Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we're highlighting lung transplant indications for the general pulmonologist, knowing when to refer. Joining me is Dr. Moustafa Younis. He's an Assistant Professor of Medicine in the Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Florida College of Medicine.

Dr. Younis, thank you so much for joining us today. Many people think lung transplant is only a kind of an end-of-the-line option. At what point in a patient's disease course—and we'll talk about some different diseases here today—should general pulmonologists begin thinking and talking about transplant as a possible future step?

Dr. Moustafa Younis: Thank you for having me, Melanie. So, it's a misconception that lung transplant is only an end-of-the-line option, especially when it comes to referral. So, it should not be viewed as a last resort. The goal is to refer patients as early as possible and early enough that they still have options, not when they're already in crisis.

As a general principle, we begin thinking about lung transplant when a patient's lung disease carries an estimated two-year mortality of around 50% or more despite optimal medical therapy. So, I want to underline that. So, they have to be on the right medical therapy for their disease. And despite that, they are progressing or there are certain markers within their disease that is associated with worse progression. And therefore, they should be referred at that point.

Aside from where they are at this point, you should also look at the trajectory of the disease. And for example, there are certain diseases that referral almost immediately after diagnosis, because they can progress very unpredictably. For example, IPF or MDA5-associated ILD, patients with short telomere syndrome or PVOD, patients with pulmonary veno-occlusive disease. These are just to mention a few. These have very unpredictable progress, and they could very rapidly deteriorate. And therefore, for some of these diagnoses, as soon as they're diagnosed, they should be referred irrespective of how they're doing at that second.

But generally, for the general pulmonologist, there's a common theme, irrespective of the diagnosis of when there are certain markers that you should consider for referral for lung transplant. One of which is oxygen need. If a patient's on oxygen need as a result of their lung disease, whether at rest or on exertion, irrespective of their disease, they should be referred for transplant.

If they have pulmonary hypertension, specifically group 3 pulmonary hypertension as a result of their disease, they should be referred for transplant. If they are hypercapnic outside of their acute exacerbations, and they require non-invasive ventilation. If they're obviously, on mechanical ventilation or ECMO as a result of their end-stage lung disease, they have frequent hospitalizations or exacerbations and, most importantly, if they have significant decline in their exercise capacity or their quality of life.

Another point I want to highlight here is referral is not the same as listing for transplant. The evaluation process may take several days. And usually, what I tell patients is it has three different outcomes. Either the patient is a perfect candidate for transplant if they need it at this point, which is unfortunately rarely the case. Or the second option, which is the complete opposite, they have a significant major barrier that prohibits them from being a candidate. Or third of all, which is the most common option where we land for most patients, is they have certain modifiable barriers that need to be addressed before listing or considering them for transplant. For example, part of our workup for patients at risk of coronary artery disease is they get left heart caths as part of their transplant eval. Some of them truly do have CAD, and they need a stent, for example, and they need to be on DAPT, a dual antiplatelet therapy, for at least three months if it was placed selectively. And therefore, even if they need the transplant right now, well, we have to wait for at least three months.

Another example, which is also very common, is extremes of BMI. Patients need time to gain or lose weight. It might take months, might take even a year, up to a year to gain or lose that weight. And therefore, these are just a few examples, just to mention a few of certain opportunities that we can take advantage of when these patients are referred very early on rather than in their critical illness.

In addition, from a patient's stand, you know, whenever they hear lung transplant, they're shocked, right? And they're very hesitant when it's first mentioned. But after meeting with us, getting to know us, getting to know and more education about the process, it gives them time to understand the process, getting to know us, and they become much more comfortable making an informed decision at that point. So bottom line, timing matters. An early referral preserves options, allows optimization of the patients to have the best possible outcome post-transplant.

Melanie Cole, MS: Thank you so much, Dr. Younis. That was a very comprehensive explanation and really understanding that point that earlier is better for referral. Now, when we think of certain conditions, COPD, CF, bronchiectasis, what are the practical clinical and physiologic thresholds that really should prompt a pulmonologist to refer a patient for transplant evaluation as you were just discussing?

Dr. Moustafa Younis: I'm glad you grouped all these disease together, because they're under that obstructive lung disease kind of umbrella. And the most important factor for these patients compared to like ILD and other disease that are associated with a very high mortality, these patients, you focus more a bit on the quality of life. It matters the most. Some patients might have severe disease but maintain an acceptable quality of life, while others with slightly better lung function are significantly limited. That's why symptoms and functional status remains an extremely important aspect when we consider these obstructive lung disease.

Another important principle is that patients should already be receiving optimal disease-specific therapy. In this day and age, for example, the number of CF transplants has dramatically reduced after the CFTR modulators like Trikafta for CF and so on, have been developed and are more commonly used. So, if a patient qualifies for Trikafta, they should have a trial of Trikafta before even considering them for transplant. And the same applies for COPD, if they're on inhalers, whether they need lung volume reduction, whether endoscopic or bronchoscopic, rehab, oxygen therapy. So, whatever the disease-specific therapy is, they should have received it.

Now, more specifically, when looking at COPD, patients should be referred when they have a BODE score greater than 4. So, a BODE score is a score that looks at FEV1, six-minute walk test, a lot of different marks, MRC, dyspnea scale, and BMI. So if they have a score greater than four, or they're progressing by one point over two years, then they should be referred. The FEV1 cutoff when looking at PFTs is less than 25%. Again, quality of life despite maximal medical therapy, as I mentioned previously.

And back to that common theme that I mentioned earlier, for all lung disease, if they're having frequent severe exacerbations requiring hospitalization, ICU admission, BiPAP, intubation, irrespective, that's an indication for a referral. If they're on oxygen, either at rest or on exertion, if they're hypercapnic outside of their acute exacerbations, or if they have group 3 pulmonary hypertension, they should be referred for evaluation for transplant. As for CF, the threshold is a bit lower because these are younger patients. Therefore, we want to give them the best chance and catch them early on.

So, the FEV1 cutoff for those patients is 30% or lower on its own, or 40% and lower if they have additional high-risk features that's associated with higher risk of mortality. Again, hypoxia, hypercapnia, low six-minute walk test, pulmonary hypertension. If they're losing weight, that's an important point in patients with CF. If they're progressively losing weight, that's an indication that their lung disease is progressing, and that's despite nutritional optimization. Again, exacerbations. An additional two points that are not usually thought about when we think about CF is if they're having massive hemoptysis requiring embolization, then that's an indication for a referral, because you don't know if the next time you're going to be able to control that hemoptysis. And same thing for pneumothorax, secondary pneumothorax in the setting of CF, that's an indication for referral.

And lastly, you can lower that threshold even more. An FEV1 of 50 or less, but what you're seeing is they're fine right now, but based on their trajectory, they used to be FEV1 80% a few months ago, and they're rapidly progressing. And you don't have any options for therapy. They do not qualify for CFTR depending on their gene and so on. Therefore, they should be referred too, even though someone might think FEV1 of 50 is a bit too early.

And generally, females, patients with a BMI less than 18, they also have concomitant diabetes or multi-drug resistant organisms such as Burkholderia or abscessus. These are also associated with worse survival. And therefore, they should be referred upon diagnosis. As for non-CF bronchiectasis, kind of similar criteria to CF bronchiectasis, but non-CF bronchiectasis again is an umbrella. It's a tree. It has a lot of branches. There's a lot of different causes with variable disease progression.

But overall, it tends to be slower and has a lower mortality risk. For non-CF bronchiectasis specifically, there are two additional scores in addition to the lung function similar to CF kind of criteria that we mentioned, is to also consider the FACIT score more than or equal to 5, or the bronchiectasis severity index, which is basically similar to the FACIT score but includes BMI and FEV1.

The FACIT score looks at FEV1, age, colonization with pseudomonas, and the radiological extent of the bronchiectasis, and then also the mMRC dyspnea scale. So again, incorporates all these different markers, one of which is quality of life or how symptomatic they are, their lung function, their imaging findings. So, it's really a multidisciplinary kind of assessment of the patient.

Melanie Cole, MS: It certainly is. And those are important points and very specific as well. Now, you mentioned briefly interstitial lung disease and particularly idiopathic pulmonary fibrosis. You mentioned that umbrella a little bit. What are some of the key red flag changes in lung function or symptoms that signal it's time to refer, even if the patient, which can sometimes be the case, still feels functional day to day?

Dr. Moustafa Younis: So specifically for ILD, it is probably the disease where we have the lowest threshold for referral. Some fibrotic lung diseases are very unpredictable, like I mentioned earlier. Some may be completely stable for months, but have something as simple as a viral infection, common cold, a flu, parainfluenza, whatever viral infection, and that tips them over into an acute exacerbation.

Acute exacerbation of ILD, specifically IPF, to be more specific, is associated with extreme higher mortality, more than 50%. For that reason, specifically for IPF, they should be referred as soon as the diagnosis is made, even if their lung function is great. We know it tends to be a progressive disease. That might change down the road as we are having new therapies now being released. Now, for example, inhaled TYVASO is now also approved for IPF, and there's nerandomilast in addition to the Esbriet and the Ofev, that we used to have before. So, we're having more and more therapies. But nonetheless, at this point in time, it still tends to be a progressive disease.

And all these medication tends to maybe slow the progression of the disease. But overall, they still tend to have a bad outcome overall. That's if they have an IPF diagnosis. Well, what if they have definite or probable UIP on imaging, but they don't really meet full criteria for IPF, or they have UIP because of a different reason, rheumatoid arthritis or whatever other disease process? Either radiologically or histopathological UIP is also an indication for referral.

As I mentioned earlier, patients with short telomere syndrome, and one of my colleagues, Dr. Jannsen, did a podcast on that, so you guys can go and watch that. So, patients with short telomere syndrome also tend to have worse disease or patients with familiar pulmonary fibrosis.

General theme for patients with ILD, aside from these diagnoses that I mentioned earlier, if their FVC is less than 80% or their DLCO is less than 40% on their PFTs, or you are seeing progression in their FVC by 10% or their DLCO by 15% over two years despite therapy, then these patients should be referred.

And again, similar to the prior criteria, that general theme that I mentioned, they're hypoxic, they're hypercapnic, which is not usually common in ILD unless they have some other reason like neuromuscular weakness, for example, or if they're having group 3 pulmonary hypertension, or exacerbations. These are all signs of end-stage lung disease for which they should be referred.

Melanie Cole, MS: Dr. Younis, when we think of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, and you mentioned these a little bit briefly as well, expand for us on the specific hemodynamic or risk stratification markers that really should trigger that early transplant referral.

Dr. Moustafa Younis: So, here when we talk about pulmonary hypertension, right? Those are different groups. There's five different groups of pulmonary hypertension. Specifically, when we're looking at pulmonary arterial hypertension, group 1 PH, then there are certain criteria that have been developed by the European Society of Cardiologists and the European Respiratory Society. Together, along with World Symposium on Pulmonary Hypertension, they came up with kind of some scoring system for patients with PAH, and they risk stratified these patients into low, intermediate, or high risk based on certain parameters. These parameters include clinical parameters like their signs, symptoms, syncope, angina, heart failure, and so on. Exercise testing, such as six-minute walk test; biomarkers such as BNP or NT-BNP; imaging criteria based on echo or cardiac MRI, like RV dilation, RV dysfunction, pericardial effusion, and so on; and then right heart cath hemodynamics.

So, the goal in patients with PAH is to be able to achieve and maintain a low-risk profile based on these criteria within six months. If despite optimal therapy, which usually starts with dual therapy, despite this therapy and you still have not been able to reach a low-risk profile within six months, you should consider a referral for transplant evaluation.

Now, that aside, there's also a REVEAL score. There's a REVEAL score 2.0. So if you look at that, and that REVEAL score is more than or equal to 8, despite, again, appropriate PAH therapy, then these patients should be referred for transplant eval if they have progressive RV dysfunction despite therapy. If you're thinking about initiating IV therapy, then refer them for transplant evaluation and if they're being hospitalized because of their PAH.

Now, when you look at that kind of scoring system, what are kind of features that are associated with kind of higher risk features? So if they're very symptomatic, they're having significant heart failure symptoms, significant anginal symptoms; if their six-minute walk test is very low, if the BNP is very elevated or the NT-BNP, and then when you look at the echo, there's significant RV dilation. There's increase of the RV to LV ratio, and you're seeing also RV dysfunction. So if you're seeing a lower TAPSE, whether or an overall decrease in function of the RV based on echo or cardiac MRI, that's usually a sign of a more severe disease.

And then, lastly, if you're seeing a pericardial effusion of PAH, that is truly a sign of end-stage PAH. When we're looking at right heart cath hemodynamics, there are certain features associated with worse disease. So if you're seeing a high right atrial pressure with a low cardiac output, irrespective of what their mean PA pressure is, that's usually a sign of pretty severe disease.

In addition, aside from these criteria, patients with PVOD or pulmonary capillary hemangiomatosis tends to have very poor response to therapy and tend to progress very quickly. So, you need to refer these patients as soon as you consider or think about a PVOD diagnosis. Also, not as severe, but patients with familial scleroderma or scleroderma-associated PAH tend to have worse disease, and patients with progressive PA aneurysms, or if they're having a life-threatening complication such as hemoptysis, that prompts urgent referral.

One thing that I wanted to mention here when it comes to PAH is that kidney and liver dysfunction is often a consequence of severe disease or right heart failure. You have bad heart failure, you have cardiorenal disease, and then also you have congestion in the liver. So, you tend to see some dysfunction in these two organs. And when you look at the relative or increased risk factors when we're thinking about transplant in general, generally kidney disease or low GFR or patients with liver disease, these patients that are increased risk and historically used to be a contraindication. Again, I'll talk about contraindications.

But here specifically, if you see these features, that's not a sign that these patients do not qualify for lung transplant. These tend to improve with lung transplant, the kidney and liver dysfunction, because the problem is truly the PAH and kind of poor perfusion as a result. So most importantly, specifically for PAH, they don't have to fail every available therapy. If you start them on therapy and within six months, you can't get them to low-risk, go ahead and refer them.

Melanie Cole, MS: Dr. Younis, you just mentioned that you're going to talk about some contraindications. Let's talk about those now. Some of the absolute and relative contraindications to lung transplant. So now, we're past the evaluation stage and we're looking at patient selection. How strict are these in real-world practice?

Dr. Moustafa Younis: So, that's changed a lot over the years, and that varies significantly from one transplant center to another. Generally speaking, there are still several absolute contraindications that are fairly consistent across transplant centers.

One is as simple as the patient really doesn't want a transplant or can't consent for a transplant. If they have a malignancy that's high risk, stage IV, there's no treatment options, cannot get them in remission, they have poor survival as a result of their other disease process, not truly their lung disease, then that's a contraindication for transplant. Patients with end-stage kidney or other organ disease, unless they are being considered for multi-organ transplant.

Patients that are having an active heart attack, there's no way they're going to handle a seven or eight-hour surgery. Their heart just won't tolerate it. If they had a stroke within 30 days, we tend to wait at least 30 days thereafter. And if they're in severe septic shock, severe bad infection, or they have some extrapulmonary disseminated infection that cannot be controlled or treated, you need to get that controlled before even thinking about it.

HIV, that has changed over time, but HIV with detectable viral load and lack of controlled HIV is still a generally absolute contraindication across all centers. Someone with, unfortunately, progressive cognitive impairment or severe dementia, there's no way they're going to be able to take 10 to 20 pills daily or twice a day and measure labs and come to clinic.

And then, patients that have repeated episodes of non-adherence despite recurrent counseling. With lung transplant, there are certain medication that are like kind of your backbone of your immunosuppression. If you miss a few doses, that might increase the risk of rejection and losing these lungs. And in the end, we want to honor the patient, so we might be hurting them if we transplant non-adhering patients. Again, it has to be a recurrent theme despite counseling.

And then, if they're actively using, so if there are any substances such as tobacco, vaping, marijuana, or IV drugs, that is generally an absolute contraindication, which is across more institutions.

But the thing is, I think, the most pulmonologists are generally aware of what are the absolute contraindications. But I think, what we call these relative contraindications or the relative risk factors, and that's where the majority of situations usually fall. And that's again, where practice differs considerably between transplant programs.

Here at UF, we're fortunate to be one of the more aggressive transplant centers. We receive many referrals for patients who were declined elsewhere because we have extensive experience managing these complex cases. But it doesn't mean that we just transplant anyone and everyone. Instead, our multidisciplinary team asks just truly one simple question: Are we going to help this patient or do we think we're going to harm them by exposing them to transplant?

Instead of looking at one risk factor on its own, we just take a look at the overall picture. What's their overall medical condition? How frail they are? How much support they have, especially when they have higher risk features associated, you know, we anticipate certain complications after transplant. Do they have good psychosocial support? Do they have good caregivers? Are they generally adherent? What are their other comorbidities? And try to optimize them as a whole, even if they're complex or even if they have these increased risk factors.

So, a lot of these used to be considered absolute contraindications, like years ago, but we've evolved since then, and our experience has grown. And not only us, but the field in general continues to change rapidly. For example, if you look at the ISHLT Consensus document for selection of lung transplant recipients, you'll see that one of the increased risk factors or relative contraindications is age more than 70. Well, a good percentage of patients, we transplant are more than the age of 70. We've transplanted patients up the age of 75 and 76. Looking at that same table, if they have CAD that requires a CABG at the time of transplant, that used to be a relative contraindication. Well, here at UF, that's a very common thing that we do.

Patients that have severe esophageal dysmotility, because it's associated with increased risk of reflux and reduction down the road. Well, we've developed a good protocol here to actually improve these patients' outcomes after transplant, similar to patients that do not have esophageal dysmotility.

So for us, severe esophageal dysmotility is not a problem whatsoever. Certain BMI cutoffs, they used to be BMI less than 30. Used to be strict, less than 30. Well, now we're more a bit more flexible because we know that BMI is not the best marker to reflect overall central obesity and weight and so on.

So, these are just some examples, just to mention a few. An additional one, Mycobacterium abscesses. Used to be a big no-no. If someone has Mycobacterium abscesses, that's a big no-no. Well, right now, we have a lot of different treatment options in which we are able to control these patients before sending them for a transplant. It really varies from one transplant center to another. But the field is changing significantly, and a lot of these relative contraindications are no longer contraindications.

Melanie Cole, MS: Well, Dr. Younis, it certainly is an exciting time in your field. As we wrap up, I'd like you to speak a little bit briefly about timing and window of opportunity that affect those outcomes, the mistakes that you've seen in referral timing. But for clinicians in smaller or resource-limited settings, give us some practical strategies for building that relationship with regional transplant centers such as yourself and ensuring that smooth referral and co-management. Your best advice in summary here.

Dr. Moustafa Younis: Definitely. So, the common theme or the two biggest mistakes I see, the first one is waiting too long. and that's why I actually wanted to talk about this topic, because it's one of the hardest conversations for us when we have to tell a patient that they're no longer a transplant candidate or they missed their window of opportunity, when if they were referred a bit earlier, they would have been candidates. I believe that we can help definitely way more patients if these patients are referred early.

A second common mistake I see is that clinicians, again, decide in a way on their own that the patient is not a transplant candidate. It's evolving a lot, and every transplant program has a different threshold. And we're really pushing the boundary every day, and we're seeing good outcomes when we do that.

You know, for example, patients that have a history of cancer. Well, we've actually transplanted a few patients that had chemotherapy-related pulmonary toxicity. So, they were just being treated for cancer, but we had to individualize and personalize that treatment for these patients. We had to discuss multidisciplinary, not only us from a pulmonary standpoint and the whole transplant team, but also involving the hem-onc team, different teams that are specialized in these kind of disease processes.

All these rigid criteria are no longer as rigid. And therefore , unless it's something that's very obvious, a very absolute contradiction, like a patient doesn't really want a transplant, then think twice about before deciding on your own that the patient is not a candidate. So again, when in doubt, refer. And the worst outcome is usually referring too late, not referring too early.

And then, as for how we build these relations, so actually the good news is the transplant centers in general, not only us, are increasingly viewing pulmonologists as partners. We don't take over care. We work in parallel. And here at University of Florida, we made outreach really a major priority. We're actually taking that step, and we're doing regular visits to community hospitals, pulmonary practices throughout the region to establish a relationship, and therefore make it easier and streamline that referral process.

Our goal is to make that process as easy as possible. And we all work in parallel. We want what's best for these patients. And if there's any listeners, that would like to establish a relationship with our transplant program, or simply discuss a patient, whether a patient might benefit from referral, we'd be more than happy to help. They can reach out to our transplant liaison, Dr. Gries. Her phone number is 412-770-7636. She was very kind enough to share her personal number. So, that's really what our team is doing here. This is her personal phone number. You can reach out to her any time to discuss any patient. if you're not sure whether they would benefit or not, just reach out, and we can definitely help and make that process as smooth as possible and as easy as possible for physicians so that we can help as many patients as possible.

Melanie Cole, MS: What great information, Dr. Younis. Thank you so much for joining us and really sharing your incredible expertise for referring physicians. 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, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole.