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Seminars AATS International Roundtable of Lung Transplantation for COVID-19

2022; Elsevier BV; Volume: 34; Issue: 3 Linguagem: Inglês

10.1053/j.semtcvs.2022.05.012

1532-9488

R. Taylor Ripley, Gabriel Loor, Ankit Bharat, Tiago Machuca, Marcelo Cypel, Konrad Höetzenecker,

Organ and Tissue Transplantation Research

Dr. R. Taylor Ripley (Houston, Texas):On behalf of the American Association for Thoracic Surgeons, thank you for joining us for Seminars International Roundtable Discussion of Lung Transplantation for COVID-19. My name is Taylor Ripley, and I'm the Thoracic Editor for Seminars in Thoracic and Cardiovascular Surgery, as well as a thoracic surgeon at Baylor, College of Medicine in Houston, Texas. As everyone is aware, COVID-19 continues to ravage all of our communities. Based on World Health Organization data from the end of July, 2021, over a 196 million confirmed cases and 4.2 million deaths have occurred worldwide. While these numbers are huge, they may significantly underestimate the actual disease burden, given that many patients contract the disease and some die without an established diagnosis. Fortunately, vaccinations are effective against COVID-19 and 735 million people worldwide are fully vaccinated (July, 2021). However, a large percentage of the population remains unvaccinated. Additionally, mutations in the virus such as the Delta variant are changing the rate and methods of transmission. These factors are contributing to the continued disease burden which indicates that we will deal with this disease for the foreseeable future. For many patients who have the disease, chronic respiratory failure develops—even with clearance of the virus. Which leads us to the topic of our discussion today. It is my pleasure to introduce the panel of internationally distinguished lung transplant surgeons and members of the American Association of Thoracic Surgeons, who have all performed lung transplantation from COVID-19. Today, I'd like to thank Dr. Bharat from Northwestern, Dr. Hoetzenecker from the Medical University of Vienna, Dr. Machuca from the University of Florida, Dr. Cypel from University of Toronto, and Dr. Loor from Baylor College of Medicine for joining us for this discussion of their experience. I'd like to start off the discussion with our panelists by noting that Dr. Cypel, in Lancet Respiratory Medicine, discussed 10 considerations that should be assessed for patient under evaluation for lung transplant. The first question I would like to propose a group is: How do you determine whether lungs will recover from COVID-19, or whether the damage is irreversible and transplantation is indicated? Dr. Gabe Loor (Houston, Texas): I think that's a very important question. I think that Dr. Bharat's paper in Science brought awareness that there are fundamental fibrotic changes that occur in these lungs. And that, in and of itself, is not sufficient as to warrant transplantation for a patient. But how we decide when it is time for transplant is extremely difficult and I'm very interested to hear the panel's discussion. I think its risks and benefits waiting versus the risks of transplant. The upfront risks aren't huge, but the long-term risks can be substantial in terms of chronic lung dysfunction. Dr. Ankit Bharat (Chicago, Illinois): I can give my 2 cents here. This is a question that I think we're going to just have to continually work on understanding. Right now, this question is just a matter of opinion and institutional experiences. I don't think we can set any hard criteria right now. But what I will tell you is based on a lot of work done by our research group and some of our collaborators, we clearly have established that some patients with severe COVID-19 end up developing permanent lung damage. There's no question about that. And one of the fundamental differences in these patients compared to other types of infections, for example, a bacterial infection and even influenza, is that in that subset of patients who have severe COVID-19 and develop permanent lung damage have the damage to the fundamental framework of the lung. So, the actual architecture of the lung gets completely destroyed and that then established irreversibility in these patients, and that is something that we don't see commonly in influenza and other types of respiratory illnesses. The second thing that we found is that in some patients when that permanent damage starts to occur, they start to show specific markers. One of the things that we have discovered was the presence of these keratin 17 cells. These are cells that represented a differentiation defect between AT1 and AT2 cells. It's also a common hallmark in—as we are understanding more and more about this—some other types of fibrosis like IPF (interstitial pulmonary fibrosis). And then one of the things we're trying to do right now is to develop an ELISA (enzyme-linked immunosorbent assay) based assay from the BAL (bronchioalveolar lavage) that would help maybe predict this question about irreversibility. A lot of work is being done, but I will say that clearly there is a subset of patients who are going to need transplants. So how do we, at the current time, determine which patients need it versus waiting too long? I think that the way we approach this at our center is to bring in multiple people from different specialties and having these discussions over and over again about individual patients. The things that have come out is number 1, you want to give every patient sufficient time. And that sufficient time period is also somewhat arbitrary, but we always try to give patients minimum of 4–6 weeks on the best medical treatment. Now, that doesn't mean that at the end of 4–6 weeks you list them for transplant. What that means is, after 4–6 weeks we continue to assess these patients and as long as they're making recovery, or if there is a consensus among the group that there is a possibility of further lung recovery, we will continue to support those patients. The trigger to pull lung transplant is based on once we see specific changes radiographically with diffused end stage bronchiectasis changes, development of extreme Ebola or extensive lung necrosis, which the team does not think can be a reversible process. The other thing is, in some patient's development of long-term fibrosis but really bad compliance over the weeks and months. Or finally, one of the important things that we always consider is a potential for lethal complications. They're starting to develop things like severe pulmonary hypertension, that's setting off severe lung necrosis and damage and then multi-drug resistant nosocomial infections. In those patients you may want to—or at least we think that we may want to pull the trigger for transplant a little bit sooner. It's a complicated question. Something I think, because the group of these patients are so heterogeneous and our understanding is evolving, we have to look at it case by case. And I cannot overemphasize the importance of this multidisciplinary discussion. Not just 1 discussion, but over days and weeks that discussion for each patient. Dr. Marcelo Cypel (Toronto, Canada): I can also follow on that. I totally agree with everything that Ankit just mentioned. We also take a similar approach. We start looking at the patient after 6 weeks. They are on ECMO (extracorporeal membrane oxygenation). That's when we start looking. And we do ICU (intensive care unit) rounds, and we say, this patient is over 6 weeks, now could this patient be a candidate? And that's when we start the multidisciplinary discussion. I think we've been very impressed also in—as Ankit was saying—in one way, some patients develop this fibrosis. We've also been very impressed with the capability of the lungs to improve after looking completely destroyed on imaging. We had the benefit here of having a very centralized ECMO system where basically almost every ECMO for COVID-19 in the catchment area, 15 million of the provinces of Ontario, come to our center. So, we treated over 150 patients on ECMO for COVID here. And we had the chance again to observe many patients developing lung recovery after several weeks or months after being very diseased. And I think radiologically there are some observations which I think are important. When you have a completely consolidated lung, that's something we don't get too worried about because consolidation, and opacities, and so on. Of course, we get more worried when we start seeing bronchiectasis or traction bronchiectasis, and also bullous destruction of the lung because those will be very hard to go back to a more normal state. When you have those changes associated with poor physiology and over 6 weeks, that's when we start to screen those patients. Dr. Tiago Machuca (Gainesville, Florida): If I can share the experience here at University of Florida, I think we follow very similar approaches. I think that imaging is important for us, but I don't think we can jump into making any definitive conclusions with 1 snapshot. Time is very important. The more time you give for these patients you're going to improve their rehabilitation potential. What we do is essentially follow the patient and when they start to develop some signs of fibrosis or bullous destruction, we want to make sure that that is progressive—that it's not with 1 isolated, focal area of fibrosis, or bronchiectasis or bullous destruction. You're going to follow that patient and when that severity starts to become more diffused is when we really start thinking about transplantation. I really think that the determination of irreversibility is really the most important and pressing aspect of lung transplantation for COVID. I think we need to be careful not to list these patients early on. Obviously if you transplant this patient that can have a potential of lung recovery, you're going to be limiting the patient's life expectancy. And as Marcelo alluded, I think we are learning a lot in the field with COVID in terms of how resilient the lung can be. We did consider several patients that were transferred to us, and they were only placed on ECMO because transplantation was a possibility. So late ECMO initiations—and as long as the radiological findings are related to ground-glass opacities or consolidation I think that there's still a very high likelihood of lung recovery. So, I think timing and when you see the lesions like fibrosis, bullous destruction, and other hallmarks of chronic lung disease such as bronchiectasis, pulmonary hypertension and when they are progressive over time, I think is when you really start thinking about transplantation. And I think the other aspect that Ankit mentioned is, we all know that these patients eventually start to develop complications. When these complications start to be life-threatening—repeated episodes of a secondary bacterial infection, septic shock, or bacteremia—you really need to be worried about timing, right? You want to wait to determine that that lesion is irreversible, but you also do not want to have that patient in repeated life-threatening complications to a point that he is no longer a viable transplant candidate. Dr. Konrad Hoetzenecker (Vienna, Austria): I agree with a lot of things that have just been mentioned. I don't honestly agree with the timeframe of 6 weeks or to state that 6 weeks is the absolute minimum you should wait before considering a patient for transplantation. Similar to the Toronto experience, most COVID ECMOs of the eastern region of Austrian had been inserted in the hospital where I work. Therefore, the Lung Transplant Program follows these patients immediately after they are put on ECMO. Some patients became transplant candidates after 2 weeks, 3 weeks because they developed lung necrosis because they had repeated septic episodes. If you just wait for 6 weeks before considering a patient for transplantation, you will lose these patients with a complicated course – I always refer to them being the "real" ARDS patients. The other portion of patients that become transplant candidates after 6–8 weeks, are more like IPF patients. They're in a chronic state of disease with scars in their lungs and they simply fail to recover. Also, in regard to technical aspects of the transplantation, I have the feeling these are 2 different kinds of diseases. The ARDS patients are more complex to transplant. They usually lose a lot of blood, and the transplantation itself is more difficult. But the chronic fibrotic patients are more like bridged IPF patients. There is less blood turnover and they quickly recover after the procedure. And I think talking only about when is the right time to consider transplantation misses a lot of patients who die before they could even reach the 6-week time point. And we must not forget that mortality despite best conservative treatment is still about 50%, even in experienced ICUs. A lot of patients that could be saved with a transplantation are lost by arbitrarily defining a time when you can start to consider them for lung transplantation. At the end of the day, it's a very individual situation. Some patients might become a candidate after 3 weeks if there are big abscess formations or if they develop ECMO related complications. I remember 1 patient who had severe bleeding, with recurrent hemothoraces. And of course, the lung never sealed the thoracic cavity because it could not expand. After the transplantation everything was much better and I'm sure we would have lost the patient would we would have waited for 6 weeks. Time to consider transplantation is a moving target, we don't have any data yet to guide us. At the end of the day, it's a very individual decision and we still learn with every single case. Dr. Ripley: This discussion leads to a question about timing. We're debating 6 weeks as being too long or the optimal period. Are you talking about 6 weeks after respiratory failure for COVID or 6 weeks on ECMO? And do you distinguish ECMO and time on ECMO from the actual time of the disease process to when the patients either were first sick or at least first admitted to an ICU? Dr. Bharat: We look at the onset of severe ARDS. That's the time period that we start looking at someone who was admitted with mild symptoms for a few days—that for us, doesn't start the clock. But it's not, as Konrad and everybody pointed out, about a hard stop or start-or-stop. It's really putting everything in perspective. In our experience we've seen that most patients do tend to get better or at least start to show signs of recovery within that 4–6 weeks window. And I think consideration of transplant sooner than that—I mean you can encourage their risk of over treating that, which I think for something like lung transplant is quite burdensome. You don't want to be over treating a lot of these patients. And a lot of these patients are quite young, and you've shortened their overall lifespan compared to a spontaneous recovery. But as other speakers mentioned, if they have severe complications that cannot be managed with the ECMO and ventilator we would escalate the timeline a little bit. But to what you said, Taylor, we generally look at the onset of severe ARDS as when we start to assess lung recovery, not necessarily from when patients were admitted or had mild symptoms. Dr. Cypel: I also agree with the clock start in the respiratory failure. And I take Konrad's point quite well. Vienna has a long tradition of doing transplant for ARDS patients before COVID, so they do have good experience on that. You know, I think when we put it on paper, like we're writing on the back of the tutorial, and we say 6 weeks—I think as we speak here, we have to be careful. And the reason to put an arbitrary timeline is that of course we are expert centers here, but the major worry we have is that people would start transplanting patients after a very short time because of significant ARDS across the board and I think that clearly wouldn't be right. I think 1 thing is what we set as a potential guideline, but of course, there is the individualization of cases that we all need to make. But I think we all feel that around the 6-week mark is when we should start looking more seriously. But again, individualizing cases more. Dr. Loor: Taylor, I agree with Marcelo on all accounts. I think you certainly feel better about it if you've allowed some time to transpire. Some centers have certain built-in mechanisms where, as you know Taylor, in our place we have this 30-day positivity and negativity situation where they try to make sure that it's been at least 30 days from a contracting a virus standpoint. So that alone sets up a little bit of a barrier. That notwithstanding, what Konrad mentioned, which is not missing these patients who you do have to catch early, I think that some programs have some already. Some stop gaps where the transplant team is probably not even fully aware until 30 days have transpired. And with those lenses, the amount of times that they've asked us to evaluate patients, those patients either get transplanted, they're not candidates, and by that time I've seen very few recover unfortunately. Once they're on ECMO and it's been past 6 weeks, I think it's been very few that have had a full recovery. The ones that have not been candidates for transplant, a few of those have actually recovered. And you had to wait for a variety of reasons, but I think you definitely feel better about it once it gets past 30 days or 4–6 weeks. Dr. Machuca: I think it's very important for us to reinforce the concept that this timeline of 4–6 weeks from respiratory failure, we consider that just to start transplant conversations and considerations. I think it's not uncommon, all of you here probably face that when you're talking about lung transplantation for COVID. That some may miss this concept and mention that, 'I had a patient that was on ECMO for 2, 3, 4 months and recovered'. I really think we need to stick with the idea that 6 weeks of respiratory failure is to start consideration to look at other transplantation criteria. Does this patient have signs of irreversible lung damage? And does it meet the other proposed criteria? Does a multidisciplinary team of experts that have experience with ECMOs bridge to recovery and determined that this is really irreversible? The 6-week proposed time frame is so you can consider more strongly transplantation and look at additional criteria. It doesn't mean that by 6 weeks that patient did not recover on ECMO so now let's list. I think that's very important. Dr. Ripley: I want to briefly mention that patients over time have increasing complications. So, should lung transplantation for patients on ECMO be limited to single organ failure? And as a corollary, should patients be able to provide first-person consent in order to undergo the transplantation? Dr. Loor: I'd be really interested to see what the group thinks. That's the huge question. Typically, we like a patient to be awake. Awake on ECMO, at least. Ideally, maybe ambulatory. We do ideally like to have single organ, but COVID has tested a lot of our criteria. You have patients presenting in a comatose state, who are young, and they have single organ, and they can't get them off sedation. Sedation is a very challenging thing to try to wean some of these patients off without them desalting. As you know, we do like to wait until they're awake and we can get that sedation down and we do whatever it takes from an ECMO status to try to get to that point. But a lot of times, I do wonder, and I worry that there's some patients that they don't get the option of a transplant because you can't quite get them there. So, curious to see what the rest of the group is doing. Dr. Machuca: For us, we really push hard to have patients awake. And I think probably you all have dealt with the scenario of patients being transferred to you after 1 month on ECMO. The patient doesn't even have a tracheostomy and is sedated and often paralyzed for a long time. This is a lengthy process, and in our experience, it is not uncommon to see a patient taking a month to start waking up and starting to participate in physical therapy, but we really feel that that is the ideal scenario. This patient should be at least participating in physical therapy and awake to be able to make decisions. And with regards to multi-organ transplant, we have embarked on that. We have performed two combined double lung kidney transplants. I think this is the scenario that often times we face in terms of additional organ failure and in very, very specific selected cases of patients that have proven that they have a great rehab potential—very strong family support, and their willingness to really work with the team to overcome all the barriers to recovery. I think it's important and at the end of the day, it all comes to the morbidity potential. That additional organ that you are considering, how much of a morbidity are they going to add? How much of a recovery is going to be impaired by that? And I think in what we saw in these two cases recovery was very uneventful and we did not have any additional issues when you compare them to the double lung after COVID ARDS. Dr. Bharat: I agree with what Tiago said. I think multi-organ transplant is definitely a reasonable consideration in a highly select group of patients. Now, I would say a couple of things—we have a few patients also listed for lung-kidney. We haven't done one yet. They've been listed for a while. The issues that we face; number 1, patients who are really sick from COVID and have been on ECMO and have many complications, the intraop blood loss is quite significant in these patients. They go through this period—they become quite unstable and then coming out of the lung transplant they could be on lot of pressers, and you could be requiring a lot of fluid. In those circumstances, consideration of a second organ, particularly things like kidneys, could be challenging. Certainly, it can be done. A lot of things that could potentially be considered as a strategy, separated by 12–14 hours or so. But you just have to be careful because the intraop events from a double lung transplant for COVID could be quite dramatic. That could have substantial implications on a second organ. The other thing is a number of these patients because they've been in the hospital for a while, they could be highly sensitized so they could have a lot of high PRA and those kind of things. And certainly, that requires a lot of blood transfusion, so that could also have impact in organs, like kidneys and so forth and you don't want to be dealing with a lot of rejection soon after the transplant. The point I'm trying to make is this has to be a highly select group of patients, but it should be considered. And then the other thing about getting the patient's awake, I think Konrad may want to chip in a little bit more, the first patient that we transplanted was in the same situation where we could not wake her up. She was 28 years old, and we had to just pull the trigger here. But what we've tried to do is what's been mentioned; tried to give these patients enough time to wake them up. And as our ICU team, and our pulmonologist, and critical care team become more comfortable weaning the sedation off, getting them off the PEEP. Once the decision is made that transplant is a consideration, we are seeing a lot of these patients are able to get woken up. In the thirty or so transplants we've done, except for the first one, we've been able to wake every single patient up. And the point of that is number 1, we always want to make sure that this is consistent with the patient's wishes. Families always trying to say don't do it, they're trying to do everything to save their loved one, but is this something that the patient wants? Is it going to be compliant? You also want to make sure there is no neurological effects from the coronavirus itself, which is being more and more well described. I would say that I certainly recognize the importance of leaving that open ended for a select group of patients, who we think clearly would want the transplant, clearly would not cover, and clearly don't have coronavirus induced neurological damage. Absolutely could be considered in a highly select group of patients, but I think for the majority of the cases we should absolutely try to wake them up and give them sufficient time before we make the consideration for transplant. Dr. Loor: What's the group's experience been with hyperbilirubinemia? My experience has been that I really don't like to operate in that setting, when the bilirubin's too high, because then you get into liver dysfunction and what Ankit was mentioning in the blood loss, vasoplegia, etc. We try to wait until it comes down, but I feel like there's some phenotypes of COVID where you get this hyperbilirubinemia, and it doesn't resolve. Has anybody considered a lung-liver in these cases? What's your experience been like? Dr. Hoetzenecker: I think that's a very good question. We haven't considered this as a contraindication and many of our 21 patients had heightened bilirubin levels, which we considered not that important. Traditionally, in ARDS literature there is a cut-off of 1.9 milligrams per deciliter bilirubin when considering lung transplantation. We know now and I've just read a recent publication from Hannover, that 30% of post-COVID ARDS patients have significant liver damage despite their lung recovery. In our transplanted patients we saw a similar number, 30%–40% who developed liver dysfunction after the transplantation. Many of them had normal bilirubin levels before the transplantation. Some had slightly elevated levels, which we considered to be consistent with critical illness cholangiopathy, cholangitis maybe, but we didn't pay that much attention. Now we see that this can be a significant problem after the lung transplantation. All of their grafts are fully functional, many of them are discharged home, and then they suddenly developed a picture similar to a secondary sclerosing cholangitis. We have two patients now who will even require liver transplantation. They're on the liver list. This is a very interesting topic. We haven't really realized this scenario before and I think that's important during the decision process if you plan to list a patient for lung transplantation. In contrast to this, kidney failure is not a big issue. 20% of our transplanted COVID patients had a temporary kidney failure at the time of listing. We knew that their kidney was well-functioning before the COVID infection, and all of their kidneys fully recovered after the transplantation. I don't think any of those would have been candidates for a combined liver-kidney, and we usually just do the lung transplantation, wait and the kidney usually recovers. In terms of awake bridging, we again follow a somehow different strategy in Vienna. We don't consider an awake status as a necessity for being listed, if the indication for a lung transplantation is given, if the team thinks that the native lungs cannot recover or there are secondary hits like an infection, which makes the recovery very unlikely, then a next of kin consent is enough to list the patient. Once the indication is set, we don't want to waste time by trying to wake-up a patient so that he can participate in physiotherapy. The likelihood, at least in our hands is very low, only about 20% of acute ARDS patients can be bridged awake Therefore, we transplant up front and then recover the patients afterwards. And this is the same rough road which Tiago, Ankit, or Marcelo described in their pre-transplant patients. Recovery after the transplantation is similarly difficult, it takes a couple of weeks until patients regain their muscular functions, but it is feasible to do this after the transplantation. Dr. Cypel: If I can just follow up on that Konrad, I think that's a great comment. For us, we also try to wake up everyone and have a conversation. For the COVID patients it is very difficult to get them awake, especially in the first 3 weeks. And I think it's part of this inflammatory process, and as Ankit mentioned, there is a much higher incidence of brain injury as well related to COVID that is probably under recognized that's a part of this difficulty waking these patients in this inflammatory phase. But once they go beyond that inflammatory phase, I think it becomes easier to wake them up when you get to the fourth or fifth week. The other important part is to work very closely with your ICU team on that because it's very common that these patients will desaturate when they are getting more awake. And the first thing that they will do is to sedate them again, right? So, we had to go to a lot of persistence to say, let the guy sat 80% that's fine, his lactate is normal, and look at the oxygen delivery more than oxygen saturation. I think that's a process which we are learning as well and it's very important. Another thing is, I agree that the family can have a very good idea of the patient wishes. But interestingly, we did have a couple of patients that we discussed about transplantation while they were on the ECMO, and they didn't want to go through with it. We do see situations like that. Those are the patients that could be a bad situation if you had transplanted without their consent, so I think we still have to try to persist on getting first person consent. Dr. Ripley: On a related topic, we've been talking about transplant patients who have ARDS, are critically ill, and are on ECMO. Are you all seeing patients in clinic who've actually recovered from acute illness but have chronically high oxygen requirements similar to pulmonary fibrosis? Dr. Loor: We have a follow-up COVID clinic, and we have seen several of these patients. But all of the patients that I've been involved with transplanting, at least 80%–90% of them, have been in hospital situation—maybe only 1 or 2. The other ones seem to very gradually be getting better but sometimes it takes a year or 2 years. But they're on the radar screen. Dr. Bharat: Similarly, we also have what we call a Comprehensive COVID