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Introduction and Objectives: Risk stratification in pulmonary arterial hypertension (PAH) is essential to provide more aggressive treatment for patients at higher risk. Nevertheless, recently introduced simplified prognostic tools neglect the genetic background. Additionally, pulmonary veno-oclusive disease (PVOD) has never been considered in risk assessment strategies., Methods: We analyzed consecutive patients in the Spanish registry of PAH (REHAP) genetically tested, between 2011 and 2022. We applied the 4-strata COMPERA 2.0 model, comparing these results with an amplified score including genetics. Cox regression models were compared using Harrel c-statistics. The application of the model was specifically tested in PVOD before inclusion., Results: We identified 298 patients tested genetically among the group of idiopathic, familial, drug-induced PAH and PVOD patients in the REHAP registry. When we analyzed only patients with all available variables of interest at baseline (World Health Organization functional class, 6-minute walk test, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and included in the 4-strata model (n=142), after a median follow-up of 58.2 months, 17.6% of patients died and 11.3% underwent lung transplant. The application of the 4-strata model in our population demonstrated a good prognostic capacity (Harrel c of 0.689), which was not improved by the introduction of genetics (c-index 0.690). This last model showed a tendency for a better identification of patients at intermediate-low and intermediate-high risk, and no differences between intermediate-high and high-risk strata., Conclusions: In this work, the addition of genetics to the COMPERA 4-strata model achieved a similar global prognostic capacity but changed the identification of different risk strata in a cohort of young genetically tested patients., (Copyright © 2022 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Total lymphoid irradiation (TLI) is an alternative treatment for chronic lung allograft dysfunction (CLAD). However, data regarding its efficacy and tolerance are scarce. This study included patients with CLAD treated with TLI at our center between 2011 and 2018. Clinical characteristics before and after TLI and related complications were analyzed. Forty patients with CLAD (twenty-nine bronchiolitis obliterans syndrome [BOS], nine restrictive allograft syndrome [RAS], and two mixed) were included. Significant attenuation of the forced expiratory volume in 1-sec (FEV 1 ) decline slope was observed in all phenotypes, in both the BOS and RAS. The median FEV 1 12, 6, and 3 months pre-TLI were as follows: 1980 (IQR 1720-2560), 1665 (IQR 1300-2340) and 1300 (IQR 1040-1740) ml (p < .001), while the median FEV 1 at 3, 6, and 12 months post-TLI was 1110 (IQR 810-1440), 1130 (IQR 860-1470), and 1115 (IQR 865-1490) ml (p = .769). No dropouts due to radiation toxicity were observed. The mean survival according to the Karnofsky Performance Status Scale (KPS) >70 or ≤70 at baseline was 1837 (IQR 259-2522) versus 298 (IQR 128-554) days (p < .0001), respectively. In conclusion, TLI may stop FEV 1 decline in both BOS and RAS. Moreover, a good KPS score may be an important prognostic factor., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81)., Conclusion: Although ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression., (Copyright © 2021 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

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., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

KL-6 is an antigen produced mainly by damaged type II pneumocytes that is involved in interstitial lung disease. Chronic lung allograft dysfunction (CLAD) after lung transplantation (LT) is a major concern for LT clinicians, especially in patients with restrictive allograft syndrome (RAS). We investigated KL-6 levels in serum and bronchoalveolar lavage fluid (BALF) as a potential biomarker of the RAS phenotype. Levels of KL-6 in serum and BALF were measured in 73 bilateral LT recipients, and patients were categorized into 4 groups: stable (ST), infection (LTI), bronchiolitis obliterans syndrome (BOS), and RAS. We also studied a healthy cohort to determine reference values for serum KL-6. The highest levels of KL-6 were found in the serum of patients with RAS (918 [487.8-1638] U/mL). No differences were found for levels of KL-6 in BALF. Using a cut-off value of 465 U/mL serum KL-6 levels was able to differentiate RAS patients from BOS patients with a sensitivity of 100% and a specificity of 75%. Furthermore, higher serum KL-6 levels were associated with a decline in Forced Vital Capacity (FVC) at 6 months after sample collection. Therefore, KL-6 in serum may well be a potential biomarker for differentiating between the BOS and RAS phenotypes of CLAD in LT recipients., Competing Interests: The authors have declared that no competing interests exist.

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 FEV 1 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., (Copyright © 2018 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: 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., Methods: 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., Results: 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 (P < 0.001). 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., Conclusions: 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.

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., (Copyright © 2017. Published by Elsevier SAS.)

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. We retrospectively reviewed the clinical records of 333 patients who underwent LT in our institution between 2009 and 2014. We compared two 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. 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 this study, the risk factors associated with VTE were male gender and interstitial lung disease. 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., (© 2017 Steunstichting ESOT.)

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 age >55 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., (Copyright © 2017. Published by Elsevier Inc.)

Background: Real use of lung (LT) and heart-lung (HLT) transplantation in pulmonary arterial hypertension (PAH) is unknown. The objectives were to describe the indication of these procedures on PAH treatment in a national cohort of PAH patients, and to analyze the potential improvement of its indication in severe patients., Methods: Eligibility for LT/HLT was assessed for each deceased patient. Incident patients from REHAP diagnosed between January 2007 and March 2015 and considered eligible for LT/HLT were grouped as follows: those who finally underwent transplantation (LTP) and those who died (D-Non-LT)., Findings: Of 1391 patients included in REHAP, 36 (3%) were LTP and 375 (27%) died. Among those who died, 36 (3%) were D-Non-LT. LTP and D-Non-LT were equal in terms of age, gender, and clinical status. Ten percent of those who died were functional class I-II. Patients functional class IV were less likely to undergo LT (8.3% LTP vs. 30.6% D-Non-LT, p = 0.017). Patients with idiopathic and drug/toxin-associated PAH were more likely to undergo LT (44.4% LTP vs. 16.7% D-Non-LT, p = 0.011)., Conclusions: The present results show that the use of LT/HLT could double for this indication. Relevant mortality in early functional class reflects the difficulties in establishing the risk of death in PAH.

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., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: COPD and emphysema due to alpha-1 antitrypsin deficiency (AATD) are the first and fourth indications for lung transplantation worldwide, respectively. Despite this, there is little information regarding the health status of these patients at the time of transplantation., Methods: Patients who received a lung transplant in the Hospital Vall d'Hebron between July 1993 and August 2013 were identified and data from the evaluation prior to the transplant were collected., Results: A total of 217 patients who received a lung transplant for COPD and 19 in whom the indication was AATD were included. These patients were severely impaired at the time of the evaluation for lung transplantation, although the trend in recent years has been to evaluate patients at earlier stages of the disease. Baseline characteristics were similar in both groups except that patients with AATD were younger [43 (7.7) vs. 53.6 (6.1) years old, P<.001], with less exposure to tobacco [23.9 (15) vs. 50 (29) packs-year, P<002] and lower PCO2 [41.7 (7.6) vs. 47.9 (9.7) mmHg, P<.004]., Conclusions: The number of patients receiving a lung transplant for COPD has progressively increased and the tendency is to perform the evaluation in earlier stages of the disease. Patients receiving transplants for COPD and AATD had similar characteristics at the time of the evaluation, although AATD patients were younger and had less exposure to tobacco and lower PCO2., (Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.)

Treatment of pulmonary arterial hypertension has achieved significant progress over the past 20 years. Currently, 3 groups of drugs have proven useful for the treatment of this disease: endothelin receptor antagonist, phosphodiesterase inhibitors and prostacyclin and its analogues. It is recommended to initiate treatment with one of these drugs, the choice depending on the initial severity of patient disease and the preferences of the treating physician. When the patient does not have a satisfactory response, new drugs acting at a different pathway are most commonly added. At this time, considering referral for lung transplantation could be an alternative. Most experts recommend grouping maximum experience in what is known as expert centers. Treatment has led to better survival in these patients, but there is still a long way to cure this life-threatening disease., (Copyright © 2014 Elsevier España, S.L.U. All rights reserved.)

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 (<20%). Correlations between cyclosporine CsA concentration at each time point, AUC₀₋₄ h , and AUC₀₋₁₂ h were also calculated., Results: Six (60%) patients presented low CVs and four (40%) high CVs. In patients with low CVs, the best correlation of AUC₀₋₁₂ h was with CsA concentration at two h post-dose (C₂) (r = 0.674, p = 0.002), whereas in those with high CV, the best correlation was with C5 (r = 0.800, p = 0.003). In the latter group, the correlation with C₂ was low (r = 0.327, p = 0.32), whereas the correlation with C₀ was high (r = 0.709, p < 0.05)., Conclusions: Intra-individual variability of CsA pharmacokinetics may be high in many LT recipients. In patients with high CV, the use of C₀ levels may be more appropriate for CsA monitoring than C₂ levels., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Tacrolimus twice-daily (TAC BID) is widely used in lung transplantation (LT), but there are little data on the use of tacrolimus once-daily (TAC QD) in this population. The objective of this study was to compare the pharmacokinetics (PK) of TAC BID and TAC QD in stable, adult LT patients., Methods: Phase II, open-label, single-center, single-arm, prospective pilot PK study. Nineteen LT recipients with more than 6 months of postoperative follow-up and on TAC BID-based therapy were converted to TAC QD on a 1:1 (mg/mg) basis. Patients had been stable during the previous 3 months, and cystic fibrosis patients were excluded. One 24-hr PK profile was obtained on day -14 while patients were under TAC BID. A second PK profile was obtained 14 to 28 days after switching (day 0) to the same dose of TAC QD. Pre- and post-switch 24-hr PK profiles were compared., Results: Mean AUC0-24 hr was 279.8 ng mL/hr for TAC BID and 278.7 ng mL/hr for TAC QD (P=0.92). AUC0-12 hr of TAC BID was higher than the AUC12-24 hr. There was a good correlation between AUC0-24 hr and C24 for both QD (r=0.96) and BID (r=0.94) formulations. There were no differences in the adverse events occurring with the two formulations., Conclusions: Tacrolimus bioavailability in steady state is similar in BID and QD formulations after conversion in stable LT recipients, excluding those with cystic fibrosis. Thus, our results indicate TAC BID can be safely switched to the more convenient QD formulation in this population.

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Accepted treatment for severe pulmonary arterial hypertension (PAH) includes intravenous epoprostenol and lung transplantation (LT). Inhaled iloprost plus oral sildenafil (Ilo-Sil) is an alternative strategy that may also delay the need for LT., Patients and Methods: This was a long-term descriptive study in eight patients with PAH functional class (FC) IV with right heart failure, four of them potential candidates for LT, who were treated with Ilo-Sil as an alternative to epoprostenol., Results: At the start of the study, patients (seven women; mean age, 43.8 [range, 34-66] years) were in FC IV and unable to perform the 6-minute walk test. Mean cardiac index was 1.9 (range, 1.4-2.1) L/min/m(2). Treatment with Ilo-Sil provoked a rapid and sustained improvement; mean walking distance at 3 months was 322 ± 90 m and no patient remained in FC IV. Survival at 1 and 5 years was 100% and 75%, respectively. Of the four potential LT candidates, one underwent transplantation after 6.8 years and one died after 1.2 years., Conclusions: These results suggest that therapy with Ilo-Sil represents an acceptable alternative in patients with severe and unstable PAH., (Copyright © 2013. Published by Elsevier Inc.)

Background: Pulmonary hypertension is a serious disease that, in its terminal phase, requires lung transplantation., Patients and Methods: A retrospective study was undertaken of 15 patients with pulmonary hypertension who underwent lung transplantation between 1994 and 2004. Clinical data recorded before the procedure and during follow-up were reviewed., Results: Pulmonary hypertension was reported as idiopathic in 8 patients (53%) and related to consumption of toxic oil in 2. The remaining causes were documented as chronic peripheral pulmonary embolism, histiocytosis X, venoocclusive disease, scleroderma, and simple corrected congenital heart defect in 1 patient each. The mean values of the hemodynamic variables were 100, 50, and 67 mm Hg for systolic, diastolic, and mean pulmonary artery pressure, respectively; 2.63 L/min for cardiac output; and 20.9 Wood units for total pulmonary resistance. The mean time between diagnosis of pulmonary hypertension and lung transplantation was 5.9 years (range, 0.4-20 y). Seven patients were in functional class III and 8 in functional class IV. The mean 6-minute walk distance was 204 m (range, 0-360 m). Four patients (26%) died during the during the perioperative period and 9 (60%), 7 (46%), and 6 (40%) were still alive at 1, 3, and 5 years, respectively., Conclusions: Double-lung transplantation is a therapeutic option that, in certain cases, has similar outcomes to those achieved with the most aggressive medical treatment for pulmonary hypertension.

Survival after lung transplantation (LT) is hampered by the development of chronic lung allograft dysfunction (CLAD). There is no treatment available to reverse CLAD once diagnosed, but early intervention could modify the progressive lung function decline. Thus, biomarkers are need for early detection of CLAD. High levels of donor derived cell-free DNA (ddcfDNA) have been described to precede acute cellar rejection and antibody mediated rejection diagnosis. The aim of this study is to assess if there is any association between ddcfDNA and chronic lung allograft dysfunction (CLAD). This is a longitudinal study in which ddcfDNA levels were determined in 100 LT recipients at the 3rd, 6th, 9th, 12th, 24th and 36th month after LT. Firstly, real-time PCR was performed to detect an informative INDEL polymorphism for each donor/recipient pair. Secondly, levels of ddcfDNA were determined by quantifying the informative INDEL by digital PCR in the plasma of the recipient. Clinical data was collected during a three years follow-up to determine infections, antibody mediated and acute cellular rejection, and CLAD. Globally, we noted an upward trend of ddcfDNA levels at 1, 2 and 3 years of follow-up when referred to 3 months. Levels of ddcfDNA were compared between CLAD and no CLAD patients at different time points, and a cut-off value of 1.86% at 12 months could identify those patients with higher probability of developing CLAD (Figure 1). Determine ddcfDNA levels in plasma could be a useful non-invasive biomarker for CLAD prediction. This study was partially funded by ISCIII ("PI17/01485"), co-funded by ERDF and SEPAR (552/2017). [ABSTRACT FROM AUTHOR]

Survival after lung transplantation is limited in large part due to the high incidence of chronic lung allograft dysfunction (CLAD). Infection is a recognized risk factor for the development of CLAD, and both acute infection and chronic lung allograft colonization with microorganisms increase the risk for CLAD. The aim of our study was to analyze nasopharyngeal (NP) microbiome composition and modifications following lung transplantation, with a focus on its relationship with CLAD. This was a longitudinal study in which we analyzed bacterial microbiome in NP swab samples in 68 lung transplanted (LT) patients the day of the transplant, when patients were discharged, at 2-5 months and 12 months after lung transplantation. We also analysed NP swab samples from 10 healthy subjects. CLAD was assessed after 2 years of follow-up. DNA was extracted from the NP swabs. To create the amplicon library, the hyper-variable region (V4) of the 16S ribosomal RNA gene was amplified by standard PCR. Amplicons were purified and sequenced in barcoded pools using Illumina MiSeq technology. Raw sequence reads were demultiplexed by using idemp. The resulting single-end reads were processed using the Dada2 pipeline obtaining an amplicon sequence variant table to which taxonomy was assigned. Alpha diversity, including Shannon and Observed indices, and beta diversity metrics were calculated. We compared these metrics and particular taxa relative abundances between samples of LT patients at different time points and samples of healthy subjects. From the 68 studied patients, 13 developed CLAD during the two years of follow-up. We observed a significant decrease in the Observed index at the day of the discharge and 2-5 months after transplant when compared with healthy subjects. One year after transplant, CLAD patients had higher Shannon diversity than LT patients who did not develop the dysfunction. On the other hand, a lower beta diversity was observed between healthy subjects and patients with no CLAD. Besides, we detected an increased genus in NP swab samples associated with no CLAD also observed in NP samples from healthy subjects. Nasopharyngeal overall microbiome composition, as well as relative abundances of particular taxa of non-CLAD patients, was closest to the one from healthy subjects suggesting a better outcome of the transplant if better microbiome normalization. [ABSTRACT FROM AUTHOR]

Chronic lung allograft dysfunction (CLAD) is the main cause of long-term mortality in lung transplantation (LT). The main phenotypes of CLAD are bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS) and mixed. Biomarkers for early identification of CLAD are needed. KL-6, an antigen produced mainly by damaged type II pneumocytes, has been described as a RAS-biomarker. The aim of our study was to assess the utility of serum KL-6 levels as a CLAD biomarker. This was a longitudinal study in which KL-6 levels were measured in 52 bilateral LT patients at 3, 6, 9, 12, 18 and 24 months after LT. At the same time-points, clinical features and pulmonary function were determined. CLAD diagnosis was assessed during a three years follow-up. Seventeen out of 52 patients developed CLAD (11 BOS and 6 patients RAS or mixed). No differences in demographics were found, but patients with RAS or mixed phenotypes had a higher incidence of positive Donor-Specific Antibodies (DSA). Also, serum KL-6 levels before CLAD diagnosis were higher in the patients who developed RAS-mixed (563 [439.7-752.8 U/ml]) compared to patients diagnosed with BOS (356.7 [265.7-492.2 U/ml]) or those without CLAD (372.8 [274.8-606.9 U/ml]) at 6 months after LT, although not statistically significant (p=0.187). However, a KL-6 cut-off of 520.4 U/ml at 6-month post-transplant was able to differentiate RAS-mixed from non- RAS-mixed patients with a sensitivity of 80% (IC95 28.36-99.49%) and specificity of 72.73% (IC95 57.21-85.04%). When analyzing serum KL-6 levels in all samples, even those obtained after CLAD diagnosis, RAS patients had higher levels which progressively increase along follow-up (see table). Serum KL-6 could be a useful biomarker for RAS prediction. [ABSTRACT FROM AUTHOR]

The aim of the study was to review the experience of lung transplantation (LT) in HIV-seropositive patients in a referral center. 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. 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). 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. [ABSTRACT FROM AUTHOR]

Lymphangioleiomyomatosis (LAM) is a rare slowly progressive disease that leads to respiratory failure. The aim of this study was to analyse the results of lung transplantation (LT) in LAM patients and the sirolimus effect in LT. LAM patients from a referral centre were retrospectively reviewed. Those who underwent LT were considered for the analysis. Demographics, postoperative complications, survival, recurrence of LAM and pulmonary function test (PFT) were analysed. All patients followed a standard triple immunosuppressive therapy based on tacrolimus, mycophenolate mofetil and corticosteroids. Sirolimus was introduced in our centre in November 2007 as a treatment for LAM patients and was indicated in cases of abnormal FEV1 or presence of angiomyolipomas. From 1980 to 2018, 76 LAM patients have been followed-up. Of these, 28 (37%) patients underwent LT. Twenty (71%) were bilateral LT (BLT) and 8 (29%) single LT (SLT). Pre-transplant PFT were: FVC 53±18%, FEV1 35±18% and FEV1% 48±19%. The best post-transplant pulmonary function was achieved at a median of 8 (7-13) months and 18 (8-35) months for SLT and BLT, respectively. Following BLT, the best PFT results were FVC 85±14%, FEV1 88±14% and FEV1% 104±20. In case of SLT, the best FVC was 63 ±12%, FEV1 53±7% and FEV1% 85±10%. Two (7%) patients developed LAM recurrence, in both cases, immunosuppressive treatment was adjusted and the purine synthesis inhibitor was changed to sirolimus. Survival after LT was 67% at 5 years and 58% at 10 years with a mean follow-up after LT of 11.7 years. Since the introduction of sirolimus in 2007, no newly diagnosed LAM cases were submitted to LT. While on sirolimus only 9 patients underwent LT. Survival in LAM patients submitted to LT exceeds 10 years. LT in LAM patients allows an improvement in spirometric values. A significant decrease in the number of LT indications in LAM has been observed since the introduction of sirolimus treatment. [ABSTRACT FROM AUTHOR]