687CHAPTER 57 Pediatric Lung Transplantation Airway remodeling and eventually obstruction EMT Oxidative stress, proteases and ECM deposition Infiltration of inflammatory cells into lumen Fibroblast ac[.]
CHAPTER 57 Pediatric Lung Transplantation 687 Airway remodeling and eventually obstruction Oxidative stress, proteases and ECM deposition EMT Mucus Injury Bronchial epithelium Infiltration of inflammatory cells into lumen Damaged epithelium Cytokines Chemokines Growth factors Chronic inflammation Fibroblast activation Fibrocyte attraction A Allograft Survival Transplantation Graft Loss Time Period Pre-Tx Abs Ab depletion (??) IVIG/rituximab B Surgical Trauma Infection Inflammation Organ storage Improved Postsurgical Care • Fig 57.7 Injurious Alloimmunity HLA matching Ab depletion IVIG/rituximab Acute Rejection Supportive care Autoimmunity Ab depletion (??) IVIG/rituximab IL-17 directed Rx Chronic Rejection Failure No Rx Irreversible damage stimuli leading to airway remodeling through a sequence of events culminating in allograft failure (A) Pathophysiology by which injurious stimuli lead to airway remodeling (B) Known lung allograft events that can culminate in alllograft failure and potential treatment or prevention strategies Ab, Antibody; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition; IL-17, interleukin-17; IVIG, intravenous immunoglobulin; HLA, human leukocyte antigen; Pre-Tx, pretreatment; Rx, prescription 688 S E C T I O N V Pediatric Critical Care: Pulmonary cytokine profiles, and induction of specific T-cell subpopulations Studies validating its efficacy in treating CLAD have shown promise but have been limited owing to size, noncomparable adjuvant immunosuppression, and short follow-up.82 Nonetheless, ECP is recommended in most centers as rescue treatment in CLAD.83 Other treatments and therapies have been proposed but used with little success Fig 57.7 depicts a proposed schema of the sequence of events leading to allograft failure.84 The temporal sequence of initial inflammatory events following solid organ transplantation—such as surgical stress, viral infections, gastroesophageal reflux disease, and mismatched human leukocyte antigen—leads to inflammatory injury to the allograft These risk factors potentially play an important role in the acute rejection episode Further, presence of pretransplant antibodies to self-antigens could also lead to higher incidence of alloimmunity and allograft rejection Early inflammatory injury could potentiate tissue remodeling and exposure of cryptic self-antigens, leading to autoimmunity and potential development of CLAD Summary Lung transplantation is a well-established treatment for children who have end-stage lung disease resulting from many causes Improved surgical and organ preservation techniques have brought transplantation to a broader set of patients A deeper understanding of immunobiology and treatment for injury to the graft have led to slight improvements in longer-term survival Nonetheless, long-term survival rates remain significantly lower than for transplantation of other solid organs, limited by reduced availability of donor organs, impaired mucus clearance, recurrent stimulation of innate immune defenses, increased risk for infection, and, most important, CLAD In order for lung transplantation to realize its full potential, better understanding of and treatment for acute and chronic rejection and CLAD must occur Thus, it is essential that providers of pediatric critical care and pulmonary medicine become more familiar with the nuances of care for children undergoing lung transplantation Key References Goldfarb S, Hayes, D, Levvey B, et al The international thoracic organ transplant registry of the International Society for Heart and Lung Transplantation: twenty-first pediatric lung and heart—lung transplantation report—2018; Focus Theme: Multiorgan Transplantation J Heart Lung Transplant 2018;37:1196-1206 Lee J, Christie J Primary graft dysfunction Proc Am Thorac Soc 2009;6: 39-46 Spray T, Mallory G, Canter C, Huddleston C Pediatric lung transplantation J Thorac Cardiovasc Surg 1994;107:990-1000 Starnes V, Marshall S, Lewiston N, Theodore J, Stinson E, Shumway N Heart-lung transplantation in infants, children, and adolescents J Pediatr Surg 1991;26:434-438 Van Herck A, Verleden SE, Sacreas A, et al Validation of a post-transplant chronic lung allograft dysfunction classification system J Heart Lung Transplant 2019;38(2):166-173 Venkateswaran RV, Patchell VB, Wilson IC, et al Early donor management increases the retrieval rate of lungs for transplantation Ann Thorac Surg 2008;85:278-286 The full reference list for this chapter is available at ExpertConsult.com e1 References Faro A, Mallory G, Visner F, et al American Society of Transplantation executive summary on pediatric lung transplantation Am J Transplant 2007;7:285-292 Goldfarb S, Hayes, D, Levvey B, et al The international thoracic organ transplant registry of the International Society for Heart and Lung Transplantation: twenty-first pediatric lung and heart—lung transplantation report—2018; Focus Theme: Multiorgan Transplantation J Heart Lung Transplant 2018;37:1196-1206 Yusen RD, Edwards LB, Kucheryavaya AY, et al The Registry of the International Society for Heart and Lung Transplantation: thirtysecond official adult lung and heart-lung transplantation report—2015; focus theme: early graft failure J Heart Lung Transplant 2015; 34(10):1264-1277 Turner DA, Cheifetz IM, Rehder KJ, et al Active rehabilitation and physical therapy during extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach Crit Care Med 2011;39(12):2593-2598 Schmidt F, Sasse M, Boehne M, et al Concept of “awake venovenous extracorporeal membrane oxygenation” in pediatric patients awaiting lung transplantation Pediatr Transplant 2013;17(3):224-230 Hayes D Jr, Kukreja J, Tobias JD, et al Ambulatory venovenous extracorporeal respiratory support as a bridge for cystic fibrosis patients to emergent lung transplantation J Cyst Fibros 2012;11(1):40-45 Puri V, Epstein D, Raithel SC, et al Extracorporeal membrane oxygenation in pediatric lung transplantation J Thorac Cardiovasc Surg 2010;140:427-432 Turner DA, Cheifetz IM, Rehder KJ, et al Active rehabilitation and physical therapy during extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach Crit Care Med 2011;39(12):2593-2598 Schmidt F, Sasse M, Boehne M, et al Concept of “awake venovenous extracorporeal membrane oxygenation” in pediatric patients awaiting lung transplantation Pediatr Transplant 2013;17(3):224-230 10 de Perrot M, Granton JT, McRae K, et al Impact of extracorporeal life support on outcome in patients with idiopathic pulmonary arterial hypertension awaiting lung transplantation J Heart Lung Transplant 2011;30:997-1002 11 Maeda K, Ryan K, Conrad CK, Yarlagadda VV An alternative cannulation approach for venovenous extracorporeal membrane oxygenation in children for long-term ambulatory support J Thorac Cardiovasc Surg 2018;156:e13-e14 12 Gazit AZ, Sweet SC, Grady RM, Huddleston CB First experience with a paracorporeal artificial lung in a small child with pulmonary hypertension J Thorac Cardiovasc Surg 2011;141(6):e48-e50 13 Grossman RF, Frost A, Zamel N, et al Results of single-lung transplantation for bilateral pulmonary fibrosis: the Toronto Lung Transplant Group N Engl J Med 1990;322(11):727-733 14 Goldfarb S, Levvey S, Cherikh W, et al Registry of the International Society for Heart and Lung Transplantation: Twentieth Pediatric Lung and Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time J Heart Lung Transplant 2017 36(10):1070-1079 15 Verleden GM, Raghu G, Meyer KC, et al A new classification system for chronic lung allograft dysfunction J Heart Lung Transplant 2014;33(2):127-133 16 Van Herck A, Verleden SE, Sacreas A, et al Validation of a posttransplant chronic lung allograft dysfunction classification system J Heart Lung Transplant 2019;38(2):166-173 17 DerHovanessian A, Wallace D, Lynch J, et al Chronic lung allograft dysfunction: evolving concepts and therapies Semin Respir Crit Care Med 2018;39(2):155-171 18 Bittle GJ, Sanchez PG, Kon ZN, et al The use of lung donors older than 55 years: a review of the United Network of Organ Sharing database J Heart Lung Transplant 2013;32:760-768 19 Venkateswaran RV, Patchell VB, Wilson IC, et al Early donor management increases the retrieval rate of lungs for transplantation Ann Thorac Surg 2008;85:278-286 20 Keshavjee SH, Yamazaki F, Yokomise H, et al The role of dextran 40 and potassium in extended hypothermic lung preservation for transplantation J Thorac Cardiovasc Surg 1992;103:314-325 21 De Perrot M, Fischer S, Liu M, et al Prostaglandin E1 protects lung transplants from ischemia-reperfusion injury: A shift from pro- to anti-inflammatory cytokines Transplantation 2001;72:1505-1512 22 Van De Wauwer C, Neyrinck AP, Geudens N, et al Retrograde flush following warm ischemia in the non-heart-beating donor results in superior graft performance at reperfusion J Surg Res 2009;154:118-125 23 Van Raemdonck DE, Jannis NC, Rega FR, et al Extended preservation of ischemic pulmonary graft by postmortem alveolar expansion Ann Thorac Surg 1997;64:801-808 24 Cypel M, Yeung JC, Hirayama S, et al Technique for prolonged normothermic ex vivo lung perfusion J Heart Lung Transplant 2008;27:1319-1325 25 Cypel M, Liu M, Rubacha M, et al Functional repair of human donor lungs by IL-10 gene therapy Sci Transl Med 2009;1:4ra9 26 Yeung JC, Wagnetz D, Cypel M, et al Ex vivo adenoviral vector gene delivery results in decreased vector-associated inflammation pre- and post-lung transplantation in the pig Mol Ther 2012;20:1204-1211 27 Starnes V, Marshall S, Lewiston N, Theodore J, Stinson E, Shumway N Heart-lung transplantation in infants, children, and adolescents J Ped Surgery 1991;26:434-438 28 Spray T, Mallory G, Canter C, Huddleston C Pediatric lung transplantation J Thoracic Cardiovascular Surgery 1994;107:990-1000 29 Bolman R, Shumway S, Estrin J, et al Lung and heart-lung transplantation Evolution and new applications Ann Surg 1991;214(4):456-468 30 Arcasoy SM, Kotloff RM Lung transplantation N Engl J Med 1999;340:1081-1091 31 Pasque M, Trulock E, Cooper J, et al Single lung transplantation for pulmonary hypertension Single institution experience in 54 patients Circulation 1995;92(8):2252-2258 32 Schaellibaum G, Lammers A, Faro A, et al Bilateral lung transplantation for pediatric idiopathic pulmonary arterial hypertension: a multi-center experience Pediatr Pulmonol 2011;46:1121-1127 33 Starnes VA, Woo MS, MacLaughlin EF, et al Comparison of outcomes between living donor and cadaveric lung transplantation in children Ann Thorac Surg 1999;68(6):2279-2283 34 Woo MS, MacLaughlin EF, Horn MV, et al Living donor lobar lung transplantation: the pediatric experience Pediatr Transplant 1998; 2(3):185-190 35 Goldfarb S, Levvey B, Edwards L, et al The Registry of the International Society for Heart and Lung Transplantation: Nineteenth Pediatric Lung and Heart–Lung Transplantation Report—2016; Focus Theme: Primary Diagnostic Indications for Transplant J Heart Lung Transplant 2016;35(10):1196-1205 36 Hayes D Jr., McConnell PI, Tobias JD, et al Survival in children on extracorporeal membrane oxygenation at the time of lung transplantation Pediatr Transplant 2015;19:87- 93 37 Thakuria L, Davey R, Romano R, et al Mechanical ventilation after lung transplantation J Crit Care 2016;31:110-118 38 Currey J, Pilcher DV, Davies A, et al Implementation of a management guideline aimed at minimizing the severity of primary graft dysfunction after lung transplant J Thorac Cardiovasc Surg 2010;139(1):154-161 39 Pilcher DV, Scheinkestel CD, Snell GI, et al High central venous pressure is associated with prolonged mechanical ventilation and increased mortality after lung transplantation J Thorac Cardiovasc Surg 2005;129(4): 912-918 40 Lasocki S, Castier Y, Geffroy A, et al Early cardiac tamponade due to tension pneumopericardium after bilateral lung transplantation J Heart Lung Transplant 2007;26(10):1069-1071 41 Lee J, Christie J Primary graft dysfunction Proc Am Thorac Soc 2009;6:39-46 42 Christie J, Carby M, Bag R, et al Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition A consensus statement of the International Society for Heart and Lung Transplantation J Heart Lung Transplant 2005;24(10):1454-1459 e2 43 Diamond JM, Lee JC, Kawut SM, et al Lung Transplant Outcomes Group Clinical risk factors for primary graft dysfunction after lung transplantation Am J Respir Crit Care Med 2013;187(5):527-534 44 Moreno I, Vicente R, Mir A, et al Effects of inhaled nitric oxide on primary graft dysfunction in lung transplantation Transplant Proc 2009;41(6):2210-2212 45 Porteous MK, Diamond JM, Christie JD Primary graft dysfunction: lessons learned about the first 72 h after lung transplantation Curr Opin Organ Transplant 2015;20:506-514 46 Bellier J, Lhommet P, Bonnette P, et al Extracorporeal membrane oxygenation for grade primary graft dysfunction after lung transplantation: Long-term outcomes ClinTransplant 2019;33(3):e13480 47 Garfein ES, Ginsberg ME, Gorenstein L, et al Superiority of endto-end vs telescoped bronchial anastomosis in single lung transplantation for pulmonary emphysema J Thorac Cardiovasc Surg 2001;121: 149-154 48 Anile M, Diso D, Rendina, E, et al Airway anastomosis for lung transplantation J Thorac Dis 2016;8(suppl 2):S197-S203 49 Seeliger B, Drick N, Avsar M, et al Risk factors and outcomes of vocal cord paralysis after lung transplantation - a retrospective cohort study Transpl Int 2019;32(6):626-634 50 Feltracco P, Serra E, Barbieri S, et al Noninvasive ventilation in postoperative care of lung transplant recipients Transplant Proc 2009;41(4):1339-1344 51 Hilbert G, Gruson D, Vargas F, et al Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever and acute respiratory failure N Engl J Med 2001;344(7):481-487 52 Stéphan F, Barrucand B, Petit P, et al High-flow nasal oxygen vs noninvasive positive airway pressure in hypoxemic patients after cardiothoracic surgery: a randomized clinical trial JAMA 2015; 313(23):2331-2339 53 Furuya Y, Jayarajan S, Taghavi S, et al The impact of alemtuzumab and basiliximab induction on patient survival and time to bronchiolitis obliterans syndrome in double lung transplantation recipients Am J Transplant 2016;16:2334-2341 54 Sweet S Induction therapy in lung transplantation Transpl Int 2013;26:696-703 55 Martinu T, Chen D, Palmer S Acute rejection and humoral sensitization in lung transplant recipients Proc Am Thorac Soc 2009;6:54-65 56 Martinu T, Howell DN, Palmer SM Acute cellular rejection and humoral sensitization in lung transplant recipients Semin Respir Crit Care Med 2010;31:179-188 57 Snyder LD, Palmer SM Immune mechanisms of lung allograft rejection Semin Respir Crit Care Med 2006;27(5):534-543 58 Hsiaio H, Scozzi D, Gauthier J, et al Mechanisms of graft rejection after lung transplantation Curr Opin Organ Transplant 2017;22:29-35 59 Hopkins P, Aboyoun C, Chhajed P, et al Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients J Heart Lung Transplant 2002;21:1062-1067 60 Stewart S, Fishbein MC, Snell GI, et al Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection J Heart Lung Transplant 2007;26:1229-1242 61 Palmer SM, Davis RD, Hadjiliadis D, et al Development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome Transplantation 2002;74:799-804 62 Girnita AL, Duquesnoy R, Yousem SA, et al HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction Am J Transplant 2005;5:131-138 63 Hachem RR, Yusen RD, Meyers BF, et al Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation J Heart Lung Transplant 2010;29:973-980 64 Takemoto SK, Zeevi A, Feng S, et al National conference to assess antibody-mediated rejection in solid organ transplantation Am J Transplant 2004;4:1033-1041 65 Berry G, Burke M, Andersen C, et al Pathology of pulmonary antibody-mediated rejection: 2012 update from the Pathology Council of the ISHLT J Heart Lung Transplant 2013;32:14-21 66 Levine DJ, Glanville AR, Aboyoun C, et al Antibody-mediated rejection of the lung: A consensus report of the International Society of Heart and Lung Transplantation J Heart Lung Transplant 2016; 35:397-406 67 Martinu T, Chen DF, Palmer SM Acute rejection and humoral sensitization in lung transplant recipients Proc Am Thorac Soc 2009;6:54-65 68 Everly MJ A summary of bortezomib use in transplantation across 29 centers Clin Transpl 2009;323-337 69 Stegall MD, Gloor JM Deciphering antibody-mediated rejection: new insights into mechanisms and treatment Curr Opin Organ Transplant 2010;15(1):8-10 70 Vos R, Verleden S, Verleden F Chronic lung allograft dysfunction: evolving practice Lung Transplantation 2015;20:483-491 71 Pakhale S, Hadjiliadis D, Howell D, et al Upper lobe fibrosis: A novel manifestation of chronic allograft dysfunction in lung transplantation J Heart Lung Transplant 2005;24:1260-1368 72 Van Herck A, Verleden S, Sacreas A, et al Validation of a posttransplant chronic lung allograft dysfunction classification system J Heart and Lung Transplant 2019;38:166-173 73 Welsh CH, Wang TS, Lyu DM, et al An international ISHLT/ATS/ ERS clinical practice guideline: summary for clinicians Bronchiolitis obliterans syndrome complicating lung transplantation revision Ann Am Thorac Soc 2015;12:118-119 74 Osho A, Castleberry A, Snyder L, et al Differential outcomes with early and late repeat transplantation in the era of the lung allocation score Ann Thorac Surg 2014;98:1914-1921 75 Hall D, Belli E, Gregg J, et al Two decades of lung retransplantation: a single-center experience Ann Thorac Surg 2017;103: 1076-1083 76 Sivakumar P, Ntolios P, Jenkins G, et al Into the matrix: Targeting fibroblasts in pulmonary fibrosis Curr Opin Pulm Med 2012;18: 462-469 77 Vos R, Verleden S, Ruttens D, et al Pirfenidone: a potential new therapy for restrictive allograft syndrome? Am J Transplant 2013;13: 3035-3040 78 Verleden S, Ruttens D, Vandermeulen E, et al Restrictive chronic lung allograft dysfunction: where are we now? J Heart Lung Transplant 2015;34:625-630 79 Tepede A, Yogaratnam D Nintedanib for Idiopathic Pulmonary Fibrosis J Pharm Pract 2019;32:199-206 80 Rook A, Cohen J Therapeutic applications of photopheresis Derm Clin 1993;11:339-347 81 Andreu G, Achkar A, Couetil J, et al Extracorporeal photochemotherapy treatment for acute lung rejection episode J Heart Lung Transplant 1995;14:793-796 82 Benden C, Speich R, Hofbauer G, et al Extracorporeal photopheresis after lung transplantation: A 10-year single center experience Transplantation 2008;86:1625-1627 83 Ratcliffe N, Dunbar NM, Adamski J, et al National Institutes of Health State of the Science Symposium in Therapeutic Apheresis: scientific opportunities in extracorporeal photopheresis American Society for Apheresis Transfus Med Rev 2015;29:62-70 84 Angaswamy N, Tiriveedhi V, Sarma NJ, et al Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection Hum Immunol 2013;74:1478-1485 e3 Abstract: Lung transplantation for infants and children is an accepted but rarely exercised option for treatment of end-stage lung disease, with outcomes equivalent to those for adults However, widespread misconceptions regarding pediatric outcomes often forestall timely and appropriate referral to specialty centers The treatment is complex, but lung transplantation provides substantial survival benefit and markedly improved quality of life for children and their families This chapter presents updated information for pediatricians to use when counseling families with children confronted by progressive end-stage pulmonary or cardiovascular disease We provide general guidelines to consider for referral and discuss allocation of organs in children, information regarding standard treatment protocols, and survival outcomes Key words: Pediatric lung transplantation, candidate selection, immunosuppression, survival, bronchiolitis obliterans, CLAD, RAS ... retrieval rate of lungs for transplantation Ann Thorac Surg 2008;85:278-286 The full reference list for this chapter is available at ExpertConsult.com e1 References Faro A, Mallory G, Visner F, et al... Kucheryavaya AY, et al The Registry of the International Society for Heart and Lung Transplantation: thirtysecond official adult lung and heart-lung transplantation report—2015; focus theme: early... Granton JT, McRae K, et al Impact of extracorporeal life support on outcome in patients with idiopathic pulmonary arterial hypertension awaiting lung transplantation J Heart Lung Transplant 2011;30:997-1002