Search

Background Outcomes after lung retransplantation (LRT) remain inferior compared with primary lung transplantation (PLT). This study examined the impact of center volume on 1-year survival after LRT. Methods Using the United Network for Organ Sharing database, the study abstracted patients undergoing PLT and LRT between January 2006 and December 2017, excluding combined heart-lung transplants and multiple retransplants. One-year survival rates after PLT and LRT were compared using propensity score matching. In the LRT cohort, multivariable Cox models with and without time-dependent coefficients were fitted to examine association between transplant center volume and 1-year survival. Center volume was categorized on the basis of inspection of restricted cubic splines. Results A total of 20,675 recipients (PLT 19,853 [96.0%] vs LRT 822 [4.0%]) were included. One-year survival was lower for LRT recipients in the matched cohort (PLT 84.8% vs LRT 76.7%). There was steady improvement in 1-year survival after LRT (2006 to 2009 72.1% vs 2010 to 2013 76.6% vs 2014 to 2017 80.1%). Higher center volume was associated with better 1-year survival after LRT. This survival difference was noted in the initial 30 days after transplantation (intermediate vs low volume hazard ratio, 0.282 [95% confidence interval, 0.151 to 0.526]; high vs low volume hazard ratio, 0.406 [95% confidence interval, 0.224 to 0.737]), but it became insignificant after 30 days. Conclusions Superior 1-year survival after LRT at higher-volume centers is predominantly the result of better 30-day outcomes. This finding suggests that LRT candidates may be referred to higher-volume centers for surgery.

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

Background Pulmonary embolism (PE) is unexpectedly detected in some donor lungs during organ procurement for lung transplantation. Anecdotally, such lungs are usually implanted; however, the impact of this finding on recipient outcomes remains unclear. We hypothesized that incidentally detected donor PE is associated with adverse short-term and long-term outcomes among lung transplant recipients. Methods We analyzed a prospectively maintained database of all lung donors procured by a single surgeon and transplanted at our institution between 2009 and 2018. A standardized approach was used for all procurements and included antegrade and retrograde flush. Pulmonary embolism was defined as macroscopic thrombus seen in the pulmonary artery during the donor procurement operation. Results A total of 501 consecutive lung procurements were performed during the study period. The incidence of donor PE was 4.4% (22 of 501). No organs were discarded owing to PE. Donors with PE were similar to donors without PE in baseline characteristics and Pa o 2. Recipients in the two groups were also similar. Pulmonary embolism was associated with a higher likelihood of acute cellular rejection grade 2 or more (10 of 22 [45.5%] vs 120 of 479 [25.1%], P = .03). Multivariable Cox modeling demonstrated an association between PE and the development of chronic lung allograft dysfunction (hazard ratio 2.02; 95% confidence interval, 1.23 to 3.30; P = .005). Conclusions Lungs from donors with incidentally detected PE may be associated with a higher incidence of recipient acute cellular rejection as well as reduced chronic lung allograft dysfunction-free survival. Surgeons must use caution when transplanting lungs with incidentally discovered PE. These preliminary findings warrant corroboration in larger data sets.

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.

The purpose of this study was to recognize clinically meaningful differences in lung transplant outcomes based on local or distant lung procurement. This could identify if the lung allocation policy change would influence patient outcomes.This single-center retrospective cohort study analyzed adult patients who underwent lung transplant from 2006 to 2017. Donor and recipient data were abstracted from a collaborative, prospective registry shared by our local organ procurement organization, and tertiary medical center. Short-term outcomes, 1-year survival, and hospitalization costs were compared between local and distant lung transplants defined by donor service area.Of the 722 lung transplants performed, 392 (54%) had local donors and 330 (46%) had distant donors. Donors were similar in age and cause of death. Recipients were significantly different in diagnosis and local recipients had lower median lung allocation scores (local, 37.3 and distant, 44.9; P .01). Distant lung transplants had longer total ischemic times (local, 231 ± 52 minutes and distant, 313 ± 48 minutes; P .01). The rate of major complications, length of hospital stay, and 1-year survival were similar between groups. Distant lung transplants were associated with higher median overall cost (local, $183,542 and distant, $229,871; P .01). Local lung transplants were more likely to be performed during daytime (local, 333 out of 392 [85%] and distant, 291 out of 330 [61%]; P .01).Local lung transplants are associated with shorter ischemic times, lower cost, and greater likelihood of daytime surgery. Short- and intermediate-term outcomes are similar for lung transplants from local and distant donors. The new lung allocation policy, with higher proportion of distant lung transplants, is likely to incur greater costs but provide similar outcomes.

A key component of both innate and adaptive immunity, new understandings of the complement system are expanding its roles beyond that traditionally appreciated. Evidence is accumulating that complement has an intracellular arsenal of components that provide not only immune defense, but also assist in key interactions for host cell functions. Although early work has primarily centered on T cells, the intracellular complement system likely functions in many if not most cells of the body. Some of these functions may trace their origins to the primitive complement system that began as a primeval form of C3 likely tasked for protection from intracellular pathogen invasion. This later expanded to include extracellular defense as C3 became a secreted protein to patrol the vasculature. Other components were added to the growing system including regulators to protect host cells from the indiscriminate effects of this potent system. Contemporary cells may retain some of these vestigial remnants. We now know that a) C3 serves as a damage-associated molecular pattern (in particular by coating pathogens that translocate into cells), b) most cells store C3 and recycle C3(H2O) for immediate use, and c) C3 assists in cellular survival and metabolic reprogramming. Other components also are part of this hidden arsenal including C5, properdin, factors H and B, and complement receptors. Importantly, better definition of the intracellular complement system may translate into new target discovery to assist in creating the next generation of complement therapeutics.

Pattern recognition receptors (PRRs) are germline-encoded sensors best characterized for their critical role in host defense. However, there is accumulating evidence that organ transplantation induces the release or display of molecular patterns of cellular injury and death that trigger PRR-mediated inflammatory responses. There are also new insights that indicate PRRs are able to distinguish between self and non-self, suggesting the existence of non-clonal mechanisms of allorecognition. Collectively, these reports have spurred considerable interest into whether PRRs or their ligands can be targeted to promote transplant survival. This review examines the mounting evidence that PRRs play in transplant-mediated inflammation. Given the large number of PRRs, we will focus on members from four families: the complement system, toll-like receptors, the formylated peptide receptor, and scavenger receptors through examining reports of their activity in experimental models of cellular and solid organ transplantation as well as in the clinical setting.

Purpose Antibody mediated rejection (AMR) has become an increasingly recognized form of lung transplant rejection. Our group recently identified Pseudomonas aeruginosa infection as a risk factor for clinical AMR but whether infection is sufficient for donor specific antibody (DSA) production and AMR remains unknown. Here we ask in a mouse model of orthotopic lung allograft transplantation whether airway infection with P. aeruginosa promotes DSA generation and AMR. Methods Balb/c lungs were transplanted into the following recipients: B6 WT (wildtype), uMT KO (No B cells), AID/uS KO (Have B cells but are unable to secrete Ig), CD19 Cre , CD19 Cre x TLR4fl/fl and CD19 Cre x MyD88fl/fl. Lung recipients were immunosuppressed with costimulatory blockade on post-operative day (POD) 0 (CD40L Ab) and POD 2 (CTLA4Ig) to induce allograft acceptance. On POD 21 recipients received intratracheal saline or 2 x 105 pfu/g body weight of live P. aeruginosa (clinical isolate M57-15) and then treated with ciprofloxacin from POD 22 to 25. On POD 42 peripheral blood was assessed for DSA and graft tissue evaluated for C4d deposition or quantitated for plasma cells (PC) by flow cytometric analysis (FACS). Results P. Aeruginosa infection stimulated high amounts of DSA generation and marked C4d deposition. In contrast, C4d deposition was nearly absent in uMT and AID/uS KO recipients. Infected recipients with TLR4 or MyD88 targeted-deficiency in B cells had sharply lower DSA when compared to WT controls. P. aeruginosa infection drove a 4-fold expansion of allograft resident PCs that was largely dependent on maintaining B cell TLR4-MyD88 signaling. In contrast, the spleen and bone marrow had only modest changes in PC abundance despite infection. Surprisingly, re-transplantation of P. aeruginosa-infected lung allografts into secondary uMT KO recipients revealed that lung allograft-resident PCs are capable of producing large amounts of DSA. Conclusion Collectively, these data show that P. aeruginosa infection abrogates established lung transplant tolerance through engaging innate immune signaling pathways within the B cell compartment. Additionally, we make the novel observation that the lung is a suitable environment for PC development with implications for clinical AMR.

Purpose It is unclear whether mechanical ventilator settings impact the risk of primary graft dysfunction (PGD) after lung transplantation. Importantly, ventilator settings are typically based on recipient rather than donor weight and height. In this study, we examined the relationship between lung protective ventilation based on donor size and PGD. Methods We analyzed 373 adult bilateral lung transplant recipients at our center between 1/2010 and 1/2017. We collected recipient, donor, and ventilator data after transplantation. We defined PGD as PGD 3 between 24 and 72 hours after transplantation and lung protective ventilation as a maximum tidal volume Results In univariate analysis, maximum tidal volume expressed as ml/kg of donor ideal body weight was associated with a significantly increased risk of PGD 3, (OR=1.42; 95%CI = 1.12-1.72, p>0.001). Similarly, lack of lung protective ventilation was associated with a significantly increased risk of PGD 3 (OR=5.56; 95%CI = 1.89-16.34, p=0.002). PGD risk factors that were significant in the univariate analysis were included in the multivariate analysis. In multivariate analysis, maximum tidal volume remained an independent predictor of PGD 3. Similarly, lack of lung protective ventilation remained an independent predictor of PGD 3. Conclusion Higher tidal volumes and not receiving lung protective ventilation were associated with an increased risk of PGD 3 between 24 and 72 hours. This suggests that adjusting ventilator settings based on donor size and lung protective ventilation after transplantation may mitigate the risk of PGD.

Purpose CARV infections are associated with an increased risk of CLAD development and progression. Inhaled corticosteroids are used to treat airway inflammation , but there is a dearth of data regarding their use in lung transplantation . This study aimed to examine the effect of inhaled beclomethasone on the development and progression of CLAD after CARV. Methods Single-center, double blind, pilot, randomized, placebo controlled trial of inhaled beclomethasone in adult LTR diagnosed with a CARV between Jan 2017 and Dec 2017. Patients were randomized in a 1:1 ratio stratified by BOS stage (BOS 0/0p vs 1/2) within 7 days of CARV. Study drug was continued for 6 months. The primary endpoint was freedom from new or progressive CLAD (defined as a 15% decline in pre CARV FEV1). Secondary endpoints included all-cause mortality and development of new DSA post-CARV. Results 7 patients were randomized to inhaled beclomethasone and 8 to placebo. Baseline demographics were well matched between groups including gender, age at LTR, time from LTR to CARV, upper vs lower CARV, BOS stage, and DSA at the time of study enrollment (Table 1). There was no difference in freedom from CLAD or CLAD progression between the 2 groups (Figure 1). No patients died or developed new DSA during the study period. Conclusion Inhaled beclomethasone was not associated with a lower incidence of new or progressive CLAD after CARV when compared to placebo. However, this study had limited power and sample size. Additional studies are necessary to assess the potential benefit of inhaled corticosteroids in LTR after CARV.

Purpose We aimed to identify clinical predictors of a favorable response to treatment with extracorporeal photopheresis (ECP) in lung transplant (Tx) recipients with CLAD. Methods Lung Tx recipients followed at Barnes-Jewish Hospital treated with ECP for CLAD were retrospectively identified. Patient characteristics, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were recorded for the 6 month(mo)s prior to and 12 mos after initiation of ECP. FEV1 was plotted vs. time, and a linear regression line was drawn through the data points. The slope (ml/mo) of the linear regression line was compared pre- and post- ECP using the Wilcoxon signed rank test. FEV1 and FVC were recorded as 0 at the time of re-Tx or death. A favorable response was defined as post-ECP FEV1 slope (ml/mo) > 0. Univariate and multivariable logistic regression models were created to identify covariates associated with a favorable response. Results 208 lung Tx recipients treated with ECP for CLAD between 11/1991-4/2017 were identified. During the study period, 16 patients were treated with 2 separate courses of ECP, totaling 223 ECP treatment courses. Recipient, donor and transplant characteristics are listed in Table 1. The median time to initiation of ECP from date of Tx was 1286.0 days (IQR: 646.8-2839.5). The median rate of change in FEV1 was -94.78 ml/mo (-195.88 ∼ -48.24) pre-ECP, and -13.74 ml/mo (-43.04 ∼ 0.98) post-ECP (p 58/223 (26.0%) treatment courses met criteria for a favorable response. Complications developed in 15 (6.7%) patients and were mostly catheter related. In univariate and multivariable logistic regression, none of the covariates (age, gender, primary diagnosis, rate of FEV1 decline pre-ECP, time from Tx, time from BOS diagnosis, RAS, early BOS) were significantly associated with response. Conclusion Over 25% of patients with CLAD had a favorable response with an improvement in FEV1 in the 12 mos after ECP initiation. However, we could not identify clinical predictors of a favorable response.

Purpose This study aimed to classify and grade airway complications after lung transplant and to evaluate the risk of airway complications associated with antifibrotic use at a single lung transplant center. Methods All cases of lung transplantation at Barnes-Jewish Hospital between 1/1/2015 and 5/31/2018 were reviewed. Airway complications were graded using the 2018 ISHLT Consensus Statement on Adult Anastomotic Airway Complications. Antifibrotic use within 2 weeks of transplant was evaluated for association with airway complications by logistic regression. Results Based on the ISHLT Consensus definition, 159/261 patients (60.9%) had an airway complication; among these, only 20 (7.6%) were considered severe. There was no association between diagnosis for transplant and the development of an airway complication. AF use was associated with severe ischemic airway complication; among 58 who were on an AF agent pre-transplant, 8 (13.8%) developed an airway complication after transplant (odds ratio [OR] 2.547; 95% confidence interval [CI], 0.988 to 6.567; p = 0.053). This association was significant for nintedanib (OR 3.767; 95% CI, 1.119 to 12.681; p = 0.032) but not pirfenidone (OR 1.471; 95% CI, 0.465 to 4.660; p = 0.511). AF use was also associated with development of anastomotic stenosis; 14/58 (24.1%) developed anastomotic stenosis (OR 2.074; 95% CI, 1.004 to 4.283; p = 0.049). This association was not significant for nintedanib (OR 2.044; 95% CI, 0.693 to 6.022; p = 0.195) or pirfenidone (OR 1.781; 95% CI, 0.774 to 4.100; p = 0.175). AF use was not associated with anastomotic dehiscence; 8/58 (13.8%) developed a dehiscence (OR 1.139; 95% CI, 0.484 to 2.681; p = 0.765). Conclusion The grading system proposed by the 2018 ISHLT Consensus Statement led to identification of airway complication in >60% of lung transplants in this cohort, but most were considered mild and did not require intervention. Antifibrotic use was associated with increased risk of severe ischemic airway complications and anastomotic stenosis.

Invasive aspergillosis (IA) is the most common invasive mold infection in solid organ transplant (SOT) recipients, occurring in 1-15% of recipients, with a 12-week mortality rate of 20-60%.1 Lung transplant (LTx) recipients are at the highest risk for IA among all SOT recipients, ranging from ulcerative tracheobronchitis, anastomotic site involvement and airway wall necrosis, to pneumonia, mediastinitis, empyema and disseminated fungemia. Additionally, Aspergillus colonization is an independent risk factor for chronic lung allograft dysfunction. Resultingly, a majority of LTx programs now use antifungal prophylaxis against Aspergillus. This article is protected by copyright. All rights reserved.

Background It is uncertain whether the effort and expense of performing a second walk for the 6-min walk test improves test performance. Hence, we attempted to quantify the improvement in 6-min walk distance if an additional walk were to be performed. Methods We studied patients consecutively enrolled into the National Emphysema Treatment Trial who prior to randomization and after 6 to 10 weeks of pulmonary rehabilitation performed two 6-min walks on consecutive days (N = 396). Patients also performed two 6-min walks at 6-month follow-up after randomization to lung volume reduction surgery (n = 74) or optimal medical therapy (n = 64). We compared change in the first walk distance to change in the second, average-of-two, and best-of-two walk distances. Results Compared with the change in the first walk distance, change in the average-of-two and best-of-two walk distances had better validity and precision. Specifically, 6 months after randomization to lung volume reduction surgery, changes in the average-of-two ( r = 0.66 vs r = 0.58, P = .01) and best-of-two walk distances ( r = 0.67 vs r = 0.58, P = .04) better correlated with the change in maximal exercise capacity (ie, better validity). Additionally, the variance of change was 14% to 25% less for the average-of-two walk distances and 14% to 33% less for the best-of-two walk distances than the variance of change in the single walk distance, indicating better precision. Conclusions Adding a second walk to the 6-min walk test significantly improves its performance in measuring response to a therapeutic intervention, improves the validity of COPD clinical trials, and would result in a 14% to 33% reduction in sample size requirements. Hence, it should be strongly considered by clinicians and researchers as an outcome measure for therapeutic interventions in patients with COPD.