Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we're exploring the role of short telomere syndrome in lung transplant outcomes. Joining me is Dr. Brandon Janssen. He's a transplant pulmonologist and critical care specialist and a Clinical Assistant Professor of Medicine in the Division of Pulmonary Critical Care and Sleep Medicine at the University of Florida.

Dr. Janssen, thank you so much for joining us today. We're going to start a little bit with the big picture. When we talk about telomeres, we're talking about one of the fundamental mechanisms of cellular aging that we know about. So for listeners and providers who may not think about this every day, they may not be in this space, how do you explain telomeres and their biological role? Let's kind of give a little physiology lesson here.

Dr. Brandon Janssen: I think that's a perfect place to start. So, the human body is made up of cells and some of those cells divide across a person's lifespan and others don't. And those cells that divide, they require a replication of their material in their DNA, and that DNA is composed of two paired strands that essentially face an opposite direction. But the cellular machinery that creates a copy of that dNA only works in one direction. So, this sort of creates a problem for the cellular reputation process where you have one strand that can be copied essentially continuously without much problem. And then, you have the other strand that is called the lagging strand that has to be copied in fragments called okazaki fragments.

 And it's this fragmented replication process that can lead to a loss of genetic material with each replication cycle of the cell. As you can imagine, it's a problem if with each replication of the cell, you lose genetic material that's responsible for making parts of that cell. So, evolution solved this problem by essentially creating these throwaway caps that sit at the tips of your chromosomes. And it's these throwaway caps that act as a sacrificial buffer during the replication process that little pieces of those caps are lost with each replication cycle. And it's those caps that are called telomeres. And so, you can think of telomeres sort of loosely being analogous to the plastic tips on your shoestrings. they just kind of sit at the chromosome and help provide protection for the replication process.

Melanie Cole, MS: Wow. That was an excellent explanation. You're a great educator. So as they function to protect that chromosomal integrity, what happens biologically when telomeres shorten beyond a critical threshold? How do we define short telomere syndrome? What are the spectrum of disorders does this fall under part of an umbrella?

Dr. Brandon Janssen: Yes. So, telomere shortening happens normally with each replication cycle, and it can be thought of as a biomarker for cellular aging. And we think that, in general, cells can divide around 40 to 60 times before they reach a condition called senescence or apoptosis. And senescence is really just a process where a cell no longer divides, and apoptosis is programmed cell death. And it was later found in research that a limit of 40 to 60 divisions is at least in part related to telomere length. And there's a few exceptions to this, mainly stem cells and germ cells, where there's an enzyme called telomerase that actually counteracts and rebuilds the telomeres each time there's a replication cycle. So, on one hand, short telomeres can be thought of as a bad thing because it activates cell death and cell senescence. And that can also be thought of as a good thing, because the absence of the ability to replicate indefinitely can lead to things like cancer.

And so, the way that short telomere syndrome can present in patients with underlying lung disease. So, in the lungs, the lungs have an epithelial surface that maintains and repairs the gas exchange surface of the lungs. And if you have telomeres that are prematurely short, then those cells can undergo stress and not be able to repair themselves normally. And then, this can lead to a maladaptive repair process where the cells in the lungs can have early senescence, early cell death, and ultimately lead to tissue fibrosis in the lungs. And so, this mechanism that ties short telomere syndrome to fibrosis in the lungs has been validated in animal studies where they were able to demonstrate that telomere dysfunction by itself, specifically confined to these type II alveolar cells was sufficient alone to produce this age-dependent lung fibrosis.

So, a lot of the patients that we see with short telomere syndrome and pulmonary fibrosis, we think that this is the underlying manifestation. And so, short telomere syndrome can present in many different ways. And usually, it affects tissues that are always dividing. So, you can think of tissues of the bone marrow, the skin, the GI tract, or the mucosa, because these tissues essentially have as a part of their program to always be replenishing themselves.

For those reasons, patients can present with isolated cytopenias, so low cell counts. Their skin can present with this lacy reticular appearance or pigment changes. You can see changes in the nails. You can see non-specific GI symptoms and the things like esophageal stenosis. And then, one of the more common ways that patients with short telomere can present and probably like the classically taught way is that they tend to have premature graying of the hair, because hair cells have high melanocyte stem cell turnover. And so, that high turnover combined with short telomeres tends to cause premature graying. And, so a natural question might be, "Well, what do you consider premature?" And we consider premature as a patient with graying of the hair in their 20s and 30s.

Other ways that it might present, I think I already mentioned that it can present in the lungs. And that's not because necessarily that the lungs have a high amount of automatic cellular turnover as a program, but the turnover of cells in the lungs tends to happen as a result of repeated injury or exposures. And so, you might have a patient with isolated lung disease for that reason. But you can also have another organ affected, mainly the liver. And so, we do tend to see patients that have isolated liver disease, liver cirrhosis, liver fibrosis, and other related issues in the liver. And that might be the way that those patients present.

Melanie Cole, MS: That's so interesting. So, shifting a bit to the pulmonary side, I'd like you to speak about the relationship between short telomeres and advanced lung diseases like idiopathic pulmonary fibrosis. How does that actually contribute to disease progression at the tissue level, Dr. Janssen? And what are some of those implications in advanced lung disease?

Dr. Brandon Janssen: So in the lungs. the lung epithelial surface is maintained by type II alveolar cells, and those cells undergo quite a bit of turnover as it relates to exposures to things in the environment. And so, as a person with short telomeres has more exposures, they tend to have a stress of the regenerative capacity of the cells in the lungs that repair that epithelium. And over time, that can lead to cell death and fibrosis.

And so, short telomere syndrome can commonly present with interstitial lung disease for that reason. But it can also present with a condition called emphysema, which is typically a condition that we see in smokers. And the most common diagnosis that's associated with short telomere is idiopathic pulmonary fibrosis. And actually, patients with short telomere syndrome that have idiopathic pulmonary fibrosis are associated with a more rapid disease progression and worse survival. And that sort of highlights the importance of early referral to a lung transplant center because those patients tend to behave differently when they have shortened telomere length.

And then, the other less common way that this can present is as emphysema. And so, that tends to especially occur in patients who have a smoking history. And so, there's another condition that presents in smokers with early emphysema. It's called alpha-1 antitrypsin deficiency, or it can even present in patients who don't smoke. So if you have a patient with emphysema that is occurring at a relatively young age or with a relatively low inhalation exposure history, and you test for alpha-1 antitrypsin and that's negative. And I think it's good to think of short telomere syndrome in that setting.

Melanie Cole, MS: Okay. So at what point in disease course would someone like you should transplant teams be thinking about short telomere syndrome, lung transplant evaluation? Speak about listing considerations and where that comes into this picture.

Dr. Brandon Janssen: Well, really our recommendation and the recommendation of our guidelines at the International Society of Heart and Lung Transplantation really recommend referral of patients with known or suspected short telomere to occur at the time of diagnosis. In part due to this knowledge that we have that they tend to experience a rapid disease progression, tend to have worse survival, and they also tend to have a high complexity burden during the evaluation process.

And so, not uncommon for our patients with short telomere to come to us with various issues that we have to sort of differentiate quickly. They may need things like bone marrow biopsies for low blood counts. We may need to get hematology consultation. If we find that they have liver involvement, they may need liver biopsies to assess for cirrhosis, we often have to get our hepatology teams involved. Not unheard of, but extreme cases we may even consider patients for multi-organ transplantation who we transplanted both their lungs and their liver because of short telomere syndrome.

And so, really short telomere adds quite a bit of complexity to lung transplant and the entire evaluation process is when you have high complexity with transplant, time is your best friend. So. Early referral of these patients is extremely important.

Melanie Cole, MS (Host): Well, early referral and that's so important when you're talking about those indications. But Dr. Janssen, we're at this critical decision point, as you said, it can, You know, exacerbate quickly, how does that diagnosis influence the evaluation as far as modifying the listing criteria for these patients? Are there contraindications? Tell us a little bit. And while you're telling us that, talk about management on the wait list.

Dr. Brandon Janssen: Short telomere syndrome creates many perioperative and even postoperative challenges for us in transplant. And just as an example. patients with short telomere syndrome are likely to have a longer listing because it takes us a little bit longer to find suitable donors that have favorable infectious disease and immune risk profiles.

And a specific example of that might be that, we know that patients with short telomere syndrome have a relatively low bone marrow reserve because of the telomere length there. And so, we're going to try and fit them with donors that have low potential for things like CMV reactivation or CMV mismatches because we know that the treatment for those conditions are highly suppressive of the bone marrow, like drugs, like valganciclovir, as an example.

We're also going to look for patients that don't have very many immune mismatches that might necessitate a process called desensitization. So in some cases of transplant, we can have relatively mild mismatches from a crossmatch standpoint, and we can treat them ahead of time with T-cell depleting agents like antithymocyte globulin and doing plasma exchange. But we know that T-cell depleting agents are very toxic to the bone marrow of patients with short telomere syndrome. And so, that would be something that we'd try to avoid and trying to avoid that can lead to a longer time on the wait list while we're looking for an appropriate donor.

Another specific example might be exposure to toxoplasmosis. An another consideration in lung transplant that we have to place patients on a medication called Bactrim or another similar medication to prevent PJP after transplant. And one of the primary medications that we use is called Bactrim. And Bactrim can be pretty hard on the bone marrow. And so, in patients with short telomere syndrome, we commonly have to use alternative medications that you give as an inhalation to prevent PJP. But unfortunately, if you have risk of toxoplasmosis after transplant, you need the medication Bactrim. You can't just have one of these inha inhalational medications. And so, that can create an issue where we need to give medications like Bactrim, but that can be toxic to the bone marrow. So, we try to avoid a mismatch of toxoplasmosis, which means where the donor has exposure to toxo, but the recipient does not. We try to avoid that in the lung transplant process so that we can avoid giving Bactrim if needed.

Other things that we consider, you know, patients with short telomere after transplant may need treatment with granulocyte colony-stimulating factor, also called Neupogen, to help restore blood counts when they're low from our immunosuppression. They tend to require more frequent need for blood transfusions, which can be immunogenic after transplant. They not uncommonly develop cytopenias, sometimes even early in the post-transplant course, like for example, in our ICU. And we'll have to either reduce the dose or discontinue medications like mycophenolate mofetil for that reason.

And then, less common circumstances, patients that have ultra short telomeres with less than the first percentile, they can have mucocutaneous problems like impaired wound healing.

And for those patients, we have to be hypervigilant for anastomotic complications like dehiscence and other types of wound healing problems. And so, really, the pre-transplant monitoring that you have for these patients is basically the same as the post-transplant monitoring that they need across their lifespan after the transplant. We need to continue to monitor for things like liver disease, continue to screen them for malignancy, continue to evaluate their bone marrow function with laboratory testing, and just be constantly making modifications as needed as we go.

Melanie Cole, MS: Such great information. As we get ready to wrap up, Dr. Janssen, I'd like you to speak about the role that a multidisciplinary input—hematology, genetics—play in this whole process you've described for us today. And are there any research or innovations that you're most excited about that you'd like other providers to take away from this great discussion that we're having today?

Dr. Brandon Janssen: Our multidisciplinary teams are extremely valuable to us. They really help to guide our decision-making about patients going through the pre-transplant and even post-transplant process. We commonly face issues like hematologic or other skin-related malignancies after transplant in these patient populations. And so, having access to these specialists is critical for us to help co-manage these patients who are extremely complex at baseline.

And some of the things I'm most excited about are relatively basic. One of the challenges that we face is limited access to testing for short telomere syndrome. It's a highly specialized test. And for us at the University of Florida, it's a send out test, which is very common for most transplant programs. And so, one of the things I'm excited about is the improvement in the technology for telomere length testing to the point where it can be a more ubiquitous availability to transplant programs and allow for ease of testing and more patients to be testing, which will help solve the problem of underdiagnosis and underrepresentation of the short telomere syndrome patients.

Melanie Cole, MS: Thank you so much, Dr. Janssen, for joining us today and really sharing your incredible expertise and information with us today. And to learn more about this and other healthcare topics at UF Health Shands Hospital, please visit innovation.ufhealth.org. And to listen to more podcasts from our experts, you could always visit ufhealth.org/medmatters.

That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole.