Acute cellular rejection (ACR) is a significant risk factor for chronic lung allograft dysfunction (CLAD). Although clinically manifest and higher grade (≥A2) ACR is generally treated with augmented immunosuppression, management of minimal (grade A1) ACR remains controversial. In our program, patients with subclinical and spirometrically stable A1 rejection (StA1R) are routinely not treated with augmented immunosuppression. We hypothesized that an untreated first StA1R does not increase the risk of CLAD or death compared to episodes of spirometrically stable no ACR (StNAR). The cohort was drawn from all consecutive adult, first, bilateral lung transplantations performed between 1999 and 2017. Biopsies obtained in the first-year posttransplant were paired with (forced expiratory volume in 1 second FEV₁). The first occurrence of StA1R was compared to a time-matched StNAR. The risk of CLAD or death was assessed using univariable and multivariable Cox proportional hazards models. The analyses demonstrated no significant difference in risk of CLAD or death in patients with a first StA1R compared to StNAR. This largest study to date shows that, in clinically stable patients, an untreated first A1 ACR in the first-year posttransplant is not significantly associated with an increased risk for CLAD or death. Watchful-waiting approach may be an acceptable tactic for stable A1 episodes in lung transplant recipients.

Background Chronic lung allograft dysfunction (CLAD) remains the leading cause of late death after lung transplantation. Epithelial injury is thought to be a key event in the pathogenesis of CLAD. M30 and M65 are fragments of cytokeratin‐18 released specifically during epithelial cell apoptosis and total cell death, respectively. We investigated whether M30 and M65 levels in bronchoalveolar lavage (BAL) correlate with CLAD subtypes: restrictive allograft syndrome (RAS) vs. bronchiolitis obliterans syndrome (BOS). Methods BALs were obtained from 26 patients with established CLAD (10 RAS, 16 BOS) and 19 long‐term CLAD‐free controls. Samples with concurrent infection or acute rejection were excluded. Protein levels were measured by ELISA. Variables were compared using Kruskal‐Wallis, Mann‐Whitney‐U‐test and Chi‐squared tests. Association of M30 and M65 levels with post‐CLAD survival was assessed using a Cox PH models. Results M65 levels were significantly higher in RAS compared to BOS and long‐term CLAD‐free controls and correlated with worse post‐CLAD survival. Conclusion Lung epithelial cell death is enhanced in patients with RAS. Detection of BAL M65 may be used to differentiate CLAD subtypes and as a prognostic marker in patients with established CLAD. Understanding the role of epithelial cell death in CLAD pathogenesis may help identify new therapeutic targets to improve outcome.

While 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 2010-2016, consisting of 668 patients. Risks for death/re-transplantation, 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-999, 1000-9999, and ≧10000 IU/mL. In multivariable models, CMV VL was significantly associated with death/re-transplantation (≧10000 IU/mL: HR=2.65 (1.78-3.94), p<0.01), but was not associated with CLAD, whereas CMV serostatus mismatch was (D+R-: HR=2.04 (1.30-3.21), p<0.01). 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/re-transplantation, but not for CLAD or RAS/mixed. CMV serostatus mismatch may have an impact on CLAD through a pathway independent of DNAemia.

Chronic lung allograft dysfunction (CLAD) is the major cause of death after lung transplantation. Angiotensin II (AngII), the main effector of the renin–angiotensin system, elicits fibrosis in both kidney and lung. We identified six AngII-regulated proteins (Ras homolog family member B (RHOB), bone marrow stromal cell antigen 1 (BST1), lysophospholipase 1 (LYPA1), glutamine synthetase (GLNA), thrombospondin 1 (TSP1) and laminin subunit β2 (LAMB2)) that were increased in urine of patients with kidney allograft fibrosis. We hypothesised that the renin–angiotensin system is active in CLAD and that AngII-regulated proteins are increased in bronchoalveolar lavage fluid (BAL) of CLAD patients.We performed immunostaining of AngII receptors (AGTR1 and AGTR2), TSP1 and GLNA in 10 CLAD lungs and five controls. Using mass spectrometry, we quantified peptides corresponding to AngII-regulated proteins in BAL of 40 lung transplant recipients (stable, acute lung allograft dysfunction (ALAD) and CLAD). Machine learning algorithms were developed to predict CLAD based on BAL peptide concentrations.Immunostaining demonstrated significantly more AGTR1⁺cells in CLADversuscontrol lungs (p=0.02). TSP1 and GLNA immunostaining positively correlated with the degree of lung fibrosis (R²=0.42 and 0.57, respectively). In BAL, we noted a trend towards higher concentrations of AngII-regulated peptides in patients with CLAD at the time of bronchoscopy, and significantly higher concentrations of BST1, GLNA and RHOB peptides in patients that developed CLAD at follow-up (p<0.05). The support vector machine classifier discriminated CLAD from stable and ALAD patients at the time of bronchoscopy (area under the curve (AUC) 0.86) and accurately predicted subsequent CLAD development (AUC 0.97).Proteins involved in the renin–angiotensin system are increased in CLAD lungs and BAL. AngII-regulated peptides measured in BAL may accurately identify patients with CLAD and predict subsequent CLAD development.

Background: Over the last few decades, the efficacy of biological therapies for COPD has been evaluated by different randomized controlled trials (RCTs). Still, the evaluation of real-world data and patient-reported outcome measures (PROMs) have not been performed in this field before. In the current work, we present a systematic literature review of the real-world data and PROMs of biological treatments for COPD. Methods: Three large databases (MEDLINE/PubMed, Scopus, and ScienceDirect) were utilized for the systematic literature review. Clinical studies (RCT, cohorts, case series/reports) assessing patients with COPD treated by any biological therapy were included. Results: The review resulted in twelve eligible studies (nine randomized controlled trials and three “real-world” case series/reports). The evaluation of PROMs in the included studies was mainly limited to the severity and burden of respiratory symptoms. Most biological therapies were associated with improved PROMs compared to the baseline, although not for the placebo. Dupilumab was the only biologic therapy with proven efficacy in RCT for both objective and subjective measures. One prior study reported patients’ self-perceived drug effects, and none evaluated patients’ perceived disease status. Only 25 patients were assessed in a real-world setting for all biologic therapies combined. Real-world data were retrospective in the form of case reports or series. Conclusions: There are limited data on patients’ experience with biological therapies for COPD. While real-world data and PROMs are missing, biases such as a placebo effect must be considered, requiring their incorporation with objective outcomes from prospective controlled trials.