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Background: Mycophenolic Acid (MPA) is the most used anti-proliferative in lung transplantation, but its pharmacokinetic (PK) variability has precluded therapeutic drug monitoring. Both genetic and clinical factors have been implicated in MPA variability. This study aimed to integrate genetic and clinical factors with PK measurements to quantify MPA exposure., Methods: We performed 12-hour pharmacokinetic analysis on 60 adult lung transplant recipients maintained on MPA for immunosuppression. We genotyped a SLCO1B3 polymorphisms previously associated MPA metabolism and collected relevant clinical data. We calculated area under the curve (AUC 0-12 ) and performed univariate linear regression analysis to evaluate its association with genetic, clinical, and pharmacokinetic variables. We performed lasso regression analysis to create final AUC estimation tools., Results: PK-only measurements obtained 2, 3, and 8 hours after MPA administration (C 2 , C 3, and C 8 ) were strongly associated with MPA AUC 0-12 (R 2 67%, 67% and 68% respectively). Clinical and genetic factors associated with MPA AUC 0-12 included the MPA dose (p = 0.001), transplant diagnosis (p = 0.015), SLCO1B3 genotype (p = 0.049), and body surface area (p = 0.050). The best integrated single-sampling strategy included C 2 and achieved an R 2 value of 80%. The best integrated limited-sampling strategy included C 0 , C 0.25 , and C 2 and achieved an R 2 value of 90%., Conclusions: An integrated limited sampling strategy (LSS) for MPA allows increased accuracy in prediction of MPA AUC 0-12 compared to PK-only modeling. Validation of this model will allow for clinically feasible MPA therapeutic drug monitoring and help advance precision management of MPA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neutrophils exacerbate pulmonary ischemia-reperfusion injury (IRI) resulting in poor short and long-term outcomes for lung transplant recipients. Glycolysis powers neutrophil activation, but it remains unclear if neutrophil-specific targeting of this pathway will inhibit IRI. Lipid nanoparticles containing the glycolysis flux inhibitor 2-deoxyglucose (2-DG) were conjugated to neutrophil-specific Ly6G antibodies (NP-Ly6G[2-DG]). Intravenously administered NP-Ly6G(2-DG) to mice exhibited high specificity for circulating neutrophils. NP-Ly6G(2-DG)-treated neutrophils were unable to adapt to hypoglycemic conditions of the lung airspace environment as evident by the loss of demand-induced glycolysis, reductions in glycogen and ATP content, and an increased vulnerability to apoptosis. NP-Ly6G(2-DG) treatment inhibited pulmonary IRI following hilar occlusion and orthotopic lung transplantation. IRI protection was associated with less airspace neutrophil extracellular trap generation, reduced intragraft neutrophilia, and enhanced alveolar macrophage efferocytotic clearance of neutrophils. Collectively, our data show that pharmacologically targeting glycolysis in neutrophils inhibits their activation and survival leading to reduced pulmonary IRI., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Tocilizumab (TCZ), an IL-6 inhibitor, has shown promise in the treatment of donor-specific antibodies (DSA) and chronic antibody-mediated rejection (AMR) in renal transplant recipients. However, its use in lung transplantation has not been described. This retrospective case-control study compared AMR treatments containing TCZ in 9 bilateral lung transplant recipients to 18 patients treated for AMR without TCZ. Treatment with TCZ resulted in more clearance of DSA, lower recurrence of DSA, lower incidence of new DSA, and lower rates of graft failure when compared to those treated for AMR without TCZ. The incidence of infusion reactions, elevation in transaminases, and infections were similar between the 2 groups. These data support a role for TCZ in pulmonary AMR and establish preliminary evidence to design a randomized controlled trial of IL-6 inhibition for the management of AMR., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

BACKGROUNDCellular stressors influence the development of clonal hematopoiesis (CH). We hypothesized that environmental, inflammatory, and genotoxic stresses drive the emergence of CH in lung transplant recipients. METHODSWe performed a cross-sectional cohort study of 85 lung transplant recipients to characterize CH prevalence. We evaluated somatic variants using duplex error-corrected sequencing and germline variants using whole exome sequencing. We evaluated CH frequency and burden using χ2 and Poisson regression, and we evaluated associations with clinical and demographic variables and clinical outcomes using χ2, logistic regression, and Cox regression. RESULTSCH in DNA damage response (DDR) genes TP53, PPM1D, and ATM was increased in transplant recipients compared with a control group of older adults (28% versus 0%, adjusted OR [aOR], 12.9 [1.7-100.3], P = 0.0002). Age (OR, 1.13 [1.03-1.25], P = 0.014) and smoking history (OR 4.25 [1.02-17.82], P = 0.048) were associated with DDR CH. Germline variants predisposing to idiopathic pulmonary fibrosis were identified but not associated with CH. DDR CH was associated with increased cytomegalovirus viremia versus patients with no (OR, 7.23 [1.95-26.8], P = 0.018) or non-DDR CH (OR, 7.64 [1.77-32.89], P = 0.024) and mycophenolate discontinuation (aOR, 3.8 [1.3-12.9], P = 0.031). CONCLUSIONCH in DDR genes is prevalent in lung transplant recipients and is associated with posttransplant outcomes including cytomegalovirus activation and mycophenolate intolerance. FUNDINGNIH/NHLBI K01HL155231 (LKT), R25HL105400 (LKT), Foundation for Barnes-Jewish Hospital (LKT), Evans MDS Center at Washington University (KAO, MJW), ASH Scholar Award (KAO), NIH K12CA167540 (KAO), NIH P01AI116501 (AEG, DK), NIH R01HL094601 (AEG), and NIH P01CA101937 (DCL).

Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2+ monocyte-driven BOS development. Moreover, we found TGF-β receptor 2-dependent differentiation of CCR2+ monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8+ T cells that inflicted airway injury through Blimp-1-mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β-dependent network that couples CCR2+ monocyte recruitment and differentiation to alloimmunity and BOS.

The Translational Science TS22 conference in Chicago in April 2022 was the first time post-pandemic that members of the Association of Clinical and Translational Science were able to meet up in person to share scientific advances. Given the remaining level of risk due to COVID-19, the meeting was designed as hybrid allowing virtual participation to some of the presentations. Prior to the meeting, JCTS Junior Editors were invited to report on the plenary sessions of the meeting. The present perspective constitutes a summary of three plenary sessions., (© The Author(s) 2022.)

Background: Mechanical ventilation immediately after lung transplantation may impact the development of primary graft dysfunction (PGD), particularly in cases of donor-recipient size mismatch as ventilation is typically based on recipient rather than donor size., Methods: We conducted a retrospective cohort study of adult bilateral lung transplant recipients at our center between January 2010 and January 2017. We defined donor-based lung protective ventilation (dLPV) as 6 to 8 ml/kg of donor ideal body weight and plateau pressure <30 cm H 2 O. We calculated the donor-recipient predicted total lung capacity (pTLC) ratio and used logistic regression to examine relationships between pTLC ratio, dLPV and PGD grade 3 at 48 to 72 hours. We used Cox proportional hazards modelling to examine the relationship between pTLC ratio, dLPV and 1-year survival., Results: The cohort included 373 recipients; 24 (6.4%) developed PGD grade 3 at 48 to 72 hours, and 213 (57.3%) received dLPV. Mean pTLC ratio was 1.04 ± 0.18. dLPV was associated with significantly lower risks of PGD grade 3 (OR = 0.44; 95% CI: 0.29-0.68, p < 0.001) and 1-year mortality (HR = 0.49; 95% CI: 0.29-0.8, p = 0.018). There was a significant association between pTLC ratio and the risk of PGD grade 3, but this was attenuated by the use of dLPV., Conclusions: dLPV is associated with decreased risk of PGD grade 3 at 48 to 72 hours and decreased 1-year mortality. Additionally, dLPV attenuates the association between pTLC and both PGD grade 3 and 1-year mortality. Donor-based ventilation strategies may help to mitigate the risk of PGD and other adverse outcomes associated with size mismatch after lung transplantation., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Factors contributing to donor-specific HLA antibody (DSA) development after lung transplantation have not been systematically evaluated. We hypothesized that the isolation of Pseudomonas aeruginosa in respiratory specimens would increase the risk of DSA development. Our objective was to determine the risk of DSA development associated with the isolation of Pseudomonas aeruginosa after lung transplantation. We conducted a single-center retrospective cohort study of primary lung transplant recipients and examined risk factors for DSA development using Cox regression models. Of 460 recipients, 205 (45%) developed DSA; the majority developed Class II DSA (n = 175, 85%), and 145 of 205 (71%) developed DSA to HLA-DQ alleles. Univariate time-dependent analyses revealed that isolation of Pseudomonas from respiratory specimens, acute cellular rejection, and lymphocytic bronchiolitis are associated with an increased risk of DSA development. In multivariable analyses, Pseudomonas isolation, acute cellular rejection, and lymphocytic bronchiolitis remained independent risk factors for DSA development. Additionally, there was a direct association between the number of positive Pseudomonas cultures and the risk of DSA development. Our findings suggest that pro-inflammatory events including acute cellular rejection, lymphocytic bronchiolitis, and Pseudomonas isolation after transplantation are associated with an increased risk of DSA development., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan-Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37-44.04), p = 0.021; rs4149117 HR 7.28 (1.27-41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06-3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13-4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.

Although neutropenia is a common complication after lung transplant, its relationship with recipient outcomes remains understudied. We evaluated a retrospective cohort of 228 adult lung transplant recipients between 2008 and 2013 to assess the association of neutropenia and granulocyte colony-stimulating factor (GCSF) treatment with outcomes. Neutropenia was categorized as mild (absolute neutrophil count 1000-1499), moderate (500-999), or severe (<500) and as a time-varying continuous variable. Associations with survival, acute rejection, and chronic lung allograft dysfunction (CLAD) were assessed with the use of Cox proportional hazards regression. GCSF therapy impact on survival, CLAD, and acute rejection development was analyzed by propensity score matching. Of 228 patients, 101 (42.1%) developed neutropenia. Recipients with severe neutropenia had higher mortality rates than those of recipients with no (adjusted hazard ratio [aHR] 2.97, 95% confidence interval [CI] 1.05-8.41, P = .040), mild (aHR 14.508, 95% CI 1.58-13.34, P = .018), or moderate (aHR 3.27, 95% CI 0.89-12.01, P = .074) neutropenia. Surprisingly, GCSF treatment was associated with a higher risk for CLAD in mildly neutropenic patients (aHR 3.49, 95% CI 0.93-13.04, P = .063), although it did decrease death risk in severely neutropenic patients (aHR 0.24, 95% CI 0.07-0.88, P = .031). Taken together, our data point to an important relationship between neutropenia severity and GCSF treatment in lung transplant outcomes., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Lung Transplant recipients are at increased risk of complicated diverticular disease. We aim to assess the rate of diverticular surgery in a postlung transplantation population and identify risk factors for surgery. We performed a retrospective cohort study of lung transplant recipients from 2007 to 2011. Demographic variables were evaluated with the Mann-Whitney U and chi-squared tests. Cox regression was performed to evaluate 1- and 2-year landmark survival, assess predictor variables of diverticular surgery and evaluate impact of surgery on CLAD development. Of 17 of 158 patients (10.7%) underwent diverticular-related surgery. Surgical patients had significantly worse survival than nonsurgical patients at 1 year [aHR 2.93 (1.05-8.21), P = 0.041] and 2 year [aHR 4.17 (1.26-13.84), P = 0.020] landmark analyses. Transplant indication of alpha-1 antitrypsin disease and cystic fibrosis were significantly associated with the need for diverticular surgery. Emergent surgery was associated with poorer survival [aHR 5.12(1.00-26.27), P = 0.050]. Lung transplant patients requiring surgery for complicated diverticular disease have significantly poorer survival than those who do not require surgery. Surgery was more common in patients transplanted for A1AT and CF. Optimal assessment and risk stratification of diverticular disease is necessary to prevent excessive morbidity and mortality following transplantation., (© 2019 Steunstichting ESOT.)

Rationale: Allosensitization may be a barrier to lung transplant. Currently, consideration is not given to allosensitization when assigning priority on the lung transplant waiting list. Objectives: We aimed to examine the association between allosensitization and waiting list outcomes. Methods: We conducted a retrospective single-center cohort study of adults listed for lung transplant at our center between January 1, 2006, and December 31, 2016. We screened candidates for human leukocyte antigen antibodies before listing and examined the association between allosensitization and waiting list outcomes, including likelihood of transplant and death on the waiting list, using a competing risk model. Calculated panel-reactive antibody (CPRA) was used as a continuous measure of allosensitization. Results: Among 746 candidates who were listed for lung transplant during the study period, 263 (35%) were allosensitized, and 483 (65%) were not. In unadjusted analysis, allosensitized candidates had a decreased likelihood of transplant compared with nonallosensitized candidates (subhazard ratio [sHR], 0.71; 95% confidence interval [CI], 0.60-0.83; P  < 0.001) and were more likely to die on the waiting list (sHR, 1.66; 95% CI, 1.08-2.58; P  < 0.001). In multivariable modeling, increasing CPRA was associated with an increased risk of death and a decreased likelihood of transplant (sHR for death, 1.15 per 10% increase in CPRA; 95% CI, 1.07-1.22; P  < 0.001; sHR for transplant, 0.89 per 10% increase in CPRA; 95% CI, 0.86-0.91; P  < 0.001). Conclusions: Broad allosensitization was associated with longer waiting times, decreased likelihood of transplant, and increased risk of death among candidates on the waiting list for lung transplant. Consideration of allosensitization in organ allocation strategies might help mitigate this increased risk in highly allosensitized candidates.

Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage-associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)-induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Lung transplant (LTx) recipients have low long-term survival and a high incidence of bronchiolitis obliterans syndrome (BOS). However, few long-term, multicenter, and precise estimates of BOS-free survival (a composite outcome of death or BOS) incidence exist., Methods: This retrospective cohort study of primary LTx recipients (1994-2011) reported to the International Society of Heart and Lung Transplantation Thoracic Transplant Registry assessed outcomes through 2012. For the composite primary outcome of BOS-free survival, we used Kaplan-Meier survival and Cox proportional hazards regression, censoring for loss to follow-up, end of study, and re-LTx. Although standard Thoracic Transplant Registry analyses censor at the last consecutive annual complete BOS status report, our analyses allowed for partially missing BOS data., Results: Due to BOS reporting standards, 99.1% of the cohort received LTx in North America. During 79,896 person-years of follow-up, single LTx (6,599 of 15,268 [43%]) and bilateral LTx (8,699 of 15,268 [57%]) recipients had a median BOS-free survival of 3.16 years (95% confidence interval [CI], 2.99-3.30 years) and 3.58 years (95% CI, 3.53-3.72 years), respectively. Almost 90% of the single and bilateral LTx recipients developed the composite outcome within 10 years of transplantation. Standard Registry analyses "overestimated" median BOS-free survival by 0.42 years and "underestimated" the median survival after BOS by about a half-year for both single and bilateral LTx (p < 0.05)., Conclusions: Most LTx recipients die or develop BOS within 4 years, and very few remain alive and free from BOS at 10 years post-LTx. Less inclusive Thoracic Transplant Registry analytic methods tend to overestimate BOS-free survival. The Registry would benefit from improved international reporting of BOS and other chronic lung allograft dysfunction (CLAD) events., (Copyright © 2018 Elsevier Ltd. All rights reserved.)