Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. and today, we're highlighting chronic lung allograft dysfunction. Where are we in 2025? Joining me is Dr. Adriana Valverde Zuniga. She's a lung transplant respirologist, and an Associate Professor of Medicine in the Division of Pulmonary Critical Care and Sleep Medicine at the University of Florida College of Medicine.

 Dr. Valverde, thank you so much for joining us today. I'd like to start with this topic. This is a very interesting topic. Can you define how we currently conceptualize chronic lung allograft dysfunction in this day and age, how the definition has evolved over the past decade or so? Tell us a little bit about CLAD and how often it occurs.

Adriana Valverde Zuniga, MD: Thank you, Melanie, for the kind introduction and for the invitation to speak here today. So, this is a very important topic for a lung transplant patient, because as you may know, like 50% of our patients develop a CLAD at five years mark. So as lung transplant physicians, we like to call CLAD our Achilles tendon. That means that we are actively working on trying to reduce the CLAD rates in order to improve the survival of our patients.

So basically, when we speak about CLAD, it's when we start seeing a loss in the pulmonary function after the transplant, of course, that is related with a chronic rejection. And this is basically a terminology that was first documented like around 1993. At this point, the FEV1 was the most consistent marker of chronic dysfunction, and it was defined the term BOS, which means bronchiolitis obliterans syndrome. After this, the terminology has varied in the years. And it was around 2010 when it was actually introduced, the terminology CLAD itself. And the RAS phenotype was proposed as a different phenotype from the BOS.

In 2014, it was recognized by the ISHLT, which is like International Society of Heart and Lung, the two different phenotypes. And also, at that point, it was introduced the term ALOD, which is the acute lung allograft dysfunction, and is defined as the drop of more than 10% of the FEV1 of the patient. So, starting in 2019, ISHLT recognized the CLAD definition of possible, probable and definite. And also, different stages were defined at that point, according to the FEV1.

So to go back to your question, we can define a CLAD as the decline of more than 20% of the baseline FEV1 of the patient post-op, at least separated by three weeks of difference. So, what happens is after the lung transplant, we will be performing regularly spirometries on our patients. Usually, for the first months, we will do it weekly. And after that, we will space them, but it will be like always like around one month period during the first year. So, that will allow us to calculate the best lung function possible. And that's the average of the two better FEV1 separated at least three weeks.

So after this, once that we have the baseline, that's how we define the baseline, when the patient drops the lung function, we are going to suspect that something is happening, and that's when we start suspecting CLAD itself.

Melanie Cole, MS: Well, thank you for that. That was an excellent explanation. And Dr. Valverde, you mentioned the phenotypes. And by assigning them, does this matter? Why do they matter when we're talking about this definition?

Adriana Valverde Zuniga, MD: Yeah. Of course, they really matter. And I am going to tell you why. So first of all, once that we start seeing this decline in the lung function, usually what the literature recommends is to start performing investigations when the drop is more than 10%. So, I always think of CLAD, like kind of Sherlock Holmes investigations, because CLAD is a diagnosis that is made by exclusion. So, you need to make sure that nothing else is happening. That means the patient is not having an acute infection or an episode of acute cellular rejection, an episode of antibody-mediated rejection as well or any other factors like airway stenosis or extrapulmonary factors as well.

So once that we rule out everything and we consistently see like this decline in the lung function, we can start saying this is possible CLAD. And if this decline is maintained between three weeks and three months, we call this probable CLAD. And if this happens for more than three months, then we will set that the patient is definitely on CLAD. And that's when we phenotype this patient. And we phenotype the patient, not only based on the spirometry itself, but we also do it based on the plethysmography, which is the total lung volumes, and also the CT findings.

So, there are four different phenotypes, but there are two that are like the most prevalent and also the most important ones. So, the first one is the BOS that I already mentioned that it was actually the first that was described in 1993. So basically, this phenotype is defined by obstruction in the spirometry. And also, when you look at the CT scan, like there are no opacities. There can be like some kind of bronchiectasis in the CT scan and some kind of air trapping, but no opacities. And very important, the plethysmography has to show no restriction, so that means that the TLC has no decline.

For the second phenotype, which is the RAS, the restrictive phenotype, basically this one is characterized by the presence of restriction in the plethysmography. That means that the TLC, which is the total lung capacity, will decline more than 10% from the baseline. Very important. There has to be no obstruction in the spirometry. And usually, we can find a lot of opacities in the CT scan that are usually more prominent in the apices of the lung. And it has like this kind of retractions and interstitial thickening as well that is very characteristic of this phenotype with traction bronchiectasis also.

And after this, we have two more phenotypes that actually the mixed one, which has obstruction, has also the drop in the TLC, and has also opacities; and also, the undefined phenotype. The most important difference between BOS and RAS is in terms of survival. So, we have seen that RAS patients behaves very poorly compared with BOS. Basically, we can see that their survival is even worse than cancer patients. And like, most of the time, we are not able to stop the process of chronic rejection on them. Otherwise, BOS, they can be like more responsive, and they can stabilize and then drop again and then stabilize. So, it's not like this quick drop that we can see with most of the RAS patients.

Melanie Cole, MS: Dr. Valverde, are there factors you can point to that have been shown to predispose lung transplant patients to the development of CLAD? When we think of GERD, when we think of infections, and you mentioned rejection. And while you're telling us that, is there an immunologic basis for CLAD that you can point to as well?

Adriana Valverde Zuniga, MD: All of those factors play a very important role in CLAD actually. So to start with infections, we have seen that several kind of infections, but most importantly, CMV reactivations, pseudomonas, aspergillosis, basically plays a very important role in CLAD development. But also as you were pointing, like rejection plays a very important role. So, the patients that have recurrent episodes of acute cellular rejection are more prone to develop CLAD. But also, there is an immunological risk with the patients that have a mismatch on their HLA with the donor, and they are more prone to develop the novel antibodies against the new lungs.

And in that context, there are the DQ antibodies, which are class two antibodies, are worse than the other ones. They have shown to confer more risk compared with other kind of the novel DSAs. So basically, the patient that will have more risk is the patient that develops the novel antibodies. But on top of that, if these antibodies are DQs, they will have even four times more risk to develop CLAD. It's very important when we look back, because most of the times at this point, at least, we are not allocating lungs based only on DQ mismatches. That is something that the Toronto group has been exploring. But when you look back, there are two things in terms of the DQ, two different kindS of antibodies, the DQ2 and the DQ7, that has been shown to cause worse outcomes in terms of immunological reaction basically. And this, of course, can at the end cause the CLAD itself, contribute to the CLAD development basically.

 You also mentioned GERD. And GERD is a very important complication. it's not a complication, it's a very important comorbidity that can happen in our patients. We are very strict with all the GI testing in our program at UF because we feel that reflux itself can trigger a lot of all these immunological responses. So GERD, it's a very important thing that we need to take into account, and that's why we always have a team between SLP and our GI team that is very skilled and we perform different investigations from esophagogram, manometry, pH as well to make sure that the patient has nothing that we can optimize in terms of GERD. Because GERD cannot only like cause inflammation and the developing of the CLAD, but also it can triggers the antibody production according to some of the literature.

Melanie Cole, MS: Yeah, that's an interesting association, which lends itself to the multidisciplinary factor and approach where many colleagues are also contributing to questions and the conditions. So when we look at the treatment, Dr. Valverde, historically treatment options for established CLAD have been rather limited. So, what's exciting right now? Which interventions are emerging? Tell us a little bit about what's going on right now.

Adriana Valverde Zuniga, MD: So, I think, basically, all the lung transplant community is trying their best to find a way to prevent the CLAD development or even to find like biomarkers that can help us to identify the patients that will progress towards that. So, we can basically stop the injury. But so far, it's very important, the role that is playing, the cell-free DNA, that of course it has to be interpreted in terms of all the rest of the testing. But this provides us a good idea if the patient has like ongoing concerns that we need to dig further. Also, it's very important that some of the different teams are also exploring the potential role of CT scan in finding different markers of CLAD development as well. And those two, basically in terms of diagnosis.

In terms of therapeutics, you are right, there is not a lot right now that changed the course of CLAD itself. There is a lot we can do like in terms of preventing CLAD. Basically, we can make sure that the patient has good immunosuppression. That's the most important thing. Also, we can make sure as we discuss that the patient has no GERD. And we can plan for some interventions like fundoplication or something else if needed as well.

And in terms of different medications, we have the azithromycin. The azithromycin basically reduce the neutrophilic inflammation of the airway and also reduce the expression of the interleukin A. So basically, it has been documented in some studies that it can in a subset of patients basically reverse the drop in the lung function. And those are the patients that are responsive to azithromycin.

So, there are different ways of using the azithromycin worldwide. Sometimes the program prefers to start the azithromycin since the beginning to prevent any dropping. And sometimes it started when there is a drop of more than 10%, and other times when actually CLAD is already established. But azithromycin is still a good option. There are other medications, the literature is less. Like, for example, the lukast, that is an antagonist of the receptor of the leukotrienes. And it has been studied mainly by the Leuven group, and some programs used Montelukast as prevention, but there is not a lot of data as well.

There is also the possibility to use cytolytic therapies. Like, for example, if we have a patient that is even with bolus, so we gave them a steric bolus and they continue to progress very rapidly, like those that we think they are behaving like rapidly progressive CLAD. So for those patients, we can also use like Thymoglobulin to try to block all the inflammation and all that response. So, that's an option as well.

And one of the options that is more important right now is actually the extracorporeal photopheresis that has been a studied like in different centers around the world. But I will say that London and Vienna are two of the centers that have invested more in this therapy. It's generally very well tolerated, actually. And basically, what it does is that it induces the apoptosis of some of the lymphoid cells, mainly NK lymphocytes and also the T cells as well. And this is mediated by the exposition to ultraviolet light Class A. So basically, when the lymphocytes got exposed to this kind of light, it stabilizes also the T‑RECS and it helps to stabilize the inflammation and also to prevent the further progression of the CLAD itself. However, there is a lack of control studies, but this is an option that we can use. It has been a study in both in BOS and also in RAS kind of phenotype as well. But I have to say, to be totally honest, that there is a point where we have limited options and that the only option available will be to offer a retransplant for the patient.

Melanie Cole, MS: Well, that's right where I was going next. So, what role does retransplantation play in the modern era? When do you consider that? Speak a little bit about patient selection and the important criteria.

Adriana Valverde Zuniga, MD: Yeah. So basically, it's very interesting because we have seen a growth in the re-transplant population, of course, because now there is more experience performing lung transplantation worldwide. This is like the only treatment that actually will prolong the survival of the CLAD patients.

It's very important that in order to be able to offer a retransplant, we need to see if the reason why the first graft failed is something that we can fix. For example, if the patient was having a lot of infections, it's something we can do for that. Or if this was triggered because of GERD, can we fix that before offering a retransplant? Also, it's very important to take into account how much time did the first lung transplant last? Because by definition the retransplant will last less than the first transplant. So for example, if the graft failed at two years, only if we re-transplant that patient, that means we are offering them probably less than that. So, that makes sense for the patient. You know, that's something we need to consider.

Also, it's very important that for retransplant candidates, we do not desensitize. So, it has to be a match donor in terms of the HLA. And also, for RAS patients, they have worse survival and also the retransplant itself, it's more difficult technically speaking because they have more adhesions and they tend to bleed more. So, all those things we need to consider in order to think about retransplanting a patient basically.

Melanie Cole, MS: This is fascinating, Dr. Valverde. And as we wrap up, I'd like you to speak about how you envision the next five years in CLAD research and management. What role you feel that artificial intelligence and machine learning might play in predicting CLAD risk or tailoring management to the individual patient and what you want the messages to be to share with colleagues that are working to improve the long-term outcomes for lung transplantation.

Adriana Valverde Zuniga, MD: So, I hope during the next years we will be able to take all the different tools that we already have and implement them with AI in order to be able to create a tool that allows to diagnose the CLAD more early in order to make interventions that help us to prevent further damage of the graft basically.

So as I was saying before, there are different centers that are working on different CT techniques to try to quantify different small airway damage that can be part of the pathophysiology of the rejection itself. So where I see this going is al of this getting together in a way that AI can help us to interpret better who's going to develop the rejection, and also to be able to catch these patients early and start doing interventions early before the graft has suffered.

So, I think all the lung transplant community is working very hard towards that. I know there are some efforts trying to assess different tools like for example, the FeNO, to try to look for eosinophilic inflammation in the airways as well, this eosinophilic inflammation that can also be related with the CLAD development itself. So, I think we are going towards that. Also, there is very impressive interventions happening, like for example, in the Vienna team that they are trying to do a more personalizing immunosuppression with different tools like for example, the torque teno virus. So, there is a lot of exciting things happening to be totally honest, and I'm excited for what the future will hold in this area.

Melanie Cole, MS: This was an absolutely fascinating conversation and very enlightening and informative. You've really given us a lot of information to consider as this moves forward. So, thank you and I hope you'll join us again as the research shows more improvement for lung transplantation. And to learn more about this in other healthcare topics at UF Health Shands Hospital, please visit innovation.ufhealth.org. And to listen to more podcasts from our experts, you can always go to ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole.