Chronic Obstructive Pulmonary Disease (COPD) is the sixth leading cause of death in the U.S., affecting nearly 16 million adults. Dr. Gerard Criner, Director of the Temple Lung Center, recently joined the Global Forum on Lung Transplantation to explore the role of lung transplantation for COPD.
COPD patients may need lung transplants when their condition progresses to end-stage disease, or patients may become unresponsive to conventional treatments such as medication and oxygen therapy. Lung transplantation offers improved breathing, exercise capacity, and improved quality of life, ultimately extending life expectancy in eligible candidates.
This comprehensive webinar provides an introduction to the epidemiology of COPD, when to consider lung transplantation, the differences between single and double lung transplantation, and potential alternatives to transplant, and highlights Temple’s multidisciplinary expertise in managing complex COPD cases, including leveraging innovative technologies and strategies to optimize patient outcomes.
Hello and thank you very much for allowing me to present this outstanding symposium. I've been asked to talk about lung transplantation in patients with COPD. My name is Gerard Kriner and I'm the professor and founding chair of the Department of Thoracic Medicine and Surgery at the Lewis Cat School of Medicine at Temple University in Philadelphia, Pennsylvania USA. These are my disclosures of grants received and monies I have received for consultation regarding study design and study result interpretation. I should also state that I'm a member of the Gold COPD Board of Directors and I'm a member of the Gold COPD Scientific Committee. This is an outline of what I intend to present today. I will briefly set the stage for the severity of COPD. One to consider transplantation in patients with COPD, discuss the issue of single versus double lung transplantation in patients with COPD and then briefly discuss other interventions that can be done in patients with COPD who are being considered for lung transplantation or alternatively to help the patients posting lung transplantation to improve their outcome. I'd like to briefly review for you the burden of COPD so that you understand the importance of this disease and the necessity to consider the issue of transplantation for some patients with COP DC OPD is a major cause of disability and mortality in the world as well as the United States in the world. It's the third leading cause of death in the United States. It's the sixth leading cause of death. About 100 and 56,000 patients die from COPD annually in the United States. That's about one patient death for every four minutes in the United States. COPD afflicts nearly 16 million individuals but many more, maybe 50% more have COPD, but don't yet know it. More than half of those diagnosed with COPD are women in the United States and other high income countries. Smoking is the leading cause of COPD where most people who have COPD, either currently smoke or used to smoke in the developing world. However, air pollution plays a much greater role and half of all the cases not are not related to smoking. Um Tobacco use. This slide shows a common picture of a patient with COPD who has a predominant emphysematous phenotype and illustrates why COPD is such a morbid and mortal disease? COPD with predominantly an emphysematous phenotype causes severe hyperinflation which markedly impairs lung function, chest wall recoil diaphragm and other respiratory muscle mechanics, as well as cardiac feeling and ejection fraction. COPD markedly increases the development of breathlessness decreases, the quality of life leads to respiratory failure. And in patients who are severely hyperinflated. All these factors can contribute to increased mortality in patients with COD and severe hyperinflation. Besides hyperinflation, COPD, patients are markedly affected by the development of exacerbations which are sentinel events in the life of a patient with COPD. 20% of the decline of lung function in patients with COPD, who are either frequent exacerbators or infrequent exacerbators can be attributed to the development of an exacerbation. Exacerbations have negative impact on health status, rates of hospitalization and disease progression, exacerbations, impair physical activity and have a major negative impact on the patient's quality of life. Exacerbations also play a major role in progressive and irreversible lung damage and each exacerbation leads to an increased risk of death. And since severe exacerbations tend to cluster an overall increase cumulative mortality. This slide out outlines when to consider to refer patients for lung transplantation for COPD and when to actively list them for lung transplantation. Patients with COPD should be considered for referral for transplantation if they have progressive disease. Despite maximum medical treatment, if they are not candidates for lung reduction surgery or bronchoscopy treatments for lung reduction. If they have a multidimensional boat index, that is 5 to 6 units. If they have a partial pressure of carbon carbon dioxide, it's greater than 50 millimeters of mercury or a partial pressure of oxygen, that's less than 60 millimeter uh mil uh mill millimeters of mercury. And finally, if they have a uh fev one that's less than 25% of predicted patients with CCOPD should be considered for active listing for transplantation. If their bone index is greater than seven, if the FV, uh V one is less than 15 to 20% are predicted if they have had more than three or more severe exacerbations during the prior year, or if they've had one severe exacerbation causing respiratory failure. And finally, if they have concomitant, moderate to severe pulmonary hypertension. So, we have just reviewed the morbidity and mortality of COPD and the negative prognostic factors that exist in this patient population. Despite those facts over the past two decades, the number of patients undergoing transplant is increased due to the increased number of patients with interstitial lung diseases, undergoing lung transplantation. However, the number of patients with COPD receiving lung transplantation has decreased by about 30% over the last two decades. This is the case. Despite data that shows that lung transplantation could be an important intervention not only to improve quality of life but survival in some patients with advanced COPD. In this paper, the authors identified COPD patients in the United Network for organ sharing data set that were transplanted from May 2005 to August 2016. And compared it to 604 patients who were assigned to receive pulmonary rehabilitation and optimal medical treatment in the national emphysema treatment trial. In this propensity and matched analysis, transplant patients had overall better survival uh compared to medically managed patients in a national emphysema treatment trial, especially if they had a six minute walk distance, that was less than 1000 ft or 300 m or an FEV one, that was less than 20% of predicted. These are data from the International Society of Heart and Lung transplantation that reviewed all the adult lung transplants for COPD done globally. From 1992 through June 2017, survival was calculated using the Kaplan Meyer method which incorporates information from all transplants from whom any follow up has been provided. As this slides illustrates there is a significant increase in survival for bilateral double lung transplantations compared to patients with single lung transplantation that begins to show separation after about 1.5 years, post lung transplantation. As a result of these data and data from single centers that demonstrates improved long term survival with double versus single lung transplantation in patients transplanted for COPD, there has been a marked increase in a number of patients that receive double over single lung transplantation. Double lung transplantation is shown here in a purple in the green single lung transplantation by almost a ratio of 7 to 1 favoring double lung transplantation over single lung transplantation. So what's the explanation for why single lung transplantation does not carry the same improvement in survival that double lung transplantation affords for patients with COPD? Well, this study attempts to provide some answers of what complications can arise in patients undergoing single lung transplantation compared to double lung transplantation for patients with COPD. In its retrospective study of 100 and 61 single lung transplantations, complications in the native lung were recorded and distributed into two groups early versus late complications. And what they found is that atelectasis, pneumothorax, pneumonia, as well as consequences of hyperinflation increases the morbidity and mortality of patients with COPD undergoing single lung transplantation. As this figure to the right shows there is an increased mortality that is seen immediately post transplantation with single lung transplantation in COPD patients that continued over the first two years of follow up post lung transplantation. Another issue that can complicate the outcome of patients with single lung transplant for COD is the development of lung cancer in the remaining native lung. We retrospectively reviewed our institutions eight year experience with lung transplantation and search for patients with a post transplant diagnosis of lung cancer, neoplasm or mass. We identified 24 individuals with a de novo lung cancer, post lung uh transplantation in 905 recipients at our center, 21 of these patients were diagnosed with non small cell cancer and three small cell cancer. The remaining native lung was involved in most single lung recipients. With 17 out of the 24 patients developing neoplasm in the native lung patients with a diagnosis of lung cancer had a mean survival as shown in the figure to the right of approximately 17.6 months after the diagnosis. Although double lung transplantation may afford a superior outcome in terms of long term survival. Many patients who are severely ill with COPD, die on the waiting list and die before receiving transplantation. A broader view is needed to consider both the balance of long term survival. In light of survival. On the waiting list, single lung transplantation may afford some benefits compared to double lung transplantation and decreasing the wait time and providing the ability to transplant twice as many patients. If a donor block is divided between two different recipients. In this study, 6700 patients with COPD on the unos waiting list, 4.8% of them died and 320 or 4.7% were removed due to clinical deterioration. Such that almost 10% of the patients died on the waiting list because they are waiting for a double lung transplant. Medium survival. On the wait list was longer with people who were restricted for double lung transplant only. That was um about two year lower survival compared with patients listed as unrestricted for single or double lung transplantation factors in this study that increased weightless mortality included female sex, sex, increased pulmonary artery pressures and increased wait time. Median survival post transplant was 5.3 years in the single lung transplant. Patient population versus 6.5 years in the double lung transplant population. Restricted listing preference that is segregating patients for double lung transplantation. Preferred, preferred is associated with increased weight list mortality. But double lung transplant recipients had seve uh superior post transplant survival on average about 1.2 years. Because the lung out system in the CAS system does not prioritize COPD concern for increased weightless mortality with restricted listing preference for only double lung transplant may continue to drive the use of single lung transplant despite better posttransplant survival and double lung transplantation. Well, another factor that considers recipient age when considering the implication of single or double lung transplantation on survival in patients with COPD. As shown by these slide, three slides. Looking at patients between the age of 18 to 3940 to 59 and above 60 years of age, there is less difference in survival outcome with single versus double lung transplantation in patients above the age of 60 or even those between the age of 40 to 59. When comparing single versus double lung transplantation at Temple, over 60% of our recipients for lung transplantation are over 60 years of age. Our patient population is much older than the national average that receive lung transplantation. Because our surgical and medical program at Temple is able to handle the issues that afford patients who are severely ill with COPD uh over an older age to be able to successfully receive transplantation for immediate and long term survival. As a result of our patient population being older our COPD patient because of our referral uh patterns uh attracting patients that are more severe and the capabilities of our IC um pulmonologist to provide aggressive and timely care for patients with COPD. Following single lung transplantation, we predominantly have treated patients with COPD with single rather than double lung transplantation. Over the last decade. To illustrate this point, we tend to use single over double lung transplantation about 2.4 to 1 in the last decade. This allows us to treat many more patients with COPD than we otherwise would if we only restricted ourselves to double lung transplant. And our medium time waiting for transplant is faster at approximately two months compared to other programs overall to improve long term survival in lung transplantation. Uh COPD patients must have the eye on what the possible complications are. This slide illustrates that the five most important complications is the development of obliterated bronchiolitis development of malignancy as we reviewed infection graft failure and also um cardiovascular consequences. This slide shows that regardless of age or single or double lung transplantation, that long term survival continues to face challenges due to the occurrence of obliterated bronchiolitis in patients that receive a single or double lung transplantation. And regardless if they are less than 50 years of age or greater than 50 years of age. So, appropriate genetic matching, detection of cellular rejection, humeral rejection, and effective targeting of immune suppression medication and use of vaccines and avoidance and timely treatment and detection of bacterial and viral infections are required to minimize the impact of obliterated bronchiolitis affecting the long term survival of COPD patients receiving single or double lung transplantation. This is an outline of patients referred to temple for bronchoscopy lung reduction for patients with COPD and have an emphysematous phenotype. One can see that of the 1st 595 patients that were referred to us. Only 44% of these patients were candidates for bronchoscopy lung reduction. While 20% of these patients were candidates for lung volume reduction surgery because of the features of their anatomy or physiology. And 29% of these patients were better suited for lung transplantation because they had either more advanced disease or other concomitant problems such as coexistent pulmonary hypertension or interstitial lung opacities. Because of this, our transplant program is intertwined and integrated with our lung reduction program. Lung reduction can be done by surgical means as shown here where 30% of the most diseased portion of the lung predominantly from the upper lobes is resected or to the right of the slide are bronchoscopy approaches uh which use one way and the bronchial valves. There's currently two products that are approved in the United States and these are both utilized to provide uni low bar occlusion to allow volume reduction by creating low bar at electus. Now, the basis of improvement of patients with lung reduction with severe COPD due to emphysema emanates from the national emphysema treatment trial or net. This is a multi center randomized clinical trial that compared medical treatment that was optimized with lung reduction surgery bilaterally to treat patients with severe emphysema. This was funded by our National Insurance insurance carrier Medicare and the science was run by the National Lung Heart Blood Institute. This slide summarizes the results in 1218 patients that were randomized to receive either surgical treatment compared to optimal medical treatment. As one can see in all subjects, there was a 15% survival in patients to see receive bilateral lung reduction surgery compared to optimized medical treatment. These patients had also a significant improvement in exer exercise 0.4 greater favoring surgical treatment and had a marked improvement. We used a double, the usual MC ID of four is an improvement and this was three fold greater in patients who receive surgical therapy. Some patients who are too sick for lung reduction. These are patients that have an fev less than 20% with homogeneous emphysema and cat scan. And they should clue these individuals and divide patients into non high risk individuals with upper lobe versus non upper lobe, predominant emphysema. And if size or not, those patients who are have upper lobe during exercise size have the greatest improvement with lung, 43% improvement in survival at seven years, they have a marked improvement in exercise performance and a marked improvement in quality of life. Similar findings in terms of improvement in exercise and quality of life is seen in those patients that aren't ventilatory, limited with upper lobe predominant disease. But the survival advantage is not so robust. And then patients with non upper lobe disease or homogeneous emphysema have lesser improvements in terms of survival, the low exercise subgroup or uh mortality or improvement in quality of life. However, surgery has complications if one looks at the net data, 90% mor uh 90 day mortality in patients that receive bilateral lung reduction surgery was 4.3% greater compared to patients who had optimal medical treatment in a non high risk group. 90% of patients end up having air leaks um and had to stay in the hospital about seven days and then the cardiopulmonary morbidity was about 50% with patients developing pneumonia, exacerbations, prolonged voluntary support, et cetera. So, although there are significant benefits from surgery in this population, there also is significant complications. As a result of that, we search for other ways to make this procedure safer as well as meaningfully uh important bronchoscopy techniques. Using one way in the bronchial valves or re uh coils were started to create targeted low battle lusis endoscopic measures of trying to remodel the lung with biologic lung reduction or thermal ablation. And then finally placing artificial airways into emphysema lung with the use of endobronchial stents. These three major um avenues were used to create lung reduction without um surgical approaches. And since then, two prospective randomized control trials have shown the benefit with one way endobronchial valves and improving patient's outcome. These are two approved types of endobronchial valves currently used in the United States. The zephyr valve through the liberate protocol and the spring valve system shown in the improved protocol. These are the primary outcome and secondary outcome from the liberate study as an example which showed at one year in patients with severe irreversible airflow obstruction, who were otherwise were maximally medically treated that approximately 47.7% of the group post endo bronchial valve placement with uni low bar inclusion and volume reduction had a 15% greater improvement in fev one. This ended up being an absolute improvement in FEV one at 100 and miles at one year and in, in a group difference and improvement in six minute walk by 39.9 m and a reduction in SGRQ, which is an improvement of 7.9 points, which is almost double the MC ID at one year. If you look overall at the patients in a responder analysis, using these thresholds of responder outcome, 50 to 60% of patients had an improvement in lung function. Patient reported outcomes for improvement in quality of life and a reduction in dysnea and was tethered to the mechanism of improvement. A targeted low volume reduction in 85% of the cases. So the improvement in physiologic and functional uh parameters was associated with the mechanism of action. A decrease in air trapping. Well, what happens in patients that don't meet the metrics that have collateral ventilation or non intact fissures. There's other attempts endoscopically to try to achieve these outcomes with the use of activating coils, the use of thermal ablation or airway stance. These are in some way, they still being examined in the United States. They are approved in some places of the world such as Asia and in Europe and can be tools that can help patients uh with hyperinflation, do the emphysema who don't have intact fissures or collateral ventilation positive and some people that fail. However, we've recently reported in 67 patients who failed bronchoscopy lung reduction, that lung volume reduction surgery is a viable option. And with this surgery, we're able to improve pulmonary function and decrease patients dyspnea score. Such that in aggregate, our program looks at patients who come to us with severe COPD if they're a candidate first, because they have emphysema for endobronchial valve treatment, bronchoscopy for lung reduction or lung vine reduction surgery. If they're not a candidate, endoscopically or lung transplantation, if they have the special features of more advanced disease with gas exchange failure or concomitant, pulmonary hypertension or pulmonary fibrosis. And this is an example of how we can combine treatments to support patients who undergo transplant with using the variety of these techniques. This is a patient who underwent single lung transplantation on the right for alpha one antitrypsin deficiency. This patient developed native lung, severe hyperinflation, postoperatively. They had to be placed on ec mode to support them. At that time, you can see this hyperinflated lower lobe, we placed endobronchial valves in this patient. And you can see the marked reduction in left lower lobe hyper uh inflation over a period of 24 to 48 hours. Patient ECMO discontinuation in 12 hours and extubated within 48 hours. So this is how gold sees the interplay between surgical and interventional treatments with advanced emphysema. If a patient comes to you and he has an emphysema is predominant phenotype with hyperinflation. If they have a large bulla, they undergo bully if they have no large bulla, but they have emphysema. It's divided into heterogeneous or homogeneous patterns based on HR CT and based on fissure integrity or collateral ventilation status, they then undergo treatment, lung reduction either endoscopically or surgically based on their pattern of emphysema and their collateral ventilation status. If a patient is not a candidate for ballet toy or lung reduction, then they undergo lung transplantation. In some cases. As I just showed you, patients undergo a lung transplant and then have lung reduction place in the native lung or some patients undergo lung reduction, either bronchoscopy or surgically and then years later undergo lung transplantation. So we use these combination of programs to help to support our patients with COPD across the continuum of medical interventional and surgical treatments. So, in summary lung transplantation for COPD is predominantly associated with an improvement in quality of life. Not an increase in survival, except for certain patients with severe A ATD or those patients who are severely impaired with high bone scores. The mean survival post lung transplantation for COPD is approximately six years and over 70% of lung transplants conducted in COPD, patients are double versus single lung transplantations. Although as the temporal program shows single lung transplantation can be an effective way to treat patients with emphysema. If you have special features that your program can handle that accompanies this procedure in that patient population, bilateral lung transplantation leads to longer survival of patients with COPD, especially those less than 60 years of age. However, single lung transplantation can decrease weightless mortality and offer more patients with COPD transplantation options if you do single lung transplantation. However, you have to be concerned about aggressive follow up for lung cancer detection in the single uh uh remaining native lung and also be able to handle, handle the consequences of natal native lung hyperinflation in some patients who are transplanted with single lung transplantation for COPD. Thank you very much for allowing me to participate. Have a great conference. I'm sorry I could be there to attend, but I hope to be there in the future. Thank you very much.
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