Evolving Knowledge and New Horizons Ganesh Raghu Roberto G

Lung Transplantation

Evolving Knowledge and New Horizons

Ganesh Raghu Roberto G. Carbone Editors

123 Lung Transplantation Ganesh Raghu • Roberto G. Carbone Editors

Lung Transplantation

Evolving Knowledge and New Horizons Editors Ganesh Raghu Roberto G. Carbone Division of Pulmonary Department of Internal Medicine Critical Care, and Sleep Medicine University of Genoa Department of Medicine Genoa University of Washington Italy Seattle, WA USA

ISBN 978-3-319-91182-3 ISBN 978-3-319-91184-7 (eBook) https://doi.org/10.1007/978-3-319-91184-7

Library of Congress Control Number: 2018950336

© The Editor(s) (if applicable) and The Author(s) 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Printed on acid-free paper

This Springer imprint is published by the registered company Springer International Publishing AG part of Springer Nature The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Epigraph

Difficulty in breathing with limited life span to breathing easy with extended life following lung transplantation. —Ganesh Raghu

v I dedicate this book to all the donors and recipients of lung transplantation and to the caregivers and families of pre- and post-lung transplant patients. —Ganesh Raghu

The capacity to help others is a blessing. I dedicate this book to those who donated life to others and to those who, by their heroic decision to donate the organs of their loved ones, gifted new life to others. —Roberto G. Carbone Preface

Management of advanced or end-stage nonmalignant lung diseases is always challenging to the pulmonary specialist as the path of the breath of life for patients with lung diseases comes to an end with no further medical treat- ments to extend life. The frustrations and sense of despair that the patient, their loved ones, families, friends, caregivers, and physicians are confronted with are significant. While many patients unfortunately succumb to advanced lung diseases, new horizons have opened up for patients suffering from end-stage lung disease, thanks to pioneers including Cooper, Pearson, and Viganò, by mak- ing lung transplantation a reality to these patients, who are otherwise healthy. Since the advent of lung transplantation, nearly 6000 patients have received lung transplantations between 1988 and 1995, increasing progres- sively to 17,715 bilateral lung transplantations between 2005 and 2010, with a statistically significant (p < 0.0001) smaller risk of rejection compared to the preceding period considered. Indeed, lung transplantation has evolved into standard of care for these patients, with improved quality of life and enhanced survival for patients with idiopathic pulmonary fibrosis (IPF), cystic fibrosis, etc. Indeed, lung transplantation is a potential option for the patient who has reached advanced stages, but, unfortunately, it is not an option for all patients who have reached advanced stages and for whom there are no further medical treatment interventions to stabilize their lung problems. The general pulmonologist needs to be aware of the indications and contraindications of lung transplantation as well as of post-lung transplant management, risks, complications, and outcomes in order to be able to help patients understand the complexity and benefits of lung transplantation as well as be prepared for the anticipated outcomes. Pulmonologists also must help patients improve and/or maintain their physical stability and overall fitness as possible while coping with advanced stages of diseases such as IPF, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary hypertension, pulmonary sar- coidosis, interstitial pneumonia associated with connective tissue diseases such as systemic sclerosis, rheumatoid arthritis, and polymyositis, and other orphan lung diseases. This is the first book to discuss all aspects of lung transplantation and is intended to equip the general pulmonologist/physician worldwide with all the necessary tools, awareness, and knowledge to help patients with management of advanced stages, preparation for lung transplantation, and care post-lung

ix x Preface transplantation. This book also serves as a clinical guide to refer appropriate patients early for consideration for lung transplantation worldwide. We have organized the chapters into four broad parts and have leading global experts who have written on the different topics pertinent to medical, surgical, psychological, and social aspects of lung transplantation. Additionally, we have summarized the history of lung transplantation and discussed the immunological aspects and epigenetic changes with vascular injury after lung transplantation. The first part discusses eligibility criteria including specific evaluation, timing for listing, indications and contraindications for lung transplantation, pretransplant considerations, psychosocial patient evaluation, and lung allocation score, in combination with the impact of new revisions and successive outcome. A particular emphasis is given to lung transplantation with regard to COPD, cystic fibrosis, and interstitial lung diseases with pulmonary fibrosis. Issues related to the donor lung with detailed consideration of immunology, physiology, epigenetics, and surgical treatment are discussed in the second part. The third part discusses medical management of the lung transplantation recipient including cellular and humeral rejection, prevention of viral and nonviral infection, lung allograft dysfunction, and complications such as bronchiolitis obliterans pneumonia, gastro-esophageal reflux, and essential topics including bronchoscopy, imaging, and lung rejection pathology. Finally, the last part highlights directions for the future to bridge the gaps in the field of lung transplantation. We are very grateful to all the leading experts in the field for agreeing to discuss their expertise in their chapters and for their contribution to this book dedicated to lung transplantation.

Ganesh Raghu Roberto G. Carbone Seattle, WA, USA Genoa, Italy Contents

Part I General Principles and Considerations for Lung Transplantation

1 The History of Lung Transplantation...... 3 Andrea Maria D’Armini, Valentina Grazioli, and Mario Viganò 2 Single- and Bilateral Lung Transplantation: Indications, Contraindications, Evaluation, and Requirements for Patients to Be Considered Eligible ...... 17 Gerard J. Meachery and Paul A. Corris 3 Pretransplant Considerations in Patients with Obstructive Lung Disease: COPD, Lymphangioleiomyomatosis, Cystic Fibrosis, and Non-CF Bronchiectasis...... 41 Shahnaz Ajani and Robert M. Kotloff 4 Pretransplant Considerations in Patients with Pulmonary Fibrosis ...... 57 Roberto G. Carbone, Assaf Monselise, Keith M. Wille, Giovanni Bottino, and Francesco Puppo 5 Pulmonary Vascular Disease: Specific Evaluation and Timing for Listing Eligible Patients to Receive Lung Transplantation and Management of the Pre-lung Transplant Patient ...... 71 Alison S. Witkin and Richard N. Channick 6 Psychosocial Evaluation of the Patient Considered for Lung Transplant...... 85 Thomas M. Soeprono and Ganesh Raghu 7 Prognostic Markers and the LAS for Lung Transplantation: Impact of New Revisions for Successful Outcome...... 93 M. Patricia George and Matthew R. Pipeling

xi xii Contents

Part II The Donor Lung and the Lung Transplant Recipient

8 Management of the Donor and Recipient: Surgical Management...... 113 Andrea Mariscal and Shaf Keshavjee 9 Immunology in Lung Transplantation...... 139 Idoia Gimferrer and Karen A. Nelson 10 Physiologic and Epigenetic Changes with Pulmonary Vascular Injury After Lung Transplantation...... 161 Steven Kenneth Huang, Roberto G. Carbone, and Giovanni Bottino

Part III The Lung Transplant Recipient: Medical Management

11 Medical Management of the Lung Transplant Recipient: Extrapulmonary Issues...... 185 Erika D. Lease and Ganesh Raghu 12 Management of Cellular and Humoral Rejection: Prevention, Diagnosis, and Treatment...... 195 Erika D. Lease and Ganesh Raghu 13 Pathology of Lung Rejection: Cellular and Humoral Mediated ...... 209 Anja C. Roden and Henry D. Tazelaar 14 Prevention and Treatment Regimens for Non-viral Infections in the Lung Transplant Recipient...... 231 Martin R. Zamora 15 Respiratory Viruses and Other Relevant Viral Infections in the Lung Transplant Recipient...... 241 Ali Abedi, Reed Hall, and Deborah Jo Levine 16 Lung Allograft Dysfunction (LAD) and Bronchiolitis Obliterans Syndrome...... 263 Bart Vanaudenaerde, Robin Vos, Stijn Verleden, Elly Vandermeulen, and Geert Verleden 17 Gastroesophageal Reflux and Esophageal Dysmotility in Patients Undergoing Evaluation for Lung Transplantation: Assessment, Evaluation, and Management ...... 279 Robert B. Yates, Carlos A. Pellegrini, and Brant K. Oelschlager 18 Management of Airway Stenosis in the Lung Allograft: Bronchoscopy Procedures ...... 301 Hardeep Singh Kalsi and Martin R. Carby 19 Imaging of Lung Transplantation...... 313 Jitesh Ahuja, Siddhartha G. Kapnadak, and Sudhakar Pipavath Contents xiii

Part IV Lung Transplantation: Future Directions

20 New Horizons in Lung Transplantation...... 329 Pablo Gerardo Sanchez, Dustin M. Walters, and Michael S. Mulligan 21 Gaps and Future Directions in Lung Transplantation . . . . 345 Keith C. Meyer and Ganesh Raghu Index...... 361 Contributors

Ali Abedi, MSc, MD Department of Pulmonary and Critical Care Medicine, University of Texas Health San Antonio, San Antonio, TX, USA Jitesh Ahuja, MBBS, MD Department of Radiology, University of Washington Medical Center, Seattle, WA, USA Shahnaz Ajani, MD Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University Hospital, Emory University School of Medicine, Emory Transplant Center, Atlanta, GA, USA Giovanni Bottino, MD Department of Medicine, University of Genoa— DIMI, Genoa, Italy Roberto G. Carbone, MD, FCCP Department of Internal Medicine, University of Genoa, Genoa, Italy Martin R. Carby, MBBS, BSc, FRCP Transplant Unit, Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, London, UK Department of Cardiothoracic Transplantation, Harefield Hospital, Harefield, UK Richard N. Channick, MD Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA Paul A. Corris, MBBS, FRCP Department of Respiratory Medicine, Freeman Hospital and Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK Andrea Maria D’Armini, MD Department of Cardiothoracic and Vascular Surgery, University of Pavia, School of Medicine, Foundation IRCCS Policlinico San Matteo, Pavia, Italy Idoia Gimferrer, MD, PhD, D(ABHI) Department of Immunogenetics/ HLA, Bloodworks Northwest, Seattle, WA, USA Valentina Grazioli, MD Department of Cardiothoracic and Vascular Surgery, University of Pavia, School of Medicine, Foundation IRCCS Policlinico San Matteo, Pavia, Italy Reed Hall, PharmD Pharmacy, University Hospital—University Health System, San Antonio, TX, USA

xv xvi Contributors

Steven Kenneth Huang, MD Department of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA Hardeep Singh Kalsi, MBBS, IBSc(Hons), MRCP Transplant Unit, Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, London, UK Department of Cardiothoracic Transplantation, Harefield Hospital, Harefield, UK Siddhartha G. Kapnadak, MD Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center, Seattle, WA, USA Shaf Keshavjee, MD, MSc, FRCSC, FACS Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada Robert M. Kotloff, MD Department of Pulmonary Medicine, Cleveland Clinic, Cleveland, OH, USA Erika D. Lease, MD Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, WA, USA Deborah Jo Levine, MD Department of Pulmonary and Critical Care Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, USA Andrea Mariscal, MD Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada Gerard J. Meachery, MB BCh (HONS), FRCP, FRCP Department of Respiratory Medicine, Freeman Hospital, Newcastle Upon Tyne, UK Keith C. Meyer, MD, MS Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Assaf Monselise, MD Departments of Dermatology and Internal Medicine, Clalit Health Services, Tel-Aviv, Israel Michael S. Mulligan, MD Department of Surgery, University of Washington, Seattle, WA, USA Karen A. Nelson, PhD, D(ABHI) Department of Immunogenetics/HLA, Bloodworks Northwest, Seattle, WA, USA Brant K. Oelschlager, MD Division of General Surgery, Department of Surgery, University of Washington Medical Center, Seattle, WA, USA M. Patricia George, MD Department of Medicine, National Jewish Health, Denver, CO, USA Carlos A. Pellegrini, MD, FACS Department of Surgery, University of Washington, Seattle, WA, USA Contributors xvii

Sudhakar Pipavath, MD Department of Radiology, University of Washington Medical Center, Seattle, WA, USA Matthew R. Pipeling, MD Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Francesco Puppo, MD Department of Internal Medicine, University of Genoa, Genoa, Italy Ganesh Raghu, MD, FCCP, FACP Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine University of Washington, Seattle, WA, USA Center for Interstitial Lung Disease, ILD, Sarcoid and Pulmonary Fibrosis Program, University of Washington Medicine, Seattle, WA, USA Scleroderma Clinic, University of Washington Medicine, Seattle, WA, USA Anja C. Roden, MD Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, USA Pablo Gerardo Sanchez, MD, PhD Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, Seattle, WA, USA Thomas M. Soeprono, MD Department of Psychiatry, University of Washington, Seattle, WA, USA Henry D. Tazelaar, MD Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA Bart Vanaudenaerde, MSc, PhD Laboratory of Respiratory Diseases, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Elly Vandermeulen, PhD Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Geert Verleden, MD, PhD, FERS Lung Transplantation Unit, University Hospital Gasthuisberg, Leuven, Belgium Stijn Verleden, PhD, MSc Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Mario Viganó, MD Department of Cardiothoracic and Vascular Surgery, University of Pavia, School of Medicine, Foundation IRCCS Policlinico San Matteo, Pavia, Italy Robin Vos, MD, PhD Laboratory of Respiratory Diseases, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Lung Transplant and Respiratory Intermediate Care Unit, Department of Respiratory Medicine, University Hospitals Leuven, Leuven, Belgium Dustin M. Walters, MD Department of Thoracic and Cardiovascular Surgery, University of Virginia, Charlottesville, VA, USA xviii Contributors

Keith M. Wille, MD Department of Medicine, Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Alison S. Witkin, MD Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA Robert B. Yates, MD Department of Surgery, Northwest Hospital and Medical Center, University of Washington Medicine, Seattle, WA, USA Martin R. Zamora, MD Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA Part I General Principles and Considerations for Lung Transplantation The History of Lung Transplantation 1 Andrea Maria D’Armini, Valentina Grazioli, and Mario Viganò

Milestones in Transplantation demonstrated that bronchial arteries and nerves History are unnecessary in the lung function of the recipient [1]. “… if there is a father of heart and lung Alexis Carrel (University of Chicago) transplantation. (Fig. 1.3) is another important pioneer in the lung then Demikhov certainly deserves this title” (C. Barnard). transplantation field. His innovations in surgical techniques, mainly in end-to-end anastomosis The miracle of Cosmas and Damian (martyrs, (for which he received the Nobel Prize in 1912), 287 A.D.) depicted the first evidence of trans- allowed the beginning of a new era dedicated to plantation. According to tradition, these martyrs whole organ transplantations [2]. In 1907, Carrel grafted the leg from a barely deceased Ethiopian and C.C Guthrie (University of Chicago) per- onto a Caucasian patient, in order to replace his formed a heterotopic heart-lung transplantation ulcerated leg. See Fig. 1.1. on the neck of a cat; it died 3 days later, probably In modern times, Vladimir P. Demikhov from an acute rejection [3, 4]. (Moscow) (Fig. 1.2a), a Russian physiologist, In 1954, Joseph E. Murray (Massachusetts) presented the first important stimulus in devel- performed the first human kidney transplanta- oping transplantation science: he transplanted a tion on twins in order to avoid rejection prob- dog head onto the neck of another dog in 1940, lems. This experience established the first and this dog survived for several days [1]. evidence of the feasibility of transplants applied Furthermore, he performed the first lung trans- to human [5]. The most important landmark in plantation (right inferior lobe) on a dog, and the lung transplantation history was the first human dog survived for 7 days; it died from a pneumo- single-lung transplantation performed in 1963 thorax due to a bronchial suture dehiscence [1]. by the pioneer James D. Hardy (University of Demikhov continued these attempts at trans- Mississippi) [2]. Four years later, Christiaan plantations in dogs (Fig. 1.2b). The complica- Barnard (University of Cape Town) (Fig. 1.4) tion which doomed his first lung transplant realized the first human-to-human heart trans- attempt became the main challenge in his fol- plantation [2]. lowing attempts; simultaneously, Demikhov However, despite these and other achieve- ments and promising results, lung transplanta- A. M. D’Armini · V. Grazioli (*) · M. Viganò tion developed with delay when compared to Department of Cardiothoracic and Vascular Surgery, transplantation of other organs such as the heart, University of Pavia, School of Medicine, Foundation kidney, and liver. This was due mainly to the IRCCS Policlinico San Matteo, Pavia, Italy lung’s frailty, to the major exposure to infections e-mail: [email protected]

Fig. 1.1 The Healing of Justinian by Saint Cosmas and Saint Damian. Fra Angelico (circa 1438–1440) (Source: https:// commons.wikimedia. org/wiki/File:Fra_ Angelico_-_The_ Healing_of_Justinian_ by_Saint_Cosmas_and_ Saint_Damian_-_ WGA00519.jpg. Fra Angelico [Public domain], via Wikimedia Commons)

a b

Fig. 1.2 (a) Vladimir Demikhov (1916–1998) (Source: ITAR-TASS News Agency/Alamy Stock Photo). (b) The last dog head transplant performed by Dr. Demikhov (Source: Bundesarchiv, Bild 183–61478-0004/Weiß, Günter/CC-BY-SA 3.0) 1 The History of Lung Transplantation 5

Fig. 1.4 Dr. Christiaan Barnard (1922–2001) (Used with permission of University Stamp Co., Inc./University Archives, Westport, CT, USA)

from the external world, and to the absence of systemic bronchial connections after the transplantation [2].

The Pre-Hardy First Human Lung Transplant Era: Lessons Learned from Animal Models of Lung Transplantation

In 1950, Henri Metras (Marseille) described an innovative experiment concerning the venous anastomosis of a lung transplantation in a dog Fig. 1.3 Dr. Alexis Carrel (1873–1944) in 1912 (Source: involving the pulmonary veins with the left https://commons.wikimedia.org/wiki/File:Alexis_Carrel_ atrium cuff [6]. He also demonstrated the (1912).jpg#filelinks. Forms part of George Grantham Bain Collection, Library of Congress. Public Domain) possibility of preserving the bronchial arterial 6 A. M. D’Armini et al. support with a connection to the subclavian They also demonstrated that the use of cortisone artery. Furthermore, he was the first to succeed in could efficiently increase the survival of the allotransplantation [6]. recipient [10]. In 1950, Vittorio Staudacher (Milan) com- Nevertheless, despite these advancements, the pared allotransplantation and autotransplantation main issue still being debated was the role of in dogs in order to better investigate the physio- hilar vascular and nerve structures [11]. Table 1.1 pathology of rejections [7]. In the same manner, lists the most important stages of this phase: the A. A. Juvenelle (Buffalo University) attempted grafted lung has normal functional pattern if part reimplantation (autotransplantation) in canine of the recipient lung remains in place, and the models for physiological studies [8]. This study autonomic nerves are important for pulmonary would be continued later in 1953 by W. B. function. However, there is no explanation Neptune (Philadelphia), who conducted canine regarding the reduction of lung function post- experiments on bronchial anastomosis and inves- transplantation [11]. tigated post-transplant dehiscence and the result- Finally, immunosuppressive therapy received ing recipient death. He proved that the use of attention through the work of David A. Blumenstock adrenocorticotropic hormone (ACTH) actually in 1961 (New York) and James D. Hardy in 1963 improved survival [9]. In 1954, Creighton (Mississippi) [12, 13], specifically concerning the A. Hardin and C. F. Kittle (Kansas) established possible use of cortisone, ACTH, total body irradi- the functional capacity of a lung allotransplant. ation, and splenectomy.

Table 1.1 Lessons from animal models of lung transplantation Author/Study Year Lesson Bogardus 1958 Normal grafted lung function if part of recipient lung remains in place (Washington)a Faber and Beattle 1958 (Chicago) b Nigro (Chicago)c 1962 Importance of autonomic nerves for lung function Yeh (Georgia)d 1962 Hardy 1963 (Mississippi)e Haglin 1963 Experiments on baboons prove normal functional lung and increase survival with (Minneapolis)f respect to surveys realized on dogs. The same conclusion is reached also when recipient pneumonectomies are performed. This demonstrated that the rule of autonomic nerve in lung function is species-specific aBorgadus GM. An Evaluation in Dogs of the Relationship of Pulmonary, Bronchial, and Hilar Adventitial Circulation to the Problem of Lung Transplantation. Surgery. 1958;43:849–856 bFaber LP, Beaitie EJ Jr. Respiration Following Lung Denervation. Surg Forum. 1958;9:383–385 cNigro SL, Evans RH, Benfield JR, Gago O, Fry WA, Adams WE. Physiologic Alterations of Cardiopulmonary Function in Dogs Living one and one-Half Years on Only a Reimplanted Right Lung. J Thorac Cardiovasc Surg. 1963;46:598–605 dYeh TJ, Ellison LT, Ellison RG. Functional Evaluation of the Autotransplanted Lung in the Dog. Am Rev Resp Dis. 1962;86:791–797. eShumway SJ, Shumway NE. Thoracic Transplantation. Part I. Historical Background. Cambridge, MA: Blackwell Science;1995 fHaglin J, Telander RL, Muzzall RE, Kiser JC, Strobel CJ. Comparison of Lung Autotransplantation in the Primate and Dog. Surg Forum. 1963;14:196–198 1 The History of Lung Transplantation 7

Lessons from the First Human Lung the maldistribution of ventilation and perfusion in Transplantation by Hardy the grafted lung [16]. Subsequently, the anastomosis dehiscence problem became the main topic. In 1963, James D. Hardy (Fig. 1.5) performed the From 1963 to 1983, many laboratories focused first human lung transplantation on a prisoner their studies on [11]: affected by lung central carcinoma with nodal metastases; the left graft lung was harvested from 1. Pulmonary denervation: Based on Haglin’s a man who died of massive acute myocardial work (Minneapolis, 1963), S. Nakae (Texas infarction [11, 14]. Immunosuppressive therapy, Southwestern) conducted studies in 1967 test- consisting of azathioprine, cortisone, and cobalt ing the efficiency of lung transplantation on irradiation of the thymic region, was also admin- rhesus monkeys, dogs, and cats; only rhesus istered [11, 14]. The patient survived for 18 days, monkeys had normal pattern lung ventilation and the death was ascribed to kidney failure and after the transplantation [17]. He tested differ- malnutrition [11, 14]. ent techniques on four categories of animals From 1963 to 1973, several lung transplanta- from different species: mediastinal denervation attempts were performed, but with little suc- tion with tracheal transaction and reanastomo- cess. Indeed, only sporadic experiments showed sis onto dogs, cats, and rhesus monkeys. The significant results, such as the one by Fritz Derom fourth group consisted of dogs that underwent in 1968 (Belgium), who reported a 10-month total mediastinal denervation [17]. The con- posttransplantation survival [15]. clusion of his work was that humans and pri- In 1970, Frank J. Veith (New York) confirmed mates have a different respiratory reflex the feasibility of single-lung transplantation [16]. compared to dogs, and, for this reason, they However, several troublesome issues still existed: have a normal functional lung pattern after the unadapted immunosuppression and consequent lung transplantation [17]. graft rejection, the infection problems, and, finally, 2. Pulmonary vascular physiology after lung transplantation: Several studies up until 1960 had underlined the frequency of pulmonary hypertension after lung transplantation and ligation of the contralateral pulmonary artery [18–20]. This problem was mainly due to venous anastomosis obstruction. In order to prevent this complication, Frank J. Veith and K. Richards introduced the concept of left atrium cuff in 1970 [21]. 3. Dehiscence of bronchial anastomosis: This complication was the focal point of interest of the “Toronto Lung Transplantation Group,” the main thoracic surgical center in Toronto, Fig. 1.5 Dr. James D. Hardy (1918–2003): “…research founded by F. Griff Pearson in 1968 (Fig. 1.6) became a vital part of my professional life….” (Used with permission of the University of Mississippi. Medical and later directed by Joel D. Cooper (Fig. 1.7). Center. Source: https://www.umc.edu/uploadedImages/ It was Joel D. Cooper who in 1978 first per- UMCedu/Content/Administration/Institutional_ formed a right lung transplantation in a Advancement/Public_Affairs/News_and_Publications/ 19-year-old man who was ventilator-depen- Press_Releases/2013/2013-06-10/Hardy%20in%20 Scrubs.jpg) dent and affected by pulmonary failure due to 8 A. M. D’Armini et al.

17 days and died from bronchial anastomosis dehiscence [22]. The autopsy reported circum- ferential area of necrosis, poor healing of pulmonary artery, and atrium anastomosis [22].

Due to the results of the Toronto Centre experiments and different trials from similar groups, the human transplant program was temporarily interrupted in order to assess the bronchial anastomosis in laboratory studies [2, 11].

The 1970s to the Early 1990s: Fig. 1.6 Dr. F. Griff Pearson (1926–2016). Removal of The Bronchial Anastomosis kidneys, donor for lung transplant (Used courtesy of Era—Lung Transplantation University Health Network Archives, Toronto, Canada) Dilemma

In 1981, M. Goldberg (Toronto Group) first evalu- ated the combined use of cortisone and azathioprine after lung transplantation in canine models and reported bronchial anastomosis damage associated with this technique; later, he analyzed these drugs separately in order to underline the sensitiv- ity of bronchial dehiscence to steroids [23]. Another study compared the use of different immunosuppression drugs in dogs: in the first group, dogs were treated with a combination of steroid and azathioprine; in the second group, only cyclosporine A was used; the third control group was composed of untreated dogs [24]. This analysis revealed that the correct regimen for healing anastomosis for dogs was with cyclosporine A [24]. At this time, important efforts were focused on finding a method providing bronchial arterial blood flow to the anastomosis site. R. M. Stone in 1966 (Toronto Group) demonstrated the restoration of bronchial circulation in only 4 weeks in Fig. 1.7 Drs. Thomas Todd, Joel Cooper, Alec Patterson, dogs following a primary phase of cyanosis, and Griffith Pearson (seated). Toronto General Hospital edema, and secretion retention mainly due to Division of Thoracic Surgery (1987) (Used with permis- irregular bronchial mucosa blood supply [25]. sion of Joel D. Cooper, MD, FACS, Chief of Thoracic In 1970, N. L. Mills (New York) proposed the Surgery, Department of Surgery, University of Pennsylvania Health System) connection of the left bronchial artery and the intercostal arteries to the aorta as an alternative inhalation injuries sustained during a home fire solution for left lung transplantation [26]. The [22]. A veno-venous extracorporeal membrane control group of dogs without reimplantation oxygenator (ECMO) was previously posi- evidenced more postoperative complications, tioned and maintained for few days after the such as ulcerations, poor healing anastomosis, transplant [22]. The patient survived for and stenosis [26]. 1 The History of Lung Transplantation 9

F. Griff Pearson (Toronto), using angiography in 1970, demonstrated the bronchial artery recon- struction after 4 weeks from lung asportation and reimplantation in dog models, thanks to the connection of the bronchial arterial channels into the bronchial wall [27]. This result was also successively confirmed by J. J. Rabinovich (Moscow) through left inferior lung lobe autotransplantation [28]. In 1977, Stanley S. Siegelman (New York) analyzed allotransplantation versus autotransplantation/reimplantation in canine models in a manner that was different from previous studies Fig. 1.8 Dr. Norman E. Shumway (1923–2006) (inset [29]. He noticed that, during the second week and at patient’s left) performing the first adult US heart after the transplant, an arterial network develops transplant with Dr. Edward Stinson, January 7, 1968 (Source: http://bulletin.facs.org/wp-content/uploads/ around the bronchial anastomosis and that, after 2012/05/Shumway.jpg. Used with permission of the 31 days, a copious arterial pattern is generally American College of Surgeons, Chicago, IL, USA) present behind the anastomosis [29]. Furthermore, he announced that no correlation existed between the possible regeneration of bronchial flow and Eisenmenger’s syndrome, and transposition of the bronchial anastomosis dehiscence: some animals great vessels, respectively. In all the cases, cyclo- with bronchial flow restoration had bronchial sporine A was the immunosuppression therapy: it dehiscence in any case, but the opposite situation became the primary agent for immunosuppression was also observed [29]. [31]. It was generally associated with azathioprine Hence, the cause of the lung transplantation or mycophenolate, followed by induction therapy dilemma could be attributed to two different with basiliximab. The survival range of these sources: the immunosuppression therapy and the three attempts was from 12 h to 23 days [31]. correlated rejection. With Goldberg’s study in The Stanford Group underlined the importance of mind, O. Lima and Joel D. Cooper (Toronto) preserving the vagus nerves and the left recurrent introduced the omentopexy technique in 1982: laryngeal nerve during recipient dissection [31]. using an omental pedicle appropriately vascular- In 1982, the Toronto Group performed a right ized and able to avoid infections, the bronchial lung transplantation on a patient with respiratory anastomosis was reinforced and its healing facili- failure due to an accidental paraquat poisoning; tated [30]. the left lung also ended up being transplanted After all these experimental results, the [32]. However, paraquat induced generalized Toronto Lung Transplantation Group restarted its myopathy which caused the patient’s death attempts of lung transplantation in humans. 3 months later [32]. The selection criteria of the recipient came under scrutiny, and, at this time, only patients affected by idiopathic pulmonary The Successful Lung fibrosis and end-stage disease without important Transplantation Era: From the comorbidities and who were not ventilator- Mid-1990s to the Present dependent could be treated by transplantation [2]. November 7, 1983, marked the beginning of In 1982, Bruce A. Reitz and Norman E. Shumway the successful lung transplantation era with a (Fig. 1.8) performed the first three heart-lung right lung transplant in a patient who survived for transplantations in humans at the University nearly 5 years: the bronchial anastomosis was of Stanford [31]. The three recipients were performed using omentopexy, and immunosup- affected by primary pulmonary hypertension, pression with azathioprine, cyclosporine, and ste- 10 A. M. D’Armini et al. roid was introduced [2, 33]. After nearly 5 years, omentopexy, avoided the laparotomy, and the patient died from transbronchial biopsy com- reduced surgical time [36]. plications [2, 33]. E. S. Garfein described the superiority of the For patients affected by cystic fibrosis or end-to-end bronchus anastomosis versus the tele- chronic obstructive pulmonary diseases (COPD) scoped one in 2001: a higher incidence of anasto- with bilateral impairment, a heart-lung transplant motic complications was seen for the telescoped was at this point under consideration [2, 11]. versus the end-to-end anastomosis, in particular However, there were several areas of concern: ischemia, dehiscence, and severe stenosis [37]. At heart transplant was unnecessary; heart or/and this point, certain centers adopted the end-to-end lung rejection could develop simultaneously or anastomosis, and others adopted the telescoped separately; postoperative follow-up was more one, with the range of complications slightly complicated; a right heart dysfunction could be higher for the telescoped anastomosis [37]. reversible after lung transplantation [2, 11]. In 2002, C. Schröder introduced a modified In light of these concerns, J. H. Dark intro- intussuscepting technique to avoid complications duced, in 1986, the en bloc double-lung transplan- (malacia, granulation tissue, or subcritical stenosis) tation with distal tracheal anastomosis, pulmonary that still remained with end-to-end or telescoped artery anastomosis at the main pulmonary artery anastomosis [38]. The modified technique uses a level, and venous anastomosis with the left atrium running suture for the membranous portion, just cuff [34]. This procedure was complicated due three U stitches (at 0°, 90°, and 180°) and two or to the necessity of the cardiopulmonary bypass three figure-of-eight sutures in between; it allows but also due to the possible tracheal anastomosis for an improved coaptation of the bronchial walls dehiscence [2]. Consequently, the Toronto Group and reduces the ledge of the bronchus that pro- introduced the sequential bilateral lung transplant, trudes into the lumen of the other one [38]. implanting each lung separately with transverse At this juncture, new issues arose: the selection bilateral thoracosternotomy incision [2]. of donor and recipient; the best timing for trans- With regard to bronchial anastomosis, Joel plant and allocation system, lung preservation, and D. Cooper in 1987 described the use of an inter- immunosuppression; and the diagnosis of/therapy rupted or running sutures with Prolene® (Ethicon, for rejection [2]. Lung transplantation at this time Somerville, NJ, USA) for the cartilaginous was indicated for all end-stage pulmonary diseases portion and interrupted sutures with Vicryl® [39]: pulmonary vascular diseases, obstructive (Ethicon, Somerville, NJ, USA) for the membra- lung pathologies, and restrictive lung diseases. nous portion (the “end-to-end bronchus anasto- In 1990, Stanford University performed the mosis”) associated with the omentopexy by the first lung transplant from a living donor: a omental mobilization with a small upper abdomi- 45-year-old mother donated a third of her right nal midline incision and its placement in subxi- lung to substitute for the whole right lung of her phoid position [35]. The omentopexy was 12-year-old daughter affected by bronchopulmo- successively abandoned in place of local tissue nary dysplasia [40]. This option was not accepted used to surround bronchial anastomosis [2]. as a rule due to the high risk to the pulmonary J. H. Calhoon and J. K. Trinkle introduced reserve of the donor [41]. However, the lack of the “telescoped bronchus anastomosis”: a run- organ donors imposed the introduction of best ning suture for the posterior and membranous lung preservation strategies [41]: as reported by part of the bronchus and an interrupted figure- Thomas M. Egan (Fig. 1.9), “improved methods of-eight suture for the anterior portion [36]. for preservation will increase the supply of suit- Considering that generally there is some size able lungs…efficient use of donor organs remains discrepancy between the two bronchial stumps, of paramount importance” [39]. In the beginning, the anastomosis telescopes one ring [36], and the Toronto Group used hypothermic cold saline the donor bronchus was invaginated into the solution before adopting the Euro-Collins solu- recipient bronchus by one or two cartilaginous tion to rinse lungs [2]. Later, S. Fujimura demon- rings [37]. This new technique did not use strated the preservation of dog lungs for more 1 The History of Lung Transplantation 11

(SRTR) with the OPTN supported the scientific and clinical status of solid organ transplant in the United States [42]. In 1990, the donor lung allocation system was based on ABO match and cumula- tive time on the waiting list; first, the candidate was placed into the donor service area of the donor hospital and thereafter into an area 500 nautical miles distant from this hospital [42]. In 1998, the “final rules” of the allocation system based on clinical criteria and medical urgency were drafted, with the purpose of sharing organs and reducing the number of deaths on the waiting list [43]. Finally, in 2005, a new system of allocation was created by the OPTN, the Lung Allocation Score (LAS): a donor priority was assigned based on a score calculated using the waiting list survival (urgency criteria) and the 1-year survival after transplant; this score has been regularly updated; is still in use in the United States, Germany, and the Netherlands; and is used by the Eurotransplant Program when the match is outside of the donor’s country [2]. Information sharing internationally in the field of heart and lung transplant became mandatory at this Fig. 1.9 Dr. Thomas M. Egan (Source: https://www.med. point in order to improve knowledge in this field; unc.edu/ct/images/Egan%20photo%202%202-11.jpg. therefore, in 1981, Norman E. Shumway founded Used with permission of University of North Carolina Health Care) the International Society for Heart and Lung Transplantation (ISHLT), a voluntary registry and data sharing organization and a source for classifica- than 24 h with a low-potassium dextran solution tions and guidelines that are still used to this day [2]. [2, 39]. This became known as the “Fujimura In 1993, the ISHLT introduced the concept of solution” and was used in the following years to bronchiolitis obliterans syndrome (BOS) as a flush lungs during the preservation period [2, 39]. chronic allograft dysfunction in order to address post-lung transplantation dysfunction [2]. Recently, restrictive allograft syndrome was recognized as a Changes in the Allocation of Donor new form of chronic lung rejection [2]. Regarding Lung to Recipient in 1986: immunosuppression therapy, the associated use of Allocation Prioritized Based calcineurin inhibitor, steroid, and either azathio- on Severity of the Recipient Status prine or mycophenolate mofetil has continued as a Rather Than the Order of Listing drug strategy after lung transplantation [2]. At this point, the topic of bronchial artery In 1986, the Health Resources and Services revascularization after lung transplantation was Administration (HRSA) in the United States intro- being revisited, and it is important to mention sev- duced the Organ Procurement and Transplantation eral developments. Since H. H. J. Schreinemakers Network (OPTN) to create a connection between [44, 45], who reemphasized the possible role of the solid organ donation organizations and the bronchial ischemia in airway healing impairment transplantation system [42]. Prior to this, the United and previously described the use of an intercosto- Network for Organ Sharing (UNOS) operated the bronchial artery pedicle [46], different attempts OPTN, under a contract with the HRSA [42]. were subsequently published. L. Couraud The Scientific Registry for Transplant Recipients described the possible use of a vein graft [47, 48]. 12 A. M. D’Armini et al.

In 1993, R. C. Daly and Magdi H. Yacoub mothermic ex vivo organ experiences was described described the possible use of the left internal tho- by Alexis Carrel and C. A. Lindbergh in 1935 [53, racic artery in double-lung transplantation to 54], while the first EVLP was presented by D. W. obtain an immediate revascularization of the Jirsch in 1970 [55]. However, these experiences whole tracheobronchial tree [49]. In 1994, they failed due to the loss of the lung alveolar-capillary showed analogous data concerning the single-lung barrier, the onset of edema, and the vascular resis- transplantation [45]. In 1996, M. A. Norgaard tance increase during EVLP [53]. The Steen highlighted the convincing results of the correla- Solution (XVIVO Perfusion, Göteborg, Sweden) tion between the healing bronchial airway and was introduced as lung perfusion to maintain the bronchial artery revascularization and the long- fluid in the intravascular space and supply nutrients term patency of the mammary artery [50]. Lastly, for pulmonary homeostasis [56–58]. At this junc- the wide experience of Copenhagen Group showed ture, the main issue was the duration of the preser- the use of mammary artery for single-/double-lung vation period, which was less than 60 min. Hence, transplantation or heart-lung transplant [48, 51]. in 2008, the Toronto Group introduced a new EVLP The entire role and long-term outcome of method in order to extend this time to longer than bronchial revascularization should be confirmed 12 h and, thus, gain time to assess, recondition, and by future multicenter studies [52]. repair the donor lungs [53, 59]. Actually, the Toronto In order to increase the donor organ number, dif- method is the one most used for the EVLP: it con- ferent strategies have been introduced, such as sists of creating an optimal environment for the extending donor criteria and/or using deceased car- donor lung operation, a protective ventilation set- diac donors (DCD) [53]. The field of normothermic ting without circuit-induced injuries (using flow ex vivo lung perfusion (EVLP) developed in parameter to prevent mechanical shear stress), and response to questionable and injured lungs in order adopting a perfusate with a chemical composition to expand donor criteria [53]. The first report of nor- appropriate for homeostasis [53]. See Fig. 1.10.

86% N2 8% CO Leukocyte 2 filter 6% O2

from PV Reservoir to PA

Pump

Deoxygenator- Ventilator heat exchanger EVLP lung chamber

Fig. 1.10 Cypel ex vivo lung circuit. EVLP normother- Steen S, Ingemansson R, Eriksson L, Pierre L, Algotsson mic lung circuit allowing both functional assessment and L, Wierup P, Liao Q, Eyjolfsson A, Gustafsson R, Sjöberg repair. Note insert’s red tank indicating a hypoxic gas. For T. First human transplantation of a nonacceptable donor more information see Cypel M, Liu M, Rubacha M, Yeung lung after reconditioning ex vivo. Ann Thorac Surg. JC, Hirayama S, Anraku M, Sato M, Medin J, Davidson 2007;83(6):2191–4 (Used with permission of Dr. James BL, de Perrot M, Waddell TK, Slutsky AS, Keshavjee G. Chandler and the American College of Surgeons, from S. Functional repair of human donor lungs by IL-10 gene http://bulletin.facs.org/2012/01/sanctity-2/#. therapy. Sci Transl Med. 2009;Oct 28:1(4):4ra9; and WqBgCGrwaM9) 1 The History of Lung Transplantation 13

Despite the controversy that emerged at the the lung: laboratory studies and clinical potential. Ann Surg. 1963;157:707–18. beginning of DCD attempts due to the frailty of 14. Hardy JD, Webb WR, Dalton ML, Walker the donor lungs, there were reports of successes; GR. Lung homotransplantations in man. JAMA. starting with one first reported in 1995 by R. B. 1963;186:1065–74. Love [60], later attempts also confirmed posi- 15. Derom F, Barbier F, Ringoir S, Versieck J, Rolly G, Berzsenyi G, Vermeire P, Vrints L. Ten month survival tive results, as demonstrated by G. I. Snell in after lung homotransplantations in man. J Thorac 2008 [61] and successive ones by Jeremie Reeb Cardiovasc Surg. 1971;61:835–46. [62] and Marcelo Cypel [63]. Thus, a new cate- 16. Veith FJ. Lung transplantation. Ann Thorac Surg. gory of lung donor developed: the uncontrolled 1970;9:580–3. 17. Nakae S, Webb WR, Theodorides T, Sugg donation after circulatory determination of WL. Respiratory function following cardiopulmonary death donor (uDCDD) associated with the use denervation in dog, cat, and monkey. Surg Gynecol of EVLP. Good postoperative outcomes have Obstet. 1967;125:1285–92. been reported [53, 64, 65]. 18. Yeh TJ, Ellison LT, Ellison RG. Functional evaluation of the autotransplanted lung in the dog. Am Rev Resp Dis. 1962;86:791–7. 19. Linberg EJ, Demetriades A, Armstrong BW, References Konsuwan N. Lung reimplantation in the dog. JAMA. 1961;178:486–7. 1. Demikhov VP. Experimental transplantation of vital 20. Blumenstock DA, Kahn DR. Replantation and trans- organs. New York: Consultants Bureau; 1962. plantation of the canine lung. J Surg Res. 1961;1:40–7. 2. Vigneswaran W, Garrity E, Odell J. Lung transplanta- 21. Veith FJ, Richards K. Improved technic for canine tion: principles and practice. General topics. History lung transplantation. Ann Surg. 1970;171:553–8. of lung transplantation. Boca Raton: CRC Press; 22. Nelems JMB, Rebuck AS, Cooper JD, Goldberg M, 2015. Halloran PF, Vellend H. Human lung transplantation. 3. Carrel A, Guthrie CC. Anastomosis of blood vessels Chest. 1980;78:569–73. by the patching method and transplantation of kidney 23. Lima O, Cooper JD, Peters WJ, Ayabe H, Townsend (classical article reprinted from JAMA 1906;47:1648- E, Luk SC, Goldberg M. Effects of methylpredniso- 51). Yale J Biol Med. 2001;74:243–7. lone and azathioprine on bronchial healing following 4. Carrel A. The surgery of blood vessels, etc. Bull John lung autotransplantation. J Thorac Cardiovasc Surg. Hopkins Hosp. 1907;18:18–28. 1981;82:211–5. 5. Murray JE, Merril JP, Harrison JH. Kidney transplan- 24. Goldberg M, Lima O, Morgan E, Ayabe HA, Luk S, tation between seven pairs of identical twins. Ann Ferdman A, Peters WJ, Cooper JD. A comparison Surg. 1958;148:343–57. between cyclosporin A and methylprednisolone plus 6. Metras H. Note preliminare sur la greffe totale azathioprine on bronchial healing following canine du pumon chez le chien. Proc Acad Sci (Paris). lung autotransplantation. J Thorac Cardiovasc Surg. 1950;231:1176–8. 1983;85:821–6. 7. Staudacher V, Bellinazzo P, Pulin A. Primi rilievi 25. Stone RM, Ginsberg RJ, Colapinto RF, Pearson su tentativi di reimpianti autoplastici e di trapianti FG. Bronchial artery regeneration after radical hilar omoplastici dei lobi pulmonari. Chirurgia (Milano). stripping. Surg Forum. 1966;17:109–10. 1959;5:233–27. 26. Mills NL, Boyd AD, Gheranpong C, Spencer FC. The 8. Juvenelle AA, Citret C, Wiles CE, Stewart significance of bronchial circulation in lung transplan- JD. Pneumonectomy with replantation of the lung tation. J Thorac Cardiovasc Surg. 1970;60:866–74. in the dog for physiologic study. J Thorac Surg. 27. Pearson FG, Golberg M, Stone RM, Colapinto 1951;21:111–5. RF. Bronchial arterial circulation restored after reim- 9. Neptune WB, Weller R, Bailey CP. Experimental lung plantation of canine lung. Can J Surg. 1970;13:243–50. transplantation. J Thorac Surg. 1953;26:275–89. 28. Rabinovich JJ. Re-establishment of bronchial arter- 10. Hardin CA, Kittle CE. Experiences with transplanta- ies after experimental lung lobe autotransplantation. tion of the lung. Science. 1954;119:97–8. J Thorac Cardiovasc Surg. 1972;64:119–26. 11. Shumway SJ, Shumway NE. Thoracic transplan- 29. Siegelman SS, Hagstrom JWC, Koerner SR, Veith tation. Part I. Historical background. Blackwell FJ. Restoration of bronchial artery circulation after Science: Cambridge; 1995. canine lung allotransplantation. J Thorac Cardiovasc 12. Blumenstock DA, Collin JA, Thomas ED, Ferrebee Surg. 1977;73:792–5. JW. Homotransplants of the lung in dogs. Surgery. 30. Lima O, Goldberg M, Peters WJ, Ayabe H, Townsend 1962;51:541–5. E, Cooper JD. Bronchial omentopexy in canine 13. Hardy JD, Eraslan S, Dalton ML Jr, Alican F, Turner lung transplantation. J Thorac Cardiovasc Surg. MD. Re-implantation and homotransplantations of 1982;83:418–21. 14 A. M. D’Armini et al.

31. Reitz BA, Wallwork JL, Hunt SA, Pennock JL, 46. Schreinemakers HH, Weder W, Miyoshi S, Harper Billingham ME, Oyer PE, Stinson EB, Shumway BD, Shimokawa S, Egan TM, McKnight R, Cooper NE. Heart-lung transplantation: successful therapy JD. Direct revascularization of bronchial arteries for for patients with pulmonary vascular disease. N Engl lung transplantation: an anatomical study. Ann Thorac J Med. 1982;306:557–64. Surg. 1990;49:44–53. 32. Toronto Lung Transplant Group. Sequential bilateral 47. Couraud L, Baudet E, Martigne C, Roques X, Velly lung transplantation for Paraquat poisoning. J Thorac JF, Laborde N, Dubrez J, Clerc F, Dromer C, Vallieres Cardiovasc Surg. 1985;89:734–42. E. Bronchial revascularization in double-lung trans- 33. Toronto Lung Transplant Group. Unilateral lung plantation: a series of 8 patients. Bordeaux Lung and transplantation for pulmonary fibrosis. N Engl J Med. Heart-Lung Transplant Group. Ann Thorac Surg. 1986;314:1140–5. 1992;53:88–94. 34. Dark JH, Patterson GA, Al-Jilaihawi AN, Hsu H, Egan 48. Pettersson G, Nørgaard MA, Arendrup H, Brandenhof TM, Cooper JD. Experimental en bloc double-lung P, Helvind M, Joyce F, Stentoft P, Olesen PS, Thiis JJ, transplantation. Ann Thorac Surg. 1986;42(4):394–8. Efsen F, Mortensen SA, Svendsen UG. Direct bron- 35. Cooper JD, Pearson FG, Patterson GA, Todd TR, chial artery revascularization and en bloc double lung Ginsberg RJ, Goldberg M, DeMajo WA. Technique of transplantation—surgical techniques and early out- successful lung transplantation in humans. J Thorac come. J Heart Lung Transplant. 1997;16:320–33. Cardiovasc Surg. 1987;93(2):173–81. 49. Daly RC, Tadjkarimi S, Khaghani A, Banner NR, 36. Calhoon JH, Grover FL, Gibbons WJ, Bryan CL, Yacoub MH. Successful double-lung transplantation Levine SM, Bailey SR, Nichols L, Lum C, Trinkle with direct bronchial artery revascularization. Ann JK. Single lung transplantation. Alternative indi- Thorac Surg. 1993;56:885–92. cations and technique. J Thorac Cardiovasc Surg. 50. Nørgaard MA, Olsen PS, Svendsen UG, Pettersson 1991;101(5):816–24. G. Revascularization of the bronchial arteries in 37. Garfein ES, Ginsberg ME, Gorenstein L, McGregor lung transplantation: an overview. Ann Thorac Surg. CC, Schulman LL. Superiority of end-to-end ver- 1996;62:1215–21. sus telescoped bronchial anastomosis in single lung 51. Nørgaard MA, Efsen F, Arendrup H, Olsen PS, transplantation for pulmonary emphysema. J Thorac Svendsen UG, Pettersson G. Surgical and arterio- Cardiovasc Surg. 2001;121(1):149–54. graphic results of bronchial artery revascularization 38. Schröder C, Scholl F, Daon E, Goodwin A, Frist WH, in lung and heart lung transplantation. J Heart Lung Roberts JR, Christian KG, Ninan M, Milstone AP, Transplant. 1997;16:302–12. Loyd JE, Merrill WH, Pierson RN III. A modified 52. Pettersson GB, Yun JJ, Nørgaard MA. Bronchial bronchial anastomosis technique for lung transplanta- artery revascularization in lung transplantation: tech- tion. Ann Thorac Surg. 2003;75(6):1697–704. niques, experience, and outcomes. Curr Opin Organ 39. Egan TM, Kaiser LR, Cooper JD. Lung transplanta- Transplant. 2010;15:572–7. tion. Curr Probl Surg. 1989;26:673–751. 53. Reeb J, Cypel M. Ex vivo lung perfusion. Clin 40. Goldsmith MF. Mother to child: first living donor Transpl. 2016;30(3):183–94. lung transplant. JAMA. 1990;264:2724. 54. Carrel A, Lindbergh CA. The culture of whole organs. 41. American Thoracic Society, Medical Section of the Science. 1935;81:621–3. American Lung Association. Lung transplantation. 55. Jirsch DW, Fisk RL, Couves CM. Ex vivo evalua- Report of the ATS workshop on lung transplantation of stored lungs. Ann Thorac Surg. 1970;10(2): tion. American Thoracic Society, Medical Section of 163–8. the American Lung Association. Am Rev Respir Dis. 56. Steen S, Sjoberg T, Pierre L, Liao Q, Eriksson L, 1993;147:772–6. Algotsson L. Transplantation of lungs from non-heart 42. Egan TM, Murray S, Bustami RT, Shearon TH, beating donor. Lancet. 2001;357:825–9. McCullough KP, Edwards LB, Coke MA, Garrity ER, 57. Steen S, Liao Q, Wierup PN, Bolys R, Pierre L, Sweet SC, Heiney DA, Grover FL. Development of Sjöberg T. Transplantation of lungs from non-heart- the new lung allocation system in the United States. beating donors after functional assessment ex vivo. Am J Transplant. 2006;6:1212–27. Ann Thorac Surg. 2003;76(1):244–52. 43. Health Resources and Services Administration 58. Steen S, Ingemansson R, Eriksson L, Pierre L, (HRSA), Department of Health and Human Services Algotsson L, Wierup P, Liao Q, Eyjolfsson A, (HHS). Organ procurement and transplantation net- Gustafsson R, Sjöberg T. First human transplan- work. Final Rule. Fed Regist. 2013;78:40033–42. tation of a nonacceptable donor lung after recon- 44. Schreinemakers HHJ, De Leyn PRJ, Marcus M, ditioning ex vivo. Ann Thorac Surg. 2007;83(6): Wouters P, Moerman F, Flameng W, Lerut A, Cooper 2191–4. J. Role of bronchial arteries in lung function. Ann 59. Cypel M, Yeung JC, Hirayama S, Rubacha M, Fischer Thorac Surg. 1992;54:395–7. S, Anraku M, Sato M, Harwood S, Pierre A, Waddell 45. Daly RC, McGregor CG. Routine immediate direct TK, de Perrot M, Liu M, Keshavjee S. Technique for bronchial artery revascularization for single-lung prolonged normothermic ex vivo lung perfusion. J transplantation. Ann Thorac Surg. 1994;57:1446–52. Heart Lung Transplant. 2008;27(12):1319–25. 1 The History of Lung Transplantation 15

60. Love RB, Stringham JC, Chomiak PN, Warner T, D, Edwards LB, Stehlik J, Hertz M, Whitson BA, Pellett JR, Mentzer RM. Successful lung transplan- Yusen RD, Puri V, Hopkins P, Snell G, Keshavjee tation using a non-heart-beating donor [abstract]. J S, International Society for Heart and Lung Heart Lung Transplant. 1995;14:S88. Transplantation. International Society for Heart and 61. Snell GI, Levvey BJ, Oto T, McEgan R, Pilcher Lung Transplantation donation after Circulatory D, Davies A, Marasco S, Rosenfeldt F. Early lung Death Registry Report. J Heart Lung Transplant. transplantation success utilizing controlled dona- 2015;34(10):1278–82. tion after cardiac death donors. Am J Transplant. 64. Egan TM. Lung transplant from an uncontrolled 2008;8(6):1282–9. donation after circulatory determination of death 62. Reeb J, Keshavjee S, Cypel M. Expanding the lung donor: moving to other countries. Am J Transplant. donor pool: advancements and emerging path- 2016;16(4):1051–2. ways. Curr Opin Organ Transplant. 2015;20(5): 65. Egan TM, Requard JJ. Uncontrolled donation after 498–505. circulatory determination of death donors (uDCDDs) 63. Cypel M, Levvey B, Van Raemdonck D, Erasmus M, as a source of lungs for transplant. Am J Transplant. Dark J, Love R, Mason D, Glanville AR, Chambers 2015;15(8):2031–6. Single- and Bilateral Lung Transplantation: Indications, 2 Contraindications, Evaluation, and Requirements for Patients to Be Considered Eligible

Gerard J. Meachery and Paul A. Corris

Abbreviations ILD Interstitial lung disease IPAH Idiopathic pulmonary arterial BLT Bilateral lung transplant hypertension BMI Body mass index IPF Idiopathic pulmonary fibrosis CF Cystic fibrosis ISHLT International Society for Heart CHDAPAH Congenital heart disease-associated and Lung Transplantation pulmonary arterial hypertension LAD Lung assist device COPD Chronic obstructive pulmonary LAS Lung allocation score disease LLLT Living lobar lung transplantation CPB Cardiopulmonary bypass NSIP Non-specific interstitial CT Computed tomography pneumonitis CTEPH Chronic thromboembolic pulmo- NTM Non-tuberculous mycobacteria nary hypertension NYHA FC New York Heart Association DLCO Diffusing capacity for carbon Functional Class monoxide PAH Pulmonary arterial hypertension ECLS Extracorporeal lung support PH Pulmonary hypertension ECMO Extracorporeal membrane SLT Single-lung transplant oxygenation SSc Systemic sclerosis FEV1 Forced expiratory volume in one UIP Usual interstitial pneumonitis second UNOS United Network for Organ Sharing FVC Forced vital capacity US United States HLT Heart-lung transplant

G. J. Meachery (*) Department of Respiratory Medicine, Introduction Freeman Hospital, Newcastle Upon Tyne, UK Despite significant advances in pharmacological e-mail: [email protected] and remedial therapies, there remains a large pro- P. A. Corris portion of patients with end-stage lung disease who Department of Respiratory Medicine, Freeman require lung transplantation as a definitive method Hospital and Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK of treatment to enhance life expectancy and improve e-mail: [email protected] health-related quality of life. Multiple factors deter-