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.

Background Donor-derived cell-free DNA (dd-cfDNA) has emerged as a biomarker for antibody-mediated rejection (AMR), but its performance characteristics have not been evaluated in a large contemporary heart transplant population. Objectives The study aimed to characterize the incidence and timing of biopsy-proven AMR and evaluate the performance characteristics of dd-cfDNA for AMR. Methods The authors included 2,240 subjects from the SHORE (Surveillance HeartCare Outcomes Registry) registry transplanted between 2017 and 2022 with verified biopsy, dd-cfDNA, echocardiographic, and donor-specific antibody (DSA) data. They evaluated the performance characteristics of dd-cfDNA for AMR and the incidence of AMR in different clinical contexts. Results AMR was present in 2.6% of biopsies with significant variability depending on the clinical context: AMR occurred in 1.1% of biopsies with normal graft function and no DSAs vs 20.4% of biopsies with known DSA and graft dysfunction. In patients with neither DSA nor graft dysfunction, the incidence of AMR was 0.7% for dd-cfDNA levels <0.20%, 1.2% for levels between 0.20% and 0.49%, and 6.7% for dd-cfDNA levels ≥0.50%. In patients with known DSA but no graft dysfunction, the incidence of AMR was 1.4% for dd-cfDNA levels <0.20%, 4.8% for levels between 0.20% and 0.49%, and 15.5% for dd-cfDNA levels ≥0.50%. Conclusions The authors document significant context dependent variability of AMR incidence and the utility of dd-cfDNA in predicting biopsy yield. These data complement prior studies on the interpretation of peripheral gene expression profiling and dd-cfDNA for rejection monitoring and should further obviate the need for surveillance biopsies. (Surveillance HeartCare Outcomes Registry [SHORE]; NCT03695601).

Purpose: To present preliminary data from the AlloSure Lung Assessment and Metagenomics Outcomes (ALAMO) registry and determine the donor-derived cell-free DNA (dd-cfDNA) trajectory post-lung transplant by transplant type

Purpose: Characterize the intermediate term clinical outcomes using donor derived cell-free DNA (ddcfDNA) testing and assess associations with donor specific antibody (DSA), culture (CX), acute cellular rejection (ACR), and chronic lung allograft dysfunction (CLAD), incidence after Lung Transplantation (LT).

It has been established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocyte pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists in the current pandemic. ACE2 serves as a regulatory enzyme in maintaining homeostasis between proinflammatory angiotensin II and anti-inflammatory angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome. Augmentation of the ACE2/Ang 1,7 axis represents a critical target in the supportive management of coronavirus disease 2019-associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists, requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.

BACKGROUND: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. METHODS: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. RESULTS: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). CONCLUSIONS: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.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (EBV-PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a 7-year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (P < .02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33-8.21, P = .01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, P = .03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57-76.09, P < .0001). Early PTLD (first year) was associated with alemtuzumab use (P = .04), whereas IPF was a predictor for late PTLD (after first year) (P = .002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P = .04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.

In 2009, the International Society for Heart and Lung Transplantation recognized the importance and challenges surrounding generic drug immunosuppression. As experience with generics has expanded and comfort has increased, substantial issues have arisen since that time with other aspects of immunomodulation that have not been addressed, such as access to medicines, alternative immunosuppression formulations, additional generics, implications on therapeutic drug monitoring, and implications for special populations such as pediatrics and older adults. The aim of this consensus document is to address critically each of these concerns, expand on the challenges and barriers, and provide therapeutic considerations for practitioners who manage patients who need to undergo or have undergone cardiothoracic transplantation. (C) 2020 International Society for Heart and Lung Transplantation. All rights reserved.

The purpose of this study was to examine the influence of extracorporeal membrane oxygenation (ECMO) as a bridge to reoperative lung transplantation (LT) on outcomes and survival. A total of 1960 LT recipients transplanted a second time between 2005 and 2017 were analyzed using the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN). Of these recipients, 99 needed ECMO as a bridge to reoperative LT. Mean age was 50 +/- 14 years, 47% were females, and the group with ECMO was younger [42 (30-59) vs. 55 (40-62) years]. In both univariate and multivariable analyses (adjusting for age and gender), the ECMO group had greater incidence of prolonged ventilation >48 h (83% vs. 40%, P < 0.001) and in-hospital dialysis (27% vs. 7%, P < 0.001). There were no differences in incidence of acute rejection (15% vs. 11%, P = 0.205), airway dehiscence (4% vs. 2%, P = 0.083), stroke (3% vs. 2%, P = 0.731), or reintubation (20% vs. 20%, P = 0.998). Kaplan-Meier survival analysis showed the ECMO group had reduced 1-year survival (66.6% vs. 83.0%, P < 0.001). After covariate adjustment, the ECMO group only had increased risk for 1-year mortality in the 2005-2011 era (HR = 2.57, 95% CI = 1.45-4.57, P = 0.001). For patients who require reoperative LT, bridging with ECMO was historically a significant predictor of poor outcome, but may be improving in recent years.

Purpose Long-term survival in lung transplant recipients (LTR) is limited in large part due to chronic lung allograft dysfunction (CLAD). Donor-specific antibodies (DSA) have been previously associated with more rapid high-grade rejection and mortality. Characteristics of these DSA may predict which antibodies are more harmful than others. The purpose of this investigation was to determine if C1q+ DSA is associated with increased CLAD in LTRs versus no DSA and C1q- DSA. Methods This was a single-center, retrospective cohort study of adult LTRs. Clinical data was extracted from the electronic medical record and laboratory systems. Patients were tested by Luminex Single Antigen Bead (SAB) IgG and C1q. IgG-SAB MFI > 1000 and C1q-SAB MFI > 500 were considered positive. DSA that were positive at more than one time point were classified as persistent, while those that were not were considered transient. Patients were grouped as no DSA, C1q- DSA, or C1q+ DSA. The primary outcome was CLAD. Secondary outcomes included CLAD subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Outcomes were assessed using Kaplan-Meier methods and multivariable Cox regression with a time-dependent covariate. Results 582 LTRs were analyzed. 335 (57.6%) had no DSA, 194 (33.3%) were DSA+ C1q-, and 53 (9.1%) were DSA+ C1q+. Of 247 LTRs who developed any DSA, Class II DSA (206 LTRs, 84%) were more common than Class I DSA (106, 43%), including those with both classes. 177 LTRs (72%) had persistent DSA, including all 53 with C1q+ DSA . There was no difference in time to CLAD for any DSA vs no DSA (p=0.26). Patients with persistent DSA had shorter time to CLAD vs no DSA and transient DSA (p=0.04) and trended towards significance on multivariable assessment (HR: 1.70 95%CI: 1.00-2.92, p=0.05). DSA+ Cq1+ had shorter time to CLAD vs no DSA and DSA+ C1q- (p<0.001). This difference was maintained on multivariable analysis (HR:2.10 95%CI: 1.34-3.31) controlling for age, single vs double, and acute cellular rejection. Similar findings were observed in multivariable analyses for BOS (HR:2.02 95%CI: 1.26-3.25) and RAS (HR: 2.15 95% CI: 1.30-3.57). Conclusion Persistent DSA were associated with shorter time to CLAD. C1q+ DSA were associated with increased hazard of CLAD, BOS, and RAS. Larger cohorts are needed to evaluate other clinical outcomes. Long-term survival in lung transplant recipients (LTR) is limited in large part due to chronic lung allograft dysfunction (CLAD). Donor-specific antibodies (DSA) have been previously associated with more rapid high-grade rejection and mortality. Characteristics of these DSA may predict which antibodies are more harmful than others. The purpose of this investigation was to determine if C1q+ DSA is associated with increased CLAD in LTRs versus no DSA and C1q- DSA. This was a single-center, retrospective cohort study of adult LTRs. Clinical data was extracted from the electronic medical record and laboratory systems. Patients were tested by Luminex Single Antigen Bead (SAB) IgG and C1q. IgG-SAB MFI > 1000 and C1q-SAB MFI > 500 were considered positive. DSA that were positive at more than one time point were classified as persistent, while those that were not were considered transient. Patients were grouped as no DSA, C1q- DSA, or C1q+ DSA. The primary outcome was CLAD. Secondary outcomes included CLAD subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Outcomes were assessed using Kaplan-Meier methods and multivariable Cox regression with a time-dependent covariate. 582 LTRs were analyzed. 335 (57.6%) had no DSA, 194 (33.3%) were DSA+ C1q-, and 53 (9.1%) were DSA+ C1q+. Of 247 LTRs who developed any DSA, Class II DSA (206 LTRs, 84%) were more common than Class I DSA (106, 43%), including those with both classes. 177 LTRs (72%) had persistent DSA, including all 53 with C1q+ DSA . There was no difference in time to CLAD for any DSA vs no DSA (p=0.26). Patients with persistent DSA had shorter time to CLAD vs no DSA and transient DSA (p=0.04) and trended towards significance on multivariable assessment (HR: 1.70 95%CI: 1.00-2.92, p=0.05). DSA+ Cq1+ had shorter time to CLAD vs no DSA and DSA+ C1q- (p<0.001). This difference was maintained on multivariable analysis (HR:2.10 95%CI: 1.34-3.31) controlling for age, single vs double, and acute cellular rejection. Similar findings were observed in multivariable analyses for BOS (HR:2.02 95%CI: 1.26-3.25) and RAS (HR: 2.15 95% CI: 1.30-3.57). Persistent DSA were associated with shorter time to CLAD. C1q+ DSA were associated with increased hazard of CLAD, BOS, and RAS. Larger cohorts are needed to evaluate other clinical outcomes.

Background. A lung transplant patient with invasive aspergillosis (IA) manifested symptoms of voriconazole-induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of the second-generation triazoles was considered. Methods. Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions. Results. Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (<5.4 µm) of 2.8 µm, 2.0, 86%; 3.4 µm, 2.4, 78%; and 3.0 µm, 2.3, 79% for voriconazole and 6, 12 mg/mL of posaconazole, respectively. Aspergillus fumigatus isolate from the patient was more susceptible to voriconazole, and hence aerosolized voriconazole was introduced around the third month posttransplant at 40 mg TID for 1 week, 40 mg BID for 1 week, followed by 40 mg daily thereafter, along with IV caspofungin (50 mg/d) and liposomal amphotericin B (300 mg/d). The aerosol regimen was well tolerated by the patient with undetectable trough plasma levels of voriconazole. Bronchoscopy at the fourth month revealed improvement in anastomotic plaques with reduction in bronchoalveolar lavage galactomannan values (7.48–2.15 ng/mL). This consolidated aerosolized and intravenous regimen was maintained until 2.97 years posttransplant. Conclusions. The intravenous solutions of both second-generation triazoles showed characteristics that were suitable for aerosol delivery. Our report further adds to the therapeutic experience with the use of aerosolized voriconazole for IA in a lung transplant patient.

Objective. To design, integrate the curriculum for, and evaluate an innovative program to facilitate placement of students into postgraduate pharmacy residency training programs involving direct patient care. Methods. The Pharmacotherapy Scholars Program (PSP) was designed to prepare fourth-professional year students to become highly proficient in a direct patient care role and to successfully match with postgraduate residency training programs. The following elements were included in the year-long curriculum: integrated synchronous advanced pharmacy practice experiences with personal advising, team-based mentoring, peer-to-peer learning, longitudinal research, and professional development. Program goals were modeled after the accreditation standards for postgraduate year one (PGY1) pharmacy residency programs. Program faculty members ensured that the PSP had a broad scope, included rigorous student assessments, had a strong research focus, and provided scholarship opportunities. Results. Sixty-eight students completed the program from fall 2013 through spring 2019. The overall residency match rate was 93%. Students' performance on both knowledge and clinical skills assessments significantly improved after completing the program. There was an approximately 15% increase in knowledge and a 30% improvement in clinical skills based on comprehensive readiness assessments and an intermittent clinical examination that used patient simulation, respectively. Conclusion. The Pharmacotherapy Scholars Program is an innovative training program designed to enhance PharmD students' preparation for advanced clinical training. Students who completed the PSP achieved a high PGY1 residency placement rate while demonstrating significant improvements in pharmacotherapy knowledge and clinical skills in direct patient care activities.

Occupational lung diseases (OLD) including silicosis, asbestosis, and pneumoconiosis progress to end stage lung disease requiring lung transplantation (LT). Prognosis and treatment of OLDs are poorly understood and a paucity of data exists regarding LT outcomes. Additionally, transplant operative complexity for patients with OLD is high. A single center retrospective review of all single and bilateral LT recipients between May 2005 and Oct 2016 was performed. Patients were grouped by OLD, and nearest neighbor matching was performed at a ratio of 1:3 cases to controls. Thirty cases were matched to 88 controls. Seventeen patients (57%) with OLD required intraoperative support with either extra‐corporeal membrane oxygenation (ECMO) or cardiopulmonary bypass ( P = 0.02), and 5 (17%) required delayed chest closure ( P = 0.05) which was more frequent than matched controls. In addition, operative time was significantly longer in patients with OLD ( P = 0.03). Despite these factors, there were no significant differences in immediate post‐operative outcomes including mechanical ventilator support, post‐operative ECMO, and tracheostomy. Chronic lung allograft dysfunction and long‐term survival were also similar between cases and controls. OLDs should not preclude LT. The operation should be performed at experienced centers.