Autoimmunity Is a Significant Feature of Idiopathic Pulmonary Arterial Hypertension.

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.

Factors affecting adherence with treatment advice in a clinical trial of patients with severe asthma.

BACKGROUND: Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management. METHODS: We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma. RESULTS: Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68-5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51-5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32-0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07-53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice. CONCLUSIONS: Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies.

The CRASH report: emergency management dilemmas facing acute physicians in patients with pulmonary arterial hypertension.

Treatment of acute emergencies in patients with pulmonary arterial hypertension (PAH) can be challenging. In the UK and Ireland, management of adult patients with PAH is centred in eight nationally designated pulmonary hypertension (PH) centres. However, many patients live far from these centres and physicians in local hospitals are often required to manage PAH emergencies. A committee of physicians from nationally designated PH centres identified the 'most common' emergency clinical scenarios encountered in patients with PAH. Thereafter, a review of the literature was performed centred on these specified topics and a management approach was developed based on best available evidence and expert consensus. Management protocols were developed on the following PAH emergencies: chest pain (including myocardial ischaemia), right ventricular failure, arrhythmias, sepsis, haemoptysis ('CRASH'), as well as considerations relevant to surgery, anaesthesia and pregnancy. Emergencies are not uncommon in PAH. While expertise in PAH management is essential, all physicians involved in acute care should be aware of the principles of acute management of PAH emergencies. A multidisciplinary approach is necessary, with physicians from tertiary PH centres supporting care locally and planning safe transfer of patients to PH centres when appropriate.

Sendaway capillary NT-proBNP in pulmonary hypertension.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac ventricular wall stress that is incorporated into pulmonary hypertension (PH) risk stratification models. Sendaway sampling may enable patients to perform NT-proBNP tests remotely. This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing. METHODS: Reference venous NT-proBNP was collected from PH patients. Samples for capillary and venous sendaway tests were collected contemporaneously, mailed to a reference laboratory and processed at 3 and 7 days using a Roche Cobas e411 device. Differences in paired measurements were analysed with Passing-Bablok regression, percentage difference plots and the % difference in risk strata. RESULTS: 113 patients were included in the study. 13% of day 3 capillary samples were insufficient. Day 3 capillary samples were not equivalent to reference samples (Passing Bablok analysis slope of 0.91 (95% CI 0.88 to 0.93) and intercept of 6.0 (95% CI 0.2 to 15.9)). The relative median difference was -7% and there were acceptable limits of agreement. Day 3 capillary NT-proBNP accurately risk stratified patients in 93.5% of cases. By comparison, day 3 venous results accurately risk stratified patients in 90.1% of cases and were equivalent by Passing-Bablok regression. Delayed sampling of sendaway tests led to an unacceptable level of agreement and systematically underestimated NT-proBNP. CONCLUSIONS: Sendaway NT-proBNP sampling may provide an objective measure of right ventricular strain for virtual PH clinics. Results must be interpreted with caution in cases of delayed sampling.

Extracorporeal photopheresis (ECP) in the treatment of chronic lung allograft dysfunction (CLAD): a prospective, multicentre, open-label, randomised controlled trial studying the addition of ECP to standard care in the treatment of bilateral lung transplant patients with CLAD (E-CLAD UK).

BACKGROUND: Long-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop via multiple immune pathways, is captured under the umbrella term chronic lung allograft dysfunction (CLAD). Despite the availability of powerful immunosuppressive drugs, there are presently no treatments proven to reverse or reliably halt the loss of lung function caused by CLAD. The aim of the E-CLAD UK trial is to determine whether the addition of immunomodulatory therapy, in the form of extracorporeal photopheresis (ECP), to standard care is more efficacious at stabilising lung function in CLAD compared with standard care alone. METHODS AND ANALYSIS: E-CLAD UK is a Phase II clinical trial of an investigational medicinal product (Methoxsalen) delivered to a buffy coat prepared via an enclosed ECP circuit. Target recruitment is 90 bilateral lung transplant patients identified as having CLAD and being treated at one of the five UK adult lung transplant centres. Participants will be randomised 1:1 to intervention plus standard of care, or standard of care alone. Intervention will comprise nine ECP cycles spread over 20 weeks, each course involving two treatments of ECP on consecutive days. All participants will be followed up for a period of 24 weeks.The primary outcome is lung function stabilisation derived from change in forced expiratory volume in one second and forced vital capacity at 12 and 24 weeks compared with baseline at study entry. Other parameters include change in exercise capacity, health-related quality of life and safety. A mechanistic study will seek to identify molecular or cellular markers linked to treatment response and qualitative interviews will explore patient experiences of CLAD and the ECP treatment.A patient and public advisory group is integral to the trial from design to implementation, developing material to support the consent process and interview materials. ETHICS AND DISSEMINATION: The East Midlands-Derby Research Ethics Committee has provided ethical approval (REC 22/EM/0218). Dissemination will be via publications, patient-friendly summaries and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT number 2022-002659-20; ISRCTN 10615985.

Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland.

RATIONALE: Incident pulmonary arterial hypertension was underrepresented in most pulmonary hypertension registries and may have a different disease profile to prevalent disease. OBJECTIVES: To determine the characteristics and outcome of a purely incident, treatment-naive cohort of idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension and to determine the changes in presentations and survival over the past decade in the United Kingdom and Ireland. METHODS: All consecutive newly diagnosed patients from 2001 to 2009 were identified prospectively. MEASUREMENTS AND MAIN RESULTS: A total of 482 patients (93% idiopathic, 5% heritable, and 2% anorexigen-associated pulmonary arterial hypertension) were diagnosed, giving rise to an estimated incidence of 1.1 cases per million per year and prevalence of 6.6 cases per million in 2009. Younger patients (age ≤ 50 yrs) had shorter duration of symptoms, fewer comorbidities, better functional and exercise capacity, higher percent diffusing capacity of carbon monoxide, more severe hemodynamic impairment, but better survival compared with older patients. In comparison with the earlier cohorts, patients diagnosed in 2007-2009 were older, more obese, had lower percent diffusing capacity of carbon monoxide,(,) and more comorbidities, but better survival. Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) equation, REVEAL risk score, and Pulmonary Hypertension Connection Registry survival equation accurately predicted survival of our incident cohort at 1 year. CONCLUSIONS: This study highlights the influence of age on phenotypes of incident pulmonary arterial hypertension and has shown the changes in demographics and epidemiology over the past decade in a national setting. The results suggest that there may be two subtypes of patients: the younger subtype with more severe hemodynamic impairment but better survival, compared with the older subtype who has more comorbidities.

Lung transplantation for interstitial lung disease: evolution over three decades.

BACKGROUND: Interstitial lung disease (ILD) has emerged as the most common indication for lung transplantation globally. However, post-transplant survival varies depending on the underlying disease phenotype and comorbidities. This study aimed to describe the demographics, disease classification, outcomes and factors associated with post-transplant survival in a large single-centre cohort. METHODS: Data were retrospectively assessed for 284 recipients who underwent lung transplantation for ILD in our centre between 1987 and 2020. Patient characteristics and outcomes were stratified by three eras: 1987-2000, 2001-2010 and 2011-2020. RESULTS: Median patients' age at time of transplantation was significantly higher in the most recent decade (56 (51-61) years, p<0.0001). Recipients aged over 50 years had worse overall survival compared with younger patients (adjusted HR, aHR 2.36, 95% CI 1.55 to 3.72, p=0.0001). Better survival was seen with bilateral versus single lung transplantation in patients younger than 50 years (log-rank p=0.0195). However, this survival benefit was no longer present in patients aged over 50 years. Reduced survival was observed in fibrotic non-specific interstitial pneumonia compared with idiopathic pulmonary fibrosis, which remained the most common indication throughout (aHR 2.61, 95% CI 1.40 to 4.60, p=0.0015). CONCLUSION: In patients transplanted for end-stage ILD, older age and fibrotic non-specific interstitial pneumonia were associated with poorer post-transplant survival. The benefit of bilateral over single lung transplantation diminished with increasing age, suggesting that single lung transplantation might still be a feasible option in older candidates.

Ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis lung disease.

RATIONALE: Ceramide accumulates in the airway epithelium of mice deficient in cystic fibrosis transmembrane conductance regulator, resulting in susceptibility to Pseudomonas aeruginosa infection and inflammation. OBJECTIVES: To investigate quantitatively ceramide levels in the lower airway of people with cystic fibrosis compared with pulmonary hypertension, emphysema, and lung donors. METHODS: Immunohistochemistry was performed on the lower airway epithelium of explanted lungs (eight cystic fibrosis, emphysema, and pulmonary hypertension, respectively) and eight donor lungs using ceramide, neutrophil elastase, and myeloperoxidase antibodies. High-performance liquid chromatography-mass spectrometry was performed on tissue from five lungs with cystic fibrosis and five with pulmonary hypertension. MEASUREMENTS AND MAIN RESULTS: Staining for ceramide was significantly increased in the lower airway epithelium of people with cystic fibrosis (median, 14.11%) compared with pulmonary hypertension (3.03%; P = 0.0009); unused lung donors (3.44%; P = 0.0009); and emphysema (5.06%; P = 0.01). Ceramide staining was increased in emphysematous lungs compared with pulmonary hypertension (P = 0.0135) and unused donors (P = 0.0009). The number of neutrophil elastase- and myeloperoxidase-positive cells in the airway was positively correlated with the percentage of epithelium staining for ceramide (P = 0.001). Ceramide staining was significantly increased in lungs colonized with Pseudomonas aeruginosa (10.1%) compared with those not colonized (3.14%; P = 0.0106). Significantly raised levels of ceramides C16:0, C18:0, and C20:0 were detected by mass spectrometry in lungs with cystic fibrosis compared with pulmonary hypertension. Differences in C22:0 were not significant. CONCLUSIONS: Immunoreactive ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis. Detected by mass-spectrometry ceramide species C16:0, C18:0, and C20:0 but not C22:0 are increased.

Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial.

BACKGROUND: Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). METHODS: We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed. FINDINGS: Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28·4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18·5% of patients in the control group (adjusted odds ratio [aOR] 1·71 [95% CI 0·80-3·63]; p=0·17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30·7% of patients) compared with the control group (5·0% of patients; aOR 11·48 [95% CI 1·35-97·83]; p=0·026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose. INTERPRETATION: Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low. FUNDING: This study was funded, in part, by the Medical Research Council UK.

Idiopathic pulmonary arterial hypertension and co-existing lung disease: is this a new phenotype?

Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients (IPAH lung disease ) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease (IPAH no lung disease ). Patients with 'IPAH lung disease ' have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with 'IPAH no lung disease '. We described the outcome of the cohort of patients with 'IPAH no lung disease ' in a previous paper. Here, we have compared incident 'IPAH lung disease ' patients with 'IPAH no lung disease ' patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001-2009. Compared with 'IPAH no lung disease ' (n = 355), 'IPAH lung disease ' patients (n = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in 'IPAH lung disease ' and 'IPAH no lung disease '. However, survival of 'IPAH lung disease ' was lower than 'IPAH no lung disease ' (one year survival: 72% compared with 93%). This survival was significantly worse in 'IPAH lung disease ' even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. 'IPAH lung disease ' patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with 'IPAH no lung disease ' patients. This suggests that 'IPAH lung disease ' are a separate phenotype and should not be lumped with 'IPAH no lung disease ' in clinical trials of Group 1 pulmonary arterial hypertension.

Survival in portopulmonary hypertension: Outcomes of the United Kingdom National Pulmonary Arterial Hypertension Registry.

BACKGROUND: Portopulmonary hypertension (PoPH) is a rare condition associated with poor survival, and the effect of modern therapies that target pulmonary arterial hypertension (PAH) on long-term outcome is unknown. This study investigated the baseline characteristics and survival in the cohort of patients diagnosed with PoPH in the United Kingdom National Pulmonary Hypertension Service. METHODS: A retrospective review was conducted of all incident treatment-naïve patients with PoPH within the United Kingdom national registry diagnosed between January 2001 and December 2010. RESULTS: Patients with PoPH (n = 110) had survival rates of 85%, 60%, and 35% at 1, 3, and 5 years. The prevalence of PoPH was 0.85 cases/1 million. Mean age at diagnosis was 53 ± 12 years, with a balanced distribution in gender. Alcohol (n = 57) and hepatitis C (n = 10) were the most common causes of portal hypertension. Phosphodiesterase V inhibitors were the most frequently used targeted therapy, in 63.6% (n = 70) of patients, endothelin receptor antagonists were used in 10% (n = 11) and prostacyclin analogs in 12.7% (n = 14). Univariate and multivariate analysis of baseline characteristics did not demonstrate a significant influence of severity of portal hypertension or liver cirrhosis, World Health Organization Functional Class, cardiopulmonary hemodynamics, or year of diagnosis on survival. CONCLUSIONS: Survival of patients with PoPH remains poor despite targeted therapy and worse than patients with idiopathic PAH. The benefit of PAH therapies in PoPH on long-term morbidity and mortality outcomes needs further consideration and study.

Observational study of lung transplant recipients surviving 20 years.

BACKGROUND: Lung transplant recipients have reduced long-term survival compared with other solid organ recipients. There is a lack of published data on the characteristics of very long term survivors. METHODS: We describe the demographics, clinical history and post-procedure function of all lung transplant recipients who have survived greater than 20 years at our centre. RESULTS: At the time of analysis there were 21 (16.4%) of 128 patients who survived over 20 years. The mean age at transplantation was 31.8 ± 9.9 years. Five of 21 had undergone single-lung, eight double-lung and eight heart-lung transplant procedures. At the last evaluation, mean percentage predicted FEV1 in recipients of single and double lung were 51.3% and 57.9% respectively. By 20 years, 19 (90.5%) patients had developed bronchiolitis obliterans syndrome (BOS) with three (14%) BOS 1, six (29%) BOS 2 and 10 (48%) BOS 3 and two (9.5%) free from BOS. The median time to onset of BOS was 9.7 years (range 1.6-17.9). Of eight patients (38%) who required renal replacement, four (19%) had successfully undergone renal transplantation and four (19%) were on haemodialysis. Only one patient (5%) had symptomatic osteoporosis. Nineteen patients (90%) were treated for hypertension. Five patients (24%) had diabetes, all with an underlying diagnosis of cystic fibrosis and four of them developing diabetes post operatively. CONCLUSIONS: In our experience, 20-year survivors of lung transplantation had a delayed onset of BOS and morbidities due to immunosuppression that can be appropriately managed leading to long-term survival.

Pregnancy after lung and heart-lung transplantation.

BACKGROUND: Advances in lung transplantation have enabled women to successfully undertake pregnancies. This study explored outcomes in this group, including changes in lung function, kidney function, and calcineurin inhibitor (CNI) levels. METHODS: A retrospective review identified 19 transplant recipients who had ever become pregnant at our center, and manual reviews of their medical records were completed for 14. Results of spirometry, serum creatinine, CNI doses and trough levels, and comorbidities were collected. RESULTS: Eight births occurred (42% success rate). Six patients have since died, with pregnancy contributing to 1 death. Five pregnancies were unplanned, with only 1 resulting in birth. Six pregnancies ended with spontaneous termination, and 2 were terminated for medical reasons. Mean age was 31.4 years (range, 22-39 years), and mean time from transplant was 76.2 months (range, 26-139 months). Complications included preeclampsia in 2, diabetes of pregnancy in 1, and abnormal liver enzymes in 1. Within 6 months of delivery, there were 2 cases of pneumonia, 2 cases of obliterative bronchiolitis, 1 case of tuberculosis, and 1 case of mild acute rejection. Forced expiratory volume in 1 second was stable at 3 (-1.5%; p = 0.55) and 12 months (1.4%; p = 0.84) after pregnancy. Mean change in Forced expiratory volume in 1 second during full-term pregnancies was -2.4% (p = 0.29), and the mean change in forced vital capacity was -0.8% (p = 0.55). In the first trimester, 83% of patients had a fall in creatinine, and a universal fall in CNI trough levels was seen. CONCLUSIONS: In carefully selected patients, planned pregnancy after lung transplant can be successful. Complications are common, and close monitoring of immunosuppression and renal function is needed.

Targeted Antibiotic Prophylaxis for Lung Transplantation in Cystic Fibrosis Patients Colonised with Pseudomonas aeruginosa Using Multiple Combination Bactericidal Testing.

Early infection is a recognised complication after lung transplantation in patients with cystic fibrosis (CF). Our centre uses multiple combination bactericidal testing (MCBT) when determining appropriate peritransplant prophylactic regimens. To evaluate our strategy, we compared the incidence of posttransplant infection in patients whose peritransplant antimicrobial regimens were determined using MCBT versus standard sensitivity testing. Patients with CF who were infected with Pseudomonas aeruginosa and underwent lung transplantations between 2000 and 2010 were included. Data was collected from clinical records and our microbiology database. Microorganisms cultured were mapped against antibiotic resistance, method of sensitivity testing, and antibiotics administered peritransplant. 129 patients were identified (mean age 28, male : female, 63 : 66). Fifty patients (38.8%) had antibiotics determined by MCBT. Two patients in the MCBT group developed septicaemia, 13 in the conventional group (P ≤ 0.05, 2-tailed Fisher's test). Sepsis was attributable to P. aeruginosa in one patient from the MCBT group and seven patients in the conventional group (P = 0.15). P. aeruginosa was recovered from the posttransplant pleural fluid of one patient who received MCBT-guided prophylaxis, six patients in the conventional group (P = 0.25). Patients given antibiotics based on MCBT had significantly lower rates of septicaemia and lower rates of empyema.

Pulmonary arterial hypertension and lung transplantation.

Transplantation remains the only therapeutic option for selected patients with advanced pulmonary arterial hypertension (PAH) who continue to deteriorate despite optimal pulmonary vasodilator therapy - including intravenous prostanoids and combination therapy. Identification of poor prognostic markers in PAH, including persistence in the New York Heart Association functional class III and IV, and adverse pulmonary hemodynamics at right heart catheterization should prompt early referral for transplantation. There is a need for inclusion of more discriminatory markers of PAH prognosis in donor-lung allocation scores to identify patients at risk and optimize survival to transplantation, given the current shortage of donor organ availability worldwide. Double-lung transplantation is the recommended operation for idiopathic PAH. Heart-lung transplantation is reserved for selected patients with idiopathic PAH with severe right ventricular dysfunction, or congenital heart disease with complex or ventricular septal defect-associated PAH. Novel surgical strategies, including atrial septostomy or the pumpless Novalung® lung assist device with conduits, from the pulmonary artery to the left atrium, can be considered as a bridge to transplant for patients with rapid clinical decline, despite maximal medical therapy. Recent transplant outcomes for PAH are encouraging, albeit with early postoperative risks, a requirement for long-term surveillance, immunosuppression and transplant immunosuppression-specific morbidity.

Lung transplantation for patients with cystic fibrosis and Burkholderia cepacia complex infection: a single-center experience.

BACKGROUND: Pre-operative infection with organisms from the Burkholderia cepacia complex (BCC), particularly B cenocepacia, has been linked with a poorer prognosis after transplantation compared to patients with cystic fibrosis (CF) without this infection. Therefore, many transplant centers do not list these patients for transplantation. METHODS: We report the early and long-term results of a cohort of lung transplant recipients with CF and pre-operative BCC infection. Patients with pre-transplantation BCC infection were identified by case-note review. BCC species status was assigned by polymerase chain reaction (PCR)-based techniques. Survival rates were compared to recipients with CF without BCC infection. Survival rates in BCC subgroups were also compared, and then further analyzed pre- and post-2001, when a new immunosuppressive and antibiotic regime was introduced for such patients. RESULTS: Two hundred sixteen patients with CF underwent lung transplantation and 22 had confirmed pre-operative BCC infection, with 12 of these being B cenocepacia. Nine B cenocepacia-infected recipients died within the first year, and in 8 BCC sepsis was considered to be the cause of death. Despite instituting a tailored peri-operative immunosuppressive and microbiologic care approach for such patients, post-transplantation BCC septic deaths occurred frequently in those with pre-transplantation B cenocepacia infection. In contrast, recipients infected with other BCC species had significantly better outcomes, with post-transplantation survival comparable to other recipients with CF. CONCLUSIONS: Mortality in patients with B cenocepacia infection was unacceptably high and has led to our center no longer accepting patients with this condition onto the lung transplant waiting list. Long-term survival in the non-B cenocepacia BCC group was excellent, without high rates of acute rejection or bronchiolitis obliterans syndrome (BOS) longer term, and these patients continue to be considered for lung transplantation.

Simvastatin attenuates release of neutrophilic and remodeling factors from primary bronchial epithelial cells derived from stable lung transplant recipients.

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.

Azithromycin attenuates effects of lipopolysaccharide on lung allograft bronchial epithelial cells.

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.

Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome.

INTRODUCTION: A recent pilot study noted clinical benefit of macrolide therapy in the management of six lung transplant recipients with bronchiolitis obliterans syndrome (BOS), a condition previously regarded as irreversible. OBJECTIVE: To examine the effect of low-dose macrolides on lung function in lung allograft recipients with established BOS and to assess whether this benefit is sustained. METHODS: We retrospectively evaluated the effect of azithromycin (250 mg alternate days) on clinical status and lung function in 20 allograft recipients with established BOS, confirmed by decline in FEV(1) or FEF(25-75); consistent high-resolution computed tomography findings; and exclusion of acute rejection, infection, or anastomatic complications. Azithromycin was introduced at mean 82 months after transplantation. BOS staging at initiation of treatment was BOS 3 (10), BOS 2 (2), BOS 1 (6), and BOS0-p (2). All patients were on maintenance immunosuppression comprising cell-cycle inhibitor, oral corticosteroids, and calcineurin inhibitor. RESULTS: There was a significant increase in FEV(1) of median 110 ml (range, -70 to 730 ml) between baseline and 3 months of azithromycin therapy (p = 0.002). This improvement was sustained beyond 3 months in the majority of patients, who had initially benefited from azithromycin (up to 11 months follow up). CONCLUSIONS: This case series confirms the benefit of azithromycin in not only halting, but reversing the declining lung function seen in patients with BOS. This benefit appears to be maintained over time. Low-dose macrolides offer a new and exciting therapeutic strategy for the treatment of progressive BOS, and further clinical and translational mechanistic studies are required.