Thank you for getting up early and coming to our discussion today. I'm excited for what I think is going to be both an informative and fun session. We have three speakers. I'll just do a quick introduction and then I think we're going to have time for questions which I hope and I'm anticipating there will be many. So please feel free to be asking questions and picking our brains about this topic. So our topic this morning is telomeres and interstitial lung disease, what we need to know and we're going to have really three objectives. Hopefully when you leave this session you're going to have a better understanding of the interaction between telomere lengths and interstitial lung disease. We're going to review in detail the implications of what telomere length and particularly telomere shortening has for transplant outcomes and then understand both current research as well as really pragmatic issues of what telomere measurements are for our clinical practices. So I'm just going to make sure everyone in the room knows what a telomere is and it will be quick but just to remind everyone that, you know, the telomeres are the caps at the ends of our chromosomes and they really form a protective sort of function to protect the chromosome from damage as the cell divides and replicates. So these are TTAGGG tandem repeats, so long repeats on the end of the chromosome. And the length is variable in each of us and inheritable. So that component of length is kind of what we're going to be focusing on particularly when they're short. Now every time a cell divides some of that telomere, the repeats get cut off and there's a balance in the system with a division of this telomerase which synthesizes new repeats to add back on to minimize the shortening. But really at the end of the day, the net balance or effect favors telomere shortening with each cell division as we age. And this probably serves some sort of tumor suppressive mechanism as we age. So it's just the normal balance of things that our telomeres will shorten but telomerase tries to balance that. Telomerase has, in a very simplest of reductive sort of thinking, has two components. There's the telomerase reverse transcriptase and the telomerase RNA which is the template for that, making the repeats on the end of the telomere. And this graphic here on the left-hand side sort of shows some of the components of the telomerase complex and where we've seen mutations in some of the genes. And this really is part of why we're talking about telomeres and ILD is that telomere and short telomeres, genetics, we're learning more and more that a significant number of our patients with interstitial lung diseases have a telomere biology disorder or some genetic predisposition to short telomeres. So at least 30% of individuals with familial ILD have abnormal telomeres. And if we have a patient that has both ILD and some hematologic abnormalities, that increases the odds that there's a telomere biology disorder. Five percent, at least five percent, probably more of sporadic IPF patients have an underlying telomere biology disorder or short telomeres. And we know that at least 30% of patients with short telomeres, we can name an identifiable genetic variant. And the telomeres, when they're short, they have both prognostic and therapeutic implications that we're learning more and more about. The genes and a mutation in one of those genes really can explain about 25 to 30% of what we call familial ILDs. So really a significant component in understanding telomere biology helps us understand more about interstitial lung diseases. And so this is a sort of a schematic of what the telomere interaction and what this is maybe how this is working. It's a multi-hit model, right? We have this telomere length that we inherit, and the shorter it is, the less able we are to manage damage from our environment, either exogenous or endogenous sort of endothelial reticulum stress, et cetera. And so having a short telomere sets you up for earlier lung damage and more problems. So we'll talk a little bit about that multi-hit and what the short telomere means, but having short telomeres alone without probably environmental interaction is probably not enough to cause a lung disease. So with that, I want to introduce our faculty. We're going to start first with Narada Patel, who's going to give us a nice, rational, balanced discussion of the telomere shortening in the setting of lung transplant. And then we'll move on to Dr. Deji Adegunsoy and Dr. Chad Newton, who will talk to us on both ends on how telomere measurements should be done in patients with ILD. So Dr. Patel, thank you. All right. I'll be talking a little bit about implications of telomere shortening. I have nothing to disclose except for the fact that I'm an ILD and transplant pulmonologist, so I would wear my opinions on that through that perspective. We'll talk a little bit about the considerations that go into evaluating patients with shortened telomeres when it comes to determining candidacy for lung transplantation, as well as describe the impact of shortened telomeres on morbidity, mortality, and management challenges after lung transplantation. And then I'll just really say some things that you already know, so just bear with this introduction slide. But we know that even with therapies that can halt, reverse, and slow down ILD progression, there are patients who progress and require lung transplantation as a potentially lifesaving and life-altering treatment. ILD is the leading diagnosis for which lung transplantation happens, and you can see here in the teal markers, oh, see, in the teal bars over there on the right side, the crosshairs, that it really is taking over the portion of patients that get transplanted. And then you can imagine that based on what we just learned, that given that ILD patients who have shortened telomeres can present at younger ages and have a poorer prognosis in terms of lung disease, it's no surprise that lung transplant centers see a higher number of patients with short telomeres than the general ILD population. In some studies, up to 32% that Dr. Newton might tell you about. We're here a little bit to talk a little bit about the systemic manifestations of the telomere biology disorders, only because after transplant, we take these diseased lungs out, but we are left with this body that needs to not only go through surgery, but deal with all of the post-transplant management considerations and give them the long-term prognosis that they deserve after going through the surgery. We know that this is a multi-system disease, particularly in patients with the most shortened telomere lengths and certain genetic abnormalities, that leads to things like malignancy, particularly skin cancers, but even things like gastrointestinal and urogenital cancers, liver disease, and it's not typical liver disease in a lot of these patients, and they oftentimes have subclinical or even clinically overt cholestasis, cirrhosis, and portal hypertension that's different from some of the other liver diseases that we're more familiar with. And the most important, perhaps, challenge in this patient population is when they have bone marrow disorders as a result of this. There's things that range from simple macrocytosis to anemia to thrombocytopenia, but also leukopenia and overt myelodysplastic syndrome and leukemias. So all of this goes into deciding why and when we transplant patients, and this comes from the consensus statement from the ISHL-T, which really goes through the contraindications for a lung transplant, which, one, is malignancy with a higher risk of recurrence and death related to cancer. This is self-evident. And then liver cirrhosis or portal hypertension or synthetic dysfunction unless being considered for a multi-organ transplant. So you can see that our patients are short in telomeres. These are things that we'll have to scrutinize perhaps a little bit more before checking off on their kinesi. And this was a statement from the same guideline that said that patients with telomereopathies should undergo detailed evaluation, potentially including bone marrow biopsy due to their concurrent risk of hematologic abnormalities, including myelodysplastic syndromes. And so therein lays the importance of seeing these patients pre-evaluation. The patients generally are referred to a lung transplant center, and we can talk about the timing of that at another time, but really along their course of ILD, particularly IPF, if they're a suitable candidate, they will be referred. And at that point, if they haven't already, the lung transplant center will consider whether or not they should be sent for short telomere length testing to see if they are this subgroup of our patients that may have higher risks. And if they do, the consideration will be made to say, do they need a referral to hepatology and additional testing, such as imaging, evaluation of portal pressures, as well as consideration for liver biopsy, and then hematology consultation, including possible need for bone marrow biopsy. And we all know that this takes a little bit of time. And then the experts get together, look at this data, because again, it's a rare syndrome in population, and then it comes to the listing decision. And then after the patient's listed, there's a wait time, right? Those of you who have looked at the difference in terms of allocation, in the spring of this year, there was a continuous allocation score that's now in place in terms of determining in the United States the priority for listing for lung transplant patients. And the determination, there was a higher wait based on five-year survival. And because of that, this then helps increase lower scores for patients, or increase scores for patients who are younger, but then for patients who are older patients who have ILD and or telomere bilitis disorders, there may be a longer wait time given their lower scores. And then they get transplanted. And remember that any time along this path, particularly these patients with shortened telomeres that have a poor survival may not make it to the point that they're still eligible as candidates for lung transplantation. So it's important to consider how long this can sometimes take, and how long our patients can potentially wait for this life-saving treatment. And then I'll talk a little bit about the post-transplant end of things, extra pulmonary manifestations of this that we talked about, the prevention, monitoring, and management, as well as things that we are starting to understand is the implications of short telomeres on the immune system, and perhaps increased risk of certain infections, and other morbidity and mortality after lung transplantation. So we talked about this guy who we were worried about this risk for malignancy. And after transplant, we are very interested in making sure we prevent and treat malignancy early, skin cancer being the most common. I don't need to say this to you guys in Hawaii, that skin cancer protection with sunscreen is going to be the first step, but also doing things like avoiding, perhaps, voriconazole that we know is an agent that we use oftentimes for fungal prophylaxis in treatment, but can also increase risk of cancer, and thinking about avoiding it for patients we know are of increased risk. The liver should be monitored for injury and avoidance. But I think the main considerations that we have after transplant at this stage is impact on the bone marrow. You can imagine with patients who are anemic to begin with, if they have bleeding postoperatively, or even when we consider about whether or not we need to support the patients before transplant on ECMO, the hemolysis that ensues, or the bleeding that ensues in patients who have poor bone marrow reserve may lead to increased transfusion requirements that then leads to things like sensitization that then further limits their adrenal pool, and may increase waitlist time. So all of the things that we consider, cytopenias that may, obviously, leukopenia that can impact risk of infection, and then poor marrow reserve, particularly in the face of things that we do to patients to get them to keep this donor in them, right? This is induction agents like anti-thymocyte globulin, cell cycle inhibitors like azathioprine and mycophenolate mofetil that we know can be particularly, have particular increased risk in this patient population with shortened telomeres, but we see that even more so. And the challenge then becomes, how do we immunosuppress these patients to allow the lungs to sustain their longevity? There's also medications like ganciclovir and valganciclovir that we depend upon to help prevent and treat cytomegalovirus infections in these patients, but that can be bone marrow depleting, and then again, the consequences of ECMO in poor marrow results, particularly things like thrombocytopenia and bleeding. There have been cases of GVHD reported, and then of course, the increased risk of hematologic malignancy that you can see at any point during the post-transplant course certainly complicates things. I'll talk briefly about the risk of infection, as a lot of the things that we're talking about in the study you can see is 2019, we're really just beginning to understand the implications of shortened telomeres and telobiology disorders on the immune system. This is probably the one that has the most evidence for this. CMA and lung transplant is something that is important and they can cause pneumonitis, hepatitis, colitis, and cytopenias, but more importantly, it has an association with increased risk of chronic lung allograft dysfunction that may portend the overall prognostic value in these patients. We know that patients have increased risk of developing CMV who have shortened telomeres compared to those who don't upon cessation of antiviral practices, in fact, four times higher than those patients who don't have shortened telomeres. We also think that the patients who get CMV disease have a higher rate of complications, including relapse, organ involvement, and ganciclovir resistance, not to mention that the ganciclovir that we use to treat these patients can further potentiate the leukopenia. And this is the challenges that we have. You know, we have agents that prevent this dangerous CMV infection, valganciclovir is very effective, but the challenges, particularly in these patients, include cytopenias, and we can say, let's just keep them on it forever, but the cost sometimes is prohibitive in these patients. There are more effective, lower risk for cytopenias alternatives, like latermovir, but further study needs to be done on their efficacy, but more importantly, cost and coverage is still an issue and having for this. So this still remains a challenge for patients with post-transplant who develop with shortened telomeres. All right, so this is my last slide, so just bear with me. It's quite busy, but it does represent what we know of in the last maybe eight years of the evolution of our understanding of the implications of shortened telomeres and telomere biology disorders on patients after a lung transplant, and the authors here have contributed to this literature, so a shout out to them, I will say, I mean, the presenters here. So the first thing that was noticed in 2015 is that these patients with shortened telomeres had certain things that weren't right. This was not compared to the normals, but there was a suggestion by the UCSF group that these patients had something, there was a descriptive paper, but then alongside these authors, several other centers were noticing the same thing, and then comparing things, and one of the earlier studies showed that patients who have shortened telomeres and certain genetic predisposition may have had a higher risk of acute kidney injury, as well as what we thought we recognized was the bone marrow complications of this, and other authors did not find an impact. You can see that in the red, I have increased risk, yellow, no impact, and then green, decreased risk. The next author did not find that in that cohort, there was an increased risk of acute kidney injury, or in that subset of bone marrow complications, although there may be some limitations to that analysis, but they did find that there was some protection from acute cellular rejection in this group that may have, that had shortened telomeres, and additional studies have been done with more of a larger series of patients, and more comparators, that again, Dr. Newton's study showed that it was, these patients who have shortened telomere length, less than 10%, had a higher risk of primary graft dysfunction, chronic lung allograft dysfunction, and mortality after a lung transplant. Importantly, they did not find in their analysis that there was a higher risk of acute kidney injury, or bone marrow complications, or acute cellular, or freedom from acute cellular rejection in that series. Again, this is ongoing, and the most recent study showed that there was increased risk of, again, primary graft dysfunction, bone marrow complications, and chronic lung allograft dysfunction, and mortality in this cohort, compared to non-shortened telomere ILD patients. I will say that, although we are always concerned about higher risks of PGD-clad and mortality, even kudos to probably the treating physicians in both of these centers, that even the patients who had shortened telomeres fared quite well in terms of their mortality, compared to national averages. So this was not the type of mortality that we say, we're not doing transplantation in patients who have ILD with shortened telomeres, but really that we should think about why these patients are different, and see how we can mitigate these differences to give the patients the best prognosis. And then more recently, there was a suggestion that these patients that have shortened telomeres may have higher risk of anastomotic complications after lung transplantation, both stenosis and dehiscence. So having said that, I will summarize by saying patients with shortened telomeres can have more rapid progression, underscoring the importance of early referral to lung transplantation, particularly when you consider that they may warrant additional testing and consultation before determination of candidacy, and our changes in our lung allocation system that may cause increased wait times for certain patients. And then secondly, the post-transplant course is more likely to have certain complications, including things that we know, we think we pretty much know for sure, things like bone marrow impact, and perhaps hematologic malignancies, perhaps CMV diuremia, and perhaps even other infections that I didn't put in there, but we're just starting to understand. And then definitely better understanding the implications on CLAD, and more importantly, how we use this knowledge and our science and differences between what we know how this telomere biology disorders impact the immune system, and how perhaps we can modify our management to improve the prognoses for these patients after lung transplantation. All right. So I will go ahead and just, I will skip the further study, because this is really just, and I'll stop because I think we'll talk about a lot of the further studies when we talk about it as a group, but I wanted to just go ahead and introduce the next speaker. So just to talk to us a little bit about why we need to measure these shortened telomeres in all of our patients, I will introduce Deji Adegonzoye. Thank you, Dr. Patel, for that introduction. And thank you all for coming here this morning. It's a pleasure to see so many delightful faces in the audience and on the panel as well. It's bright and early, and so thank you for coming. The cab driver that actually brought me here this morning said, I don't believe, and no one believes you guys are here for the conference. It's Hawaii, right? It's a landfill with coconut milk and honey and palm trees and beautiful sunsets, so thank you for being here this morning. So I thought I had the easier part of the debate, but Dr. Patel just completed my work for me. I feel like I can walk away and it's all done. These are my disclosures, which are relevant to this talk this morning. I'll start with three simple questions, and I just want to, with a show of hands, just indicate yes or no. So how many of us in the audience believe that all patients with diabetes should have a A1C levels measured. Just, okay. So pretty much consensus in the room. How many of us believe that all those with osteoporosis should probably have a bone mineral density, I see hands shooting up already, measured at some point? Okay, pretty much everybody as well. How about coronary artery disease and measuring serum cholesterol levels? Everybody. All right, so what makes this difference then? You tell me that you believe we should make these markers, measure these markers in these individuals because you think there's inherent value to it. Diagnostic value, guiding treatment, risk stratification, and secondary prevention and all that. So that really does make sense. So why shouldn't we do that in ILD? I believe that all patients with ILD should have CDMAs measured. And I'll try to convince you beyond what Dr. Patel has shown you already why we think that should be so. In the U.S. here, we often live in a bubble, right? We have life expectancy on average of about 80 years. If you don't believe me, the president is in his 80s, current president. And none of our former presidents just turned 99 here in the U.S. So when I say median, half of patients will live beyond 80, the other half will die before 80. That's a long life expectancy. And we don't often think about sub-Saharan Africa and other countries where the life expectancy for men is often 47, for women, 52. Half of patients will live before 47 and die before then, others will live slightly beyond 47. That's very concerning. And when we think about that in context of IPF, one of the most devastating ILD forms, the median life expectancy in IPF is three to five years, rivaling non-small cell lung cancer. Most patients with ILDs are diagnosed in their 60s. So what does that mean? They get to lead to 65, maybe 68, and that's it. So that essentially shaves off the benefits of the last 50 years in terms of gains in life expectancy and takes two decades away from their life expectancy. That is really worrisome. And that is the ILD that we deal with. So what if there was a biomarker, something we can do to influence those detrimental outcomes? You heard from earlier on about telomere-related genes and telomere biology and telomere length and how it influences this. I'm not gonna delve into the details too much, but we can actually use telomere length as a biomarker to make a change, meaningful change in these patients. We know that telomere lengths are often determined by telomere-related gene variants. When these variants occur in patients, they tend to have telomere shortening, which can translate to detrimental outcomes. In fact, about a third of patients with families with pulmonary fibrosis do have these gene-like mutations in telomeres, the enzyme that helps to protect telomeres or in the telomere-related genes. And these are prevalent across board for the different ILDs, not just IPF like I showed you, chronic HP, rheumatoid arthritis, connective tissue disease, scleroderma. Across board, we see these telomere-related gene variants that can begin to influence telomere length and carry real-life implications. And how do we see this in clinic? Those at the highest risk often have clinical manifestations, a shock of gray hair, they have aplastic anemia, unexplained liver cirrhosis. You had a few of this with Dr. Patel as well. So we can often tell who is at higher risk for having telomere shortening in clinic. So we don't necessarily need to do much more beyond that. All right, how about across board? Well, we know that shortening telomeres occur not just in familial ILD, clusters of families who have a close relative, first or second degree with pulmonary fibrosis, but even in sporadic pulmonary fibrosis as well. The cartoon on the left-hand side shows you patients who had their telomere lengths measured, and you can see that for those who had ILD, they had telomere shortening much more than control patients or even their spouses who have lived with them for years. So across board, telomere shortening in ILD is a problem. It's prevalent, it's common, and it has real-life implications. We took a random sample at the University of Chicago of 100 patients with ILD, diverse forms of ILDs, and that's what you see on the right-hand side, measured their telomere lengths by Flowfish, the gold standard. And what we found was a large proportion of them had telomere lengths below the 10th percentile. That's the data on the right-hand side. So it is a real problem that we see in practice. It lives and walks amongst us. Can it help with diagnostic specificity? Apparently, yes. Those with idiopathic forms of ILD, unclassifiable forms of ILD, typically have shorter telomere lengths compared to those with a known cause for their ILD, connective tissue disease, hypersensitive pneumonitis, and others. And so it can help to ascertain the rigor, the accuracy with which we make our diagnosis in clinical practice. And I'll tell you, Dr. Newton, who's my opponent, contributed to this paper. It's bolded right there. All right, now this is something Dr. Newton actually published, right? So he told us that telomere length is really critical for looking at lung function decline. It helps identify those with more aggressive disease. In terms of the general metrics of disease progression, forced vital capacity, FVC decline, it's helpful. How about life expectancy? I told you at the very beginning of this. It doesn't matter how you look at it. When you stratify patients into quartiles, the shorter the telomere length, the worse the mortality. In fact, the data I'm showing you on the right-hand side is out of two different centers. One is Dr. Newton's center in Dallas. The other is my center at UChicago. And consistently across board, telomere shortening predicted outcomes. Again, across the different RLD subtypes, it predicts mortality. And it doesn't matter how you slice or dice it. You can look at telomere length in terms of quartiles, in terms of the median, in terms of percentiles. Doesn't matter. On the right-hand side, what you see there is telomere length dichotomized based on the median telomere length. Those who had TL50 below the median had worse life expectancy. And the panel in the middle there shows you that it seems to be an exponential inverse proportional relationship. The shorter the telomere length, the higher the mortality risk or the hazard ratio for death. And it doesn't matter what subtype you're looking at. Whether it's IPF, IPAP, CT, the RLD, shorter telomere length translates to higher mortality risk. But it can also help guide therapeutic decisions. And this is something that's new and important. We see our oncology colleagues do this all the time in the oncology space. Targeted therapy or precision care. And so when you think about IPF, Dr. Newton actually, at Dallas, looked at their cohort. And what they found was for those who had IPF, who had gotten prednisone, isotherapy, and N-acetylcysteine, they had worse outcomes if they had telomere length below the 10th percentile. They then went ahead to look at a clinical trial cohort, perhaps the largest clinical trial in IPF looking at immunosuppression, the PANTHER-IPF study. And they found that the cost of death in the people who died was largely due to short telomeres when they got prednisone, N-acetylcysteine, and isothioprine. So the mortality risk in immunosuppression in IPF appears to be driven by those with short telomeres, critically short telomeres below the 10th percentile. We also looked at this in HP, fibrotic HP. Again, we're in Hawaii. And I like to say this is the disease that the pulmonologist loves to hate. Why? It's linked to all the good things in life. Hot tubs, spas, saunas, like, you know, whatever it is, music, bagpipers long, you love birds, bird fanciers disease, you like drinking wine, winemakers disease, you like taking cheese, cheese, I can go on and on and on. So all the good things of life have been linked to this disease, unfortunately. Even in HP, with immunosuppression, telomere length matters. And so the shorter the telomere length, when you have telomere length below the fourth quartile, it doesn't appear to make a difference if you get immunosuppression with mycophenolate or not. For those who had longer telomeres, they seemed to have a survival benefit when they got immunosuppression with mycophenolate. Now, Dr. Newton thought this was really important. And he went ahead and looked at it in critically short telomeres in a larger cohort. And he showed that for these patients who had critically short telomeres, there was a six-fold increase in mortality, six times when you got short telomeres that are critically short. I don't need to say anything more. You heard from Dr. Patel earlier on about how it can help guide therapy for lung transplant, both in the pre-transplant era and the post-transplant era. Again, Dr. Newton showed that, look, this is really important for CLAD. It can help predict who gets CLAD and who does not. And so beyond that, it also helps to guide polypharmacy. Those with short telomeres tend to have a lot more medications on board than those without. So we probably should be checking it in patients before and after lung transplant. It also helps to provide actionable data for primary prevention, which is what we're all about, preventing ILD if we can, and also preventing the complications. I'm not going to go into the complications. You heard a lot about that from Dr. Patel earlier on. But it has real-life implications for the progeny of the individuals, for their offspring, for their kids. It can help to determine who's at higher risk for genetic anticipation, where to get the disease up to 10 years earlier than their parents. And you see a pedigree study on the right-hand side depicting just that. It's also important for patient counseling. How do I tell you what you ought to do if I don't know? And so additional data points really help to guide discussion, guide genetic counseling, and guide interventions for these patients. So in conclusion, don't listen to me. Listen to Dr. Newton. These are the things he said in his very own words. Telomere length represents a biomarker that may aid in risk stratification. We believe that telomere length is a feasible surrogate marker for baseline evaluation in alveolar epithelial cells. It may identify patients with IPF who are at risk for poor outcomes. And he would argue that the molecular classification specifically with telomere length could improve our ability to predict disease cause in a wide variety of ILD subtypes. So why wait? I'll tell you, now is the moment. This is the time. Let's get telomere lengths measured in all patients with ILD. Thank you. I'll actually introduce him so that we can go on with this debate. So we have Dr. Newton from University of Texas Southwestern. He's an esteemed colleague. And it's an honor to be with him on this panel. All right, well, there you have it. So that was amazing. I wish I would have put a lot more red boxes and pictures of Deji up here, but I didn't. So I am going to tell you today why we should not measure telomere lengths. But I'm going to focus on a key aspect here of all patients who have interstitial lung disease, OK? So here are my disclosures. The other disclosure that's not on there is, as has been said before, so I specialize in ILD. And I'm particularly interested in how we could potentially use telomere length and other genomic markers to influence the way that we make our decisions in practice, right? Not just for patients who are at risk of having short telomere lengths because of their family history or because of their clinical manifestations, but how could we use the genetic information that we're learning to actually influence all of our patients who have interstitial lung disease? What's the most important thing that we should know? How is this going to help me make my decision? And then how am I going to know if it's the right decision or the wrong decision? So I'm going to focus on those key aspects today. The first thing we have to think about is how do we normally do this? What is our current approach to the diagnosis and management of patients with interstitial lung disease? Our current approach has three main aspects, OK? After we establish a diagnosis of interstitial lung disease, then the guidelines state that we should try to figure out what caused it. Why is it there? And give it a name. What's the ILD subtype? And using that name plus additional information that informs what we would expect from a disease progression risk or mortality risk, and using that information together, then we come up with a management plan for the patient that's actually sitting in front of us in clinic, right? Not an abstract patient, someone that's sitting in front of us. This is what we do all day, every day. So I'm going to talk about how telomere length could potentially improve some of the ways that we do this. But critically ask, are we actually there yet? If we know someone's telomere length, along with this other information, does it actually improve what I do for that patient on that day? So first, does telomere length improve our ILD categorization, OK, our current ILD categorization? So we first started evaluating this in patients with idiopathic pulmonary fibrosis. And there's lots of studies now that show that about a quarter to a half of patients with idiopathic pulmonary fibrosis, sporadic idiopathic pulmonary fibrosis, have critically short telomere lengths. But it's not restricted to IPF. We've shown in several other cohorts and other investigators have shown the same thing, that up to a quarter to a third of patients with hypersensitivity pneumonitis, unclassifiable ILD, and even rheumatoid arthritis ILD have telomere lengths that are less than 10th percentile. That's a lot of patients. But it's not just restricted to those subsets, right? We know that even in scleroderma, there's a smaller subset of patients with telomere length less than 10th. And then if you look at big cohorts of other connective tissue diseases, there's a smaller but yet significant portion of patients who also have telomere lengths. So if you look at this, this basically encompasses all the forms of interstitial lung disease that we care for now in our current categorization scheme. And we see that there are patients in all of those groups that have telomere lengths that are short. So if I know, if I have a patient sitting in front of me and they have a CT scan that shows ILD, knowing their telomere length does not help me figure out what diagnosis they have, right? And that is what, that's kind of where our current schema lies. We have to know what caused it. Telomere length does not tell us what caused it, okay? So telomere length itself does not help us improve our current ILD stratification. Maybe that's a statement on how we actually currently approach ILDs, but either way, that's where we stand now. So the next question is, can telomere length improve our risk stratification? And I'll just stick with yes, right? It can. So we know in IPF, we know in HP, we know in unclassifiable, we know in several other ILD diagnostic groups that shorter telomere length is associated with worse survival for all of these. And even if you look at big mixed populations of pulmonary fibrosis, right? This is one by Dr. Atikonsoye, that shorter telomere length is associated with worse survival, okay? So regardless of whatever bin you put this patient in, if you know their telomere length, they're probably gonna have a shorter survival than the average patient who has longer telomere lengths. Whoops. Telomere length also informs how they're gonna behave, right, so are they gonna progress? So we and others have shown that if you have shorter telomere lengths, again, regardless of the interstitial lung disease diagnosis you give them, they probably are gonna progress a little bit faster. So their decline in lung function is gonna be exacerbated compared to patients who have longer telomere lengths. But the question really is, you know, how can we grade the impact of telomere length when we put into context all the other information we gather for these patients, right? There is nothing we do in medicine where we take one piece of data and make decisions from, right, we take everything within clinical context. So let me give you an example here. So if we just had telomere length and we graphed it against outcome risk, some sort of bad outcome risk, whether that's mortality or progression or whatever, telomere length is either short or long. So we would basically be able to fill out the opposing quadrants here. But the question is, or the thing that comes up in practice most frequently is what about the other boxes? So these are a couple of my patients, right? So I'll point to you, again, I'm a card-carrying telomere checker, okay? But this is some of the holes that we have in our current understanding. So I have an 83-year-old male. He's had IPF for a couple of years. His lung function is severely impaired and he's been on guideline-directed antifibrotic therapy for two years and is still rapidly progressing, okay? So we would all agree that that patient is probably high risk for some bad outcome in the near future. The thing is, his telomere lengths are actually not short. He's at the 50th percentile, so he falls into the kind of outside where we would expect someone that is progressing so rapidly with IPF to fall on the telomere length spectrum. On the other hand, I have another lady. She's 59 years old. She has biopsy-proven fibrotic HP. She loves birds. We diagnosed this about four years ago and she has preserved lung function, okay? She's been stable for two years just after removing the birds from her home. And so she's actually doing quite well. So everyone in this room would say, we've identified what we think is causing it. We could argue about that later, but we think we identified what's causing it. She's been stable after doing the thing that we thought we needed to do after we made the diagnosis. The thing is, she has familial pulmonary fibrosis. She has a TIRT mutation and her telomere lengths are extremely short. She's less than first percentile. So by telomere length, you would think that she's at high risk and she may be, but right now she's in this category, right? She's kind of in a lower risk category based on her trajectory over time, over the last four years, right? This is not a short amount of time in the world of ILDs, right? This is a relatively long time. She has been stable. So getting to the next question, can we use telomere length to improve medication selection? So again, I'm gonna point to a few studies that we did. So this is one that Dr. Adigan-Soye talked about. So we looked at IPF patients. We stratified them, the participants of the PANTHER trial. Those that had shorter telomere lengths that were randomized to immunosuppressant regimen, prednisone, azathioprine, and NAC, they had worse survival. Dr. Adigan-Soye showed that patients who had fibrotic HP, when stratified by exposure to mycophenolate and short telomere lengths, those that had short telomere lengths had no kind of difference in their mortality, but people who had longer telomere lengths who were put on mycophenolate had improved survival, so still differential risk. And then we recently showed, as Dr. Adigan-Soye demonstrated, that patients who had unclassifiable ILD, a fibrotic HP, who were stratified to either mycophenolate or azathioprine actually had worse outcomes, worse two-year transplant-free survival. So this data would suggest that we could use telomere length to inform what drugs we choose when we're choosing a drug. So we know that telomere lengths are associated, right? The key word there is associated with faster progression, worse survival, and probably a differential response to immunosuppression. And we and others have shown this across a wide variety of interstitial lung diseases, and there's a big data, a long list of papers that prove this point, right? So the question is, why should we not be using telomere length for all patients with interstitial lung disease? So again, there's still big gaps in what we know about telomere length and how to implement it. We have lots of data that say that telomere length is associated with all these things that we talked about. But how do we implement that at the bedside? I mean, the first big question is how do we even measure it, right? FlowFish is the CLIA-certified, kind of gold standard test that we use in clinic. But all the data that we've shown is based on qPCR. It is likely that those two things overlap, but we don't know that for sure. What threshold should we be using from qPCR versus FlowFish, right? Should we categorize telomere length? And if we do categorize it to figure out these relative risk, then what do we standardize that to? What are the optimal thresholds? What's the sensitivity? What's the specificity? What's the positive predictive value if I check someone in front of me to help me guide my decisions? We still don't know the answers to those questions. And then what are the actual outcomes that we should be looking at, right? Most of these data look at change in FEC, look at mortality. We know that those are clearly important, but we haven't looked at quality of life. We haven't looked at non-pulmonary manifestations in these patients with a lung-dominant disease. These are still major gaps that we need to answer to understand how to implement telomere length testing. As far as medication strategy, what's actually the best treatment approach to patients with non-IPF ILD? We have evidence base for IPF. We have an evidence base for scleroderma. There's not a huge evidence base, at least randomized controlled trials for fibrotic HP, for unclassifiable ILD. So what is the gold standard in which we should compare using telomere-informed treatment decisions? We still don't exactly know. So we need to answer these questions to be able to know that using a telomere-length informed decision-making is actually going to improve outcomes for our patients, right? We need to know what the optimal measurement modality is. We need to be able to outline informative thresholds and calculate test characteristics, and then incorporate all that other information that we use on a regular basis to know, does telomere length add to that information? All right. We need prospective validation, ideally stratified randomized controlled trials for telomere-informed medication selection. All the data that we've shown today is retrospective, and it's informative, but it's not the end-all be-all or should not be considered that. And then we need to define the optimal application of telomere-length measurement that actually improves our patient outcomes. What can we do for them to make them better? We still don't know the answer to that question. So based on that, I would say we're not quite ready to use telomere-length for all patients with interstitial lung disease. Thank you.

telomeres

interstitial lung disease

telomere length

inherited

lung transplant

complications

risk stratification

medications