Antibody-mediated rejection (AMR) is an increasingly recognized form of rejection and cause of graft failure after lung transplantation. AMR has been the focus of extensive research over the past decade. Despite growing awareness and recent advances in our understanding of AMR, outcomes remain dismal with a 2-year survival of only 20%. The International Society for Heart and Lung Transplantation convened a multidisciplinary workgroup of experts in AMR to review the most up-to-date research and clinical experience and to update the 2016 definition. The workgroup was divided into 9 subgroups covering a broad range of topics pertaining to AMR and used the modified Delphi method to synthesize a cohesive summary of the literature. A multidimensional definition was developed to enhance precision by reporting the specific presenting features. This Graft, Antibody, and Pathology (GAP) definition is based on the presence of Graft dysfunction, the presence and characteristics of Antibodies, and Pathological findings. The workgroup emphasized that identifying better treatments for AMR is a critical unmet need and proposed that a more precise definition might allow better management by providing a platform for testing and developing new therapies.

Donor-derived cell-free DNA (dd-cfDNA) is a validated, highly sensitive, plasma molecular biomarker of allograft injury after solid organ transplantation. Robust experiences with dd-cfDNA testing after kidney and heart transplantation have generated interest in this biomarker within the lung transplantation (LTx) community. A growing body of evidence now provides increased insight into dd-cfDNA utility for molecular monitoring of lung allograft health after transplantation. The expanding understanding of lung allograft injury to appropriately frame the advancing role of dd-cfDNA in the evolution of the diagnostic approach after LTx is described. Performance characteristics of both laboratory-based shotgun-sequenced testing from the Genome Transplant Dynamics (GTD) and Genomic Research Alliance for Transplantation (GRAfT) consortia, as well as commercially available central lab-based algorithmic next-generation sequenced dd-cfDNA tests for lung transplant recipients (LTR) (AlloSure, CareDx and Prospera, Natera) are described. Kinetics of dd-cfDNA in LTRs over time, in multiple different clinical scenarios, from several investigator groups are aggregated. Phenotypes of lung allograft injury, such as acute lung allograft dysfunction, and associated dd-cfDNA patterns and performance are identified in alignment with established definitions and evolving molecular injury insights. Certain patterns of molecular injury that may predict long-term outcomes including chronic lung allograft dysfunction and mortality are examined. Lastly, clinical approaches to testing and interpretation of dd-cfDNA results in LTRs, a practical approach to using dd-cfDNA, and a rational framework for interpreting dd-cfDNA results in LTRs are presented.

Solid organ transplantation (SOT) offers people with end-stage organ disease an increased quality of life, which includes the return of fertility and the potential for pregnancy. Although the number of pregnancies has increased, definitive recommendations have been lacking. To address reproductive health in SOT recipients, the American Society of Transplantation Women's Health Community of Practice held a virtual Controversies Conference with subject matter experts gathered to discuss topics of contraception, immunosuppression, and pregnancy in SOT recipients and pregnancy post-living donation. This publication is a synthesis of expert guidance and available data regarding pregnancy management and outcomes after all types of SOTs.

Lung transplantation is indicated for selected patients with advanced pulmonary arterial hypertension (PAH). We used a modified Delphi process to develop recommendations on care of patients with PAH undergoing lung transplantation. This Delphi panel was recruited from the Pulmonary Vascular Research Institute's Innovative Drug Discovery Initiative - Lung Transplantation Workstream, consisting of clinical and research experts in PAH and lung transplantation. In this process, 29 panelists were given open-ended questions, querying topics related to lung transplantation in PAH. A steering group converted the responses into discrete statements. Panelists then rated agreement using a Likert scale in two further survey rounds: -5 (strongly disagree) to 5 (strongly agree). Consensus was defined as mean ≥ 2.5 or ≤ -2.5, with a standard deviation not crossing zero. Consensus was reached on 141 of 223 statements. Notable areas of consensus were for early discussions about transplantation, and agreement with previously published referral and listing criteria. There was agreement that lung transplantation could be offered in sick candidates, including those with concurrent renal or hepatic insufficiency. Bilateral lung transplantation was considered the procedure of choice for most patients, with rare indications for heart-lung transplantation. Consensus on bridging strategies included use of veno-arterial extracorporeal membrane oxygenation and preemptive awake cannulation in those with severe right ventricular dysfunction. Consensus was also achieved on intraoperative use of invasive hemodynamic monitoring, and prolonged postoperative circulatory support guided by hemodynamic response and echocardiography. Patients with PAH undergoing transplantation require specialized management, which differs somewhat from other candidates.

Clinical trials in lung transplantation have been hindered by a lack of clarity on the formulation and significance of endpoints for evaluating therapeutic efficacy. To address this challenge, a multidisciplinary working group from the International Society for Heart and Lung Transplantation developed consensus recommendations on endpoints beyond mortality. These endpoints include primary graft dysfunction (PGD), chronic lung allograft dysfunction (CLAD), acute cellular rejection (ACR), antibody-mediated rejection (AMR), immunosuppression-related complications, patient-reported outcomes (PROs), and pediatric-specific considerations. For each endpoint, a subgroup reviewed measurement best practices, assessed links to clinical benefit, and evaluated the evidence supporting their utility in clinical trial settings. Consensus was established through a Delphi process involving three rounds of voting. This document provides practical guidance for operationalizing these endpoints and outlines their optimal use in clinical trials. By standardizing trial design, these recommendations aim to accelerate the development of urgently needed therapies to improve lung transplantation outcomes.

A working group under the Sensitization in Transplantation: Assessment of Risk initiative was established in 2023 to develop guidelines for analytical and clinical validity of lab-based testing for donor-derived cell-free DNA (dd-cfDNA). Measurement of dd-cfDNA as a minimally invasive marker of allograft injury has become more widely used over the last few years. To date, various technical and quantitation methods have hindered the standardization and interpretation of the results, leading to variability in understanding how to best utilize cell-free DNA in transplantation. Kits are being formulated for local laboratory testing, but we lack an organized framework for laboratory quality assurance. Further, threshold values and methods of measurement have changed over time, indicating that assay sensitivity and clinical relevance are still being refined. Harmonization and reproducibility will be critical as the field moves forward to local laboratory-based testing. The goal of this work group was to review and analyze technical and biological variables and clinical settings that could contribute to disparities in results, which will ultimately influence clinical validity and utility. High-quality, standardized decentralized dd-cfDNA testing is the essential prerequisite for conducting real-world evidence-generating multicenter studies to establish the appropriate context of use for this promising assay.

Lung allograft pathology encompasses a wide spectrum of disorders, with new entities and emerging diagnostic technologies. The main goal of this study was to document pathologists’ current global practices and highlight areas of consensus and divergence worldwide. A 24-item survey was distributed to transplant centers and responses were received from 35 specialists (51% European, 49% non-European). Most centers used both surveillance and symptom-driven assessments (77%), mainly with transbronchial biopsies (86%) and bronchoalveolar lavage (83%). Non-European centers were more likely to adopt digital pathology (OR 3.03), to use donor-derived cell-free DNA (dd-cfDNA) (OR 2.94), and supported large airway sampling (OR 2.27). Larger centers used dd-cfDNA (OR 2.75) more frequently and consider large airway sampling (OR 2.18). Responders largely supported standardized reporting (86%), reintroducing grade AX (94%), and independent bronchial lesion scoring (82%). Most endorsed an “indeterminate” category for acute and chronic rejection. These findings reflect evolving practices in the field and will inform the ongoing revision of the Lung Allograft Pathology Working Classification.

IntroductionPlasma donor-derived cell-free DNA (dd-cfDNA) is an emerging potential tool for diagnosing lung graft injury. This study explored the relevance of dd-cfDNA levels in different graft injuries thoroughly characterized after a well-established multidisciplinary team approach. The usefulness of bronchoalveolar lavage (BAL) dd-cfDNA in complementing detection of allograft injury was also investigated.MethodsPlasma dd-cfDNA was measured by next generation sequence on 127 samples from patients visited consecutively, contemporaneously with a systematic analysis of surveillance transbronchial biopsy by LASHA template, BAL analysis and immunological monitoring.ResultsPatients with immunological injury exhibited the highest plasma dd-cfDNA levels (median 2.67%), with a sensitivity of 100% while patients with non-immunological insults showed a sensitivity of 28%. The combination of BAL with plasma dd-cfDNA improved the sensitivity for detecting non-immunological injury from 28% to 71%. Random forest analysis showed that plasma dd-cfDNA >1% was among the most important variables in predicting death and chronic lung allograft dysfunction.DiscussionOur data suggests that plasma dd-cfDNA is a useful tool for immunological graft injury assessment. The performance of BAL dd-cf DNA needs to be validated on larger case series. The integration of plasma dd-cfDNA with other post-transplant follow-up investigations may allow more sensitive diagnoses and appropriate graft injury management.

TOPIC IMPORTANCE:Lung transplantation (LTx) remains the ultimate treatment for many patients with advanced lung disease. Although the age cutoffs for LTx have been debated due to variable outcomes, the number of LTx procedures performed on patients aged ≥ 65 years has significantly increased in recent decades, reflecting the realities of an aging demographic. This trend underscores the unique management challenges faced by this cohort and highlights the importance of addressing evidence gaps in their perioperative and postoperative care. REVIEW FINDINGS:This literature review highlights that, despite the challenges, recent data indicate favorable outcomes for patients aged ≥ 65 years undergoing LTx. Although this article primarily focuses on postoperative care, it also addresses some perioperative considerations, including the use of extracorporeal life support as well as the choice of the procedure type and donor considerations. It additionally incorporates current knowledge about early and late postoperative complications, including neurologic, cardiovascular, and renal, among others, along with their management strategies and current practice patterns. SUMMARY:In conclusion, this review emphasizes the need to optimize care for older LTx recipients. The evidence regarding ideal management practices for this population is limited. We highlight the necessity for comprehensive postoperative management guidelines and identify key areas for further research to establish evidence-based protocols for this growing demographic.

Background Improved diagnostic testing (DT) of infections may optimize outcomes for solid organ transplant recipients (SOTR), but a comprehensive analysis is lacking.Methods We conducted a systematic literature review across multiple databases, including EMBASE and MEDLINE(R), of studies published between 1 January 2012-11 June 2022, to examine the evidence behind DT in SOTR. Eligibility criteria included the use of conventional diagnostic methods (culture, biomarkers, directed-polymerase chain reaction [PCR]) or advanced molecular diagnostics (broad-range PCR, metagenomics) to diagnose infections in hospitalized SOTR. Bias was assessed using tools such as the Cochrane Handbook and PRISMA 2020.Results Of 2362 studies, 72 were eligible and evaluated heterogeneous SOT populations, infections, biospecimens, DT, and outcomes. All studies exhibited bias, mainly in reporting quality. Median study sample size was 102 (range, 11-1307). Culture was the most common DT studied (N = 45 studies, 62.5%), with positive results in a median of 27.7% (range, 0%-88.3%). Biomarkers, PCR, and metagenomics were evaluated in 7, 19, and 3 studies, respectively; only 6 reported sensitivity, specificity, and positive/negative predictive values. Directed-PCR performed well for targeted pathogens, but only 1 study evaluated broad-range PCR. Metagenomics approaches detected numerous organisms but required clinical adjudication, with too few studies (N = 3) to draw conclusions. Turnaround time was shorter for PCR/metagenomics than conventional diagnostic methods (N = 4 studies, 5.6%). Only 6 studies reported the impact of DT on outcomes like antimicrobial use and length of stay.Conclusions We identified considerable evidence gaps in infection-related DT among SOT, particularly molecular DT, highlighting the need for further research. This systematic literature review (2012-2022) assessed infection diagnostic testing in solid organ transplant recipients. Studies demonstrated wide heterogeneity, lacking data on accuracy and impact on clinical outcomes. Additional studies on novel infection diagnostic testing in solid organ transplant recipients are greatly needed.

BACKGROUND: Pulmonary antibody -mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor -specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody -mediated rejection diagnosis in lung transplant patients. METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody -mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post -transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter -pathologist agreement was assessed. RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody - mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post -lung transplantation complications. Inter - pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclu- sion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased anti- body -mediated rejection certainty levels by 25%. CONCLUSIONS: The study supports the role of the mTOR pathway in antibody -mediated rejection - related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody -mediated rejection. J Heart Lung Transplant 2024;43:403-413 (c) 2023 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference-held in Banff, Alberta-focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and its impact on lung transplant outcomes were discussed. Key conclusions from the discussion were: (1) recognition of limitations in current standard of care assessment of lung allograft dysfunction; (2) agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathologic data, inclusive of all lesions associated with graft outcome (eg, non-rejection pathology); and (3) optimism regarding promising novel diagnostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes.

Background Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. Methods Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus >= 4 WU and <5 WU versus >= 5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. Results Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs( -1)0.3 m). Patients with a PVR of <= 5 WU without a treatment delay had a change of 5.5 m compared with -8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. Conclusion Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.

Pulmonary hypertension (PH) is often present in patients presenting for kidney transplant listing. While PH can complicate kidney transplant (KTx), with multidisciplinary management that includes both the transplant center and pulmonary hypertension center or experts both pre- and post-transplant. This review summaries the approach and management of PH in KTx candidates and recipients, along with expected outcomes and controversies surrounding arteriovenous fistula and graft management.