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Background: Successful lung transplantation for patients with pulmonary fibrosis from telomerase mutations may be limited by systemic complications of telomerase dysfunction, including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes in 14 lung transplant recipients with telomerase mutations., Methods: Subjects underwent lung transplantation between February 2005 and April 2014 at 5 transplant centers. Data were abstracted from medical records, focusing on outcomes reflecting post-transplant treatment effects likely to be complicated by telomerase mutations., Results: The median age of subjects was 60.5 years (interquartile range = 52.0-62.0), 64.3% were male, and the mean post-transplant observation time was 3.2 years (SD ± 2.9). A mutation in telomerase reverse transcriptase was present in 11 subjects, a telomerase RNA component mutation was present in 2 subjects, and an uncharacterized mutation was present in 1 subject. After lung transplantation, 10 subjects were leukopenic and 5 did not tolerate lymphocyte anti-proliferative agents. Six subjects developed recurrent lower respiratory tract infections, 7 developed acute cellular rejection (A1), and 4 developed chronic lung allograft dysfunction. Eight subjects developed at least 1 episode of acute renal failure and 10 developed chronic renal insufficiency. In addition, 3 subjects developed cancer. No subjects had cirrhosis. At data censorship, 13 subjects were alive., Conclusions: The clinical course for lung transplant recipients with telomerase mutations is complicated by renal disease, leukopenia with intolerance of lymphocyte anti-proliferative agents, and recurrent lower respiratory tract infections. In contrast, cirrhosis was absent, acute cellular rejection was mild, and development of chronic lung allograft dysfunction was comparable to other lung transplant recipients. Although it poses challenges, lung transplantation may be feasible for patients with pulmonary fibrosis from telomerase mutations., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The prognosis of pulmonary hypertension (PH), especially idiopathic pulmonary arterial hypertension (IPAH), has improved during the recent years. The Swiss Registry for PH represents the collaboration of the various centres in Switzerland dealing with PH and serves as an important tool in quality control. The objective of the study was to describe the treatment and clinical course of this orphan disease in Switzerland., Methods: We analyzed data from 222 of 252 adult patients, who were included in the registry between January 1999 and December 2004 and suffered from either PAH, PH associated with lung diseases or chronic thromboembolic PH (CTEPH) with respect to the following data: NYHA class, six-minute walking distance (6-MWD), haemodynamics, treatments and survival., Results: If compared with the calculated expected figures the one, two and three year mean survivals in IPAH increased from 67% to 89%, from 55% to 78% and from 46% to 73%, respectively. Most patients (90%) were on oral or inhaled therapy and only 10 patients necessitated lung transplantation. Even though pulmonary endarterectomy (PEA) was performed in only 7 patients during this time, the survival in our CTEPH cohort improved compared with literature data and seems to approach outcomes usually seen after PEA. The 6-MWD increased maximally by 52 m and 59 m in IPAH and CTEPH, respectively, but in the long term returned to or below baseline values, despite the increasing use of multiple specific drugs (overall in 51% of IPAH and 29% of CTEPH)., Conclusion: Our national registry data indicate that the overall survival of IPAH and presumably CTEPH seems to have improved in Switzerland. Although the 6-MWD improved transiently, it decreased in the long term despite specific and increasingly combined drug treatment. Our findings herewith underscore the progressive nature of the diseases and the need for further intense research in the field.

The case history is presented of a lung transplant recipient who developed malignant mesothelioma. This is thought to be the first such report. Mesothelioma should be suspected in lung transplant recipients with a haemorrhagic pleural effusion in the native lung when there is no convincing evidence for bronchogenic carcinoma or post transplant lymphoproliferative disease, even in the absence of exposure to asbestos.

Background: We noted that patients with cystic fibrosis tended to need higher doses of sedatives during bronchoscopy. We undertook this study to assess the sedative drug doses administered during bronchoscopy in lung transplant recipients and to assess if there is a change in the dosage requirements over time following lung transplantation., Methods: In all, 773 transbronchial biopsy procedures performed via flexible bronchoscopy were analyzed in 140 consecutive lung transplant recipients. Conscious sedation was achieved with intermittent boluses of intravenous midazolam and fentanyl. Intravenous propofol boluses of 10 to 30 mg were administered when optimal sedation was not achieved with midazolam doses of 0.20 to 0.25 mg/kg and fentanyl 2 to 2.5 micrograms/kg., Results: Mean doses of midazolam and fentanyl administered were 0.15+/-0.07 mg/kg (range 0.02 to 0.44 mg/kg) and 1.8+/-0.8 micrograms/kg (range 0.1 to 6.67 micrograms/kg) respectively. Midazolam and fentanyl doses administered to patients with cystic fibrosis were the highest compared to those with other disease types (P<0.0001). Examining the sedative doses administered over time following transplantation, there was a significant linear (P<0.001) and quadratic (P=0.0023) effect of time for midazolam and a significant linear (P=0.003) and a trend (P=0.08) for a quadratic effect for fentanyl. Propofol was effectively used in seven lung transplant recipients in whom adequate sedation could not be achieved with high doses of midazolam and fentanyl., Conclusions: There is an increase in sedative drug requirement with time for both midazolam and fentanyl after transplantation, which is significantly higher in patients with cystic fibrosis.

Background: Chlamydia pneumoniae is established as a common agent of acute respiratory tract infection and has been implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease. Airway disease is a prominent cause of morbidity and mortality after lung transplantation. We investigated the role of C pneumoniae as a pulmonary pathogen after lung transplantation., Methods: Eighty lung transplant recipients underwent 232 bronchoscopies with bronchoalveolar lavage with or without transbronchial lung biopsy during 1 year for surveillance of rejection and infection, or where clinically indicated., Results: C pneumoniae was detected using nested polymerase chain reaction in 9 of 36 (25%) recipients studied within 30 days of lung transplantation, 3 of whom remained positive on repeat lavage and died from airway disease in the first year post-operatively. By comparison, all 27 recipients with negative lavage survived >1 year. Lavage was positive for C pneumoniae in 18 of 71 (25%) recipients studied >30 days after lung transplantation, 5 of whom had pneumonia and 8 of whom had bronchiolitis obliterans syndrome. Eleven also had acute pulmonary allograft rejection., Conclusions: Persistent infection with C pneumoniae (whether donor-derived, de novo or re-activated) appears deleterious to pulmonary allograft function and is associated with early mortality, rejection and bronchiolitis obliterans syndrome after lung transplantation. A trial of empiric antibiotic therapy for C pneumoniae may therefore be warranted in the attempt to prevent progressive inflammatory airway disease.

The association of cytomegalovirus (CMV) infection with the development of bronchiolitis obliterans syndrome (BOS) is unclear. We studied 341 lung transplant recipients to assess whether histopathologically diagnosed CMV pneumonia treated with ganciclovir was a risk factor for development of BOS and patient survival. We also analyzed the relationship between CMV donor/recipient serologic status and BOS plus the temporal association between acute rejection and CMV pneumonia. Freedom from BOS for patients with (n = 151) and without (n = 190) CMV pneumonia was 83 and 90% (1 year), 52 and 56% (3 years), and 29 and 38% (5 years), respectively (p = 0.2660). Cumulative survival of patients with and without CMV pneumonia was 90 and 93% (1 year), 70 and 74% (3 years), and 58 and 63% (5 years), respectively (p = 0.1811). There were no significant differences in either development of BOS or patient survival with any combination of donor/recipient serostatus for CMV. Acute rejection occurred in the month preceding CMV pneumonia in 62 of 193 (32%) cases. Histopathologically confirmed CMV pneumonia treated with ganciclovir is not a risk factor for BOS or patient survival, nor is any particular CMV serologic donor/recipient group. CMV pneumonia often follows acute rejection, perhaps as a result of augmented immunosuppression.

Background: Dysregulated fibroblast proliferation is thought to play an important role in the progression of bronchiolitis obliterans (BO) after lung transplantation. Augmented immunosuppression is often used to treat BO. We investigated the effect of methylprednisolone (mPRED), cyclosporine A (CsA), tacrolimus (FK506), azathioprine (AZA), mycophenolate mofetil (MMF), and everolimus (rapamycin derivative [RAD]) on the proliferative capacity of fibroblasts cultured from transbronchial biopsies of lung transplant recipients., Methods: Primary cultures of human lung fibroblasts were obtained from 14 transbronchial biopsies of lung transplant recipients. Subconfluent cells were serum starved for 24 hr followed by growth stimulation in the presence or absence of the respective drug in six concentrations ranging as follows: 0.01 to 100 mg/L for mPRED; 0.01 to 50 mg/L for CsA and AZA; 0.001 to 5 mg/L for FK506 and MMF; and 0.00001 to 1 mg/L for RAD. Proliferation was quantified by [3H]thymidine incorporation and direct cell count. A toxic drug effect was excluded by trypan blue., Results: Drug concentrations (mg/L) causing a 50% inhibition of fibroblast proliferation were mPRED 4; CsA 20; FK506 0.3; AZA 7; MMF 0.3; and RAD 0.0006. Drug concentrations (mg/L) causing inhibition of fetal bovine serum-induced proliferation were mPRED 60; CsA 45; FK506 3; AZA 35; MMF 1; and RAD 0.003., Conclusions: RAD and MMF were the most potent antifibroproliferative drugs and were effective at concentrations achieved clinically, supporting their use for the treatment of patients with early BO. Our method holds promise as an in vitro model to assess the likely in vivo responses of human lung fibroblasts to specific immunosuppressive drugs.

Objective: We present our experience with the use of the Ultraflex (nitinol) stents in the management of airway complications in lung transplant (LT) recipients., Methodology: Nine LT recipients underwent insertion of uncovered Ultraflex stents. Mean change in FEV1, duration to formation of granulation tissue and follow-up post-stent insertion were compared with results obtained in LT recipients who had undergone Gianturco stent (n = 10) and Wallstent insertion (n = 16)., Results: Mean improvement in FEV1 after insertion of Gianturco, Wallstent and Ultraflex stents was 670 +/- 591 mL, 613 +/- 221 mL and 522 +/- 391 mL, respectively. No patient with an Ultraflex stent developed mucus plugging or stenosis at stent extremity at a follow up of 263 +/- 278 days. The mean and median duration to stenosis at stent extremity for patients with Gianturco stents was 102 +/- 85 days and 73 days, respectively, compared with 132 +/- 87 days and 142 days, respectively, for patients with Wallstents. Stricture formation in the middle of the Ultraflex stent occurred bilaterally, at the level of anastomosis in one patient in whom stent placement was undertaken in the presence of inflammation. Stent migration in one patient was related to undersizing of the stent diameter relative to the airway diameter. A larger diameter relative stent was subsequently inserted successfully., Conclusion: Ultraflex stents appear to have fewer long-term complications when used in the management of airway complications following LT.

Following single lung transplantation, the native lung remains a potential source of morbidity from spontaneous pneumothorax, hyperinflation, bacterial and fungal infection and malignancy. The case of a single lung transplant recipient for idiopathic pulmonary fibrosis who developed a recurrent, non-resolving, spontaneous multiloculated pneumothorax in the native lung following thoracoscopic talc pleurodesis is reported. The pneumothorax ultimately resolved following insertion of a nitinol stent for coexisting bronchostenosis in the transplanted lung. In a single lung transplantation recipient in whom a native lung pneumothorax reoccurs or persists despite appropriate initial management, it may be useful to undertake bronchoscopy to exclude the possibility of bronchostenosis in the transplanted lung.

Lung transplantation has become an accepted treatment modality for end stage lung disease including emphysema, fibrosing alveolitis, cystic fibrosis, pulmonary hypertension and bronchiectasis. Despite the use of potent immunosuppressive drugs, acute rejection occurs frequently, especially in the first few weeks and months after transplantation. Bacterial, viral and fungal infections frequently occur in lung transplant recipients. Rapid diagnosis and adequate treatment of infections is needed. The side effects with the use of long term immunosuppressive agents includes renal toxicity, hypertension, neurotoxicity, hyperlipidemia, leucopoenia, hyperglycaemia, weight gain, osteoporosis and malignancy. However, obliterative bronchiolitis (OB) which is regarded as a chronic rejection process remains the dominant cause of morbidity and mortality in the long-term survivors of lung transplantation. This article focuses on the postoperative and long term management of lung transplant recipients.

Infectious complications are frequent following lung transplantation. Tracheobronchial aspergillosis is the predominant fungal infection in these patients. Infections with Scedosporium apiospermium (Pseudoallescheria boydii) and Scedosporium prolificans (Scedosporium inflatum) have mainly been described in bone marrow transplant recipients and only occasionally in solid organ transplant recipients. We analysed risk factors, the clinical course and outcome of seven lung transplant recipients who developed pulmonary scedosporium infection. Scedosporium apiospermium was documented in bronchoalveolar lavage (BAL) of all seven and Scedosporium prolificans in the BAL of four of these patients. Scedosporium was detected 9-58 months after transplantation. Five of the seven patients had been treated for several months with itraconazole because of previous detection of aspergillus in BAL. All seven patients with scedosporium infection showed airway problems, including early ischemic airway stenosis in one and bronchiolitis obliterans syndrome in the other six patients. Combined treatment with itraconazole and fluconazole was not able to eradicate scedosporium. Four of the seven patients died with advanced bronchiolitis obliterans 3-35 months after the diagnosis of pulmonary scedosporium infection. Three patients are currently alive 3, 6 and 7 years after transplantation, showing persistent scedosporium infection. In conclusion, pulmonary scedosporium infection was seen in lung transplant recipients with structurally abnormal airways and under long-term therapy with itraconazole. Eradication of scedosporium proved difficult, but under combined treatment with itraconazole and fluconazole this opportunistic infection did not disseminate.

Study Objectives: To assess the efficacy and complications of different interventional bronchoscopic techniques used to treat airway complications after lung transplantation., Design: Retrospective study., Setting: Heart-lung transplant unit of a university hospital., Patients: From November 1986 to January 2000, interventional bronchoscopy was performed in 41 of 312 lung transplant recipients (13.1%) for tracheobronchial stenosis, bronchomalacia, granuloma formation, and dehiscence., Interventions: Dilatation, stent placement, laser or forceps excision., Measurements and Results: Mean (+/- SE) improvement in FEV(1) in 26 patients undergoing dilatation for a stenotic or a combined lesion was 93 +/- 334 mL or 8 +/- 21%. In seven of these patients not proceeding to stent placement, mean improvement in FEV(1) was 361 +/- 179 mL or 21 +/- 9%. Patients needing stent placement after dilatation had a mean change in FEV(1) after dilatation of - 5 +/- 325 mL or 3 +/- 23%, and an improvement of 625 +/- 480 mL or 52 +/- 43% after stent insertion. Mean improvement in FEV(1) for patients treated with stent insertion for bronchomalacia was 673 +/- 30 mL or 81 +/- 24%. Complications of airway stents were migration (27%), mucous plugging (27%), granuloma formation (36%), stent fracture (3%), and formation of a false passage (6%). Mortality associated with interventional bronchoscopy was 2.4% (1 of 41 patients). For patients with airway complications successfully undergoing interventional bronchoscopy, the overall 1-year, 3-year, and 5-year survival rates were 79%, 45%, and 32%, respectively, vs 87%, 69%, and 56% for those without airway complications (p < 0.05)., Conclusion: Only a small number of patients with airway stenosis after lung transplantation will respond to bronchial dilatation alone. Patients with airway complications after lung transplantation have a higher mortality than patients without airway complications.

Although transbronchial lung biopsy (TBBx) is widely acknowledged as the "gold standard" for diagnosis of acute rejection, controversy exists regarding the need to perform follow-up procedures. Over a 5-yr period, we performed 1,142 TBBx of which 173 were follow-up TBBx in 99 patients with pulmonary allograft rejection greater than or equal to International Society for Heart and Lung Transplantation (ISHLT) grade A(2) on initial TBBx. Rejection on the previous 173 TBBx was associated with lymphocytic bronchiolitis/bronchitis (LBB) > or = ISHLT grade B(2) in 82 patients and with cytomegalovirus (CMV) pneumonitis in 16 patients. Persistent rejection (> or = A(2)) was observed in 45 of 173 (26%) follow-up TBBx. Persistent B grade rejection (> or = B(2)) was present in 28 patients whereas new B grade rejection developed in 11 patients with > or = A(2) grade rejection. Rejection > or = B(2) was significantly (p < 0.05) associated with rejection > or = A(2). Fifteen follow-up TBBx showed new B grade rejection without signs of > or = A(2) rejection. A new diagnosis of CMV pneumonitis was made in 33 of 173 (19%). CMV pneumonitis occurred in 35 follow-up TBBx, four associated with > or = A(2) rejection and eight with > or = B(2) rejection. The overall incidence of bronchiolitis obliterans syndrome (BOS) in both groups was similar. Patients with persistent rejection on follow-up TBBx developed BOS at a median of 1.3 yr and median of 2.0 yr (p = not significant [NS]) posttransplantation. The practice of follow-up TBBx after rejection within 2 yr posttransplant is clinically useful as it provides valuable diagnostic information.

Background: Survival after lung transplantation is limited by the development of bronchiolitis obliterans (BO) that is a fibroproliferative process and regarded as the histological marker of chronic rejection. To study further the pathogenesis of BO we attempted to establish primary fibroblast cell cultures from transbronchial lung biopsies (TBBs)of lung transplant recipients., Methods: One to two TBB samples from each patient were collected in sterile phosphate-buffered saline. Biopsies were cut into small pieces and placed onto 25-cm2 culture flasks for cell culture and kept under standard cell culture conditions (21% O2, 5% CO2, 37 degrees C). Culture medium consisted of RPMI 1640, 10% fetal calf serum, L-glutamine, HEPES, and antibiotics. After reaching confluence, fibroblasts were passaged into 75-cm2 flasks., Results: The success rate of establishing fibroblast cultures from transbronchial lung biopsies was 54% (27/50). Cell growth was independent of patient age, transplant type, underlying lung disease, indication for transbronchial lung biopsies, grade, or type of re jection and infection., Conclusions: We have established a novel method of culturing fibroblasts from lung transplant recipients. We consider this method as an unique human in vitro model to study the pathogenetic mechanisms leading to BO.

Human lung transplantation was successfully performed in the early eighties and is now an option for patients with endstage lung disease, which is associated with poor survival. Most frequent indications for lung transplantation are emphysema, cystic fibrosis, fibrosing alveolitis, primary pulmonary hypertension and Eisenmenger's syndrome. Single lung transplantation (SLT) is most often performed in emphysema, fibrosing alveolitis and other diseases which are not associated with chronic infection of the lung. Double lung transplantation was recently replaced by the technique of sequential single lung or bilateral lung transplantation (BLT). Cardiopulmonary bypass can often be avoided and problems of the airway anastomosis are less frequent using BLT. Main indications for this procedure are cystic fibrosis, bronchiectasis and primary pulmonary hypertension (PPH). In PPH often only SLT is performed. Cor pulmonale is reversible following SLT or BLT even if the heart is not replaced. Combined heart-lung transplantation (HLT) is reserved for some cases of Eisenmenger's syndrome and few centers still prefer HLT in patients with cystic fibrosis. Patients are usually accepted for transplantation when they are considered to have life expectancy of 12 to 24 months. Quality of life and physical working capacity are severely decreased and patients suffer dyspnea NYHA grade III or IV. Most of the patients are hypoxic and need continuous oxygen therapy. Hypercapnia is also a negative predictive factor for survival without transplantation. In PPH cardiac index of less than 2 litres/m2 is associated with poor outcome. Not only absolute values for FEV1 and pO2 have to be considered in finding the best moment for assessment for transplantation but the clinical course of the disease during previous months and years also has to be taken into account. Contraindications to transplantation include acute infection, concomitant diseases of other organs, bronchial carcinoma and psychiatric disorders if noncompliance is likely. To achieve good results after lung transplantation, proper donor and recipient selection, experienced surgery and careful postoperative management are essential. Complications must be diagnosed early to provide effective treatment. Most complications occur within the first months after surgery. Early complications include primary organ failure, pleural bleeding, problems at the site of the airway anastomosis, infection and acute rejection. Acute rejection is common but can be treated successfully if diagnosed early.(ABSTRACT TRUNCATED AT 400 WORDS)