Chronic Lung Allograft Dysfunction Research Articles

Extracorporeal photopheresis (ECP) in the treatment of chronic lung allograft dysfunction (CLAD): a prospective, multicentre, open-label, randomised controlled trial studying the addition of ECP to standard care in the treatment of bilateral lung transplant patients with CLAD (E-CLAD UK)

BackgroundLong-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop...

Everolimus Treatment for Chronic Lung Allograft Dysfunction in Lung Transplantation

Our study aims to evaluate the effect of everolimus treatment on lung function in lung transplant (LT) patients with established chronic lung allograft dysfunction (CLAD). Methods: This retrospective study included LT patients in two reference LT units who started everolimus therapy to treat CLAD from October 2008 to October 2016. We assessed the variation in the maximum forced expiratory volume in the first second (FEV1) before and after the treatment. Results: Fifty-seven patients were included in this study. The variation in the FEV1 was −102.7 (149.6) mL/month before starting everolimus compared to −44.7 (109.6) mL/month within the first three months, +1.4 (63.5) mL/month until the sixth month, and −7.4 (46.2) mL/month until the twelfth month (p < 0.05). Glomerular filtrate remained unchanged after everolimus treatment [59.1 (17.5) mL/min per 1.73 m2 at baseline and 60.9 (19.6) mL/min per 1.73 m2, 57.7 (20.5) mL/min per 1.73 m2, and 57.3 (17.8) mL/min per 1.73 m2, at 1, 3, and 6 months, respectively] (p > 0.05). Everolimus was withdrawn in 22 (38.6%) patients. The median time to withdrawal was 14.1 (5.5–25.1) months. Conclusions: This study showed an improvement in FEV1 decline in patients with CLAD treated with everolimus. However, the drug was withdrawn in a high proportion of patients.

Impact of Transient and Persistent Donor-Specific Antibodies in Lung Transplantation

Lung transplantation (LuTx) is an established treatment for patients with end-stage lung diseases, however, outcomes are limited by acute and chronic rejection. One aspect that has received increasing attention is the role of the host’s humoral alloresponse, particularly the formation of de novo donor-specific antibodies (dnDSAs). The aim of this study was to investigate the clinical significance of transient and persistent dnDSAs and to understand their impact on outcomes after LuTx. A retrospective analysis was conducted using DSA screening data from LuTx recipients obtained at the Medical University of Vienna between February 2016 and March 2021. Of the 405 LuTx recipients analyzed, 205 patients developed dnDSA during the follow-up period. Among these, 167 (81%) had transient dnDSA and 38 (19%) persistent dnDSA. Persistent but not transient dnDSAs were associated with chronic lung allograft dysfunction (CLAD) and antibody-mediated rejection (AMR) (p < 0.001 and p = 0.006, respectively). CLAD-free survival rates for persistent dnDSAs at 1-, 3-, and 5-year post-transplantation were significantly lower than for transient dnDSAs (89%, 59%, 56% vs. 91%, 79%, 77%; p = 0.004). Temporal dynamics of dnDSAs after LuTx have a substantial effect on patient outcomes. This study underlines that the persistence of dnDSAs poses a significant risk to graft and patient survival.

The gut microbiome in end-stage lung disease and lung transplantation.

Gut dysbiosis has been associated with impaired outcomes in liver and kidney transplant recipients, but the gut microbiome of lung transplant recipients has not been extensively explored. We assessed the gut microbiome in 64 fecal samples from end-stage lung disease patients before transplantation and 219 samples from lung transplant recipients after transplantation using metagenomic sequencing. To identify dysbiotic microbial signatures, we analyzed 243 fecal samples from age-, sex-, and BMI-matched healthy controls. By unsupervised clustering, we identified five groups of lung transplant recipients using different combinations of immunosuppressants and antibiotics and analyzed them in relation to the gut microbiome. Finally, we investigated the gut microbiome of lung transplant recipients in different chronic lung allograft dysfunction (CLAD) stages and longitudinal gut microbiome changes after transplantation. We found 108 species (58.1%) in end-stage lung disease patients and 139 species (74.7%) in lung transplant recipients that were differentially abundant compared with healthy controls, with several species exhibiting sharp longitudinal increases from before to after transplantation. Different combinations of immunosuppressants and antibiotics were associated with specific gut microbial signatures. We found that the gut microbiome of lung transplant recipients in CLAD stage 0 was more similar to healthy controls compared to those in CLAD stage 1. Finally, the gut microbial diversity of lung transplant recipients remained lower than the average gut microbial diversity of healthy controls up to more than 20 years post-transplantation. Gut dysbiosis, already present before lung transplantation was exacerbated following lung transplantation.IMPORTANCEThis study provides extensive insights into the gut microbiome of end-stage lung disease patients and lung transplant recipients, which warrants further investigation before the gut microbiome can be used for microbiome-targeted interventions that could improve the outcome of lung transplantation.

Flexible bronchoscopy in pediatric lung transplantation.

Pediatric lung transplantation represents a treatment option for children with advanced lung disease or pulmonary vascular disorders who are deemed an appropriate candidate. Pediatric flexible bronchoscopy is an important and evolving field that is highly relevant in the pediatric lung transplant population. It is thus important to advance our knowledge to better understand how care for children after lung transplant can be maximally optimized using pediatric bronchoscopy. Our goals are to continually improve procedural skills when performing bronchoscopy and to decrease the complication rate while acquiring adequate samples for diagnostic evaluation. Attainment of these goals is critical since allograft assessment by bronchoscopic biopsy is required for histological diagnosis of acute cellular rejection and is an important contributor to establishing chronic lung allograft dysfunction, a common complication after lung transplant. Flexible bronchoscopy with bronchoalveolar lavage and transbronchial lung biopsy plays a key role in lung transplant graft assessment. In this article, we discuss the application of bronchoscopy in pediatric lung transplant evaluation including historical approaches, our experience, and future directions not only in bronchoscopy but also in the evolving pediatric lung transplantation field. Pediatric flexible bronchoscopy has become a vital modality for diagnosing lung transplant complications in children as well as assessing therapeutic responses. Herein, we review the value of flexible bronchoscopy in the management of children after lung transplant and discuss the application of novel techniques to improve care for this complex pediatric patient population and we provide a brief update about new diagnostic techniques applied in the growing lung transplantation field.

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.

Extreme elevations of donor-derived cell-free DNA increases the risk of chronic lung allograft dysfunction and death, even without clinical manifestations of disease.

Lung transplant recipients are traditionally monitored with pulmonary function testing (PFT) and lung biopsy to detect post-transplant complications and guide treatment. Plasma donor-derived cell free DNA (dd-cfDNA) is a novel molecular approach of assessing allograft injury, including subclinical allograft dysfunction. The aim of this study was to determine if episodes of extreme molecular injury (EMI) in lung transplant recipients increases the risk of CLAD or death. This multicenter prospective cohort study included 238 lung transplant recipients. Serial plasma samples were collected for dd-cfDNA measurement by shotgun sequencing. EMI was defined as a dd-cfDNA above the third quartile of levels observed for acute rejection (dd-cfDNA level of ≥ 5% occurring after 45 days post-transplant). EMI was categorized as Secondary if associated with co-existing acute rejection, infection or PFT decline; or Primary if not associated to these conditions. EMI developed in 16% of patients at a median 343.5 (IQR: 177.3-535.5) days post-transplant. Over 50% of EMI episodes were classified as Primary. EMI was associated with an increased risk of severe CLAD or death (HR: 2.52, 95% CI: 1.10 - 3.82, p= 0.024). The risk remained consistent for Primary EMI (HR: 2.34, 95% CI 1.18-4.85, p=0.015). Time to first EMI episode was a significant predictor of the likelihood of developing CLAD or death (AUC=0.856, 95% CI =.805-908, p<.001). Episodes of EMI in lung transplant recipients are often isolated and not detectable with traditional clinical monitoring approaches. EMI is associated with an increased risk of severe CLAD or death, independent of concomitant transplant complications.

Impaired esophagogastric junction relaxation and lung transplantation outcomes.

The implications of impaired esophagogastric junction relaxation (i.e. esophagogastric junction outflow obstruction and achalasia) in lung transplants recipients (LTRs) are unclear. Thus, we examined the prevalence and clinical outcomes of LTRs with an abnormally elevated integrated relaxation pressure (IRP) on high-resolution manometry before lung transplantation (LTx). After IRB approval, we reviewed data on LTRs who underwent LTx between January 2019 and August 2022 with a preoperative median IRP >15mmHg. Differences in overall survival and chronic lung allograft dysfunction (CLAD)-free survival between LTRs with a normalized median IRP after LTx (N-IRP) and those with persistently high IRP (PH-IRP) were assessed using Kaplan-Meier curves and the log-rank test. During the study period, 352 LTx procedures were performed; 44 (12.5%) LTRs had an elevated IRP before LTx, and 37 (84.1%) completed a postoperative manometry assessment (24 [70.6%] males; mean age, 65.2 ± 9.1years). The median IRP before and after LTx was 18.7 ± 3.8mmHg and 12 ± 5.6mmHg, respectively (P < 0.001); the median IRP normalized after LTx in 24 (64.9%) patients. Two-year overall survival trended lower in the N-IRP group than the PH-IRP group (77.2% vs. 92.3%, P =0.086), but CLAD-free survival (P =0.592) and rates of primary graft dysfunction (P =0.502) and acute cellular rejection (P =0.408) were similar. An abnormally elevated IRP was common in LTx candidates; however, it normalized in roughly two-thirds of patients after LTx. Two-year survival trended higher in the PH-IRP group, despite similar rates of primary graft dysfunction and acute cellular rejection as well as similar CLAD-free survival between the groups.

The nature of chronic rejection after lung transplantation: a murine orthotopic lung transplant study.

Chronic rejection is a major complication post-transplantation. Within lung transplantation, chronic rejection was considered as airway centred. Chronic Lung Allograft Dysfunction (CLAD), defined to cover all late chronic complications, makes it more difficult to understand chronic rejection from an immunological perspective. This study investigated the true nature, timing and location of chronic rejection as a whole, within mouse lung transplantation. 40 mice underwent an orthotopic left lung transplantation, were sacrificed at day 70 and evaluated by histology and in vivo µCT. For timing and location of rejection, extra grafts were sacrificed at day 7, 35, 56 and investigated by ex vivo µCT or single cell RNA (scRNA) profiling. Chronic rejection originated as innate inflammation around small arteries evolving toward adaptive organization with subsequent end-arterial fibrosis and obliterans. Subsequently, venous and pleural infiltration appeared, followed by airway related bronchiolar folding and rarely bronchiolitis obliterans was observed. Ex vivo µCT and scRNA profiling validated the time, location and sequence of events with endothelial destruction and activation as primary onset. Against the current belief, chronic rejection in lung transplantation may start as an arterial response, followed by responses in venules, pleura, and, only in the late stage, bronchioles, as may be seen in some but not all patients with CLAD.

Advances in lung transplantation: 60 years on.

Lung transplantation is a well-established treatment for advanced lung disease, improving survival and quality of life. Over the last 60 years all aspects of lung transplantation have evolved significantly and exponential growth in transplant volume. This has been particularly evident over the last decade with a substantial increase in lung transplant numbers as a result of innovations in donor utilization procurement, including the use donation after circulatory death and ex-vivo lung perfusion organs. Donor lungs have proved to be surprisingly robust, and therefore the donor pool is actually larger than previously thought. Parallel to this, lung transplant outcomes have continued to improve with improved acute management as well as microbiological and immunological insights and innovations. The management of lung transplant recipients continues to be complex and heavily dependent on a tertiary care multidisciplinary paradigm. Whilst long term outcomes continue to be limited by chronic lung allograft dysfunction improvements in diagnostics, mechanistic understanding and evolutions in treatment paradigms have all contributed to a median survival that in some centres approaches 10 years. As ongoing studies build on developing novel approaches to diagnosis and treatment of transplant complications and improvements in donor utilization more individuals will have the opportunity to benefit from lung transplantation. As has always been the case, early referral for transplant consideration is important to achieve best results.

Iatrogenic esophageal dysmotility as a barrier to transplantation in pulmonary arterial hypertension

Esophageal dysmotility is identified as a contraindication to lung transplantation at some centers due to increased risks of acute rejection, pulmonary infection, and chronic lung allograft dysfunction. Phosphodiesterase-type 5 inhibitors (PDE5i) are a cornerstone pharmacotherapy for pulmonary arterial hypertension (PAH) and are known to exert off-target effects that may impact lung transplant candidacy, including impaired esophageal contractility and decreased lower esophageal sphincter tone. We report two patients with PAH who were initially declined listing for lung transplantation due to iatrogenic esophageal dysmotility induced by PDE5is. Upon discontinuation of PDE5i therapy, these patients experienced significant improvement in esophageal motility within 14 days and met criteria for transplant listing at their centers. Recognizing and mitigating the off-target effects of PDE5i medications is critical for maximizing access to transplant for patients with PAH.

Rehabilitative goals for patients undergoing lung retransplantation.

Lung retransplantation (LRT) involves a second or subsequent lung transplant (LT) in a patient whose first transplanted graft has failed. LRT is the only treatment option for irreversible lung allograft failure caused by acute graft failure, chronic lung allograft dysfunction, or postoperative complications of bronchial anastomosis. Prehabilitation (rehabilitation before LT), while patients are on the waiting list, is recognized as an essential component of the therapeutic regimen and should be offered throughout the waiting period from the moment of listing until transplantation. LRT is particularly fraught with challenges, and prehabilitation to reduce frailty is one of the few opportunities to address modifiable risk factors (such as functional and motor impairments) in a patient population in which there is clearly room to improve outcomes. Although rehabilitative outcomes and quality of life in patients receiving or awaiting LT have gained increased interest, there is a paucity of data on rehabilitation in patients undergoing LRT. Frailty is one of the few modifiable risk factors of retransplantation that is potentially preventable. As such, it is imperative that professionals involved in the field of retransplantation conduct research specifically exploring rehabilitative techniques and outcomes of value for patients receiving LRT, because this area remains unexplored.

Malignancy risk and mortality after lung transplantation: A single-institution experience over 31 years

BackgroundMalignancy is a long-term complication of lung transplantation (LTx); however, contemporary Australian data and detailed evaluation of non-reportable cancers are lacking. MethodsRetrospective review of LTx recipients’ medical records and registry data linkage were performed to identify histologically proven malignancies. Baseline clinico-demographic variables were collected, and cancer incidence was compared with reported data for the general Australian population. ResultsThere were 1,715 LTx in 1,631 patients between 1989-2021, with a follow-up of 9,696 person-years. 893 (54.8%) patients were male, and the median age at first LTx was 54.7 years. There were 886 deaths with a median overall survival of 7.5 years (95% CI 6.8-8.3 years). 1,774 separate invasive cancer events occurred across 407 patients, of which, 1,588 (89.5%) were non-melanoma skin cancers (NMSCs). This translated to a 9-fold increased incidence of NMSCs, and a 4-fold increased incidence of other cancers compared with the general population. Cancer mortality reached parity with chronic lung allograft dysfunction ten years post-first transplant, and was independently associated with age (HR per year increase in age 1.02 [95% CI 1.01-1.03], p=0.001), EBV primary mismatch (HR 3.24 [95% CI 1.68-6.25], versus non-mismatch, p=0.002) and cancer count (HR per cancer event 1.19 [95% CI 1.13-1.24], p<0.0001), but was not associated with a pre-transplant malignancy history. ConclusionsOur 31-year single-center experience demonstrates that malignancies are a significant mortality burden to long-term LTx survivors, dominated by NMSCs that are poorly reported in cancer datasets. A history of pre-transplant malignancy was associated with shorter time to post-transplant malignancy, but was not associated with cancer death.

Spectrum of chronic lung allograft dysfunction pathology in human lung transplantation

BackgroundLong-term survival after lung transplantation (LTx) remains limited by Chronic Lung Allograft Dysfunction (CLAD), which includes two main phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), with possible overlap. We aimed to detail and quantify pathological features of these CLAD sub-types. MethodsPeripheral and central paraffin-embedded explanted lung samples were obtained from 20 consecutive patients undergoing a second LTx for CLAD, from 3 lobes. Thirteen lung samples, collected from non-transplant lobectomies or donor lungs, were used as controls. Blinded semi-quantitative grading was performed to assess airway fibrotic changes, parenchymal and pleural fibrosis, as well as epithelial and vascular abnormalities. ResultsCLAD lung samples had higher scores for all airway- and lung-related parameters compared to controls. There was a notable overlap in pathological scores between BOS and RAS, with a wide range of scores in both conditions. Parenchymal and vascular fibrosis scores were significantly higher in RAS compared to BOS (p=0.003 for both). We observed a significant positive correlation between the degree of inflammation around each airway, the severity of epithelial changes and airway fibrosis. Immunofluorescence staining demonstrated a trend towards a lower frequency of club cells in CLAD, and a higher frequency of apoptotic club cells in BOS samples (p=0.01). ConclusionsCLAD is a spectrum of airway, parenchymal, and pleural fibrosis, as well as epithelial, vascular, and inflammatory pathological changes, where BOS and RAS overlap significantly. Our semi-quantitative grading score showed a generally high inter-reader reliability and may be useful for future CLAD pathological assessments.

(614) - Radiographic Phenotypes and Inter-Rater Agreement at Chronic Lung Allograft Dysfunction (CLAD) Onset

(614) - Radiographic Phenotypes and Inter-Rater Agreement at Chronic Lung Allograft Dysfunction (CLAD) Onset

(120) - Airway Oscillometry Reactance Area Provides Independent Prognostication for Graft Loss in Recipients with Chronic Lung Allograft Dysfunction

(120) - Airway Oscillometry Reactance Area Provides Independent Prognostication for Graft Loss in Recipients with Chronic Lung Allograft Dysfunction

(360) - Signs of Aspiration on Lung Allograft Transbronchial Biopsy are Associated with Reflux, Airway Bile Acids, and Chronic Lung Allograft Dysfunction (CLAD)

(360) - Signs of Aspiration on Lung Allograft Transbronchial Biopsy are Associated with Reflux, Airway Bile Acids, and Chronic Lung Allograft Dysfunction (CLAD)

(603) - High-Grade Eosinophils on Diagnostic Transbronchial Biopsy are Associated with Chronic Lung Allograft Dysfunction After Lung Transplantation

(603) - High-Grade Eosinophils on Diagnostic Transbronchial Biopsy are Associated with Chronic Lung Allograft Dysfunction After Lung Transplantation

(687) - Is Chronic Lung Allograft Dysfunction More Common After Lung Transplantation for Pulmonary Complications of Hematopoietic Stem Cell Transplantation?

(687) - Is Chronic Lung Allograft Dysfunction More Common After Lung Transplantation for Pulmonary Complications of Hematopoietic Stem Cell Transplantation?

(606) - Long-Term Maintenance of Pulmonary Function in the Contralateral Unaffected Lung with Chronic Lung Allograft Dysfunction After Bilateral Living-Donor Lobar Lung Transplantation

(606) - Long-Term Maintenance of Pulmonary Function in the Contralateral Unaffected Lung with Chronic Lung Allograft Dysfunction After Bilateral Living-Donor Lobar Lung Transplantation