold standard, is very difficult to identify. And so if we put all of our eggs in one basket, we may have the problems we're having when we're trying to look at clinical trials and look at outcomes because what I might be calling CLAD, or acute rejection histologically, others may not. So lots of challenges in that risk factor to make it a biomarker. What about challenges as DSA as an endpoint? Again, there's so much variability between DSA labs and the way that we monitor them as centers. So I might not ever do a surveillance DSA, whereas my colleagues may do them four times a year. If you're not looking for them, you might not find them. Remember in the literature, there's a big spectrum between 20% and up to 60% of how much DSA is found or how frequently they're found in their patients. Well, it also depends on how often they're monitoring them. And then when you talk about reproducibility lab to lab, that's also an issue. And then sometimes DSA is not detectable, even though you look for it and it's there. For all intensive purposes, they have all the other criteria for AMR. They might be possible, probable AMR, but they don't have a circulating DSA. And that could be because either their assay may not be available at that center or that particular antibody has not been identified yet in a correct assay. Then there's non-HLA antibodies, which we talked about a lot in the AMR session in terms of being able to get the right platforms and to the right, oopsie, sorry, the right, there we go, in the right hands. It's not ready, we know, for prime time, but it's still definitely there. So we have a lot of challenges in identifying acute graft dysfunction. And that really belongs to each one of these risk factors. There's overlap diagnoses, there's non-specificity, there's non-sensitivity, there's definite changes in the way each person looks at these risk factors. So I think there's a lot of challenges is even identifying the risk factors. So what does that teach us and how can we get to where we need to do? Well, we know we have these challenges and we can use those challenge. Number one, we can reflect on the need for better understanding of our current techniques, histology, DSA, other things. We can also reflect on the need for more standardized monitoring. And I think that's something that we're working on and looking, sorry guys, looking for better standardized monitoring in uniform situations. And then we can reflect on the need for additional diagnostic tests. So in terms of the number one, for better understanding of our current techniques, we have a bunch of great guidelines, but they're old. And what we are doing is obviously we're looking at reiterations as we gain experience every five to seven years. So the new AMR consensus is coming out in 23. The new pathology update on rejection grading is coming out in 24, 25. These are things we have to keep doing all the time to keep us up on where we are and where our experience is. The LASHER, the Lung Allograft Standardized Histologic Analysis Template, was just published by in 20, just in the last few months by a group of pathologists and a few pulmonologists looking at how we can now better describe lesions and work on these lesions center to center. Instead of saying you have an A3 rejection, you may have everything that is included in an A3 rejection without saying A3 rejection. Look at the actual lesion, and this will be better communicated center to center instead of saying, I think there's A3. You can say there's perivascular infiltrates up to this point, and that's what you have. So I think these are things that are gonna help us to better standardize what we have now because what we have now is what we have to use. What about the reflect for the need of more standardized monitoring? We're all monitoring patients differently, and that may seem like things may be different when they're not. Okay, I'm gonna take a breath. So what about number three, consideration of additional diagnostic platforms for earlier identification? And this is where we really wanted to spend a little time, but we're running short. But we know that all of these things are coming up very quickly, up through use in just regular daily practice. Many of these are from different platforms, from molecular analysis, from biopsies, brushing, BALs and blood and things that are being used daily. We know that currently there's not one good strategy to help to identify CLAD. I think we're gonna need the old biomarkers and the new biomarkers for early risk. So really, I know that was a whirlwind, but I think I got us kind of caught up to date. And really, CLAD is the main cause of death after the first year post-transplant. And really, we need a better understanding and earlier identification and monitoring of acute rejection and other risk factors that is imperative to delay or prevent CLAD. And our current diagnostic approaches are just not specific enough for what we need. They're not precise, and they're not standardized. And this is making it difficult not only for making good clinical trials, but also for looking at response to therapy day by day in the clinic. The low sensitivity and our specificity reflect the need for larger studies and really getting better monitoring systems. So I know that was fast. If we have time, which I know we won't, you can come up to me after and get some questions answered. But we need to intervene early on risk factors that will take us to the new direction away from CLAD. And I hope I didn't speak too fast, but thank you very much. Okay, I think we're on track. Thank you for coming. Thank you for staying, and I'm gonna do my best to get through this as fast as possible. Again, my name is Harpreet Singh-Grewal. I'm a lung transplant pulmonologist at Columbia. I have no disclosures. I'm gonna be speaking about upcoming treatments for CLAD. I'm gonna skip the definitions and the pathophysiology, and I'm gonna straight go to the therapies just to kind of respect everybody's time. So just skipping out on some of the current definitions that were highlighted earlier in the talk, and pathology and risk factors that were discussed, they tend to be multifactorial from direct injury environment and immunology directed that can lead to fibrosis and subsequent CLAD development. Again, current therapies, we are looking at azithromycin that we utilize, augmentation of immune suppression. We also tend to do gastric reflux surgeries to prevent acid insults, extracorporeal for freezes, and then I'll discuss these five. This is sort of the crux of the talk are the five possible future therapies that I wanted to focus on. Antifibrotics, there has been some data. These are all the studies that I thought were important. There was an ICHLD abstract on a phase two study that showed it's safe and tolerable, and we do have good data from patients in ILD that have shown tolerability and safety. And then there's a study done, STOP-CLAD phase two study single center. It was stopped early because of COVID. Their target was 60 patients. They only got to 24. No difference in FEV1 or radiographic decline. Again, it was terminated early. There are two current trials that results are pending on, phase two slash three multicenter 90 patients per BOS. That's in a European study, and then another one that looks at OFAB for BOS, multicenter BOS double lung transplants. What about inhaled cyclosporine? This goes back to NEJM 2006. As you can see, patients who were put on inhaled cyclosporine, although there was no difference in acute rejection, they had better BOS-free survival and overall survival. This was followed up to look at inhaled cyclosporine in patients who did develop BOS. Small number, but lung function stabilized and survival was a little bit better. Currently multicenter BOS1, 2, and 3 are ongoing, and we're hoping to see some good results from this. JAK inhibitors. JAK kinase pathway leads to recruitment of inflammatory milieu, and essentially upregulates inflammatory cells, including T cells that lead to airway injury. There's a very nice paper from Duke that shows that pathophysiology. Initial phase one, two study, 23 patients in total, all double lung. About 20% had an increase in their FEV1 by more than 10%. Certainly, biggest complication was infection. CMV reactivation at 30%. Multicenter phase three study upcoming. Let's hope they don't see too many infectious complications. Mesenchymal stem cell therapy, again, initially published in 2016. Phase 1a, that showed safety in infusion, and this was followed up in 2022. Group one was the same group that was also in the phase 1a study, so they got redosed with mesenchymal stem cells, and then the other next two groups had differing dosages, and essentially showed lung function stabilized in these patients, and there's a phase two study that's ongoing that's recruiting. Hopefully, that'll also show promising results. This is, I thought, interesting, because as Dr. I'm sorry. I'm sorry. I know. I'm so sorry. I'm trying to rush. I apologize. I do apologize. I know. We both are here. Yes, as Dr. Levine mentioned, that immune component that leads to class, so I thought this was an interesting study. This is tolerance induction. Essentially, what they did, they took these monkeys, and they did a lung transplant, and subsequently did a bone marrow transplant at four months. Two of them developed PTLD. Hence, they're not shown here, but there were four, out of which, with one that didn't engraft, as you can see, has whiteout of the lung, as well as histology that's showing, essentially, graft dysfunction or rejection. And then, the other three monkeys were all ranging from 299 days to 813 days without immunosuppression, with donor chimerism that was preserved. This was an abstract in 2019 that looked at patients. So, these are patients with primary immunodeficiency that require bone marrow transplant. Two patients failed bone marrow engraftment. Three did. One was immunosuppression-free at two years, and the second one was 10 months post-lung transplant with low-dose immunosuppression that was, at the time, planned to be taken off. And the third person was not mentioned in this particular abstract. Again, phase one slash two study. They're trying to enroll 16 patients. Again, this is gonna be a specific population that's gonna need bone marrow, unless we figure out a way to create tolerance. So, take-home points for CLAD. I hope that was fast enough. It was very good. It's better than I did. CLAD is complex. Obviously, there's results of these sort of interesting therapies that are out there. And then, I think tolerance induction is gonna be interesting, and if CLAD has some component of immune system, and if we can induce that tolerance, we perhaps may not see it in those patients. Okay, with that, thank you so much. We should give a standing ovation. Thanks. Probably the worst talk I've given, but thank you so much. You got through.

lung transplantation

donor lung allocation

lung composite allocation score system

organ distribution

ex vivo lung perfusion

extended criteria donor lungs

standardized monitoring

chronic lung allograft dysfunction

CLAD treatments

ongoing clinical trials