Chronic Lung Allograft Dysfunction Phenotypes Research Articles

Ventilatory capacity in CLAD is driven by dysfunctional airway structure

Chronic lung allograft dysfunction (CLAD) encompasses three main phenotypes: bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS) and a Mixed phenotype combining both pathologies. How the airway structure in its entirety is affected in these phenotypes is still poorly understood. A detailed analysis of airway morphometry was applied to gain insights on the effects of airway remodelling on the distribution of alveolar ventilation in end-stage CLAD. Exvivo whole lung μCT and tissue-core μCT scanning of six control, six BOS, three RAS and three Mixed explant lung grafts (9 male, 9 female, 2014-2021, Leuven, Belgium) were used for digital airway reconstruction and calculation of airway dimensions in relation to luminal obstructions. BOS and Mixed explants demonstrated airway obstructions of proximal bronchioles (starting at generation five), while RAS explants particularly had airway obstructions in the most distal bronchioles (generation >12). In BOS and Mixed explants 76% and 84% of bronchioles were obstructed, respectively, while this was 22% in RAS. Bronchiolar obstructions were mainly caused by lymphocytic inflammation of the airway wall or fibrotic remodelling, i.e. constrictive bronchiolitis. Proximal bronchiolectasis and imbalance in distal lung ventilation were present in all CLAD phenotypes and explain poor lung function and deterioration of specific lung function parameters. Alterations in the structure of conducting bronchioles revealed CLAD to affect alveolar ventilatory distribution in a regional fashion. The significance of various obstructions, particularly those associated with mucus, is highlighted. This research was funded with the National research fund Flanders (G060322N), received by R.V.

Long-term management and outcome of lung transplantation in Japan.

The long-term survival after lung transplantation (LT) is favorable in Japan. However, long-term survivors after LT are subject to late complications, including chronic lung allograft dysfunction (CLAD), malignancy, infection, and chronic kidney disease (CKD) because of the need for lifelong immunosuppression. The rates of single cadaveric LT (CLT) and living-donor lobar LT (LDLLT) are higher than that of bilateral CLT in Japan. Here, we will describe the management of late complications and long-term outcome after LT in Japan. Attention should be paid to not only the phenotype of CLAD but also the difference in CLAD after CLT and after LDLLT as well as the timing of lung re-transplantation for advanced CLAD, especially after single CLT. Since post-transplant lymphoproliferative disorder is the most common malignancy after LT, infection monitoring for infection-related malignancies and appropriate screening are keys to the early diagnosis and treatment of malignancy after LT. The long-term management of infection after LT is also important, especially with regard to community-acquired pathogens, Aspergillus, and cytomegalovirus. When providing long-term care after LT, physicians should be aware of CKD and the timing of renal replacement therapy in cases with severe CKD. The widespread use of computed tomography and dialysis in Japan are beneficial for long-term survivors of LT. The similar survival outcomes of single CLT and LDLLT, compared with bilateral CLT, might contribute to improved long-term survival in Japan. Pulmonologists are encouraged to become further involved in long-term management after LT in Japan.

Diagnostic performance of electronic nose technology in chronic lung allograft dysfunction.

There is a need for reliable biomarkers for the diagnosis of chronic lung allograft dysfunction (CLAD). In this light, we investigated the diagnostic value of exhaled breath analysis using an electronic nose (eNose) for CLAD, CLAD phenotype, and CLAD stage in lung transplant recipients (LTR). We performed eNose measurements in LTR with and without CLAD, visiting the outpatient clinic. Through supervised machine learning, the diagnostic value of eNose for CLAD was assessed in a random training and validation set. Next, we investigated the diagnostic value of the eNose measurements combined with known risk factors for CLAD. Model performance was evaluated using ROC-analysis. We included 152 LTR (median age 60 years, 49% females), of whom 38 with CLAD. eNose-based classification of patients with and without CLAD provided an AUC of 0.86 in the training set, and 0.82 in the validation set. After adding established risk factors for CLAD (age, gender, type of transplantation, time after transplantation and prior occurrence of acute cellular rejection) to a model with the eNose data, the discriminative ability of the model improved to an AUC of 0.94 (p=0.02) in the training set and 0.94 (p=0.04) in the validation set. Discrimination between BOS and RAS was good (AUC 0.95). Discriminative ability for other phenotypes (AUCs ranging 0.50-0.92) or CLAD stages (AUC 0.56) was limited. Exhaled breath analysis using eNose is a promising novel biomarker for enabling diagnosis and phenotyping CLAD. eNose technology could be a valuable addition to the diagnostic armamentarium for suspected graft failure in LTR.

Alterations in Pulmonary Physiology with Lung Transplantation.

Lung transplant is a treatment option for patients with end-stage lung diseases; however, survival outcomes continue to be inferior when compared to other solid organs. We review the several anatomic and physiologic changes that result from lung transplantation surgery, and their role in the pathophysiology of common complications encountered by lung recipients. The loss of bronchial circulation into the allograft after transplant surgery results in ischemia-related changes in the bronchial artery territory of the allograft. We discuss the role of bronchopulmonary anastomosis in blood circulation in the allograft posttransplant. We review commonly encountered complications related to loss of bronchial circulation such as allograft airway ischemia, necrosis, anastomotic dehiscence, mucociliary dysfunction, and bronchial stenosis. Loss of dual circulation to the lung also increases the risk of pulmonary infarction with acute pulmonary embolism. The loss of lymphatic drainage during transplant surgery also impairs the management of allograft interstitial fluid, resulting in pulmonary edema and early pleural effusion. We discuss the role of lymphatic drainage in primary graft dysfunction. Besides, we review the association of late posttransplant pleural effusion with complications such as acute rejection. We then review the impact of loss of afferent and efferent innervation from the allograft on control of breathing, as well as lung protective reflexes. We conclude with discussion about pulmonary function testing, allograft monitoring with spirometry, and classification of chronic lung allograft dysfunction phenotypes based on total lung capacity measurements. We also review factors limiting physical exercise capacity after lung transplantation, especially impairment of muscle metabolism. © 2023 American Physiological Society. Compr Physiol 13:4269-4293, 2023.

Efficacy and safety of total lymphoid irradiation in different chronic lung allograft dysfunction phenotypes.

Total lymphoid irradiation (TLI) is an alternative treatment for chronic lung allograft dysfunction (CLAD). However, data regarding its efficacy and tolerance are scarce. This study included patients with CLAD treated with TLI at our center between 2011 and 2018. Clinical characteristics before and after TLI and related complications were analyzed. Forty patients with CLAD (twenty-nine bronchiolitis obliterans syndrome [BOS], nine restrictive allograft syndrome [RAS], and two mixed) were included. Significant attenuation of the forced expiratory volume in 1-sec (FEV1 ) decline slope was observed in all phenotypes, in both the BOS and RAS. The median FEV1 12, 6, and 3 months pre-TLI were as follows: 1980 (IQR 1720-2560), 1665 (IQR 1300-2340) and 1300 (IQR 1040-1740) ml (p<.001), while the median FEV1 at 3, 6, and 12 months post-TLI was 1110 (IQR 810-1440), 1130 (IQR 860-1470), and 1115 (IQR 865-1490) ml (p=.769). No dropouts due to radiation toxicity were observed. The mean survival according to the Karnofsky Performance Status Scale (KPS) >70 or ≤70 at baseline was 1837 (IQR 259-2522) versus 298 (IQR 128-554) days (p<.0001), respectively. In conclusion, TLI may stop FEV1 decline in both BOS and RAS. Moreover, a good KPS score may be an important prognostic factor.

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry.

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death beyond 2 years after lung transplantation and develops in 50% of all patients by 5 years post-transplant. CLAD is diagnosed on the basis of a sustained drop of 20% for at least 3 months in the forced expiratory volume (FEV1), compared to the best baseline value achieved post-transplant. CLAD presents as two main phenotypes: bronchiolitis obliterans syndrome (BOS) is more common and has better prognosis than restrictive allograft syndrome (RAS). Respiratory oscillometry is a different modality of lung function testing that is highly sensitive to lung mechanics. The current study investigated whether spectral and intrabreath oscillometry can differentiate between CLAD-free, BOS- and RAS-CLAD at CLAD onset, i.e., at the time of the initial 20% drop in the FEV1. Methods: A retrospective, cross-sectional analysis of 263 double lung transplant recipients who underwent paired testing with oscillometry and spirometry at the Toronto General Pulmonary Function Laboratory from 2017 to 2022 was conducted. All pulmonary function testing and CLAD diagnostics were performed following international guidelines. Statistical analysis was conducted using multiple comparisons. Findings: The RAS (n = 6) spectral oscillometry pattern differs from CLAD-free (n = 225) by right-ward shift of reactance curve similar to idiopathic pulmonary fibrosis whereas BOS (n = 32) has a pattern similar to obstructive lung disease. Significant differences were found in most spectral and intrabreath parameters between BOS, RAS, and time-matched CLAD-free patients. Post-hoc analysis revealed these differences were primarily driven by BOS instead of RAS. While no differences were found between CLAD-free and RAS patients with regards to spectral oscillometry, the intrabreath metric of reactance at end-inspiration (XeI) was significantly different (p < 0.05). BOS and RAS were differentiated by spectral oscillometry measure R5, and intrabreath resistance at end expiration, ReE (p < 0.05 for both). Conclusion: Both spectral and intrabreath oscillometry can differentiate BOS-CLAD from CLAD-free states while intrabreath oscillometry, specifically XeI, can uniquely distinguish RAS-CLAD from CLAD-free. Spectral and intrabreath oscillometry offer complementary information regarding lung mechanics in CLAD patients to help distinguish the two phenotypes and could prove useful in prognostication.

PD-0176 Efficacy and safety of total lymphoid irradiation in chronic lung allograft dysfunction phenotypes

PD-0176 Efficacy and safety of total lymphoid irradiation in chronic lung allograft dysfunction phenotypes

The Lung Microbiome is Similar Across CLAD Phenotypes

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is the leading long-term contributor to mortality after lung transplant. The lung microbiome predicts subsequent development of CLAD, but whether lung bacteria differ between CLAD phenotypes is unknown. <h3>Methods</h3> Using a biorepository of acellular bronchoalveolar lavage (BAL) fluid, we identified specimens which were collected within 90 days of CLAD onset. CLAD phenotype was assigned based on the presence of absence of obstruction, restriction, and computed tomography (CT) scan opacities, in accordance with ISHLT guidelines. Bacterial DNA burden was measured with BioRad QX200 Droplet Digital PCR and 16S rRNA gene sequencing was performed using the Illumina MiSeq platform. Bacterial burden was compared using Wilcoxon rank-sum. Community composition was compared using PERMANOVA and <i>mvabund</i> (a model-based approach to analysis of multivariable abundance data). <h3>Results</h3> Eighty (80) patients had a BAL specimen from near CLAD onset available for analysis. Of these, 41 (51%) had BOS, 13 (16%) had RAS, 6 (8%) had Mixed CLAD, and 20 (25%) had an undefined/unclassifiable phenotype. There were no differences in lung bacterial burden (<i>p</i>=0.56, Panel A) or overall community composition between CLAD phenotypes (<i>p</i>=0.53, Panel C). Shannon diversity index did differ between CLAD phenotypes, with lower average diversity observed in the patients with an unclassifiable CLAD phenotype (1.0 ± 0.4) vs. BOS (2.2 ± 0.8), RAS (2.1 ± 0.8), Mixed (2.1 ± 0.7), or undefined CLAD (2.1 ± 0.4, overall <i>p</i>=0.02, Panel B). This difference persisted even after accounting for clinical evidence of infection (BAL neutrophilia and bacterial culture results did not differ between groups). <h3>Conclusion</h3> Lung microbiome characteristics are largely similar across CLAD phenotypes, although lower within-specimen diversity is seen in patients with unclassified CLAD.

Electronic Nose for Distinguishing Chronic Lung Allograft Dysfunction Phenotypes

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) increases risk of death of lung transplant recipients (LTR). Although the main CLAD phenotypes bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) differ in spirometric and radiological characteristics, establishing the final diagnosis can be challenging. Yet, differentiation between BOS and RAS is crucial, since prognosis of the phenotypes considerably differs. Timely diagnosis of CLAD and CLAD phenotypes remains problematic due to a lack of accurate markers of CLAD. Promising evidence suggests that electronic nose (eNose) technology has 86% accuracy for the detection of CLAD and may even identify CLAD phenotype. Therefore, we aimed to assess the diagnostic accuracy of exhaled breath analysis using an eNose to distinguish between CLAD phenotypes. <h3>Methods</h3> In `this cross-sectional study, exhaled breath of consecutive LTR with ISHLT criteria based CLAD was collected using an eNose (SpiroNose). Patients with mixed or undefined phenotype were excluded (n = 13). Statistical analyses were conducted using partial least square discriminant analysis and receiver operating characteristics (AUC) analysis to assess differences in breathprint between CLAD phenotypes. <h3>Results</h3> A total of 25 LTR with CLAD were included during outpatient follow-up. 56% were male, median age was 63 (range 32 - 77) years, time after LTx was 9.7 (2.5 - 18.8) years, and time till onset of CLAD was 5.8 (1.7 - 18.8) years. Based on ISHLT criteria, 20 LTR were diagnosed with BOS, and 5 with RAS. The eNose accurately discriminated between BOS and RAS with an AUC of 0.94 (CI 0.85-1.00, Figure 1), a sensitivity of 100%, specificity of 90%, and an accuracy of 92%. <h3>Conclusion</h3> The BOS and RAS phenotype differ in breathprint. Exhaled breath analysis using an eNose is a promising tool to distinguish between CLAD phenotypes. Validation of results is needed in a larger dataset, as well as assessment whether this technique allows earlier diagnosis of CLAD and its phenotype.

Characteristics of AMR Predicts Prognosis and Phenotype of CLAD

<h3>Purpose</h3> Antibody mediated rejection (AMR) has been linked to development of chronic lung allograft dysfunction (CLAD) either bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). It has never been assessed if AMR characteristics could predict evolution towards a phenotype of CLAD and post-treatment outcomes. <h3>Methods</h3> Data from patients treated for AMR in our center with antibody depleting therapy (ADT) (plasma exchange, high dose corticosteroids, rituximab and intravenous immunoglobulin) were reviewed. We subsequently distinguished patients presenting with late acute graft failure (LAGF) or not. LAGF was defined as acute allograft failure associated with radiological or histopathological signs compatible with acute fibrinous and organizing pneumonia (AFOP), diffuse alveolar damage (DAD) or organizing pneumonia (OP). Evolution towards CLAD and survival was investigated using Fisher's exact test and Kaplan-Meier survival curve with log-rank test. Predictive factors of death after treatment were analyzed using multiple stepwise logistic regression. <h3>Results</h3> Forty eight patients were treated with ADT for AMR. At baseline, 67% presented with CLAD (38% BOS, 44% RAS, 18% mixed). 71% presented with a clinical picture of LAGF while 29% did not. After ADT, for patients who survived long enough for reevaluation (n=42), there was a majority of patients who evolved towards a CLAD phenotype BOS in the group without LAGF (BOS n=9, RAS n=4, no CLAD n=1) and towards CLAD phenotype RAS in the LAGF group (BOS n=6, RAS n=21, no CLAD n=1) (P = 0.0148). Kaplan-Meier survival curves displayed lower survival for patients with AMR and LAGF versus patients with AMR without LAGF (P=0.0335) (figure 1). Multivariate analysis showed that LAGF (P=0.0388) and acute respiratory failure (P=0.0040) were independent predictive factors for death. <h3>Conclusion</h3> AMR may present in two distinct phenotypes: one with LAGF which evolves towards RAS with poor prognosis and a second without LAGF which evolves towards BOS with better outcomes after ADT.

Chronic lung allograft dysfunction phenotype and prognosis by machine learning CT analysis.

Chronic lung allograft dysfunction (CLAD) is the principal cause of graft failure in lung transplant recipients and prognosis depends on CLAD phenotype. We used a machine learning computed tomography (CT) lung texture analysis tool at CLAD diagnosis for phenotyping and prognostication compared with radiologist scoring. This retrospective study included all adult first double lung transplant patients (January 2010-December 2015) with CLAD (censored December 2019) and inspiratory CT near CLAD diagnosis. The machine learning tool quantified ground-glass opacity, reticulation, hyperlucent lung and pulmonary vessel volume (PVV). Two radiologists scored for ground-glass opacity, reticulation, consolidation, pleural effusion, air trapping and bronchiectasis. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of machine learning and radiologist for CLAD phenotype. Multivariable Cox proportional hazards regression analysis for allograft survival controlled for age, sex, native lung disease, cytomegalovirus serostatus and CLAD phenotype. 88 patients were included (57 bronchiolitis obliterans syndrome (BOS), 20 restrictive allograft syndrome (RAS)/mixed and 11 unclassified/undefined) with CT a median 9.5 days from CLAD onset. Radiologist and machine learning parameters phenotyped RAS/mixed with PVV as the strongest indicator (area under the curve (AUC) 0.85). Machine learning hyperlucent lung phenotyped BOS using only inspiratory CT (AUC 0.76). Radiologist and machine learning parameters predicted graft failure in the multivariable analysis, best with PVV (hazard ratio 1.23, 95% CI 1.05-1.44; p=0.01). Machine learning discriminated between CLAD phenotypes on CT. Both radiologist and machine learning scoring were associated with graft failure, independent of CLAD phenotype. PVV, unique to machine learning, was the strongest in phenotyping and prognostication.

Novel biomarkers of chronic lung allograft dysfunction: is there anything reliable?

Chronic lung allograft dysfunction (CLAD) remains a major barrier preventing long-term survival following lung transplantation. As our clinical knowledge regarding its definition and presentation has significantly improved over the last years, adequate biomarkers to predict development of CLAD, phenotype of CLAD or prognosis post-CLAD diagnosis are definitely needed. Radiological and physiological markers are gradually entering routine clinical practice. In-depth investigation of biological samples including broncho-alveolar lavage, biopsy and serum has generated potential biomarkers involved in fibrogenesis, airway injury and inflammation but none of these are universally accepted or implemented although progress has been made, specifically regarding donor-derived cell-free DNA and donor-specific antibodies. Although a lot of promising biomarkers have been put forward, a very limited number has made it to routine clinical practice. Nevertheless, a biomarker that leads to earlier detection or more adequate disease phenotyping would advance the field enormously.

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.

Potential novel biomarkers for chronic lung allograft dysfunction and azithromycin responsive allograft dysfunction

Chronic Lung Allograft Dysfunction (CLAD), manifesting as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS), is the main reason for adverse long-term outcome after Lung Transplantation (LTX). Until now, no specific biomarkers exist to differentiate between CLAD phenotypes. Therefore, we sought to find suitable cytokines to distinguish between BOS, RAS and Azithromycin Responsive Allograft Dysfunction (ARAD); and reveal potential similarities or differences to end-stage fibrotic diseases. We observed significantly increased Lipocalin-2 serum concentrations in RAS compared to BOS patients. In addition, in RAS patients immunohistochemistry revealed Lipocalin-2 expression in bronchial epithelium and alveolar walls. Patients with ARAD showed significantly lower Activin-A serum concentrations compared to Stable-LTX and BOS patients. Further, increased serum concentrations of Lipocalin-2 and Activin-A were predictors of worse freedom-from-CLAD in Stable-LTX patients. These biomarkers serve as promising serum biomarkers for CLAD prediction and seem suitable for implementation in clinical practice.

Risk Assessment of Chronic Lung Allograft Dysfunction Phenotypes after Living-Donor Lobar Lung Transplantation According to the 2019 ISHLT Classification System

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is known as one of the major fatal disorders in the long-term phase after lung transplantation. Because CLAD is a heterogeneous disease, proper classification of phenotypes is important to understand each pathogenesis. In this study, we retrospectively evaluated the impact of new 2019 ISHLT classification system on living-donor lobar lung transplantation (LDLLT). <h3>Methods</h3> Between 1998 and 2019, a total of 96 patients underwent LDLLT at our hospital, and 73 patients who underwent bilateral LDLLT were included in this study. CLAD after bilateral LDLLT were diagnosed and classified according to the ISHLT consensus report in 2019. <h3>Results</h3> The median follow-up time was 10.3 years. A total of 27 (37.0%) patients were diagnosed as CLAD, including bronchiolitis obliterans syndrome (BOS) (n = 8, 29.6%), restrictive allograft syndrome (RAS) (n = 11, 40.7%), mixed (n = 1, 3.7%), undefined (n = 2, 7.4%), and unclassified (n = 5, 18.5%). CLAD developed in the unilateral lung in 26 patients. Five-year survival of the patients developing CLAD after LDLLT was 84.1%, whereas 5-year survival of the patients after CLAD onset was 58.4%. Survival after CLAD onset was worse in the patients with RAS (p=0.008) and undefined (p=0.003) than those with BOS. Though survival after CLAD onset did not differ between the patients with or without CT opacities (p=0.40), the patients with restriction on pulmonary function test had significantly worse survival than those without restriction (Figure, p=0.001). <h3>Conclusion</h3> While the patients with BOS had better prognosis, the presence of restriction on pulmonary function test could predict worse prognosis of the CLAD patients after bilateral LDLLT.

A Comparison of Serological Markers and Exosome Content between Lung Transplant Recipients with BOS and RAS

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is a common cause of death among lung transplant recipients (LTxRs). Two phenotypes of CLAD have been recognized; bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), each with distinct clinical presentations, radiologic features, and prognosis. We have demonstrated increased levels of circulating exosomes containing lung self-antigens (SAgs), transcription factors, co-stimulatory molecules, and microRNA (miRNA) in LTxRs with BOS. Goal is to determine immunologic and molecular differences between LTxRs with BOS and RAS. <h3>Methods</h3> Antibodies (Abs) to SAgs (Kα1Tubulin, Collagen V) were identified using ELISA from LTxRs with BOS (n=12) and RAS (n=8). Donor specific antibodies (DSA) to HLA-DR, DQ were quantified using Luminex single antigen. Exosomes were isolated using ultracentrifugation, purified by 0.2µ filtration followed by size determination by Nanosight. Exosome contents were determined by western blot with Abs to SAgs, NFkB, 20S proteasome, HLA-DQ, DR, and poly immunoglobulin receptor protein (PIGR). Nanostring was done to identify miRNAs. <h3>Results</h3> Three of 12 (25.0%) LTxRs with BOS, 1 of 8 (12.5%) with RAS developed Abs against SAgs (p=0.0027). All 8 (100%) LTxRs with RAS, 5 (41.7%) with BOS developed DSA to HLA-DR, DQ (p<0.0001). Compared to stable, all patients with CLAD contained exosomes with increased SAgs, NFkB, CIITA, 20S proteasome, PIGR, HLA-DQ, DR. However, there were significant quantitative differences between LTxRs with BOS and RAS (Table 1). In addition, miRNA profiling showed a higher concentration of 5 different miRNAs in LTxRs with BOS and 9 different miRNAs in LTxRs with RAS. miRNAs in BOS and RAS are related to TGF-β signaling pathways. <h3>Conclusion</h3> This study demonstrates that Abs to SAgs, DSA to HLA DR, DQ, and exosome content differs between LTxRs with BOS and RAS. These differences suggest that humoral immunity may play a prominent role in the pathogenesis of RAS compared to BOS.

Twelve-month effects of everolimus on renal and lung function in lung transplantation: differences in chronic lung allograft dysfunction phenotypes.

Background:Chronic lung allograft dysfunction (CLAD), a complication affecting the survival of lung transplanted patients, includes two clinical phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Everolimus is used in CLAD because of its antiproliferative mechanism. In lung transplant patients treated with everolimus, the clinical course of renal and lung function has not yet been assessed systematically in CLAD, BOS and RAS patients for more than 6 months.Methods:We retrospectively evaluated the 12-month follow-up of renal and lung function of lung-transplanted patients switched to everolimus and evaluated the reduction in immunosuppressant dosage (ISD) and mortality. Subgroups were based on indication for everolimus treatment: CLAD and non-CLAD patients, BOS and RAS among CLAD patients.Results:We included 26 patients, 17 with CLAD (10 BOS, seven RAS). After 1 year from the everolimus switch, we observed renal function improvement (serum creatinine −17%, estimated glomerular filtration rate +24%) and stable pulmonary function [forced expiratory volume in the first second (FEV1) −0.5%, forced vital capacity (FVC) +0.05%]. RAS patients had progressive functional loss, whereas BOS patients had FEV1 improvement and FVC stability. All-cause mortality was higher in the CLAD versus non-CLAD group (41% versus 11%), without differences between BOS and RAS patients (p > 0.05). All patients had significant and persistent ISD reduction.Conclusion:Lung transplant patients treated with everolimus had improvements in renal function and reduced ISD. We observed sustained improvements in lung function for CLAD related to BOS subgroup results, whereas RAS confirmed the 1-year worsening functional trend. Data seem to suggest one more piece of the puzzle in CLAD phenotyping.

Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction

Chronic lung allograft dysfunction (CLAD) is the major complication limiting long-term survival in lung transplant recipients (LTRs), with those developing donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) previously found to have increased risk for CLAD. However, as DSA responses vary in timing of development, specificity, breadth, persistence, and complement-binding capacity, we hypothesized that these characteristics would impact CLAD and survival outcomes. We retrospectively analyzed DSA characteristics and outcomes in a single-center cohort of 582 LTRs who had serum samples collected prospectively from 2010 to 2016. Luminex-based single antigen bead assays were performed to assess DSA. DSAs were detected in 247 LTRs (42%), of which 124 (21.3%) were de novo DSAs and 53 (9.1%) were complement-binding (C1q+). CLAD developed in 208 LTRs (35.7%) during the follow-up period, with 67.8% determined as bronchiolitis obliterans syndrome phenotype and 32.2% as restrictive allograft syndrome phenotype. We found a shorter time to CLAD in LTRs with persistent DSAs (p = 0.04) and HLA-DQ-specific DSAs (p = 0.03). LTRs who developed C1q+ DSAs had significantly shorter time to CLAD (p < 0.001), with 100% of C1q+ DSAs being persistent and no differences between CLAD phenotypes. CLAD-free survival was significantly reduced in LTRs who developed C1q+ DSAs (p = 0.001), HLA-DQ-specific DSAs (p = 0.03), and multiple DSAs (p = 0.02). Together, our findings demonstrate that DSA characteristics of persistence, HLA-DQ specificity, and C1q+ DSAs are associated with shorter time to CLAD. Additionally, C1q+, HLA-DQ-specific, and multiple DSAs are associated with decreased CLAD-free survival. These characteristics may improve DSA risk stratification for deleterious outcomes in LTRs.

Risk assessment of chronic lung allograft dysfunction phenotypes: Validation and proposed refinement of the 2019 International Society for Heart and Lung Transplantation classification system

Chronic lung allograft dysfunction (CLAD) is a heterogeneous condition. Characterization of CLAD phenotypes is essential to enhance the understanding of pathogenesis and guide new therapies. The study objective was to validate the new International Society for Heart and Lung Transplantation (ISHLT) CLAD classification system and further explore patients who do not fall into the defined CLAD sub-categories. We performed a single-center, retrospective cohort study of adult, first, bilateral lung transplants performed from 2010 to 2015. Patients with CLAD were classified on the basis of the 2019 ISHLT consensus document. CLAD phenotypes and other potential predictors of survival after CLAD onset were assessed using Kaplan-Meier and Cox proportional hazards models. Among the 174 subjects with CLAD, 104 (59.8%) had bronchiolitis obliterans syndrome (BOS), 16 (9.2%) restrictive allograft syndrome (RAS), 9 (5.2%) mixed, and 19 (10.9%) undefined phenotype. A total of 26 patients (14.9%) did not match any of these 4 categories and remained unclassified. Allograft survival post-CLAD onset was longer for patients with BOS (median, 500 days) than patients with RAS (median, 372 days) or mixed (median, 328 days). The 45 patients (26.8%) with undefined/unclassified phenotype were combined and recategorized on the basis of the presence or absence of characteristic RAS-like opacities on chest imaging; those with RAS-like opacities had significantly worse allograft survival than patients with BOS (hazard ratio, 2.14; 95% confidence interval, 1.17-3.93; p = 0.014) and similar survival to RAS or mixed phenotype. The new ISHLT CLAD phenotype classification is informative with regards to post-CLAD outcomes. Chest imaging demonstrating persistent parenchymal or pleural fibrosis may be used for risk-stratification of patients who do not match the major CLAD phenotypes.

When tissue is the issue: A histological review of chronic lung allograft dysfunction.

Although chronic lung allograft dysfunction (CLAD) remains the major life-limiting factor following lung transplantation, much of its pathophysiology remains unknown. The discovery that CLAD can manifest both clinically and morphologically in vastly different ways led to the definition of distinct subtypes of CLAD. In this review, recent advances in our understanding of the pathophysiological mechanisms of the different phenotypes of CLAD will be discussed with a particular focus on tissue-based and molecular studies. An overview of the current knowledge on the mechanisms of the airway-centered bronchiolitis obliterans syndrome, as well as the airway and alveolar injuries in the restrictive allograft syndrome and also the vascular compartment in chronic antibody-mediated rejection is provided. Specific attention is also given to morphological and molecular markers for early CLAD diagnosis or histological changes associated with subsequent CLAD development. Evidence for a possible overlap between different forms of CLAD is presented and discussed. In the end, "tissue remains the (main) issue," as we are still limited in our knowledge about the actual triggers and specific mechanisms of all late forms of posttransplant graft failure, a shortcoming that needs to be addressed in order to further improve the outcome of lung transplant recipients.