Gerard Meachery

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.

Outcomes of lung transplantation for cystic fibrosis in a large UK cohort

Background: Lung transplantation is an important option to treat patients with advanced cystic fibrosis (CF) lung disease. The outcomes of a large UK cohort of CF lung transplantation recipients is reported. Methods: Retrospective review of case notes and transplantation databases. Results: 176 patients with CF underwent lung transplantation at our centre. The majority (168) had bilateral sequential lung transplantation. Median age at transplantation was 26 years. Diabetes was common pretransplantation (40%). Polymicrobial infection was common in individual recipients. A diverse range of pathogens were encountered, including the Burkholderia cepacia complex (BCC). The bronchial anastomotic complication rate was 2%. Pulmonary function (forced expiratory volume in 1 s % predicted) improved from a pretransplantation median of 0.8 l (21% predicted) to 2.95 l (78% predicted) at 1 year following transplantation. We noted an acute rejection rate of 41% within the first month. Our survival values were 82% survival at 1 year, 70% at 3 years, 62% at 5 years and 51% at 10 years. Patients with BCC infection had poorer outcomes and represented the majority of those who had a septic death. Data are presented on those free from these infections. Bronchiolitis obliterans syndrome (BOS) and sepsis were common causes of death. Freedom from BOS was 74% at 5 years and 38% at 10 years. Biochemical evidence of renal dysfunction was common although renal replacement was infrequently required (<5%). Conclusion: Lung transplantation is an important therapeutic option in patients with CF even in those with more complex microbiology. Good functional outcomes are noted although transplantation associated morbidities accrue with time.

A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation

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.

An association of particulate air pollution and traffic exposure with mortality after lung transplantation in Europe

Air pollution from road traffic is a serious health risk, especially for susceptible individuals. Single-centre studies showed an association with chronic lung allograft dysfunction (CLAD) and survival after lung transplantation, but there are no large studies. 13 lung transplant centres in 10 European countries created a cohort of 5707 patients. For each patient, we quantified residential particulate matter with aerodynamic diameter ≤10 µm (PM10) by land use regression models, and the traffic exposure by quantifying total road length within buffer zones around the home addresses of patients and distance to a major road or freeway. After correction for macrolide use, we found associations between air pollution variables and CLAD/mortality. Given the important interaction with macrolides, we stratified according to macrolide use. No associations were observed in 2151 patients taking macrolides. However, in 3556 patients not taking macrolides, mortality was associated with PM10 (hazard ratio 1.081, 95% CI 1.000–1.167); similarly, CLAD and mortality were associated with road lengths in buffers of 200–1000 and 100–500 m, respectively (hazard ratio 1.085– 1.130). Sensitivity analyses for various possible confounders confirmed the robustness of these associations. Long-term residential air pollution and traffic exposure were associated with CLAD and survival after lung transplantation, but only in patients not taking macrolides. Long-term residential air pollution/traffic exposure associated with CLAD and survival after lung transplantation http://ow.ly/Izxj304uA5k

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 Fishers 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.

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.

P243 Influenza A outbreak in a UK respiratory centre

Introduction In March 2013, 12 patients on a single ward in a tertiary respiratory transplant centre contracted influenza within 72 hours. There was no corresponding community outbreak. Staff with symptoms went off sick. Trust policies outlining respiratory infection and isolation existed but there were no guidelines for this specific novel situation. We found no published reports of such an event in England. Methods Patients quickly developed pyrexias and respiratory symptoms. All had throat swabs and blood cultures. Influenza A, H3N2 variant, was identified. A team of infection control and respiratory physicians, nurses and managers met regularly to implement these measures: Closure of ward and cohorting of bays Ward avoidance for non-essential personnel and anyone with symptoms Cancellation of non-essential procedures Strict hand hygiene and use of PPE and FFP3 masks Stockage of oseltamivir for treatment for all affected high risk staff and patients and prophylaxis offered to all ward patients and exposed high risk staff. No crossover of ward staff to transplant patients. Contact tracing of all immunocompromised patients on ward up to one week and all high risk patients 48 hours prior to the index case; advice on prophylaxis and their GPs contacted. Writing an information sheet for staff and GPs Increased and terminal ward cleaning Results On the respiratory ward, 151 bed days were lost and 53 on two other wards. Fourteen patients (including two on another ward) had positive swabs for H3N2. There were 27 symptomatic staff members; 15 had swabs, two were positive. All patients and two staff members were given treatment oseltamivir. Fourteen patients and two staff members had prophylaxis. No influenza complications or deaths occurred. The department staff had 45% influenza vaccination uptake in 2012/2013. All affected patients had been vaccinated. Conclusions Containment, pathogen identification, prompt treatment and contact tracing were priorities, to limit number of individuals affected. This is widely applicable. Our departmental staff vaccination rate is below Department of Health targets. Importance of vaccination needs emphasising, whilst recognising that vaccine effectiveness against all laboratory-confirmed influenza in primary care is 51% for 2012/2013.

Single- and Bilateral Lung Transplantation: Indications, Contraindications, Evaluation, and Requirements for Patients to Be Considered Eligible

Single- and double-lung transplantation epitomize the final therapeutic options available to selected patients with advanced, end-stage lung disease refractory to all methods of available medical management. The lack of evidence supporting effective lung transplant practices is widely acknowledged, necessitating the need for expert opinion practice guidelines. In this chapter we present the key recommendations for consideration when referring and listing an individual for lung transplantation. We critique seminal papers that have revised our selection process for single- and bilateral lung transplant recipients and outline the indications and contraindications unique to different lung pathologies. We define our current clinical practice based on the best available international expert opinions and review future developments of treatments and novel approaches to deal with the continued lack of suitable donor organs.

Outcomes of lung transplantation in adults with bronchiectasis

BackgroundLung transplantation is a well-established treatment for end-stage non-cystic fibrosis bronchiectasis (BR), though information regarding outcomes of transplantation remains limited. Our results of lung transplantation for Br are reported here.MethodsA retrospective review of case notes and transplantation databases was conducted for patients that had underwent lung transplantation for bronchiectasis at the Freeman Hospital between 1990 and 2013.ResultsFourty two BR patients underwent lung transplantation, the majority (39) having bilateral sequential lung transplantation. Mean age at transplantation was 47.1 years. Pre-transplantation osteoporosis was a significant non-pulmonary morbidity (48%). Polymicrobial infection was common, with Pseudomonas aeruginosa infection frequently but not universally observed (67%). Forced expiratory volume in 1 second (% predicted) improved from a pre-transplantation mean of 0.71 L (22% predicted) to 2.56 L (79 % predicted) at 1-year post-transplantation. Our survival results were 74% at 1 year, 64% at 3 years, 61% at 5 years and 48% at 10 years. Sepsis was a common cause of early post-transplantation deaths.ConclusionsLung transplantation for end-stage BR is a useful therapeutic option, with good survival and lung function outcomes. Survival values were similar to other bilateral lung transplants at our centre. Pre-transplantation Pseudomonas infection is common.

Cystic fibrosis, lung transplantation and clostridium difficile associated disease

RO-194 – Classification at 6 weeks and fibrosis/atrophy at one year Variables at one year Classification of biopsies at 6 weeks p (neg vs. bord) p (neg vs. rej) p (bord vs. rej) Negative (n=100) Borderline (n=43) Rejection (n=14) Interstitial fibrosis 0.80 (0.71) 0.91 (0.43) 0.71 (0.47) 0.36 0.66 0.17 Tubular atrophy 1.03 (0.63) 0.98 (0.34) 0.71 (0.46) 0.60 0.073 0.028 Mean (SD). were placed on MPP (pulsatile perfusion machine, RM3) and all patients received the same immunosuppressive treatment. Estimated MDRD and inuline clearance were analysed until 36 months after transplantation and systematic biopsies were performed at M3 and M12 to evaluate the chronic interstitial fibrosis (IF) by colour image quantification. Our experience with RM3 perfusion machine leads us to perform a SKG when the resistance index (RI) is lower than 0.4 after 6 hours of perfusion and a DKG when the RI is between 0.4 and 0.6. Donor’s and recipient’s characteristic (mean age, gender), mean numbers of HLA mismatch were not significantly different. The mean duration time of MPP and the mean warm ischemic time were higher in the DKG than in the SKG group (1319 vs 689 min, p= 0.05 and 105 vs 121 min, p=0.017). Patient and graft survivals were 100% in both groups. PNF (not observed in our cohort) and DGF rate were not statistically different between the 2 groups (100% vs 78%). Acute rejection rate was not different between the groups. Graft outcomes and IF results are reported table 1. Table 1. Evolution of graft function and histology