Immunosuppressive therapy in lung transplantation: state of the art

The coming of age of lung transplantation is accompanied by an immunosuppressive armamentarium that has been brought forward from other transplant indications. Widely employed on the basis of few small randomized studies, and mostly single-center experience or empirical expert knowledge, anti-rejection therapeutic strategies in pulmonary transplantation have hardly been rigorously evaluated in large-scale prospective international trials. This review compiles the available findings on the use of current immunosuppressants in clinical lung transplantation, accentuating high level-of-evidence study results. Reporting on recent meeting and registry data, and assembling ongoing relevant trials from international databases, this article serves as an update on the state of the art of immunosuppression in lung transplantatio

Posttransplant sinus surgery in lung transplant recipients with cystic fibrosis: a single institutional experience

Chronic rhinosinusitis is hypothesised to play a major role in lung transplant recipients with cystic fibrosis. Paranasal sinuses are considered to accumulate a significant bacterial load, potentially leading to lung allograft infection with ensuing complications such as bronchiolitis obliterans syndrome, i.e. allograft rejection. We therefore would like to present our combined medical and surgical treatment plan, which consists of an endoscopic fronto-spheno-ethmoidectomy as well as a meticulous daily nasal care program. The microbiological results show that our combined concept is effective, whereas especially daily nasal care with isotonic saline solution is the cornerstone in preventing significant colonisation of the sinuses and spreading bacteria to the lower respiratory tract causing lung allograft infection. Regarding the surgical part of our treatment, it should be emphasised that all sinuses and ethmoidal air cells should be widely opened. Edges such as bony overhangs should be smoothened to avoid mucus retention and consecutive bacterial recolonisation requiring subsequent revision surger

Extended Nitric Oxide Measurements in Exhaled Air of Cystic Fibrosis and Healthy Adults

In cystic fibrosis (CF) lung disease, exhaled nitric oxide (FeNO) is not raised, but rather is normal or even decreased when measured at a single expiratory flow. FeNO measurements at several flow rates allow differentiation between alveolar and bronchial nitric oxide (NO) production. Extended FeNO measurements therefore should be useful to localize the FeNO deficit in CF airways. FeNO was measured in stable CF adults with moderate lung disease and in healthy controls. Bronchial NO fluxes (JNO,Br) and alveolar NO concentrations (CAlv) were calculated from FeNO measurements at flow rates of 100, 150 and 200ml/s using a method previously described. Thirty-two adults were included in the study, 12 of whom had CF. CF adults had significantly lower FeNO values at all flow rates. The median JNO,Br was significantly lower in CF adults than in healthy controls [0.31nl/s (range=0.11-0.63) vs. 0.70nl/s (0.27-3.52); P<0.001], while the median CAlv was similar in both groups [1.7ppb (0.3-3.9) vs. 1.2 (0.1-5.2)]. Pulmonary NO exchange did not differ significantly between subgroups of CF patients with and without chronic Pseudomonas aeruginosa infection. No significant correlation was detectable between FEV1/VC and JNO,Br and CAlv, respectively. Extended FeNO measurements can separate alveolar and bronchial NO outputs in CF adults. The lower FeNO in adults with moderate to severe CF lung disease is likely to be the result of lower bronchial NO outpu

Donor predicted post-operative forced expiratory volume in one second predicts recipients' best forced expiratory volume in one second following size-reduced lung transplantation

Objective: The limited number of available grafts is one of the major obstacles of lung transplantation. Size-reduced lung transplantation allows the use of oversized grafts for small recipients. Optimal lung size matching is vital to achieve best functional outcome and avoid potential problems when using oversized grafts. We hypothesise that donor-predicted postoperative forced expiratory volume in 1s (ppoFEV1) correlates with the recipient best FEV1 after size-reduced lung transplant, being useful for the estimation of function outcome. Methods: All patients undergoing size-reduced or standard bilateral lung transplantation were included (1992-2007). Donor ppoFEV1 was calculated and corrected with respect to size reduction and correlated with recipient measured best FEV1 post-transplant. In addition, pre- and postoperative clinical data including surgical complications and outcome of all size-reduced lung transplant recipients were compared with standard lung transplant recipients. Results: A total of 61 size-reduced lung transplant recipients (lobar transplants, n=20; anatomic or non-anatomic resection, n=41) were included and compared to 145 standard transplants. The mean donor-recipient height difference was statistically significant between the two groups (p=0.0001). The mean donor ppoFEV1 was comparable with recipient best FEV1 (2.7±0.6 vs 2.6±0.7 l). There was a statistically significant correlation between donor ppoFEV1 and recipient best FEV1 (p=0.01, r=0.688). The 30-day mortality rate and 3-month, 1- and 5-year survival rates were comparable between the two groups. Conclusions: In size-reduced lung transplantation, postoperative recipient best FEV1 could be predicted from donor-calculated and corrected FEV1 with respect to its size reduction. Compared to standard lung transplantation, equivalent morbidity, mortality and functional results could be obtained after size-reduced lung transplantatio

Lung transplantation for cystic fibrosis: a single center experience of 100 consecutive cases†

OBJECTIVE Lung transplantation is the ultimate treatment option for patients with end-stage cystic fibrosis (CF) lung disease. Despite poorer reports on survival benefit for CF patients undergoing lung transplantation, several centers, including ours were able to show a survival benefit. This study compares our center's experience with 100 consecutive recipients in two different eras. METHODS All CF patients who underwent lung transplantation at our center were included (1992-2009). Survival rates were calculated and compared between the earlier era (before 2000) and later era (since 2000). RESULTS CF patients constituted 35% of all transplantations performed at our institution. Mean age at transplantation was 27 years (range 12-52). Fifty-one percent of the patients were female. Waiting list time was lower in the earlier era compared to the later era (p=0.04). Lobar transplantation was performed in 10 cases. Thirty-four percent of the cases required downsizing of the graft. In 33% of the cases, transplantations were done on cardiopulmonary bypass. There were no anastomotic complications. Total intensive care unit stay was significantly lower in the later era compared to earlier era (p=0.001). The other parameters such as C-reactive protein at the time of transplantation, total cold ischemic time, and total operation time were comparable between the two eras. Overall 30-day mortality was 5%. The 30-day mortality was significantly lower in the second period (p=0.006). In the earlier era, 3-month, 1-year, and 5-year survival were 85±6%, 77±8%, and 60±9%, respectively, and in the later era improved to 96±2%, 92±3%, and 78±5% (p=0.03). CONCLUSION Improved results obtained in the early postoperative period since 2000 is most likely due to change in surgical management approach. Improved surgical outcome for CF patients can be obtained, especially in experienced transplant center

Ganciclovir/Valganciclovir Prophylaxis Decreases Cytomegalovirus-Related Events and Bronchiolitis Obliterans Syndrome after Lung Transplantation

Background. Until recently, cytomegalovirus (CMV) infection represented a major threat to lung transplant recipients. Preliminary studies have shown that antiviral prophylaxis might improve the outcome for these patients. Methods. We extended our initial pilot trial of prolonged prophylaxis with either oral ganciclovir (1 g 3 times per day) or valganciclovir (450 mg twice per day). The trial included 96 patients who were at risk for CMV-related events. Results. CMV prophylaxis resulted in a significant decrease in CMV-related events (i.e., active infection and disease), from 75% in a control group and for 274 cases from the literature who did not receive prophylaxis to a cumulative incidence of 27% (P<.001). Only 11% of the prophylaxis recipients experienced CMV disease (P<.001). Moreover, at 5 years, there was a significant decrease in the rate of bronchiolitis obliterans syndrome, from 60% to 43% (P=.002), and an improved rate of survival, from 47% to 73% (P=.036), irrespective of the immunosuppressive regimen received. CMV strains with UL97 mutations were recovered from 7 of 12 analyzed cases, but the presence of this mutation had no impact on the severity of CMV disease. Conclusions. A regimen of prolonged ganciclovir or valganciclovir prophylaxis decreased the rate of active CMV infection and disease, reduced the incidence of bronchiolitis obliterans syndrome, and improved the survival rate. Drug-resistant CMV strains may occur, but such strains appeared to have no impact on the outcome of CMV-related event

Extended donor lungs: eleven years experience in a consecutive series

Objective: The aim of this study was to delineate the profile of extended donor lungs in comparison to ideal donor lungs and to analyse their outcome. Particular attention was given to donor lungs with a low PaO2 (≪250mmHg) before harvesting or with multiple extended criteria. Methods: Between 1993 and 2003, 148 patients (79 women, 69 men, mean age 39.9 years) underwent lung transplantation. Indications were cystic fibrosis in 35.8%, emphysema in 26.4%, pulmonary fibrosis in 12.2%, pulmonary hypertension in 9.5%, and others in 16.1%. Donor data and recipients medical files were reviewed. Criteria for donor lungs were considered extended if one or more of the following criteria were met: age ≫55 years, smoking ≫20 pack-years, PaO2 before harvesting ≪300mmHg, pathologic chest X-ray, and purulent secretion at bronchoscopy. A comparison between recipients from ideal and from extended donor lungs was performed with respect to the median duration of mechanical ventilation, the median length of stay at the intensive care unit, postoperative complications, the 30-day and the 1-year survival, and the 6-month follow-up spirometry. Results: Sixty-three (42.6%) donor lungs were considered extended and 20 (31.7%) met more than one criteria. Outcome comparison between recipients from ideal (I) and extended (II) donor lungs did not statistically differ in postoperative complications (18.8% (I) vs. 26.9% (II), P=0.32), mean duration of mechanical ventilation (d) (4.4±2.7 (I) vs. 2.6±2.1 (II), P=0.2), mean length of stay at the ICU (d) (11.5±8.8 (I) vs. 9.2±6.9 (II), P=0.4), 6-month pulmonary function (FEV1=83±23% of the predicted value (I) vs. 82±18% (II), P=0.81), 30-day survival (90.6% (I) vs. 93.7% (II), P=0.56), 1-year survival (83.5% (I) vs. 81% (II), P=0.83). Thirty-day survival was also comparable even in recipients from donor lungs with PaO2≪250mmHg (n=8) (90.6% (I) vs. 87.5%, P=0.57). The number of extended criteria had no impact on the outcome. The combination of PaO2≪300mmHg with purulent secretion at bronchoscopy seemed to influence the early outcome of recipients from extended donor lungs negatively. Conclusions: Our results suggest that the use of selected extended donor lungs does not compromise the outcome after transplantation. PaO2 ≪250mmHg before harvesting of the lungs is not an absolute contra-indication for transplantatio

Impact of preoperative right-ventricular function and platelet transfusion on outcome after lung transplantation

Objective: Lung transplantation has become an established treatment option for end-stage pulmonary diseases. However, outcome depends on preoperative condition and co-morbidity. Furthermore, perioperative blood-product use is known to be associated with worse outcome even in transplant surgery. We investigated the impact of poor preoperative right-ventricular function and blood-product use on outcome after lung transplantation. Methods: The medical records of 169 lung-transplant recipients from 1996 to 2006 were examined. Duration of hospital stay, hours on mechanical ventilation, duration of stay in the intensive care unit, perioperative complications, death during hospital stay, and long-term survival were recorded. These outcome parameters were analyzed regarding coherence with right-ventricular function and the perioperative administration of crystalloids, colloids, allogeneic red blood cells, fresh frozen plasma, and platelets. Results: Patients with poor preoperative right-ventricular function had a significant increase in postoperative hours on ventilation (p=0.005), intensive care stay (p=0.003), and in-hospital death (p=0.012). The hours on ventilation increased also with high intra-operative fluid administration (p=0.026). Blood-product use was associated with prolonged mechanical ventilation and intensive care stay. After multivariate analysis, transfusion of platelets (p=0.022) was an independent prognostic factor for in-hospital death. Hours of mechanical ventilation was the only independent prognostic factor for long-term mortality (p=0.014). Conclusions: Perioperative transfusion of platelets is an independent prognostic factor for perioperative mortality. Furthermore, the study indicated that poor preoperative right-ventricular function might worsen perioperatively after lung transplantation. Therefore, pre-transplant treatment of pulmonary hypertension to protract right-ventricular failure and a restrictive use of allogeneic blood products may be options to improve outcom

Donor and recipient treatment with the Lazaroid U-74006F do not improve post-transplant lung function in swine

Objective: U-74006F is the only Lazaroid which is currently in clinical use. A number of experimental studies demonstrate that Lazaroids reduce ischemia/reperfusion injury in various organ systems. We evaluated the effect of U-74006F on reperfusion injury in a large animal model of lung allo-transplantation. Methods: Two different treatment modalities were evaluated and compared with corresponding control groups. Unilateral left lung transplantation was performed in 21 weight-matched pigs (24-31 kg). Donor lungs were flushed with 1.5 l cold (1°C) LPD solution and preserved for 20 h. In group I (n=5), donor animals were pretreated with U-74006F (10 mg/kg i.v.) 20 min before harvest. In addition U-74006F was added to the flush solution (10 mg/l). In group III (n=6), the Lazaroid was given to the donor before flush and to the recipient before reperfusion (3 mg/kg i.v.). Group II and IV (n=5) served as control. One hour after reperfusion, the recipient contralateral right pulmonary artery and bronchus were ligated to assess graft function only. Extravascular lung water index (EVLWI), mean pulmonary artery pressure, cardiac output, and gas exchange were assessed during a 5 h observation period. Lipid peroxidation (TBARS) and neutrophil migration (MPO activity) were measured at the end of the assessment in lung allograft tissue. Results: A significant change of TBARS concentration was shown in group III (group III 78.7±4.6 pmol/g vs. group IV 120.8±7.2 pmol/g (P=0.0065) normal lung tissue 41.3±4.2 pmol/g). MPO activity was reduced in group III 3.74±0.25 δOD/mg per min vs. group IV 4.97±0.26 δOD/mg per min (P=0.027), normal lung tissue 1.04±0.27 δOD/mg per min). Pulmonary hemodynamics and gas exchange after reperfusion did not differ between groups. In group I and III, a tendency towards a reduced EVLWI was noted. Conclusion: We conclude that combined treatment of donor and recipient with U-74006F reduces free radical mediated injury in the allograft. However, this intervention did not result in a significant reduction of post-transplant lung edema or improvement of pulmonary hemodynamics. Donor pretreatment alone did not improve lung allograft reperfusion injury. These results indicate that the benefit of U-74006F is too small to consider clinical application in lung transplantatio