Markus Hofer

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 = .002). 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 events.

True survival benefit of lung transplantation for cystic fibrosis patients: the Zurich experience.

BACKGROUND Lung transplantation is the ultimate therapy for end-stage cystic fibrosis (CF) lung disease; however, the debate continues as to whether lung transplantation improves survival. We report post-transplant outcome in CF at our institution by comparing 5-year post-transplant survival with a calculated 5-year survival without lung transplantation, using a predictive 5-year survivorship model, and describe pre-transplant parameters influencing transplant outcome. METHODS CF patients undergoing lung transplantation at our center were included (1992 to 2007). Survival rates were calculated and compared, and univariate and multivariate Cox regression analyses were used for statistical assessment. RESULTS Eighty transplants were performed in CF patients, 11 (13.8%) of whom were children. Mean age at transplant was 26.2 years (95% confidence interval: 24.4 to 28.0). The Liou raw score at transplant was -20 (95% confidence interval: -16 to -24), resulting in an estimated 5-year survival without transplantation of 33 +/- 14%, compared with a 5-year post-transplant survival of 68.2 +/- 5.6%. Further improvement was noted in the recent transplant era (since 2000), with a 5-year survival of 72.7 +/- 7.3%. Univariate analysis revealed that later year of transplant and diagnosis of diabetes influenced survival positively. Pediatric age had no negative impact. In the multivariate analysis, only diabetes influenced survival, in a positive manner. CONCLUSION Lung transplantation performed at centers having experience with the procedure can offer a true survival benefit to patients with end-stage CF lung disease.

Impact of Sinus Surgery on Pseudomonal Airway Colonization, Bronchiolitis Obliterans Syndrome and Survival in Cystic Fibrosis Lung Transplant Recipients

Background: Lung transplantation (LTx) is a therapy for patients with cystic fibrosis (CF) end-stage lung disease. Pseudomonal airway colonization (PAC) is common in CF. Objectives: We investigated the influence of post-transplant sinus surgery and daily nasal douching on PAC after LTx and the influence of PAC on survival and bronchiolitis obliterans syndrome (BOS). Methods: CF patients transplanted at our centre were included (November 1992 to December 2009). Clinical data, including microbiological data before and after LTx were collected. Survival and BOS following LTx were compared for CF recipients with and without PAC by Kaplan-Meier statistics and Cox regression analysis. Results: Ninety-four CF patients were transplanted, of whom 82 (87%) underwent sinus surgery after transplantation, and 65% of 66 patients with pre-transplant PAC had persistent PAC after transplantation. Upper and lower PAC is related. Patients without PAC after transplantation had a significantly better survival rate, and BOS was less frequent with a later onset. PAC was the only significant parameter for the development of BOS stage 2 in the multivariate analysis for cytomegalovirus infection, acute rejection and PAC. Conclusions: Sinus surgery and daily nasal douching reduced PAC in LTx recipients. Absence of post-transplant PAC had a positive impact on post-transplant survival and the development of BOS.

Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation

BACKGROUND Diabetes mellitus (DM) is common in CF and associated with more severe disease. It is unclear whether DM influences outcome of lung transplantation (LTx). METHODS One hundred twenty-three CF patients evaluated for LTx at our centre were included. Survival was calculated. RESULTS Patients with and without DM did not differ with regard to gender, age, FEV(1) and BMI prior to LTx. Eighty patients (65%) had a diagnosis of DM before and 13 (11%) only after LTx. Recipients with DM had a significantly higher 1- and 5-year survival (89% and 71%) than those without (71% and 51%). In the multivariate Cox-regression analysis, DM had no impact on LTx-survival. CONCLUSIONS One- and five-year survival rates after LTx tend to be better in CF recipients with DM compared to those without DM. No impact of DM on the development of BOS was found.

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 centers 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 centers.

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 surgery.

Practical Approach to Emergencies in Lung Transplant Recipients: How We Do It

Lung transplant recipients (LTRs) are prone to medical complications and emergencies due to the transplanted organ being in constant direct contact with the environment and the need for life-long profound immunosuppression (IS). As a result of these specific circumstances, the medical and surgical management of LTRs frequently differs from usual standard care. Therefore, we outline here some of the principles we take into account when dealing with the most frequent medical emergencies encountered in our lung transplant cohort in Zurich. The main topics dealt with are: diagnostics and treatment of infections, gastrointestinal emergencies, IS and other medication issues as well as work-up of unclear inflammatory signs and peri-operative precautions in LTRs. Early post-operative transplant complications, rare medical emergencies and surgical problems are not covered. Our report is intended to help internists and pulmonologists new to the field to obtain a better understanding of the peculiarities of LTRs and their management.

Itraconazole Comedication Increases Systemic Levels of Inhaled Fluticasone in Lung Transplant Recipients

Background: After lung transplantation (LTx), inhaled corticosteroids may be prescribed and at the same time prophylaxis against fungal infections with itraconazole is common. In our center, the addition of inhaled fluticasone propionate to systemic immunosuppression resulted in clinical Cushing’s syndrome in 4 lung transplant recipients on itraconazole comedication. Objectives: The current study was undertaken to compare systemic levels of inhaled fluticasone in patients with and without concomitant itraconazole therapy. Methods: The single-center, prospective controlled study was performed in the LTx program in Zurich, Switzerland. Twenty stable recipients, 1–7 years after LTx, on a prednisone maintenance dose (5–7.5 mg/day) gave informed consent and were assigned to 2 groups: (A) without itraconazole comedication and (B) currently on itraconazole, being continued during the study period. The patients of both groups started inhalation of 1 mg fluticasone propionate twice daily for 14 days with a powder disc inhaler. Plasma fluticasone levels were measured before the start of the study and on day 14. Results: Fluticasone levels before starting the treatment were below the detection limit in all 17 patients (7 in group A and 10 in group B) adhering to the study protocol. Baseline characteristics (underlying disease, age at LTx, time since LTx, FEV1) were comparable between the 2 groups. On study day 14, plasma fluticasone levels had increased to detectable levels in all patients (A: 273 ± 124 pg/ml, B: 701 ± 131 pg/ml), i.e. to significantly higher (p = 0.038) concentrations in patients on itraconazole. Conclusions: Itraconazole comedication substantially increases systemic levels of inhaled fluticasone, most likely by inhibiting the cytochrome P450 3A4 enzyme system and thus the clearance of fluticasone. Accumulation of fluticasone can result in increased systemic effects and therefore comedication has to be taken into consideration when inhaled fluticasone is prescribed.

Mycophenolate mofetil reduces alveolar inflammation, acute rejection and graft loss due to bronchiolitis obliterans syndrome after lung transplantation

BACKGROUND Bronchiolitis obliterans syndrome (BOS) is still the main complication after lung transplantation. Besides other improvements in post-operative management, newer immunosuppressive regimens might decrease the devastating sequelae of this complication. METHODS We compared the prospectively collected data of lung transplant recipients treated either with azathioprine (AZA; n = 48) or mycophenolate mofetil (MMF; n = 108), who underwent regular monthly surveillance bronchoscopies for at least 6 post-operative months. RESULTS Patients on MMF had significantly fewer acute (P < 0.001) and recurrent (P < 0.001), as well as less severe rejection episodes (P = 0.01). In addition, MMF significantly reduced the number of alveolar lymphocytes, eosinophils and neutrophils (P < 0.001), and decreased the hemosiderin score reflecting non-specific alveolar-capillary damage (P < 0.001). Although there was no change in the three stages of BOS, there was a trend towards improved survival (P = 0.062) and a significant decrease in graft loss due to BOS (P = 0.049) in patients receiving MMF. CONCLUSIONS Immunosuppression with MMF significantly decreased the incidence, severity and recurrence of acute rejection episodes in lung transplant recipients. Parameters of alveolar inflammation and alveolar-capillary damage were also decreased. As a potential consequence, MMF significantly reduced graft loss due to BOS and tended to improve overall survival in these patients.

Nasal polyposis in lung transplant recipients with cystic fibrosis.

BACKGROUND Chronic rhinosinusitis with nasal polyposis is common in patients with cystic fibrosis (CF). There are still many open questions regarding factors related to this condition. Furthermore, the prevalence of nasal polyposis and its implications for the outcomes in lung transplant recipients with cystic fibrosis are unknown. METHODS All CF patients who underwent lung transplantation at our centre between November 1992 and December 2009 were included. Nasal polyp status was determined endoscopically at time sinus surgery and its relationships to gender, age at lung transplantation, Liou raw score, body mass index, FEV1%predicted, diabetes mellitus, pre-transplant pseudomonas colonisation of the sinuses and the lungs, pre-transplant corticosteroid use and type of mutation of the CFTR gene were analysed. The post-transplant survival times and the incidence of bronchiolitis obliterans syndrome in patients with or without nasal polyposis were compared. RESULTS Nasal polyps were found in 19% (17 patients) of the 89 lung transplant recipients, whose data was available for statistical analysis. None of the factors analysed was related to the nasal polyp status. The post-transplant survival times and the incidence of bronchiolitis obliterans syndrome did not significantly differ between patients with or without nasal polyposis. CONCLUSIONS CF-related nasal polyposis occurs in a relevant fraction of lung transplant recipients. A specific effect of nasal polyposis on post-transplant outcome could not be confirmed. Nevertheless, there was a trend to NP recurrence in patients with post-transplant sinonasal pseudomonas colonisation and is a tendency of less chronic rejection in CF patients with nasal polyps.