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Overview of Clinical

Jonathan C. Yeung and Shaf Keshavjee

Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario M5G 2C4, Canada Correspondence: [email protected]

Since the first successful lung transplant 30 years ago, lung transplantation has rapidly become an established standard of care to treat end-stage lung disease in selected patients. Advances in lung preservation, surgical technique, and immunosuppression regimens have resulted in the routine performance of lung transplantation around the world for an increas- ing number of patients, with wider indications. Despite this, donor shortages and chronic lung allograft dysfunction continue to prevent lung transplantation from reaching its full potential. With research into the underlying mechanisms of acute and chronic lung dysfunction and advances in personalized diagnostic and therapeutic approaches to both the donor lung and the lung transplant recipient, there is increasing confidence that we will improve short- and long-term outcomes in the near future.

he worldwide burden of pulmonary diseases dehiscence, and difficulties with this anastomo- Tcontinues to increase and now ranks firmly siswouldplagueclinicallungtransplantationfor among the leading causes of death (Lozano et al. the next 40 years. Henri Metras, in 1950, report- 2013). Since its introduction in the early 1980s, ed the first successful dog lung transplant and lung transplantation has matured into a success- the first bronchial artery and left atrial anasto- ful therapy for selected patients with end-stage moses (Metras 1950). In a nonhuman primate lung disease, because of careful investigation model, Haglin et al. (1963) performed lung re- into donor management, organ preservation, implantation and showed that these lungs were recipient management, and immunosuppres- able to maintain function postoperatively, de- sion (Christie et al. 2012). This review provides spite denervation. On June 11, 1963, Hardy et

www.perspectivesinmedicine.org an overview of modern clinical lung transplan- al. (1963) reported the first human lung trans- tation and anticipated future directions. plant; however, the patient died from kidney failure after 18 d. The first real survivor during this early era of lung transplantation was a pa- HISTORY tient of Fritz Derom’s in Belgium (Derom et al. Attempts at lung transplantation have occurred 1971). This patient, however, survived only as early as 1946 when Vladimir Demikhov, a So- 10 mo. The failure of this early experience in viet scientist, attempted single-lung transplan- clinical lung transplantation can be summarized tation in a dog (Langer 2011). This transplant by inadequate immunosuppression and diffi- ultimately failed from bronchial anastomotic culties with the bronchial anastomosis.

Editors: Laurence A. Turka and Kathryn J. Wood Additional Perspectives on Transplantation available at www.perspectivesinmedicine.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a015628 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015628

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J.C. Yeung and S. Keshavjee

The advent of cyclosporine brought about American Thoracic Society (ATS) selection cri- significant improvements in patient survival fol- teria include appropriate age, clinically and lowing liver and (Calne physiologically severe disease, ineffective or un- et al. 1978). This led to a resurgence of interest in available medical therapy, substantial limita- /lung transplantation in Stanford and lung tions in activities of daily living, limited life transplantation in Toronto (Starzl et al. 1981). expectancy, adequate cardiac function with- The first successful combined heart–lung trans- out significant coronary disease, ambulatory plant was completed by Reitz and colleagues and with rehabilitation potential, acceptable nutri- showed that a grafted lung could survive and tional status, and satisfactory psychosocial pro- function in a recipient (Reitz et al. 1982). Re- file and emotional support system (Orens et al. search performed by Cooper’s group in Toronto 2006). Patients who undergo lung transplanta- showed that corticosteroid use appeared to be a tion subject themselves to lifelong immunosup- significant factor in the weakness of the bron- pression and surveillance. Thus, candidates for chial anastomosis (Goldberg et al. 1983). With lung transplantation who have smoking or drug the use of cyclosporine, corticosteroid use could dependency, psychiatric issues affecting compli- be reduced, leading to improved bronchial heal- ance with postoperative care, or absence of a ing. In 1986, the Toronto Lung Transplant Pro- reliable social support network will generally gram reported the first successful single-lung not be listed for lung transplantation. Previous transplantations for two patients with pulmo- malignancy, particularly in the 2 yr leading up nary fibrosis (Cooper et al. 1987). This team to potential transplantation, is also a contrain- went on to perform the first successful double- dication because of the need for lifelong im- lung transplant, first with an en bloc technique munosuppression. Indeed, although immuno- that used a tracheal anastomosis, then evolving suppression will potentiate infection, chronic to the bilateral sequential transplantation tech- infection is an intrinsic part of septic lung dis- nique that not only improved airway healing, eases and creates a challenge in these patients. In but also had the additional benefit of avoiding cystic fibrosis patients, nontuberculous myco- cardiopulmonary bypass, if desired (Patterson bacterial, multi-drug-resistant bacteria, and As- et al. 1988). Thistechnique remains the standard pergillus are commonly isolated (Helmi et al. technique in use to this day. 2003; Gilljam et al. 2010). An effort is made to eradicate or at least minimize these organisms before and following transplantation. Moreover, INDICATIONS AND CONTRAINDICATIONS in the presence of septic lung disease, a bilateral TO LUNG TRANSPLANTATION lung transplant is the only operation that can be www.perspectivesinmedicine.org The indications for lung transplantation can be performed because leaving a septic lung in a broadly separated into the following main cate- patient to be immunosuppressed is not advis- gories of end-stage lung diseases: obstructive able. The replacement of both organs removes lung disease, septic lung disease, fibrotic lung the burden of infectious organisms and allows disease, and vascular lung disease. Of these cat- for successful transplantation in the presence of egories, chronic obstructive pulmonary disease most septic lung conditions. One notable excep- (COPD), cystic fibrosis (CF), interstitial pulmo- tion is the Burkholderia cepacia complex (Bcc), nary fibrosis (IPF), and primary pulmonary ar- an organism with a significant negative impact terial hypertension make up the most common on posttransplant survival (Murray et al. 2008). indication in each category, respectively (Chris- In multiple reports, patients infected with Bcc, tie et al. 2012). Lung transplantation for pulmo- particularly the subspecies Burkholderia cenoce- nary malignancy has also been shown to be pacia, have a clearly worse survival than those effective in highly selected patients (Machuca without. Consequently, some transplant centers and Keshavjee 2012). consider Bcc infection an absolute contraindi- The current International Society for Heart cation to transplantation, but this remains con- and Lung Transplantation (ISHLT) and also the troversial (Chaparro et al. 2001).

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Lung Transplantation

Patients with significant dysfunction of oth- and then normalized to give an LAS. Higher er vital organs also represent potential contrain- scores are allocated lungs sooner. Since the in- dications to lung transplantation. Owing to age, troduction of the LAS system, waitlist times have general prevalence, and smoking, cardiac dys- decreased, and the number of transplants has function is the most common concomitant increased (Iribarne et al. 2009). Moreover, LAS organ dysfunction in the lung transplant popu- scores have gradually increased, representing the lation. Noninvasive and invasive cardiac testing increasing urgency of patients getting listed. is performed during workup to ensure adequate cardiac function, and concomitant coronary ar- PEDIATRIC LUNG TRANSPLANTATION terial bypass grafting can be performed at the time of lung transplantation if the left ventricu- Lung transplantation for children has also lar function is preserved (Patel et al. 2003). evolved into acceptable therapy (Wells and Historically, age .65 has been considered Faro 2006). In the United States, more than a relative contraindication to lung transplan- 100 children currently await lung transplanta- tation given the propensity toward worse tion. The indications for pediatric lung trans- outcomes in that group. However, 7.7% of plant differ from those for adults and stratify lung transplants performed in the recent era basedonage.Children ,1 yrofagesufferlargely (2004–2011) were in patients .65 (Christie from congenital defects such as congenital heart et al. 2012). Another 21.6% were performed in disease, surfactant dysfunction, and pulmonary patients between 60 and 65. Careful assessment vascular disorders (Benden et al. 2013). Cystic of comorbidities, rather than age alone, deter- fibrosis (CF) becomes the primary indication mines candidacy for transplantation. after 1 yr of age, with the majority of adolescent lung transplants being performed for CF. Iden- tifying acceptable candidates for pediatric lung DONOR LUNG ALLOCATION transplantation is difficult, particularly in the In the United States, lung allocation was initially very young. Theworldwide experience is limited based on wait times alone with no consideration in this population, and the natural history of of disease severity or potential benefit. Many many of these congenital diseases is not always recipients were placed early on the waiting list clear. Moreover, readiness of the parents to em- in order to accrue time, but when a lung was bark on the demanding preoperative and post- ultimately made available, the patient may not operative care necessary of pediatric lung trans- have yet deteriorated to a point requiring trans- plantation must be carefully assessed. Allocation plantation. On the other hand, patients in more of organs to pediatric recipients uses the LAS www.perspectivesinmedicine.org dire need of atransplant would often not survive system in patients 12 yr of age or older (Sweet long enough to accrue enough time to be of- 2009).Forpatientsunder12 yrofage,theUnited fered a graft. In 2005, a new strategy for lung States uses a two-priority system in addition to allocation was introduced (Egan et al. 2006) wait times (Colvin-Adams et al. 2012). Patients known as the (LAS). This meeting criteria (Table 1) are priority 1 and re- score is conceptually based on the degree of ceive consideration for graft allocation first need for a transplant and the probabilityof post- following geographic and blood-type criteria transplant survival. To calculate this, a measure considerations. In the very young, where isohe- of urgency (expected number of days lived with- magglutinins have not yet developed, ABO-in- out a transplant during an additional waitlist compatible lung transplantation has been shown year) and a measure of survival following trans- to be a feasible option (Grasemann et al. 2012). plantation (expected number of days lived in the first year posttransplant) are calculated using BRIDGING TO LUNG TRANSPLANTATION statistical models based on the patient’s clinical and physiological characteristics. The urgency Often, patients needing lung transplantation measure is subtracted from the benefit measure become critically ill before a set of donor organs

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J.C. Yeung and S. Keshavjee

Table 1. Pediatric priority 1 criteria post-Novalung utilization) (de Perrot et al. Respiratory failure as defined by one or more of the 2011). following: For patients who suffer from more than pure Continuous mechanical ventilation hypercapnic respiratory failure, full venovenous Fraction of inspired oxygen (FiO2) .50% to or venoarterial ECLS is a better choice. Novel maintain saturation levels of .90% bicaval dual lumen cannulas, such as the Avalon An arterial or capillary PCO2 of .50 mm Hg or a cannula, allow venous–venous ECMO to be venous PCO2 of .56 mm Hg started via a single cannulation site in the neck Pulmonary hypertension as defined by any of the (Wanget al. 2008). In case series, patients await- following and on medical therapy: ing lung transplantation have avoided intuba- Pulmonary vein stenosis involving three or more tion and could continue an exercise regimen vessels while on ECMO (Garcia et al. 2011; Cypel and Suprasystemic PA pressures Keshavjee 2012). Cardiac index 2 L/min/m2 Data from Colvin-Adams et al. (2012). DONOR SELECTION Once a donor has been identified and allocated is available. Traditionally, intubation and ECLS to a potential recipient, the donor organs must (extracorporeal lung support) were the sole mo- be checked for quality and procured from the dalities available for bridging to transplanta- donor. Like all of solid , tion. In the past few years, novel artificial lung lung transplantation is even more limited by technologies have been developed that allow the number of available donor organs. Shortag- critically ill patients to be maintained tempo- es in lung transplantation, however, are com- rarily over months (Fischer et al. 2006). One of pounded by a low utilization rate of offered do- these devices is the Novalung, a hollow fiber nor organs. The United Network for Organ oxygenator with a uniquely low trans-device Sharing data reports that lungs were used from perfusion resistance. This allows for pumpless only 1708 of 8143 deceased donors in 2012—a function from the arterial to venous circulation. utilization of only 21% (National Data 2012). Patients in respiratory failure can be divided As a comparison, 7419 of those same donors into those with hypercapnic respiratory failure, were kidney donors. The current International those with hypoxemic respiratory failure, or Society for Heart and Lung Transplantation those with both. Because removal of CO2 re- (ISHLT) criteria outlining an ideal donor are quires only a low membrane flow on the order based on strict criteria established during the www.perspectivesinmedicine.org of 0.5–1 L/min, this can be achieved using the development of lung transplantation (Table 2). pumpless arteriovenous cannulation. An exten- Although this has helped establish safe clinical sion of this strategy can be applied to patients with pulmonary hypertension awaiting trans- Table 2. ISHLT criteria for lung acceptance plantation. By inserting the device between the pulmonary artery and the left atrium, the Age ,55 yr right heart can be unloaded into the Novalung ABO compatibility device (Strueber et al. 2009). This provides a Clear chest radiograph PaO .300 on FiO ¼ 1.0, PEEP 5 cm H O decompressing and oxygenating shunt. This 2 2 2 Tobacco history ,20 pack/yr treatment strategy unloads the right ventricle, Absence of chest trauma allowing it to recover, and also leads to recovery No evidence of aspiration/sepsis of renal and hepatic dysfunction. All of this has No prior cardiopulmonary surgery dramatically improved the survival to and after Sputum gram stain—absence of organisms lung transplantation for patients with primary Absence of purulent secretions at bronchoscopy pulmonary arterial hypertension (22% waitlist From Orens et al. (2003); reproduced, with permission, mortality pre-Novalung, 0% waitlist mortality from the authors.

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lung transplantation, this combination of strin- one area where removal of the lung from the gent donor criteria coupled with an increased inflammatory milieu of the brain-dead donor susceptibility of donor lungs to injury leads to and a period of time for recovery and removal of a conservative and low utilization rate (Orens extravascular water with ex vivo lung perfusion et al. 2003). has had a significant impact on donor lung uti- lization as described below. DONOR LUNG INJURY Currently, the largest pool of donor organs is DONATION AFTER CARDIAC DEATH those retrieved from brain-death donors. In As an alternative source for lungs, some trans- these donors, cessation of neurologic function plant programs have begun to reexplore the use results in a legal definition of death (Wijdicks of donation after cardiac death (DCD) (Koot- et al. 2010), but organs remain viable for a pe- stra et al. 2002; Steinbrook 2007). Because the riod of time owing to preserved cardiac func- majority of patients succumb as a result of car- tion and ICU support. Although this situation diac arrest, the use of DCDs could potentially is seemingly ideal for organ transplantation, open a completely new pool of donor organs of many factors can contribute to donor lung in- such magnitude that ultimately the entire de- jury during the process of donor death and mand could be met. Renewed interest in the subsequent donor maintenance in the inten- potential use of lungs from DCDs followed a sive care unit (ICU). Direct trauma, aspiration, series of experiments in dogs by Egan and co- pneumonia, and complications of ICU care workers in the early nineties (Egan et al. 1991; such as ventilator-induced lung injury, atelecta- Ulicny et al. 1993). His group showed that lung sis, oxygen toxicity, and volume overload are all cells remain viable for a certain period after cir- common causes of injury. More importantly, it culatory arrest (Alessandrini et al. 1994; D’Ar- is well recognized that the process of brain death mini et al. 1994). The lung is the sole solid organ itself can injure potential donor organs. Follow- that is not dependent on perfusion for aerobic ing brain death, a systemic inflammatory re- metabolism but rather uses a mechanism of pas- sponse known as a “cytokine storm” transpires. sive diffusion through the alveoli for substrate Increased proinflammatory cytokines have been delivery (Keshavjee et al. 1992; Date et al. 1993; found in organs following brain death in rodent Egan 2004; Van Raemdonck et al. 2004). models (Takada et al. 1998) and in brain-dead At the First International Workshop on patients (Lopau et al. 2000), and lung injury DCDs in Maastricht in the Netherlands in similar to acute respiratory distress syndrome 1995, four types of donors were identified, so- www.perspectivesinmedicine.org (ARDS) can occur as a result of this systemic called Maastricht categories (Table 3) (Kootstra inflammation following brain death. A second et al. 1995). Categories I (dead on arrival) and II “storm” that occurs following brain death is the (unsuccessful resuscitation) comprise the un- catecholamine storm. In an attempt to protect controlled donors. Categories III (awaiting car- cerebral perfusion during brain death, the body releases a large amount of catecholamines. This surge of catecholamines causes significant sys- Table 3. Maastricht categories of donation after car- temic hypertension, which results in elevated diac death left-sided heart pressures and consequent inter- I Dead on arrival to hospital Uncontrolled stitial edema and sometimes even alveolar hem- II Unsuccessful resuscitation Uncontrolled orrhage in the lung, resulting in a state known as III Awaiting cardiac arrest Controlled neurogenic pulmonary edema. This generally IV Cardiac arrest following brain Controlled precludes the use of the lungs for transplanta- death tion because of poor oxygenation. However, V Cardiac arrest in a hospital Uncontrolled neurogenic pulmonary edema is a leaky capil- inpatient lary syndrome that is fully recoverable. This is Data from Sa´nchez-Fructuoso et al. (2000).

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diac arrest) and IV (cardiac arrest in brain-dead to before cardiac arrest; therefore, lung evalua- donor) include the controlled donors. A fifth tion is less assured. category, cardiac arrest in a hospital inpatient, has recently been added (Sa´nchez-Fructuoso ORGAN PRESERVATION et al. 2000). Several centers worldwide have now adopt- In the initial early experience of lung transplan- ed DCD programs in their clinical routine of tation, donors were brought into an adjacent lung transplantation, and most reported series operating room, and the donor lungs were de- deal with controlled donation after withdrawal flated and topically cooled in situ for preserva- from life support (category III) (Erasmus et al. tion (Cooper et al. 1987). The lungs were then 2006; Butt et al. 2007; Oto et al. 2007; Van stored deflated and submerged in hypothermic Raemdonck et al. 2008). The total reported ex- saline solution and placed on ice for hypother- perience with this category now amounts to mic preservation. Despite short ischemic times, more than 100 patients worldwide. The major- immediate postoperative care was fraught with ity of reported series using category III DCDs significant postoperative primary graft dysfunc- have comparable results to a series of donation tion and poor preservation of the pulmonary after brain death (DBD) patients. A recent re- and bronchial microcirculation. Only with sub- view of the U.S. experience using data retrospec- sequent advances in lung preservation has lung tively collected from the UNOS database has transplantation been able to be established as shown an overall survival after lung transplan- a clinical routine. Modern lung preservation is tation of 94%, 94%, 94%, 94%, and 87% at 1, 3, a continuum that begins at the time of declara- 6, 12, and 24 mo, respectively, for recipients re- tion of death and ends after reperfusion in the ceiving lungs from DCD donors, compared recipient. In the preretrieval phase, care is taken with 92%, 88%, 84%, 78%, and 69%, respec- to maintain euvolemia and to avoid ventilator tively, from DBD (Mason et al. 2008). barotrauma. A methylprednisolone bolus of 1 g is given to the donor as an anti-inflammatory agent to mitigate brain-death-induced inflam- DONOR LUNG EVALUATION mation and also in part to replace any steroid Evaluation of an offered donor lung block is deficiencies (Follette et al. 1998; Venkateswaran largely a clinical process. Other than blood et al. 2008). At the time of retrieval, the lungs are group and organ size matching, the majority prepared for transport flushed with a preserva- of the evaluation is relatively subjective and oc- tion solution and inflated with oxygen. Use of curs at the time of retrieval (Boasquevisque et al. an extracellular-type flush preservation solution www.perspectivesinmedicine.org 2009). Before opening the chest, a chest X-ray is with low potassium, coupled with glucose and taken and a bronchoscopy performed to exclude dextran, was found to be best for prolonged cold gross infection or anatomical abnormalities. preservation (Keshavjee et al. 1989, 1992). This The gas exchange capacity of the donor lungs has become the standard of lung preservation in is assessed with an oxygen challenge. Once the the majority of lung transplant programs. PGE1 chest is open, the surgeon performs a final gross (prostaglandin E1) is a vasodilator that is given physical evaluation by macroscopic observation before flush to reduce the pulmonary vascular and palpation to assess lung compliance and resistance in order to help produce a homo- edema and to exclude intrinsic lung disease, ar- geneous flush. It also has anti-inflammatory eas of contusion, pneumonic infiltrates, or nod- properties useful for lung preservation and re- ules. Observation of the ventilated lungs during perfusion injury (De Perrot et al. 2001). A ret- deflation is used to further assess pulmonary rograde in situ lung flush is also performed with compliance. If the lungs are deemed usable, the same solution, again to improve the homo- they are retrieved and sent to the transplant cen- geneity of the flush (Varela et al. 1997; Van De ter for implantation. Evaluation of the DCD Wauwer et al. 2009). The lungs are inflated donor is similar, but functional testing is limited with 50% oxygen before their removal from

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Lung Transplantation

the body in order to maintain the delicate alve- LUNG TRANSPLANT PROCEDURES olar structure and to provide oxygen for metab- olism (Van Raemdonck et al. 1997). This is an Different lung transplant procedures have been important distinction of lung preservation as developed to meet certain situations. Most fa- compared with other organ preservation in miliar are: the single-lung transplant, where ei- that the lung is stored in an aerobic hypothermic ther a left or a right lung is transplanted into a ischemic state so that aerobic metabolism can recipient and the contralateral native lung is left continue during the storage phase, albeit at a in place; and the bilateral lung transplant, where reduced rate. both lungs are transplanted. The decision to Recently, a novel strategy of clinical lung transplant one or two lungs depends on the in- preservation has been developed by our group. dication for transplantation and recipient fac- Known as ex vivo lung perfusion, lungs are con- tors, as well as donor availability. Emerging data tinuously perfused anterograde with an acellu- suggest that bilateral lung transplantation re- lar perfusate and ventilated with room air with sults in prolonged survival because it provides an ICU ventilator at normothermia (Cypel et al. more functional lung tissue as a buffer against 2008). An oxygenator fed with a hypoxic gas lung dysfunction (Thabut et al. 2008; Weisset al. is used to deoxygenate the perfusate and add 2009). For the same reason, marginal donor or- CO2 to the perfusate. Wehave shown that donor gans are often more likely to be used when im- lungs can be preserved for at least 12 h safely planted as a bilateral lung transplant. However, using this method. Because the lungs will func- double-lung transplantation is a more complex tion using this strategy of preservation, they can operation, which necessitates a longer operative be further evaluated as to their suitability for time that needs to be balanced against potential transplantation, but, more importantly, can be added morbidity. In addition, in jurisdictions treated actively to improve their performance where donor availability is severely lacking, (Cypel et al. 2009). DCD lungs, given the less transplanting two recipients with single lungs than optimal opportunity for lung evaluation may reduce waitlist mortality. Specific indica- after cardiac arrest, can greatly benefit from tions also call for double-lung transplantation. this technique. Marginal lungs can also be resus- Because of the presence of infection, septic lung citated during this time using existing and fu- disease patients require a double-lung trans- ture therapies (Yeung et al. 2012). In a recent plant to prevent infection of the lung graft clinical trial, marginal lungs normally rejected from the native lung. Although not an absolute for transplantation were evaluated and resusci- indication, bilateral lung transplantation for tated using ex vivo lung perfusion and then vascular lung disease with elevated pulmonary www.perspectivesinmedicine.org transplanted with resulting outcomes equiva- arterial pressures is best because it avoids diffi- lent to contemporaneous controls (Cypel et al. culties with hemodynamic instability and severe 2011, 2012). Because the large majority of of- primary graft dysfunction postoperatively. fered donor lungs are rejected because of injury, Although the abovementioned lung trans- this expansion of the donor pool is significant plant procedures are by far the most common, and could greatly help meet the need for donor alternative procedures have been developed that lungs. In the future, we envision that retrieved can be used in unique situations. The donor lungs could be sent to organ evaluation and lung can be nonanatomically volume-reduced repair centers for final assessment and treat- to fit into a smaller recipient (Noirclerc et al. ment for repair before distribution to recipients 1992). For larger size discrepancies, an adult do- around the country. A case report describing the nor lung can be downsized anatomically to im- retrieval of injured lungs at one center, EVLP plant a lower or upper lobe on either side in a repair at a second center, and then transplanta- smaller recipient (bilateral lobar transplant) tion at a third center across multiple political (Starnes et al. 1994). Another innovative opera- jurisdictions acts as a proof-of-concept for this tion is the split left-lung bilateral lobar trans- approach (Wigfield et al. 2012). plantation technique, which allows for a large

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donor to donate a single left lung to a smaller the graft airway at that level. Following chest recipient or child, where the left upper lobe and opening, mobilization of each of the native lungs left lower lobe are implanted to the right and left is performed. The lung with the poorest func- chest, respectively (Couetil et al. 1997). Living tion is removed first, and implantation of the donor lobar transplantation is applied in juris- first graft begins. Once complete, this first allo- dictions where the legal and cultural climate is graft is perfused and ventilated. The recipient is not conducive toward deceased donor trans- then dependent on this lung’s function as the plantation, such as in . In this situation, contralateral side is removed and the second the right lower lobe is removed from one donor lung implanted. Hemodynamic instability, ele- and transplanted into the right chest, and the left vated pulmonary arterial pressure, or hypox- lower lobe is removed from another donor and emia necessitates the use of cardiopulmonary transplanted into the left chest. Date and col- bypass. Ultimately, only 25% of recipients leagues in Japan have a large experience with with no pulmonary vascular disease will require this technique and have shown excellent out- CPB (de Hoyos et al. 1993). comes (Date et al. 2004). Experience in the Unit- ed States with this technique has waned since the POSTOPERATIVE CARE introduction of the LAS allocation system. Combined heart/lung transplantation is re- Care of the lung recipient in the immediate post- served for cases in which irreversible heart dis- operative period focuses on ventilatory and he- ease occurs in conjunction with irreversible modynamic support and weaning. In uncom- lung disease. In most cases, severe right heart plicated cases, ventilator weaning can proceed dysfunction can be reversed after isolated lung quickly over the first 6–12 h. Because of in- transplantation, and thus heart/lung transplan- creased vascular permeability and severed lym- tation is generally reserved for patients with left phatics of the transplanted lung, development of heart dysfunction. some element of pulmonary edema is not un- common. Therefore, attempts to minimize pul- monary capillary wedge pressure and central ve- SURGICAL TECHNIQUE nous pressure are made while balancing for the In general, most lung transplant centers avoid need to maintain systemic perfusion (Pilcher the routine use of cardiopulmonary bypass et al. 2005). Often, vasopressors and inotropes (CPB) during lung transplantation. For single- are used rather than infusion of volume. lung transplantation, the diseased lung is excised The major fear postoperatively is failure and the new lung implanted while the patient is of the transplanted lung to function. Such a www.perspectivesinmedicine.org supported on the contralateral native lung. If the scenario can be mimicked by volume overload, patient cannot be supported this way because of cardiacdysfunction, pneumonia, aspiration, an- significant hypoxia, hypercarbia, or hemody- tibody-mediated rejection, pulmonary throm- namic instability, then CPB is instituted. boembolism, or technical complications such Bilateral lung transplants are performed as as occlusion of venous outflow (de Perrot et al. sequential single-lung transplants via a clam- 2003). In the absence of these conditions, pri- shell incision or bilateral anterolateral thoracot- mary graft dysfunction (PGD) becomes the di- omies if preferred and technically feasible (Ta- agnosis of exclusion. PGD is the major cause of ghavi et al. 1999). The sequential transplant morbidity and mortality in the first 72 h follow- strategy not only allows for the avoidance of ing transplantation. It can be considered the ex- CPB in most (60%–75%) cases, but also avoids pression of all injury acquired by the lung while a tracheal anastomosis, which was used in the in the donor through to the time of reperfusion. original en bloc double-lung transplant opera- Generally, this injury presents as pulmonary tion (Griffith et al. 1994). The tracheal anasto- edema resulting in decreased compliance and mosis was fraught with anastomotic complica- ineffective oxygenation. This pulmonary edema tions related to the precarious blood supply of results from increased permeability of pulmo-

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nary capillaries and alveolar damage and is rem- sial in lung transplantation. Use of induction iniscent of ARDS. The ISHLT has published a therapy is thought to promote strong early im- grading system for PGD similar to that for munosuppression during the time when graft ARDS (Christie et al. 2005). Patients are scored rejection is most likely to occur and may allow on this grading system at the time immediately for a less toxic maintenance regimen going for- posttransplant, and then at 24, 48, and 72 h ward. Although prospective, randomized, pla- posttransplant. Those who have PGD 3 persist- cebo-controlled trials did not show significant ing to the 72-h point have the worst short- and benefit, and large RCTs do not currently exist, long-term outcomes (Whitson et al. 2006). registry data show that 50% of lung transplant Treatment of PGD is supportive. Careful use programs use induction therapy based on logi- of sedation and paralysis, close hemodynam- cal extrapolation from the demonstrated benefit ic monitoring, and avoidance of nosocomial of induction therapy in otherorgan randomized pneumonia are important. Nitric oxide has control trials (Hachem et al. 2008; Hartwig et al. beenshowntoimproveoxygenation,reducepul- 2008). monary artery pressure without affecting sys- temic pressure, and shorten the duration of me- OUTCOMES chanical ventilation in case series (Date et al. 1996; Ardehali et al. 2001). Its primary effect is Although lung transplantation has been shown likely due to improvement in V/Q matching be- to confer increased survival to patients with cause NO is delivered to alveoli that are ventilat- end-stage lung disease, survival following lung ed, although NO also has important anti-in- transplantation is still only 50% at 5 yr (Chris- flammatory properties related to neutrophil, tie et al. 2010). The major causes of death fol- macrophage, and platelet function (Coggins lowing lung transplantation vary with the time andBloch2007).PGE1 infusioncanalsobehelp- following transplantation. Thirty-day mortality ful in treating severe PGD because it down-reg- is generally related primarily to surgical issues, ulates inflammation in the acutely reperfused donor lung preservation, and primary graft dys- lung. When maximal treatment fails, ECLS function (PGD) (Studer et al. 2004). Infectious should be started as a bridge to recovery (Fischer causes, malignancy, and chronic lung allograft et al. 2007). ECLS can allow for gas exchange dysfunction (CLAD) predominate in the subse- while avoiding harsh ventilation strategies that quent posttransplant period. Despite significant can further injure the graft. Although the expe- improvements in short-term outcomes owing to rience is limited, the literature suggests that improved preservation and surgical technique, ECLS should be started early in the onset of se- the long-term survival after lung transplanta- www.perspectivesinmedicine.org vere graft dysfunction, usually within 24 h of tion remains at around a 50% 5-yr survival be- lung transplant severe PGD, and be limited to a cause of the development of CLAD (Christie short trial of 4–7 d (Fiser et al. 2001). et al. 2012). Next to the shortage of donor organ supply, CLAD remainsthe most significant chal- lenge to the long-term success of lung transplan- POSTOPERATIVE IMMUNOSUPPRESSION tation and should be a focus of research in this Lung transplant immunosuppression generally area. consists of a three-drug regimen with the exact composition being center dependent. A calci- CHRONIC LUNG ALLOGRAFT neurin inhibitor (cyclosporine or tacrolimus), DYSFUNCTION a nucleotide blocking agent (azathioprine or MMF), and corticosteroids make up the three CLAD is a recent term coined to describe the drugs. Induction therapy, the use of a potent increasingly complex and heterogeneous condi- immunosuppression agent to deplete T cells tions causing long-term lung dysfunction fol- such as anti-IL2R antibodies, anti-CD52 anti- lowing transplantation (Sato 2013). Historically, bodies, or antithymocyte globulin, is controver- chronic lung dysfunction was thought to pre-

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J.C. Yeung and S. Keshavjee

sent only as bronchiolitis obliterans syndrome fects, but the exact mechanism is unclear (Yates (BOS), where the progressive development of et al. 2005; Murphy et al. 2008; Vos et al. 2011). obliterative bronchiolitis led to a fall in FEV1 Switching classes of immunosuppression may and ultimately to graft loss. A novel subtype of be of some benefit in slowing progression of BOS (now CLAD) was first recognized as a dis- the disease, but no therapy has yet been shown tinct entity in 2005 (Pakhale etal. 2005)and then to reverse the disease process. The only definitive subsequently functionally and histologically treatment for end-stage CLAD is retransplanta- characterized in further detail by Sato et al. tion, but limited organ availability and generally (2011, 2013). Now known as restrictive allograft poorer outcomes render this approach contro- syndrome (RAS), this form of CLAD presents versial. histologically as fibrosis in the peripheral lung Although CLAD limits long-term survival, tissue rather than in small airways, resulting in survival alone is an incomplete measurement of a decline in total lung capacity in addition to a transplant benefit. To patients, quality of life decline in FEV1. This solidified the understand- (QOL) can be as important as quantity of life, ing that all chronic lung dysfunction is not BOS and lung transplantation can almost be consid- andsetthe stageto focusthe attention of the lung ered a type of treatment in which, in some in- transplant communityon exploring various dif- stances, qualityof life is improved even if little or ferentpotentialformsofCLADandthepotential no gain in quantity of life occurs. Multiple lon- multiple underlying contributing pathophysio- gitudinal studies have recently shown improve- logic mechanisms. Other phenotypes of CLAD ments in QOL following lung transplantation, havenowbeendescribed,includingneutrophilic some as early as 3 mo posttransplant (Gross allograft syndrome (NRAD), and fibrous BOS et al. 1995; Cohen et al. 1998; Lanuza et al. (FBOS) (Vanaudenaerde et al. 2008). 2000). More than 90% of lung transplant survi- The pathogenesis of BOS was initially vors are satisfied with their decision to undergo thought to represent a type of chronic rejection, transplantation. that is, an alloimmune-dependent process, but alternative alloimmune-independent processes CONCLUDING REMARKS are now thought to contribute to the develop- ment of BOS and CLAD in general. Primary Lung transplantation has become firmly estab- graft dysfunction, viral and bacterial infections lished as a treatment of end-stage lung disease. of the graft, and gastroesophageal reflux and Increased adoption of lung transplantation is aspiration have been shown to predispose a graft currently limited by the availability and suitabil- toward CLAD (Davis et al. 2003; Botha et al. ity of donor organs. Unique to lung transplan- www.perspectivesinmedicine.org 2008; Snyder et al. 2010). It is thought that these tation is the low utilization rate of the existing processes, in addition to damaging the graft di- donor lungs because of the frequent findings of rectly, activate innate immune processes, which lung injury. The recently developed ex vivo lung then propagate the injury via the adaptive im- perfusion preservation strategy is now estab- mune system (Palmer et al. 2005). Autoimmune lished in Toronto and in selected centers in Eu- processes have also been shown to play a role. rope, with trials in the United States underway. Exposure of typically cryptic antigens such as This technique improves evaluation and also type-V collagen and K-a1 tubulin during the allows for the delivery of therapy to treat injured lung transplant process may help drive the donor lungs in a targeted fashion allowing for CLAD process (Burlingham et al. 2007; Goers their use. Exploration and development of ex et al. 2008). vivo repair strategies tailored to each donor Treatment options for CLAD are currently lung will be important toward a “personalized limited. The use of azithromycin in a random- medicine” approach to the diagnosis and treat- ized controlled trial has been shown to slow the ment of the donor lung. progression of CLAD, potentially through its The major factor limiting positive long- anti-inflammatory,antibiotic, or promotilityef- term outcomes remains the development of

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CLAD. Although the pathogenesis is still not Lung Graft Dysfunction part II: Definition. A consensus completely elucidated, it is well accepted that statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 24: 1454–1459. this represents graft dysfunction resulting from Christie JD, Edwards LB, Kucheryavaya AY, Aurora P, Dob- multiple etiologies. Many novel mechanisms bels F, Kirk R, Rahmel AO, Stehlik J, Hertz MI. 2010. The have recently been recognized to contribute to- Registry of the International Society for Heart and Lung Transplantation: Twenty-seventh official adult lung and ward CLAD, and subtypes with different clinical heart-lung transplant report–2010. J Heart Lung Trans- courses have been identified. 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14 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015628 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press

Overview of Clinical Lung Transplantation

Jonathan C. Yeung and Shaf Keshavjee

Cold Spring Harb Perspect Med 2014; doi: 10.1101/cshperspect.a015628

Subject Collection Transplantation

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