Purpose: Grit and resilience are associated with improvements in mood, therapeutic adherence, quality of life, and survival in several chronic illnesses; their association with lung transplant outcomes is unknown. We hypothesized that greater mental toughness is associated with shorter index hospital length of stay (LOS).

Purpose: Ex vivo lung perfusion (EVLP) allows for evaluation of marginal donor lungs, but its widespread adoption is limited by lack of center expertise and logistical support for in-house EVLP. Clinical trials have demonstrated the feasibility of remote EVLP at a centralized facility to expand access to centers without in-house EVLP. The outcomes of remote EVLP outside of clinical trials are unclear due to scarcity and incomplete data. Our team will report on 1-year outcomes for the use of remote EVLP utilizing centralized lung evaluation system (CLES) via a third-party provider in a real world, non-clinical trial setting at two transplant centers (Mayo Clinic Florida (n=24) and Vanderbilt University (n=21)) from December 2, 2020, to March 20,2023.

Purpose Lung transplant recipients with short lymphocyte telomeres are predisposed to cytopenias, allograft dysfunction, and malignancy. However, the impact of granulocyte telomere length (gTL) is understudied in lung transplantation; short gTL and telomere gap (difference in lymphocyte and granulocyte TL) are sensitive markers of bone marrow dysfunction and disease severity in other settings. Methods We instituted peripheral blood Flow-FISH telomere testing (Repeat Dx) in pre-transplant patients with interstitial lung disease in 12/2020 and performed a retrospective analysis of gTL and 6-month outcomes including infection, acute rejection (ACR), and need for granulocyte colony stimulating factor (G-CSF), on patients transplanted through 4/2022. Data were analyzed using Fisher's exact, Mann-Whitney, or Kruskal-Wallis testing. Results We performed 76 transplants from 12/2020-4/2022, of which 44 patients had interpretable telomere testing. Five (11%) had normal age-adjusted gTL, while 24 (55%) had low TLs (<10th percentile) and 15 (34%) had very low TLs (<1st percentile). Short gTLs were more common in whites (p=0.04) and males (p=0.05), but not higher LAS (p=0.07), or age (p=0.09). There were no significant associations between gTL and infection (N: 80%, L: 58%, VL: 67%), ACR (N: 20%, L: 38%, VL: 60%), need for G-CSF (N: 40%, L: 38%, VL: 27%), or other outcomes (Figure). Analysis using telomere gap had similar findings. Granulocyte and lymphocyte TL were highly correlated (p<0.01). Conclusion Granulocyte telomere lengths and telomere gap are not associated with differences in 6-month outcomes in lung transplant recipients.

Purpose In kidney transplant, relative change in % donor-derived cell-free DNA (%dd-cfDNA) is superior to absolute thresholds for detection of injury, though in lung transplantation a cut-off of 1% is used as an arbiter of acute lung allograft dysfunction (ALAD). We previously showed that a normal dd-cfDNA% level in patients >2 years post-lung transplantation without allograft injury is 0.45% (IQR 0.21 - 0.64) with a relative change value of 73%. We now seek to determine test characteristics for the ability of a relative change >73% to distinguish graft injury vs. an absolute value >1%. Methods We performed an observational study of lung recipients >2 years post-transplantation without CLAD, measuring plasma dd-cfDNA every 3-4 months (CareDx). ALAD was adjudicated based on symptoms, decline in FEV1 >10%, infection, de novo donor specific antibodies, or biopsy-proven acute rejection. Chi-squared and Mann-Whitney U testing were used for statistical comparisons of binary and continuous data, respectively. Results Seventy patients had >3 baseline dd-cfDNA measurements and were included in this analysis. In this cohort 29 (41%) patients developed ALAD. There were no significant baseline differences in age, sex, race, transplant type, lung diagnosis, or primary graft dysfunction, between subjects that developed ALAD or not. Leading causes of ALAD included respiratory viruses (34%), decline in FEV1 of unclear etiology (21%), and possible antibody-mediated rejection (17%). Relative change of %dd-cfDNA >73% of baseline had a 90% sensitivity, 88% specificity, 84% positive predictive value (PPV), and 92% negative predictive value (NPV) to detect ALAD. An absolute threshold of 1% was associated with a sensitivity of 52%, specificity of 78%, PPV of 63% and NPV of 70%. Conclusion Relative change in %dd-cfDNA >73% of baseline identifies ALAD better than an absolute threshold of 1% in patients >2 years post- lung transplant.

Purpose Recipients of marginal donor lungs conditioned by ex-vivo lung perfusion (EVLP) have non-inferior short and long-term outcomes compared to recipients of non-EVLP lungs. Whether EVLP increases the risk of de novo donor specific anti-HLA antibodies (dnDSA) early post-transplant has not been reported. Methods We performed a single-center, retrospective analysis between 10/2019- 7/2021. EVLP was performed at a specialized center (Lung Bioengineering). Post-lung transplant (LTx) management was similar in both groups. DSA was measured at 1-month post-LTx using a Luminex single-antigen assay. Differences in baseline variables between groups were analyzed using Fisher's exact, Wilcoxon rank-sum or Kruskal-Wallis tests. Multiple logistic regression analysis was then performed to assess the relationship between EVLP and dnDSA, including covariates that were significant on univariate assessment at p<0.2. Results DSA were measured in 76 consecutive LTx recipients (LTRs) in the study period; 12 received EVLP-conditioned lungs and 64 did not. Baseline demographics were similar between cohorts except for total ischemic times (Fig 1). At 1-month post-LTx 3 patients (25%) in the EVLP cohort developed class II DSA (all DQ). In the non-EVLP cohort 6 patients (9%) developed class I DSA antibodies (all B) and 11 patients (17%) developed class II DSA (8 with DQ and 3 with DR). When adjusting for gram negative infection and transfused red blood cells, there was no difference in dnDNA incidence between cohorts (Fig 2). Conclusion The use of EVLP-conditioned donor lungs is not associated with increased incidence of dnDSA early post-LTx.

Purpose Acute respiratory failure (ARF) necessitating mechanical ventilation (MV) is the leading cause of ICU readmission after lung transplantation and is associated with a 6-month survival of <50%. Management strategies for patients with non-infectious causes of severe ARF are under-reported. We hypothesized that aggressive, early treatment of non-infectious ARF with awake venovenous extracorporeal membrane oxygenation (VV-ECMO) and augmented immunosuppression would improve outcomes. Methods This is a retrospective, single-center case series between 1/1/2018-12/1/2020. Lung transplant recipients (LTRs) with severe ARF with diffuse allograft infiltrates on chest X-ray and PaO2/FiO2 <150 were considered for VV-ECMO. All LTRs received empiric broad antibiotics. If initial cultures were negative, augmented immunosuppression with a combination of high-dose steroids, plasma exchange, intravenous immunoglobulin, rituximab, antithymocyte globulin or alemtuzumab was initiated. VV-ECMO support was via a bicaval, dual lumen single cannula. Results Ninety-nine LTRs were re-admitted to an ICU during the study period, with 5 meeting criteria for non-infectious severe ARF. Median duration of ECMO was 21 days (IQR 7-28). Four of the five patients received antibody and/or augmented T-cell depleting therapies, and 12-month survival was 80%. (Fig 1). Lung function stabilized following the ARF insult in survivors (Fig 2). Conclusion Treatment with awake VV-ECMO and augmented immunosuppression in LTRs with severe non-infectious ARF is associated with excellent 12-month outcomes that are better than previously reported with MV.

Purpose Donor-derived cell free DNA (dd-cfDNA) is a well-studied biomarker of early allograft injury, though kinetics of dd-cfDNA outside the early period is understudied. We measured levels of plasma dd-cfDNA in stable lung transplant recipients (LTRs) >2-years post-transplant to determine if dd-cfDNA varies with allograft longevity. Methods We performed a prospective, observational study of LTRs that were > 2-years post-transplant and had stable lung function. Plasma dd-cfDNA (CareDx) was measured at outpatient visits. Patients were considered at baseline if they were hospital-free in the prior 30-days, FEV1 was >90% baseline, and they were sans fever, cough, or dyspnea. Patients treated with augmented immunosuppression for ALAD / CLAD were excluded. LTRs were categorized into three allograft-age cohorts (2-3, 3-5, or > 5 years post-transplant). Statistics were performed using SSPS (IBM); chi-squared testing and ANOVA was used for binary and continuous data, respectively. Results Baseline dd-cfDNA was measured in 59 LTRs meeting inclusion criteria. Overall median dd-cfDNA was 0.45% (IQR 0.30-0.65). (Fig. 1). Median plasma dd-cfDNA was 0.51% (IQR 0.34-0.63), 0.35% (IQR 0.12-0.59), and 0.43% (IQR= 0.29-0.67) for LTRs 2-3years, 3-5 years and >5-years post-transplant, respectively (p=0.91). Baseline demographics were similar between cohorts for all variables except transplant type (Table 1). Conclusion Plasma dd-cfDNA is <1% in clinically stable LTRs > 2-years post-transplant and does not vary with allograft survival. Future studies will determine whether changes in dd-cfDNA from baseline can predict CLAD onset.

Purpose Lung transplant (LTx) recipients have increased risk of infection with SARS-CoV-2 and have reduced efficacy from COVID-19 vaccination. The Delta variant of SARS-CoV-2 has increased virulence compared to earlier variants. We hypothesized that LTx recipients would have increased susceptibility to Delta variant infection despite vaccination. Methods We performed a retrospective cohort study of 314 LTx recipients followed between 1/1/2020-9/30/2021. Diagnosis of SARS-CoV-2 infection by PCR was recorded; Delta variant comprised >99% of strains from 6/1/2021-9/30/2021. Data regarding COVID-19 vaccination status, symptom development, hospitalization, intubation, and death were collected. Results Forty-four patients (14%) were diagnosed with COVID-19, 18 (41%) of which were Delta variant. The rate of infection with Delta was 4-fold higher than with earlier strains (Figure, 0.016 vs. 0.004 cases / patient months, p<0.001). Fifteen (83%) patients diagnosed with Delta variant were fully vaccinated at the time of infection (p<0.001). The rate of infection with Delta variant in vaccinated and unvaccinated individuals was similar (0.017/patient months with vaccine, 0.015/patient months without vaccine, p=0.84). The majority (>89%) of patients had respiratory symptoms in both groups. More patients with Delta variant received monoclonal antibody infusions (89% vs. 54%, p=0.021) and fewer patients with Delta variant had resolution of disease (50% vs. 92%, p<0.001). There was a trend towards greater O2 needs with Delta variant (p=0.07). Hospitalization (38% vs. 23%), intubation (11% vs. 4%), and death (11% vs. 4%) were numerically greater with Delta variant, although not statistically significant. Conclusion The incidence rate of SARS-CoV-2 infection was significantly greater with Delta variant in LTx recipients, despite high prevalence of full vaccination during the Delta wave. Further study in larger cohorts is needed to determine whether booster vaccines can reduce such infectivity.

Purpose Short telomere lengths (TL) are seen in 10% of lung transplant recipients (LTRs) with interstitial lung disease (ILD). Short TL and immunosuppression predispose to carcinogenesis. We assess whether LTRs with short TLs have a compounded malignancy risk. Methods This is a single-center retrospective analysis from 1/2012 - 1/2017. LTR records were queried for TL, malignancy, and cancer risk factors. TL was assayed in ILD candidates with cytopenias, abnormal liver function and coagulation, splenomegaly, premature graying, or ILD family history. Lymphocyte TL was assessed via flow-FISH (Repeat Dx) and was age-adjusted; values <10th percentile were defined as short. LTRs were administered standard induction and maintenance immunosuppression, and antimicrobial prophylaxis. . LTRs underwent age-appropriate cancer screening. Statistical analysis was performed using SSS (StatCorp); Fisher's Exact, Pearson's Chi square, and Wilcoxon's rank sum tests were used for binary, categorical and continuous data, respectively. P-values ≤ 0.05 were significant. Results 19/233 (8.2%) LTRs had short TLs. There were no inter-cohort differences in baseline traits (Table 1). Five (26.3%) LTRs with short TLs developed malignancy, compared to 45 (21%) patients with presumed normal TLs. There was a significant difference in hematologic malignancy rate in those with short TLs (40% vs. 0%, p=0.009). There was no difference in time to cancer diagnosis or survival (Table 3). Conclusion LTRs with short TLs may be predisposed to hematologic malignancy. Study limitations include size, the single-center, retrospective design, and that only a sub-set of patients had TL measured.

This study demonstrates a benefit to specialized hepatic screening in high-risk patients referred for lung transplantation.

Advanced hepatic fibrosis and cirrhosis are absolute contraindications to lung transplantation. [ 1] However, whether fatty liver disease with mild–moderate fibrosis contributes to increased adverse outcomes post-lung transplantation remains unknown. We present a retrospective analysis of patients transplanted at Brigham and Women's Hospital between 2015 and 2017 to identify whether patients with mild–moderate non-alcoholic fatty liver disease (NAFLD) experience increased short-term complications compared to patients with normal liver architecture. Patients with advanced (F3–F4) fibrosis and/or cirrhosis were considered non-suitable transplant candidates, a priori . This study was powered for a difference in index hospital-free days within the first 30 days of 25% (α=0.05, β=0.8). Secondary outcomes included index intensive care unit (ICU)-free days within the first 10 days post-transplant, perioperative blood product transfusion, incidence of index hospitalisation arrhythmias and delirium, need for insulin on discharge post-transplant, tacrolimus dose required to maintain a trough of 8–12 ng·mL −1 at index hospital discharge, and 1-year post-transplant incidence of insulin-dependent diabetes, acute kidney injury, acute cellular rejection, unplanned hospital readmissions and infection. 150 patients underwent lung transplantation between 2015 and 2017 and were included in the analysis; of these patients 40 (27%) had evidence of NAFLD. Median index hospital-free days for patients with NAFLD were non-inferior to those without (16 days, IQR 10.5–19.5 versus 12 days, IQR 0–18.0, p=0.03). Regarding secondary outcomes, both index hospitalisation and 1-year outcomes were non-inferior between patients with NAFLD and those with normal liver architecture. This study demonstrates that mild–moderate severity NAFLD may not be a contraindication to lung transplantation.