BACKGROUND: Respiratory syncytial virus (RSV) infection in lung transplant recipients is associated with high morbidity. This study evaluated the RSV fusion inhibitor presatovir in RSV-infected lung transplant recipients. METHODS: In this international Phase 2b, randomized, double-blind, placebo-controlled trial (NCT02534350), adult lung transplant recipients with symptomatic confirmed RSV infection for <= 7 days received oral presatovir 200 mg on day 1 and 100 mg daily on days 2 to 14, or placebo (2:1), with follow-up through day 28. There were 2 coprimary endpoints: time-weighted average change in nasal RSV load from day 1 to 7, calculated from nasal swabs, in the full analysis set ([FAS]; all patients who received study drug and had quantifiable baseline nasal RSV load) and time-weighted average change in nasal RSV load from day 1 to 7 in the subset of patients with pretreatment symptom duration at the median or shorter of the FAS. Secondary endpoints were changes in respiratory infection symp-toms assessed using the Influenza Patient-Reported Outcomes questionnaire and lung function mea-sured by spirometry. RESULTS: Sixty-one patients were randomized, 40 received presatovir, 20 placebo, and 54 were included in efficacy analyses. Presatovir did not significantly improve the primary endpoint in the FAS (treatment difference [95% CI], 0.10 [-0.43, 0.63] log10 copies/ml; p = 0.72) or the shorter symptom duration subgroup (-0.12 [-0.94, 0.69] log10 copies/ml; p = 0.76). Secondary endpoints were not different between presatovir and placebo groups. Presatovir was generally well tolerated. CONCLUSIONS: Presatovir treatment did not significantly improve change in nasal RSV load, symptoms, or lung function in lung transplant recipients. J Heart Lung Transplant 2023;42:908-916 (c) 2023 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Alpha-1 antitrypsin (AAT) augmentation is effective in slowing the progression of emphysema due to AAT deficiency (AATD) but cannot prevent eventual progression to end-stage lung disease and complete respiratory failure, which is the leading cause of death for individuals with severe AATD. When patients develop end-stage lung disease, lung transplantation is the only treatment option available, and this can improve lung physiology and patient health status. The available data suggest that survival rates for lung transplantation are significantly higher for patients with AATD-related chronic obstructive pulmonary disease (COPD) compared with non-AATD-related COPD, but, conversely, there is a higher risk of common post-lung transplant complications in patients with AATD versus non-AATD COPD. Nevertheless, lung transplantation (single and bilateral) is favorable for patients with AATD. After respiratory failure, the second leading cause of death in patients with AATD is liver disease, for example, cirrhosis and hepatocellular carcinoma, caused by the accumulation of mutant forms of AAT retained within the liver. As with lung disease, the only treatment option for end-stage liver disease is liver transplantation. Survival rates for patients with AATD undergoing liver transplantation are also favorable, and patients, particularly pediatric patients, have benefitted from advancements in peri-/post-surgical care. As the majority of AAT is produced by the liver, the AAT phenotype of the recipient becomes that of the donor, meaning that AAT serum levels should be normalized (if the donor is AAT-replete), halting further lung and liver disease progression. However, post-liver transplant respiratory function may continue to decline in line with normal age-related lung function decline. In the most severe cases, where patients have simultaneous end-stage lung and liver disease, combined lung and liver transplantation is a treatment option with favorable outcomes. However, there is very little information available on this procedure in patients with AATD.

Autologous C-kit+ cells robustly prolong cardiac allografts. As C-kit+ cells can transdifferentiate to hematopoietic cells as well as non-hematopoietic cells, we aimed to clarify the class(es) of C-kit-derived cell(s) required for cardiac allograft prolongation. Autologous C-kit+ cells were administered post-cardiac transplantation and allografts were evaluated for C-kit+ inoculum-derived cells. Results suggested that alloimmunity was a major signal for trafficking of C-kit-derived cells to the allograft and demonstrated that C-kit+ inoculum-derived cells expressed CD11b early after transfer. Allograft survival studies with CD11b-DTR C-kit+ cells demonstrated a requirement for C-kit+-derived CD11b+ cells. Co-therapy studies demonstrated near complete abrogation of acute rejection with concomitant CTLA4-Ig therapy and no loss of prolongation in combination with Cyclosporine A. These results strongly implicate a C-kit-derived myeloid population as critical for allograft preservation and demonstrate the potential therapeutic application of autologous C-kit+ progenitor cells as calcineurin inhibitor-sparing agents and possibly as co-therapeutics for durable graft survival.

Respiratory syncytial virus (RSV) is responsible for significant morbidity and mortality in the lung transplant population. Oral and aerosolized ribavirin may improve outcomes in lung transplant patients with RSV; however, data relating ribavirin concentrations in plasma and intracellular ribavirin triphosphate (iRTP) concentrations in blood and bronchoalveolar lavage (BAL) fluid cells with efficacy and safety are lacking. We describe ribavirin and iRTP concentrations within various compartments in two adult lung transplant recipients with RSV who were sampled throughout successful treatment courses with oral and inhaled ribavirin. In patient 1, iRTP BAL concentrations decreased by 45% over 3 days after changing inhaled ribavirin to oral (6.32 to 3.43 pmol/10(6)cells). In patient 2, iRTP BAL concentrations were 103 pmol/10(6)cells after 5 days of oral followed by 5 days of inhaled ribavirin. Further study is needed to describe ribavirin pharmacokinetics in the respiratory compartment to inform clinical use of ribavirin for respiratory viruses.

Background Alpha 1 Antitrypsin Deficiency (AATD) is a genetic cause of emphysema/chronic obstructive pulmonary disease (COPD) and liver disease, making AATD patients a high-risk surgical group. Additionally, patients may eventually require lung and/or liver transplantation or lung volume reduction surgery (LVRS). This narrative review discusses perioperative considerations for elective procedures in AATD patients, and reviews patient outcomes in AATD-related transplantation and LVRS. Data sources PubMed search terms included: “pre-/peri-/post-operative management”; “COPD”; “AATD”; “lung/liver transplant”; “lung volume reduction.” Conclusions Lung and liver transplantation in AATD patients are associated with very good long-term survival rates that are comparable to, and sometimes superior to, other transplant indications. Although not currently recommended in AATD, LVRS may have a role in a minority of patients. The value of Alpha 1 Antitrypsin (AAT) augmentation therapy following lung transplantation requires further study. Wherever possible, AAT therapy should be continued in the period around elective surgeries.

The induction of tolerance to transplanted organs is a major objective in transplantation immunology research. Lymphocyte function-associated antigen-1 (LFA-1) interactions have been identified as a key component of the T-cell activation process that may be interrupted to lead to allograft tolerance. In mice, αLFA-1 mAb is a potent monotherapy that leads to the induction of donor-specific transferable tolerance. By interrogating important adaptive and innate immunity pathways, we demonstrate that the induction of tolerance relies on CD8+T-cells. We further demonstrate that αLFA-1 induced tolerance is associated with CD8+CD28-T-cells with a suppressor phenotype, and that while CD8 cells are present, the effector T-cell response is abrogated. A recent publication has shown that CD8+CD28- cells are not diminished by cyclosporine or rapamycin, therefore CD8+CD28- cells represent a clinically relevant population. To our knowledge, this is the first time that a mechanism for αLFA-1 induced tolerance has been described.

A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.

Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including primary graft dysfunction. Decades of reports show that reactive oxygen species generated during lung IR contribute to pulmonary vascular endothelial barrier disruption and edema formation, but the specific target molecule(s) that "sense" injury-inducing oxidant stress to activate signaling pathways culminating in pathophysiologic changes have not been established. This review discusses evidence that mitochondrial DNA (mtDNA) may serve as a molecular sentinel wherein oxidative mtDNA damage functions as an upstream trigger for lung IR injury. First, the mitochondrial genome is considerably more sensitive than nuclear DNA to oxidant stress. Multiple studies suggest that oxidative mtDNA damage could be transduced to physiologic dysfunction by pathways that are either a direct consequence of mtDNA damage per se or involve formation of proinflammatory mtDNA damage-associated molecular patterns. Second, transgenic animals or cells overexpressing components of the base excision DNA repair pathway in mitochondria are resistant to oxidant stress-mediated pathophysiologic effects. Finally, published and preliminary studies show that pharmacologic enhancement of mtDNA repair or mtDNA damage-associated molecular pattern degradation suppresses reactive oxygen species-induced or IR injury in multiple organs, including preclinical models of lung procurement for transplant. Collectively, these findings point to the interesting prospect that pharmacologic enhancement of DNA repair during procurement or ex vivo lung perfusion may increase the availability of lungs for transplant and reduce the IR injury contributing to primary graft dysfunction.

BACKGROUND: Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo.METHODS: We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS. Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days.RESULTS: Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat [mITT] cohort). RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT [mITTc]). ALN-RSV01 was found to be safe and well-tolerated. At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (13.6% vs 30.3%, p = 0.058), which was significant in the per-protocol cohort (p = 0.025). Treatment effect was enhanced when ALN-RSV01 was started <5 days from symptom onset, and was observed even without ribavirin treatment. There was no significant impact on viral parameters or symptom scores.CONCLUSIONS: These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients. (C) 2016 International Society for Heart and Lung Transplantation. All rights reserved.

Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.

PurposeParamyxovirus infections (PMVI), consisting of respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (hMPV), are associated with significant morbidity in lung transplant recipients (LTR) but management recommendations are lacking. We report the results of a worldwide survey of PMVI perceptions and current practices in LTRs.MethodsAn IRB-approved 73 question 5-part survey was circulated via Qualtrics to the worldwide membership of the pharmacy, ID, and pulmonary ISHLT councils post 2013-14 virus season. Responses were deidentified and descriptive statistics were used.Results56 responses from 43 centers (of 136, 31.6% response) were recorded. 87% report PMVI as a significant problem and are concerned about subsequent BOS (94%), lymphocytic bronchiolitis (63%), graft failure (57%), OB (54%) and ACR (54%). 93% use PCR-based diagnostics. PMVI URI/LRTI are typically diagnosed when relevant symptoms exist (95%/93%), 75% obtain PFTs at diagnosis, 76% identify FEV1 fall of >10% and any new/worsening (87%/82%) oxygen requirement to be significant. Most treat PMVI with symptoms (69%) or hypoxia (82%). Most treat symptomatic RSV (82%), PIV (61%), hMPV (59%); 11% provide no therapy. Ribavirin (RBV) is used by 71% orally, 42% by aerosol and 18% IV. 89% and 77.1% use adjunct steroids and IVIg; only 3% use palivizumab for RSV. 57% prefer oral RBV and 30% aerosol. Those employing multiple routes use aerosol or IV for sicker patients (24%) and 35% use oral for ambulatory patients. Most use an aerosol dose of 2 g q8h for intubated/non-intubated (47%/63%) patients, for 5 days (60%) and consider bronchospasm (70%) limiting. Most use an IV/oral dose of 15-20 mg/kg/d divided q8h (52%), reduced to 10-15 mg/kg/d in CrCl 10-50 mL/min (30%), 8-10 mg/kg/d (41%) in ESRD, for 7-10 days (68%), and consider anemia (65%), thrombocytopenia (65%), leukopenia (52%) and renal dysfunction (43%) limiting. Most monitor labs ≥twice weekly (61%) for 1-2 weeks (35%). Most don't obtain followup samples (54%); but 52% continue treatment if repeat is positive. 86% obtain followup PFTs 2-4 weeks (59%) post diagnosis.ConclusionMost report concern for allograft outcomes post PMVI and use PCR-based diagnostics. Management is heterogeneous but most use ribavirin-based therapy especially for RSV. Further studies using different regimens are needed. PurposeParamyxovirus infections (PMVI), consisting of respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (hMPV), are associated with significant morbidity in lung transplant recipients (LTR) but management recommendations are lacking. We report the results of a worldwide survey of PMVI perceptions and current practices in LTRs. Paramyxovirus infections (PMVI), consisting of respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (hMPV), are associated with significant morbidity in lung transplant recipients (LTR) but management recommendations are lacking. We report the results of a worldwide survey of PMVI perceptions and current practices in LTRs. MethodsAn IRB-approved 73 question 5-part survey was circulated via Qualtrics to the worldwide membership of the pharmacy, ID, and pulmonary ISHLT councils post 2013-14 virus season. Responses were deidentified and descriptive statistics were used. An IRB-approved 73 question 5-part survey was circulated via Qualtrics to the worldwide membership of the pharmacy, ID, and pulmonary ISHLT councils post 2013-14 virus season. Responses were deidentified and descriptive statistics were used. Results56 responses from 43 centers (of 136, 31.6% response) were recorded. 87% report PMVI as a significant problem and are concerned about subsequent BOS (94%), lymphocytic bronchiolitis (63%), graft failure (57%), OB (54%) and ACR (54%). 93% use PCR-based diagnostics. PMVI URI/LRTI are typically diagnosed when relevant symptoms exist (95%/93%), 75% obtain PFTs at diagnosis, 76% identify FEV1 fall of >10% and any new/worsening (87%/82%) oxygen requirement to be significant. Most treat PMVI with symptoms (69%) or hypoxia (82%). Most treat symptomatic RSV (82%), PIV (61%), hMPV (59%); 11% provide no therapy. Ribavirin (RBV) is used by 71% orally, 42% by aerosol and 18% IV. 89% and 77.1% use adjunct steroids and IVIg; only 3% use palivizumab for RSV. 57% prefer oral RBV and 30% aerosol. Those employing multiple routes use aerosol or IV for sicker patients (24%) and 35% use oral for ambulatory patients. Most use an aerosol dose of 2 g q8h for intubated/non-intubated (47%/63%) patients, for 5 days (60%) and consider bronchospasm (70%) limiting. Most use an IV/oral dose of 15-20 mg/kg/d divided q8h (52%), reduced to 10-15 mg/kg/d in CrCl 10-50 mL/min (30%), 8-10 mg/kg/d (41%) in ESRD, for 7-10 days (68%), and consider anemia (65%), thrombocytopenia (65%), leukopenia (52%) and renal dysfunction (43%) limiting. Most monitor labs ≥twice weekly (61%) for 1-2 weeks (35%). Most don't obtain followup samples (54%); but 52% continue treatment if repeat is positive. 86% obtain followup PFTs 2-4 weeks (59%) post diagnosis. 56 responses from 43 centers (of 136, 31.6% response) were recorded. 87% report PMVI as a significant problem and are concerned about subsequent BOS (94%), lymphocytic bronchiolitis (63%), graft failure (57%), OB (54%) and ACR (54%). 93% use PCR-based diagnostics. PMVI URI/LRTI are typically diagnosed when relevant symptoms exist (95%/93%), 75% obtain PFTs at diagnosis, 76% identify FEV1 fall of >10% and any new/worsening (87%/82%) oxygen requirement to be significant. Most treat PMVI with symptoms (69%) or hypoxia (82%). Most treat symptomatic RSV (82%), PIV (61%), hMPV (59%); 11% provide no therapy. Ribavirin (RBV) is used by 71% orally, 42% by aerosol and 18% IV. 89% and 77.1% use adjunct steroids and IVIg; only 3% use palivizumab for RSV. 57% prefer oral RBV and 30% aerosol. Those employing multiple routes use aerosol or IV for sicker patients (24%) and 35% use oral for ambulatory patients. Most use an aerosol dose of 2 g q8h for intubated/non-intubated (47%/63%) patients, for 5 days (60%) and consider bronchospasm (70%) limiting. Most use an IV/oral dose of 15-20 mg/kg/d divided q8h (52%), reduced to 10-15 mg/kg/d in CrCl 10-50 mL/min (30%), 8-10 mg/kg/d (41%) in ESRD, for 7-10 days (68%), and consider anemia (65%), thrombocytopenia (65%), leukopenia (52%) and renal dysfunction (43%) limiting. Most monitor labs ≥twice weekly (61%) for 1-2 weeks (35%). Most don't obtain followup samples (54%); but 52% continue treatment if repeat is positive. 86% obtain followup PFTs 2-4 weeks (59%) post diagnosis. ConclusionMost report concern for allograft outcomes post PMVI and use PCR-based diagnostics. Management is heterogeneous but most use ribavirin-based therapy especially for RSV. Further studies using different regimens are needed. Most report concern for allograft outcomes post PMVI and use PCR-based diagnostics. Management is heterogeneous but most use ribavirin-based therapy especially for RSV. Further studies using different regimens are needed.

RATIONALE:In 2005, the lung allocation score (LAS) was implemented to prioritize organ allocation to minimize waiting-list mortality and maximize 1-year survival. It resulted in transplantation of older and sicker patients without changing 1-year survival. Its effect on resource use is unknown. OBJECTIVES:To determine changes in resource use over time in lung transplant admissions. METHODS:Solid organ transplant recipients were identified within the Nationwide Inpatient Sample (NIS) data from 2000 to 2011. Joinpoint regression methodology was performed to identify a time point of change in mean total hospital charges among lung transplant and other solid-organ transplant recipients. Two temporal lung transplant recipient cohorts identified by joinpoint regression were compared for baseline characteristics and resource use, including total charges for index hospitalization, charges per day, length of stay, discharge disposition, tracheostomy, and need for extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS:A significant point of increased total hospital charges occurred for lung transplant recipients in 2005, corresponding to LAS implementation, which was not seen in other solid-organ transplant recipients. Total transplant hospital charges increased by 40% in the post-LAS cohort ($569,942 [$53,229] vs. $407,489 [$28,360]) along with an increased median length of stay, daily charges, and discharge disposition other than to home. Post-LAS recipients also had higher post-transplant use of extracorporeal membrane oxygenation (odds ratio, 2.35; 95% confidence interval, 1.56-3.55) and higher incidence of tracheostomy (odds ratio, 1.52; 95% confidence interval, 1.22-1.89). CONCLUSIONS:LAS implementation is associated with a significant increase in resource use during index hospitalization for lung transplant.

Background. The use of single lung transplantation (SLTx) for chronic obstructive pulmonary disease is often viewed as inferior therapy compared with bilateral lung transplantation (BLTx). We hypothesized from our experience that subpopulations of recipients with emphysema exist in which SLTx represents therapy that is equivalent to BLTx, therefore allowing more patients access to transplantation.Methods. Consecutive patients undergoing LTx for emphysema between 1992 and 2012 at a single institution were identified and analyzed retrospectively. A similar cohort from the United Network of Organ Sharing (UNOS) national database was identified for comparison. Five-year survival in patients receiving SLTx and those receiving BLTx were compared using Kaplan-Meier survival curves and log-rank tests.Results. Two hundred thirty-six patients meeting criteria were identified from our institution. Two hundred six underwent SLTx, and 30 underwent BLTx. Five-year survival for single-center SLTx (53.2% +/- 3.6%) and BLTx (56.7% +/- 10.2%) was not significantly different (p = 0.753). The national database included 7,256 patients meeting selection criteria, with 4,408 undergoing SLTx and 2,848 undergoing BLTx. Five-year survival among the national cohorts was lower for SLTx (46.4% +/- 0.8%) compared with BLTx (55.9% +/- 1.1%) (p < 0.0001). However, 5-year survival for our single-center SLTx experience (53.2% +/- 3.6%) was comparable to the national BLTx cohort (55.9% +/- 1.1%) (p = 0.539).Conclusions. Five-year survival after SLTx for emphysema was comparable to that for BLTx in cohorts from our institution and from the UNOS national database. Further study should focus on the mechanism behind these improved outcomes. Given the potential for a larger number of life-years saved, SLTx should continue to be considered a therapeutic option in appropriately selected patients with chronic obstructive pulmonary disease (COPD). (C) 2015 by The Society of Thoracic Surgeons

Because of the high incidence of morbidity and mortality associated with invasive fungal infections, antifungal prophylaxis is often used in solid organ transplant recipients. However, this prophylaxis is not universally effective and may contribute to the selection of emerging, resistant pathogens. Here we present a rare case of invasive infection caused by Microascus trigonosporus species complex in a human, which developed during voriconazole prophylaxis in a lung transplant recipient. Nebulized liposomal amphotericin B was used in addition to systemic therapy in order to optimize antifungal drug exposure; this regimen appeared to reduce the patient’s fungal burden. Despite this apparent improvement, the patient’s pulmonary status progressively declined in the setting of multiple comorbidities, ultimately leading to respiratory failure and death.