Although cytomegalovirus (CMV) viremia/DNAemia has been associated with reduced survival after lung transplantation, its association with chronic lung allograft dysfunction (CLAD) and its phenotypes is unclear. We hypothesized that, in a modern era of CMV prophylaxis, CMV DNAemia would still remain associated with death, but also represent a risk factor for CLAD and specifically restrictive allograft syndrome (RAS)/mixed phenotype. This was a single-center retrospective cohort study of all consecutive adult, first, bilateral-/single-lung transplants done between 2010-2016, consisting of 668 patients. Risks for death/retransplantation, CLAD, or RAS/mixed, were assessed by adjusted cause-specific Cox proportional-hazards models. CMV viral load (VL) was primarily modeled as a categorical variable: undetectable, detectable to 999, 1000 to 9999, and ≥10 000 IU/mL. In multivariable models, CMV VL was significantly associated with death/retransplantation (≥10 000 IU/mL: HR = 2.65 [1.78-3.94]; P < .01), but was not associated with CLAD, whereas CMV serostatus mismatch was (D+R–: HR = 2.04 [1.30-3.21]; P < .01). CMV VL was not associated with RAS/mixed in univariable analysis. Secondary analyses with a 7-level categorical or 4-level ordinal CMV VL confirmed similar results. In conclusion, CMV DNAemia is a significant risk factor for death/retransplantation, but not for CLAD or RAS/mixed. CMV serostatus mismatch may have an impact on CLAD through a pathway independent of DNAemia.

BACKGROUND: Our program uses a desensitization protocol that includes intraoperative therapeutic plasma exchange (iTPE) for crossmatch-positive lung transplants, which improves access to lung transplant for sensitized candidates while mitigating immunologic risk. Although we have reported excellent outcomes for sensitized patients with the use of this protocol, concern for perioperative bleeding appears to have hindered broader adoption of it at other programs. We conducted a retrospective cohort study to quantify the impact of iTPE on perioperative bleeding in lung transplantation. METHODS: All first-time lung transplant recipients from 2014 to 2019 who received iTPE were compared to those who did not. Multivariable logistic regression was used to determine the association between iTPE and large -volume perioperative transfusion requirements (>= 5 packed red blood cell units within 24 hours of transplant start), adjusted for disease type, transplant type, and extracorporeal membrane oxygenation or cardiopulmonary bypass use. The incidence of hemothorax (requiring reoperation within 7 days of lung transplant) and 30 -day posttransplant mortality were compared between the 2 groups using chi-square test. RESULTS: One hundred forty-two patients (16%) received iTPE, and 755 patients (84%) did not. The mean number of perioperative pRBC transfusions was 4.2 among patients who received iTPE and 2.9 among patients who did not. iTPE was associated with increased odds of requiring large -volume perioperative transfusion (odds ratio 1.9; 95% confidence interval: 1.2-2.9, p -value = 0.007) but was not associated with an increased incidence of hemothorax (5% in both groups, p = 0.99) or 30 -day posttransplant mortality (3.5% among patients who received iTPE vs 2.1% among patients who did not, p = 0.31). CONCLUSIONS: This study demonstrates that the use of iTPE in lung transplantation may increase perioperative bleeding but not to a degree that impacts important posttransplant outcomes. J Heart Lung Transplant 2024;43:414-419 (c) 2023 International Society for Heart and Lung Transplantation. All rights reserved.

BACKGROUND:Surveillance bronchoscopies with bronchoalveolar lavage (BAL) and transbronchial biopsies (TBB) are primarily used to detect acute cellular rejection (ACR) or infection in lung transplant (LTx) recipients. We previously identified a BAL protein signature associated with chronic lung allograft dysfunction (CLAD) or death/retransplant in patients with stable minimal (grade A1) ACR. This present study aimed to determine whether similar BAL biomarkers predict outcomes in stable patients when ACR grade is undetermined. METHODS:The cohort included all adult, first bilateral LTx performed 2010-2017. Clinical status was categorized as unstable or stable based on the presence or absence of a ≥ 10% drop in FEV1. Clinically-stable patients with grade AX TBB (inadequate biopsies) during the first year post-transplant, not preceded by ACR (grade A≥1 or B≥1), were included. IL6, S100A8, IL10, TNF-receptor-1, IL1α, pentraxin3, and CXCL10 were measured in the BAL using a multiplex bead assay. Associations with subsequent CLAD or death/retransplant were assessed using multivariable Cox proportional hazards models, adjusted for relevant clinical covariates. RESULTS:Among 107 patients with stable AX biopsies at a median of 188 days post-transplant, the median times from biopsy to CLAD and death/retransplant were 972 and 1410 days, respectively. CXCL10 was significantly associated with CLAD, while IL6, S100A8, pentraxin3, TNF-receptor-1, and IL10 were associated with death/retransplant (p < 0.05 for all). CONCLUSION:A focused BAL protein signature in stable patients with ungradable TBB early post-transplant may predict worse outcomes. Such select BAL biomarkers may identify patients who require more aggressive management strategies or closer monitoring.

BACKGROUND: Aspiration is a known risk factor for adverse outcomes post -lung transplantation. Airway bile acids are the gold -standard biomarker of aspiration; however, they are released into the duodenum and likely reflect concurrent gastrointestinal dysmotility. Previous studies investigating total airway pepsin have found conflicting results on its relationship with adverse outcomes post -lung transplantation. These studies measured total pepsin and pepsinogen in the airways. Certain pepsinogens are constitutively expressed in the lungs, while others, such as pepsinogen A4 (PGA4), are not. We sought to evaluate the utility of measuring airway PGA4 as a biomarker of aspiration and predictor of adverse outcomes in lung transplant recipients (LTRs) early post -transplant. METHODS: Expression of PGA4 was compared to other pepsinogens in lung tissue. Total pepsin and PGA4 were measured in large airway bronchial washings and compared to preexisting markers of aspiration. Two independent cohorts of LTRs were used to assess the relationship between airway PGA4 and chronic lung allograft dysfunction (CLAD). Changes to airway PGA4 after antireflux surgery were assessed in a third cohort of LTRs. RESULTS: PGA4 was expressed in healthy human stomach but not lung. Airway PGA4, but not total pepsin, was associated with aspiration. Airway PGA4 was associated with an increased risk of CLAD in two independent cohorts of LTRs. Antireflux surgery was associated with reduced airway PGA4. CONCLUSIONS: Airway PGA4 is a marker of aspiration that predicts CLAD in LTRs. Measuring PGA4 at surveillance bronchoscopies can help triage high -risk LTRs for anti-reflux surgery. J Heart Lung Transplant 2024;43:973-982 (c) 2024 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The acute rejection score (A-score) in lung transplant recipients, calculated as the average of acute cellular rejection A-grades across transbronchial biopsies, summarizes the cumulative burden of rejection over time. We assessed the association between A-score and transplant outcomes in 2 geographically distinct cohorts. The primary cohort included 772 double lung transplant recipients. The analysis was repeated in 300 patients from an independent comparison cohort. Time-dependent multivariable Cox models were constructed to evaluate the association between A-score and chronic lung allograft dysfunction or graft failure. Landmark analyses were performed with A-score calculated at 6 and 12 months posttransplant. In the primary cohort, no association was found between A-score and graft outcome. However, in the comparison cohort, time-dependent A-score was associated with chronic lung allograft dysfunction both as a time-dependent variable (hazard ratio, 1.51; P < .01) and when calculated at 6 months posttransplant (hazard ratio, 1.355; P = .031). The A-score can be a useful predictor of lung transplant outcomes in some settings but is not generalizable across all centers; its utility as a prognostication tool is therefore limited.

BACKGROUND: Airway epithelial injury is thought to be a key event in the pathogenesis of chronic lung allograft dysfunction (CLAD). We investigated whether markers of epithelial activity and injury in bronchoalveolar lavage fluid (BAL) correlate with CLAD diagnosis and major CLAD phenotypes: bronchiolitis obliterans syndrome (BOS) vs restrictive allograft syndrome (RAS)-related phenotypes (including RAS, mixed phenotype, and all other patients with RAS-like opacities).METHODS: CLAD status and phenotypes were retrospectively determined in a cohort of all consecutive adult, first, bilateral lung transplants performed 2010-2015, with available BAL samples. All patients with RAS-related phenotypes were included and 1:1 matched with BOS patients based on the time from transplant to CLAD-onset. Subjects who were CLAD-free for a minimum of 3 years post -transplant were 1:1 matched to CLAD patients and included as controls. Proteins that maintain the barrier function of the airway epithelial mucosa (club cell secretory protein, surfactant protein-D and epithelial mucins: MUC1, MUC5AC, MUC5B, MUC16), as well as epithelial cell death markers (M30 & M65 representing epithelial cell apoptosis and overall death, respectively), were measured in BAL obtained within 6-months post CLAD onset using a double-sandwich ELISA or a multiplex bead assay. Protein levels were compared using Mann-Whitney-U-test. Association between protein levels and graft survival was assessed using Cox proportional hazards models, adjusted for CMV serology mismatch status and CLAD phenotype.RESULTS: Fifty-four CLAD (27 BOS, 11 RAS, 7 mixed, 9 others with RAS-like opacities) patients and 23 CLAD-free controls were included. Median BAL levels were significantly higher in patients with CLAD compared to CLAD-free controls for M30 (124.5 vs 88.7 U/L), MUC1 (6.8 vs 3.2 pg/mL), and MUC16 (121.0 vs 30.1 pg/mL). When comparing CLAD phenotypes, M30 was significantly higher in patients with RAS-related phenotypes than BOS (160.9 vs 114.6 U/L). In multivariable models, higher M30 and MUC5B levels were associated with decreased allograft survival after CLAD onset independent of phenotype (p < 0.05 for all).CONCLUSIONS: Airway epithelial mucins and cell death markers are enhanced in the BAL of patients with CLAD and can assist in differentiating between CLAD phenotypes and post-CLAD outcomes. Abnormal airway mucin expression and epithelial cell death may be involved in the pathogenesis of CLAD, and therefore their detection may aid in future selection of targeted therapies. J Heart Lung Transplant 2023;42:1152-1160 & COPY; 2023 International Society for Heart and Lung Transplantation. All rights reserved.

Abstract Background With the advent of next-generation sequencing, digital pathology, and other high-dimensional data sources used in modern research, improved data management is required to maintain organization and relationship to the corresponding patient and their outcomes. The complexity of the data often limits interpretation by clinicians not highly versed in its analysis. Conversely, data scientists may not be able to interpret the data in the correct clinical context. We describe here a relational database and custom tools which coordinates clinical, organoid, and genomic data in the study of esophageal adenocarcinoma. Methods Database architecture was designed with pillars of clinical data and outcome, organoid culture data, and next-generation sequencing data. Data dictionaries were composed for all tables in the database architecture. Oracle Database was utilized and populated with datasets formatted to adhere to data dictionaries. Application Express was used to develop web applications for users to enter, query, and analyze data. Automatic nightly backups, robust login security, and tiers of access protect confidential data against system failures, human error, and data theft. Custom tools with graphical user interfaces were developed for survival curve generation and organoid drug-screening results, to facilitate clinician use. Results This database now encompasses over 21 data tables comprising clinical, surgical, recurrence, treatment response, tissue sample storage, organoid research, and genomic data. Data scientists can link omic data directly to patient clinical data and clinician researchers can rapidly obtain patient and organoid survival data for covariates of choice using a graphical user interface. Conclusion Proper data management requires a substantial initial investment in designing of database architecture, deployment of software and servers, formatting of data, and the creation of front-end user applications. The investment is well worth the cost, however, as a centralized database allows for rapid querying of data that would otherwise be scattered or require individualized analysis for each project. This also facilitates the interactions between data scientists and clinician researchers.

The long-term benefits of lung transplantation (LTx) are limited by pathogenic alloimmune responses that drive injury, inflammation, and chronic dysfunction. Human leukocyte antigen-G (HLA-G) plays a key role in the modulation of these pathways. This study assesses the impact of the HLA-G genotype on immunologic risk and survival following LTx. This retrospective cohort study included 289 bilateral LTx. Recipient and donor HLA-G genotypes were analyzed to identify associations with de novo donor-specific antibodies, acute rejection, chronic lung allograft dysfunction, and allograft survival. We further assessed these associations, both individually and in paired analysis, based on a grouped haplotype classification of HLA-G expression. Donor HLA-G single nucleotide polymorphisms were associated with allograft injury, the onset of chronic lung allograft dysfunction following injury, and allograft survival. Recipient HLA-G single nucleotide polymorphisms were associated with allograft injury, cellular rejection, and donor-specific antibody formation. "Low HLA-G expression" donor haplotypes were associated with impaired allograft survival, as were "low HLA-G expression" donor-recipient haplotype pairs. This study provides compelling evidence for the role of HLA-G in modulating immunologic risk after LTx. Our results highlight the importance of both donor and recipient HLA-G genotypes on the overall risk profile and underscore the lasting influence of donor genotype on lung transplant outcomes.

Background:Chronic lung allograft dysfunction (CLAD) is the major cause of death post-lung transplantation, with acute cellular rejection (ACR) being the biggest contributing risk factor. Although patients are routinely monitored with spirometry, FEV1 is stable or improving in most ACR episodes. In contrast, oscillometry is highly sensitive to respiratory mechanics and shown to track graft injury associated with ACR and its improvement following treatment. We hypothesize that intra-subject variability in oscillometry measurements correlates with ACR and risk of CLAD.Methods:Of 289 bilateral lung recipients enrolled for oscillometry prior to laboratory-based spirometry between December 2017 and March 2020, 230 had ≥ 3 months and 175 had ≥ 6 months of follow-up. While 37 patients developed CLAD, only 29 had oscillometry at time of CLAD onset and were included for analysis. These 29 CLAD patients were time-matched with 129 CLAD-free recipients. We performed multivariable regression to investigate the associations between variance in spirometry/oscillometry and the A-score, a cumulative index of ACR, as our predictor of primary interest. Conditional logistic regression models were built to investigate associations with CLAD.Results:Multivariable regression showed that the A-score was positively associated with the variance in oscillometry measurements. Conditional logistic regression models revealed that higher variance in the oscillometry metrics of ventilatory inhomogeneity, X5, AX, and R5-19, was independently associated with increased risk of CLAD (p < 0.05); no association was found for variance in %predicted FEV1.Conclusion:Oscillometry tracks graft injury and recovery post-transplant. Monitoring with oscillometry could facilitate earlier identification of graft injury, prompting investigation to identify treatable causes and decrease the risk of CLAD.

Our program previously reported successful outcomes following virtual crossmatch (VXM)-positive lung transplants managed with perioperative desensitization, but our ability to stratify their immunologic risk was limited without flow cytometry crossmatch (FCXM) data before 2014. The aim of this study was to determine allograft and chronic lung allograft dysfunction (CLAD)-free survival following VXM-positive/FCXM-positive lung transplants, which are performed at a minority of programs due to the high immunologic risk and lack of data on outcomes. All first-time lung transplant recipients between January 2014 and December 2019 were divided into 3 cohorts: VXM-negative (n = 764), VXM-positive/FCXM-negative (n = 64), and VXM-positive/FCXM-positive (n = 74). Allograft and CLAD-free survival were compared using Kaplan-Meier and multivariable Cox proportional hazards models. Five-year allograft survival was 53% in the VXM-negative cohort, 64% in the VXM-positive/FCXM-negative cohort, and 57% in the VXM-positive/FCXM-positive cohort (P = .7171). Five-year CLAD-free survival was 53% in the VXM-negative cohort, 60% in the VXM-positive/FCXM-negative cohort, and 63% in the VXM-positive/FCXM-positive cohort (P = .8509). This study confirms that allograft and CLAD-free survival of patients who undergo VXM-positive/FCXM-positive lung transplants with the use of our protocol does not differ from those of other lung transplant recipients. Our protocol for VXM-positive lung transplants improves access to transplant for sensitized candidates and mitigates even high immunologic risk.

Background Morbidity and mortality in lung transplant recipients are often triggered by recurrent aspiration events, potentiated by oesophageal and gastric disorders. Previous small studies have shown conflicting associations between oesophageal function and the development of chronic lung allograft dysfunction (CLAD). Herein, we sought to investigate the relationship between oesophageal motility disorders and long-term outcomes in a large retrospective cohort of lung transplant recipients. Methods All lung transplant recipients at the Toronto Lung Transplant Program from 2012 to 2018 with available oesophageal manometry testing within the first 7 months post-transplant were included in this study. Patients were categorised according to the Chicago Classification of oesophageal disorders (v3.0). Associations between oesophageal motility disorders with the development of CLAD and allograft failure (defined as death or re-transplantation) were assessed. Results Of 487 patients, 57 (12%) had oesophagogastric junction outflow obstruction (OGJOO) and 47 (10%) had a disorder of peristalsis (eight major, 39 minor). In a multivariable analysis, OGJOO was associated with an increased risk of CLAD (HR 1.71, 95% CI 1.15–2.55, p=0.008) and allograft failure (HR 1.69, 95% CI 1.13–2.53, p=0.01). Major disorders of peristalsis were associated with an increased risk of CLAD (HR 1.55, 95% CI 1.01–2.37, p=0.04) and allograft failure (HR 3.33, 95% CI 1.53–7.25, p=0.002). Minor disorders of peristalsis were not significantly associated with CLAD or allograft failure. Conclusion Lung transplant recipients with oesophageal stasis characterised by OGJOO or major disorders of peristalsis were at an increased risk of adverse long-term outcomes. These findings will help with risk stratification of lung transplant recipients and personalisation of treatment for aspiration prevention.

Abstract Background Bronchoalveolar lavage (BAL) is a key tool in respiratory medicine for sampling the distal airways. BAL bile acids are putative biomarkers of pulmonary microaspiration, which is associated with poor outcomes after lung transplantation. Compared to BAL, large airway bronchial wash (LABW) samples the tracheobronchial space where bile acids may be measurable at more clinically relevant levels. We assessed whether LABW bile acids, compared to BAL bile acids, are more strongly associated with poor clinical outcomes in lung transplant recipients. Methods Concurrently obtained BAL and LABW at 3 months post-transplant from a retrospective cohort of 61 lung transplant recipients were analyzed for taurocholic acid (TCA), glycocholic acid (GCA), and cholic acid by mass spectrometry and 10 inflammatory proteins by multiplex immunoassay. Associations between bile acids with inflammatory proteins and acute lung allograft dysfunction were assessed using Spearman correlation and logistic regression, respectively. Time to chronic lung allograft dysfunction and death were evaluated using multivariable Cox proportional hazards and Kaplan–Meier methods. Results Most bile acids and inflammatory proteins were higher in LABW than in BAL. LABW bile acids correlated with inflammatory proteins within and between sample type. LABW TCA and GCA were associated with acute lung allograft dysfunction (OR = 1.368; 95%CI = 1.036–1.806; P = 0.027, OR = 1.064; 95%CI = 1.009–1.122; P = 0.022, respectively). No bile acids were associated with chronic lung allograft dysfunction. Adjusted for risk factors, LABW TCA and GCA predicted death (HR = 1.513; 95%CI = 1.014–2.256; P = 0.042, HR = 1.597; 95%CI = 1.078–2.366; P = 0.020, respectively). Patients with LABW TCA in the highest tertile had worse survival compared to all others. Conclusions LABW bile acids are more strongly associated than BAL bile acids with inflammation, acute lung allograft dysfunction, and death in lung transplant recipients. Collection of LABW may be useful in the evaluation of microaspiration in lung transplantation and other respiratory diseases.

Rationale The diffusing capacity of the lung for carbon monoxide corrected for haemoglobin (D-LCOcor) measures gas movement across the alveolar-capillary interface. We hypothesised that D-LCOcor is a sensitive measure of injurious allograft processes disrupting this interface. Objectives To determine the prognostic significance of the D-LCOcor trajectory on chronic lung allograft dysfunction (CLAD) and survival. Methods A retrospective analysis was conducted of all bilateral lung transplant recipients at a single centre, between January 1998 and January 2018, with one or more D-LCOcor measurements. Low baseline D-LCOcor was defined as the failure to achieve a D-LCOcor >75% predicted. Drops in D(LCOcor )were defined as >15% below recent baseline. Results 1259 out of 1492 lung transplant recipients were included. The median (range) time to peak D-LCOcor was 354 (181-737) days and the mean +/- sD D-LCOcor was 80.2 +/- 21.2% pred. Multivariable analysis demonstrated that low baseline D-LCOcor was significantly associated with death (hazrd ratio (HR) 1.68, 95% CI 1.27-2.20; p<0.001). Low baseline D(LCOcor)was not independently associated with CLAD after adjustment for low baseline forced expiratory volume in 1 s or forced vital capacity. Any D(LCOcor )declines >= 15% were significantly associated with death, independent of concurrent spirometric decline. Lower percentage predicted D-LCOcor values at CLAD onset were associated with shorter post-CLAD survival (HR 0.75 per 10%-unit change, p<0.01). Conclusion Low baseline D-LCOcor and post-transplant declines in D-LCOcor were significantly associated with survival, independent of spirometric measurements. We propose that D-LCOcor testing may allow identification of a subphenotype of baseline and chronic allograft dysfunction not captured by spirometry. There may be benefit in routine monitoring of D-LCOcor after lung transplantation to identify patients at risk of poor outcomes.

The Toronto Lung Transplant Program has been using a peri-operative desensitization regimen of plasma exchange, intravenous immune globulin, and antithymocyte globulin in order to accept donor-specific antibody (DSA)-positive lung transplants safely since 2008. There are no long-term data on the impact of this practice on allograft survival or the development of chronic lung allograft dysfunction (CLAD). We extended our prior study to include long-term follow-up of 340 patients who received lung transplants between January 1, 2008 and December 31, 2011. We compared allograft survival and CLAD-free survival among patients in three cohorts: DSA-positive, panel reactive antibody (PRA)-positive/DSA-negative, and unsensitized at the time of transplant. The median follow-up time in this extension study was 6.7 years. Among DSA-positive, PRA-positive/DSA-negative, and unsensitized patients, the median allograft survival was 8.4, 7.9, and 5.8 years, respectively (p = .5908), and the median CLAD-free survival was 6.8, 7.3, and 5.7 years, respectively (p = .5448). This follow-up study confirms that long-term allograft survival and CLAD-free survival of patients who undergo DSA-positive lung transplants with the use of our protocol do not differ from other lung transplant recipients. Use of protocols such as ours, therefore, may improve access to transplant for sensitized candidates.

Background. Procuring a good quality transbronchial-biopsy sample is essential for diagnosing acute cellular rejection after lung transplantation (LT). Insufficient transbronchial-biopsy samples are graded “AX.” We hypothesized that AX samples may be associated with a higher risk for chronic lung allograft dysfunction (CLAD) or death/retransplant, through a potential anatomic or physiologic underlying pulmonary process or because of undiagnosed acute cellular rejection episodes. Methods. We conducted a single-center, retrospective, cohort study drawn from all consecutive adult, first, bilateral LT between 1999 and 2015. We reviewed all biopsies obtained within the first year posttransplant and compared outcomes of patients with ≥1 AX to patients with no AX. Association of any AX or percent AX with time to CLAD or death/retransplant was assessed using Cox Proportional Hazards models. Results. The cohort consisted of 809 patients with a median of 6 (interquartile range 5–6) biopsies and 16.7% (interquartile range 0–25) AX samples within the first year posttransplant. Four hundred thirty-nine (54.3%) subjects had ≥1 AX sample obtained within the time period. Median time to CLAD or death/retransplant, from 1 year posttransplant, was 761 (320, 1587) and 1200 (662, 2308) days, respectively. In the multivariable analysis, there was no difference in risk for CLAD (hazard ratio = 1.05, 95% confidence interval, 0.87-1.28, P = 0.60), or death/retransplant (hazard ratio = 1.14, 95% confidence interval, 0.92–1.42, P = 0.24) between patients with ≥1 AX biopsy versus none. Among subjects with ≥1 AX, having >50% AX biopsies was not associated with outcome. Conclusions. This is the first study to demonstrate that AX biopsies are not associated with an increased risk of CLAD or death/retransplant after LT and may not require to repeat the biopsy.

Ex vivo lung perfusion (EVLP) has being increasingly used for the pretransplant assessment of extended-criteria donor lungs. Mathematical models to predict lung acceptance during EVLP have not been reported so far. Thus, we hypothesized that predictors of lung acceptance could be identified and used to develop a mathematical model describing the clinical decision-making process used in our institution. Donor lungs characteristics and EVLP physiologic parameters included in our EVLP registry were examined (derivation cohort). Multivariable logistic regression analysis was performed to identify predictors independently associated with lung acceptance. A mathematical model (EX vivo lung PerfusIon pREdiction [EXPIRE] model) for each hour of EVLP was developed and validated using a new cohort (validation cohort). Two hundred eighty donor lungs were assessed with EVLP. Of these, 186 (66%) were accepted for transplantation. ΔPO2 and static compliance/total lung capacity were identified as independent predictors of lung acceptance and their respective cut-off values were determined. The EXPIRE model showed a low discriminative power at the first hour of EVLP assessment (AUC: 0.69 [95% CI: 0.62-0.77]), which progressively improved up to the fourth hour (AUC: 0.87 [95% CI: 0.83-0.92]). In a validation cohort, the EXPIRE model demonstrated good discriminative power, peaking at the fourth hour (AUC: 0.85 [95% CI: 0.76-0.94]). The EXPIRE model may help to standardize lung assessment in centers using the Toronto EVLP technique and improve overall transplant rates.

In lung transplant recipients with suspected restrictive allograft syndrome/mixed phenotype and a preserved forced vital capacity, accurate phenotyping requires routine measurements of total lung capacityhttps://bit.ly/3e2qxdP

Definitions for chronic lung allograft dysfunction (CLAD) phenotypes were recently revised (2019 ISHLT consensus). Post-CLAD onset phenotype transition may occur as a result of change in obstruction, restriction, or RAS-like opacities (RLO). We aimed to assess the prevalence and prognostic implications of these transitions. This was a single-center, retrospective cohort study of bilateral lung transplants performed in 2009-2015. CLAD phenotypes were determined per ISHLT guidelines. CLAD phenotype transition was defined as a sustained change in obstruction, restriction or RLO. We specifically focused on phenotype changes based on RLO emergence. Association of RLO development with time to death or retransplant were assessed using Kaplan-Meier and Cox proportional hazards models. Among 211 patients with CLAD, 47 (22.2%) experienced a phenotype transition. Nineteen patients developed RLO. Development of RLO phenotype after CLAD onset was associated with a shorter time to death/retransplant when considering the entire CLAD patient cohort (HR = 4.00, CI 2.74-5.83, P < 0.001) and also when restricting the analysis to only patients with a Non-RLO phenotype at CLAD onset (HR 9.64, CI 5.52-16.84, P < 0.0001). CLAD phenotype change based on emergence of RAS-like opacities implies a worse outcome. This highlights the clinical importance of imaging follow-up to monitor for phenotype transitions after CLAD onset.

BACKGROUND: Acute cellular rejection (ACR) remains the most significant risk factor for chronic lung allograft dysfunction (CLAD). While clinically significant or higher-grade (>= A2) ACR is generally treated with augmented immunosuppression (IS), the management of clinically stable grade A1 ACR remains controversial. At our center, patients with clinically stable grade A1 ACR are routinely not treated with augmented IS. While the overall outcomes in this group of patients at our center are equivalent to patients with stable AO pathology, CLAD and death rates remain overall high. We hypothesized that a distinct cytokine signature at the time of early minimal rejection state would be associated with worse outcomes. Specifically, we aimed to determine whether bronchoalveolar lavage (BAL) biomarkers at the time of first clinically stable grade A1 ACR (CSA1R) are predictive of subsequent CLAD or death. METHODS: Among all adult, bilateral, first lung transplants, performed 2010-2016, transbronchial biopsies obtained within the first-year post-transplant were categorized as clinically stable or unstable based on the presence or absence of >= 10% concurrent drop in forced expiratory volume in 1 second (FEV1). We assessed BAL samples obtained at the time of CSA1R episodes, which were not preceded by another ACR (i.e., first episodes). Twenty-one proteins previously associated with ACR or CLAD were measured in the BAL using a multiplex bead assay. Association between protein levels and subsequent CLAD or death was assessed using Cox Proportional Hazards models, adjusted for relevant peritransplant clinical covariates. RESULTS: We identified 75 patients with first CSA1R occurring at a median time of 98 days (range 485-197) post-transplant. Median time from transplant to CLAD or death was 1247 (756.5-1921.5) and 1641 days (1024.5-2326.5), respectively. In multivariable models, levels of MCP1/CCL2, S100A8, IL10, TNF-receptor 1, and pentraxin 3 (PTX3) were associated with both CLAD development and death (p < 0.05 for all). PTX3 remained significantly associated with both CLAD and death after adjusting for multiple comparisons. CONCLUSION: Our data indicate that a focused BAL protein signature, with PTX3 having the strongest association, may be useful in determining a subset of CSA1R patients at increased risk and may benefit from a more aggressive management strategy. (C) 2021 International Society for Heart and Lung Transplantation. All rights reserved.

IntroductionPrior studies assessing outcomes of lung transplants from cigarette-smoking donors found mixed results. Oscillometry, a non-invasive test of respiratory impedance, detects changes in lung function of smokers prior to diagnosis of COPD, and identifies spirometrically silent episodes of rejection post-transplant. We hypothesise that oscillometry could identify abnormalities in recipients of smoking donor lungs and discriminate from non-smoking donors.MethodsThis prospective single-center cohort study analysed 233 double-lung recipients. Oscillometry was performed alongside routine conventional pulmonary function tests (PFT) post-transplant. Multivariable regression models were constructed to compare oscillometry and conventional PFT parameters between recipients of lungs from smoking vs non-smoking donors.ResultsThe analysis included 109 patients who received lungs from non-smokers and 124 from smokers. Multivariable analysis identified significant differences between recipients of smoking and non-smoking lungs in the oscillometric measurements R5-19, X5, AX, R5z and X5z, but no differences in %predicted FEV1, FEV1/FVC, %predicted TLC or %predicted DLCO. An analysis of the smoking group also demonstrated associations between increasing smoke exposure, quantified in pack years, and all the oscillometry parameters, but not the conventional PFT parameters.ConclusionAn interaction was identified between donor-recipient sex match and the effect of smoking. The association between donor smoking and oscillometry outcomes was significant predominantly in the female donor/female recipient group.