Hi, guys, everyone bathroomed up and ready? Okay, so we're going to talk about lung transplant. Again, just like for the pH talk, as I discussed, there's probably more slides than we'll go through in detail, but they're good, just good to have as your, to look at before the boards, and again, bolded those things that I think may be important for the boards. I think oftentimes lung transplant isn't in a lot of different meetings, and so this may be a good review for those of you who haven't heard about it for a little bit as well. So I did put things, likely won't be on the board, but to kind of keep updates on what's going on in the field, especially as we're doing more. So this is kind of what we're going to talk about. And remember, lung transplant still is the best therapy for many patients, not all, with certain end-stage lung disease for which we have no other surgical therapy or medical therapy available. When you look at, this is an older slide from the ICHLT, but maybe the most recent in terms of this slide, and I like it, is that over time, this is international, from the International Society of Heart Lung Transplant, the progression or increase of transplants in the last decade has really increased exponentially. So I think all of the transplant centers should be proud of themselves for increasing these numbers throughout the world. Same thing goes for the U.S. This is from the SRTR, and it kind of shows you there was a little bit of a decrease around the time of COVID, but basically patients are still increasing the numbers of transplants in the U.S. Certainly it's always been that there's been more bilateral lung transplants being performed because there is an improved outcome than singles, but there's still room for these patients who are older, may have comorbidities, or may have a surgical issue to have a single lung transplant. These have remained relatively stable, while the bilaterals are really the place where people are really increasing the numbers. You can see that this green line, which is restrictive lung disease, maybe ILD and IPF, are really the lion's share of why we do transplants now. COPD, which used to be one of the highest, is pretty stable, as are others. A new fact in the last three or four years is that cystic fibrosis, since all of the new therapies for CF have been available, really have delayed or prevented lung transplants. So those have declined significantly, as well as pH did the same thing many years ago when we had therapies available for us. So both of those have declined in numbers, and ILD, IPF really have taken up the most of all the transplants. So although we've been doing really well in terms of our numbers, really internationally, we still have the problem that we're lagging behind other organs in survival. This is a slide, again, from a few years ago from the ISHLT, which shows in different eras this is a survival, and basically the survival hasn't changed a ton in terms of long-term survival with the median survival only at about seven years. And why is that? I think the big reason is when you look at the reason people have morbidity and mortality after lung transplant, within the first year there's a cadre of reasons that you could mainly infection, but after about a year, chronic lung allograft dysfunction, or CLAD, or chronic rejection, really takes over and really maintains the high point for the reason patients die after transplant for the rest of the patient's life. And as you can tell, you know, over time this idea of progressing in terms of CLAD increases as time goes on, and really CLAD has a kind of combination of risk factors, both immune and non-immune injury, that really takes over with the progression of time, and we'll follow that up when we talk about rejection. You know, guidelines for when to refer and what types of patients to select in terms of candidacy has changed almost every few years. And even in between the times of these different guidelines, different centers are being more aggressive. They're doing things that maybe other centers may not consider, and that kind of pushes the needle forward. And so the most recent set of guidelines is in 2021, and that's from the ISHLT, and this is the article I think it's really good to have to really, it goes into detail that we aren't going to go into today about different times of referral for different patients, different types of disease states, and different comorbidities. It also goes through specific indications and contraindications. In general, which we'll have time for today, in general things haven't changed much, really a high risk of death from their lung disease within two years if transplant isn't performed, as well as a high likelihood that patients will survive from other morbidities after their transplant. So if they have severe heart disease and renal failure and all these other things that may impair their survival later on, they still may not be a good transplant candidate even if they made this candidacy item. And then absolute contraindications. This has changed frequently over the years. Relative contraindications may turn into absolute or absolute may turn into relative. All depending on the center's experience and what they feel confident in doing. There are absolute contraindications as well. This paper will go through all of this. Heart-lung transplant, as you can see, this is an international evaluation, and look at this is only about 50 transplants in the world were done in 2018, and the thing is is that in the U.S. only about 25 were performed last year. The reason to do a heart-lung transplant would be for patients who have advanced cardiac and advanced lung disease that are not amenable to either an isolated heart or lung transplant. Most patients with pulmonary arterial hypertension, which used to be a much more common indication, are still doing well with just an isolated bilateral lung transplant depending on multiple indices in their hemodynamics and whether they're on inotropes and whether their right ventricle will be able to remodel, as most are. It's a very, very thorough and long pre-transplant evaluation. I think this looks a lot like, maybe a little bit bigger than the pulmonary hypertension workup we looked at, but really includes things from clinical, serological, hemodynamic, psychosocial nutrition and social areas, and really is important in each, each are important in their own right to see if a patient could undergo a lung transplant successfully. In terms of post-transplant recipient monitoring and management, you know, you want to think about this as you're looking at the patient and you're looking at the graft. Obviously, they're one and the same, but when you're talking about graft monitoring, we in transplant centers, we're looking at pulmonary function tests because that is the way we really diagnosed a little bit of graft dysfunction, whether it be acute or chronic or at least identify it, and then doing surveillance bronchoscopies. About 80% of programs in the world are doing surveillance bronchoscopy, and then obviously if they need a bronchoscopy because of decrease in PFTs, those are being done as well. There's newer biomarkers we can talk about in the question and answers, none of them are exactly ready for prime time, but are being used by centers intermittently. And then imaging is also important. But then you look at the recipient monitoring, I mean you really need to not just look at what's going on with the graft, but remember, based on our immunosuppression, these patients are at higher risk for infection, they're at higher risk for malignancy, they do have drug-drug interactions, they have drug adverse effects or adverse reactions, and those need to be followed very, very closely. So along with regular history, physical, and labs, you're looking at CMV reactivation, you're looking for medication side effects, which can affect the liver, the kidney, the skin, it can affect many different things, and you can induce new diabetes. These patients are very closely followed for all of these comorbidities that is aside from the graft. Again, this is just a chart that, you know, and you can take it or leave it, but I made it up based on what I've been used to in terms of a post-transplant surveillance monitoring, when you do things, how often you should do things, but no matter what, you can see that it's very thorough. Most patients are getting either home spirometry or spirometry in the office every time they see them, as well as imaging, labs, and surveillance bronchoscopies. Obviously, if someone's clinically worsening, you would do all of the above. I think we came up for our first question. What diagnosis is this biopsy consistent with? A, chronic lung allograft dysfunction or CLAD, B, acute cellular rejection, C, CMV pneumonitis, or D, invasive aspergillosis? Excellent. Well, 58% of people got it right, and 35% did a good job knowing because actually acute cellular rejection is a risk factor for chronic lung allograft dysfunction, so it's not the right answer, but it can be associated, and we'll go through that. So the answer is B, and we'll talk about acute cellular rejection in a minute. This is just a slide showing us that there's many different types of rejection. What we're going to talk about today is going to be acute rejection and chronic rejection. Acute rejection is really recognized within 24 hours and probably is very, very rare and uncommon, probably not on your boards. Acute rejection is split up into acute cellular rejection, which is likely going to be on the boards, but acute antibody rejection, probably not yet, ready for prime time, and then chronic lung allograft dysfunction, which has two phenotypes, the most common bronchiolitis obliterans syndrome, and then restrictive allograft syndrome. So in terms of timing, really the timeline of allograft dysfunction really is based on the type, and really identifying it early is important. So acute cellular rejection, really within the first two years, is the most common time period, but you can see it later on. Antibody-mediated rejection, which we'll talk about, really comes up earlier on but can last longer and clad. Again, we talked about really being after one year, but most likely after two. So let's talk a little bit about acute cellular rejection or acute rejection, again, split up into ACR, acute cellular, and AMR. Acute cellular rejection is really mediated by T cells that recognize HLA or other antigens on the graph. Although we'll talk a little bit about AMR, I just want to let you know they can both lead to clad, they're both risk factors, and they can exist together. Acute cellular rejection, the most common, it really is most common in the first two years. It's the most commonly diagnosed, basically because we've been looking for it for a long time and we know exactly what we're looking for. It does have a high association with chronic lung allograft dysfunction, both severity, how severe the ACR is, and the frequency. So if you have one episode of minimal rejection, you may not have a big association with clad, whereas if you have several or very, very high severe ACR, it would be more common to lead to clad. Again, the common risk factors are decreased immunosuppression, whether because the patient was not following his immunosuppression or maybe an interaction that made the drug go down. The diagnosis, clinical assessment is very nonspecific. They can have shortness of breath, they can have a minimal fever, they may have a little bit of a cough, but they very commonly and more commonly are nonsymptomatic. Imaging also is nonspecific, not a lot of changes, maybe a haziness, maybe a little bit of an effusion, but really nonspecific. Pulmonary function is the way we identify it with a decreased FEV1 and FEF, but again, nonspecific. So acute diagnosis would be definitively by histopathologic diagnosis. And this is the ISHLT grading of the ACR, and it's really this, and you saw this before, this kind of perivascular neutrophilic infiltrates around the vessel in a very mild part of the disease, and as the disease progresses, can go out into the interstitium. And then this is the grading, which you won't have to know, but it has both a parenchymal grade as well as a bronchial grade. So these are really the gold standard, and what will be probably on the exam is that a perivascular mononuclear infiltrate around the vessel, and that is the gold standard. But again, even though that's a gold standard, and this is just an aside, there's still a very large intervariable reading between pathologists about what is and what isn't. So even though it's the gold standard, there's a lot of changes. There are documents now that was just published this summer looking at how we can better identify this without having to go through all this intervariability based on a grid of just different tests done by the pathologists. So that should hopefully help. Therapy for acute cellular ejection really is usually quite successful, and that's very good for the patient. They are very happy to hear that it's easily treated for an easy mild to moderate ACR, usually high-dose steroids followed by a taper. Oftentimes we switch around the maintenance therapy, and then when we are doing that, we usually give prophylaxis for infection. Therapy for refractory ACR, a very, very severe ACR, may be another course of steroids. And again, maybe adding ECP or extrapolar photophoresis, and sometimes anti-lymphocyte antibodies. Antibody-mediated rejection is different. It's a B-cell rejection, and it's when the binding of the recipient antibodies directed at the antigens of the donor. So it's antibody-mediated rejection. It's really long established in the kidney and some in the heart, and really it's been only evolving in the last 10, 15 years in lung transplant. We know that antibodies have always had an association with rejection. Donor-specific antibodies or antibodies directed to the donor are absolutely now identified as risk factors for CLAD, decreased CLAD-free survival, and just general survival. So donor-specific antibodies are important, and we check them quite often. This is guidelines from the 2016 ISHLT consensus group looking at how do we diagnose pulmonary AMR, and at that time, it was decided that circulating donor-specific antibodies, allograft dysfunction, features of AMR, staining for complement binding in the graft, and exclusion of other causes were reasons to identify this as antibody-mediated rejection. This guideline is being redone right now and should be out in the first of the new year looking at identifying better ways to identify antibody-mediated rejection. If identifying AMR is difficult, treating it is even more difficult. These therapies are not easily implemented, they're not benign, and sometimes they're not available based on insurance and based on where patients are. It's really to decrease or deplete antibody production or, once it's there, to deplete the antibody itself using either Plex therapy, other kind of B-cell depleting therapies like Rituximab and other proteasome inhibitors, IVIG, and complement binding. So these are what's used, but there's no actual standard of care. CLAD or chronic lung allograft dysfunction, again, is the most common cause of mortality in lung transplants after the first year, and it is divided itself into two distinct phenotypes, an obstructive form, bronchiolitis obliterans syndrome, as well as restrictive allograft syndrome, which is a restrictive form. Chronic lung allograft dysfunction in 2019 also had an update in its identification. It's a kind of clinical pathologic diagnosis, but the identification is made based on functional status, so based on PFTs. So basically, if a patient has a substantial greater than 20% drop in their FEV1 and it's persistent for greater than three months, then you can call it definite CLAD. Before that, it could be possible and probable CLAD. And so once the patient is identified with CLAD, then you start looking at these two different phenotypes. So the FEV1 goes down for greater than three months. You say, does the patient have RAS or BOS? And really, this is based on histologic, which oftentimes you don't have, so radiographic as well as functional characteristics. So if you have a patient with BOS, which is an obstructive kind of characteristic of CLAD, you'd have an obstructive PFTs. If you have RAS, which is restrictive, you would have restriction on the PFTs, but you'd also have some type of infiltrates, chronic scarring on the infiltrates as well, whereas BOS really has more of an obstructive type of look on the CAT scan. Of note, these are only two of the phenotypes that are known. There's probably a mixed phenotype, and then there's probably a lot that we don't even know about. All of these are based under the umbrella of chronic lung allograft dysfunction. And there's many risk factors we've already talked about a little bit for chronic lung allograft dysfunction. Again, these are immune, which is in green, and the non-immune that are in blue, sorry, let me get back to that. Donor-specific antibodies on their own is a risk factor for CLAD, but acute cellular rejection, as we talked about, acute antibody-mediated rejection, and lymphocytic broncholitis, which is a form of acute rejection, are all risk factors for CLAD. Non-immune risk factors are primary graft dysfunction, reflux disease, and many of the infections we're going to talk about later today. CLAD interventions, there are very limited evidence for any of these, and more for less evidence for RAS and less improvements with RAS than BOS. The best usually you can get with these therapies are hope for stabilization of your PFTs. Azithromycin has been used and is being looked at to be used right at the beginning of transplant instead of after developing CLAD. Obviously, treatment for some of the risk factors like GERD, extracorporeal photophoresis, if done early enough, has shown benefit. Antifibrotic agents are plus-minus being looked at in Europe on several trials, as is monolucast, and other new agents are being looked at right now and could be out by January or February of this year. And then retransplant is always an option for some patients. It's probably between 2% and 3% of patients throughout lung transplant who are available or amenable to a relung transplant. Remember, for relung transplant, the evidence of survival is probably not as good as the primary transplant itself. Infections after lung transplant, obviously much higher risk of infection than in other solid organ transplant, and it's not just because of the higher amount of immunosuppression. Many of these patients have airway colonization, and they really have denervation of some of their cough reflex for at least a while. And so with the decreased mucociliary clearance, there's always reasons, and many of these patients are CF patients or bronchiectatic patients who've had infections and are colonized, and this may recur afterwards. Bacterial infections most commonly come perioperatively or post-transplant early on, and with the most common bugs as being staph and pseudomonas, which predominate. There really is increasing concern for things like acinobacter, multidrug-resistant gram-negative infections as well as stenotrophomonas. These are kind of indolent bugs that keep coming up and can and have been shown to lead to CLAD. One more thing on this is that bacterial infections aren't just pneumonia, and you need to look at the anastomosis, which we'll look at in a minute, as well as just bronchitis and other areas. Viruses, again, are very important because they're not only included in what happens in the patient, you know, right then and there, but how it can lead to other things. The most commonly associated is CMV, cytomegalovirus, but it's also with others. CMV has been associated with acute cellular and antibody media rejection and CLAD. And the community-acquired respiratory viruses or CARVs have also been associated as well. In terms of CMV, it is so important we check it almost every week when they're in the hospital and then very frequently after transplant because it is such a high risk for these patients. The most, the highest risk for patients are those patients who have, the donor is positive and the recipient is negative when they get the transplant. That's because it's a higher risk for reactivation. Those with the lower are donor negative, recipient negative, and intermediate are the donor positive, recipient positive, or donor negative, recipient positive. But again, I think this is a good question for the boards in terms of really looking at this high risk. Fungal infection, the most common worldwide is aspergillus in terms of post-transplant. But remember, endemically, I think we had a question earlier of someone from Nebraska who had a lot of granulomatous disease. You know, histo in the southwest, cocci in the Midwest, blasto, these are all things you have to take into consideration. Again, scutosporium, lamentospora, which is a really big one now, and fusarium are all very difficult and sometimes can lead to very bad outcomes. So these are very new kind of emerging fungal infections that are important. Immunocomplications after transplant, besides rejection and infection, remember these patients are the most immunocompromised of all solid organ candidates. And basically, PTLD, the post-transplant lymphoproliferative disorder, and skin cancer are both very high in these patients, as are other malignancies, whether it be solid organ malignancies or blood cell malignancies. There's a big push now at looking at short telomere syndromes, and in terms of patients with ILD, they have a very high risk of conversion to AML and other blood cancers that we really need to look at. And some of these are looked at as, well, maybe they may not be candidates. So there is a high risk of all types of malignancies. Renal dysfunction, that's mainly a cause from our medications. A lot of them we'll see have that as one of their risk factors. Reflux, cytopenias, again, the patient has short telomere or anything like that, they're going to be at risk because our therapies also cause thrombocytopenia, as well as leukopenia. Diabetes, hypertension, hyperlipidemia, again, steroids and other drugs we have also cause that. Primary graft dysfunction, you may not see it unless you're in a center, because it really does occur within 72 hours after transplant. And it really is an acute lung injury-like picture that can lead to ARDS-like picture. It's thought to be an ischemic reperfusion injury, but many studies looking at other risk factors that can help us kind of evaluate that. Really, the management is just like you would do any other ARDS type of thing. First of all, you'd rule out heart infection and other types of other problems, like a venous anastomosis, stenosis. All these things you would rule out, and then you would treat supportively. Oftentimes, they are needing to go on ECMO. It can get that bad. The International Society of Heart Lung Transplant has graded this, all based on when the PGD was evaluated and what grade they got. So the grade is based on infiltrates, and it's based on PF ratio. So really, 72 hours, grade 3 PGD is really the only one that's shown to be associated with poor outcomes. Airway complications are important. Early on and late. Early, you can have infection or dehiscence of the airway, and then late, you may see some stenosis and also some bronchomalacia. The best way to look at it is PFTs. You may see your flow volume loop look like a concave, looking for an obstructive picture. On imaging, you may have, number one, a persistent pneumothorax on a chest X-ray, but you also may see persistent narrowing on a CT scan of that airway. You may see just a little bit of mediastinal air, as well, around the airway, and you need to do a bronchoscopy. We just did one a couple of days ago that he had a persistent pneumothorax. When you looked at the anastomosis, it looked pretty clear, but when you put fluid in it and it bubbled up, it really was a defect. So these are important when looking early on. Later on, these patients just have increased shortness of breath. They have decreasing PFTs, and they have a stenosis that we'll look at right now. Again, early complications looking at dehiscence and infections, whether they be fungal or bacterial, and then stenosis later on, which can be important from patients who've had some kind of ischemia or a long ischemic time. They can get stenotic, and they may need a stent after dilation. Again, bronchomalacia, same thing. Here's another question. I don't know when mine doesn't come up, but we'll read it first. Fifty-seven-year-old male with IPF, eight months post-transplant. He had a right single transplant. He had a cough, fevers, and FEV1 did decline below 15%. Immunosuppression is tacrolimus, CELCEPT, prednisone, and he was on valganciclovir, Bactrim, and posaconazole as his prophylaxis. His prior surveillance bronchoscopy showed no infection, no rejection, and it was just a couple weeks earlier. The CBC was stable. His CMV was non-detectable. His EBV was high. His EBV, or Epstein-Barr virus, was 1,700 copies per mil, and his tacrolimus level was stable at 11.4. Here is his CT scan, and you can see he was a right single lung transplant, so something going on here. And the transbronchial biopsy showed this picture here, which doesn't look exactly normal. And now we can go on to the answer. The next step, excuse me, the next best step in this patient's management is which of the following? Excuse me. Administer a big steroid bolus, B, begin evaluation for retransplant, C, continue current immunosuppression and begin IV ganciclovir, and D, decrease the current immunosuppression and consider rituximab. And people are already voting out of the block. And I think we'll hit it. And excellent. Fifty-four percent of people got it right. Decrease the current immunosuppression and consider rituximab. This is PTLD, or post-transplant lymphoproliferative disorder. One of the therapies is to decrease immunosuppression, so giving a steroid bolus would be the opposite of that. Begin evaluation for retransplant. This isn't CLAD. This is, so this, and this patient would need to be treated before he could be considered for that. Continue the current immunosuppression and begin IV ganciclovir. I think this would be the answer if you thought it was CMV. And that would be the right answer if it was CMV, but it wasn't. It was post-transplant lymphoproliferative disorder. And that is, it is increased in lung transplant, as opposed to other organs, up to nine percent. It's a B-cell predominant non-Hodgkin's lymphoma. And it's associated with an EBV, increased EBV ribose. So this patient was at risk. Most at risk are seroconverted recipients, so those that were negative and the donor was positive. And because of that, children are the most highest risk, because many of them haven't developed the positivity through their life. So the therapy is decreasing the immunosuppression, rituximab, which is usually very effective, if not chemotherapy and sometimes surgical indication, if needed. Most of the time, you're going to see it in the lungs, but we've seen it in the kidney. We've seen it in the bowel. We've seen it in the skin. We've seen it in other organs. We have someone in the hospital right now on, who has it in, he had it in an EGD, and so it's on EGD biopsy. So I think it's something to look out for. Okay, medications after transplant. All of these medications can cause an increase in tacrolimus, except A, calcium channel blocker, posaconazole B, C, azithromycin, or D, rifampin. And mix of people, so a third got it right of rifampin, and that's going to be just really looking at these calcineurin inhibitors, whether it be cyclosporine or tacrolimus, who would cause the drug-drug interaction. So there's, it goes through the CYP3A4 route, so any of those that increase, that are CYP3A4 enzyme inhibitors, including azoles, grapefruit juice, and calcium channel blockers, would all increase that level. CYP3A4 inducers would decrease the level. So rifampin, if there's a patient who is being treated for, I don't know, TB or MAC, you may need to really look at that. So this is something good to just look at, and the ones that I put in bold are the ones that are the most common. So that's more of a memorization thing based on that. Lots of different medications, whether it be rejection, infection, or prophylaxis. Again, most patients are on maintenance therapy with tacrolimus, prednisone, and mycophenylate mofetil, but they all include something from this area. A lot of times you won't see someone with a DNA synthetase inhibitor because maybe they have a leukopenia or a problem that they can't take one of these. And tor inhibitors are used often as well, intermittently. And then there's some on board looking at bilatacept. It's not great in lung transplant, but others are being evaluated. And this is just a nice slide showing us that most patients, greater than 90% of patients are on tacrolimus, and the triad of tacrolimus, cell sept, and prednisone. This is just a nice table that you can look at, and maybe right before the boards, and see which of the drugs are going to be most sensitive to different adverse effects from those drug-drug interactions. Infection prophylaxis, usually center-specific, especially perioperatively. Fungi, most people are prophylaxed with azoles perioperatively, and for a variable amount of time, some for three months, some for a year. It all depends on center-specific protocols. CMV, we're always wanting to prophylax that, especially in the CMV negative recipient, positive donor. And so valgancyclovir is the one used. Bactrim is used, really, for pneumocystis, and that's lifelong. And one other thing I just wanted to touch on, may not be on the boards, but we're talking about the new allocation system. So the way that lungs are allocated in the U.S. has now changed since March of 2023, used to be based mainly on both on really prioritizing urgency of candidacy, as well as how long the patient will live after the transplant, and that was the major goal of looking at that. But now, knowing that there's a lot of, kind of, disparities in terms of biological, different characteristics and distance and all other things related to transplant centers, this has recently changed. So now, it still includes some of the things that were in the old, remember, lung allocation score. Some of that is still within this, and that's 50% of what the allocation score is. But now, we're also including points for things that patients may not have exactly the right characteristics for. So this score now is really determined not just by the candidate score, but it's determined by the candidate and the specific donor specifics. So you'll get a score for your patient, and then when that offer comes up, it will be really looking at that donor-recipient match, which is probably a little bit more specific than before. Obviously, the candidate with the highest points for that organ will get that priority. Now, what's involved in this is now reducing some of the disadvantages of biological disadvantages, so based on blood type, whether a patient has antibodies or is sensitized, and height. We know that very, very small patients are disadvantaged in terms of donors. Also, promoting patient access. So pediatric donors, they automatically get a lot of points, and patients who, not so much in lungs, but if they're a prior living donor, they may get some benefit. But then really promoting the efficient management of the organ placement system. It's very difficult to try to figure out the best way to do this, but this really looked at travel efficiency. Centers were traveling all over the country for maybe not that great of lungs, or they really had, how do we fix this so that efficiency for this particular donor and this particular recipient will get that donor, whether it be because of their acuity or because that they're disadvantaged. So this is just being evaluated now. We just had a call, I think, a couple weeks ago about how people think it's going. I think it has some deficiencies, like all different systems, but looking at how to better allocate these lungs. So I've never gotten through this talk this fast. I still have two minutes, but really key points for the boards are really gonna be indications for lung transplants and types of procedures. So bilateral versus single. Remember, bilateral is most patients, and all patients with separative lung disease, and know the post-transplant complications. I think things that are definitely fair game would be chronic lung allograft dysfunction, acute cellular rejection, the problems with CMV, how to treat CMV. PTLD, I think, is important. I think also knowing some of the infections that come up, like fungal infections and other viruses. Side effects of immunosuppression, that adverse effects, as well as drug-drug interactions is important. We didn't really go through that table in detail, but calcineurin inhibitors, their main risk factor for dysfunction is renal dysfunction, and valganciclovir can cause renal dysfunction, as well as cytopenias. Cellcept and other cell cycle inhibitors can cause cytopenias, and drug-drug interactions, again, are important. Azoles and calcineurin inhibitors are probably the most common. But thank you so much. I'll be available for questions after that. Thank you.

lung transplantation

lung diseases

chronic lung allograft dysfunction

transplant complications

immunosuppression

long-term outcomes

new lung allocation system