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INTRODUCTION: Immune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients. METHODS: A multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months. RESULTS: Twenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225-525ng/mL) in 14 (15.2%) patients and low (ATP

Bronchiolitis obliterans; Clinical research; Lung transplantation Bronquiolitis obliterante; Investigación clínica; Trasplante de pulmón Bronquiolitis obliterant; Recerca clínica; Trasplantament de pulmó Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6–32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients. The study was funded by PARI Pharma GmbH. Open access funding enabled and organized by ProjektDEAL.

Resumen Introduccion La supervivencia del trasplante pulmonar (TP) viene condicionada fundamentalmente por el desarrollo de disfuncion cronica del injerto (DCI). El retrasplante pulmonar (RP) es una alternativa para una poblacion seleccionada con DCI. El objetivo del estudio fue revisar la experiencia de RP en nuestro centro. Pacientes y metodos Se ha realizado un estudio retrospectivo de los pacientes sometidos a RP entre agosto de 1990 y julio de 2017. Resultados Se realizaron 14 RP de un total de 998 (1,4%) TP. Doce RP se dieron por causa de DCI: 10 (71,4%) por sindrome de bronquiolitis obliterante y 2 (14,3%) por sindrome restrictivo del injerto. En 2 pacientes el RP se realizo en los 30 dias siguientes al primer TP. En el RP por DCI el tiempo medio entre el TP y el RP fue de 48 meses. Tras el RP el tiempo medio de ventilacion mecanica fue de 32 dias. El incremento del FEV1 tras el RP fue del 24 ± 18%. Los mejores valores en la espirometria se observaron a los 7,3 meses. La supervivencia media de la serie fue de 43,8 meses, en los pacientes con sindrome de bronquiolitis obliterante fue de 63,4 meses mientras que en los pacientes con sindrome restrictivo del injerto fue de 19,5 meses. Solo un paciente de los 2 RP precoces sobrevivio a este. Conclusion El RP es una opcion terapeutica en pacientes seleccionados con DCI. Sin embargo, estos resultados no son reproducibles si el RP se realiza en los primeros dias.

Background The relationship between community-acquired respiratory viruses (CARVs) and chronic lung allograft dysfunction (CLAD) in lung transplant recipients is still controversial. Methods We performed a prospective cohort study (2009–2014) in all consecutive adult patients (≥18 years) undergoing lung transplantation in the Hospital Universitari Vall d’Hebron (Barcelona, Spain). We systematically collected nasopharyngeal swabs from asymptomatic patients during seasonal changes, from patients with upper respiratory tract infectious disease, lower respiratory tract infectious disease (LRTID), or acute rejection. Nasopharyngeal swabs were analyzed by multiplex polymerase chain reaction. Primary outcome was to evaluate the potential association of CARVs and development of CLAD. Time-dependent Cox regression models were performed to identify the independent risk factors for CLAD. Results Overall, 98 patients (67 bilateral lung transplant recipients; 63.3% male; mean age, 49.9 years) were included. Mean postoperative follow-up was 3.4 years (interquartile range [IQR], 2.5–4.0 years). Thirty-eight lung transplant recipients (38.8%) developed CLAD, in a median time of 20.4 months (IQR, 12–30.4 months). In time-controlled multivariate analysis, CARV-LRTID (hazard ratio [HR], 3.00 [95% confidence interval {CI}, 1.52–5.91]; P = .002), acute rejection (HR, 2.97 [95% CI, 1.51–5.83]; P = .002), and cytomegalovirus pneumonitis (HR, 3.76 [95% CI, 1.23–11.49]; P = .02) were independent risk factors associated with developing CLAD. Conclusions Lung transplant recipients with CARVs in the lower respiratory tract are at increased risk to develop CLAD., “Community-acquired respiratory viruses (CARVs) lower respiratory tract infection” should be better than viral lower respiratory tract infection. It should be: CARVs lower respiratory tract infection, acute rejection and cytomegalovirus pneumonitis were independently associated with chronic lung allograft dysfunction.

Background Venous thromboembolism (VTE) is a major complication after lung transplantation (LT). However, its pathophysiology remains unknown, and coagulation profiles have yet to be described. Objective The aim of this study was to longitudinally assess coagulation status after LT. Methods We performed a prospective study and described the coagulation profiles of 48 patients at 5 different time-points: before LT and at 24–72 h, 2 weeks, 4 months, and 1 year after LT. Results At baseline, almost all analyzed coagulation factors were within the normal range, except for FVIII, which was above the normal range. Von Willebrand factor (vWF) and FVIII were increased after LT and remained high at 1 year after transplantation. The cumulative incidence of VTE was 22.9%. Patients who developed VTE had higher FVIII activity 2 weeks after LT. Conclusions This is the first study to describe coagulation profiles up to 1 year after LT. We show that most markers of a procoagulant state normalize at 2 weeks after LT, but that values of FVIII and vWF remain abnormal at 1 year. This problem has received little attention in the literature. Larger studies are necessary to confirm the results and to design appropriate prophylactic strategies.

Diagnòstic; Farmacoteràpia; Malalties del tracte respiratori Diagnóstico; Farmacoterapia; Enfermedades del tracto respiratorio Diagnosis; Drug therapy; Respiratory tract diseases There are few published data on long-term treatment with sirolimus in lymphangioleiomyomatosis (LAM). The objective of this study was to describe the long-term effect of sirolimus in a series of LAM patients followed up in a referral centre, focusing on pulmonary function. We retrospectively reviewed a series of 48 patients with LAM diagnosed, followed up and treated with sirolimus in a single centre. Response to sirolimus was evaluated at 1 and 5 years. A negative sirolimus response was defined as an FEV1 decline greater than − 75 ml/year. A mixed-effects model was used to estimate the longitudinal changes in FEV1 (average slope), both as absolute (ml/year) and as predicted values (%predicted/year). From a total of 48 patients, 9 patients underwent lung transplantation and 4 died during the study. Mean (95% CI) FEV1 slope over 5 years was − 0.14 (− 26.13 to 25.85) ml/year in the whole LAM group, 42.55 (14.87 to 70.22) ml/year in the responder group, − 54.00 (− 71.60 to − 36.39) ml/year in the partial responder group and − 84.19 (− 113.5 to − 54.0) ml/year in the non-responder group. After 5 years of sirolimus treatment 59% had a positive response, 30% had a partial response and 11% had a negative response. Our study found that sirolimus treatment had a positive long-term effect on most LAM patients. E.R.L. received a pre-doctoral Grant from the Spanish Society of Pulmonology and Thoracic Surgery.

Background Infection is the most common cause of mortality within the first year after lung transplantation (LTx). The management of perioperative antibiotic therapy is a major issue, but little is known about worldwide practices. Methods We sent by email a survey dealing with 5 daily clinical vignettes concerning perioperative antibiotic therapy to 180 LTx centers around the world. The invitation and a weekly reminder were sent to lung transplant specialists for a single consensus answer per center during a 3-month period. Results We received a total of 99 responses from 24 countries, mostly from Western Europe (n = 46) and the USA (n = 34). Systematic screening for bronchial recipient colonization before LTx was mostly performed with sputum samples (72%), regardless of the underlying lung disease. In recipients without colonization, antibiotics with activity against gram-negative bacteria resistant strains (piperacillin / tazobactam, cefepime, ceftazidime, carbapenems) were reported in 72% of the centers, and antibiotics with activity against methicillin-resistant Staphylococcus aureus (mainly vancomycin) were reported in 38% of the centers. For these recipients, the duration of antibiotics reported was 7 days (33%) or less (26%) or stopped when cultures of donor and recipients were reported negatives (12%). In recipients with previous colonization, antibiotics were adapted to the susceptibility of the most resistant strain and given for at least 14 days (67%). Conclusion Practices vary widely around the world, but resistant bacterial strains are mostly targeted even if no colonization occurs. The antibiotic duration reported was longer for colonized recipients.

This study describes the clinical presentation, treatment, and outcomes of SARS-CoV-2 infection in lung transplant recipients (LTRs). This is a multicenter, retrospective study of all adult LTRs with confirmed SARS-CoV-2 infection from March 4 until April 28, 2020 in six Spanish reference hospitals for lung transplantation. Clinical and radiological data, treatment characteristics, and outcomes were reviewed. Forty-four cases were identified in that period. The median time from transplantation was 4.2 (interquartile range: 1.11-7.3) years. Chest radiography showed acute parenchymal abnormalities in 32 (73%) cases. Hydroxychloroquine was prescribed in 41 (93%), lopinavir/ritonavir (LPV/r) in 14 (32%), and tocilizumab in 19 (43%) patients. There was a strong interaction between tacrolimus and LPV/r in all cases. Thirty-seven (84%) patients required some degree of respiratory support and/or oxygen therapy, and 13 (30%) were admitted to intermediate or intensive critical care units. Seventeen (39%) patients had died and 20 (45%) had been discharged at the time of the last follow-up. Deceased patients had a worse respiratory status and chest X-ray on admission and presented with higher D-dimer, interleukin-6, and lactate dehydrogenase levels. In this multicenter LTR cohort, SARS-CoV-2 presented with high mortality. Additionally, the severity of disease on presentation predicted subsequent mortality.

Background: Cytomegalovirus (CMV) infection remains a prevalent problem in lung transplantation (LT) despite prophylaxis use in seropositive (R+) patients. CMV-specific cell-mediated immunity (CMI) might predict patients at risk. Methods: 60 consecutive R+ LT patients were included. CMV-specific CMI against IE-1 and pp65 was assessed with an ELISPOT assay during prophylaxis and upon its completion. Patients were divided into high (HR) and low risk (LR) according to CMI ROC curves. The primary endpoint was late-onset infection. Results: 31 (52%) patients developed CMV viremia and 1 (2%) developed CMV disease. CMV-specific CMI to IE-1 was significantly lower in those developing CMV infection (120.3±29.3 vs 262.8±313.3, p=0.045). HR patients ( 10000 copies), CMI differences increased (Log-rank=0.012, HR 4.23) (Figure 1). HR patients also showed a higher CMV replication load (62378±76862 vs 8510±12367, p=0.005). Sensitivity, specificity, PPV and NPV of CMV-specific CMI predicting clinically relevant CMV infection was 80%, 56%, 38% and 89% respectively. Conclusions: CMV-specific CMI after prophylaxis withdrawal can discriminate R+ LT patients at different risk of late-onset CMV infection.

Objectives: After a lung transplant (LT), infections due to multiresistant bacteria and mold may require an increase in treatments, which can lead to more side effects, resistance and a potential increase in the incidence of chronic graft dysfunction. The aim of this study is to describe the use of antimicrobials which are usually administered orally or intravenously, and their response. Methods: Observational study of patients with LT who were started on non conventional nebulized antimicrobials in 2018-2019. We analyzed culture results, lung function and the presence of exacerbations. Results: Micafungin, voriconazole, linezolid and vancomycin were given to 6 patients with persistent fungal infections who had not responded to usual treatments. Two of the patients received nebulized micafungin for Scopulariopsis spp tracheobronchitis. Nebulized voriconazole was used in 2 patients with tracheobronchitis due to Lomentospora prolificans and Aspergillus flavus and one of these patients also had infection due to Corynebacterium spp, so he and another patient received nebulized linezolid. Another patient with Corynebacterium spp infection was started on nebulized vancomycin. The median (p25-p75) for time of treatment was 9 (6-32) months and only one patient stopped treatment due to poor tolerance. In four patients, the cultures were negative after a month and all patients had fewer exacerbations. Conclusions: The use of nebulized antimicrobials such as micafungin, voriconazole, linezolid and vancomycin seems to be safe and could be beneficial in some infections.

Monitoring CMV-specific Cell-mediated immunity (CMV-CMI) has been shown to be useful predicting late-onset CMV infection in different solid organ transplants, but few data has been reported after Lung Transplantation (LT). CMV-CMI against two major CMV antigens (IE-1, pp65) was evaluated in 60 seropositive LT at 6-month prophylaxis withdrawal. LT with late-onset CMV infection showed significantly lower (IE-1)CMV-CMI than patients who did not (p=0.045), being more evident in patients developing high viral loads (p=0.010). Notably, (IE-1)CMV-CMI independently predicted high first late-onset viral replication (OR 4.358, 1.043-18.215).CMV-specific CMI may be a useful new immune tool guiding CMV preventive strategies after LT.

Objective Lung transplantation (LT) has been proposed as a treatment for advanced interstitial lung disease (ILD) and/or pulmonary hypertension (PH) associated to systemic sclerosis (SSc) but few studies have been reported. The aim of this study was to describe the clinical features, complications and survival of a single-center cohort of patients with SSc that underwent LT and to compare their survival with a group of non-SSc transplanted patients. Methods Fifteen patients with SSc were transplanted between May 2005 and April 2015. Standard international criteria were used to determine eligibility for LT. The severity of gastroesophageal involvement was not considered as a major contraindication if symptoms were under control. Results Eight (53.3%) patients had diffuse cutaneous SSc. Eleven (73%) underwent bilateral LT. The main indication for LT was ILD, with or associated PH in 4 cases. Acute cellular rejection and infections were the most frequent complications. Functional lung tests tended to keep stable after transplantation. Median survival was 2.4 years (Q1–Q3: 0.7–3.7 years). We did not find differences in survival between patients transplanted with SSc versus those transplanted due to non-SSc ILD or PH. SSc complications were scarce with no patient developing PH after LT. Conclusions LT was an effective treatment for advanced ILD and/or PH associated to SSc in our study. Gastroesophageal reflux was not a limitation for LT in SSc in this study. Complications and survival did not differ from non-SSc patients undergoing LT.

Background Venous thromboembolism (VTE) is a frequent complication after solid organ transplantation (SOT) and, specifically, after lung transplantation (LT). The objectives of this study were to evaluate prophylaxis with enoxaparin and to describe risk factors for VTE after LT. Methods We retrospectively reviewed the clinical records of 333 patients who underwent LT in our institution between 2009 and 2014. We compared 2 consecutive cohorts, one that received enoxaparin only during post-transplant hospital admissions and a second cohort that received 90-day extended prophylaxis with enoxaparin. Cumulative incidence function for competing risk analysis was used to determine incidence of VTE during the first year after transplantation. Risk factors were analyzed using a Cox proportional hazards regression model. Results The cumulative incidence of VTE was 15.3% (95% CI: 11.6-19.4). Median time from transplant to the event was 40 (p25-p75, 14-112) days. Ninety-day extended prophylaxis did not reduce the incidence of VTE. In the present study, the risk factors associated with VTE were male gender and interstitial lung disease. Conclusions VTE is a major complication after LT, and 90-day extended prophylaxis was not able to prevent it. Large, multicenter, randomized clinical trials should be performed to define the best strategy for preventing VTE. This article is protected by copyright. All rights reserved.

El trasplante de pulmón se ha consolidado como una opción de tratamiento en pacientes con enfermedades respiratorias crónicas avanzadas y no neoplásicas mejorando la sobrevida y la calidad de vida en candidatos bien seleccionados. Una buena coordinación con un centro de trasplante es fundamental para posibilitar un mejor acceso al trasplante de nuestros pacientes. Se trata de ofrecer todos los recursos disponibles a pacientes sin comorbilidades significativas que tienen más probabilidad de beneficiarse del trasplante. Existen guías internacionales que ayudan a decidir cuando el paciente debe ser derivado, ingresar a lista y el momento del trasplante. Esta revisión es un análisis crítico de los actuales criterios de referencia y aborda una serie de aspectos del paciente que deben ser tomados en cuenta y que pretenden dar mayor claridad al neumólogo general de cuando y que pacientes enviar a un centro de trasplante.

Purpose The aim of the study was to review the experience of lung transplantation (LT) in HIV-seropositive patients in a referral center. Methods Prospectively, from the first VIH patient accepted for LT in our center we followed all the cases of HIV-infected patients submitted to LT from October 2018 to July 2019. Demographics, CD4 counts and VIH viral loads before and after LT, postoperative and specific VIH complications like opportunistic infections, drug interactions and drug adjustments were recorded. Results In the study period seven VIH patients have been submitted for LT. Only one patient was rejected due to unacceptable surgical risk. The other six patients were accepted; one of them is still on the waiting list, and five patients have been transplanted. Demographics and VIH related characteristics are shown in Table 1. Combined antiretroviral therapy had to be change in two cases: one changed from dultegravir, rilpivirine to emtricitabina, tenofovir and dolutegravir to avoid interactions with pantoprazole; the other one changed from neviparina, raltegravir to emtricitabina, tenofovir, alafenamida and raltegravir to manage renal disfunction. Post-LT results are presented in Table 2. Mean follow up time is 14 (SD 4) months. Only one patient has passed away due to Stenotrophomonas maltophilia graft pneumonia. At the end of the study the other four patients have been discharged and are improving the pulmonary function tests (Table 2). Conclusion The experience of the first five VIH LT patients in Spain shows that LT is feasible without increasing the risk of infectious or immunological complications.

Cytomegalovirus; Immuno-guided prophylaxis; Lung transplantation Citomegalovirus; Profilaxis inmunoguiada; Trasplante de pulmón Citomegalovirus; Profilaxi immuno-guiada; Trasplantament de pulmó INTRODUCTION: Prolonged use of antivirals to prevent the development of cytomegalovirus (CMV) disease in lung transplant patients has been shown to have significant side effects, for which alternatives are being sought to reduce their use. The monitoring of cell immunity against CMV could be an alternative as it has shown to be useful in identifying transplant patients at low risk of infection, who could benefit from shorter prophylaxis. The aim of the CYTOCOR study is to demonstrate that the combination of a reduced prophylaxis strategy with subsequent CMV-specific immunological monitoring would allow CMV infection to be controlled in lung transplant patients as effectively as the usual strategy (prophylaxis followed by pre-emptive therapy), while reducing the side effects of antivirals due to the shorter duration of prophylaxis. METHODS AND ANALYSIS: Phase III randomised, open, multicentre, parallel, non-inferiority clinical trial to study the efficacy and safety of the combination of a prophylaxis strategy up to month +3 post-transplant followed by immuno-guided prophylaxis using the QuantiFERON-CMV technique up to month +12 post-transplant to prevent CMV disease in CMV-seropositive lung transplant recipients. This strategy will be compared with a combination of a usual prophylaxis strategy up to month +6 post-transplant followed by pre-emptive therapy up to month +12. To study the incidence of CMV disease, patients will be followed up to 18 months post-transplantation. A total of 150 patients are expected to be recruited for the study. ETHICS AND PUBLIC DISSEMINATION: The clinical trial has been approved by the Research Ethics Committees and authorised by the Spanish Agency of Medicines and Medical Devices (AEMPS).If the hypothesis of this clinical trial is verified, the dissemination of the results could change clinical practice by increasing knowledge about the safety and efficacy of discontinuing valganciclovir prophylaxis in lung transplant recipients. We would like to acknowledge the support of the Spanish Network for Research in Infectious Disease (REIPI, RD16/0016), the Group for the Study of Infections in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and SCReN (Spanish Clinical Research Network) funded by the ISCIII-Sub-Directorate General for Research Assessment and Promotion through project PT13/0002/0010-PT17/0017/0012 and PT17/0017/0032.

Shahid Husain, MD, MS, Amparo Sole, MD, PhD, Barbara D. Alexander, MD, MHS, Saima Aslam, MD, MS, Robin Avery, MD, Christian Benden, MD, Eliane M. Billaud, PharmD, PhD, Daniel Chambers, MBBS, MD, Lara Danziger-Isakov, MD, Savitri Fedson, MD, Kate Gould, MD, Aric Gregson, MD, Paolo Grossi, MD, PhD, Denis Hadjiliadis, MD, Peter Hopkins, MD, Me-Linh Luong, MD, Debbie J.E. Marriott, MD, Victor Monforte, MD, Patricia Munoz, MD, PhD, Alessandro C. Pasqualotto, MD, PhD, Antonio Roman, MD, Fernanda P. Silveira, MD, Jeffrey Teuteberg, MD, MS, Stephen Weigt, MD, Aimee K. Zaas, MD, MHS, Andreas Zuckerman, MD, and Orla Morrissey, MD, PhD

The aim of this study was to compare the pharmacokinetic profile, tolerability, and safety of a novel once-daily extended-release formulation of tacrolimus (LCPT) with that of once-daily prolonged-release tacrolimus (ODT) in stable adult lung transplant (LT) recipients.Phase II, open-label, single-arm, single-center, prospective pilot pharmacokinetic study. Study population comprised 20 stable LT recipients receiving ODT, mean age 55.9 years (range, 38-67 years), 13 (65%) men. Patients were switched to LCPT in a 1:0.7 (mg/mg) conversion dose. Follow-up was 6 months, and cystic fibrosis patients were excluded. Two 24-hour pharmacokinetic profiles were obtained for each patient, the first on day -14 and the second on day +14 after switching to LCPT. Pharmacokinetic parameters and safety were compared.Mean (SD) area under the concentration-time curve from 0 to 24 hours was 253.97 (61.90) ng/mL per hour for ODT and 282.44 (68.2) ng/mL per hour for LCPT. Systemic exposure was similar in both (Schuirmann two 1-sided test). Mean (SD) dose was 5.05 (1.67) mg in ODT and 3.36 (1.03) mg in LCPT (P = 0.0002). Time to maximum concentration was 125 minutes for ODT and 325 minutes for LCPT (P0.001). Correlation between area under the concentration-time curve from 0 to 24 hours and C24 was 0.896 (r) for ODT and 0.893 (r) for LCPT. There were no differences in adverse effects. At 6 months, conversion dose was 1:0.59 (mg/mg) in patients with unchanged minimum plasma concentration target levels.Switching from ODT to LCPT was safe and well tolerated in stable LT recipients without cystic fibrosis. A significantly lower dose of LCPT allows similar bioavailability. A conversion ratio 1:0.6 could be enough to maintain similar target levels.

Introduction Long-term survival of lung transplantation (LT) patients is mainly limited by the development of chronic lung allograft dysfunction (CLAD). Lung retransplantation (LR) is an alternative for a selected population. The aim of this study was to review the LR experience in our center. Patients and methods We conducted a retrospective study of patients undergoing LR between August 1990 and July 2017. Results Fourteen LR out of a total of 998 (1.4%) LT were performed. Twelve patients (85.7%) underwent LR due to CLAD: 10 (71.4%) because of bronchiolitis obliterans syndrome and 2 (14.3%) due to restrictive allograft syndrome. LR was performed in 2 patients within 30 days of the first LT. In those who underwent LR due to CLAD, mean time between the first LT and LR was 48 months, and mean duration of invasive mechanical ventilation was 32 days. The increase in FEV1 after LR was 24±18%. The best spirometry values were observed after 7.3 months. Mean survival of the cohort was 43.8 months. In patients with bronchiolitis obliterans syndrome, mean survival was 63.4 months, while in those with restrictive allograft syndrome, it was 19.5 months. Only 1 of the 2 early LR patients survived. Conclusion LR is a therapeutic option in selected patients with CLAD, with acceptable survival. Indication for LR early after LT shows poor outcomes.

Cancer is the third most common cause of death among lung transplant (LT) recipients who survive for more than 1 year. The purpose of this study was to analyze the incidence and risk factors for cancer after LT in a Spanish cohort. The epidemiology and risk factors for cancer were retrospectively analyzed in LT recipients from 2 cities in Spain, Madrid and Barcelona. Of the 1353 LT patients initially included in the study, 125 (9.2%) developed cancer after a mean of 3.7 years. This frequency was 5-fold higher than in the general population. The most prevalent tumors were skin cancer (32%), lymphoproliferative disease (18%), and lung cancer (16.5%). In 4 patients, lung cancer was diagnosed on the day of the operation. The risk of cancer increased with age55 year (hazard ratio [HR] 2.89 [1.64-5.09]; P .001), in men (HR 2.8 [1.4-5.6]; P = .004), and in heavy smokers (20 pack-years) (HR 2.94 [1.64-5.27]; P .001). Other factors such as sun exposure were not found to be risk factors. In conclusion, prevalence of cancer is high in LT recipients in a Mediterranean country. Skin tumors, lymphoproliferative disease, and lung cancer are the most prevalent cancers. Age, male sex, and smoking were the main risk factors for cancer in this population.

The aim of this study was to assess the outcome and tolerability of prophylactic nebulized liposomal amphotericin B (n-LAB) in lung transplant recipients (LTR) and the changing epidemiology of Aspergillus spp. infection and colonization. We performed an observational study including consecutive LTR recipients (2003-2013) undergoing n-LAB prophylaxis lifetime. A total of 412 patients were included (mean postoperative follow-up 2.56 years; IQR 1.01-4.65). Fifty-three (12.8%) patients developed 59 Aspergillus spp. infections, and 22 invasive aspergillosis (overall incidence 5.3%). Since 2009, person-time incidence rates of Aspergillus spp. colonization and infection decreased (2003-2008, 0.19; 2009-2014, 0.09; P = 0.0007), but species with reduced susceptibility or resistance to amphotericin significantly increased (2003-2008, 38.1% vs 2009-2014, 58.1%; P = 0.039). Chronic lung allograft dysfunction (CLAD) was associated with Aspergillus spp. colonization and infection (HR 24.4, 95% CI 14.28-41.97; P = 0.00). Only 2.9% of patients presented adverse effects, and 1.7% required discontinuation. Long-term administration of prophylaxis with n-LAB has proved to be tolerable and can be used for preventing Aspergillus spp. infection in LTR. Over the last years, the incidence of Aspergillus spp. colonization and infection has decreased, but species with reduced amphotericin susceptibility or resistance are emerging. CLAD is associated with Aspergillus spp. colonization and infection.

Resumen Introduccion La EPOC y el enfisema secundario a deficit de alfa-1 antitripsina (DAAT) son la primera y la cuarta causa de trasplante pulmonar en el mundo, respectivamente, a pesar de lo cual disponemos de poca informacion sobre la situacion en la que estos pacientes llegan al trasplante. Metodos Se identifico a los pacientes trasplantados por EPOC y por enfisema secundario a DAAT en el Hospital Vall d’Hebron entre julio de 1993 y agosto de 2013 y se recogieron datos de la evaluacion previa al trasplante. Resultados Se incluyo a un total de 217 pacientes trasplantados por EPOC y 19 por enfisema secundario a DAAT. Los pacientes evaluados para trasplante por estas enfermedades presentaban una afectacion grave de su enfermedad aunque en los ultimos anos se observo una tendencia a realizar la evaluacion en estadios mas precoces. Ambos grupos presentaban caracteristicas similares, excepto que los pacientes con DAAT eran mas jovenes (43 [7,7] vs. 53,6 [6,1] anos; p Conclusiones El numero de pacientes trasplantados por EPOC ha aumentado progresivamente, observandose una tendencia a realizar la evaluacion de trasplante en estadios mas tempranos de la enfermedad. Los pacientes evaluados para trasplante por EPOC y por enfisema secundario a DAAT presentan caracteristicas similares, aunque estos ultimos eran mas jovenes, tenian un menor consumo de tabaco y menor PCO2.

Resumen Fundamento y objetivo Las enfermedades pulmonares intersticiales (EPI) constituyen, despues del enfisema, la segunda indicacion de trasplante pulmonar (TP). El objetivo del presente estudio es la revision de los resultados del TP en la EPI en el Hospital Vall d’Hebron (Barcelona). Pacientes y metodo Se estudian retrospectivamente 150 pacientes, 87 (58%) varones, con una edad media de 48 anos (extremos 20-67), en los que se indico un TP por una EPI entre agosto de 1990 y enero de 2010, y que representan el 30% del total de TP (150/496) realizados en Cataluna. Ciento cuatro (69%) fueron trasplantes unipulmonares (TUP), y 46 (31%), trasplantes bipulmonares (TBP). Los diagnosticos postoperatorios fueron: 94 (63%) neumonia intersticial usual, 23 (15%) neumonia intersticial no especifica, 11(7%) neumonia intersticial no clasificable y un 15% miscelanea. Se describen los resultados funcionales, las complicaciones y la supervivencia. Resultados La supervivencia actuarial fue del 87, 70 y 53% a uno, 3 y 5 anos, respectivamente. Las causas de muerte mas frecuentes incluyen la disfuncion precoz del injerto y el desarrollo de rechazo cronico en forma de bronquiolitis obliterante (BOS). El incremento medio postoperatorio de la capacidad vital forzada y del forced expiratory volume in the first second (FEV 1 , «volumen espiratorio forzado en el primer segundo») fue similar en el TUP y el TBP. El mejor FEV 1 posterior al TP se alcanzo al decimo mes (extremos 1-36). El 16% de los pacientes se reintegro al trabajo. En algun momento de la evolucion se diagnostico rechazo agudo, confirmado histologicamente en 53 (35%) pacientes. La prevalencia de BOS entre los supervivientes fue del 20% al ano, 45% a los 3 anos y del 63% a los 5 anos. Conclusion El TP es hasta ahora el unico tratamiento capaz de alargar la vida de los pacientes con EPI avanzada y en nuestro medio ha permitido que uno de cada 6 pacientes haya vuelto a trabajar. Sin embargo, el rechazo cronico sigue siendo el principal problema a resolver en el futuro.

Background There has been little study on the variability of CsA pharmacokinetics in stable lung transplant (LT) recipients without cystic fibrosis. This study was conducted to determine the prevalence of high intra-individual variability of CsA in LT recipients and its implications in CsA monitoring. Methods Twenty-nine pharmacokinetic curves were performed in 10 consecutive stable patients from a single center. The intra-individual coefficient of variation (CV) of the AUC0–12 h was calculated in each case. Patients were grouped according to whether their CV was high (≥20%) or low (

The long-term success of lung transplantation (LT) is limited by chronic lung allograft dysfunction (CLAD). Different phenotypes of CLAD have been described, such as bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). The purpose of this study was to investigate the levels of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) as markers of these CLAD phenotypes. BALF was collected from 51 recipients who underwent (bilateral and unilateral) LT. The study population was divided into three groups: stable (ST), BOS, and RAS. Levels of interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured using the multiplex technology. BALF neutrophilia medians were higher in BOS (38%) and RAS (30%) than in ST (8%) (P=.008; P=.012). Regarding BALF cytokines, BOS and RAS patients showed higher levels of INF-γ than ST (P=.02; P=.008). Only IL-5 presented significant differences between BOS and RAS (P=.001). BALF neutrophilia is as a marker for both CLAD phenotypes, BOS and RAS, and IL-5 seems to be a potential biomarker for the RAS phenotype.

Immunologic complications after lung transplantation (LT) include acute cellular rejection (ACR), antibody-mediated rejection (AMR), and most forms of chronic allograft dysfunction (CAD). ACR is an inflammatory process in which the reaction is mediated by the T-cell population. Most episodes of ACR fully recover with treatment, but repeated bouts are considered to be a risk factor for CAD. Biomarker cytokines interleukin (IL)-10, IL-15, IL-6, CCL5, CCR2 and IFNγ may play significant roles in this complication. Formerly bronchiolitis obliterans syndrome (BOS) or chronic rejection or most forms of CAD were considered to be immunologic complications not amenable therapeutic measures. CAD, the main limitation for long-term survival in LT, is characterized histologically by airway epithelial cell apoptosis and luminal fibrosis in the respiratory bronchioles causing airflow obstruction and, in some cases, lung parenchymal affectations causing restrictive lung disease. Several biomarkers have been studied in CAD, IL-6, IL-8, IL-17, IL-23, IL-13, IFN γ, and TGF β cytokines, pH, bile acid, and tripsine of gastroesophageal reflux and toll-like receptors of innate immunity. Herein we have reviewed the literature of biomarkers involved in lung rejection.

Background Prophylaxis with inhaled liposomal amphotericin B has proven to be safe and effective for preventing infection due to Aspergillus spp in lung transplant recipients. However, the liposome contains a large quantity of phospholipids, and inhalation of these substances could potentially change the composition of pulmonary surfactant. The aim of this study was to determine the lipid composition of pulmonary surfactant in patients receiving inhaled liposomal amphotericin B prophylaxis. Methods A prospective, open, controlled multicenter study was conducted in 2 groups: 19 lung transplant recipients who received regular prophylaxis with inhaled amphotericin B (study group) and 19 recipients who did not receive inhaled prophylaxis (control group). From both groups, 15 ml of the third aliquot of bronchoalveolar lavage fluid was obtained and phospholipid content determined in the active fraction of surfactant (large aggregates) and in the inactive fraction (small aggregates). Large aggregate cholesterol content was also determined. Results Patient demographic data and characteristics were similar in the 2 groups. No between-group differences in median phospholipid content were found for large aggregates (study group, 0.4 [range, 0.18–1.9] μmol vs controls, 0.36 [range 2.15–0.12] μmol; p = 0.69) or small aggregates (study group, 0.23 [range, 0.1–0.58] μmol vs controls, 0.29 [range, 0.18–0.65] μmol; p = 0.33). The small aggregate-to-large aggregate phospholipid ratio, commonly used as a marker of alveolar injury, showed no differences between the groups (study group, 0.56 vs controls, 0.69; p = 0.28). Nor were there differences in the cholesterol content of large aggregates (study group, 0.04 μmol [range 0.01–0.1] vs controls, 0.04 μmol [range 0.02–0.27); p = 0.13). Conclusions These results seem to indicate that prophylaxis with nebulized liposomal amphotericin B does not cause changes in the lipid content of pulmonary surfactant.

The antiproliferative effect of everolimus provides a therapeutic option in the immunosuppression therapy of lung transplantation, by reducing both the risk of acute rejection and the process of progressive fibrosis that determines chronic graft rejection. However, few data on the use of everolimus in lung transplantation have been published to date, and the specific indications of the drug, along with the most adequate time for its introduction or dosing, have not been defined yet. The aim of this article is to propose recommendations for the use of everolimus in lung transplant recipients, including indications, dosing schedules and the use of concomitant immunosuppression. This consensus document has been developed by experts of all the Spanish lung transplant groups from the review of the existing literature and the clinical experience.

Chronic allograft dysfunction (CLAD) is the main limitation for Lung Transplantation (LT) survival. There is known 2 forms of CLAD: obliterative bronchiolitis syndrome (BOS) and restrictive allograft syndrome (RAS). The detection of the glycoprotein KL-6 in bronchoalveolar lavage (BAL) or serum in LT population may discriminate between both. The objective of the study was to analyse KL-6 levels in BAL and in serum from LT population in differents situations : stable (ST) , infection (LTI), BOS and RAS. Patients and methods - Forty four patients with bilateral LT and who survived more than 3 months were included. The population were divided in 4 groups : 14 ST patients, 10 LTI patients, 12 BOS patients and 8 patients with RAS. BAL and serum samples from the 44 patients were analysed with the Kit KL-6 ( Eidia Co.,Ltd.,Tokyo, Japan). U Mann Whitney were used to analysed differences between groups Results - KL-6 levels in serum were higher in RAS patients at a median of 1042 [IQR 504,9 to 1592]. Significant differences were shown between RAS vs ST, LTI and BOS patients with p-value of 0,0001, 0,0031 and 0,0055 respectively. KL-6 levels in BAL were higher in ST patients at a median of 262,3 [ IQR 117,9 to 661,8 ]. Significant differences were only shown between ST vs LTI patients (p=0,0088) and LTI vs BOS patients ( p=0,0168). Conclusion - KL-6 measured in serum from LT population with RAS are the highest values compared with the rest. KL-6 in serum seems to be better biomarker for RAS than in BAL.

Introduction: Infections are the main cause of morbi-mortality in lung transplant recipients (LT). The hypogammaglobulinemia (HGG) after lung transplantation has been related to an increased frequency and severity of these infections. Objective: to assess the incidence and severity of HGG in LT candidates. Material and methods: Prospectively, from January 2014 until September 2015 a determination of serum globulin (SGG) was performed (IgG, IgM, IgA) on all LT candidates and their medical records were reviewed. We considered normal IgG levels > 700 mg/dl; mild HGG IgG 600-700mg/dl; moderate HGG IgG 400-600mg/dl and severe HGG IgG> 400 ml/ dl. Results: There were 99 LT candidates. 63 were male (63.6%) with a mean age of 54.1 years (range 27-66). The predominant lung diseases were chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) with 45.4% both. 18 patients (18.1%) had HGG (IgG): 2/18 patients (11.1%) had mild HGG; 12/18 (66.6%) moderate HGG and 4/18 (22.2%) severe HGG. 4 of these patients had a combined form of HGG (IgG and IgM). Thirteen patients with HGG were COPD (13/18, 72.2%): mild HGG 1/13, moderate HGG 8/13 and severe HGG 4/13. Four patients with ILD had HGG, one mild and three moderate. During the study 5/18 patients (27.7%) with HGG were transplanted. Two of them received replacement therapy while were in active list; only one of them had improved GGS levels without reaching normal level Conclusions: 18/99 (18.1%) LT candidates had HGG which was moderate-severe in the most cases 16/18 (88%). The COPD patients had the highest prevalence of HGG 13/18 (72.2%) (p = 0.012), being in 12/13 patients moderate-severe type.

Aims Restrictive Allograft Syndrome (RAS) and idiopathic pleuroparenchymal fibroelastosis (IPPFE) are two different diseases reported to share the same histology. RAS relates to chronic allograft dysfunction in lung transplantation with IPPFE being a rare condition in native lungs. Our aim is to compare their histologies, alongside biopsies of usual interstitial pneumonia (UIP), to determine if there are differences that might help to elucidate the pathogenesis. Methods and Results We selected 4 post-mortem allograft lungs from patients who developed clear clinical RAS pattern, 5 biopsies diagnosed as IPPFE, 5 UIP biopsies and 5 sections of normal lung. Histopathologic features were described without knowledge of clinical and radiological features. Both RAS allografts and IPPFE biopsies showed intra-alveolar fibrosis and elastosis (IAFE), but RAS allografts also showed concomitant obliterative bronchiolitis, vascular lymphoplasmacytic inflammation within fibro-intimal thickening, less fibroblastic foci at the advancing edge of the fibrosis (1 against 14.4 FF in 2mm2) and a slight reduction of the capillary network compared to UIP (p=0.07) and controls (p=0.06). The main differences seen in UIP were the lack of IAFE and the presence of honeycomb change. Conclusions RAS and PPFE histopathology both show IAFE, but display various differences, particularly in their vascular morphology that may allow further understanding of pathogenesis. This article is protected by copyright. All rights reserved.

Cytomegalovirus (CMV) infection remains a major complication of solid organ transplantation. Because of management of CMV is variable among transplant centers, in 2011 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, new publications have clarified or questioned the aspects covered in the previous document. For that reason, a panel of experts revised the evidence on CMV management, including immunological monitoring, diagnostics, prevention, vaccines, indirect effects, treatment, drug resistance, immunotherapy, investigational drugs, and pediatric issues. This document summarizes the recommendations.

Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are serious diseases with similar pathophysiologic aspects. The prognosis of patients with these conditions is highly uncertain, particularly incident cases. Methods: A Cox proportional hazards model was applied to a group of 85 patients (81% women, mean age 52 (18 - 82) years) with PAH (80%) and non-surgical CTEPH (20%) to evaluate risk factors for mortality. The following variables were included in the model: age, etiology, baseline 6-minute walk test (6 mWT), cardiac index, and improvement in the 6 mWT following initiation of first medical treatment. Results: In the multivariate analysis, the response to treatment, assessed by an improvement on the 6 mWT, was the most relevant prognostic factor in these patients (RR, 4.832 (95% CI, 1.888 - 12.364); p = 0.001). The remaining variables studied in this model had less influence on the prognosis: age > 50 years (RR, 0.744 (95% CI, 0.26 - 2.133); p = 0.582); etiology of connective tissue disease-associated PAH (RR, 3.145 (95% CI, 0.995-9.946); p = 0.051) or CTEPH (RR, 0.654 (95% CI, 0.179 - 2.387); p = 0.521) with respect to idiopathic PAH; baseline 6 mWT (RR, 1.173 (95% CI, 0.599 - 4.895); p = 0.315); or cardiac index (RR, 2.295 (95% CI, 0.793 - 6.642); p = 0.125). Conclusions: There is a high degree of uncer-tainty regarding the prognosis of PAH and CTEPH at the start of appropriate treatment. Our results support the idea that the initial treatment response is of paramount importance as prognostic factor in these patients.

The present guidelines have been prepared with the consensus of at least one representative of each of the hospitals with lung transplantation programs in Spain. In addition, prior to their publication, these guidelines have been reviewed by a group of prominent reviewers who are recognized for their professional experience in the field of lung transplantation. Within the following pages, the reader will find the selection criteria for lung transplantation candidates, when and how to remit a patient to a transplantation center and, lastly, when to add the patient to the waiting list. A level of evidence has been identified for the most relevant questions. Our intention is for this document to be a practical guide for pulmonologists who do not directly participate in lung transplantations but who should consider this treatment for their patients. Finally, these guidelines also propose an information form in order to compile in an organized manner the patient data of the potential candidate for lung transplantation, which are relevant in order to be able to make the best decisions possible.

Resumen La presente normativa ha sido elaborada con el consenso de, al menos, un representante de cada uno de los hospitales con programa de trasplante pulmonar en Espana. Ademas, previamente a su publicacion, ha sido revisada por un grupo de revisores destacados por su reconocida trayectoria en el campo del trasplante pulmonar. En las siguientes paginas, el lector encontrara los criterios de seleccion de pacientes candidatos a trasplante pulmonar, cuando y como remitir un paciente a un centro trasplantador y, finalmente, cuando incluir al paciente en lista de espera. Se ha atribuido un nivel de evidencia a las cuestiones mas relevantes. Este documento pretende ser una guia practica para los neumologos que no participan directamente en el trasplante pulmonar pero que deben considerar este tratamiento para sus pacientes. Finalmente, se ha propuesto de una forma consensuada un documento que recoge de forma estructurada los datos del paciente potencial candidato a trasplante pulmonar que son relevantes para poder tomar la mejor decision.

Background Nebulized amphotericin B deoxycholate (n-ABD) is used to prevent Aspergillus infection in lung transplantation. Nebulized liposomal amphotericin B (n-LAB) is another option; however, no clinical data are available on the results of n-LAB for this purpose. Methods In an observational study performed in 2 centers to assess the feasibility, tolerability, and outcomes of n-LAB prophylaxis, 104 consecutive patients undergoing prophylaxis with n-LAB were compared with 49 historical controls who received n-ABD. Patient follow-up lasted 12 months. The n-LAB prophylaxis regimen was 25 mg thrice weekly starting on the first post-operative day and continuing to 60 days, 25 mg once weekly from 60 to 180 days, and the same dose once every 2 weeks thereafter. Results Aspergillus infection developed in 8 of 104 patients (7.7%) with n-LAB prophylaxis (5 colonization, 1 simple tracheobronchitis, 1 ulcerative tracheobronchitis, and 1 invasive pulmonary infection). Ulcerative tracheobronchitis and invasive pulmonary aspergillosis were regarded as invasive disease; hence, the rate of invasive disease was 1.9% (2 patients). The control group had similar rates of Aspergillus infection (10.2%; p = 0.6) and invasive disease (4.1%; p = 0.43). In 3 patients (2.9%), n-LAB was withdrawn due to bronchospasm in 2 and nausea in 1. In the control group, prophylaxis was stopped in 2 patients (4.1%) because of bronchospasm ( p = 0.7). Conclusions At the dose and frequency described, n-LAB seems effective, safe, and convenient for the prevention of Aspergillus infection in lung transplant patients.

Resumen Introduccion La hipertension pulmonar (HP) es una enfermedad grave tributaria de trasplante pulmonar (TP) en su fase terminal. Pacientes y metodos Se ha realizado un estudio retrospectivo de 15 pacientes con HP, a los que se trato con un TP en el periodo 1994–2004. Se revisan los datos clinicos antes del trasplante y el seguimiento tras este. Resultados En 8 pacientes (53%) la HP fue idiopatica y en 2 estuvo relacionada con el consumo de aceite toxico; el resto de etiologias, con un paciente cada una, fueron: embolia pulmonar cronica periferica, histiocitosis X, enfermedad venooclusiva, esclerodermia y cardiopatia congenita simple corregida. Los valores hemodinamicos medios fueron: presion arterial pulmonar sistolica, diastolica y media, 100; 50, y 67 mmHg, respectivamente; gasto cardiaco, 2,63 l/min; resistencia pulmonar total, 20,9 UW. El tiempo desde el diagnostico de HP hasta el TP fue de 5,9 (rango: 0,4-20) anos. Siete pacientes estaban en clase funcional III y 8 en clase funcional IV. La distancia media recorrida en la prueba de la marcha de 6 min fue de 204 m (rango: 0–360). La mortalidad perioperatoria fue de 4 pacientes (26%). La supervivencia a 1; 3, y 5 anos fue de 9 (60%), 7 (46%) y 6 (40%) pacientes, respectivamente. Conclusiones El TP bilateral es una opcion terapeutica que, en casos seleccionados, presenta resultados comparables al tratamiento medico mas activo de la HP.