Diagnosis Of Chronic Lung Allograft Dysfunction Research Articles

A novel web-based tool for lung transplant patients undergoing extracorporeal photopheresis

IntroductionExtracorporeal photopheresis (ECP) is considered an emerging rescue therapy for patients with CLAD (chronic lung allograft dysfunction). The aim of the study was to set up a web-based data collection tool for lung transplant patients with CLAD undergoing ECP. MethodologyThe web-based tool was developed using Oracle MySQL and coded in HTML, JavaScript and CSS (Cascading Style Sheets) and was set up with pre and post transplant data of possible interest in CLAD. The functionality assessment of the software was carried out using data from a cohort of CLAD patients undergoing ECP treatment. ResultsThe software consists of seven major sections. The validation cohort consisted of 25 lung transplant patients (13 men and 12 women, median age at transplant 51 years). A significant improvement in the rate of decline of FEV1, FVC and FEV1/FVC after introduction of ECP was observed. Forty-four percent of patients showed a <10% decline in FEV1 at 6 months. Patients with recurrent respiratory infections showed less probability of responding to ECP. ConclusionsToday informatics is an integral part of medical science and an essential tool for clinical decision-making under many circumstances, reducing costs and improving patient outcomes. The “Siena ECP Database” allowed us to identify major functional trajectories after the introduction of ECP. It showed good data collection capacity, providing significant pre- and post-transplant information associated with ECP response. Although no clear clinical profile of responders has yet been defined, BOS phenotype and absence of recurrent respiratory infections before diagnosis of CLAD seem to be associated with a positive response to ECP therapy.

Percentage of low attenuation area on computed tomography detects chronic lung allograft dysfunction, especially bronchiolitis obliterans syndrome, after bilateral lung transplantation.

The percentage of low attenuation area (%LAA) on computed tomography (CT) is useful for evaluating lung emphysema, and higher %LAA was observed in patients with chronic lung allograft dysfunction (CLAD). This study investigated the relationship between the %LAA and the development of CLAD after bilateral lung transplantation (LT). We conducted a single-center retrospective study of 75 recipients who underwent bilateral LT; the recipients were divided into a CLAD group (n=30) and a non-CLAD group (n=45). The %LAA was calculated using CT and compared between the two groups from 4 years before to 4 years after the diagnosis of CLAD. The relationships between the %LAA and the percent baseline values of the pulmonary function test parameters were also calculated. The %LAA was significantly higher in the CLAD group than in the non-CLAD group from 2 years before to 2 years after the diagnosis of CLAD (P<.05). In particular, patients with bronchiolitis obliterans syndrome (BOS) exhibited significant differences even from 4 years before to 4 years after diagnosis (P<.05). Significant negative correlations between the %LAA and the percent baseline values of the forced expiratory volume in 1 s (r=-.36, P=.0031), the forced vital capacity (r=-.27, P=.027), and the total lung capacity (r=-.40, P<.001) were seen at the time of CLAD diagnosis. The %LAA on CT was associated with the development of CLAD and appears to have the potential to predict CLAD, especially BOS, after bilateral LT.

Pulmonary epithelial markers in phenotypes of chronic lung allograft dysfunction

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). 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 (CCSP), surfactant protein-D (SP-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. 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). 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.

The healthcare resource utilization and costs of chronic lung allograft dysfunction following lung transplantation in patients with commercial insurance in the United States

Aims Chronic lung allograft dysfunction (CLAD), a common complication of lung transplantation, is the leading cause of death for lung transplant recipients. While data on lung transplant costs are available, the impact of CLAD on healthcare resource use (HRU) and cost is not well understood. The primary objective was to quantify the HRU and costs of CLAD in the US using real-world data. Methods A longitudinal retrospective analysis was performed of commercial claims data from the IQVIA PharMetrics Plus database for patients aged 18–64 who underwent lung transplantation between January 1, 2006 and September 30, 2018. Lung transplantation was identified using International Classification of Disease and Common Procedure Terminology procedure codes. Patients studied were observable for at least 12 months before and after transplantation. Patients who developed CLAD were identified using novel, diagnosis codes for incident lung disease at least one year following transplantation. Descriptive analyses were conducted to assess the study’s outcomes prior to and following a CLAD diagnosis. All-cause HRU and costs, the study’s primary outcomes, leading up to and following CLAD diagnosis were calculated. Results Among 129 transplant patients who developed CLAD, healthcare costs were substantially higher in the year following diagnosis ($198,113), compared to the year leading to diagnosis ($85,276). Inpatient admissions were responsible for most costs in years 1 and 2 following diagnosis ($99,372 and $83,348 respectively). Drug costs were higher in the 12 months post-index, compared to the 12 months pre-index ($3,600 vs $2,527). Limitations Claims data do not include clinical data, have limits determining loss of follow-up, and do not provide granularity to determine disease severity. Also, there is no ICD-10-CM code specific to CLAD or BOS. Conclusions CLAD after lung transplant is associated with substantial HRU and costs. Further work is needed to develop interventions that reduce this impact.

The Percentage of Low Attenuation Area on Computed Tomography to Detect Chronic Lung Allograft Dysfunction After Bilateral Lung Transplantation

<h3>Purpose</h3> Lung emphysematous changes may develop in patients with chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). To evaluate the severity of lung emphysema, the percentage of low attenuation area (LAA%) of the bilateral lungs calculated on computed tomography has been shown to be a useful index. This study aimed to investigate whether the LAA% was associated with the development of CLAD after bilateral LT. <h3>Methods</h3> We conducted a single-center retrospective study of 75 recipients who underwent bilateral LT from May 2008 to August 2015. The LAA% on computed tomography were calculated and compared between the CLAD group (N = 30) and the non-CLAD group (N = 45) from 2 years before to 4 years after the diagnosis of CLAD. The LAA% at 5 years after bilateral LT was designated as the control value in the non-CLAD group. The Pearson product-moment correlation coefficient was calculated between the LAA% and the percent baseline values of the forced expiratory volume in 1 s (FEV1), the forced vital capacity (FVC), and the total lung capacity (TLC) at the diagnosis of CLAD after bilateral LT. <h3>Results</h3> The median observation period after LT was 3277 (380-7691) days. The LAA% in the CLAD group was significantly higher than that in the non-CLAD group from even 2 years before the diagnosis of CLAD to 2 years after the diagnosis of CLAD (P < 0.05) (Figure 1). The difference in the LAA% between the CLAD group and the non-CLAD group tended to increase after the onset of CLAD. Furthermore, the LAA% was significantly correlated with the percent baseline values of the FEV1, the FVC, and the TLC (FEV1, r = -0.36, P = 0.0031; FVC, r = -0.27, P = 0.027; TLC, r = -0.40, P < 0.001) (Figure 2). <h3>Conclusion</h3> The LAA% was associated with the development of CLAD and increased after the diagnosis of CLAD. Moreover, the LAA% was associated with declines in the FEV1, FVC and TLC at the time of CLAD diagnosis. The LAA% appears to have the potential to predict CLAD after bilateral LT.

Prediction of Chronic Lung Allograft Dysfunction by Monitoring Serum KL-6 Levels

<h3>Purpose</h3> 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. <h3>Methods</h3> 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. <h3>Results</h3> 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). <h3>Conclusion</h3> Serum KL-6 could be a useful biomarker for RAS prediction.

Large Airway Bronchial Wash Lipidomics as Novel Biomarkers for Chronic Lung Allograft Dysfunction

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is the primary cause of long-term mortality after lung transplantation. Aspiration of bile acids has been associated with CLAD and lipidomic dysregulation. This study evaluates the role of large airway bronchial wash (LABW) lipidomics and diagnosis of CLAD. <h3>Methods</h3> LABW (n=611) samples were obtained from 305 lung transplant recipients at different timepoints. Concentrations of 26 specific lipid subfamilies were obtained using liquid chromatography mass spectrometry. Lipid percentages where stratified by highest tertiles. The primary outcome of interest was development of CLAD from sampling time. Time-to-event analysis was done using Kaplan-Meier functions and a multivariable Cox proportional hazards model adjusting for baseline comorbidities. <h3>Results</h3> Samples with CLAD at the time of collection showed higher percentages of hexosylceramides (HEXCER), CE, sphingomyelin (SM) and lactosylceramide (LACCER). A high percentage of bismethyl-phosphatidic acid (BMP), CE, phosphatidylethanolamine (PEP), dehydrosphingosine (DHSM), lysophosphatidylethanolamine (LPE), ganglioside (GM3), phosphatidyl-serine (PS) were associated with an increased hazards of CLAD by univariable analysis. A high percentage of CE (HR: 1.48, 95% CI: 1.09-2.03, <i>P</i>=0.013) were independent predictors of CLAD by multivariable analysis. High percentages of CER (HR: 0.49, 95% CI: 0.36-0.66, <i>P</i><0.001) and a high LACCER:CER ratio (HR: 0.45, 95% CI: 0.34-0.62, <i>P</i><0.001) were independently associated with decreased hazards of CLAD. <h3>Conclusion</h3> Airway lipidomic qualititative changes show a distinct phenotype that associate with the presence and risk of development of CLAD. Percentages of CE, CER and LACCER:CER ratios correlate independently with increased risk of development of CLAD. Changes in LABW lipids may serve as biomarkers for CLAD and elucidate pathophysiologic changes after transplant.

Markers of rejection of a lung allograft: state of the art.

Chronic lung allograft dysfunction (CLAD) affects approximately 50% of all lung transplant recipients by 5 post-operative years and is the leading cause of death in lung transplant recipients. Early CLAD diagnosis or ideally prediction of CLAD is essential to enable early intervention before significant lung injury occurs. New technologies have emerged to facilitate biomarker discovery, including epigenetic modification and single-cell RNA sequencing. This review examines new and existing technologies for biomarker discovery and the current state of research on biomarkers for identifying lung transplant rejection.

Variability in azithromycin practices among lung transplant providers in the International Society for Heart and Lung Transplantation Community

Chronic lung allograft dysfunction (CLAD) is the most important long-term complication after lung transplant (LTx), and clinical experience suggests significant variability in its management. We sought to capture azithromycin practices among LTx providers internationally. A survey was distributed via the International Society for Heart and Lung Transplantation and completed by 103 respondents (15 countries). Azithromycin indications, timing, and dosing varied significantly, and 37 (36%) reported inconsistency even within their center. Thirty (29%) reported initiating azithromycin prophylactically (during initial transplant hospitalization). Of 73 others, only 10 (14%) reported waiting until CLAD diagnosis (with persistent ≥20% pulmonary function decline). Most initiated azithromycin after a CLAD risk-factor and/or event, including 59 (81%) for a persistent ≥10% decrement in FEV1, 32 (44%) for lymphocytic bronchiolitis, and 27 (37%) for bronchoalveolar lavage neutrophilia. Azithromycin prescribing patterns appear to vary significantly, and further study is needed to elucidate the optimal timing and indications for its initiation after LTx.

Small airway dilation measured by endoscopic optical coherence tomography correlates with chronic lung allograft dysfunction.

.Significance: Chronic lung allograft dysfunction (CLAD) is the leading cause of death in transplant patients who survive past the first year post-transplant. Current diagnosis is based on sustained decline in lung function; there is a need for tools that can identify CLAD onset.Aim: Endoscopic optical coherence tomography (OCT) can visualize structural changes in the small airways, which are of interest in CLAD progression. We aim to identify OCT features in the small airways of lung allografts that correlate with CLAD status.Approach: Imaging was conducted with an endoscopic rotary pullback OCT catheter during routine bronchoscopy procedures (), collecting volumetric scans of three segmental airways per patient. Six features of interest were identified, and four blinded raters scored the dataset on the presence and intensity of each feature.Results: Airway dilation (AD) was the only feature found to significantly () correlate with CLAD diagnosis ( to 0.61). AD could also be fairly consistently scored between raters (, ). There is a stronger relationship between AD and the combined obstructive and restrictive (BOS + RAS) phenotypes than the obstructive-only (BOS) phenotype for two raters ().Conclusions: OCT examination of small AD shows potential as a diagnostic indicator for CLAD and CLAD phenotype and merits further exploration.

Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis.

BackgroundConnective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD).Materials and MethodsCTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients.ResultsqPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74).ConclusionsLung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.

Connective Tissue Growth Factor in Chronic Lung Allograft Dysfunction: An Explorative Study

Purpose Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD) by analyzing CTGF expression in broncho-alveolar lavage (BAL) fluid, plasma and lung tissue. Methods Sixty matched lung transplant patients were included (stable, n=20; bronchiolitis obliterans syndrome (BOS), n=20, restrictive allograft syndrome (RAS), n=20). CTGF expression was analyzed in BAL 3m post-transplant, 1y post-transplant, and at CLAD diagnosis or 2y post-transplant for stable patients. Explant lung tissue of CLAD (BOS, n=20; RAS, n=20), pulmonary GHVD (n=9), and discarded donor lungs (n=20) was immunohistochemically stained for CTGF. Results BAL CTGF protein expression was significantly higher at 3m post-transplant in patients who later developed RAS compared to stable or BOS patients (ANOVA p=0.028); while CTGF expression was similar at 1y post-transplant (ANOVA p=0.20). At CLAD diagnosis, CTGF expression was significantly increased in RAS compared to stable (p=0.0007) and BOS (p=0.042). Serial analysis revealed no difference in CTGF values between time points for stable and BOS patients (ANOVA p=0.84, p=0.92), whereas CTGF levels were significantly higher in RAS at CLAD diagnosis compared to 1y post-transplant (ANOVA p=0.029). CTGF plasma values were similar between BOS, RAS, and stable (ANOVA p=0.74). Immunohistochemistry revealed a higher percentage and intensity of CTGF positive respiratory epithelial cells in BOS and RAS lungs compared to controls (ANOVA p Conclusion Higher CTGF expression is present in BAL from RAS patients at CLAD diagnosis. Lung tissue CTGF expression is increased in end-stage RAS, BOS and pulmonary GVHD. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD, which warrants further investigation of CTGF and its potential therapeutic modulation in these conditions.

Prediction of Survival after Chronic Lung Allograft Dysfunction in Lung Transplant Recipients by Blood Profiling Using a Predefined 52 Gene Signature

Purpose Long term survival after lung transplantation (LTx) is still determined by the occurrence of chronic lung allograft dysfunction (CLAD). Early identification of high risk patients for CLAD is a large clinial unmet need. Previously, we used genome scale transcript profiling of peripheral blood mononuclear cells (PBMCs) and identified an outcome predictive 52-gene signature using a high risk and low risk score in idiopathic pulmonary fibrosis (IPF) patients. The aim of this study was to investigate whether this 52-gene signature may also be predictive for survival in CLAD, given the shared common fibrotic mechanisms between CLAD and IPF. Methods We collected blood from LTx recipients post-transplantation prior to diagnosis of CLAD and from a matched non-CLAD control group. RNA was isolated from PBMCs and we measured the 52-gene signature using Nanostring Ncounter. Risk Score was calculated using significance analysis microarrays (SAMs). Primary outcome was survival, expressed by time to death after transplantation in patients with a diagnosis of CLAD using Kaplan-Meier analyses. Secondary analysis was time to onset of CLAD in both groups. Results CLAD was diagnosed in 37 (33%) out of 112 LTx recipients (53 Male/59 Female). Thirty-five CLAD patients could be used for analyses. Four patients had a high risk and 31 patients a low risk 52-gene signature. A significant difference in overall survival was found between those two patient groups (time to death: 3.21 vs 6.84yrs; overall: p=0.04). Time to onset of CLAD was significantly different for the high risk group (time to CLAD 1.37 vs.4.30 yrs; p Conclusion High risk gene profile of a predefined 52-gene signature showed a decreased survival after diagnosis of CLAD and earlier CLAD onset. Further analysis is needed to evaluate whether this 52-gene signature can predict survival after CLAD in a larger cohort and which specific genes are up- or downregulated in rapid or gradual onset CLAD.

Phenotyping CLAD after Single Lung Transplant: Limits and Prognostic Assessment of the 2019 ISHLT Classification System

PurposePhenotyping chronic lung allograft dysfunction (CLAD) in single lung transplant (SLTX) recipients is challenging, due to the native lung contribution to pulmonary function tests (PFT). We aimed to assess the ISHLT CLAD classification and its prognostic performance in SLTX.MethodsIn this retrospective cohort of adult, first, SLTX from 2009 to 2017, patients with persistent drop in FEV1>20% were assessed by 2 independent reviewers to determine CLAD status and phenotype, specifically noting presence or absence of RAS-like opacities. Disagreements were resolved by a 3rd reviewer. Interobserver agreement (IOA) was calculated by Cohen's Kappa. Association of CLAD phenotypes with time to death/retransplant (ReTx), adjusted for age, sex, CMV mismatch and native lung condition, were assessed with Cox models.ResultsOut of 172 SLTX patients, 92 had a persistent drop in FEV1>20%, of whom 67 got a diagnosis of CLAD. We noted a moderate IOA for CLAD status (Kappa 0.69) and poor IOA for phenotype (Kappa 0.5). When applying the ISHLT criteria strictly (based on exact cut-offs for PFT, along with imaging), 34 patients had BOS (50.7%), 9 RAS/mixed (13.4%), 7 undefined (10.4%), and 17 unclassified (25.5%). We found no association of these strict phenotypes with death/ReTx (Fig A). When using adjudicated CLAD phenotypes, 31 patients had BOS (46.3%), 15 RAS/mixed (22.4%), 2 Undefined (3%), and 19 Unclassified (28.3%). Using these adjudicated phenotypes, RAS/mixed was significantly associated with higher risk of death/ReTx (HR 2.98, 95%CI [1.39-6.4]) (Fig B). Finally, the specific adjudication of RAS-like opacities had the best IOA (Kappa 0.73). Presence of RAS-like opacities was a strong predictor of death/ReTx (HR 2.3, 95%CI [1.2-4.5]) (Fig C).ConclusionPFT interpretation is challenging in SLTX. Using a classification relying more on imaging analysis that harboured good IOA, we obtained better prognostic performances than with a strict application of published physiologic cut-offs. Phenotyping chronic lung allograft dysfunction (CLAD) in single lung transplant (SLTX) recipients is challenging, due to the native lung contribution to pulmonary function tests (PFT). We aimed to assess the ISHLT CLAD classification and its prognostic performance in SLTX. In this retrospective cohort of adult, first, SLTX from 2009 to 2017, patients with persistent drop in FEV1>20% were assessed by 2 independent reviewers to determine CLAD status and phenotype, specifically noting presence or absence of RAS-like opacities. Disagreements were resolved by a 3rd reviewer. Interobserver agreement (IOA) was calculated by Cohen's Kappa. Association of CLAD phenotypes with time to death/retransplant (ReTx), adjusted for age, sex, CMV mismatch and native lung condition, were assessed with Cox models. Out of 172 SLTX patients, 92 had a persistent drop in FEV1>20%, of whom 67 got a diagnosis of CLAD. We noted a moderate IOA for CLAD status (Kappa 0.69) and poor IOA for phenotype (Kappa 0.5). When applying the ISHLT criteria strictly (based on exact cut-offs for PFT, along with imaging), 34 patients had BOS (50.7%), 9 RAS/mixed (13.4%), 7 undefined (10.4%), and 17 unclassified (25.5%). We found no association of these strict phenotypes with death/ReTx (Fig A). When using adjudicated CLAD phenotypes, 31 patients had BOS (46.3%), 15 RAS/mixed (22.4%), 2 Undefined (3%), and 19 Unclassified (28.3%). Using these adjudicated phenotypes, RAS/mixed was significantly associated with higher risk of death/ReTx (HR 2.98, 95%CI [1.39-6.4]) (Fig B). Finally, the specific adjudication of RAS-like opacities had the best IOA (Kappa 0.73). Presence of RAS-like opacities was a strong predictor of death/ReTx (HR 2.3, 95%CI [1.2-4.5]) (Fig C). PFT interpretation is challenging in SLTX. Using a classification relying more on imaging analysis that harboured good IOA, we obtained better prognostic performances than with a strict application of published physiologic cut-offs.

Gastroparesis after Lung Transplantation is Common but Not Associated with Inferior Outcomes

Purpose Gastroparesis (GP) affects 23-91% lung transplant (LT) recipients and may be associated with increased gastro-oesophageal reflux disease (GORD), an established risk factor for Chronic Lung Allograft Dysfunction (CLAD). The temporal association between GP, CLAD and GORD remains unclear. This study assessed whether patients with GP post LT experienced more GORD, CLAD and inferior nutrition-related outcomes. Methods Single centre retrospective review of adult LT recipients between January 2015 and December 2018 was conducted. GP was identified by either abnormal Gastric emptying studies (GES) or significant food residue retained within the stomach on upper endoscopy. GES were performed on patients symptomatic for gastroparesis - bloating, early satiety, nausea. Reflux was diagnosed via routine performance of 24-hour pH studies on all patients irrespective of symptoms, from 3 months post LT. Outcome variables included demographics, diagnosis of CLAD, survival at 3, 12 months, surgery duration, fundoplication pre and post LT, presence of GORD and weight trajectory post LT. Presence of GP was compared to the above variables. Results 149 patients were analysed; 27.5% (n=41) had GP, diagnosed through GE study (n=33), or Endoscopy (n=8). There was no association between GP and GORD (p=0.265), CLAD (p=0.529), 3-month (p=0.621), or 12-month (p=0.645) survival. GP was associated with an increased BMI, both as a continuous and categorical variable (BMI: 25.0 SD 4.6 vs 23.3 SD 3.9 kg/m2, p=0.030), and patients with GP were more likely to have unintentional weight loss at 6 weeks (GP: -6.2 ± 5.7%, 95% CI -4.4 to -8.1 vs. no GP: -1.7 ± 5.8%, 95% CI -3 to -0.56; p Conclusion Patients with gastroparesis post LT did not have worse short-term survival, GORD or CLAD outcomes. They were, however, more likely to experience unintentional weight loss. Intensive Dietetic input post LT is required in patients identified with GP to prevent malnutrition.

Pulmonary Markers of Epithelial Cell Activity and Injury in Chronic Lung Allograft Dysfunction

Purpose 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 (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. All patients with RAS-related phenotypes were included and 1:1 matched with BOS patients based on time from transplant to CLAD-onset. CLAD-free subjects were used as controls. Proteins that maintain the barrier function of the airway epithelial mucosa (club cell secretory protein (CCSP), surfactant protein-D (SP-D) and epithelial mucins: MUC1, MUC5AC, MUC5B, MUC16), as well as epithelial cell death markers (M30&M65 representing apoptosis and overall death, respectively), were measured in BAL obtained within 6-months from CLAD onset using a double-sandwich ELISA or a multiplex bead assay. Protein levels were compared using Kruskal-Wallis and 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 phenotype. Results Fifty-four CLAD (27 BOS, 11 RAS, 7 mixed, 9 others with RAS-like opacities) patients and 26 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. 88.9), MUC1 (6.8 vs. 3.28) and MUC16 (121.0 vs. 31.1). When comparing CLAD phenotypes, M30 was significantly higher in patients with RAS-related phenotypes compared to BOS (160.9 vs. 114.6). In multivariable models, levels of M30 and MUC5B were associated with allograft survival after CLAD onset independent of phenotype (P Conclusion Airway epithelial mucin and cell death markers are enhanced in the BAL fluid of patients with CLAD and can assist in differentiating between CLAD phenotypes. Abnormal airway mucin expression and epithelial cell death may be involved in the airway inflammatory response of CLAD and thus aid in future selection of targeted therapies.

Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.

Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.

Near-normal aerobic capacity in long-term survivors after lung transplantation.

The clinical course of lung transplantation (LT) is diverse: some patients present chronic lung allograft dysfunction (CLAD) and progressive decline in pulmonary function, but others maintain normal spirometric values and active lives.ObjectivesThe aim of this study was to elucidate whether long-term LT survivors with normal spirometry achieve normal exercise capacity, and to identify predictive factors of exercise capacity.MethodsThis was a cross-sectional multicentre study, where bilateral LT recipients who survived at least 10 years after LT, with normal spirometry, no diagnosis of CLAD and modified Medical Research Council dyspnoea degree ≤2 underwent cardiopulmonary exercise testing (CPET).Results28 LT recipients were included with a mean±sd age of 48.7±13.6 years. Oxygen uptake (V′O2) had a mean±sd value of 21.49±6.68 mL·kg−1·min−1 (75.24±15.6%) and the anaerobic threshold was reached at 48.6±10.1% of the V′O2max predicted. The mean±sd heart rate reserve at peak exercise was 17.56±13.6%. The oxygen pulse increased during exercise and was within normal values at 90.5±19.4%. The respiratory exchange ratio exceeded 1.19 at maximum exercise. The median (25–75th percentile) EuroQol-5D score was 1 (0.95–1), indicating a good quality of life. The median (25–75th percentile) International Physical Activity Questionnaire score was 5497 (4007–9832) MET-min·week−1 with 89% of patients reporting more than 1500 MET-min·week−1. In the multivariate regression models, age, sex and diffusing capacity of the lung for carbon monoxide remained significantly associated with V′O2max (mL·kg−1·min−1); haemoglobin and forced expiratory volume in 1 s were significantly associated with maximum work rate (watts), after adjusting for confounders.ConclusionWe report for the first time near-normal peak V′O2 values during CPET and normal exercise capacity in long-term LT recipients without CLAD.

Outcomes Following Extracorporeal Photopheresis for Chronic Lung Allograft Dysfunction Following Lung Transplantation: A Single-Center Experience

IntroductionSurvival following lung transplantation (LTx) is limited by the development of chronic lung allograft dysfunction (CLAD), for which there are few effective therapies and no standardized management. Several small studies have demonstrated the effectiveness of extracorporeal photopheresis (ECP) as a therapeutic option for CLAD. MethodsA retrospective descriptive audit of 12 LTx recipients who received rescue ECP for CLAD over 5 years (2013-2018) at the Alfred Hospital, Melbourne, Australia, was completed. Nonresponders to ECP were defined as patients who experienced a 20% decrease in forced expiratory volume (FEV1) within 6 weeks of commencing therapy. ResultsMean time since LTx was 849 days and mean time since diagnosis of CLAD was 131 days. Fifty-eight percent of patients were male (n = 7) and 67% responded to ECP therapy (n = 8). Among responders, the mean (95% confidence interval) decline in FEV1 pre-ECP was 9.0 mL/day (5-12 mL/day), compared to 1.4 mL/day (0-4 mL/day) post-ECP (P = .01). Among nonresponders, mean (95% confidence interval) decline in FEV1 was 7.2 mL/day (4-10 mL/day) pre-ECP and 5.0 mL/day (3-7 mL/day) post ECP (P = .2). Nonresponders were more likely to be female (P = .01) and neutropenic (P = .005). Patients with prior exposure to anti-thymocyte globulin had a lowered response to ECP. ConclusionRescue ECP arrested the decline of lung function in 67% of patients with CLAD. Sex, pre-ECP neutrophil count, and exposure to anti-thymocyte globulin may help determine response to ECP. Future clinical trials are needed to confirm this effect, help predict response to therapy, and ultimately guide the placement of ECP in the treatment algorithm for CLAD.

Lung perfusion scintigraphy to detect chronic lung allograft dysfunction after living-donor lobar lung transplantation

Because chronic lung allograft dysfunction (CLAD) develops predominantly on one side after bilateral living-donor lobar lung transplantation (LDLLT), lung perfusion scintigraphy (Q-scinti) was expected to show a perfusion shift to the contralateral unaffected lung with the development of CLAD. Our study examined the potential usefulness of Q-scinti in the diagnosis of CLAD after bilateral LDLLT. We conducted a single-center retrospective cohort study of 58 recipients of bilateral LDLLT. The unilateral shift values on Q-scinti were calculated and compared between the CLAD group (N = 27) and the non-CLAD group (N = 31) from 5 years before to 5 years after the diagnosis of CLAD. The unilateral shift values in Q-scinti were significantly higher in the CLAD group than in the non-CLAD group from 5 years before the diagnosis of CLAD to 5 years after the diagnosis (P < 0.05). The unilateral shift values in Q-scinti were significantly correlated with the percent baseline values of the forced expiratory volume in 1 s (P = 0.0037), the total lung capacity (P = 0.0028), and the forced vital capacity (P = 0.00024) at the diagnosis of CLAD. In patients developing unilateral CLAD after bilateral LDLLT, Q-scinti showed a unilateral perfusion shift to the contralateral unaffected lung. Thus, Q-scinti appears to have the potential to predict unilateral CLAD after bilateral LDLLT.