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Background: We conducted a placebo-controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation., Methods: We compared azithromycin (250 mg alternate days, 12 weeks) with placebo. Primary outcome was FEV1 change at 12 weeks., Results: 48 patients were randomised; (25 azithromycin, 23 placebo). It was established, post randomisation that two did not have BOS. 46 patients were analysed as intention to treat (ITT) with 33 'Completers'. ITT analysis included placebo patients treated with open-label azithromycin after study withdrawal., Outcome: The ITT analysis (n=46, 177 observations) estimated mean difference in FEV1 between treatments (azithromycin minus placebo) was 0.035 L, with a 95% CI of -0.112 L to 0.182 L (p=0.6). Five withdrawals, who were identified at the end of the study as having been randomised to placebo (four with rapid loss in FEV1, one withdrawn consent) had received rescue open-label azithromycin, with improvement in subsequent FEV1 at 12 weeks. Study Completers showed an estimated mean difference in FEV1 between treatment groups (azithromycin minus placebo) of 0.278 L, with 95% CI for the mean difference: 0.170 L to 0.386 L (p=<0.001). Nine of 23 ITT patients in the azithromycin group had ≥10% gain in FEV1 from baseline. No patients in the placebo group had ≥10% gain in FEV1 from baseline while on placebo (p=0.002). Seven serious adverse events, three azithromycin, four in the placebo group, were deemed unrelated to study medication., Conclusions: Azithromycin therapy improves FEV1 in patients with BOS and appears superior to placebo. This study strengthens evidence for clinical practice of initiating azithromycin therapy in BOS., Trial Registration Number: EU-CTR, 2006-000485-36/GB., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Fundoplication may improve survival after lung transplantation. Little is known about the effects of fundoplication on quality of life in these patients. The aim of this study was to assess the safety of fundoplication in lung transplant recipients and its effects on quality of life. Between June 1, 2008 and December 31, 2010, a prospective study of lung transplant recipients undergoing fundoplication was undertaken. Quality of life was assessed before and after surgery. Body mass index (BMI) and pulmonary function were followed up. 16 patients, mean ± sd age 38 ± 11.9 yrs, underwent laparoscopic Nissen fundoplication. There was no peri-operative mortality or major complications. Mean ± SD hospital stay was 2.6 ± 0.9 days. 15 out of 16 patients were satisfied with the results of surgery post fundoplication. There was a significant improvement in reflux symptom index and DeMeester questionnaires and gastrointestinal quality of life index scores at 6 months. Mean BMI decreased significantly after fundoplication (p = 0.01). Patients operated on for deteriorating lung function had a statistically significant decrease in the rate of lung function decline after fundoplication (p = 0.008). Laparoscopic fundoplication is safe in selected lung transplant recipients. Patient benefit is suggested by improved symptoms and satisfaction. This procedure is acceptable, improves quality of life and may reduce deterioration of lung function.

Background: The bronchial epithelium is a source of mediators that may play a role in the airway inflammation and remodeling of post-transplant obliterative bronchiolitis (OB). Traditional strategies have failed to have an impact on OB. Recent studies have suggested a role for azithromycin in managing the condition. In this study we aimed to determine the effect of azithromycin on LPS-mediated epithelial release of factors relevant to airway neutrophilia and remodeling in a unique population of primary bronchial epithelial cells (PBECs) derived from stable lung allografts., Methods: PBECs were established from bronchial brushings of stable lung transplant recipients and treated with lipopolysaccharide (LPS, 0.1, 1 and 10 microg/ml) for 48 hours. Interleukin-8 (IL-8), granulocyte macrophage colony-stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF) protein levels were measured by Luminex analyzer. PBECs were then incubated with LPS and azithromycin, and protein levels were again determined., Results: LPS caused a significant increase in IL-8 and GM-CSF at concentrations of 1 and 10 microg/ml, with no effect on VEGF release. Azithromycin caused a significant decrease in the LPS-stimulated IL-8 and GM-CSF release., Conclusions: LPS upregulates release of IL-8 and GM-CSF from PBECs derived from stable lung allografts. Sub-microbicidal concentrations of azithromycin attenuate this and may, therefore, alleviate infection-driven neutrophilic airway inflammation and remodeling in the allograft airway.

Obliterative bronchiolitis (OB), the major cause of chronic lung allograft dysfunction, is characterized by airway neutrophilia, inflammation, and remodeling, with progressive fibroproliferation and obliteration of small airways that ultimately leads to patient death. Statins have potential anti-inflammatory effects and have been demonstrated to confer a survival advantage in lung transplant patients. We postulated that the beneficial effects of simvastatin in lung transplantation are in part due to inhibition of the epithelial production of key mediators of neutrophil chemotaxis, inflammation, and airway remodeling. Our objective was to assess the effect of simvastatin on a unique population of primary bronchial epithelial cells (PBECs) derived from stable lung allografts, with specific reference to airway neutrophilia and remodeling. PBEC cultures were stimulated with IL-17 or transforming growth factor (TGF)-beta, with and without simvastatin. Supernatant levels of factors critical to driving airway neutrophilia and remodeling were measured. IL-17 upregulated IL-8, IL-6, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and VEGF, whereas TGF-beta increased IL-6, GM-CSF, matrix metalloproteinase (MMP)-2, and MMP-9. Simvastatin attenuated effects of both IL-17 and TGF-beta. We have demonstrated the ability of simvastatin to attenuate release of airway neutrophilic and remodeling mediators and to inhibit their upregulation by TGF-beta and IL-17. These data illustrate the potential of simvastatin to alleviate neutrophilic airway inflammation and remodeling in the transplanted lung and may have additional relevance to other neutrophilic airway conditions, such as chronic obstructive pulmonary disease.

Background: Chronic lung disease and pulmonary failure are complications that can occur after bone marrow transplantation (BMT) and are associated with severe morbidity and mortality., Methods: We report on four patients who developed chronic, progressive, and irreversible lung disease 1 to 3 years after allogeneic BMT in childhood. These patients had chronic graft-versus-host disease (n=3) or radiation-related pulmonary fibrosis (n=1). Three patients underwent double lung transplants and one patient underwent a single lung transplant 2 to 14 years after BMT., Results: All four patients tolerated the lung transplantation procedure well and showed significant clinical improvement with normalization of pulmonary function tests by 1 year posttransplant. One patient died from infectious complications 3 years after lung transplantation, and one patient died after chronic rejection of the transplanted lungs 6 years posttransplant. Two patients remain alive without significant respiratory impairment 2 and 7 years after lung transplantation., Conclusion: We conclude that lung transplantation offers a viable therapeutic option for patients who develop respiratory failure secondary to BMT.

Airway rejection after lung transplantation is recognized histologically as lymphocytic bronchiolitis (LB). We hypothesized that inhaled steroids could control LB and that changes in exhaled nitric oxide (eNO) would correlate with the development of LB and also have a role in monitoring response to treatment. A cohort of 120 lung transplant (LT) recipients attending for review and biopsy had eNO measurements, FEV1, lavage microbiology, and biopsy histology performed prospectively. Wilcoxon signed-rank test was used to assess the significance of changes in eNO and FEV1. The coefficient of reproducibility of eNO measurement in stable recipients was 2.36 ppb. Fourteen developed graft dysfunction owing to isolated LB and were treated with inhaled budesonide 800 microg twice daily. They showed significant increases in eNO at diagnosis, median (range) 10.9 ppb (4.6 to 48) ppb compared with baseline, 4.33 (1.0 to 10.76), p = 0.008, and a decrease in FEV1. After inhaled treatment, both eNO and FEV1 returned to baseline values. Seven developed acute vascular rejection (with or without LB) and were treated with oral corticosteroids; no changes in eNO occurred at diagnosis or after treatment. Serial eNO measurements provide a useful noninvasive method of identifying airway inflammation in LT recipients. Inhaled budesonide may be a useful addition to systemic immunosuppressants in controlling airway inflammation posttransplant.

Background: The role of nitric oxide (NO) in the pathophysiology of graft dysfunction following lung transplantation remains unclear. To determine whether measurement of NO in the exhaled breath of lung transplant recipients provides useful information about graft pathology, a cross sectional study was performed on a cohort of recipients as they attended for review., Methods: One hundred and four lung transplant recipients and 55 healthy non-smoking controls were included in the study. Each subject performed three consecutive single breath NO manoeuvres. In recipients NO levels were compared according to current clinical status, presence of any graft pathology, type of lung transplant procedure, indication for transplantation, and current level of immunosuppression., Results: Mean (SE) exhaled NO levels were 6.5 (0.61) ppb in the control group, 5.3 (0.46) in clinically well recipients, 10.3 (1.4) in those with lymphocytic bronchiolitis, 10.5 (1.0) in recipients with infection, and 2.5 (0.6) in those with acute vascular rejection. There was no significant difference in NO levels between the control group and lung transplant recipients as a whole (mean difference 0.29 (95% CI -1.17 to 1.75), p = 0.7). Levels were increased significantly in the presence of lymphocytic bronchiolitis (4.98 (95% CI 1.6 to 8.36), p = 0.0002) and infection (5.28 (95% CI 2.9 to 7.56), p < 0.0001), but not in acute vascular rejection (2.76 (95% CI 0.97 to 4.55), p = 0.1) compared with exhaled NO in clinically well recipients. Recipients with obliterative bronchiolitis were subdivided according to the grade of their bronchiolitis obliterans syndrome (BOS). Exhaled NO levels in those with BOS grade 1 were 10.0 (1.3) ppb and in those with BOS grades 2 or 3 were 5.1 (0.7) ppb. Compared with those who were clinically well, NO levels were increased in those with BOS grade 1 (4.74 (95% CI 1.8 to 7.69), p < 0.0001) but not in those with BOS grades 2 or 3 (0.19 (95% CI -1.55 to 1.93), p = 0.82)., Conclusions: Exhaled NO levels are increased in lung transplant recipients with lymphocytic bronchiolitis, early obliterative bronchiolitis, and infection. These conditions are all associated with the presence of airway inflammation within the graft. The findings suggest that exhaled NO measurements may have a role as a marker of pulmonary allograft dysfunction.

Coughing is a frequent side-effect of angiotensin converting enzyme (ACE) inhibitors. Its pathogenesis is thought to be related to the local accumulation of tachykinins although the role of extrinsic cholinergic pathways is unclear. The development of an ACE inhibitor induced cough in two patients who have undergone heart-lung transplantation and in whom cholinergic pathways remain denervated supports the hypothesis of a 'local' mechanism.