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• W2024004493 abstract "In the preceding 20 years, lung transplantation has evolved from an experimental endeavor into the treatment of choice for carefully selected patients with advanced lung disease (1). Depending on the recipient disease and timing of transplant, recipients enjoy improved quality of life, and for most indications lung transplant confers survival advantage. Advances in lung preservation, transplant operative technique and more precise immunosuppression have improved early survival. Currently, the two most important barriers to successful application of lung transplantation are shortage of suitable donor lungs and decreased long-term survival as a result of a form of chronic allograft deterioration, which is diagnosed by the histologic finding of obliterative bronchiolitis (OB), or the clinical correlate of bronchiolitis obliterans syndrome (BOS), characterized by a significant reduction in airflow compared with baseline values achieved in the first months following transplantation. The first attempt at human lung transplantation was made in 1963. However, long-term clinical success was not realized until 1981 with report of a successful combined heart–lung transplant (2). In 1983, the first successful isolated single lung transplant was performed (3), followed closely by en bloc double lung transplant in 1986 (4). Bilateral sequential lung transplantation emerged in 1989 (5). There have been only minor modifications in operative technique in the ensuing decade. During the decade of the 1990s, worldwide application of lung transplantation took place. There are a large number of successful programs in North and South America, Europe and Australia. Indeed, there has been a recent expansion to Japan with four approved programs. Donor availability and, as a result, the number of transplants, reached a plateau in 1994. Meanwhile, the number of patients listed for transplantation has been increasing due to improvement in patient outcomes and acceptance of the therapy by referring physicians. Most lung transplant programs have similar listing criteria. Age greater than 65 years, coexisting major medical conditions, psychological instability or inability to participate in transplant protocols are specific contraindications (1, 6). Pulmonary and physical rehabilitation have proved to be an important adjunct to pulmonary transplantation. Patients who participate in rehabilitation are better prepared to tolerate the wait for transplantation, enjoy shorter postoperative recovery periods and achieve functional status more quickly (7). At most major American lung transplant centers, current waiting time for transplant after listing is in the range of 18–24 months (8). Logistically, this time must be factored into the referral and listing process. Criteria for timing of referral for the four commonly transplanted diseases have been adopted by the major organizations with an interest in lung transplantation (Table 1). Indications for lung transplantation as reported to the International Society for Heart and Lung Transplant Registry among 10 822 transplants is shown in Figure 1. Indications for single and bilateral/double lung transplantation for 10 822 procedures. CF, cystic fibrosis; A1A, α1-antitrypsin deficiency; PPH, primary pulmonary hypertension; Retx, retransplantation; IPF, interstitial pulmonary fibrosis; Misc, miscellaneous. Reprinted from Hosenpud et al. (9) with permission from Elsevier Science. Recipient indications for adult and pediatric lung transplant recipients at Washington University in Table 2. Patients with interstitial pulmonary fibrosis typically experience a rapid decline in function and physiologic status after diagnosis. Waiting list mortality is high. Referral for transplantation evaluation should be made early in the course of the disease. Pulmonary fibrosis is suitable for single lung transplantation since high resistance to ventilation and perfusion of the native lung favors ventilation and perfusion of the transplanted allograft. Bilateral lung transplant provides reserve of more normal lung tissue. Our experience at Barnes-Jewish Hospital with these patients (n = 45) has shown that double lung transplantation provides less short-term morbidity and mortality. However, the 3-year survival favors the single lung recipients (10). Cystic fibrosis is a suppurative lung disorder resulting in bronchiectasis and obstructive physiology. Respiratory failure is the cause of death in the vast majority of patients. Pseudomonas aeruginosa is the most commonly encountered pathogen, with an increasing number of antibiotic-resistant organisms being found. An infection with Burkholderia cepacia is a specific contraindication for lung transplantation in most programs. Cystic fibrosis patients present challenges to the operative management, yet in our experience, operative mortality is less than 5% (11). Emphysema due to chronic obstructive lung disease or, more rarely, α1-antitrypsin deficiency is the most common indication for lung transplantation for a number of reasons. First, emphysema is a very common disease in Western culture. Furthermore, patients typically survive the prolonged wait for a transplant provided they receive supplemental oxygen and participate in pulmonary rehabilitation programs. Technical considerations that facilitate lung transplantation for emphysema include a large pleural space typically free of adhesions, which improves access for explantation and implantation. Significant pulmonary hypertension is uncommon; therefore cardiopulmonary bypass is rarely required for conduct of these procedures. For this condition, the major dilemma is whether single or bilateral lung transplant represents the best option. In our experience, hospital survival is similar for single and bilateral recipients. However, functional results and long-term survival favor the bilateral recipients (12). Lung transplantation following lung volume reduction surgery is technically feasible and provides equivalent results. Primary pulmonary hypertension (PPH) and secondary pulmonary hypertension are effectively treated by lung transplantation. The isolated lung graft (either single or bilateral) provides excellent long-term reduction in pulmonary afterload and permits right heart recovery (13). PPH has significantly decreased as an indication for lung transplantation because of the development of continuous intravenous prostacyclin therapy (14). Lung transplantation should be reserved for those patients who are nonresponsive to vasodilators or who are late failures with therapy. Some groups (mainly European) have continued to favor heart–lung transplantation for patients with PPH. There is general agreement that patients with complex or irreparable congenital cardiac defects require combined heart–lung transplantation. Ideal lung donors have arterial blood gas Pao2/Fio2 ratio of greater than 300 ventilated with 5 cmH2O of positive end-expiratory pressure (PEEP), clear temporal X-ray and clean airways at the time of retrieval. Unfortunately, brain death is often associated with a variety of lung pathologies, including neurogenic pulmonary edema, contusion, aspiration and infection. All of these exclude the donor lungs from consideration, using standard criteria. Patients have complete physiologic monitoring, including continuous mixed venous saturation, transesophageal echocardiography, and arterial blood pressure monitoring with femoral and radial access. Independent ventilation of each lung is mandatory, unless cardiopulmonary bypass is planned, as it is in the majority of pediatric operations. The anterolateral approach provides excellent exposure for conduct of most transplant procedures in the adult and pediatric patient. For bilateral procedures we utilize bilateral anterolateral incisions (15, 16). The explant of the native lung is conducted with particular attention to hemostasis and preservation of phrenic and recurrent laryngeal nerves. During implantation, the donor lung is kept cold by topical hypothermia. The bronchial anastomosis is performed first. The membranous portion of the bronchus is fashioned with a running suture, followed by interrupted simple or figure-of-eight sutures for the anterior cartilaginous portion. Peribronchial tissue is used to cover the anastomosis in the event of a partial bronchial dehiscence. The pulmonary artery is anastomosed with a running nylon suture. The recipient's left atrium is then clamped, the pulmonary veins are opened to create a common orifice, and the graft's left atrial cuff is anastomosed with a running nylon suture. The lung is inflated, the arterial circulation is unclamped, venting air and perfusate, and then the left atrial anastomosis is closed. Maintenance immunosuppression for lung transplantation generally is with triple therapy of cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and corticosteroids (9). Our adult program's preference is to initiate therapy with cyclosporine (therapeutic goal of 300 ng/mL), azathioprine (2–2.5 mg/kg/d), and a regimen of tapering corticosteroids to a goal of 15 mg/d by 6 months postoperatively. Only recently have tacrolimus and mycophenolate mofetil been used in lung transplantation and, to date, there are no solid data in the literature to suggest an advantage in their use. There is limited experience with sirolimus. We currently use these agents as second- or third-line drugs when standard therapy is associated with toxicity or in the setting of persistent or recurrent rejection, or for the treatment of OB or BOS. Induction protocols are not universally endorsed, nor are they uniform in structure. Adjustments are made for cytomegalovirus (CMV) donor and recipient mismatches. The role of monoclonal antibody IL-2 receptor antagonists in lung transplantation has yet to be determined. In most experienced lung transplant programs, operative mortality is less than 10%. The most recent 1-year graft survival remains at 76% (8). Although this represents an improvement, the results lag behind other solid organ graft 1-year survival rates of 82% for liver, 85% for heart, and 89% for kidney transplants. Five-year graft and patient survival figures are 42 and 44%, respectively, compared with 65–69% graft survival for kidney, liver and heart transplantation. International Heart and Lung Registry data suggest a slight improvement in survival favoring bilateral lung recipients (Figure 2). This has also been the experience of our own program (12). Actuarial survival of lung transplantaton patients (worldwide experience), from 1982 to 1999. Reprinted from Hosenpud et al. (9) with permission from Elsevier Science. Data from our adult experience at Barnes-Jewish Hospital demonstrates that early survival favors the emphysema patients, whereas late survival favors patients with αl-antitrypsin deficiency emphysema and PPH (Table 3). Five areas pose the greatest challenge to further clinical progress in lung transplantation: shortage of donors, waiting list mortality, reperfusion injury, acute rejection and BOS. There is no doubt that more cadaveric lungs could be identified and utilized for transplantation. There is a tremendous discrepancy in the number of lungs procured for transplantation per million of the population between various regions of the United States. The maximum preservation time is unknown, but lungs with 8 h of ischemia time can be safely used. We have demonstrated that long-distance harvest and harvest by other teams do not adversely affect 1- and 5-year survival (17). In addition, we have found that marginal donors can be used without compromising early or late results (18). In our program, long-distance harvest, harvest by other teams and marginal donors have been used in 75, 20 and 25% of transplants, respectively. We do not use marginal lungs in single lung recipients or in recipients with challenging indications. However, we do not hesitate to use marginal lungs in bilateral recipients, especially those with emphysema. Living lobar transplantation has emerged as a viable option for a select number of patients. This procedure, wherein lower lobes are harvested from two donors and implanted as bilateral grafts in a single recipient (typically with cystic fibrosis), was developed by the University of Southern California (USC) group. Using strict donor and recipient selection criteria, with rigorous attention to operative technique and postoperative management, they have demonstrated excellent results, with reduced incidence of BOS compared with patients receiving cadaveric organs (19). Indeed, for pediatric recipients, the USC group has come to believe that living lobar transplantation represents the preferred transplant option. However, our centers, as well as others with limited experience, do not share the enthusiasm for this procedure. Among living related lobar donor operations, we have observed a significant number of donor complications and a less than acceptable survival among recipients (20). Living lobar transplantation is technically not an option for the vast majority of patients. As an example, emphysema patients would have a pleural space that would be too large for a single lobar transplant. The requirement of a donor of identical blood type with normal lung function and no co-morbid disease may be difficult to fulfill (21). At this time the role of this procedure is in evolution as the worldwide experience increases (Figure 3). Bronchiolitis obliterans in an autopsy specimen from a pediatric lung transplant recipient. Fibrotic replacement of the submucosa of a bronchiole, with relatively normal surrounding lung parenchyma. Slide courtesy of Dr Jon Ritter, Department of Pathology, Washington University, St Louis, MO, USA. Waiting list mortality is a significant issue for patients with restrictive and suppurative lung diseases. The mean waiting time for all patients in our program has increased from ≈ 100 d in 1988–91 to greater than 700 d for our most recently recorded 3-year interval of 1997–2000. The most recent UNOS data show that 16% of patients on the waiting list for lung transplant die, compared with 12 and 7% on the liver and kidney waiting lists, respectively (8). The United States, unlike many countries, makes no allowance for severity of illness during wait for lung transplantation, with priority being determined by waiting time alone. This favors the emphysema patient and puts patients with higher waiting list mortality, e.g. cystic fibrosis and interstitial pulmonary fibrosis, at a significant disadvantage. The lung donor allocation algorithm is a complex problem. It is well known that the sickest patients are those at greatest risk of operative mortality. Advocates of a priority by disease severity system point out that those patients with diseases acquired through no fault of their own (e.g. cystic fibrosis and interstitial pulmonary fibrosis) are at an increased risk of death, while patients with smoking-induced obstructive lung disease are predominantly transplanted. On the other hand, times on the list advocates make several strong points: first, it is a system easily understood by patients and physicians; secondly, the variable natural history of end-stage lung disease is very different, and therefore different algorithms would have to be established for each disease, which may lead to manipulation of a system. At present, UNOS is developing a modification of organ allocation based on risk of death. Ischemia-reperfusion injury (IRI) is mediated by the interaction of activated neutrophils with injured pulmonary vascular endothelium. Increasing ischemic time, storage temperature, storage Fio2 and lung hyperinflation during transport worsen the pulmonary endothelial injury (22, 23). Clinically significant IRI occurs in about 15% of lung transplant recipients. IRI is characterized clinically as noncardiogenic pulmonary edema, which occurs within 12 h of lung transplantation. Treatment of the patient with IRI is supportive, with increasing oxygen concentration, PEEP, sedation and muscle paralysis, minimizing barotrauma, aggressive diuresis, and inotropic support. We have demonstrated that inhaled nitric oxide improves gas exchange and pulmonary hemodynamics in patients with severe IRI (24). Extracorporeal membrane oxygenation (ECMO) can be used in severe situations. We have utilized ECMO in 12 patients, with seven survivors. All seven survivors had ECMO instituted within 24 h of transplantation before irreversible pulmonary injury occurred (25). There are a number of strategies to limit the likelihood of reperfusion injury. Low potassium dextran solution provides superior lung preservation. Antegrade and retrograde lung flush, avoidance of hyperinflation and topical hypothermia during implantation have been shown to decrease IRI in experimental and clinical lung transplantation (22). We have demonstrated that inhaled nitric oxide administered to the donor prior to harvest, and addition of nitroprusside to the flush solution both significantly decrease subsequent reperfusion injury (26). Reperfusion injury is associated with excessive neutrophil adhesion and pro-inflammatory cytokines. In experimental transplantation, strategies to decrease neutrophil adhesion or lipid peroxidation as well as inhibit the inflammatory cascade have proved successful. In addition, we have recently demonstrated that transfection of genes for the anti-inflammatory cytokines IL-10 and TGF-β1 result in significant amelioration of IRI in a rat orthotopic single lung transplantation model (27). At present, application of this strategy in large animals or humans is limited by technical problems of gene and vector production. Despite immunosuppression dosing and levels exceeding those of other solid organ transplant regimens, biopsy-proven acute rejection occurs in up to 80% of our patients within the first year following transplantation. While this is rarely associated with clinical morbidity, it is nevertheless relevant, as numerous retrospective multivariate analyses have demonstrated that acute rejection is positively correlated with the subsequent development of chronic lung allograft dysfunction (28). The clinical presentation of acute rejection may include fever, dyspnea, pleuritic pain, or the radiologic appearance of infiltrates, pleural effusion. Typically patients develop a modest leukocytosis, fall in Pao2 and decrease in forced expiratory volume in 1 s (FEV1). A variety of noninvasive modalities to detect acute rejection have been suggested without consistent results. These include bronchoalveolar lavage (BAL) for lymphocyte analysis, spirometry, high-resolution computed tomography and nuclear medicine perfusion scanning. Increased levels of exhaled NO have been correlated with experimental and clinical lung rejection. Unfortunately, this technology is cumbersome and not uniformly reproducible. Other promising modalities including the use of MRI await clinical validation. The gold standard for diagnosing acute rejection is with histologic examination of lung parenchyma acquired with multiple transbronchial biopsies (29) The pathologic hallmark of acute allograft rejection is perivascular lymphocytic infiltration (30). The utility and safety of transbronchial biopsy have been demonstrated. Controversy exists over the ideal biopsy regimen. At our institution, we routinely perform bronchoscopy within 3 weeks of transplantation, again at 2, 3, 6, 12 months postoperatively, and as needed thereafter. Repeat evaluation is performed 6–8 weeks following treatment for acute rejection to evaluate therapeutic efficacy. Treatment of acute rejection is based on the severity of the process, recurrence, and status of the patient. Primary rejection episodes are typically treated with intravenous methylprednisolone (20 mg/kg) administered at three successive daily doses. Adjustments are made to maintenance immunosuppression if levels were deemed to be inadequate. Lymphocytolytic therapy (e.g. ATGAM, OKT3) is administered for recurrent or persistent rejection. Chronic allograft dysfunction is a clinicopathologic syndrome, characterized histologically by OB, and physiologically by significant airflow limitation developing 3 months or more after transplantation (31). Other causes, such as bronchial stricture or infection, must be excluded. Patients may be asymptomatic, or have dyspnea, cough, fevers or atypical chest comfort. Chest X-rays are typically unchanged, but evidence for hyperinflation may exist. The exact pathogenesis of the OB lesion is unknown, but evidence suggesting an immune-mediated process is accumulating. Our laboratory has discovered that development of recipient peripheral blood T-cell allorecognition of mismatched donor-derived HLA class I, and recently class II peptides is associated with the presence of BOS. Using lymphocytes recovered from BAL in post-transplant patients, we have demonstrated alloreactivity against airway epithelial cells which express donor HLA class I molecules (32). Evidence for humoral mechanisms include our demonstration of development of HLA-A locus mismatch antibodies as an independent predictor for the development of BOS (33). Further research has shown that presence of these antibodies precedes the development of BOS, therefore presenting an opportunity for intervention. Animal models of OB (strictly called obstructive airway disease [OAD] because of the caliber) utilizing heterotopic, obligatory ischemic tracheal allografts have revealed some very interesting data and could be used to assess therapy (34). The pathologic findings in the first 10 d follow a predictable course of first epithelial sloughing, which remains denuded or will develop a metaplastic cuboidal or squamous epithelium. At the same time, an alloimmune response characterized by a subepithelial infiltrate of CD4+ and CD8+ lymphocytes takes place (35). Over the next 18 d, fibroproliferation takes place, with granulation tissue accumulating in the lumen. Other data of interest emerging from this model include the finding that cyclosporine and rapamycin reduce the fibroproliferative response, and that acute CMV infection potentiates the development of OAD through enhanced expression of MHC II and platelet-derived growth factor (36). Clinical association with the incidence of acute rejection and CMV pneumonitis is positively correlated with the development of BOS (28). ISHLT data have indicated that increasing donor age and increasing ischemic time are positively correlated with development of BOS (9). Among the first 500 transplants in our program, patients who received organs from donors dying of traumatic brain injury (although, as a group, younger donors) are more likely to develop BOS. This finding is in contrast to data from other solid organ transplants and merits further investigation. Data from our patients reveal that freedom from BOS at 1 year is 80%, at 3 years is 40%, at 5 years is 25%, and at 7 years is 20%. The significance of BOS is apparent when analyzing ISHLT data for causes of death in lung transplant patients (9). At time-points greater than 1 year, greater than 80% of deaths are ascribed to pulmonary causes. More than 30% of these are due to bronchiolitis obliterans, 20% are due to ‘graft failure’ and a further 20% due to infection. It is probable that many patients in this latter category were unable to recover from pulmonary infection due to severe airflow limitation, or as a result of being immunocompromised due to adjunctive treatment for BOS. Therapy for BOS is limited to changing to alternative agents for immunosuppression. However, the efficacy of this is limited. Retransplantation for BOS is a controversial subject. This option has been used more commonly in pediatric patients. Novick et al. (37) have reported the international experience with retransplantation in patients with BOS. Operative mortality is excessive. Among operative survivors, long-term outcome is similar to first-time transplantation. Lung transplantation provides very good short- and acceptable long-term survival for patients with advanced lung disease. More widespread use of marginal and distant donors can be employed in selected recipients without compromising early or late results. Lack of suitable donor lungs and the development of BOS represent the biggest obstacles to more widespread application and long-term success of lung transplantation. The high rate of acute rejection and subsequent BOS clearly indicates that current immunosuppression strategies are inadequate. Further clinical and laboratory research into the pathogenesis of BOS will perhaps reveal new treatment options." @default.
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• W2024004493 title "Current Trends in Lung Transplantation" @default.
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