682 SECTION V Pediatric Critical Care Pulmonary for pediatric candidates have not been established However, it is generally accepted that the ideal lung donor for children should be a nonsmoker of the[.]
682 S E C T I O N V Pediatric Critical Care: Pulmonary Freedom from bronchiolitis obliterans syndrome (%) 100 75 P = 0089 50 25 1994–2003 (N = 314) 2004–6/2016 (N = 528) 0 Years • Fig 57.4 Pediatric lung transplants freedom from bronchiolitis obliterans syndrome (transplantation performed January 1994 to June 2016) • BOX 57.2 Currently Accepted Characteristics of the Ideal Donor for Pediatric Recipients Age ,55 y ABO compatibility No HLA antibody sensitization by recipient Clear chest radiograph Pao2 300 on Fio2 1.0, PEEP 5 cm H2O Tobacco history ,20 pack-years Absence of chest trauma No evidence of aspiration/sepsis No prior cardiopulmonary surgery Sputum Gram stain—absence of organisms and PMNs Absence of purulent secretions at bronchoscopy Fio2, Fraction of inspired oxygen; HLA, human leukocyte antigen; Pao2, partial pressure of arterial oxygen; PEEP, positive end-expiratory pressure; PMN, polymorphonuclear neutrophils for pediatric candidates have not been established However, it is generally accepted that the ideal lung donor for children should be a nonsmoker of the same size (chest dimension measured from the diaphragm to the apex of the lung) and blood type or ABO compatible Other than these basic criteria, the evaluation is relatively subjective and occurs at the time of retrieval The general tenets followed include that the donor should have no significant history of lung disease, including asthma There should be no pulmonary trauma or infections, gas exchange should not be impaired, and ischemic time should be minimal Pediatric lung transplant centers may apply more stringent criteria if the candidate in question is reasonably stable Donor offers from younger donors may be more desirable in some cases Depending on the need of the candidate, nonideal donors, also called extended or marginal donors, may be accepted There is limited data to either support or prohibit the use of lungs from a nonideal donor There is no evidence that a marginal donor will have any effect on either immediate or long-term morbidity or mortality except in egregious cases of the diagnosis of bronchopneumonia, the presence of purulent lower airway disease in the donor, or injury from contusions It is shown that lungs obtained from donors older than 65 years who have a significant smoking history are at risk for developing malignancy in the setting of immunosuppression As well, lungs from older donors have worse long-term graft survival.18 Many factors stemming from donor cause of death and subsequent donor maintenance in the ICU can contribute to donor lung injury The most common causes include ventilator-induced lung injury, atelectasis, oxygen toxicity, and volume overload In addition, after brain death, a systemic inflammatory response known as a cytokine storm occurs This predisposes to the development of lung injury that is similar to acute respiratory distress syndrome, (ARDS) A different type of cytokine storm that occurs following brain death is a catecholamine storm In an attempt to protect cerebral perfusion during brain death, the body will release a large amount of catecholamines This surge of catecholamines causes significant systemic hypertension, which results in elevated left-sided heart pressures and consequent interstitial edema and can sometimes cause alveolar hemorrhage, resulting in neurogenic pulmonary edema This generally precludes the use of the lungs for transplantation because of poor oxygenation However, neurogenic pulmonary edema is a leaky capillary syndrome that is fully recoverable This is one area in which removal of the lung from the inflammatory milieu of the brain-dead donor and a period of time for recovery and removal of extravascular water with ex vivo lung perfusion (EVLP) has had a significant impact on donor lung utilization The process for donor lung preservation begins at the time of declaration of death and extends until the lungs are reperfused in the recipient Prior to retrieval, fluids are managed to maintain euvolemia and barotrauma must be avoided A 1-g bolus of methylprednisolone is given to the donor to mitigate brain death– induced systemic inflammation.19 At the time of retrieval, the lungs are prepared for transport, flushed vigorously with a preservation solution, and inflated with oxygen An extracellular-type flush preservation solution with low potassium, coupled with glucose and dextran, has been established as best practice for prolonged cold preservation.20 Prostaglandin E1 (PGE1) is a vasodilator given before the dextran flush to reduce pulmonary vascular resistance and achieve a more complete flush PGE1 also has antiinflammatory CHAPTER 57 Pediatric Lung Transplantation properties useful for lung preservation and prevention of reperfusion injury.21 A retrograde flush is subsequently performed with the same solution, again, to improve the homogeneity of the flush.22 The lungs are inflated with 50% oxygen before their removal from the body in order to maintain the alveolar structure and to provide oxygen for metabolism.23 A novel strategy of perioperative lung preservation is being developed by the Toronto Lung Transplant Group Using their technique, termed ex vivo lung perfusion (EVLP), lungs are continuously perfused anterograde with an acellular perfusate and ventilated with room air with an ICU ventilator at normothermia.24 A hypoxic air mix is bubbled into the perfusate to deoxygenate and add carbon dioxide (CO2) to the perfusate This method, performed by a separate surgical team, allows for at least 12 hours of donor lung preservation EVLP allows the team to further evaluate the donor lungs as to their suitability for transplantation More important, the lungs can be treated actively to improve their performance.25 Marginal lungs can be resuscitated and rehabilitated using EVLP, expanding the donor pool.26 Surgical Approach Bilateral sequential lung transplantation is the most frequently performed lung transplantation procedure in children and is performed most often via median sternotomy The main stem bronchi and left and right pulmonary arteries are connected via endto-end anastomoses Two pulmonary veins with intact atrial connections are harvested from each donor lung Each left atrial patch is sewn onto the recipient heart This surgical approach minimizes cardiopulmonary bypass time, which reduces related complications.27–29 Though combined heart-lung transplantation had initially been a favored surgical approach, improved surgical techniques as well as the profound scarcity of donor organs have led to a dramatic decrease in the frequency of heart-lung transplantation Moreover, right-sided heart failure associated with pulmonary hypertension resolves following lung transplantation, which has obviated the need for heart and lung transplantation for primary pulmonary hypertension except in instances of severe, irreversible right heart failure.30,31 There is no difference in survival between patients who undergo bilateral sequential lung transplantation compared with those who undergo heart-lung transplantation.32 Lung transplantation alone maximizes the distribution of organs from a single donor, benefiting more children In the 1990s, living donor lobar lung transplantation was developed as a strategy for transplantation in order to decrease waiting time of severely ill children awaiting lung transplantation, but with the adoption of a new lung allocation score in 2005 and improved peritransplant strategies, wait list deaths have decreased.33 The relative efficacy of the new lung allocation scoring system, combined with the technical and ethical challenges associated with living lobar transplantation, have prevented wider adoption of the procedure in the United States.34 Presurgical Management in the Intensive Care Unit Compared with the early era of lung transplantation, the number of patients receiving a transplant from the ICU and with mechanical respiratory support has increased recently Thus, the incidence of bridging severe respiratory failure to lung transplant 683 with ambulatory VV ECMO and mechanical ventilation is increasing The risk of dying within year of transplantation increases by 58% if the patient was bridged to transplant in the intensive care unit (ICU) with mechanical ventilation (MV) support before lung transplantation.35 Intubated patients who require heavy sedation and ventilation with high airway pressures are especially prone to ventilator-induced injury and ICU-related complications, including extrapulmonary organ failure ICU-related complications—such as pressure ulcers, vascular complications, nosocomial infections, delirium, critical illness polyneuropathy/ myopathy, and airway colonization—will increase wait list mortality and mortality after transplant Candidates for lung transplant on MV support may have uncertain neurologic status Thus, an approach with “awake” ventilation, even if supported with VV ECMO, is often pursued to obtain better short-term outcomes There have been substantial improvements in extracorporeal life support (ECLS) technology and many centers are increasingly using these devices Bridge-to-recovery and bridge-to-transplant are the two basic indications for ECMO support While the adult experience is quickly expanding, the pediatric literature is limited A retrospective evaluation of the United Network for Organ Sharing database of pediatric transplantations between 2000 and 2013 in the United States determined that a small percentage (2.9%) of patients were bridged to transplant with ECMO and there was no statistically significant increase in hazard for death.36 Major advances in ECLS included use of heparin-coated circuits, development of polymethylpentene oxygenator membranes, introduction of centrifugal pumps, dual-lumen cannulas (important for small adults and the pediatric population), and miniaturized systems For these reasons, VV ECMO as a bridge to transplant is considered carefully for a small percentage of critically ill children awaiting lung transplantation Postsurgical Management Immediate postoperative care is focused on respiratory and hemodynamic management In the perioperative period, pulmonary care emphasizes reestablishment of functional residual capacity Mechanical ventilation is generally necessary for less than 48 hours but may be prolonged in the event of primary graft dysfunction There is a wide variation in MV strategies among lung transplant centers In general, lung protective approaches using low tidal volumes based on recipient’s characteristics are preferred However, in a retrospective study on patients receiving a transplant between 2010 and 2013 among three transplant centers, low tidal volume ventilation was not shown to have an effect on length of ICU stay, forced expiratory volume (FEV1) at months postsurgery, or survival to months Conversely, poor outcomes have been associated with injudicious use of higher-pressure ventilation strategies.37 To minimize hyperoxic-related injury to the lungs, the fraction of inspired oxygen is maintained at less than 60% while maintaining systemic arterial saturation at 94% to 95% Ventilator strategy uses to mL/kg tidal volumes and an inspiratory plateau pressure of less than 30 cm H2O Sufficient positive end expiratory pressure is used to fully recruit and maintain the functional residual capacity of the newly transplanted lungs Once the patient is extubated, aggressive tracheobronchial toilet, chest physiotherapy, and bronchoalveolar lavage can mobilize secretions to ensure patency of the airways Hemodynamic status must be closely monitored though data on hemodynamic management are limited Vascular permeability and myocardial function may be adversely affected by cardiopulmonary bypass, necessitating inotropic support in the perioperative 684 S E C T I O N V Pediatric Critical Care: Pulmonary period Usually, restrictive fluid support (0.9–1.0 maintenance) is encouraged Central venous pressure monitoring is beneficial in order to optimize cardiac output.38 Central venous pressure alone may be unreliable to guide volume status Hemodynamic instability may be exacerbated by diminished intravascular volume Early recognition of compromised renal function is essential, as the prescription of all medications excreted and metabolized by the kidneys will need to be promptly altered Additionally, clinical and ultrasound observations may be helpful The most common causes of hypotension in the immediate posttransplantation period include hypovolemia from overly aggressive diuresis, systemic inflammatory response syndrome from surgical insult causing low systemic vascular resistance, medication-induced hypotension (including sedatives/analgesics), lung hyperinflation, hemorrhage, tamponade, or heart failure.39,40 Management should be causally determined, generally requiring a combination of fluid volume management, transfusion of blood products, administration of vasopressors or inotropes, correction of bleeding diatheses, chest tube drainage, and, when indicated, surgical revision Recipients may experience early severe graft dysfunction as a result of lung injury incurred during or prior to organ harvest The occurrence of primary graft dysfunction (PGD) is between 10% and 35% of all patients The clinical presentation of PGD is entirely consistent with ARDS as manifested by elevated alveolar-arteriolar gradient, compromised pulmonary compliance, poor ventilation and perfusion matching, and impaired diffusion.41 PGD refers to acute respiratory failure defined by reduced oxygenation index and pulmonary infiltrates within 72 hours of lung transplantation (Table 57.2).42 In most patients, a mild and transient course is observed, but 10% to 20% of patients will be affected by a severe form (partial pressure of arterial oxygen/fraction of inspired oxygen [Pao2/Fio2] ,200) Secondary causes of hypoxemia—such as volume overload, pneumonia, acute rejection, atelectasis, or pulmonary venous outflow obstruction— should be excluded Severe PGD is associated with high hospital mortality rates of 30% to 40%, prolonged ICU stay, and impaired long-term graft function and survival It is the leading cause of mortality in the perioperative period In a multicenter study from 10 US centers, increased oxygen fraction levels at the time of graft reperfusion was associated with increased risk of subsequent PGD Severe PGD is associated with donors with any smoking history, PAH, the use of cardiopulmonary bypass, large-volume blood product transfusion, elevated pulmonary arterial pressures, or obesity.43 Improved surgical techniques and organ perfusate have diminished the severity of early graft dysfunction over the last decade TABLE Grading of Primary Graft Dysfunction 57.2 Grade Po2/Fio2 Radiographic Changes Grade 300 Absent Grade 300 Present Grade 200–300 Present Grade ,200 Present Fio2, Fraction of inspired oxygen; Po2, partial pressure of oxygen Modified from 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 Treatment of PGD is primarily supportive Most grafts will recover under careful ventilator management, diuretics, and pressor support as well as high-dose corticosteroid pulses Inhaled nitric oxide (iNO) has been shown to improve oxygenation in the presence of acute graft dysfunction, likely as a result of enhanced ventilation and perfusion matching A few observational trials suggest that use of iNO in patients with PGD may result in a better outcome Despite these limited data, iNO has been used as salvage therapy for severe allograft dysfunction following transplantation It may be useful in patients with refractory hypoxemia posttransplantation.44,45 ECMO has been successfully employed as a therapeutic modality.46 The postoperative course can be complicated by technical problems associated with the surgery At many centers, the patency of the airway anastomoses is routinely assessed within 24 hours by direct visualization with flexible bronchoscopy While the vascular anastomoses are more difficult to assess, arterial anastomoses are generally amenable to inspection with nuclear medicine studies In order to assess the venous anastomoses, transesophageal echocardiography may be necessary.47,48 Vocal cord paresis or diaphragmatic paresis can complicate virtually any major thoracic surgery, both of which derive from surgical injuries to the respective nerve Vocal cord paralysis or paresis results from injury to the recurrent laryngeal nerve, and phrenic nerve injury leads to diaphragmatic paralysis or paresis However, the clinical symptoms entailed by these issues generally are not apparent until after extubation The likelihood of phrenic nerve injury is increased in patients who have had prior thoracic surgery Most of these injuries resolve within several weeks of surgery, but serious consideration should be given to early diaphragmatic plication, as the risk of infection in the lung affected by the paretic hemidiaphragm is quite high.49 Vocal cord function may be temporarily compromised following removal of an endotracheal tube even in the absence of true injury Thus, definitive evaluation for it should be deferred to at least 72 hours after extubation In cases of respiratory failure after extubation, noninvasive ventilation may be an option to prevent reintubation.50 In immunosuppressed patients with acute respiratory failure, early initiation of noninvasive ventilation was associated with significant reductions in reintubation and an improved likelihood of survival to hospital discharge.51 For patients with profound hypoxemia, high-flow oxygen through a nasal cannula is an increasingly applied option.52 Immunosuppression The long-term success of lung transplantation is achieved with the use of immunosuppressive drugs that inhibit rejection of the lung allograft Immunosuppression strategies in lung transplantation generally consist of a triple-drug maintenance regimen composed of a calcineurin inhibitor, T-cell antiproliferative, and corticosteroids In the United States, this regimen is most often tacrolimus, mycophenolate mofetil/mycophenolic acid, and prednisone Approximately 60% of pediatric lung transplant centers use an induction regimen in the perioperative time period, though data not support the impression that induction confers either a survival benefit or reduction in the incidence of CLAD.53,54 Immunobiology Acute cellular rejection (ACR) of the transplanted lungs occurs in almost one-third of children within the first year of lung transplantation.2 Alloreactivity toward the graft is likely augmented by CHAPTER 57 Pediatric Lung Transplantation 685 local innate immune activation in various situations, such as preexisting inflammatory processes in the donor, tissue injury related to ischemia and reperfusion injury at the time of implantation, and posttransplantation infections As well, the airways are continuously exposed to the environment via inhalational toxins, pathogens, allergens, and irritating organic and inorganic particles, all of which stimulate the protective response of the innate immune system Episodes of ACR entail activation of the innate and adaptive immune responses, resulting in recruitment of alloreactive CD41 and CD81 T lymphocytes to the lung allograft, which magnify further recruitment of neutrophils, eosinophils, B lymphocytes, macrophages, and natural killer (NK) cells, causing lung injury.55,56 On the other hand, tolerance can be facilitated by regulatory Foxp31 CD41 T cells, central memory CD81 T cells, and NK cells.57,58 Rejection The clinical manifestations of ACR include fever, dyspnea, and hypoxia Chest radiograph findings are relatively nonspecific but often include perihilar infiltrates and effusions Airflow obstruction may be detected with spirometry The patient must be evaluated for both infection and rejection when these signs are detected This requires bronchoscopy to obtain bronchoalveolar lavage samples and transbronchial biopsies for histologic evidence and grading.59 At least five pieces of alveolated tissue are required for the highest level of confidence to determine the presence and grade of severity of ACR, if present Since ACR occurs in the majority of patients in the first year following lung transplantation and clinical signs of graft dysfunction are often not present, surveillance bronchoscopies are performed on a predetermined schedule in the first year posttransplantation to monitor the lung allograft for ACR The pathologist examines the transbronchial biopsy specimens for the presence ACR, lymphocytic bronchiolitis, and for evidence of chronic rejection The A grade designation describes ACR, referring solely to the extent and distribution of the mononuclear cells that form as perivascular cuffs, and includes evaluation for extension of the process beyond the vascular adventitia into adjacent alveolar septae.60 The B designation applies to the presence and severity grade of lymphocytic inflammation surrounding small airways The grade reflects the intensity of the inflammatory infiltrates surrounding bronchioles The C designation applies to whether fibrotic changes consistent with either obliterative bronchiolitis (luminal obliteration of the small airways with fibrosis) or RAS (interstitial fibrosis) is present (Fig 57.5) Of note, transbronchial biopsies are miniscule in size, and bronchioles often are not present for histologic examination Thus airway disease itself may not be reportable As well, technical issues regarding tissue preservation can be induced by crush artifact from the forceps Because of this, an “ungradable” category in lymphocytic bronchiolitis is designated for biopsies limited by those and other sampling problems Histologic evaluation of the specimens leads to the assignment of a grade: A0 indicates the absence of rejection and grade A4 indicates severe rejection.61 Treatment for ACR is initiated with high-dose intravenous methylprednisolone and bronchoscopy is repeated to weeks later to assess for resolution of abnormal histopathology For refractory ACR, optimization of the oral immunosuppression regimen concomitant with more aggressive treatment with monoclonal antibodies— such as alemtuzumab (CD52 receptor antagonist), basiliximab (CD25 a-chain antagonist), other biologicals—or photopheresis may be considered • Fig 57.5 Histopathology of obliterative bronchiolitis Antibody-Mediated Rejection The many consequences of immunologic injury to the lung from the development of donor-specific antibodies (DSAs) include persistent or recurrent episodes of ACR of all grades, lymphocytic bronchiolitis, and all subtypes of CLAD.61–63 The term antibodymediated rejection (AMR) describes the production of damaging DSA targeted against the allograft by recipient immune cells HLA molecules are the major transplant antigens that can cause AMR DSAs largely target HLA molecules The presence of graft dysfunction, complement deposition at the alveolar capillary membrane, detection of circulating DSAs, and histopathologic changes (capillaritis) are considered sufficient evidence of AMR.64 However, it is unusual that all of these criteria are met in lung transplant recipients and, if present, are detected after severe, irreversible damage has been conferred to the allograft AMR is often refractory to therapy, resulting in graft failure and death A 2012 ISHLT consensus statement includes a much broader set of histologic findings felt to be consistent with AMR if, in addition, donor-specific HLA antibodies are present and capillary complement deposition positivity is present in at least 50% of interstitial capillaries.65 This document was updated in 2016.66 There is no consensus on treatment of humoral rejection Pulse steroids, plasmapheresis, intravenous immunoglobulin, and B cell– directed therapy (Cytoxan or rituximab) are used, often in combination.67 The proteasome inhibitor bortezomib (targets plasma cells) and the complement inhibitor eculizumab are also considered in the treatment of AMR.68,69 The lung transplant community has made important headway in recognizing cases of AMR, but substantial challenges remain in standardization in the diagnosis of and determining the most optimal therapeutic options for pulmonary AMR Chronic Lung Allograft Dysfunction Broadly, the term CLAD has been adopted to include manifestations of graft dysfunction that can occur due to a variety of immunologic or nonimmunologic allograft insults (Fig 57.6).70 While there is a clear relationship between ACR and eventual development of CLAD, other etiologies that are associated with chronic graft dysfunction must be investigated and ameliorated 686 S E C T I O N V Pediatric Critical Care: Pulmonary CLAD Not Due to Chronic Rejection • Allograft related ° ° ° ° ° ° ARAD Follicular bronchiolitis Refractory acute cellular rejection Infection/colonization Antibody-mediated rejection Anastomotic stenosis • Allograft related RAS BOS • Non–allograft related ° ° ° ° Pleural disease Diaphragm dysfunction Neuromuscular dysfunction Other Acute Lung Allograft Dysfunction CLAD ALAD ° ° ° ° ° ° ° ° ° Acute rejection (cellular/humoral) Lymphocytic bronchiolitis Infection Anastomotic abnormality ARDS ABPA Pulmonary embolism Pneumothorax Other • Non–allograft related ° Pleural disease ° Measurement error • Fig 57.6 Etiology of allograft syndromes ABPA, Allergic bronchopulmonary aspergillosis; ALAD, acute lung allograft dysfunction; ARAD, azithromycin-responsive allograft dysfunction; ARDS, acute respiratory distress syndrome; BOS, bronchiolitis obliterans syndrome; CLAD, chronic lung allograft dysfunction; RAS, restrictive allograft syndrome CLAD is a diagnosis of exclusion CLAD tends to be a nonuniform process; thus, TBBx sampling is not likely to identify fibrosis early in the course posttransplantation Thus, CLAD diagnosis per se does not hinge on histopathologic evidence but rather on the development of composite findings of histopathologic, radiologic, and measured changes in allograft function Historically, chronic lung graft dysfunction was thought to present only as BOS, in which the progressive development of obliterative bronchiolitis led to a fall in the FEV1 and, ultimately, to graft loss However, in 2005, a novel subtype of BOS was first described as a distinct entity.71 Since then, different phenotypes of CLAD with distinct prognostic significance have been described The entity described by Pakhale et al.71 is now known as restrictive allograft syndrome (RAS) RAS is described histologically as fibrosis occurring predominantly in the peripheral lung tissue rather than in small airways, resulting in a decline in total lung capacity in addition to a decline in FEV1 CLAD phenotypes are characterized with a combination of pulmonary function and imaging with chest CT Of CLAD patients, 80% will have no identifiable cause for chronic graft failure, yet identifiable causes of graft dysfunction must be pursued and treated, such as ACR, AMR, chronic infection, obesity, gastroesophageal reflux disease, aspiration, and chronic inflammation Distinct phenotypes of CLAD have individual prognostic significance For example, neutrophilic allograft syndrome can be slowed or arrested with a prolonged course of oral azithromycin, whereas RAS is more rapidly progressive and associated with a worse long-term outcome and low survival.72 Treatment Options for CLAD There is no maintenance immunosuppression protocol proved to be superior for preventing CLAD nor has any advantage been demonstrated with the use of an induction regimen at the time of transplantation Intensifying the immunosuppressive treatment generally has little effect in patients with established BOS or RAS Current therapy for the BOS subset of CLAD—if not associated with AMR, infection, or inflammation—is limited to optimizing immunosuppressant levels and maintaining good pulmonary toilet to prevent postobstructive pneumonia and chronic inflammation Most practitioners will substitute tacrolimus for cyclosporine, begin a trial of azithromycin for a minimum duration of months, or proceed to fundoplication of the gastroesophageal junction if gastroesophageal reflux has been refractory to medical treatment Unfortunately, this approach tends to have limited success Photopheresis, particularly in the setting of recurrent ACR or plasmapheresis in the setting of AMR, may be of utility in abrogating rapid deterioration Failing these approaches, retransplantation is recommended in selected cases.73–75 As to treatment options for RAS, no formal treatment guidelines exist Pirfenidone is a synthetic molecule that has recently been approved for the treatment of idiopathic pulmonary fibrosis (IPF) in Europe, Canada, Japan, South Korea, and the United States In vivo and in vitro studies have shown a potent antifibrotic effect of pirfenidone, which inhibits the synthesis of transforming growth factor-b (TGF-b) and tumor necrosis factor-a (TNF-a), leading to a reduction in fibroblast proliferation and collagen synthesis and thus a slower decline in lung function in animal models of fibrosis and in IPF patients.76 Lung transplant recipients have been treated in single case series reports The treatment is currently experimental, but the case reports have demonstrated some beneficial effects (i.e., mild improvement of interstitial changes and lung function) with pirfenidone.77,78 Similarly, nintedanib is a drug indicated for the treatment of IPF that targets multiple receptor tyrosine kinases and nonreceptor tyrosine kinases that stimulate fibroblast growth factor receptor, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor These receptors have been implicated in IPF pathogenesis Nintedanib binds competitively to the adenosine triphosphate binding pocket of these receptors and blocks the intracellular signaling crucial for the proliferation, migration, and transformation of fibroblasts representing essential mechanisms of the IPF pathology.79 Extracorporeal photopheresis (ECP) has emerged as an effective option, having been used successfully in cutaneous T-cell lymphoma and graft-versus-host disease.80 ECP induces psoralenmediated deoxyribonucleic acid cross-linking and results in apoptosis of lymphoid cells, including NK and T cells These apoptotic lymphocytes are phagocytosed and eliminated upon reinfusion by immature dendritic cells, which subsequently undergo maturation and present antigenic peptides The first successful application of ECP in lung transplant recipients was reported in 1995.81 Experimental models and human studies have demonstrated ECP-associated modulation of dendritic cells, alteration of ... Immunobiology Acute cellular rejection (ACR) of the transplanted lungs occurs in almost one-third of children within the first year of lung transplantation.2 Alloreactivity toward the graft is likely... connections are harvested from each donor lung Each left atrial patch is sewn onto the recipient heart This surgical approach minimizes cardiopulmonary bypass time, which reduces related complications.27–29... The relative efficacy of the new lung allocation scoring system, combined with the technical and ethical challenges associated with living lobar transplantation, have prevented wider adoption of