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 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 graft 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 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press 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 kidney transplantation (Calne physiologically severe disease, ineffective or un- et al. 1978). This led to a resurgence of interest in available medical therapy, substantial limita- heart/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). 2 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 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