Lung Transplant as Therapy for Fibrosis and ARDS Related to COVID-19

Podcast Transcript

Announcer:

Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular, and Thoracic Institute at Cleveland Clinic. Cleveland Clinic patients benefit from a multidisciplinary approach to care. This podcast is brought to you in conjunction with Cleveland Clinic's Respiratory Institute.

Kenneth McCurry, MD:

Well, good day. I'm Dr. Ken McCurry. I'm a cardiac surgeon and the surgical director of the Lung and Heart-Lung Transplant Program here at the Cleveland Clinic and I'm here with Dr. Marie Budev today. Marie will introduce herself in just a second. We're here in this podcast to talk a little bit about COVID-19, ARDS and fibrosis, and the potential role of lung transplantation to treat those patients with advanced disease. Marie?

Marie Budev, DO, MPH:

Welcome, everyone, and good day to all of you. My name is Marie Budev and I'm the Medical Director of the Lung and Heart-Lung Transplant Program here at the Cleveland Clinic, and I'm really excited to speak to you today about this very important topic.

Kenneth McCurry, MD:

Well, I'll kick it off, maybe first, with a question to Dr. Budev. So, Marie, just to start the conversation off, can you tell us a little bit about the current status of lung transplantation in the United States and across the world, sort of what's being done, what are common reasons for patients to get a lung transplant, and maybe a little bit about the outcomes?

Marie Budev, DO, MPH:

Thanks, Ken, for that question. Many of you are familiar with other solid organ transplants, such as liver and kidney transplant. Lung transplantation within that spectrum of solid organ transplants is a small piece of the pie. In 2019, if you look at registry data, and this is registry data from the International Society of Heart-Lung Transplant, ISHLT, which I'll refer to throughout my discussion today, the data from 2019 show that there was over 4,500 lung transplants performed throughout the world. The 2020 and 2021 data will be available in a few months, but I assume that that data's gonna show an increase in transplant volumes.

Marie Budev, DO, MPH:

The number one indication for which we transplant in the United States is pulmonary fibrosis, a restrictive lung disease. And we'll talk a little bit more about this restrictive lung disease as we talk about COVID fibrosis as well, but worldwide, the number one indication for lung transplantation is still obstructive lung disease, or COPD.

Kenneth McCurry, MD:

Yeah, that's great, Marie. Thank you. So, obviously we're ... everyone listening to this will be very well aware of the impact that COVID-19 has had, really worldwide during this pandemic over the last two years. And certainly there's a variety of presentations. Some people get better very quickly, others don't. So, can you talk to us a little bit why someone with COVID-19 might need a lung transplant?

Marie Budev, DO, MPH:

Thanks, Ken. This is a really important question. So when you look at individuals that are in the ICU that have COVID, you're gonna look at how sick their lungs are as a result of the inflammatory process and what has happened in the injury that happens to the lungs. About 6% to 10% of patients who are in the ICU will end up developing ARDS. Some of these patients will have resolving ARDS due to COVID, or may not resolve, and those are the individuals that we'll talk about in more detail in a few minutes.

Marie Budev, DO, MPH:

Out of the patients that do recover after having very severe COVID-19 infection, or SARS-CoV-2 infection, one-third of them will end up having residual pulmonary fibrosis. The degree of impairment of this restrictive effect is really dependent on the patient and their inflammatory response, and this is another population that lung transplant may be considered, but we'll talk about that in a few minutes. But that's a really important question. You can see, it's only a small amount, or small portion of the population that gets extremely sick with COVID, that ends up actually having residual lung impairment.

Kenneth McCurry, MD:

Yeah. Well, thanks clarifying that, Marie. So, patients with COVID can sometimes get very severe disease from what's called ARDS, acute respiratory distress syndrome, or from fibrosis of the lungs that lung transplant may be considered for. So, can you talk to us a little bit about, you know, how many lung transplants have been performed for COVID in the United States and worldwide, sort of what are the considerations, when thinking about that and how are things progressing do you think?

Marie Budev, DO, MPH:

So I think it's important to know the historical background behind this. So when COVID, when the pandemic began, we started to see cases first come out of China. These were case series, case reports, not with a lot of granular detail, for several reasons. Some of it was probably translational, culture differences, and also, there wasn't a whole lot of set sort of standardization, how to approach a patient that had non-resolving ARDS and considering transplantation. So the cases that we saw out of China, the majority of the patients were bridged to transplant off of ECMO and were very, very ill.

Marie Budev, DO, MPH:

There wasn't a whole lot of detail in terms of selection criteria for patients or for donors at that time, because remember, donors may have also been infected with COVID. There wasn't a whole lot of guidance in terms of post-transplant immunosuppression and how to deal with it, and in the conduct of the surgery itself, the perioperative period was very vague. So a lot of us were questioning this at the early part of the pandemic, but then we were lucky enough and fortunate enough to get more case reports and case data coming out of different areas, including Europe.

Marie Budev, DO, MPH:

The first case report out of the West was from Vienna, from the Austrian group, and they described in exquisite granular detail, the course of a young woman who ended up having, ARDS due to COVID, and was on ECMO and bridged to transplant. They talked about her preoperative course, how they selected her, the ethical dilemmas that they faced, the perioperative period dealing with sensitization or matching with an organ, and then the postoperative rehabilitation. They also focused on the preoperative rehabilitation of the individual that had severe critical illness, myopathy, which is something I know you're gonna talk about in a few minutes, and overcoming that and making her an ideal candidate for transplantation.

Marie Budev, DO, MPH:

After the Vienna case report, several leaders in transplantation, including yourself and several surgeons around in North America, as well as other cases that were being done at other centers in North America started to emerge, including cases from the Cleveland Clinic.

Marie Budev, DO, MPH:

And now where we stand with this is we now have a better idea of how to select patients, how to work up these patients, and how to rehabilitate these patients, and how to select donors as well as the overall patient selection. I'd refer you to the ISHLT, the International Society for Heart Lung Transplant, taskforce guidelines for the selection of donors and recipients in this COVID-19 pandemic, and for transplantation due to COVID-19 for ARDS and pulmonary fibrosis. This is located at their website at www.ishlt.org, and its front and center right there and you can look at these guidelines and they're very helpful for any referring doctor. So I'd really urge you to look at these.

Marie Budev, DO, MPH:

Now, where do we stand? Well, it's important to know that at the beginning of the pandemic, there was great concern that as transplants were being performed for this indication, that we wouldn't be able to keep track of how and how many of these transplants were being done. So in October of 2020, it was actually UNOS, the United Network of Organ Sharing, that designated diagnosis codes that were specific to COVID-19 causes for transplant, COVID-19 ARDS or COVID-19 pulmonary fibrosis. So we were able to track the number of transplants that were being done for these indications.

Marie Budev, DO, MPH:

Looking at recent reports and inquiries from March of 2020, which is considered the beginning of this pandemic, to June of 2021, there were 147 transplants done across the country for COVID fibrosis, or COVID ARDS. 91 of these were for COVID ARDS, and 56 were for pulmonary fibrosis. The majority of these patients were bridged to transplant on ECMO and this is more than they're done for other diagnosis, for which we transplant the patients that had COVID ARDS or COVID fibrosis at higher lung allocation scores. This is how we designate or allocate organs to individuals and recipients. These patients therefore were a lot sicker than our other diagnosis that we transplant for.

Marie Budev, DO, MPH:

There was a disproportionate number of Hispanics and minorities represented in this group that were transplanted for COVID ARDS and COVID pulmonary fibrosis, which was very interesting compared to other diagnosis. Important to know from the small cohort of patients in our early experience with transplantation is that the post-transplant survival is no different for these two diagnosis compared to all other diagnosis that we transplant for. So we're learning more, we're getting better at this, and hopefully even our care of COVID is improved. Also remember vaccination, that has been the key to this, and I think hopefully as we go through this pandemic and it becomes an endemic with the vaccines that we have, that we will be seeing less and less and fewer and fewer transplants for COVID.

Kenneth McCurry, MD:

That was great, Marie. Thank you very much.

Marie Budev, DO, MPH:

I'm gonna now ask you a few questions, Ken, and I hope you'll be able to help our audience understand how important it is to consider certain factors in considering a patient for transplant referral. The first thing is that there are so many young people that are in the ICUs with COVID ARDS, or what looks like COVID fibrosis after ARDS around the country. When you get a phone call, how do you consider just offering supportive care and advice to referring doctors until these patients improve? Or how do you start to say, hey, we need to start thinking about transplant. This is an appropriate referral.

Kenneth McCurry, MD:

Yeah, it's a great question, Marie, and it's a really difficult one. You know, there's really so much that we still don't know about the recovery from COVID, at least patients with moderate or severe disease. So patients who get admitted to the hospital. There's so much that we don't know about the recovery under those circumstances and the rate of progression of that disease and what ultimately may be the outcome with regards to their lung function. So I think in general, the way that we see lung transplantation, and this is not only true with COVID-19 ARDS and pulmonary fibrosis, but also with other disease states as well, is we see it as salvage therapy, a therapy that we can offer to patients with advanced lung disease that really have no other option to live or at the very least to live a, a good quality of life. So we try very hard to do things to improve the patient's medical status prior to considering lung transplantation.

Kenneth McCurry, MD:

So with regards to specifically to COVID-19, since there's a large knowledge gap there about recovery and progression of the disease, it becomes quite a quandary as to when to consider transplantation. Obviously we want to wait long enough, if a patient has, you know, moderate or severe COVID, we want to wait long enough so that we can be sure that we've given the patient every chance that we can for recovery of their lung. But at the same time, we don't want to wait too long, particularly when patients are sick and in the ICU and complications can begin to develop. And sometimes those complications, which I'll talk about in just a second can lead to situations where we're unfortunately not able to offer transplantation.

Kenneth McCurry, MD:

So I think we generally consider a lung transplantation for COVID in sort of three scenarios. And I think we've seen these at our institution here at the Cleveland Clinic, as well as at other programs around the country. The first scenario is sort of those patients with very severe disease, severe ARDS or fibrosis that get admitted to an ICU end up on mechanical ventilation. Some of those patients respond to those initial therapies, such as proning and other pharmacologic interventions, others require ultimately conversion to ECMO for mechanical support of their lungs. And many of those patients will get better. We have a very active ECMO program here at our institution to treat those patients. We have a very aggressive and very good medical intensive care unit who have really done an outstanding job of implementing best practices in improving patients.

Kenneth McCurry, MD:

But despite that, many people will continue to progress and just are not able to separate from mechanical ventilation or from ECMO and lung transplantation can be considered, under those circumstances. We've also seen other patients that recover from that initial insult to their lungs, that initial infection, either on mechanical ventilation or not, but ultimately are left with very advanced lung disease and have significant supplemental oxygen requirement. We've seen a few of those patients that have been unable to leave the hospital, and as a result, we've considered lung transplantation and offered lung transplantation for them to improve their quality of life and hopefully prolong their life.

Kenneth McCurry, MD:

And then we're beginning to see some outpatients as well. Dr. Budev perhaps can mention this a little bit later, but our pulmonary group here at the clinic has been very active at establishing post-COVID clinics for follow up. We really don't know what the long term sequelae of mild or moderate disease is with regards to COVID and whether this may lead to sort of later pulmonary fibrosis that may ultimately require transplantation. And we've seen a few patients under those circumstances that have continued oxygen requirements and sort of declining functional status on an outpatient basis that we've considered for transplantation as well.

Marie Budev, DO, MPH:

So you make a really good point. Recovery is possible?

Kenneth McCurry, MD:

Yeah, it certainly is. Many patients do get better I think as we've seen, so it's really a minority of patients that end up with that very severe disease that on mechanical ventilation and ECMO that we would consider for lung transplantation. The way we approach this, here at the Clinic, particularly with regards to the patients with moderate or severe disease that are in the hospital, is we really have a very broad and very deep multidisciplinary team that we manage these patients with. So not only our lung transplant program, which includes surgeons, pulmonologists, intensivists, social workers, other people that are engaged, respiratory therapists, but also our cardiothoracic ICU. So, we manage these patients in a multidisciplinary fashion so that we can make best decisions with regards to the timing of lung transplantation consideration. As you alluded to earlier, Marie, we like to wait again long enough, so that we think that we've given the patient every chance that we can for their lungs to get better.

Kenneth McCurry, MD:

And in general, unless there's a compelling reason to do so, in general, we don't consider transplantation until a patient is at least about four to six weeks into a course of severe COVID. We think that that window is sort of the opportunity or the point at which if they're not getting better and we have other evidence that they have severe lung disease. So on CT scan looking at the ventilator and their pulmonary compliance, all of these factors, if they're not showing some signs of improvement by that point, then I think in general, we think that they have very severe and advanced disease that's likely not going to improve, and that's when we consider transplantation.

Kenneth McCurry, MD:

I must say we, we do many things prior to that that will hopefully still put the patient in a good situation, not only to potentially recover, but if they do require transplantation, that they'll have a good outcome. So we try to get patients awake as early as we can, so they can begin engaging in physical therapy to stay strong. We work very hard to maintain their nutritional status and, and many other things that our physical therapists do, that will not only potentially help the patient recover if the lungs do cooperate, but even if they don't and transplantation becomes necessary, it'll put the patient in a much better situation to ultimately get a lung transplant.

Marie Budev, DO, MPH:

You've brought up several key points to consider when you're trying to get someone to the point where you would call a referring center and say, "Hey, I want a transplant for my patient. What do you think?" One of them was physical therapy. Can you talk a little bit more about that and what the expectations are from a transplant center when they're looking at someone for possible transplantation for COVID ARDS or COVID fibrosis?

Kenneth McCurry, MD:

So in general, we know historically after having done this for many years now, we know that, if we transplant someone who is very de-conditioned from a neuromuscular standpoint. So someone who's bed bound, not able to participate in physical therapy for a few weeks or more, and they're very weak. We know that the outcomes will not be good. In general it just makes it very difficult to recover from a lung transplant. So we try very hard to get the patient awake prior to a lung transplant, to have them engaged in physical therapy. Our general requirements are that patients be capable of standing and walking in the ICU. Sometimes we're capable of doing that simply with a mechanical ventilator and a tracheostomy, other times it requires ECMO or mechanical circulatory support to actually use a machine to help provide oxygen and remove carbon dioxide so that the patient can participate in physical therapy and to get stronger. And that dramatically improves the outcomes for patients that we consider for transplantation.

Kenneth McCurry, MD:

So, I think for those centers that are treating patients with COVID and don't have an active lung transplant program, if you have someone who had very severe disease, I think if they're not getting better, I think early consideration for referral to a transplant center would be appropriate. And certainly it would be appropriate to try to do things under those circumstances to work from a physical therapy, standpoint, to try to keep the patient strong. So it'll put them in a better position, should transplantation be necessary.

Marie Budev, DO, MPH:

This is perfect. You've really given us some guidelines that as a referring center, what we should be doing and calling early is very important, so we can help guide you. A transplant center can help guide you on how to take care of this patient in terms of getting them ready for their referral for transplantation and ultimately the evaluation. So could you say a few words about the absolute contraindications, a patient that we would never think of transplanting for COVID ARDS or COVID-related fibrosis?

Kenneth McCurry, MD:

Yeah, it's also a great question, a very important point, I think, Marie. So, you know, we have guidelines for consideration for transplantation in general, and the way we approach it with COVID-19 is most of those guidelines or considerations I think apply in this particular circumstance as well. So sort of the absolute contraindications that we would not consider transplantation for really any patient would be an active malignancy or a recent malignancy. Certainly anything within a couple of years short of perhaps a skin cancer, but any significant other malignancy. In general, we prefer five years, but we're able to sometimes take two years of disease free survival with a malignancy. We do take age into consideration and it varies across the United States from program to program at our institution. We'll, we will actually offer to lung transplantation to certain patients well into their 70s, but we need for them to be in a good physical condition with relatively few other comorbidities. In the case, particularly for COVID-19, we commonly have restricted that to less than about 65 years of age, unless there are other considerations.

Kenneth McCurry, MD:

A couple of other important points, I think, if there's a history, a recent history of some sort of substance abuse, that would be difficult to overcome after a transplant, we generally consider that an absolute contraindication. And then it's very important that the patient under consideration for transplant have good social support and some financial structure with which to be able to acquire their medications post-transplant. So hopefully an insurance that would provide those medications for them. So the recovery after transplantation, particularly, you know, these circumstances can be difficult and it really requires a group of people to be able to support those patients.

Kenneth McCurry, MD:

I think the last few other factors are, I mentioned nutrition before, nutrition is very important, so someone ... persistent poor nutritional status, or a very low, or a very high BMI, and in general, a BMI less than 17 or a BMI of greater than 35 is a bit problematic for consideration for transplantation. And then those patients with an unknown neurologic status. And this is particularly important, I think, for the patients with very severe COVID who have been pharmacologically paralyzed in the ICU. We like to get them awake and be sure that they haven't suffered some sort of brain injury that would diminish their outcomes.

Kenneth McCurry, MD:

And the last very important point, I think, is other organ system failure. So I'm sure as many know listening to this podcast, it's very common with COVID for other organ systems to become involved. In general, we strongly prefer that patients that we're considering for transplantation for COVID-19 have single system organ failure, occasionally we will consider a patient with concomitant acute kidney failure, if we think that there's a decent chance that the kidneys will recover after transplantation.

Marie Budev, DO, MPH:

What about in terms of the COVID infection itself? When you're referring a patient for transplantation, what is the program's view on reassessing for COVID infection, other infections that may be concomitant because of this viral infection?

Kenneth McCurry, MD:

Yeah, also great points, Marie. So as you allude to, we want to be sure that COVID has cleared from the, from the lungs, that there's no active COVID infection. So our programmatic requirements are that we have a negative nasopharyngeal swab by PCR, and then we also do at least one, sometimes two BAL samples for COVID PCR to be sure that there's no active infection.

Kenneth McCurry, MD:

I think in general, once we get out of that three to four week window, we can feel pretty comfortable that there's no active, ongoing viral infection, but still that's a matter of routine for our program to do. And sometimes referring centers will do that ahead of time before they send a patient, but it's certainly not required as you allude to Dr. Budev, we, commonly entertain those questions and have discussions with referring programs to try to help guide them.

Kenneth McCurry, MD:

Your other point, I think is also an important one. So particularly the patients with very severe COVID can end up with very severe lung destruction. So sometimes have pneumothoraces, sometimes have blebs or pneumatoceles or other disease within the lung that can lead to contamination with other bacteria, sometimes very significant and resistant bacteria. And that can be a bit of a problem. In general, we don't see that as an absolute contraindication to transplantation, unless the bacteria are just not treatable. We certainly prefer for there not to be an active bacterial infection at the time of transplantation, but if patients are colonized we'll still consider them under those circumstances. And that's one of the reasons in general that we've been doing double lung transplants for patients with COVID-related lung disease.

Marie Budev, DO, MPH:

As the vaccine was developed, we've been very fortunate to see many people get immunized and less severe illness, but we're still seeing very severe illness and ARDS and fibrosis in those individuals that are not vaccinated. How does that impact their prospects as a transplant potential transplant recipient?

Kenneth McCurry, MD:

Yeah, it's a great question Marie. I think, you know, we've struggled with that as an institution, as a program, you know, we're in the business of trying to help people get better from disease and medical illnesses. One of the things that we do know is that acquired COVID infection or COVID infection in an immunosuppressed patient. So someone who is receiving immunosuppression after a solid organ transplant, we know that the mortality associated with that infection is extremely high. And unfortunately we've seen a few of our own patients here at this institution die post-transplant. So patients that were transplanted a few years ago, or more who acquired COVID early on in the pandemic and their mortality has been quite high. So in general, now at the Cleveland Clinic, we require that patients be vaccinated for COVID-19 prior to undergoing transplantation.

Marie Budev, DO, MPH:

Thank you for clarifying that. In the last few minutes we have remaining, can you review how the Cleveland Clinic has done with COVID transplants, and you know, what should people expect in terms of timing, if they come here for a referral, when would they get listed? Is this quick?

Kenneth McCurry, MD:

So it can be. So, first of all, I would say that. So at the Clinic, we've now done, I believe, around eight, transplants for COVID-related lung disease. Some of those have been patients that were admitted initially with COVID to our own institution, others have been patients that we've taken from outside institutions. Our MICU, our medical intensive care unit has done an outstanding job. Their survival is quite good with advanced COVID. So we've had fewer patients come from within our hospital, but quite a few come from outside.

Kenneth McCurry, MD:

So lungs are allocated than the United States based on acuity of illness. So in general, the patients that we're considering for transplantation with COVID-related lung disease are very sick, so they end up with a very high score. So once we think a patient is ready and list them, sometimes the weight can be quite short, sometimes within a few days, sometimes within a few weeks to get a transplant. We know, from experience, and I think others do across the country and the world, that transplantation for patients with COVID is more difficult, technically more difficult, blood transfusion requirements are higher. And, I think the post-transplant course tends to be a little longer as well, but certainly many patients have gotten out of the hospital within a few weeks of their transplant here at our institution.

Marie Budev, DO, MPH:

This has been great. Thank you for this conversation, all the points you raised. I think some key points are, number one, think about these patients that you have that have not had reversible ARDS or fibrosis due to COVID-19. Call your transplant center local early, so they can help guide you on how to get that patient ready for the referral. Physical therapy, nutrition are absolutely important in this phase to keep these patients as healthy as possible so that they can undergo transplantation and also the referral process. We're learning more and more about this as we go through the pandemic and it's going to become an endemic. It's going to be important to immunize all of our patients, making sure they get the COVID vaccine prior to their listing. I think that's something that's absolutely essential. And again, not all transplant centers are going to be performing these transplants for COVID-19 by ARDS or fibrosis. So know the centers locally close to you that are performing these transplants. Any other final points, Ken, that you'd like to share with our audience?

Kenneth McCurry, MD:

Well, I'd like to thank everyone for listening today. And I think all the points you've made are quite good. Marie, we're more than happy to engage with anyone who wants to call us to discuss the care of their patients at any time and always happy to help.

Marie Budev, DO, MPH:

Thank you, everyone. Please don't hesitate to reach out to us. My email address is budevm@ccf.org, B-U-D-E-V-M @ccf.org. And we can be found on the webpage, the Central CCF webpage for our contact information for both Dr. McCurry and myself. Please don't hesitate to reach out to us.

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