Evolution of Current Practice
Successful clinical lung transplantation was first achieved in the 1980s (1, 2) after nearly 40 instructive failures over almost 20 years (3–5). Reduced steroid doses, a dominant risk factor for both infection and airway anastomotic dehiscence (3, 6, 7), became possible with cyclosporine-based immunosuppression (8). Encouraged by preclinical results (8–11), Reitz and colleagues at Stanford achieved long-term survival after combined (en bloc) heart-lung transplantation, and demonstrated that rejection and various infections of the lung could be accurately distinguished and thus more safely and successfully treated (1, 12). Subsequently, single and then double lung transplantation were reintroduced clinically at Toronto by Cooper and colleagues (2). Improved donor management, lung preservation, immunosuppression, and antimicrobial therapy contributed to 1-year survival approaching 70% by 1990, justifying broad acceptance in the pulmonary medicine community, and explosive growth of the waiting list through the 1990s. Worldwide activity increased from a few patients per year at one center in 1984 to over 1,500 at about 100 centers in the mid-1990s. Annual lung transplant activity in the United States (about 1,000) and the rest of the world (about 500) has remained constant over the past decade (13, 14), while the U.S. waiting list has grown from about 1,500 to nearly 4,000. Consequently, only about 25% of wait-listed patients will receive a transplant in the next year, down from 60% in the mid-1990s; not counting candidates removed from the waiting list (whose reason for delisting and subsequent fate are not tracked), at least 15% will die before a suitable lung becomes available. These statistics document the practical consequences associated with the donor lung shortage but not its human toll.
Surgical practice in lung replacement has evolved considerably over two decades. Excellent clinical results have been reported with several different bronchial anastomotic techniques (15–19). Thus, at least in the context of improving graft preservation and immunosuppression and as long as a technically accurate anastomosis is performed without tension between well-vascularized tissues, intussusception, absorbable sutures, and interrupted technique are not critical. Neither omental nor intercostal pedicle flaps nor primary bronchial artery revascularization were found to decrease the incidence of bronchial anastomotic complications or the incidence or kinetics of chronic rejection (20, 21). More recently, lung transplantation through a limited access anterior thoracotomy has been introduced to minimize surgical trauma (22).
Concomitant uncorrectable cardiac pathology in the setting of end-stage lung disease still warrants en bloc replacement of the heart and lungs. However, bilateral sequential (“double”) lung transplantation has largely replaced heart-lung transplant as the preferred approach for those patients in whom chronic suppuration mandates replacement of both lungs, as in cystic fibrosis or “wet” bronchiectasis. This shift occurred based on evolving priorities for allocation of increasingly scarce hearts and lungs; simpler logistics and superior outcomes (although in expert hands results are similar (23, 24)); and ethical issues associated with assessing the quality of “domino” heart donors and the added risk for a lung recipient of cardiac allograft rejection and vasculopathy. In the United States, more patients now die on the heart-lung waiting list each year than receive a transplant (13).
The optimal procedure for the majority of end-stage lung failure patients remains controversial. For most candidates, either a single or bilateral sequential procedure provides symptomatic relief, independence from supplemental oxygen, and minimal activity restriction, and 1-year mortality and quality of life are similar (13, 14). On the other hand, 5-year survival (38% vs. 47%), time to onset of chronic rejection, exercise tolerance, objective measures of lung function, and quality of life tend to favor double-lung recipients (25). However, this observation is based on retrospective nonrandomized data, and ignores prevalent programmatic practices whereby two lungs go preferentially to younger, healthier candidates who have a better prognosis independent of their transplant outcome (26). Even if results are superior, as seems biologically plausible, especially for younger candidates, the net impact on access and outcomes must be considered for the entire population of lung transplant candidates (27).
Living donor lobar lung transplantation, pioneered by Starnes and colleagues (28), has established a niche primarily for small candidates, because an adult lower lobe is sufficient in size to occupy the pleural space only for children or small adults. It is usually performed bilaterally for patients with cystic fibrosis or ventilator dependence of various etiologies who likely will not survive the wait for a suitable cadaveric donor and have two willing, healthy, biologically compatible donors. Short- and long-term survival are similar to cadaveric transplantation despite application in extraordinarily high-risk recipient populations (28, 29). However, the procedure is ethically and logistically complicated (30), putting three lives at risk to save one, and thus is performed in significant numbers at only a few centers.
Short- and intermediate-term retransplantation outcomes similar to primary transplant have been reported for carefully selected patients (<2% of lung transplants performed) at a few programs, particularly when performed for chronic rejection (obliterative bronchiolitis [OB]) rather than primary graft failure (14, 31, 32). Because anecdotally the second allograft usually develops OB within a shorter interval than did the first, retransplantation seems sensible mainly for young patients with normal renal function and late-onset OB in the first graft.
Lung Donor Demographics
In the United States, about 15% of 6,500 cadaveric organ donors each year yield lungs that are transplanted (13, 14). As a consequence of international initiatives to reduce ethanol-related road traffic accidents, the composition of the donor pool has changed adversely: the average age (now well over 30 years) and incidence of significant comorbidities (hypertension, diabetes) and other putative risk factors for initial lung dysfunction (smoking history, radiologic abnormalities, high A-a O2 gradient, prolonged intubation) have increased among donors whose lungs are used. The proportion of organ donors whose lungs are transplanted varies dramatically by geographic region, from 5–10% in many US organ procurement areas to about 40% in Ontario and Australia. These striking disparities reflect differences in regional demographics of the donor and recipient pools, heterogeneous donor management strategies, and variably aggressive transplant program practices. Expansion of the lung donor pool will require the lung transplant community to identify and disseminate “best practices” to optimize lung function in organ donors (33); to systematically match high-risk donors with physiologically appropriate consenting recipients; and to optimally preserve, assess, and even “resuscitate” marginal or deceased donor lungs (34, 35). Lung donation after cardiac death is feasible (35–39), but not yet widely disseminated.
Lung Donor Allocation
The U.S. rules for lung allocation have recently changed dramatically (40). Until 2005, lung allocation was driven almost exclusively by accumulated time since listing (27, 41). Based on extensive data analysis, modeling, and iterative interactions among the lung transplant community, in April 2005 the United Network for Organ Sharing (UNOS) grouped wait-listed patients into five relatively homogeneous categories. Disease-specific relative risk criteria collected over the previous 6 months were used to estimate for each waitlist candidate the risk of dying before transplant, which was mathematically combined with the probability of survival for that patient after transplant to derive an integrated allocation priority score. Importantly, each patient-specific component of the score is an objective test result that can be obtained serially and updated as often as the transplant center chooses to do so, allowing rate of patient decline to be reflected in prioritization. The allocation model is intended to be revised to address inadvertent inequities or incorporate evolving priorities; it is expected to more fairly balance access for the sickest recipients with efficacy (net increase in years of life) over the entire population of waiting candidates.
Other countries utilize a wide variety of allocation algorithms, few of which incorporate objective recipient disease severity measures or probability of survival after transplant. Most allow transplant programs local to the donor to make allocation decisions before offering organs on a regional or national basis (42).
Primary Graft Dysfunction
Clinically evident ischemia/reperfusion (I/R) injury remains quite common after lung transplantation, with interstitial infiltrates and increased A-a O2 gradient observed in a substantial minority of lung recipients (43–46). Although I/R injury delays withdrawal of ventilator support in less than 30% of recipients, when severe (in about 10% of recipients), “primary graft failure” significantly prolongs intensive care unit and hospital stay and is associated with 20–30% additional 90-day mortality and 30% of deaths within 30 days (14). How the mode of brain injury influences lung function in the donor and early and late outcomes is poorly understood (48); imperfect preservation of organ function during explant and storage, and reperfusion injury following the obligatory ischemic interval also contribute to the pathogenesis of this clinically important problem. It has persisted despite introduction of an extracellular preservation solution specifically tailored to the lung (Perfadex), and wide adoption of improved procurement techniques such as retrograde perfusion through the pulmonary veins (49, 50). Controlled reperfusion with leukocyte-depleted autologous blood is a clinically available, technically straightforward approach that appears to be associated with significantly lower incidence of initial graft dysfunction, and deserves study on a broader scale (51).
Although never evaluated in a prospective, randomized study, over the past decade extracorporeal membrane oxygenation (ECMO) has increasingly been used to rescue patients with severe primary allograft failure and is usually associated with lung recovery (52–55), perhaps because of reduced ventilator-associated barotrauma.
Acute lung injury (ALI)—whether associated with I/R, systemic infection, transfusion, or hemorrhagic shock—is mediated by a variety of cytokines, chemokines, and adhesive ligand/receptor interactions (56–62). Complement activation, oxygen free radical and eicosanoid generation, and coagulation pathway interactions also contribute to inflammation, cell injury, and loss of endothelial barrier function. In the context of lung transplantation, various parenchymal cell populations as well as passenger donor macrophages or neutrophils sequestered in the lung may be primed by brain death and associated stressors. Targeting each of these cell types and pathways is logistically impractical. Rather, pivotal common mechanisms governing pathogenic pulmonary responses to inflammation represent attractive therapeutic targets. In experimental systems, S-1-P (63, 64), PAR-1 (64, 65), and adenosine-2 receptor agonists (66, 67) can reverse established ALI, perhaps by modulating the balance between Rac- and Ras-mediated signaling pathways, and might thus reverse even established primary graft dysfunction.
Once established, ALI may resolve with minimal sequelae, or the lung may undergo fibroproliferative remodeling with loss of compliance and diffusing capacity via mechanisms that are poorly understood. Recently developed scoring systems for stratifying donor risk and recipient lung injury severity (45–47) and multicenter cooperative study groups should facilitate expeditious evaluation of preventive approaches, like soluble complement receptor type 1 (68), or candidate therapeutic agents. Expression of various protective proteins during the ischemic interval after lung harvest (69, 70) awaits advances in efficient industrial-scale vector development (G.A. Patterson, personal communication, 2006).
Recipient Selection
The proportion of patients receiving lung transplant with emphysema and A1AT deficiency (50%), cystic fibrosis (15%), and idiopathic pulmonary fibrosis (15%) have remained fairly constant since 1990, with primary pulmonary hypertension, sarcoidosis, retransplant, and an assortment of other diagnoses accounting for the remainder (13). Recipient selection criteria (71) have been substantially relaxed at many programs (72). As one consequence, the average age of lung candidates and recipients is steadily increasing (13, 14, 40). Of note, some U.S. registry studies suggest that patients with emphysema derive no survival benefit from transplantation (73–75), a phenomenon perhaps related to U.S. organ allocation strategies because it is not suggested in a European analysis (76). Improving medical therapies for pulmonary hypertension have dramatically reduced the need for transplant for this diagnosis (40).
Recipient Management and Associated Outcomes
One-year survival has improved slightly over the past 10 years, from about 75% to 82% (40). Since use of extended criteria and older donors has expanded during this interval and in older recipients (increasing recipient age is an independent risk factor (14)), expected adverse consequences of these donor trends have apparently been mitigated by improving program practices in other areas (organ preparation, perioperative support, immunosuppression). However, 5-year survival remains stubbornly below 50% (13, 14, 40).
In the absence of one clearly superior approach, a wide variety of maintenance immunosuppression strategies are currently being used in lung recipients. Mycophenolate mofetil and FK506 may be associated with reduced rates of acute infection and/or improved survival relative to azathioprine and cyclosporin, respectively (77–79), but these observations are not universally replicated (80–82). Few immunosuppressive agents have been formally studied in this population, but from the ever-broadening array of agents approved by the U.S. Food and Drug Administration or European Standards Agencies for use in kidney recipients, a regimen can now be tailored to each lung recipient’s risk factors, evolving clinical circumstances, and financial situation. Newer immunosuppressive agents are now being evaluated for lung transplant indications, in part because the room for improvement in 1-year survival remains substantial and favorable effects are thus easier to measure (83). Calcineurin inhibitor-associated renal insufficiency is very common among lung recipients within 5 years (creatinine >2.5 mg/dl in >30%; dialysis or renal transplant in 5–10%). Because their antiproliferative effects may also prevent or retard progression of OB, many centers are exploring conversion from calcineurin inhibition to a “renal-sparing” target-of-rapamycin inhibitor, but a high incidence of bronchial anastamotic dehiscences halted substitution of sirolimus at transplant (84, 85). Another approach to minimize cumulative pharmacologic toxicities utilizes “induction.” Although popular, interleukin (IL)-2R blockers have not yet consistently decreased acute rejection or infectious complications (86). High-dose ATG or Campath 1H (87) with low-dose conventional immunosuppression do not prevent chronic rejection despite profound long-term lymphocyte depletion, and at intermediate-term follow-up mortality and infectious complications appear similar to other regimens. Rapid steroid withdrawal or avoidance (84) is rarely attempted in lung allograft recipients because acute rejection is common and a strong risk factor for chronic rejection, whereas chronic rejection is prevalent despite relatively intense current immunosuppressive regimens.
Looking forward, aerosols deliver high concentrations of various drugs directly to the lung, thereby increasing their therapeutic index (88), an important opportunity unique to the lung. Because its phosphorylated form is an Edg-1 receptor agonist and should promote enhanced endothelial barrier function, preoperative loading with FTY720 may be particularly useful to prevent primary graft dysfunction in lung recipients, in addition to any effects it may have on cell trafficking and adaptive immunity (89). Induction therapy could provide a foundation for peripheral or central tolerance based on immunomodulatory costimulation (90, 91) or chemokine pathway blockade (92, 93).
Control of infection, particularly of herpes-family viruses, remains a particularly important issue for lung allograft recipients, perhaps because their immune suppression is relatively intense, and the lung is relatively vulnerable to local and systemic insults that accompany acute or recrudescent infection with these organisms. Prolonged prophylaxis for cytomegalovirus with ganciclovir or an orally bioavailable variant usually prevents viremia and disease during therapy, but after prophylaxis is stopped viral activation is prevalent and, anecdotally, the organism is more often resistant to conventional pharmacotherapy. Based on the notion that recipient immunity is integral to long-term control, and taking advantage of increasingly reliable tests to diagnose presymptomatic infection, an expectant “bait-and-switch” approach was effective at preventing symptomatic cytomegalovirus disease and facilitating short- and long-term viral control, at significantly reduced fiscal and physiologic costs (94). Likewise, invasive aspergillus, either at the bronchial anastomosis or occasionally in native or graft parenchyma, is a highly morbid complication; prophylactic inhaled or systemic antifungal therapy is probably unnecessary unless airway ischemia at bronchocopy, sputum culture results, or environmental circumstances (e.g., construction or preoperative colonization) alter a particular patient’s a priori risk. When less common viruses such as adenovirus and respiratory syncytial virus invade the lung, survival is unusual because, at present, these organisms are essentially untreatable except by supportive measures.
OB describes fibrotic occlusion of small airways, the pathologic hallmark of chronic lung allograft rejection (95). OB can usually only be proven by histologic demonstration of OB on large tissue samples obtained at open lung biopsy, retransplant, or autopsy. The typical physiologic correlate of OB, bronchiolitis obliterans syndrome (BOS)—defined as a decline in FEV1 of more than 20% not attributable to acute infection or rejection—has been generally accepted as a valid proxy for OB (96). However, about 50% of patients with BOS do not have OB when pathologic material is comprehensively audited (25, 97). In these patients recent evidence shows that BOS may be caused by silent gastroesophageal reflux and chronic aspiration (98), and performing early antireflux surgery reduces the incidence of BOS (99). Adaptive immunity mediated by antibody and T-cell mechanisms clearly plays a central role in OB pathogenesis (100–103), as do immunity to lung autoantigens (104) and innate immune activation (105–109). Pharmacologic approaches to inhibit innate immune system activation, such as azithromycin (110), are moving into the clinic.
Malignancy accounts for about 10–15% of deaths during late follow-up, similar to other organ recipient populations. Given the terrible results with chemotherapy for posttransplant lymphoproliferative disease in lung recipients (111), the advent of relatively safe, effective treatment with anti-CD20 offers a welcome alternative when reduction in immunosuppression is not curative (112).
On balance, the evidence to date supports the logical notion that antibody reactive with donor antigens contributes to both acute and chronic lung injury. In a large series of Harefield’s heart-lung recipients, a positive NIH lymphocytotoxic crossmatch was associated with 50% survival among 32 patients, compared to 61% survival with a negative result (113). Strikingly, in a subset of patients with a positive T cell–directed crossmatch, zero of four patients survived beyond 70 days, compared to 68% of 100 patients with a negative crossmatch, suggesting that antibody detected by this assay is highly injurious to the graft. Among 656 first-time lung recipients from the combined Toronto and Duke experience, 20 (3%) who had a panel-reactive antibody (PRA) titer >25% exhibited significantly decreased median (1.5 vs. 5.2 years) and 1-month survival (70% vs. 90%) (114). Thus, a high PRA (anti-HLA antibodies) reflects a propensity to humoral alloreactivity and is a risk factor for acute and chronic allograft injury (102). Recent reports suggest that antibody directed against non-HLA antigens can also trigger acute lung injury (115, 116). Although two ABO-incompatible lung reported in the popular press were associated with early death (117, 118), two published cases demonstrate that anti-ABO antibody can be effectively managed by available therapy (119, 120).
In addition to crude survival statistics and costs, patients and health care payors are increasingly focused on quality of life and return to work as important measures of successful transplant outcome (121, 122). Although over 80% of surviving lung recipients report no activity restrictions at 1 and 5 years, less than 40% return to work (14): in the United States, return to gainful employment is often impeded by astronomical ongoing medication costs and unaffordable insurance premiums, effectively trapping patients on disability. Although piecemeal remedies specific to transplantation are conceivable, resolution of this catch-22 will probably require fundamental restructuring of U.S. health care financing, a daunting challenge.
Future Advances
Xenotransplantation from genetically modified pigs offers the most likely near-term prospect for alleviating the lung donor shortage, but lung xenografting poses formidable problems (123–125). Whether triggered primarily by cellular adhesive interactions or coagulation pathway incompatibilities, to fully prevent acute lung injury in this context, substantial additional work appears necessary. Investment in primate heart and lung allograft tolerance models should yield new knowledge applicable to xenografts, and to address chronic allograft rejection issues that are specific to thoracic organs (104, 126, 127). In the longer term, durable fully implantable artificial lung technology will probably require evolution of ECMO to a self-renewing biological interface propagated on new biocompatible materials (128, 129).
SUMMARY
Stable overall lung transplant activity for the past decade reflects the net effect of competing forces. Some restrict activity and patient access (low lung donation rates, adverse donor demographics, preferential double lung use), while countervailing influences include liberalization of recipient age and comorbidity criteria, relaxing donor acceptance standards, and initiatives to disseminate optimal donor management practices. Incremental improvement in 1-year lung transplant outcomes have been achieved despite use of older donors in older, sicker recipients, likely due to improved donor management and increasing availability of newer antibiotic and immunosuppressive regimens. However, 5-year survival remains disappointing at below 50%, with OB, infection, renal insufficiency, and malignancy all contributing to late attrition. These persistent problems underscore the imperative to develop tolerance induction strategies for clinical lung transplantation, and to better understand the contribution of innate immune and nonimmune mechanisms to BOS and OB. Improved policies based on wait-list and posttransplant risk factors are being implemented to fairly allocate organs, and may aid patients and their physicians in deciding whether to accept marginal organs. In addition, socioeconomic barriers will need to be addressed for the full therapeutic potential of lung transplantation to be realized.
REFERENCES
1. Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease.
N Engl J Med 1982; 306(10): 557.
2. Cooper JD, Pearson FG, Patterson GA, et al. Technique of successful lung transplantation in humans.
J Thorac Cardiovasc Surg 1987; 93(2): 173.
3. Hardy JD, Alican F. Lung transplantation.
Adv Surg 1966; 2: 235.
4. Veith FJ, Koerner SK, Hagstrom JW, et al. Experience in clinical lung transplantation.
JAMA 1972; 222(7): 779.
5. Nelems JM, Rebuck AS, Cooper JD, et al. Human lung transplantation.
Chest 1980; 78(4): 569.
6. Lima O, Cooper JD, Peters WJ, et al. Effects of methylprednisolone and azathioprine on bronchial healing following lung autotransplantation.
J Thorac Cardiovasc Surg 1981; 82(2): 211.
7. Reitz BA, Bieber CP, Raney AA, et al. Orthotopic heart and combined heart and lung transplantation with cyclosporin-A immune suppression.
Transplant Proc 1981; 13(1 Pt 1): 393.
8. Grillo HC. Surgical approaches to the trachea.
Surg Gynecol Obstet 1969; 129(2): 347.
9. Blumenstock DA, Cannon FD. Prolonged survival of lung allografts in nonidentical beagles by treatment with lethal total-body irradiation, autologous bone marrow transplantation, and methotrexate.
Transplantation 1978; 26(3): 203.
10. Reitz BA, Burton NA, Jamieson SW, et al. Heart and lung transplantation: autotransplantation and allotransplantation in primates with extended survival.
J Thorac Cardiovasc Surg 1980; 80(3): 360.
11. Norin AJ, Veith FJ, Emeson EE, et al. Improved survival of transplanted lungs in mongrel dogs treated with cyclosporin A.
Transplantation 1981; 32(3): 259.
12. Reitz BA, Gaudiani VA, Hunt SA, et al. Diagnosis and treatment of allograft rejection in heart-lung transplant recipients.
J Thorac Cardiovasc Surg 1983; 85(3): 354.
13. Pierson RN 3rd, Barr ML, McCullough KP, et al. Thoracic organ transplantation.
Am J Transplant 2004; 4(Suppl 9): 93.
14. Trulock EP, Edwards LB, Taylor DO, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult lung and heart-lung transplant report–2005.
J Heart Lung Transplant 2005; 24(8): 956.
15. Schroder C, Scholl F, Daon E, et al. A modified bronchial anastomosis technique for lung transplantation.
Ann Thorac Surg 2003; 75(6): 1697.
16. Garfein ES, Ginsberg ME, Gorenstein L, McGregor CC, Schulman LL. Superiority of end-to-end versus telescoped bronchial anastomosis in single lung transplantation for pulmonary emphysema.
J Thorac Cardiovasc Surg 2001; 121(1): 149.
17. Griffith BP, Magee MJ, Gonzalez IF, et al. Anastomotic pitfalls in lung transplantation.
J Thorac Cardiovasc Surg 1994; 107(3): 743.
18. Anderson MB, Kriett JM, Harrell J, et al. Techniques for bronchial anastomosis.
J Heart Lung Transplant 1995; 14(6 Pt 1): 1090.
19. Aigner C, Jaksch P, Seebacher G, et al. Single running suture–the new standard technique for bronchial anastomoses in lung transplantation.
Eur J Cardiothorac Surg 2003; 23(4): 488.
20. Norgaard MA, Andersen CB, Pettersson G. Does bronchial artery revascularization influence results concerning
bronchiolitis obliterans syndrome and/or obliterative bronchiolitis after lung transplantation?
Eur J Cardiothorac Surg 1998; 14(3): 311.
21. Baudet EM, Dromer C, Dubrez J, et al. Intermediate-term results after en bloc double-lung transplantation with bronchial arterial revascularization. Bordeaux Lung and Heart-Lung Transplant Group.
J Thorac Cardiovasc Surg 1996; 112(5): 1292.
22. Taghavi S, Birsan T, Seitelberger R, et al. Initial experience with two sequential anterolateral thoracotomies for bilateral lung transplantation.
Ann Thorac Surg 1999; 67(5): 1440.
23. al-Kattan K, Tadjkarimi S, Cox A, et al. Evaluation of the long-term results of single lung versus heart-lung transplantation for emphysema.
J Heart Lung Transplant 1995; 14(5): 824.
24. Stoica SC, McNeil KD, Perreas K, et al. Heart-lung transplantation for Eisenmenger syndrome: early and long-term results.
Ann Thorac Surg 2001; 72(6): 1887.
25. Appel JZ III, Davis RD. The evolution of lung transplantation: A clinical update.
Transplant Rev 2004; 18: 20.
26. Fischer S, Meyer K, Tessmann R, et al. Outcome following single vs bilateral lung transplantation in recipients 60 years of age and older.
Transplant Proc 2005; 37(2): 1369.
27. Egan TM. Ethical issues in thoracic organ distribution for transplant.
Am J Transplant 2003; 3(4): 366.
28. Starnes VA, Bowdish ME, Woo MS, et al. A decade of living lobar lung transplantation: recipient outcomes.
J Thorac Cardiovasc Surg 2004; 127(1): 114.
29. Date H, Tanimoto Y, Goto K, et al. A new treatment strategy for advanced idiopathic interstitial pneumonia: living-donor lobar lung transplantation.
Chest 2005; 128(3): 1364.
30. Bowdish ME, Barr ML, Schenkel FA, et al. A decade of living lobar lung transplantation: perioperative complications after 253 donor lobectomies.
Am J Transplant 2004; 4(8): 1283.
31. Novick RJ, Stitt LW, Al-Kattan K, et al. Pulmonary retransplantation: predictors of graft function and survival in 230 patients. Pulmonary Retransplant Registry.
Ann Thorac Surg 1998; 65(1): 227.
32. Brugiere O, Thabut G, Castier Y, et al. Lung retransplantation for
bronchiolitis obliterans syndrome: long-term follow-up in a series of 15 recipients.
Chest 2003; 123(6): 1832.
33. de Perrot M, Keshavjee S. Lung preservation.
Semin Thorac Cardiovasc Surg 2004; 16(4): 300.
34. de Perrot M, Snell GI, Babcock WD, et al. Strategies to optimize the use of currently available lung donors.
J Heart Lung Transplant 2004; 23(10): 1127.
35. Steen S, Liao Q, Wierup PN, et al. Transplantation of lungs from non-heart-beating donors after functional assessment ex vivo.
Ann Thorac Surg 2003; 76(1): 244.
36. Van Raemdonck DE, Rega FR, Neyrinck AP, et al. Non-heart-beating donors.
Semin Thorac Cardiovasc Surg 2004; 16(4): 309.
37. Loehe F, Preissler G, Annecke T, et al. Continuous infusion of nitroglycerin improves pulmonary graft function of non-heart-beating donor lungs.
Transplantation 2004; 77(12): 1803.
38. Rega FR, Jannis NC, Verleden GM, et al. Should we ventilate or cool the pulmonary graft inside the non-heart-beating donor?
J Heart Lung Transplant. 2003; 22(11): 1226.
39. Egan TM, Thomas Y, Gibson D, et al. Trigger for intercellular adhesion molecule-1 expression in rat lungs transplanted from non-heart-beating donors.
Ann Thorac Surg 2004; 77(3): 1048.
40. Barr ML, Bourge RC, Orens JB, et al. Thoracic organ transplantation in the United States, 1994–2003.
Am J Transplant 2005; 5(4 Pt 2): 934.
41. Pierson RN, Milstone AP, Loyd JE, et al. Lung allocation in the United States, 1995–1997: an analysis of equity and utility.
J Heart Lung Transplant 2000; 19(9): 846.
42. Smits JM, Mertens BJ, Van Houwelingen HC, et al. Predictors of lung transplant survival in Eurotransplant.
Am J Transplant 2003; 3(11): 1400.
43. de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia-reperfusion-induced lung injury.
Am J Respir Crit Care Med 2003; 167(4): 490.
44. Meyers BF, de la Morena M, Sweet SC, et al. Primary graft dysfunction and other selected complications of lung transplantation: A single-center experience of 983 patients.
J Thorac Cardiovasc Surg 2005; 129(6): 1421.
45. Thabut G, Vinatier I, Stern JB, et al. Primary graft failure following lung transplantation: predictive factors of mortality.
Chest 2002; 121(6): 1876.
46. Parekh K, Meyer BF. Primary lung allograft dysfunction: a clinical and experimental review.
Transplant Reviews 2005; 19: 88.
47. Sekine Y, Waddell TK, Matte-Martyn A, et al. Risk quantification of early outcome after lung transplantation: donor, recipient, operative, and post-transplant parameters.
J Heart Lung Transplant 2004; 23(1): 96.
48. Avlonitis VS, Fisher AJ, Kirby JA, Dark JH. Pulmonary transplantation: the role of brain death in donor lung injury.
Transplantation 2003; 75(12): 1928.
49. Venuta F, Rendina EA, Bufi M, et al. Preimplantation retrograde pneumoplegia in clinical lung transplantation.
J Thorac Cardiovasc Surg 1999; 118(1): 107.
50. Wittwer T, Franke U, Fehrenbach A, et al. Impact of retrograde graft preservation in Perfadex-based experimental lung transplantation.
J Surg Res 2004; 117(2): 239.
51. Ardehali A, Laks H, Russell H, et al. Modified reperfusion and ischemia-reperfusion injury in human lung transplantation.
J Thorac Cardiovasc Surg 2003; 126(6): 1929.
52. Glassman LR, Keenan RJ, Fabrizio MC, et al. Extracorporeal membrane oxygenation as an adjunct treatment for primary graft failure in adult lung transplant recipients.
J Thorac Cardiovasc Surg 1995; 110(3): 723.
53. Meyers BF, Sundt TM 3rd, Henry S, et al. Selective use of extracorporeal membrane oxygenation is warranted after lung transplantation.
J Thorac Cardiovasc Surg 2000; 120(1): 20.
54. Oto T, Rosenfeldt F, Rowland M, et al. Extracorporeal membrane oxygenation after lung transplantation: evolving technique improves outcomes.
Ann Thorac Surg 2004; 78(4): 1230.
55. Dahlberg PS, Prekker ME, Herrington CS, et al. Medium-term results of extracorporeal membrane oxygenation for severe acute lung injury after lung transplantation.
J Heart Lung Transplant 2004; 23(8): 979.
56. Gunther A, Walmrath D, Grimminger F, Seeger W. Pathophysiology of acute lung injury.
Semin Respir Crit Care Med 2001; 22(3): 247.
57. Tzouvelekis A, Pneumatikos I, Bouros D. Serum biomarkers in acute respiratory distress syndrome an ailing prognosticator.
Respir Res 2005; 6(1): 62.
58. Toy P, Popovsky MA, Abraham E, et al. National Heart, Lung and Blood Institute Working Group on TRALI. Transfusion-related acute lung injury: definition and review.
Crit Care Med 2005; 33(4): 721.
59. Dreyfuss D, Ricard JD. Acute lung injury and bacterial infection.
Clin Chest Med. 2005; 26(1): 105.
60. Guo RF, Ward PA. Role of C5a in inflammatory responses.
Annu Rev Immunol 2005; 23: 821.
61. Puneet P, Moochhala S, Bhatia M. Chemokines in acute respiratory distress syndrome.
Am J Physiol Lung Cell Mol Physiol 2005; 288(1): L3.
62. Grigoryev DN, Finigan JH, Hassoun P, Garcia JG. Science review: searching for gene candidates in acute lung injury.
Crit Care 2004; 8(6): 440.
63. McVerry BJ, Garcia JGN. Endothelial cell barrier regulation by sphingosine 1-phosphate.
J Cell Biochem 2004; 92: 1075.
64. Finigan JH, Dudek SM, Singleton PA, et al. Activated protein C mediates novel lung endothelial barrier enhancement: Role of sphingosine 1-phosphate receptor transactivation
. J Biol Chem. 2005; 280(17): 17286.
65. Bernard GR, Vincent JL, Laterre PF, et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis.
N Engl J Med 2001; 344(10): 699.
66. Seibert AF, Thompson WJ, Taylor A, et al. Reversal of increased microvascular permeability associated with ischemia-reperfusion: role of cAMP.
J Applied Physiol 1992; 72(1): 389.
67. Khimenko PL, Moore TM, Hill LW, et al. Adenosine A2 receptors reverse ischemia-reperfusion lung injury independent of beta-receptors.
J Appl Physiol 1995; 78(3): 990.
68. Keshavjee S, Davis RD, Zamora MR, et al. A randomized, placebo-controlled trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human beings.
J Thorac Cardiovasc Surg 2005; 129(2): 423.
69. Itano H, Mora BN, Zhang W, et al. Lipid-mediated ex vivo gene transfer of viral interleukin 10 in rat lung allotransplantation.
J Thorac Cardiovasc Surg 2001; 122(1): 29.
70. Martins S, de Perrot M, Imai Y, et al. Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model.
Gene Ther 2004; 11(24): 1786..
71. Maurer JR, Frost AE, Estenne M, et al. International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society.
Transplantation 1998; 66(7): 951.
72. Patel VS, Palmer SM, Messier RH, Davis RD. Clinical outcome after coronary artery revascularization and lung transplantation.
Ann Thorac Surg 2003; 75(2): 372.
73. Martinez FJ, Kotloff R. Prognostication in chronic obstructive pulmonary disease: implications for lung transplantation.
Semin Respir Crit Care Med 2001; 22(5): 489.
74. Egan TM, Bennett LE, Garrity ER, et al. Predictors of death on the UNOS lung transplant waiting list: results of a multivariate analysis.
J Heart Lung Transplant 2001; 20(2): 242.
75. Martinez FJ, Chang A. Surgical therapy for chronic obstructive pulmonary disease.
Semin Respir Crit Care Med 2005; 26(2): 167.
76. Groen H, van der Bij W, Koeter GH, TenVergert EM. Cost-effectiveness of lung transplantation in relation to type of end-stage pulmonary disease.
Am J Transplant 2004; 4(7): 1155.
77. Treede H, Klepetko W, Reichenspurner H, et al. Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols.
J Heart Lung Transplant 2001; 20(5): 511.
78. Bhorade SM, Jordan A, Villanueva J, et al. Comparison of three tacrolimus-based immunosuppressive regimens in lung transplantation.
Am J Transplant 2003; 3(12): 1570.
79. Keenan RJ, Konishi H, Kawai A, et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation.
Ann Thorac Surg 1995; 60(3): 580.
80. Knoop C, Haverich A, Fischer S. Immunosuppressive therapy after human lung transplantation.
Eur Respir J 2004; 23(1): 159.
81. Palmer SM, Baz MA, Sanders L, et al. Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection.
Transplantation 2001; 71(12): 1772.
82. Zuckermann A, Reichenspurner H, Birsan T, et al. Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial.
J Thorac Cardiovasc Surg 2003; 125(4): 891.
83. Snell GI, Levvey BJ, Zheng L, et al. Everolimus alters the bronchoalveolar lavage and endobronchial biopsy immunologic profile post-human lung transplantation.
Am J Transplant 2005; 5(6): 1446.
84. King-Biggs MB, Dunitz JM, Park SJ, et al. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation.
Transplantation 2003; 75(9): 1437.
85. Groetzner J, Kur F, Spelsberg F, et al. Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression.
J Heart Lung Transplant. 2004; 23(5): 632.
86. Garrity ER Jr., Villanueva J, Bhorade SM, et al. Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin 2 receptor antibody.
Transplantation 2001; 71(6): 773.
87. McCurry KR, Iacono A, Zeevi A, et al. Early outcomes in human lung transplantation with Thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy.
J Thorac Cardiovasc Surg 2005; 130(2): 528.
88. Iacono AT, Corcoran TE, Griffith BP, et al. Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.
Eur Respir J. 2004; 23(3): 384.
89. Tedesco-Silva H, Mourad G, Kahan BD, et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation.
Transplantation 2005; 79(11): 1553.
90. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation.
N Engl J Med. 2005; 353(8): 770.
91. Pierson RN 3rd, Crowe JE Jr., Pfeiffer S, et al. CD40-ligand in primate cardiac allograft and viral immunity.
Immunol Res 2001; 23(2–3): 253.
92. Hancock WW. Chemokine receptor-dependent alloresponses.
Immunol Rev 2003; 196: 37.
93. Nguyen BN, Schroeder C, Zhang T, et al. CCR5 blockade attenuates inflammation and cardiac allograft vasculopathy in non-human primates treated with cyclosporine A.
J Heart Lung Transplant 2006; 2: 578.
94. Brumble LM, Milstone AP, Loyd JE, et al. Prevention of cytomegalovirus infection and disease after lung transplantation: results using a unique regimen employing delayed ganciclovir.
Chest 2002; 121(2): 407.
95. Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group.
J Heart Lung Transplant 1996; 15(1 Pt 1): 1.
96. Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation.
J Heart Lung Transplant 1993; 12(5): 713.
97. Verleden GM, Dupont LJ, Van Raemdonck DE. Is it
bronchiolitis obliterans syndrome or is it chronic rejection: a reappraisal?
Eur Respir J 2005; 25(2): 221.
98. Cantu E 3rd, Appel JZ 3rd, Hartwig MG, et al. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease.
Ann Thorac Surg 2004; 78(4): 1142.
99. Davis RD Jr., Lau CL, Eubanks S, et al. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation.
J Thorac Cardiovasc Surg 2003; 125(3): 533.
100. Shoji T, Wain JC, Houser SL, et al. Indirect recognition of MHC class I allopeptides accelerates lung allograft rejection in miniature swine.
Am J Transplant 2005; 5(7): 1626.
101. Khalifah AP, Hachem RR, Chakinala MM, et al. Minimal acute rejection after lung transplantation: a risk for
bronchiolitis obliterans syndrome.
Am J Transplant 2005; 5(8): 2022.
102. Jaramillo A, Fernandez FG, Kuo EY, et al. Immune mechanisms in the pathogenesis of
bronchiolitis obliterans syndrome after lung transplantation.
Pediatr Transplant 2005; 9(1): 84.
103. Hadjiliadis D, Chaparro C, Reinsmoen NL, et al. Pre-transplant panel reactive antibody in lung transplant recipients is associated with significantly worse post-transplant survival in a multicenter study.
J Heart Lung Transplant 2005; 24: S249.
104. Sumpter TL, Wilkes DS. Role of autoimmunity in organ allograft rejection: a focus on immunity to type V collagen in the pathogenesis of lung transplant rejection.
Am J Physiol Lung Cell Mol Physiol 2004; 286(6): L1129.
105. Jackson A, Palmer S, Davis RD, et al. Cytokine genotypes in kidney, heart, and lung recipients: consequences for acute and chronic rejection.
Transplant Proc 2001; 33(1–2): 489.
106. Palmer SM, Burch LH, Davis RD, et al. The role of innate immunity in acute allograft rejection after lung transplantation.
Am J Respir Crit Care Med 2003; 168(6): 628.
107. Christie JD, Kotloff RM, Ahya VN, et al. The effect of primary graft dysfunction on survival after lung transplantation.
Am J Respir Crit Care Med 2005; 171(11): 1312.
108. Nelsestuen GL, Martinez MB, Hertz MI, et al. Proteomic identification of human neutrophil alpha-defensins in chronic lung allograft rejection.
Proteomics 2005; 5(6): 1705.
109. Bowdish ME, Arcasoy SM, Wilt JS, et al. Surrogate markers and risk factors for chronic lung allograft dysfunction.
Am J Transplant 2004; 4(7): 1171.
110. Shitrit D, Bendayan D, Gidon S, et al. Long-term azithromycin use for treatment of
bronchiolitis obliterans syndrome in lung transplant recipients.
J Heart Lung Transplant 2005; 24(9): 1440.
111. Gao SZ, Chaparro SV, Perlroth M, et al. Post-transplantation lymphoproliferative disease in heart and heart-lung transplant recipients: 30-year experience at Stanford University.
J Heart Lung Transplant 2003; 22(5): 505.
112. Reams BD, McAdams HP, Howell DN, et al. Posttransplant lymphoproliferative disorder: incidence, presentation, and response to treatment in lung transplant recipients.
Chest 2003; 124(4): 1242.
113. Smith JD, Danskine AJ, Laylor RM, et al. The effect of panel reactive antibodies and the donor specific crossmatch on graft survival after heart and heart-lung transplantation.
Transpl Immunol 1993; 1(1): 60.
114. Hadjiliadis D, Chaparro C, Reinsmoen NL, et al. Pre-transplant panel reactive antibody in lung transplant recipients is associated with significantly worse post-transplant survival in a multicenter study.
J Heart Lung Transplant 2005; 24(7): S249.
115. Magro CM, Klinger DM, Adams PW, et al. Evidence that humoral allograft rejection in lung transplant patients is not histocompatibility antigen-related.
Am J Transplant 2003; 3(10): 1264.
116. Ramachandran S, Goers T, Parekh K, et al. Epithelial specific, non-MHC antibodies, induce hyperacute rejection of human lung allografts. Presented at American Society for Histocompatibility and Immunogenetics, Washington, D.C., November 2005.
117. Resnick D. The Jesica Santillan tragedy: lessons learned.
Hastings Cent Rep 2003; 33(4): 15.
118. Transplant News, March 9, 2004; p7.
119. Pierson RN 3rd, Loyd JE, Goodwin A, et al. Successful management of an ABO-mismatched lung allograft using antigen-specific immunoadsorption, complement inhibition, and immunomodulatory therapy.
Transplantation 2002; 74(1): 79.
120. Banner NR, Rose ML, Cummins D, et al. Management of an ABO-incompatible lung transplant.
Am J Transplant 2004; 4(7): 1192.
121. Choong CK, Meyers BF. Quality of life after lung transplantation.
Thorac Surg Clin 2004; 14(3): 385.
122. Singer LG. Cost-effectiveness and quality of life: benefits of lung transplantation.
Respir Care Clin N Am 2004; 10(4): 449.
123. Nguyen BH, Zwets E, Schroeder C, et al. Beyond antibody-mediated rejection: hyperacute lung rejection as a paradigm for dysregulated inflammation.
Curr Drug Targets Cardiovasc Haematol Disord 2005; 5(3): 255.
124. Lau CL, Cantu E 3rd, Gonzalez-Stawinski GV, et al. The role of antibodies and von Willebrand factor in discordant pulmonary xenotransplantation.
Am J Transplant 2003; 3(9): 1065.
125. Collins BJ, Blum MG, Parker RE, et al. Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection
. J Appl Physiol. 2001; 90(6): 2257.
126. Massicot-Fisher J, Noel P, Madsen JC. Recommendations of the National Heart, Lung and Blood Institute Heart and Lung Tolerance Working Group.
Transplantation 2001; 72(8): 1467.
127. Azimzadeh AM, Pfeiffer S, Wu GS, et al. Humoral immunity to vimentin is associated with cardiac allograft injury in nonhuman primates.
Am J Transplant. 2005; 5(10): 2349.
128. Wu ZJ, Gartner M, Litwak KN, Griffith BP. Progress toward an ambulatory pump-lung.
J Thorac Cardiovasc Surg 2005; 130(4): 973.
129. Bartlett RH. Extracorporeal life support: history and new directions.
Semin Perinatol 2005; 29(1): 2.
