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Assessment and selection of donor lungs remain largely subjective and experience based. Criteria to accept or decline lungs are poorly standardized and are not compliant with the current donor pool. Using ex vivo computed tomography (CT) images, we investigated the use of a CT-based machine learning algorithm for screening donor lungs before transplantation. Clinical measures and ex situ CT scans were collected from 100 cases as part of a prospective clinical trial. Following procurement, donor lungs were inflated, placed on ice according to routine clinical practice, and imaged using a clinical CT scanner before transplantation while stored in the icebox. We trained and tested a supervised machine learning method called dictionary learning , which uses CT scans and learns specific image patterns and features pertaining to each class for a classification task. The results were evaluated with donor and recipient clinical measures. Of the 100 lung pairs donated, 70 were considered acceptable for transplantation (based on standard clinical assessment) before CT screening and were consequently implanted. The remaining 30 pairs were screened but not transplanted. Our machine learning algorithm was able to detect pulmonary abnormalities on the CT scans. Among the patients who received donor lungs, our algorithm identified recipients who had extended stays in the intensive care unit and were at 19 times higher risk of developing chronic lung allograft dysfunction within 2 years posttransplant. We have created a strategy to ex vivo screen donor lungs using a CT-based machine learning algorithm. As the use of suboptimal donor lungs rises, it is important to have in place objective techniques that will assist physicians in accurately screening donor lungs to identify recipients most at risk of posttransplant complications. [ABSTRACT FROM AUTHOR]

Organ transplantation is hampered by shortage of suitable organs. In countries with a legal framework, organ donation following euthanasia is an option labeled "donation after cardio-circulatory death category V" (DCD-V). We describe our experience with lung transplantation (LTx) after euthanasia and evaluate post-transplant outcome using a matched comparison to DCD-III (withdrawal from life-sustaining therapy) and donation after brain death (DBD). All bilateral LTx between 2007 and 2020 were retrospectively analyzed. Matching was performed for recipient age and gender, indication for LTx, mean pulmonary artery pressure, extracorporeal life support, and donor age, which resulted in 1:2 DCD-III and 1:3 DBD matching. Primary graft dysfunction (PGD), chronic lung allograft dysfunction (CLAD), and patient survival were analyzed. A total of 769 LTx were performed of which 22 from DCD-V donors (2.9%). Thirteen women and 9 men expressed their wish to become organ donor after euthanasia. Euthanasia request was granted for irremediable neuromuscular (N = 9) or psychiatric (N = 8) disorder or unbearable and unrecoverable pain (N = 5). PGD (grade 3, within 72 hours post-transplant) was 23.8% in the DCD-V cohort, which is comparable to DCD-III (27.9%; p = 1.00) and DBD (32.3%; p =.59). CLAD-free 3- and 5-year survival were 86.4% and 62.8%, respectively, and comparable to DCD-III (74.4% and 60.0%; p =.62) and DBD (72.6% and 55.5%; p =.32). Five-year patient survival was 90.9%, not significantly different from both DCD-III (86.0%; p = 1.00) and DBD (78.1%; p =.36). We observed that LTx with DCD-V allografts is feasible and safe, yielding no evidence for differences in short- and long-term outcome compared to matched cohorts of DCD-III and DBD. [ABSTRACT FROM AUTHOR]

Background: The warm ischemic period in non–heart-beating donor lungs may contribute to a higher degree of ischemia–reperfusion injury after lung transplantation. We investigated the impact and timing of administration of N-acetyl cysteine (NAC) on inflammatory parameters. Methods: Ischemia (I) was induced by clamping the hilum of the left lung for 90 minutes, and some protocols were followed by reperfusion (R) for 4 hours. Mice were divided into nine groups (n = 6/group): three control groups ([sham] (thoracotomy only), [I] and [I+R]); two groups with saline instillation only ([saline+I] and [saline+I+R]); and four experimental groups with NAC (50 mg/kg), administered by instillation ([NAC+I], [NAC+I+R] and [I+NAC+R]) or by aerosol ([NACaero+I+R]). Cell counts and protein levels in bronchoalveolar lavage (BAL) were determined. Results: NAC administered prior to hilar clamping led to a significant decrease in macrophages and lymphocytes and interleukin (IL)-1β levels after ischemia. NAC also resulted in significantly fewer macrophages, lymphocytes and neutrophils as well as IL-1β, keratinocyte cytokine (KC), monocyte chemoattractant protein (MCP)-1 and IL-6 levels in BAL taken after reperfusion. Conclusions: NAC treatment prior to warm ischemia attenuates inflammatory changes after both the ischemic and reperfusion periods. [Copyright &y& Elsevier]

Background: The use of non–heart-beating donors (NHBDs) for lung transplantation is a possible alternative for increasing the number of organs available. The warm ischemic period after circulatory arrest may contribute to a higher degree of primary graft dysfunction, resulting from ischemia–reperfusion injury (IRI). A better understanding of the role of inflammatory cells during the warm ischemic interval may be useful for developing new therapeutic strategies against IRI. Methods: Mice were divided in 7 groups (n = 6/group). In 3 groups, ischemia was induced by clamping the hilum of the left lung for 30, 60 or 90 minutes (Groups [30I], [60I] or [90I], respectively). In 3 more groups, the lung was reperfused for 4 hours after identical ischemic intervals (Groups [30I+R], [60I+R] or [90I+R], respectively). Surgical impact was evaluated in a sham group ([sham]). Total and differential cell counts and interleukin-1β (IL-1β) protein levels in bronchoalveolar lavage (BAL) were determined and their correlations were investigated. Results: Total cell, macrophage and lymphocyte numbers and IL-1β protein levels increased progressively with longer ischemic intervals. A significant rise in BAL macrophages and lymphocytes was observed between [60I] and [90I] (p < 0.01 and p < 0.001, respectively). BAL neutrophils only increased after reperfusion with longer ischemic intervals. A positive correlation was found in the ischemic groups between IL-1β levels and the number of macrophages (r = 0.62; p = 0.0012) and the number of lymphocytes (r = 0.68; p = 0.0002). A positive correlation was found in the reperfusion groups between IL-1β levels and the number of neutrophils (r = 0.48; p = 0.044). Conclusions: This study demonstrates for the first time that BAL macrophages and lymphocytes increase significantly during warm ischemia and correlate with IL-1β levels. [Copyright &y& Elsevier]

Chronic lung allograft dysfunction (CLAD) is a major cause of post‒lung transplant mortality, with limited medical treatment options. In this study we assessed the association of montelukast treatment with pulmonary function and outcome in lung transplant recipients with progressive CLAD. We performed a retrospective study of all lung transplant recipients transplanted between July 1991 and December 2016 at our center and who were treated for at least 3 months with montelukast for progressive CLAD, despite at least 3 months of prior azithromycin therapy. Main outcome parameters included evolution of pulmonary function and progression-free and overall survival. A total of 153 patients with CLAD (115 with bronchiolitis obliterans syndrome and 38 with restrictive allograft syndrome) were included, of whom 46% had a forced expiratory volume in 1 second (FEV 1) measure of between 66% and 80%, 31% an FEV 1 between 51% and 65%, and 23% an FEV 1 ≤50% of best post-operative FEV 1 at start of montelukast. Montelukast was associated with attenuation in rate of FEV 1 decline after 3 and 6 months, respectively (both p < 0.0001). Patients in whom FEV 1 improved or stabilized after 3 months of montelukast (81%) had significantly better progression-free (p < 0.0001) and overall (p = 0.0002) survival after CLAD onset, as compared to those with further decline of FEV 1 (hazard ratio [HR] 2.816, 95% confidence interval [CI] 1.450 to 5.467, p = 0.0022 for overall survival after CLAD onset in risk-adjusted multivariate analysis). Montelukast was associated with a significant attenuation in rate of FEV 1 decline in a substantial proportion of patients with established CLAD, which correlated with better outcome. Further study is required regarding use of montelkast. [ABSTRACT FROM AUTHOR]

BACKGROUND Chronic lung allograft dysfunction (CLAD) is the single most important factor limiting long-term survival after lung transplantation (LTx). Azithromycin has been shown to improve CLAD-free and long-term survival, yet the possible impact on early lung allograft function is unclear. METHODS A prospective, randomized, double-blind, placebo-controlled trial of pre-transplant and prompt post-transplant azithromycin treatment was performed at the University Hospitals Leuven. In each arm, 34 patients, transplanted between October 2013 and October 2015, were included for analysis. Study drug was added to standard of care and was administered once before LTx (1,000 mg of azithromycin or placebo) and every other day from Day 1 until Day 31 after LTx (250 mg of azithromycin or placebo). Primary outcome was an anticipated 15% improvement of forced expiratory volume in 1 second (FEV 1 , percent predicted) during the first 3 months post-LTx. Secondary end-points included length of intubation, days on ventilator, duration of intensive care unit and hospital stay, prevalence and severity of primary graft dysfunction, acute rejection, infection, and CLAD-free and overall survival. RESULTS FEV 1 was not significantly different between the 2 groups (p = 0.41). Patients treated with azithromycin demonstrated less airway inflammation, with lower bronchoalveolar lavage (BAL) neutrophilia and BAL interleukin-8 protein levels at Day 30 (p = 0.09 and p = 0.04, respectively) and Day 90 (p = 0.002 and p = 0.08, respectively) after LTx. Other secondary outcomes were not significantly different between placebo and azithromycin groups. CONCLUSIONS Pre-transplant and prompt post-transplant azithromycin treatment was not able to improve early lung allograft function. However, the known anti-inflammatory properties of azithromycin were confirmed (NCT01915082). [ABSTRACT FROM AUTHOR]

BACKGROUND Long-term survival after lung transplantation (LTx) is hampered by chronic lung allograft dysfunction (CLAD). Our study evaluated the prevalence and prognostic importance of obstructive and restrictive CLAD phenotypes, with or without an identifiable underlying cause, to validate the recently proposed classification system for CLAD. METHODS Data for patients who underwent LTx between 2004 and 2015 with a minimal survival of 180 days post-LTx were retrospectively collected. Double LTx patients with CLAD (defined as a persistent forced expiratory volume in 1 second decline of ≥ 20% compared with baseline) were subsequently classified according to obstructive (forced expiratory volume in 1 second /forced vital capacity [FVC] < 70%, total lung capacity > 90%, and FVC > 80%) or restrictive (total lung capacity ≤ 90% or FVC ≤ 80%) pulmonary function and to the presence of an unknown (bronchiolitis obliterans syndrome [BOS]/restrictive allograft syndrome [RAS]) or known (non-BOS/non-RAS) underlying cause. RESULTS After a median of 3.2 years, CLAD developed in 39% of double LTx patients (n = 219), of which 20% (n = 43) had an identifiable cause. Survival was worse in patients with restrictive CLAD (26%) compared with obstructive CLAD (64%; p < 0.0001). Non-BOS patients suffered from inferior survival compared with BOS patients (p = 0.0016), whereas there was no significant difference in survival between RAS and non-RAS (p = 0.17). Patients who evolved from an obstructive (BOS) to a restrictive (RAS) phenotype (10%) experienced better survival than RAS patients and a worse outcome compared with BOS patients (p < 0.0001). CONCLUSIONS Given the differences in outcome, accurate diagnosis of CLAD phenotypes is important, because this helps to inform patients about their prognosis, to reveal underlying pathogenesis, to identify homogenous patient populations for clinical trials, and to guide future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background Vitamin D may have innate immunomodulatory functions with potentially beneficial therapeutic effects in lung transplant recipients. Methods This was a single-center, double blind, randomized, placebo-controlled, prevention trial of once-monthly oral vitamin D (cholecalciferol; 100,000 IU, n = 44) vs placebo ( n = 43) during 2 years in adult lung transplant recipients enrolled from October 2010 to August 2013. Primary outcome was prevalence of chronic lung allograft dysfunction (CLAD) 3 years after transplantation. Secondary outcomes included overall survival, prevalence of acute rejection, lymphocytic bronchiolitis and infection, lung function, pulmonary and systemic inflammation, and bone mineral density. Results All included patients underwent bilateral lung transplantation and were mostly middle-aged men with prior smoking-related emphysema. Levels of 25-hydroxy vitamin D after 1 year ( p < .001) and 2 years ( p < .001) were significantly higher in the vitamin D group compared with the placebo group. No difference was observed for CLAD prevalence ( p = 0.7) or CLAD-free survival between both groups ( p = 0.7). Secondary outcomes were overall comparable between both groups (all p > 0.05). Conclusions Once-monthly oral vitamin D supplementation after lung transplantation fails to demonstrate a significant difference in CLAD prevalence, innate immunomodulatory, or a beneficial clinical effect compared with placebo. [ABSTRACT FROM AUTHOR]

Background: The use of lungs from non–heart-beating donors (NHBD) might significantly alleviate the organ shortage. The tolerable warm ischemic period after cardiac arrest, however, is limited to approximately 1 hour. If the lung could be safely protected inside the cadaver, this time period may be prolonged. This would help to obtain family consent and to organize organ retrieval. Methods: Pigs (30.8 ± 0.6 kg) were killed, left untouched for 3 hours, and divided into 3 groups. Nebulized N-acetyl cysteine (NAC) (300 mg), a precursor of the antioxidant agent glutathione, was administered during 10 minutes before death in Group I (NAC-NHBD, n = 6) and 15 minutes after death in Group II (NHBD-NAC, n = 6). In the control group, no aerosol was administered (NHBD, n = 6). After a warm ischemic interval of 3 hours, both lungs in all groups were topically cooled for 1 hour. Thereafter, the left lung was prepared for evaluation in an isolated reperfusion circuit. Hemodynamic, aerodynamic, and oxygenation parameters were measured. Wet-to-dry weight ratio (W/D) was calculated after reperfusion. The right lung was used to measure reduced glutathione (GSH) and oxidized glutathione (GSSG) levels (μmol/g) in lung homogenates and total protein levels in bronchial lavage fluid. Results: Pulmonary vascular resistance, mean airway pressure, and W/D were significantly decreased in NAC-NHBD (1930 ± 144 Dynes · sec · cm−5, 14.2 ± 0.5 cm H2O, and 7.4 ± 0.4; p &#60; 0.01, 0.01, and 0.05, respectively) and NHBD-NAC (1837 ± 180 Dynes · sec · cm−5, 13.3 ± 1.2 cm H2O, and 7.3 ± 0.3; p &#60; 0.01, 0.05, and 0.05, respectively) when compared with the control group (5051 ± 530 Dynes · sec · cm−5, 17 ± 0.4 cm H2O, 8.5 ± 0.1, respectively). GSH/GSSG ratio was significantly higher and protein levels were significantly lower in NAC-NHBD (1.7 ± 0.1 and 1315 ± 60 μg/ml; p &#60; 0.05 and 0.05, respectively) and NHBD-NAC (1.7 ± 0.2 and 1475 ± 159 μg/ml; p &#60; 0.05 and 0.05, respectively) when compared with the control group (1.2 ± 0.1 and 2150 ± 200 μg/ml). Conclusions: Nebulized NAC administered before or shortly after death attenuates early ischemia reperfusion injury via upregulation of glutathione. NAC might be a promising tool to protect the pulmonary graft from both controlled and uncontrolled NHBD. [Copyright &y& Elsevier]