Single LTx Research Articles

Dissecting Serial Immune Response Stages of Chronic Rejection after Murine Orthotopic Lung Transplantation

<h3>Purpose</h3> "Chronic rejection" (CR) after lung transplantation (LTx) is considered to be a cellular and humoral immune response, accompanied by angiogenesis and fibrosis, clinically denominated as chronic lung allograft dysfunction (CLAD). We aimed to reinvestigate the chronological stages and spatial organization of the immune response of CR. <h3>Methods</h3> Orthotopic single LTx was performed to create isograft (n=9; C57BL/6N to C57BL/6N) and two allograft (n=16; BALB/c to C57BL/6N) subgroups: 1/ observational group (n=8), with serial sacrifice at week 1, 3, 5 and 8 to evaluate the sequential, spatial and cellular events of CR; and 2/ validation group (week 10; n=8) to assess variation within CR. All mice received daily immunosuppression of 10 mg/kg cyclosporine A and 1.6 mg/kg methylprednisolone. <h3>Results</h3> In 1 isograft technical failure occurred and 8 had normal lung architecture at week 10. In 3 allografts failure occurred: 2 in the observational, 1 in the validation group. Histological evaluation of allografts allowed reconstruction of CR: STAGE 1: innate inflammation around end-arteries; STAGE 2: innate immune cells around end-arteries and end-venules; STAGE 3: adaptive immune cell organization around end-arteries; innate immune cells around end-venules; pleural infiltration of lymphocytes; STAGE 4: fibrosis around end-arteries with end-arteritis obliterans; adaptive immune cells around the end-venules; pleural lymphatic vessel growth and fibrosis; bronchiolar wall folding and sporadic intraluminal fibrotic plugging. In the validation group, we identified 2 mice in STAGE 2, 2 in STAGE 3 and 3 in STAGE 4. µCT confirmed the progression of severe (stage 4) vs mild (stage 2-3) in lung attenuation (1.05±0.04 vs 1.14±0.01; p=0.002) (Figure) and total and tidal volume. <h3>Conclusion</h3> CR demonstrated an innate onset, evolving to adaptive organization and fibrosis, starting at end-arteries and then spreading towards venules, pleura and airways. This pattern seems to resemble RAS after human LTx.

Coronary Artery Disease Screening for Lung Transplant Candidates

Purpose Lung transplant (LTx) candidates have increase age and higher incidence of Coronary Artery Disease (CAD). As CAD is often asymptomatic, its identification is not always straightforward, therefore, LTx candidates need to be submitted to a meticulous screening before entering the waitlist. Although coronary angiography (CA) is the gold standard test for this purpose, it's an invasive exam with possible complications. We revised all CA in the LTx candidates in the last 5 years regarding diagnoses, treatments and outcomes. Methods We conducted a retrospective study reviewing medical records between January/2014 - December/2019 of all LTx candidates in a single LTx center in Sao Paulo, Brazil. All candidates of 40 years-old and older undergo a CA independently of risk factor or comorbidities. Therefore, we revised all CA performed to analyze the findings, complications and outcomes in all patients submitted to this exam. Results A total of 526 LTx candidates medical records were analyzed. Coronary angiography was performed in 234 patients (44%). Of all procedures, 30 (12,8%) patients had at least 1 coronary artery injury; 28 (93,3%) of them were over 50 years old. Out of these 28 patients, 18 had LTx contraindicated, 5 were submitted to LTx, 4 died during the waiting list, 1 is still at waitlist and 2 are in evaluation pre-LTx.From all 234 CA, there were 5 (2,1%) unexpected complications: 2 right coronary vasospasms, 1 stroke, 1 descending anterior coronary artery dissection and 1 radial artery lesion. Among these complications, 3 patients had less than 50 years old.No patients were submitted to myocardial revascularization before or during the transplant and 9 (30%) patients underwent angioplasty: 8 patients had LTx contraindication because of multiple comorbidities and 1 patient is still on the waiting list. Conclusion Our study reinforces the screening for CAD among LTx candidates, especially in those over 50 years-old. Maybe, for patients between 40 - 50 years-old, CA should only be considered if risk factors are present.

Experience-Dependent Pathological Variations in Minor-Mismatched Mouse Lung Transplantation

<h3>Purpose</h3> Mouse orthotopic single lung transplantation (LTx) is a useful scientific model to explore LTx immunology. C57BL/10 (B10, H-2^b) to C57BL/6 (B6, H-2^b) minor alloantigen-mismatched LTx exhibits mild acute rejection and sometimes chronic fibrosis, mimicking human LTx where alloimmunity is dampened by immunosuppressants. We have observed variations in allograft histology across experiments, which were not explained by animal vendor or experimental conditions. The purpose of this study was to evaluate those variations objectively. <h3>Methods</h3> We performed a retrospective review of B10 to B6 LTx performed in our lab and sacrificed 28 days after LTx. LTx with an experimental intervention (e.g., usage of immunomodulatory agents or knock-out mice) were excluded. Surgeons 1 and 2 had had previous rodent LTx experience whereas Surgeons 3-5 had not. Each surgeon's first 10, middle 10, and last 10 LTx in our lab were pathologically graded in a blinded manner. Nonparametric Spearman correlation was computed to compare chronological variation across surgeons. Inter-surgeon differences were compared using two-way ANOVA. <h3>Results</h3> Data from 143 LTx were available from five surgeons' records. Surgeon 1's and 2's pathology scores were mostly stable throughout the period (e.g. for B-grade rejection, Surgeon 1 r=0.10 and p=0.60, Surgeon 2 r=-0.11 and p=0.55), whereas those of surgeons 3-5 changed over time (e.g. for B-grade rejection, Surgeon 4 r=-0.57 and p<0.01, Surgeon 5 r=0.54 and p<0.01) (Fig 1A). A similar tendency was observed in A-grade rejection and obliterative-airway fibrosis. Each surgeon's trajectory was significantly different from each other (Fig 1B). <h3>Conclusion</h3> Mouse single LTx is a powerful model to study the underlying mechanisms of LTx biology. However, the surgeon- and experience-dependent variability in histopathological findings need to be taken into account when designing experimental protocols, particularly when the model has recently been acquired by the surgeon.

Early Results after Lung Transplantation in Patients Bridged with Extracorporeal Life Support: Experience from a 7-year Period

Purpose Extracorporeal life support (ECLS) is being increasingly used in selected patients with end-stage pulmonary disease as a bridge to transplantation (BTT). In this study, we present our experience using preoperative ECLS in lung transplantation (LTx) and evaluate its impact on early outcome and survival. Methods We have performed a single-center retrospective analysis of all adult patients who were consecutively bridged to LTx using ECLS at Harefield Hospital between January 2012 and December 2018. Data were extracted from our institutional electronic medical records. Patients’ preoperative characteristics, use of perioperative ECLS, early postoperative results and in-hospital complications were analysed. Primary endpoint was 30-day mortality. Secondary endpoints were early postoperative outcomes. Results In total, 28 LTx recipients (53.6% males, mean age 32.6±10.6 years) were bridged to bilateral sequential single LTx with ECLS. The most common diagnoses were cystic fibrosis (75%), pulmonary artery hypertension (10.7%), fibrotic lung disease (7.1%), alpha-1 antitrypsin deficiency (3.6%) and others (3.6%). ECLS strategies included venovenous (VV) extracorporeal membrane oxygenation (ECMO; 71.4%), venoarterial (VA) ECMO (17.9%) and Novalung Interventional Lung Assist (iLA) device (10.7%). Median duration of bridging was 6 (range 2-53) days. Sixteen (57.1%) patients were awake and nonintubated during ECLS. Intraoperatively, 13 patients (46.4%) required cardiopulmonary bypass. Eleven patients stayed on VV ECMO, one on VA ECMO and 3 were converted to VA ECMO. Postoperatively, ECLS was utilized in 15 (53.6%) patients (6 VA ECMO/7 VV ECMO/2 Novalung). 30-day mortality was 21.4%. Median intensive care unit stay after LTx was 20 days. We have observed a delayed chest closure in 9 (32.1%) patients, surgical re-exploration for bleeding in 12 (42.9%) and renal failure requiring renal replacement therapy in 18 (64.3%). Conclusion We have performed a descriptive analysis of early postoperative outcomes of LTx in patients bridge with ECLS in a tertiary center over a 7-year period. Overall, we have demonstrated that, even if associated with high rate of early postoperative complications, ECLS as a BTT can be successfully used in selected patients with end-stage respiratory failure in a high-urgency setting.

Differential Outcomes of Lung Transplant Recipients as They Age: Is over 70 Too Old? No!

PurposeLung transplantation (LTX) is generally reserved for the young due to perioperative complications & organ utilization. We sought to evaluate the long-term outcomes of LTX in the septuagenarian.MethodsRetrospectively, LTX recipients in the UNOS transplant registry (May 1, 2005 to June 12, 2020) were stratified into 18-59, 60-69, and >=70 years of age. Recipient and transplant characteristics were evaluated for survival, cause of death (COD), length of stay (LOS) and complications. A Kaplan-Meier analysis examined long-term survival for all patients stratified by age, specifically looking at COD.ResultsA total of 27,632 recipients met inclusion criteria. As recipients aged, we found a decrease in proportion of cystic fibrosis & an increase in restrictive disease while obstructive disease peaked in the 60-69yo cohort (p<0.001). Recipient to donor age difference significantly increased with older recipients (p<0.001). >=70yo had higher rates of single LTX, male gender and white race (p<0.001). Older recipients had significantly longer recovery distances traveled with paradoxical shorter ischemic times, shorter LOS and were transplanted at higher volume centers. There was no difference with in-hospital mortality (p=0.5). Rejection during initial hospitalization and within 1 year and post-transplant dialysis incidence decreased with age. Graft and pulmonary failure were common COD in younger patients while malignancy and cardio/cerebrovascular diseases were common COD in >= 70yo (Figure).ConclusionSeptuagenarian LTX candidates may be safely transplanted with relatively few complications. Young transplant recipients appear more vulnerable to rejection and die more often of graft failure complications. Malignancy and cardio/cerebrovascular etiologies were more common COD in older recipients. Immuno-senescence and conditions of the aged are likely contributing factors to the less rejection and graft failure observations. The >=70yo should be considered a good LTX candidate. Lung transplantation (LTX) is generally reserved for the young due to perioperative complications & organ utilization. We sought to evaluate the long-term outcomes of LTX in the septuagenarian. Retrospectively, LTX recipients in the UNOS transplant registry (May 1, 2005 to June 12, 2020) were stratified into 18-59, 60-69, and >=70 years of age. Recipient and transplant characteristics were evaluated for survival, cause of death (COD), length of stay (LOS) and complications. A Kaplan-Meier analysis examined long-term survival for all patients stratified by age, specifically looking at COD. A total of 27,632 recipients met inclusion criteria. As recipients aged, we found a decrease in proportion of cystic fibrosis & an increase in restrictive disease while obstructive disease peaked in the 60-69yo cohort (p<0.001). Recipient to donor age difference significantly increased with older recipients (p<0.001). >=70yo had higher rates of single LTX, male gender and white race (p<0.001). Older recipients had significantly longer recovery distances traveled with paradoxical shorter ischemic times, shorter LOS and were transplanted at higher volume centers. There was no difference with in-hospital mortality (p=0.5). Rejection during initial hospitalization and within 1 year and post-transplant dialysis incidence decreased with age. Graft and pulmonary failure were common COD in younger patients while malignancy and cardio/cerebrovascular diseases were common COD in >= 70yo (Figure). Septuagenarian LTX candidates may be safely transplanted with relatively few complications. Young transplant recipients appear more vulnerable to rejection and die more often of graft failure complications. Malignancy and cardio/cerebrovascular etiologies were more common COD in older recipients. Immuno-senescence and conditions of the aged are likely contributing factors to the less rejection and graft failure observations. The >=70yo should be considered a good LTX candidate.

Delayed non-myeloablative irradiation to induce long-term allograft acceptance in a large animal lung transplantation model

We previously induced long-term allograft acceptance in an allogeneic lung transplantation (LTx) model in miniature swine using perioperative non-myeloablative irradiation (IRR) combined with infusion of donor specific alloantigen. In order to improve clinical applicability, we delayed induction with irradiation in this study. Left sided single LTx was performed in minipigs. Group 1 received non-myeloablative irradiation (7Gy thymus and 1.5Gy whole body IRR) before LTx and a perioperative donor specific splenocyte infusion (SpTx). Group 2 received perioperative SpTx but delayed IRR three days after LTx. Group 3 was exposed to delayed IRR without SpTx. Whereas 4 out of 7 animals from the non-delayed group never rejected their grafts and were electively sacrificed on postoperative day (POD) +500, all animals from group 2 rejected their grafts before POD 108. In group 3, 3 out of 8 animals developed long-term allograft acceptance. In all groups, donor leukocyte chimerism peaked up to 20% in peripheral blood one hour after reperfusion of the lung. Group 1 maintained prolonged chimerism beyond POD 7, whereas chimerism levels in groups 2 and 3 decreased continuously thereafter. Delayed irradiation has the potential to improve long-term graft survival, yet not as efficient as a perioperative conditioning protocol.

Perioperative transfusion practice in patients undergoing lung transplantation – experience from a 7-year period

Introduction Perioperative allogenic blood product transfusion is common in lung transplantation (LTx), particularly after an increased utilization of extracorporeal membrane oxygenation (ECMO) throughout the peritransplant period. The risks of massive transfusion of blood products are well-known, and may negatively influence LTx outcomes (1). We analyzed perioperative transfusion practice among the LTx recipients at our institution. Methods All consecutive patients who underwent LTx at Harefield Hospital between January 2012 and December 2018 were analyzed. Patients bridged to LTx with ECMO and preoperatively mechanically ventilated were included. Data were extracted from our institutional electronic system. The use of red blood cells (RBCs), fresh frozen plasma (FFP), and platelets (PLT) intraoperatively and postoperatively within the first 48 hours was investigated. Transfusion of >10 units of RBCs was considered as massive transfusion. Results A total of 304 LTx recipients (male gender 54.9%, mean age 45.9±12.3 years) underwent bilateral sequential single LTx (97.4%) or single LTx (2.6%). The most common diagnosis was cystic fibrosis (CF; 42.4%). Re-transplantation was performed in 3.3%. The percentage of recipients bridged to LTx with ECMO was 9.2% (20 patients with veno-venous [VV] ECMO, 5 with veno-arterial [VA] ECMO and 3 with Novalung). Intraoperative ECMO was required in 30 (9.9%) patients (11 VV ECMO/19 VA ECMO) and cardiopulmonary bypass (CPB) in 107 (35.2%), whereas 167 (54.9%) patients were operated off-pump. Postoperatively, ECMO was utilized in 35 (11.5%) patients (24 VA ECMO/10 VV ECMO/1 Novalung). Of these, 26 (74.3%) patients required conversion to ECMO following unsuccessful weaning from CPB, 6 (17.1%) continued to be supported after intraoperative ECMO, and 3 (8.6%) were initially operated off-pump. The median number of RBCs in the first 48 hours was 4 (0-71) units, FFP 2 (0-37) and PLT 1 (0-21). The overall incidence of patients requiring >10 units of RBCs in the first 48 hours was 22.1%, including all patients with idiopathic pulmonary arterial hypertension (IPAH), 50% of patients who underwent re-transplantation, and 31.8% of patients with CF. Patients who needed intraoperative MCS support had a higher incidence of massive transfusion (43% in the CPB group vs. 40% in the ECMO group vs. 5.4% in the off-pump group). The overall 30-day mortality rate was 6.9%, which increased to 23.9% among patients with massive transfusion. Discussion We performed a descriptive analysis of perioperative transfusion practice in a tertiary centre over a 7-year period and showed that MCS, IPAH, re-transplantation, and CF were associated with massive transfusion. Overall, we demonstrated a reasonably low incidence of perioperative blood transfusion and excellent 30-day survival. Further analysis is needed to investigate which perioperative factors may help minimize allogenic blood product usage in LTx and improve postoperative outcomes.

Respiratory mechanic evaluation using an esophageal balloon catheter in patient receiving lung transplantation. Observational study. Preliminary results

Introduction Mechanical ventilation (MV) plays a crucial role during the early post-operative period of lung transplantation (LTx). An accurate setting of MV is important in order to prevent ventilation-induced lung injury, which may lead to Primary Graft Dysfunction (PDG), and to set a protective ventilation strategy whenever this complication occurs. Unfortunately, respiratory mechanics may be unpredictable: these patients receive lungs which may not perfectly match their chest walls, causing a patient-donor size-mismatch, is conventionally defined by the ratio between recipient and donor lungs predicted-Total Lung Capacity (r-pTLC and d-pTLC, respectively) and may modify the distribution of pressures inside the respiratory system between lung and chest wall. In order to improve our understanding of the LTx respiratory mechanics and to evaluate whether ventilation setting was dangerous for the transplanted lungs, we placed an Esophageal Balloon Catheter (EBC) and analysed the esophageal pressure (Pes) in the early post-operative period of patients receiving bilateral sequential single LTx (BSSLTx). Methods We observed the respiratory mechanics of patients receiving BSSLTx over 1-year period at Molinette Hospital (Ospedale Molinette, Citta della Salute e della Scienza, Turin, Italy). For each patient respiratory mechanics was evaluated at least two times in the post-transplant period: intraoperatively (T0), just before the chest closure, and post-operatively (T1), in ICU. Patients and donors data, recipient-donor size-matching and outcomes were compared with respiratory mechanics. Results Between November 2018 and October 2019, we included 22 patients receiving LTx. Among them, 9 were excluded: 6 were single LTx, 1 was a paediatric patient and 2 patients had incomplete data. Among the 13 patients included, 3 (23%) developed PGD: 5 patients were best matched (d/pTLC 0,9 – 1,1; 5/13, 38,4%), 6 were undersized (d/pTLC 1,1; 2/13, 15,3%) but no correlation was found between size-matching and incidence of high-grade PGD (PGD grade 2 or 3) (Fig.1). We found no statistically significant difference in transpulmonary pressure (PTP i, PTP e, PTP drive), transpulmonary compliance (CTP) or chest elastance (ECW) at T0 or T1 in patients who developed PGD compared to those without PGD. However, we noticed an early raise of PTP i in patients who were going to develop PGD (no PGD δ% t0-t1 PTP i – 14,6% vs PGD δ% t0-t1 PTP i + 14,0%; p=0,1402) (Fig. 2). Moreover, we found that this early raising in PTP i (δ% t0-t1 PTP i) was statistically related with the ICU-length-of-stay (ICU-LOS) (r2=0,57; p=0,050) (Fig. 3) Discussion The overall incidence of PGD in our centre was 23%, however no correlation with patient-donor size-matching. An early raise of transpulmonary pressure was observed among patients who developed PGD and it was statistically correlated with higher ICU-LOS.

Characteristics of lung cancer in idiopathic pulmonary fibrosis with single lung transplant versus non-transplanted patients: a retrospective observational study

BackgroundPatients with idiopathic pulmonary fibrosis (IPF) have significantly higher incidence of lung cancer (LC) relative to the general population. There is a further increase in LC incidence in patients with...

Survival in Lung Transplant Recipients on a Calcineurin Free Regimen: Is It Possible?

Calcineurin inhibitors (CNI) are the cornerstone of immunosuppression in lung transplantation. The International Heart and Lung Transplant registry data estimates that almost 99% of patients are on a CNI-based immunosuppression regimen. The population of lung transplant (LTx) recipients not on a calcineurin inhibitor is exceedingly rare and their outcomes have not been previously examined in a systematic way. An IRB-approved, retrospective, observational, cohort study of LTx recipients who received CNI-free, everolimus (EVR)-based immunosuppression at the University of Colorado from January 1, 1995 - October 1, 2019. The health system's electronic medical records was queried to identify and collect data on eligible LTx recipients. All continuous variables are presented as median(range). Seven of 12 were single LTx (ILD, COPD), five were bilateral LTx,(ILD, COPD, CF) and one was a re-transplant. The majority (8/12) of patients were transitioned to CNI-free, EVR-based immunosuppression due to renal insufficiency, 3/12 due to metastatic cancer, and 1/12 due to both renal failure and cancer. Five of 12 were maintained on three agents (EVR, corticosteroid, and either methotrexate or azathioprine) and the others were on corticosteroids with EVR alone. The median time to transition to CNI-free immunosuppression was 8.8 (2.3 to 21.3) years. Median age at CNI cessation was 67 years old (40-72 years old). Median survival on CNI-free immunosuppression for all comers was 1.6 years with median survival in the deceased cohort (n=8) of 1 year (4 days to 4.6 years) and median survival in the living cohort (n=4) of 2.1 years (1.2 years to 8.2 years). At least three patients were treated with high dose steroids for presumed acute rejection after stopping the CNI. This review demonstrates that in certain situations withdrawal of CNI and transition to CNI-free, EVR- based immunosuppression may result in durable patient survival. Larger multicenter cohort analysis may be the next step in understanding the safety, efficacy and role of CNI-free immunosuppression, as equipoise would be impossible to achieve in a randomized controlled trial.

A Successful Strategy to Maximize Pulmonary Fibrosis (PF) Patient Access, Waiting List (WL) and Post-Lung Transplant (LTx) Survival

Access to LTx and rates of WL and post-Tx mortality for patients with PF are problematic. We have evolved a strategy to maximize Tx volume and improve survival for PF patients needing LTx. From 2012-2018, PF patients were priority assessed, listed and transplanted from a donor pool that included extended and DCD donors. Ex-vivo perfusion was not used. Patients were categorized as experiencing one of two competing events: LTx or WL death. Multivariable competing risk regression were performed for independent predictors of 1-yr post-listing mortality, and failure to reach LTx. From 187 patients listed, 82% (153/187) underwent LTx (median time to Tx, 2.0 mths), while 16% (29/187) died on WL (median time to death, 1.4 mths) Fig. A. Access to LTx for PF was 6.4 per million population (vs. USA = 2.9 p.m.p). Donors were 62% (88/153) extended criteria, including 24% (37/153) DCD. Single LTx was performed in 24% (36/153) of patients. PF comprised 29% (187/644) of all listed and 28% (153/547) of all transplanted patients during the study period. Multivariable predictors of 1-yr mortality from listing were: not receiving a LTx (HR 26, 95% CI 12 - 58, P < 0.0001), inpatient when listed (HR 3.2, 1.5 - 6.9, P = 0.002) and lower PaO2/FiO2 when listed (per 50mmHg less, HR 1.30, 1.04 - 1.63, P = 0.02). Multivariable predictors of failure to reach LTx were: height (per 1cm less, HR 1.11, 1.06-1.16, P<0.0001), blood type O (HR 4.3, 1.9 - 9.3, P < 0.0001) and inpatient when listed (HR 3.9, 1.8-8.5, P = 0.001). Survival after LTx is shown in Fig. B. Single or DCD LTx recipients had similar survival vs. double or DBD recipients (P = 0.6; 0.7). Follow up was 100% complete (mean: 2.5 ± 1.8 yrs). Pulmonary fibrosis continues to be presented late and requires a rapid transit to LTx. Use of extended and DCD donor organs facilitate a lower mortality risk than continued waitlist time and enable greater LTx access. Despite challenges, the majority of PF patients can reach LTx with excellent 5-yr survival.

A Data-Driven Approach to Defining the Volume-Outcome Relationship in Lung Transplantation

Advances in immunosuppression, bridging therapies, and ex vivo perfusion and ventilation have led to substantial advances in lung transplantation (LTx). Nevertheless, LTx is associated with substantial morbidity and mortality. Better outcomes have been demonstrated in "high volume" lung transplant centers, but the field lacks a definition of high volume. The present study aims to identify meaningful, data-driven volume thresholds predicting improved outcomes for LTx centers. All single and double LTx cases performed on patients over the age of 18 between 2005 and 2015 in the United Network for Organ Sharing (UNOS) database were reviewed. Patients listed for other organs or transplants performed in centers that were active for less than three of the ten years of the study period were excluded. Under 1% of patients were excluded due to lack of follow-up data. Stratum-specific likelihood ratios (SSLR) were calculated to establish volume thresholds predictive of the primary outcome of 1 year mortality. Demographic and outcomes data were compared between volume strata. A total of 20,153 recipients were included in the final cohort. We identified two thresholds based on SSLR analysis at 12 and 28 LTx/year, which yielded three distinct volume strata: low (under 12), intermediate (12-27), and high volume (over 27). The majority of transplants are performed at high volume centers, which have shorter lengths of stay (24 days vs 29 for low-volume) and better 30-day and 1-year patient survival (96.7% and 86%, vs 94.2% and 80.3% for low-volume), despite older recipients, greater ischemic time, and increased use of extended-criteria donors. The results of our study support that high volume centers outperform their low and intermediate volume counterparts and distinguish between the three volume levels. Our study adds to the existing literature by estimating targets for annual lung transplants at which centers may attain improvements in recipient outcomes.

Single Center Experience: Tricuspid Valve Insufficiency Resolution Post Lung Transplant

Tricuspid valve regurgitation (TR) is a frequent finding in patients undergoing lung transplantation (LTx). The prognostic significance and rate of regression of TR after LTx are under reported. Purpose of this study is to assess tricuspid valve regurgitation (TR) regression after lung transplantation (LTx) in patients with trivial to severe pre-operative TR. We retrospectively reviewed and prospectively collected records of 553 patients who had LTx at our institution from 2001 to 2017. Pre and post-op echocardiograms were retrospectively reviewed and was graded for severity of TR, right ventricular (RV) enlargement, tricuspid annular plane systolic excursion (TAPSE), mean pulmonary arterial pressure (mPAP) and other hemodynamics. Continuous variables were summarized with median and range (min, max) while categorical variables with frequency and percent. All statistical analyses were performed with R Statistical Software (version 3.4.2; R Foundation for Statistical Computing, Vienna, Austria). The mean age of the patients was 64 (21.0, 82.0) years and 324 (58.7%) were males. Out of all patients, the majority 302 (55.8%) suffered from IPF, followed by 84 (15.3%) PH, 79 (14.3%) COPD, 65 (11.8%) emphysema, and 31 (5.6%) CF. 417 (75.4%) had double LTx and 136 (24.6%) of patients required single LTx . Pre-operative tricuspid valve regurgitation reported as trivial (N=265, 47.9%) mild (N=235, 42.5%), moderate (N=40, 7.3%) and severe (N=13, 2.3%). TR improved from pre to post operatively in 193 (34.9%) out of 553 patients (p<0.001), while 99 (17.9%) out of 553 resulted in a worsened TR. However, of the patients that had a worsened TR, 78 of them went from trivial to mild (N=99, 79%). 81.9% (158/193) improved by one category while 18.1% (35/193) improved by two or more categories. Of those with worsened TR, the majority or (92.9%) (92/99) worsened by one category and 7% (7/99) worsened by two categories. There was a significant improvement from moderate/severe TR to mild, trivial, or none (p<0.001) 44 (N=53, 83%). There was also a significant decrease in mPAP (median: 27 (10-84) vs. 24 (9-89) p<0.001). Moderate to severe TR significantly improved after lung transplant. Our findings suggest that preoperative TR in lung recipients is mostly functional and will resolve after LTx. There is no need for tricuspid valve repair at the time of transplantation.

Use of Ceftazidime-Avibactam and Ceftolozane-Tazobactam After Lung Transplantation

IntroductionAfter lung transplantation (LTx), infections caused by multidrug-resistant (MDR) bacteria are frequent and difficult to treat. Some new antibiotics seem to be effective in treating these infections. Material and MethodsWe describe our experience in treatment of Klebsiella pneumoniae MDR and Pseudomonas aeruginosa MDR infections with ceftazidime-avibactam (CEF-AVI) and ceftolozane-tazobactam (CEFT-TAZ) in patients who underwent LTx. ResultsIn 3 patients who underwent double LTx and in 4 patients who underwent single LTx, strains of K. pneumoniae and P. aeruginosa were isolated from bronchoalveolar lavage. All patients showed worsening of respiratory functions, increasing in inflammation indexes, and, in some cases, onset of pulmonary consolidation. P. aeruginosa was treated with CEFT-TAZ for 10 days average (7-15 days) and K. pneumoniae with CEF-AVI for 14 days average (4-24 days). One patient developed a septic state caused by K. pneumoniae, requiring 24 days of therapy. None had shown side effects caused by drugs administration. One patient died after 15 days from lung transplant owing to primary graft dysfunction. ConclusionsCEF-AVI and CEFT-TAZ seems to be effective in treatment of infections caused by MDR bacteria after lung transplant.

Lung Density Analysis Using Quantitative Chest CT for Early Prediction of Chronic Lung Allograft Dysfunction.

Chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplantation (LTx). Early detection or prediction of CLAD can lead to changes in patient management that, in turn, may improve prognosis. The purpose of this study was to investigate the utility of quantitative computed tomography (CT) lung density analysis in early prediction of CLAD. This retrospective cohort was drawn from all consecutive adult, first LTxs performed between 2006 and 2011. Post-transplant monitoring included scheduled surveillance bronchoscopies with concurrent pulmonary-functions tests and low-dose chest CT. Quantitative density metrics (QDM) derived from CT scans obtained at the time of 10%-19% decline in forced expiratory volume in 1 second (FEV1) were evaluated: 114 bilateral LTx recipients (66 with CLAD and 48 stable) and 23 single LTx recipients (11 with CLAD, 12 stable) were included in the analysis. In both single and double LTx, at the time of 10%-19% drop in FEV1 from baseline, the QDM was higher in patients who developed CLAD within 3 years compared with those patients who remained stable for at least 3.5 years. The area under the receiver operating characteristic curve (AUC) was 0.89 for predicting CLAD in single LTx and 0.63 in bilateral LTx. A multipredictor AUC accounting for FEV1, QDM, presence of consolidation, and ground glass opacities increased the AUC to 0.74 in double LTx. QDM derived from a CT histogram at the time of early drop in FEV1 may allow prediction of CLAD in patients after single or double LTx.

Use of CT-SCAN score and volume measures to early identify restrictive allograft syndrome in single lung transplant recipients

Restrictive allograft syndrome (RAS) after lung transplantation (LTx) is associated with the poorer graft survival in patients with chronic lung allograft dysfunction (CLAD). Nevertheless, its diagnostic criteria have not been clearly defined after single-LTx (SLTx). Hence, we studied an SLTx cohort with CLAD to investigate the utility of both computed tomography (CT)-score/volume measures and functional spirometric criteria for the early identification of RAS in this population. We included 51 patients with SLTx (17 RAS, 17 bronchiolitis obliterans syndrome [BOS], and 17 stable condition). The criteria for RAS diagnosis in SLTx included forced vital capacity (FVC) <80% baseline (BL) or forced expiratory volume in 1 second (FEV1) <80% BL with an FEV1/FVC ratiounchanged or >0.7 and persistent CT-scan-lung opacities. We defined 4 time points (T): T-baseline, T-onset (first CT-scan-opacities), T-follow-up, and T-last. In patients with RAS, the spirometric criteria for RAS at T-onset were reached in only 47% (FVC decline <80% BL [(29%] or FEV1 <80% BL/ratiounchanged or >0.7 [41%]), whereas at the same T-onset date, the graft CT-score increased to 5 (4-6) vs 1 (0-2) at baseline (p < 0.001) (CT - score ≥2 at T-onset in 100% and ΔCT - score ≥2 in 74% of patients with RAS), and the median CT-scan graft volume decreased to 1,722 ml (vs 1,796 ml at T-baseline, p = 0.003) (decreased CT-graft - volume <90% BL in 50% of patients). In contrast, in patients with BOS, CT-score/volume were unchanged at T-onset vs T-baseline (p = 0.8, p = 0.68, respectively). Our results suggest that the use of a simple CT-score and to a lesser extent, CT-volume measures, might allow for the early identification and/or prediction of RAS in SLTx rather than functional criteria.

Donation after circulatory death in lung transplantation—five-year follow-up from ISHLT Registry

This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD). We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST]) only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model. The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p < 0.001), but donor type was not (DCD-III vs DBD; hazard ratio, 1.04 [0.90-1.19], p = 0.61). This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality.

LUNG TRANSPLANTATION IN COPD PATIENTS: IS DONOR AGE A FACTOR?

SESSION TITLE: Wednesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM PURPOSE: Patients diagnosed as chronic obstructive pulmonary diseases (COPD) are the candidates who receive the second most lung transplantation (LTx) at our center. As LTx is constrained by an inadequate number of donors, often suitable older donors are used in COPD cases. Many of these patients are candidates for either single or double LTx. Since current guidelines stipulate younger donors, we investigated the survival outcome of IPF patients receiving <=49 vs. >= 50 years old donor lungs. METHODS: Ninety three (93) COPD patients that underwent either single or double LTx at our center from February 2012 to March 2018 were reviewed retrospectively. 80 patients received organs from donor age <=49 and 13 patients received organs from donor age >= 50. Demographics, recipients' age and height, LAS, length of stay (LOS), survival days, death, types of induction, and types of surgical procedures were compared between the two groups for significance. Actuarial survival was assessed by Kaplan-Meier curve and compared by log-rank test. Data were expressed as mean ± standard deviation and p-value less than 0.05 was considered significant (Stata 14). RESULTS: Out of 93 COPD patients, demographics data showed no significant differences in recipients' age (p=0.27), gender (p=0.49), LAS (p=0.32), height (p=0.97), and BMI (p=0.17). Clinical parameters such as CPB on and off (p=0.79), Campath and Simulect induction (p=0.45), and antero-apical, clamshell, median sternotomy surgical approaches (p=0.77) did not show any significant differences comparing the two groups. Median length of stay was 17 days in both group (p=ns). Log-rank test for equality of survivor functions showed no difference between the two donor age groups (p=0.38). There was a trend towards gender significance (p=0.02) in <=49 donor age group (70M vs. 10F) and in >= 50 donor age group (8M vs. 5F). The donor age ranged from 15 to 60 years. Kaplan-Meier curve showed the survival outcome in two donor age groups (0.38). CONCLUSIONS: Outcomes after lung transplantation using donors aged 50 to 60 were similar to those observed with donors 15 to 49 years. There was a similar survival outcome in both groups. CLINICAL IMPLICATIONS: This study focuses on the older donors availability for lung transplantation in COPD patients. DISCLOSURES: no disclosure on file for STACEY BRANN; no disclosure on file for Jesus Gomez-Abraham; No relevant relationships by Mohammed Kashem, source=Web Response No relevant relationships by Suresh Keshavamurthy, source=Web Response No relevant relationships by Jacob Levy, source=Web Response No relevant relationships by Norihisa Shigemura, source=Web Response No relevant relationships by Gengo Sunagawa, source=Web Response no disclosure on file for Yoshiya Toyoda; no disclosure on file for Huaqing Zhao

Lung transplant with bronchial arterial revascularization: review of surgical technique and clinical outcomes.

Lung transplantation (LTx) is routinely performed with sacrifice of the bronchial arterial circulation. We review bronchial artery anatomy and surgical technique for LTx with direct bronchial arterial revascularization (BAR). We also update the published clinical experience, including from our center, of LTx with BAR. Published series of LTx with BAR are from single centers, and all cite high technical success rates and good short-term outcomes. Technically, double LTx (DLTx) with BAR is almost always possible if a deliberate review of bronchial artery anatomy is performed. For single LTx (SLTx), BAR is feasible in about 50% of cases. The combined Copenhagen and Cleveland Clinic experience (with BAR procedures performed or supervised by Dr. Gosta B. Pettersson) includes 131 LTx with BAR with a technical success rate >95%. Procedural success is uniformly associated with normal airway healing. Five-year survival in LTx with BAR is superior to the 5-year survival of LTx patients in the ISHLT registry. LTx with BAR is feasible and safe, and technical success ensures normal airway healing. The experience with BAR at experienced centers suggests possible long-term survival benefit. A multicenter study is needed to define the role of BAR in LTx.

Improvements in functional and cognitive status following short-term pulmonary rehabilitation in COPD lung transplant recipients: a pilot study.

BackgroundPulmonary rehabilitation (PR) following lung transplantation (LTx) is considered part of the optimal treatment in chronic obstructive pulmonary disease (COPD) for favourable post-operative outcomes. We investigated the effects of a PR intervention in the post-transplant phase with regard to lung function, exercise responses and cognitive function in COPD LTx recipients.Methods24 COPD LTx recipients (mean±sd forced expiratory volume in 1 s 75±22% predicted) were assigned to a comprehensive 3-week inpatient PR programme. Changes from PR admission to discharge in lung function variables, 6-min walk test-derived outcomes and cognitive function were assessed and examined for several factors. The magnitude of changes was interpreted by effect size (ES).ResultsIn response to the PR intervention, LTx recipients had improved lung function with regard to diffusing capacity of the lung for carbon monoxide (+4.3%; p=0.012) and static hyperinflation (residual volume/total lung capacity −2.3%; p=0.017), increased exercise capacity (6-min walk test +86 m; p<0.001), and had small to large improvements (ES range 0.23–1.00; all p≤0.34) in 50% of the administered cognitive tests. Learning skills and memory ability presented the greatest benefits (ES composite scores 0.62 and 0.31, respectively), which remained similar after stratification by single or bilateral LTx and sex.ConclusionsPR is an effective treatment for LTx recipients in the post-transplant phase, improving lung function, exercise responses, and domains of cognitive function of learning, memory and psychomotor speed. PR may facilitate the course of post-operative treatment and should be recommended in LTx.