© 2008 American Thoracic Society doi: 10.1164/rccm.200802-247UP
Update in Transplantation 20071 Institute of Cellular Medicine School of Clinical Medical Sciences, Newcastle University and Freeman Hospital, Newcastle upon Tyne, United Kingdom; and 2 Pulmonary Allergy and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Correspondence and requests for reprints should be addressed to Jason D. Christie, M.D., M.S., University of Pennsylvania, Pulmonary and Critical Care Medicine, Center for Clinical Epidemiology and Biostatistics, 719 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104. E-mail: jchristi{at}cceb.med.upenn.edu As in 2006 (1), 2007 saw a wide range of studies examining a number of central areas within the field of lung transplantation. Important review publications included an update on the state of solid organ transplantation (2) and the 24th Official Report from the International Society for Heart and Lung Transplantation (ISHLT) (3). Overall, the number of lung transplantations reported to the ISHLT registry increased to an all-time high of 2,169. Although chronic obstructive pulmonary disease remains the main indication for lung transplantation worldwide, the number of subjects transplanted for pulmonary fibrosis is rising, perhaps as a result of implementation of the Lung Allocation Score in May 2005. OUTCOMES A highly controversial article by Liou and colleagues (4) addressed lung transplantation and outcome in children with cystic fibrosis (CF). This article attempted to predict the survival benefit of lung transplantation by using the Cystic Fibrosis Foundation patient registry as well as organ transplantation and procurement network datasets. Survival was modeled after listing for lung transplantation using lung transplantation as a time-dependent covariate in a proportional hazards analysis. The set of hazard ratios was broken down into four categories defined as significant estimated benefit, significant risk of harm, insignificant benefit, or insignificant risk of harm associated with lung transplantation. The authors concluded that only five patients in their cohort of 514 children fell into the significant benefit category, with only one patient who underwent transplantation having had significant benefit. There are several important limitations to this study. First, covariates were obtained up to 3 years or more before transplant. Second, unsubstantiated assumptions were made about the relationship between listing and the decision to transplant. Third, there was significantly lower transplant survival than in a similar population from the Organ Transplantation and Procurement Network dataset. Finally, the 57% predicted 5-year waiting list survival for the study cohort was much higher than in other series both from the United Kingdom (5) and the United States (6). Thus, the statistical analysis was problematic, with the chosen comparative survival model most likely biased against a survival benefit of lung transplantation. Because there are prior data showing that the risks of death before and after transplantation are not proportional (7), the use of a proportional hazards model was not appropriate and may have contributed to the findings that lung transplantation did not have a strong effect on survival. It is important that those involved in the management of children with CF recognize that the message conveyed by this study does not lead to the inappropriate denial of children with advanced CF for referral to transplantation. Hadjiliadis and colleagues (8) reviewed the results of transplantation for CF in two large adult populations and addressed the impact of pan-resistant bacteria other than Burkholderia cepacia as compared with patients harboring sensitive bacteria. In all, 43.7% of patients harbored pan-resistant bacteria, with the vast majority being Pseudomonas aeruginosa. There was one case of Stenotrophamonas multiphilia and one of Achromabacter xyloxoxidans. Log-rank testing demonstrated decreased survival in patients with pan-resistant bacteria compared with patients with sensitive bacteria, although both groups had similar or better survival than that reported for patients with CF by the United Network of Organ Sharing (UNOS). Five-year survival in patients with pan-resistant bacteria was 58.3 ± 9.2% versus 85.6 ± 5.2% for those with sensitive bacteria. The Hanover group published results of their experience with heart–lung and lung transplantation in adults with congenital heart disease (9). A total of 46 heart–lung transplantations and five double lung transplantations were performed in patients whose underlying diagnosis included ventricular septal defect, atrial septal defect, persistent ductus arteriosus, and more complex congenital cardiac defects. All patients had pulmonary hypertension. Twelve patients had undergone previous cardiac procedures and were included in the retrospective analysis. Mean follow-up was 5.1 years and patient survival was 69% at 5 years and 53% at 10 years. The survival in this series was not different compared with survival after lung and heart–lung transplantation for other indications. The authors concluded that lung and heart–lung transplantation could be performed with acceptable risk and favorable long-term outcome in patients with adult congenital heart disease.
In a study of 79 consecutive bilateral lung transplantations for emphysema, the factors related to postoperative mortality were examined. Of the patients included, eight had RECIPIENT SELECTION Gries and colleagues reported that implementation of the Lung Allocation Score (LAS) changed the distribution of diseases transplanted, without affecting survival in recipients (11). Although these findings would imply that the net transplant benefit for subjects with idiopathic pulmonary fibrosis is deemed higher by the LAS formula, Mason and colleagues showed that survival for idiopathic pulmonary fibrosis may be worse than for other indications (12). Likewise, other authors reported on the changing landscape of recipient factors over time. Russo and colleagues used the UNOS registry to demonstrate that survival in cytomegalovirus (CMV)-positive and mismatched patients has improved such that CMV status does not affect survival in the current era (13). Gutierrez and colleagues revisited the relationship between prognosis and the age of recipient, showing that recipients older than 60 had worse survival when compared with matched younger subjects in their center (14). Nwakanma and colleagues found no difference in survival between single and bilateral transplants in recipients older than 60, even when adjusted for confounding patient selection factors using propensity scoring analysis (15). DONOR EVALUATION AND MANAGEMENT Mitchell and colleagues presented an intriguing study of the effects of donor alcohol ingestion on airway lesions using a rat heterotopic tracheal transplant model. The authors found that experimental alcohol ingestion in donor animals led to greater allograft transforming growth factor (TGF)-β expression, myofibroblast transdifferentiation, and fibrosis when coupled with alloimmune inflammation (16). These findings should lead to further studies aimed at investigating evidence for this link in humans. A glimpse of the future of donor evaluation was offered by Ray and colleagues who performed an early study of gene expression using donor biopsies in which they compared subjects with primary graft dysfunction (PGD) versus those without PGD (17). The authors found differential expression of apoptosis and stress-activated pathways between PGD and non-PGD. Future studies of donor lung biopsy or bronchoalveolar lavage may eventually guide selection of donor organs; however, this approach is still far from clinical application. Likewise, in an effort to increase the donor pool, Steen and colleagues reported the first case of transplantation of a reconditioned donor lung (18). In this case report, the authors used a special ex vivo perfusion and ventilation apparatus to "tune up" a lung that was originally not deemed acceptable. The transplanted patient who received this lung did well. De Perrot and coworkers reported satisfactory outcomes using donors older than 60; however, patients receiving organs from older donors appeared to have both worse long-term and short-term survival in unadjusted analyses (19). Venkateswaran and colleagues studied the effects of active donor management, including steroid hormone administration, in a nonrandomized experimental design. Although limited by lack of standard criteria for lung utilization, they found that early active management led to use of more lungs (20). Studies aimed at transplant donation focused on the use of donors after cardiac death. de Antonio and colleagues reported that midterm results using organs from 17 out-of-hospital non–heart-beating donors were comparable with those from standard criteria donors (21). In laboratory studies, Nishi and colleagues showed that longer preservation of lungs from non–heart-beating donors is possible in a canine model (22). Van De Wauwer focused on improving the preservation technique using retrograde flushing and topical cooling in pigs (23). PGD AND ISCHEMIA/REPERFUSION INJURY
Epidemiology and Human Studies Whitson and colleagues confirmed the association of grade 3 PGD with both worse survival and BOS, and showed that survivors of PGD have worse lung function (25). The authors concluded that the development of grade 3 PGD in the early postoperative period led to decreased survival and worse long-term pulmonary function in bilateral lung transplant recipients. Likewise, Burton and coworkers showed a relationship between the degree of lung injury immediately after transplant and worse subsequent lung function (26). The observed link between PGD with both BOS and impaired lung function could potentially be related to the effects of early organ injury on later alloimmune or fibrotic activation (27). These findings may be partially explained by the long-term effects of epithelial injury in PGD (28, 29) or the potential common link of donor factors predisposing to both PGD and BOS (14). The Lung Transplant Outcomes Group investigators provided evidence for involvement of the coagulation and fibrinolytic systems in human PGD. In this multicenter prospective cohort study, higher plasma levels of type 1 plasminogen activator inhibitor (PAI-1) and lower levels of protein C were found in patients with PGD. This observation was partially explained by elevated pretransplant right heart pressures, because higher PAI-1 levels were found in subjects with elevated pulmonary arterial pressures (30). The investigators also found that intracellular adhesion molecule (ICAM)-1, but not the von Willebrand factor antigen, was higher in subjects with PGD, implying that cell adhesion is an important mechanism in PGD (31). These findings are consistent with emerging evidence that ICAM-1 regulation is altered during the cold and warm ischemic phases during and after transplantation (32). Krenn and colleagues studied the role of vascular endothelial growth factor (VEGF) in PGD among 150 subjects. The authors found higher levels of VEGF preoperatively in recipients who eventually developed PGD (33). Calfee and colleagues reported that the receptor for advanced glycation end-products (RAGE) was associated with worse perioperative performance (28). Although this study lacked adequate statistical power to detect differences in clinical PGD, RAGE is a novel biomarker for future studies of epithelial involvement in PGD. Likewise, evidence of higher RAGE levels with impaired alveolar fluid clearance in animal models of lung injury that was favorably altered by β-agonist therapy provides an interesting backdrop for future studies of β-agonist therapy in PGD (29). Several studies were aimed at refining the early evaluation of subjects with PGD. Prekker and colleagues found that early worsening trends in the PaO2/FIO2 ratio were associated with mortality (34). These trends may be useful for guidance and early prognostication, but have not been compared with simply grading PGD by standard ISHLT criteria at later time points for use as an outcome definition in clinical studies (35). Oto and colleagues summarized data to potentially refine the PGD criteria based in part on separating type of transplant and in considering additional time points of PGD grading, thereby providing focus to guide future studies (36). Although the therapy for PGD remains largely supportive, two groups focused on the role of extracorporeal membrane oxygenation (ECMO) as salvage therapy (36, 37). Fischer and coworkers used the Extracorporeal Life Support Organization Registry and found a 42% survival with ECMO to hospital discharge in 151 subjects with PGD (37). Wigfield reported a single-center experience with similar results: approximately half of 22 subjects treated with ECMO survived to 1 year (38). Kermeen and colleagues, in a case series, successfully treated six subjects with PGD with endobronchial surfactant showing resolution of clinical PGD (39). Struber and colleagues provided some evidence of feasibility, by successfully instilling surfactant in larger human populations of transplant patients (40).
Experimental Approaches in Animal Models Adding further evidence to the role of oxidant stress in ischemia/reperfusion (I/R) lung injury, two studies focused on use of N-acetylcysteine (NAC) in mouse (42) and rat (43) lung transplant models, showing benefit with reduced lung injury in both animal models. Given the prominent role of oxidative stress in I/R injury, NAC may be an important future therapy for PGD in humans. Kohmoto and colleagues extended prior studies of carbon monoxide to illustrate that low doses of CO given to donors or recipient rats reduced I/R injury and that the protective effects of CO may be mediated through the p38 mitogen-activated protein kinase (MAPK) pathway (44). Liu and colleagues extended their prior findings of indoleamine 2,3-dioxygenase (IDO) therapy (45) to illustrate that IDO delivered with endothelium-targeted gene transfer reduces I/R injury (46). IDO is a novel agent that has antioxidant and immune-modulating properties. Mori and colleagues showed that addition of sivelestat, a neutrophil elastase inhibitor, reduced experimental I/R injury in rats (47), and Suzuki and coworkers illustrated that sivelestat also attenuated I/R injury in rats treated with endotoxin before lung harvest, mimicking potential pretransplant cryptic infections that may be present in human lung donors (48). Other novel therapies to reduce PGD include sphyngosine 1-phosphate (49), hepatocyte growth factor (50), and inhibition of the T-cell membrane protein CD26/DPP (51). ACUTE REJECTION
Acute allograft rejection remains a significant cause of morbidity after lung transplantation and persistent severe acute rejection is an important risk factor for the development of BOS. Hodge and colleagues investigated localized T-cell cytokine responses within the airways of patients with acute lung rejection after lung transplantation (52). Acute lung transplant rejection was associated with increased intracellular IFN- Reams and colleagues reported results with the use of alemtuzumab for treatment of refractory acute rejection and BOS after human lung transplantation (53). Alemtuzumab is a humanized anti–CD25 antibody that results in potent depletion of T lymphocytes. In 12 consecutive patients with recurrent acute rejection who had failed conventional treatment with methylprednisolone and antithymocyte globulin, alemtuzumab significantly improved histologic rejection scores. Despite a dramatic decline in CD4 counts in the treated patients, only one patient developed a lethal infection. Caution is required in the interpretation of this study because acute episodes of rejection are time dependent. However, these preliminary results provide the first evidence that alemtuzumab is a potentially useful therapy in lung transplant recipients with recurrent acute rejection. There is considerable interest in the role of gastric aspiration as a cause of graft injury after lung transplantation. The Newcastle group reported the association of pepsin as a biomarker of gastric aspiration in lung allografts with acute rejection (54). This cross-sectional study confirms a prior publication that pepsin, a marker of gastric aspiration, was present in lung allograft airways (55). In addition, pepsin levels were highest in lung allograft recipients with histologically verified grade A2 or greater acute rejection. Subjects with acute vascular rejection had the highest grades of airway inflammation. Recent work in a rat model of lung transplantation has shown that allografts challenged with chronic aspiration demonstrated severe acute rejection with significant monocyte infiltration, fibrosis, and lung destruction (56). At this point in time, therefore, it is not clear whether aspiration of gastric juice into the lung after lung transplantation induces alloreactivity leading to increased acute rejection or produces a histologic picture that is indistinguishable from the features of acute rejection. Further work is required in this area, particularly in determining the role of nonallogenic factors leading to lung injury after lung transplantation. BOS BOS remains the major cause of long-term morbidity and mortality after lung transplantation and is under intense research both in terms of etiology and early detection. The role of gastric acid aspiration in BOS is an important topic. The Leuven group reported the roles of acid and nonacid gastroesophageal reflux and aspiration in lung transplant patients with or without BOS (57). Forty-eight percent of patients had evidence of gastroesophageal reflux, with 27% having exclusively increased nonacid reflux as a result of treatment with proton pump inhibitors. The highest prevalence of gastroesophageal reflux was seen in patients with CF. Neither pepsin nor bile acids were reduced by the use of proton pump inhibitors. Overall, the group found that bile acids were a more specific marker associated with BOS than was pepsin. This association needs further confirmation. However, it is becoming increasingly clear that esophageal reflux with lung aspiration is a significant cause of chronic graft dysfunction after lung transplantation and therapeutic attempts to prevent reflux (e.g., using thoracoscopic fundoplication) should be considered. Exhaled biomarkers may be useful in the early detection of chronic pulmonary allograft dysfunction (58). This study compared the performance of exhaled nitric oxide and carbon monoxide as a measure of airway inflammation with slope of the alveolar plateau for helium to reflect heterogeneity of ventilation distribution for the detection of BOS stages 0-p and 1. An increase in helium slope had a better sensitivity of detection at stages 0-p and 1 than either exhaled nitric oxide or carbon monoxide. However, considering exhaled nitric oxide and carbon monoxide together improved their sensitivity. The best sensitivity was found with the three markers in combination. These parameters had high negative predictive values but low specificity and positive predicted values. The slope of the alveolar plateau for helium increased several months before post-transplantation bronchiolitis obliterans developed; a combination of physiologic measures of heterogeneity of ventilation coupled with biomarkers of inflammation proved to be the most sensitive approach. A radiologic approach to the early diagnosis of BOS using oxygen-sensitive helium 3 MRI was reported by Gast and coworkers (59). A 1.5-Tesla magnet was used in this study to assess the 3He-MRI technique in measuring the homogeneity of ventilation. The distribution of partial pressure of oxygen (PaO2) in the lung was measured and the helium MRI was also used to assess for ventilation defects. The median intrapulmonary PaO2 in patients without any rejection or allograft dysfunction was higher with fewer ventilation defects than in patients with BOS. The oxygen-sensitive 3He-MRI technique appeared capable of demonstrating physiologic differences associated with BOS and could add helpful regional information to other diagnostic techniques, such as spirometry, in the assessment and follow-up of such patients. Babu and colleagues explored the role of alloimmune rejection on ischemia in the development of fibroproliferation using a murine orthotopic tracheal transplant model (60). They showed that the transplanted airway was revascularized by development of a novel microcirculation between recipient and donor vessels at the site of the surgical anastamosis site. The microcirculation to the newly formed vascular anastamoses was partially dependent on VEGFR2 and CXCR2 pathways. In the absence of immunosuppression, acute rejection of the tracheal allograft led to the microvasculature exhibiting complement deposition, diminished endothelial CD31 expression, and absent perfusion before the onset of fibroproliferation. The 2006 update (1) discussed a study by Luckraz and colleagues suggesting that obliterative bronchiolitis after lung transplantation was associated with microvascular damage of small airways (61). The rate of decline in FEV1 after the onset of bronchiolitis obliterans has been observed to vary. Lama and coworkers characterized the course of FEV1 over time in a group of patients with BOS with the goal of determining factors that influence the rate of functional decline in FEV1. A total of 111 transplant recipients were studied. The rate of decline in FEV1 varied over time, with the steepest decline typically seen in the first 6 months after transplant. Female sex and a pretransplant diagnosis of idiopathic pulmonary fibrosis were associated with a steeper decline in FEV (62). This observation merits further investigation and is potentially explicable by an increased genetic risk to developing airway fibrotic remodeling after transplantation. A group from Marseille observed that several patients with BOS appeared to demonstrate stabilization of their loss in lung function spontaneously and therefore studied the potential role of T-regulatory cells in such patients (63). T-cell phenotype and cytokine production were assessed by flow cytometry of cells in blood, induced sputum, and bronchoalveolar lavage. Patients with stable obliterative bronchiolitis were characterized by higher numbers of T-regulatory cells, whereas progressive obliterative bronchiolitis was accompanied by increased TGF-β production. The authors concluded that T-regulatory cells could counterbalance T-cell activation and participate in the stabilization of airway obstruction. OTHER MEDICAL PROBLEMS Mason and colleagues determined the prevalence and timing of atrial fibrillation after lung transplantation and evaluated risk factors, treatment strategies, and return to sinus rhythm (64). Of 333 lung transplant recipients, 20% developed atrial fibrillation with a peak incidence 2 days postoperatively. Risk factors were older age, a diagnosis of primary pulmonary hypertension, and extremes of weight. Ninety-three percent of patients had returned to sinus rhythm by discharge and there was no short- or long-term impact on survival. The prevalence of dialysis after lung transplantation was examined to identify risk factors (65). Of a total 425 lung transplant recipients, 37 patients required dialysis. There was an increasing prevalence with time after transplantation. In the first month, the highest risk of dialysis was associated with calcineurine inhibitor dose. The median survival of patients requiring early dialysis was only 5 months, highlighting the need for prevention. In this series, successful renal transplantation was performed in four patients who developed chronic renal failure. FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form February 11, 2008; accepted in final form February 11, 2008 REFERENCES
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1-antitrypsin deficiency. Fourteen patients died in the first month after surgery. Compared with survivors, those who died had ischemic times longer than 6 hours, a greater tendency to require cardiopulmonary bypass during transplantation, and a higher incidence of hemothorax (
and tumor necrosis factor (TNF)-