Therapy For Lung Transplantation Research Articles

Phage Therapy in Lung Transplantation: Current Status and Future Possibilities.

Patients with chronic lung disease and lung transplantation have high rates of colonization and infection from multidrug-resistant (MDR) organisms. This article summarizes the current state of knowledge regarding phage therapy in the setting of lung transplantation. Phage therapy has been used in several lung transplant candidates and recipients on a compassionate use basis targeting mostly MDR gram-negative infections and atypical mycobacterial infections with demonstrated clinical safety. Phage biodistribution given intravenously or via nebulization has not been extensively studied, though preliminary data are presented. Phage interacts with both the innate and adaptive immune system; current literature demonstrates the development of serum neutralization in some cases of phage therapy, although the clinical impact seems variable. A summary of current clinical trials involving patients with chronic lung disease is presented, though none are specifically targeting lung transplant candidates or recipients. In addition to treatment of active infections, a variety of clinical scenarios may benefit from phage therapy, and well-designed clinical trials involving this vulnerable patient population are needed: pre- or peritransplantation use of phage in the setting of MDR organism colonization may lead to waitlisting of candidates currently declined by many centers, along with potential reduction of waitlist mortality rates and posttransplant infections; phage may be used for biofilm-related bronchial stent infections; and, finally, there is a possibility that phage use can affect allograft function and chronic rejection.

Preemptive antiviral therapy in lung transplantation from hepatitis C donors results in a rapid and sustained virologic response

ObjectiveThe study objective was to assess the safety and efficacy of a preemptive direct-acting antiviral therapy in lung transplants from hepatitis C virus donors to uninfected recipients. MethodsThis study is a prospective, open-label, nonrandomized, pilot trial. Recipients of hepatitis C virus nucleic acid test positive donor lungs underwent preemptive direct-acting antiviral therapy with glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks from January 1, 2019, to December 31, 2020. Recipients of nucleic acid test positive lungs were compared with recipients of lungs from nucleic acid test negative donors. Primary end points were Kaplan–Meier survival and sustained virologic response. Secondary outcomes included primary graft dysfunction, rejection, and infection. ResultsFifty-nine lung transplantations were included: 16 nucleic acid test positive and 43 nucleic acid test negative. Twelve nucleic acid test positive recipients (75%) developed hepatitis C virus viremia. Median time to clearance was 7 days. All nucleic acid test positive patients had undetectable hepatitis C virus RNA by week 3, and all alive patients (n = 15) remained negative during follow-up with 100% sustained virologic response at 12 months. One nucleic acid test positive patient died of primary graft dysfunction and multiorgan failure. Three of 43 nucleic acid test negative patients (7%) had hepatitis C virus antibody positive donors. None of them developed hepatitis C virus viremia. One-year survival was 94% for nucleic acid test positive recipients and 91% for nucleic acid test negative recipients. There was no difference in primary graft dysfunction, rejection, or infection. One-year survival for nucleic acid test positive recipients was similar to a historical cohort of the Scientific Registry of Transplant Recipients (89%). ConclusionsRecipients of hepatitis C virus nucleic acid test positive lungs have similar survival as recipients of nucleic acid test negative lungs. Preemptive direct-acting antiviral therapy results in rapid viral clearance and sustained virologic response at 12 months. Preemptive direct-acting antiviral may partially prevent hepatitis C virus transmission.

Assessing the nitric oxide efficacy in bilateral lung transplantation

Background. One of the most frequent and severe complications in the early postoperative period in lung transplantation is primary graft dysfunction resulting from ischemia-reperfusion injury. There is evidence of the effectiveness of using inhaled nitric oxide in order to prevent such injury.Objective. To assess the effectiveness of nitric oxide in the intra- and early postoperative period in bilateral lung transplantation.Material and methods. We examined 43 patients who underwent bilateral lung transplantation at the N.V. Sklifosovsky Research Institute for Emergency Medicine in the period from 2012-2021. The patients were divided into two groups. The study group consisted of 23 patients, whose complex of treatment included the use of inhaled nitric oxide. Patients in the comparison group (n=20) received a standard therapy. The end points of the study were: the mechanical ventilation duration, the frequency of using extracorporeal membrane oxygenation and its duration, mortality, dynamics of oxygenation index, blood lactate level, pH, base deficiency.Results. The use of inhaled nitric oxide therapy in patients in the intra- and early postoperative period during lung transplantation improved the ventilation-perfusion ratio, as evidenced by an increase in the oxygenation index by 1.1 times (p=0.128) and 1.3 times (p=0.026) at 48 and 72 hours after surgery, respectively. Meanwhile, the frequency of using extracorporeal membrane oxygenation during surgery was found to decrease by 1.2 times (p=0.033), and that after surgery decreased by 1.4 times (p=0.474); the mechanical ventilation duration decreased by 1.4 times (p=0.042); the duration of extracorporeal membrane oxygenation decreased by 1.6 times (p=0.028); mortality reduced by 8%.Conclusion. The use of inhaled nitric oxide therapy for lung transplantation had a positive effect on the intra- and early postoperative period, as indicated by an improvement in blood gas parameters, a reduction in the frequency and duration of veno-arterial extracorporeal membrane oxygenation, and the duration of mechanical ventilation.

Differential expression of circulating miRNAs after alemtuzumab induction therapy in lung transplantation

Alemtuzumab is a monoclonal antibody targeting CD52, used as induction therapy after lung transplantation (LTx). Its engagement produces a long-lasting immunodepletion; however, the mechanisms driving cell reconstitution are poorly defined. We hypothesized that miRNAs are involved in this process. The expression of a set of miRNAs, cytokines and co-signaling molecules was measured with RT-qPCR and flow cytometry in prospectively collected serum samples of LTx recipients, after alemtuzumab or no induction therapy. Twenty-six LTx recipients who received alemtuzumab and twenty-seven matched LTx recipients without induction therapy were included in the analysis. One year after transplantation four miRNAs were differentially regulated: miR-23b (p = 0.05) miR-146 (p = 0.04), miR-155 (p < 0.001) and miR-486 (p < 0.001). Expression of 3 miRNAs changed within the alemtuzumab group: miR-146 (p < 0.001), miR-155 (p < 0.001) and miR-31 (p < 0.001). Levels of IL-13, IL-4, IFN-γ, BAFF, IL-5, IL-9, IL-17F, IL-17A and IL-22 were different one year after transplantation compared to baseline. In no-induction group, concentration of sCD27, sB7.2 and sPD-L1 increased overtime. Expression of miR-23b, miR-146, miR-486, miR-155 and miR-31 was different in LTx recipients who received alemtuzumab compared to recipients without induction therapy. The observed cytokine pattern suggested proliferation of specific B cell subsets in alemtuzumab group and co-stimulation of T-cells in no-induction group.

Long- and short-term clinical impact of awake extracorporeal membrane oxygenation as bridging therapy for lung transplantation

BackgroundAs lung transplantation (LTx) is becoming a standard treatment for end-stage lung disease, the use of bridging with extracorporeal membrane oxygenation (ECMO) is increasing. We examined the clinical impact of being awake during ECMO as bridging therapy in patients awaiting LTx.MethodsIn this single-center study, we retrospectively reviewed 241 consecutive LTx patients between October 2012 and March 2019; 64 patients received ECMO support while awaiting LTx. We divided into awake and non-awake groups and compared.ResultsTwenty-five patients (39.1%) were awake, and 39 (61.0%) were non-awake. The median age of awake patients was 59.0 (interquartile range, 52.5–63.0) years, and 80% of the group was men. The awake group had better post-operative outcomes than the non-awake group: statistically shorter post-operative intensive care unit length of stay [awake vs. non-awake, 6 (4–8.5) vs. 18 (11–36), p < 0.001], longer ventilator free days [awake vs. non-awake, 24 (17–26) vs. 0 (0–15), p < 0.001], and higher gait ability after LTx (awake vs. non-awake, 92% vs. 59%, p = 0.004), leading to higher 6-month and 1-year lung function (forced expiratory volume in 1 s: awake vs. non-awake, 6-month, 77.5% vs. 61%, p = 0.004, 1-year, 75% vs. 57%, p = 0.013). Furthermore, the awake group had significantly lower 6-month and 1-year mortality rates than the non-awake group (6-month 12% vs. 38.5%, p = 0.022, 1-year 24% vs. 53.8%, p = 0.018).ConclusionsIn patients with end-stage lung disease, considering the long-term and short-term impacts, the awake ECMO strategy could be useful compared with the non-awake ECMO strategy.

Outcomes with alemtuzumab induction therapy in lung transplantation: a comprehensive large-scale single-center analysis.

Alemtuzumab is a monoclonal antibody targeting CD52, increasingly used as induction therapy after transplantation. The aim of this study was to analyze the outcomes of alemtuzumab induction therapy followed by a low-dose maintenance immunosuppression in a large single-center cohort of lung transplant recipients. All patients, who received alemtuzumab induction followed by a low-dose maintenance immunosuppression were included in the analysis. Short- and long-term outcomes were analyzed. 721 lung transplant recipients, transplanted between January 2008 and June 2019, were included in this retrospective study. Freedom from higher-grade ACR at 1, 5, and 10years was 98%, 96%, and 96%, respectively. Thirty-nine patients (5%) developed clinical AMR. Twenty-one percent of patients developed high-grade CKD. A total of 1488 infections were recorded. Sixteen percent were diagnosed within the first 3months. Sixty-two patients (9%) developed a malignancy during follow-up. Freedom from CLAD at 1, 5, and 10years was 94%, 72%, and 53%, respectively. Overall survival rates at 1, 5, and 10years were 85%, 71%, and 61%, respectively. Alemtuzumab induction combined with a low-dose tacrolimus protocol is safe and associated with low rates of acute and chronic rejection, as well as an excellent long-term survival.

Comparative effectiveness of "liberal" and "restrictive" modes of intraoperative infusion-transfusion therapy in lung transplantation

Introduction. Recently, researchers have paid considerable attention to the strategy of intraoperative infusiontransfusion therapy in traumatic surgical interventions. The choice of a “restrictive” regimen during surgery in many studies has reduced the incidence and severity of intra- and postoperative complications.Objective. Comparison of the effectiveness of "liberal" and "restrictive" intraoperative infusion-transfusion therapy in lung transplantation.Material and methods. The study included 58 patients who underwent bilateral lung transplantation at N.V. Sklifosovsky Research Institute for Emergency Medicine in the period 2012-2019. The patients were divided into 2 groups: the comparison group included 31 patients, the total volume of intraoperative infusion-transfusion in whom was 14386.9 ± 1310.0 ml (16.5 ml/kg/h). Group II consisted of 27 patients; their total volume of intraoperative infusion-transfusion during surgery was 10251.3 ± 740.1 ml (12.9 ml/kg/hour). The analysis we performed included the volume and composition of intraoperative infusion-transfusion therapy, the volume of blood loss, clinical and laboratory data, the duration of mechanical ventilation, the frequency of intraoperative use of veno-arterial extracorporeal membrane oxygenation and the duration of its use after surgery, mortality.Results. When using the "restrictive" fluid therapy for lung transplantation, we observed a decrease in the volume of intraoperative blood loss by 1.3 times, the volume of transfusion of blood components, including fresh frozen plasma by 37%, erythrocyte suspension by 3.1 times, and instrumental reinfusion of autoerythrocytes by 1.56 times. At the same time, we revealed a decrease by 2.7 times in the duration of the mechanical ventilation use, a decreased frequency of using veno-arterial extracorporeal membrane oxygenation during surgery by 1.3 times, and a decreased duration of using veno-arterial extracorporeal membrane oxygenation after surgery by 2.3 times. Mortality was 38.7% in group I, and 30.7% in group II.Conclusion. The “restrictive” approach to intraoperative infusion-transfusion therapy in lung transplantation seems a promising new trend requiring further study and gaining the experience.

Belatacept dosing in Lung Transplantation: is there a Method to the Madness?

Data supporting the use of belatacept in non-abdominal organs are limited to case series and small cohorts involving patients requiring conversion due to CNI intolerance or contraindication. Review articles summarizing the efficacy of belatacept salvage therapy in lung transplantation have previously been published, however, dosing regimens are highly variable and uniform guidance is lacking. In this article, indications and considerations for belatacept use in lung transplant recipients are reviewed with a specific focus on dosing regimens. Utilization of standardized dosing protocols to guide belatacept conversion will both improve the ability to directly assess outcomes and provide the opportunity to improve future patient care. A suggested framework for dosing selection and timeline for cross titration is proposed herein.

Current status of inhaled nitric oxide therapy for lung transplantation in Japan: a nationwide survey.

Currently, inhaled nitric oxide (NO) therapy for lung transplantation is not covered by public health insurance in Japan. In this study, we evaluated the perioperative use and safety of inhaled NO therapy for lung transplantation. Data regarding the duration of treatment and adverse events of inhaled NO therapy were collected for all lung transplantations performed from January 1, 2015, to December 31, 2019, at nine lung transplant facilities in Japan. During the study period, lung transplants were performed in 357 patients, among whom inhaled NO therapy was administered to 349 patients (98%). The median initial and median maximum inhaled NO doses were 10 and 20ppm, respectively. Inhaled NO therapy was introduced during surgery and continued postoperatively in 313 patients (90%) for a median of 4days. Significant improvements in oxygenation and decreases in pulmonary arterial pressure were observed in patients receiving inhaled NO therapy. Side effects of inhaled NO therapy, such as methemoglobinemia, were observed in 15 patients (4%), with a significant incidence in patients aged < 18years. Inhaled NO therapy was performed in almost all patients who underwent lung transplantation in Japan and showed reasonable efficacy. Therefore, public health insurance coverage for inhaled NO therapy during lung transplantation is recommended.

Occurrence of metastatic eccrine porocarcinoma in an immunosuppressed patient

BackgroundEccrine porocarcinoma is a rare malignancy accounting for 0.005 to 0.01% of all cutaneous tumors. However, its etiology is not well established. Herein we are reporting the occurrence of metastatic porocarcinoma of the back in a patient with a history of multiple cutaneous malignancies and chronic immunosuppression.Case presentationA 79-year-old male with a history of long-term immunosuppressive therapy for left lung transplantation and multiple cutaneous malignancies including melanoma, presented with an enlargening plaque on the right upper back. Biopsy demonstrated an infiltrative epithelial tumor with aggressive histology and ductal formation. Immunohistochemical stains for p63, CK-5/6, and CEA were diffusely positive, while CK-7 and CK-20 were negative. A diagnosis of eccrine porocarcinoma was made. He underwent complete wide excision with negative margins of the right upper back in January 2018. In November 2018, he was found to have a right posterior shoulder mass, positive right axillary lymph nodes, superficial right upper back soft tissue masses and lymphangitic carcinomatosis involving the left lung. He was transitioned to comfort care and subsequently passed from metastatic disease in December 2018.ConclusionThe occurrence of eccrine porocarcinoma in a patient on long term immunosuppressive therapy for lung transplantation suggests a possible role for chronic immunosuppression in the induction of a subset of eccrine porocarcinomas, as in other cutaneous malignancies.

Is there a place for dornase alfa therapy in lung transplantation?

Is there a place for dornase alfa therapy in lung transplantation?

Alemtuzumab induction combined with reduced maintenance immunosuppression is associated with improved outcomes after lung transplantation: A single centre experience.

Question addressed by the studyThe value of induction therapy in lung transplantation is controversial. According to the ISHLT, only about 50% of patients transplanted within the last 10 years received induction therapy. We reviewed our institutional experience to investigate the impact of induction therapy on short- and long-term outcomes.Materials/Patients and methodsBetween 2007 and 2015, 446 patients with a complete follow-up were included in this retrospective analysis. Analysis comprised long-term kidney function, infectious complications, incidence of rejection and overall survival.ResultsA total of 231 patients received alemtuzumab, 50 patients antithymocyte globulin (ATG) and 165 patients did not receive induction therapy (NI). The alemtuzumab group revealed the lowest rate of chronic kidney insufficiency (NI: 52.2%; ATG: 60%; alemtuzumab: 36.6%; p = 0.001). Both, the NI group (p<0.001) and the ATG group (p = 0.010) showed a significant increase of serum creatinine during follow-up compared to alemtuzumab patients. Furthermore, alemtuzumab group experienced the lowest rate of infection in the first year after transplantation. Finally, improved survival, low rates of acute cellular rejection (ACR), lymphocytic bronchiolitis (LB) and chronic lung allograft dysfunction (CLAD) were found in patients treated either with alemtuzumab or ATG.ConclusionAlemtuzumab induction therapy followed by reduced maintenance immunosuppression is associated with a better kidney function compared to no induction and ATG. Survival rate as well as freedom from ACR and CLAD were comparable between alemtuzumab and ATG.

Extracorporeal support, during and after lung transplantation: the history of an idea.

During recent years, continuous technological innovation has provoked an increase of extracorporeal life support (ECLS) use for perioperative cardiopulmonary support in lung transplantation. Initial results were disappointing, due to ECLS-specific complications and high surgical risk of the supported patients. However, the combination of improved patient management, multidisciplinary team work and standardization of ECLS protocols has recently yielded excellent results in several case series from high-volume transplant centres. Therein, it was demonstrated that, although the prevalence of complications remains higher in supported patients, there may be no difference in long-term graft function between supported and non-supported patients. These results are important, because most of the patients who require ECLS support in lung transplantation are young and have no other chance to survive, but to be transplanted. Moreover, there is no device for "bridging to destination" therapy in lung transplantation. Of note, the evidence in favour of ECLS support in lung transplantation was never validated by randomized controlled trials, but by everyday experience at the patient bed-side. Here, we review the state-of-the-art ECLS evidence for intraoperative and postoperative cardiopulmonary support in lung transplantation.

Correction to: Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis.

In the print publication the name of the seventh author was incorrectly published.

Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease

BackgroundIdentification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion. MethodologyPWCF homozygous for the ΔF508 mutation or heterozygous for the G551D mutation were recruited (n=48). Membrane protein expression was investigated by mass spectrometry. The effect of lung transplantation or ivacaftor therapy was assessed by ELISAs, and calcium fluorometric and μ-calpain assays. FindingsMembranes of CF neutrophils contain less cholesterol, yet increased integrin CD11b expression, and respond to inflammatory induced endoplasmic reticulum (ER) stress by activating μ-calpain. In vivo and in vitro, increased μ-calpain activity resulted in proteolysis of the membrane cholesterol trafficking protein caveolin-1. The critical role of caveolin-1 for adequate membrane cholesterol content was confirmed in caveolin-1 knock-out mice. Lung transplant therapy or treatment of PWCF with ivacaftor, reduced levels of circulating inflammatory mediators and actuated increased caveolin-1 and membrane cholesterol, with concurrent normalized neutrophil adhesion. InterpretationResults demonstrate an auxiliary benefit of lung transplant and potentiator therapy, evident by a reduction in circulating inflammation and controlled neutrophil adhesion.

Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation.

Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 and CYP3A5 genes with tacrolimus (Tac) and ABCC2, UGT1A9 and SLCO1B1 genes with mycophenolic acid (MPA), during the first six months after lung transplantation (51 patients). The genotype was correlated to the trough blood drug concentrations corrected for dose and body weight (C0/Dc). The ABCB1 variant in rs1045642 was associated with significantly higher Tac concentration, at six months post-transplantation (CT vs. CC). In the MPA analysis, CT patients in ABCC2 rs3740066 presented significantly lower blood concentrations than CC or TT, three months after transplantation. Other tendencies, confirming previously expected results, were found associated with the rest of studied SNPs. An interesting trend was recorded for the incidence of acute rejection according to NOD2/CARD15 rs2066844 (CT: 27.9%; CC: 12.5%). Relevant SNPs related to Tac and MPA in other solid organ transplants also seem to be related to the efficacy and safety of treatment in the complex setting of lung transplantation.

Induction therapy in lung transplantation

Strategies for induction in lung transplant recipients typically mirror those used in other solid organ transplant recipients. Polyclonal (Atgam, RATG) and monoclonal (OKT3) T-cell depleting agents, IL-2 Receptor antagonists (basiliximab and daclizumab) have been used most commonly. In spite of evidence from ISHLT registry reports that induction reduces acute rejection and has a small benefit in freedom from bronchiolitis obliterans and long-term survival, other studies have been less convincing in terms of long-term benefit. Future iterations of induction strategy for lung transplant recipients will hopefully utilize tolerogenic approaches currently being tested in renal transplantation.

Managing Bronchiolitis Obliterans Syndrome (BOS) and Chronic Lung Allograft Dysfunction (CLAD) in Children: What Does the Future Hold?

The success of pediatric lung transplantation continues to be limited by long-term graft dysfunction. Historically this has been characterized as an obstructive spirometric defect in the form of the bronchiolitis obliterans syndrome (BOS). It is recognized, however, that this does not reflect many of the other acknowledged etiologies of chronic lung dysfunction-noting it is the sum of the parts that contribute to respiratory morbidity and mortality after transplant. The term chronic lung allograft dysfunction (CLAD) has been coined to reflect these other entities and, in particular, a group of relatively recently described lung disorders called the restrictive allograft syndrome (RAS). RAS is characterized by a restrictive spirometric defect. Although these entities have not yet been studied in a pediatric setting their association with poor compliance, antibody-mediated rejection (AMR), and post-infectious lung damage (particularly viral) warrants attention by pediatric lung transplant teams. Current therapy for the BOS subset of CLAD is otherwise limited to changing immunosuppressants and avoiding excessive infectious risk by avoiding over-immunosuppression. Long-term macrolide therapy in lung transplantation is not of proven efficacy. Reviewing previous BOS studies to explore restrictive spirometric cases and joint projects via groups like the International Pediatric Lung Transplant Collaborative will be the way forward to solve this pressing problem.

Tailoring Immunosuppressive Therapy for Lung Transplantation

Tailoring Immunosuppressive Therapy for Lung Transplantation

Preoperative introduction and maintenance immunosuppression therapy of oral-only tacrolimus, mycophenolate mofetil and steroids reduce acute rejection episodes after lung transplantation☆

Immunosuppression therapy in lung transplantation (LTX) remains unsatisfactory due to a high incidence of infection and frequent acute rejection (AR), leading to early onset of the bronchiolitis obliterans syndrome (BOS). The long-term success of LTX is limited by BOS, associated with marked morbidity and mortality. The strongest risk factor for BOS is frequent AR. Decreasing frequent AR episodes might lead to improved long-term survival following LTX. Despite the introduction of many novel agents, the basis of currently applied protocols remains a calcineurin inhibitor, that is, cyclosporine/tacrolimus (TAC). Eighty-two lung recipients received oral-only administered immunosuppression with oral TAC, mycophenolate mofetil (MMF) and intravenous (IV) methylprednisolone as introduction 2h prior to skin incision. Intra-operatively, patients received additional methylprednisolone prior to unclamping the pulmonary arteries. Postoperatively oral TAC/MMF and prednisolone were continued and trough levels closely monitored (target 8-12 ng ml(-1)). Pulmonary function tests were performed frequently and daily after discharge by means of a self-measuring device (daily forced expiratory volume in 1s (FEV(1))) as the major part of a close follow-up and monitoring programme. Trans-bronchial biopsies were rarely performed. Patient data were collected prospectively and stored in transplantation registries. LTX survival was analysed according to the Kaplan-Meier method. The follow-up of the LTX patients through frequent ambulatory care unit visits and close monitoring of the immunosuppressive regimen and the medication response was 100% complete. The mean duration of observation per patient was 1.8 + or - 1.7 years (median 1.4, range: 0.0-6.4 years) and this study included 176.5 patient-related years of follow-up. The 1-, 3- and 5-year survival following LTX was 70%, 60% and 55%, respectively. Eight patients (10%) underwent high-dose intravenous (IV) bolus methylprednisolone treatment and taper for AR. Two additional patients developed BOS more than 4 years following LTX. The AR- and BOS-related mortality was 0% within the 7-year interval of LTX. Alterations in FEV(1) were associated with significant anastomotic airway and infectious complications, requiring frequent bronchoscopic interventions, stenting and laser therapy as well as frequent IV antibiotic treatment. The 30-day and in-hospital mortality of 19.5% was markedly related to primary graft failure and viral infection. Long-term survival was limited predominantly by cytomegalovirus (CMV) infection and sepsis. Our results suggest that a standard immunosuppressive regimen of TAC and MMF orally administered and introduced prior to skin incision for LTX surgery and maintained long-term might reduce the incidence of acute and chronic rejection. Viral infections and not BOS seemed to be the limiting factor of long-term survival.