Extracorporeal membrane oxygenation as a bridge to lung transplantation: 5-year outcomes and bridge to decision in a large, older cohort.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (BTT) has expanded considerably, though evidence-based selection criteria and long-term outcome data are lacking. The purpose of this study was to evaluate whether risk factors often used to exclude patients from ECMO BTT-specifically older age and not yet being listed for transplant-are validated by long-term outcomes. METHODS: To ensure minimum 5-year follow-up, a retrospective cohort study was performed of adult patients actively listed for lung transplantation at a high-volume center and bridged on ECMO between January 2012 and December 2017. Data was collected through January 1, 2023. RESULTS: Among 50 patients bridged on ECMO, 25 survived to transplant. Median age at listing was 58 (interquartile range [IQR], 42-65) in the transplanted group and 65 (IQR, 56.5-69) in the deceased group (P = 0.051). One-year, 3-year, and 5-year survival were 88% (22/25), 60% (15/25), and 44% (11/25), respectively, with eight patients still living at the time of review. Median time spent at home during the year post-transplant was 340 days (IQR, 314-355). Older age at listing was a negative predictor of survival on ECMO to transplant (odds ratio 0.92 [95% confidence interval, 0.86-0.99], P = 0.01). Thirteen patients were placed on ECMO prior to being listed and three were listed the same day as ECMO cannulation, with 10/16 transplanted. No significant difference in post-transplant survival was found between patients placed on ECMO prior to listing (n = 10) and those already listed (n = 15) (P = 0.93, log-rank). Serial post-transplant spirometry up to 5 years and surveillance transbronchial biopsy demonstrated good allograft function and low rates of cellular rejection. CONCLUSIONS: In one of the oldest cohorts of ECMO BTT patients described, favorable survival outcomes and allograft function were observed up to 5 years irrespective of whether patients were previously listed or bridged to decision. Despite inherent limitations to this retrospective, single-center study, the data presented support the feasibility of ECMO BTT in older and not previously listed advanced lung disease patients.

Concomitant Heart and Lung Surgery During Lung Transplantation.

INTRODUCTION: There is limited data concerning concomitant cardiac and lung surgery outcomes during lung transplantation (LTx). While some evidence suggests that cardiac surgery during LTx has no significant impact on surgical outcomes, scarce data examines the role of concomitant lung surgery (CLS). This study compares the survival outcomes of concomitant cardiac and lung surgeries during LTx. METHODS: A retrospective analysis of all single and double LTx patients from March 2012 to June 2023 at a single center was performed (n = 1099). Patients were stratified into three concomitant surgical groups: concomitant cardiac surgery (CCS), CLS, and no concomitant surgeries. Groups were compared on recipient demographics, diagnosis, and surgical intervention using analysis of variance and chi-square tests. Survival (5 y) was analyzed using Kaplan-Meier curves, log-rank test, and univariable Cox proportional hazard model where P value <0.05 was considered significant. RESULTS: In total, 1099 patients were analyzed in this study; 965 had no concomitant surgery, 100 had CCS (mode: coronary artery bypass grafting, n = 75), and 34 had CLS (mode: lung volume reduction surgery, n = 14). Between the three surgical groups, there was no significant difference in body mass index (P = 0.091), total ischemic time (P = 0.194), induction (P = 0.140), or cause of death (P = 0.240). Lung allocation score and length of stay were significantly higher in the concomitant surgical groups, especially the CLS group when compared to the no concomitant surgery group (P = 0.002, P = 004). Patients with no concomitant surgery had a higher incidence of single LTx and off-pump utilization than concomitant surgical groups (P < 0.001). Kaplan-Meier curves and log-rank tests found no significant difference in survival between groups (P = 0.849). This result is supported by Cox proportional hazard model with no significant difference in mortality risk between the CCS group (P = 0.522) and CLS group (P = 0.936) compared to no concomitant surgery during LTx. CONCLUSIONS: Our study provides promising data indicating that individuals undergoing concomitant heart or lung surgery during LTx have similar survival outcomes to those exclusively undergoing LTx. These results highlight the potential advantages of utilizing LTx to address concurrent thoracic surgical needs, such as coronary revascularization. This holds implications for optimizing patient care and decision-making when complex thoracic interventions are necessary.

Lung Transplant Type and Donor Age in Idiopathic Pulmonary Fibrosis: A Single Center Study.

BACKGROUD: Idiopathic pulmonary fibrosis (IPF) accounts for a marked proportion of diagnoses on the US lung transplant (LTx) list. The effects of single (SLT) versus double LTx (DLT) and lung donor age on survival in IPF remain unclear and were investigated in this study. METHODS: We retrospectively assessed survival of LTx recipients with IPF at a single institution from February 2012-March 2020. Survival was analyzed and compared between LTx types (SLT and DLT), donor ages, and the combined groups (LTx type & donor age) using Kaplan-Meier survival analysis and compared by log-rank test. P-values less than 0.05 were considered significant. RESULTS: Of 744 LTx patients at our institution, 307 (41.3%) were diagnosed with IPF, of which 208 (67.8%) were SLT, and 97 (31.6%) were DLT (2 excluded patients underwent heart-lung transplantation). There was no significant difference in survival due to LTx type (P = 0.41) or for patients with donor age <50 or ≥50 y (P = 0.46). Once stratified by both LTx type and donor age, analysis showed no significant difference in survival between the four groups (P = 0.69). CONCLUSIONS: With ethical consideration for organ allocation, as the average age of the US population increases, donor lungs aged ≥50 are an increasingly useful resource in LTx. Our findings suggest donor age and LTx type do not significantly affect survival. Therefore, SLT, and donor lungs aged ≥50 ought to be more readily considered as non-inferior options for LTx in patients with IPF.

Anastomotic Suturing Techniques and Their Association With Post-Lung Transplantation Complications.

INTRODUCTION: Currently, standard practice is to use the continuous suturing technique on the bronchial anastomosis during lung transplantation. This study used a large cohort to investigate and contrast continuous and interrupted suturing techniques, comparing survival outcomes and occurrence of postoperative bronchial complications to examine if utilization of interrupted suturing has merit. METHODS: Survival outcomes of 740 single-center lung transplant recipients over 8 y (February 2012-March 2020) were compared by suturing techniques: either continuous or interrupted at the bronchial anastomosis. Clinical parameters and demographics were compared between two suturing groups, with P values < 0.05 considered significant. The groups were compared for postoperative morbidity, including need for bronchial interventions. Survival was compared using Kaplan-Meier curves and log-rank tests. Cox regression analysis was run with statistically significant variables to study association with survival. RESULTS: Of the 740 patients, 462 received the continuous suturing technique and 278 received the interrupted suturing technique. Most demographic and clinical data were not statistically significant between the two groups, and those that were significant were not associated with worse survival outcomes, with the exception of the variable diagnosis. Bronchial complications were comparable between the continuous and interrupted groups (12.6% versus 10.4%, P = 0.382). Extracorporeal membrane oxygenation (ECMO) use did not differ significantly between the two groups (P = 0.12). The Kaplan-Meier curve showed comparable survival between groups (P = 0.98), and Cox regression analysis showed that only diagnosis, bronchial complications, and ECMO utilization were associated with different survival outcomes. Chronic obstructive pulmonary disorder was shown to be associated with more favorable survival outcomes as opposed to idiopathic pulmonary fibrosis and the category "other". The need for ECMO and the occurrence of a bronchial complication were also associated with worse survival outcomes. CONCLUSIONS: Both techniques showed reasonable post-transplant outcomes, as our study demonstrated similar survival outcomes and bronchial complication rates.

Guiding therapeutic plasma exchange for antibody-mediated rejection treatment in lung transplant recipients - a retrospective study.

Antibody-Mediated Rejection (AMR) due to donor-specific antibodies (DSA) is associated with poor outcomes after lung transplantation. Currently, there are no guidelines regarding the selection of treatment protocols. We studied how DSA characteristics including titers, C1q, and mean fluorescence intensity (MFI) values in undiluted and diluted sera may predict a response to therapeutic plasma exchange (TPE) and inform patient prognosis after treatment. Among 357 patients consecutively transplanted without detectable pre-existing DSAs between 01/01/16 and 12/31/18, 10 patients were treated with a standardized protocol of five TPE sessions with IVIG. Based on DSA characteristics after treatment, all patients were divided into three groups as responders, partial responders, and nonresponders. Kaplan-Meier Survival analyses showed a statistically significant difference in patient survival between those groups (P = 0.0104). Statistical analyses showed that MFI in pre-TPE 1:16 diluted sera was predictive of a response to standardized protocol (R2  = 0.9182) and patient survival (P = 0.0098). Patients predicted to be nonresponders who underwent treatment with a more aggressive protocol of eight TPE sessions with IVIG and bortezomib showed improvements in treatment response (P = 0.0074) and patient survival (P = 0.0253). Dilutions may guide clinicians as to which patients would be expected to respond to a standards protocol or require more aggressive treatment.

Elderly patients with multiple comorbidities: insights from the bedside to the bench and programmatic directions for this new challenge in lung transplantation.

In aging populations, many patients have multiple diseases characterized by acceleration of the aging process including cardiovascular diseases, metabolic diseases, and chronic kidney disease. Remarkable progress in minimally invasive, interventional therapies, such as percutaneous coronary intervention and transcatheter aortic valve replacement has enabled patients who were previously not transplant candidates because of co-existing problems to become potentially viable candidates for lung transplantation. Recently, we have observed an outstanding and steady increase in patients older 70 years of age with multiple comorbidities who are referred to our high-volume center as potential candidates for lung transplantation. However, the impact of diseases characterized by an accelerated aging process and their treatments on transplant outcomes remains unclear. This review aims to highlight these challenges in the current era of lung transplantation, review the prior literature, and discuss future directions with a multidisciplinary view including translational research, transplant medicine, and surgery, as well as from a programmatic and administrative standpoint.

Current precautions and future directions in lung transplantation during the COVID-19 pandemic - a single center cohort study.

The unprecedented public health emergency caused by the acute viral respiratory coronavirus disease (COVID-19) has drastically changed current practices in solid organ transplantation, markedly so for transplantation of the lungs, the major target of the virus. Although national and state authorities do not recommend postponing transplant procedures, most specialists are reluctant to proceed due to substantial uncertainty and increased risks in the midst of the pandemic. There is an urgent need for evidence-based directions to move forward. Here, we offer our insights as specialists at a high-volume center located in a geographical area with high infection rates.

Contemporary look at extracorporeal membrane oxygenation as a bridge to reoperative lung transplantation in the United States - a retrospective study.

The purpose of this study was to examine the influence of extracorporeal membrane oxygenation (ECMO) as a bridge to reoperative lung transplantation (LT) on outcomes and survival. A total of 1960 LT recipients transplanted a second time between 2005 and 2017 were analyzed using the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN). Of these recipients, 99 needed ECMO as a bridge to reoperative LT. Mean age was 50 ± 14 years, 47% were females, and the group with ECMO was younger [42 (30-59) vs. 55 (40-62) years]. In both univariate and multivariable analyses (adjusting for age and gender), the ECMO group had greater incidence of prolonged ventilation >48 h (83% vs. 40%, P < 0.001) and in-hospital dialysis (27% vs. 7%, P < 0.001). There were no differences in incidence of acute rejection (15% vs. 11%, P = 0.205), airway dehiscence (4% vs. 2%, P = 0.083), stroke (3% vs. 2%, P = 0.731), or reintubation (20% vs. 20%, P = 0.998). Kaplan-Meier survival analysis showed the ECMO group had reduced 1-year survival (66.6% vs. 83.0%, P < 0.001). After covariate adjustment, the ECMO group only had increased risk for 1-year mortality in the 2005-2011 era (HR = 2.57, 95% CI = 1.45-4.57, P = 0.001). For patients who require reoperative LT, bridging with ECMO was historically a significant predictor of poor outcome, but may be improving in recent years.

COVID-19 in lung transplant recipients.

Solid organ transplant recipients are considered at high risk for COVID-19 infection due to chronic immune suppression; little data currently exists on the manifestations and outcomes of COVID-19 infection in lung transplant recipients. Here we report 8 cases of COVID-19 identified in patients with a history of lung transplant. We describe the clinical course of disease as well as preexisting characteristics of these patients.

Artificial lungs--Where are we going with the lung replacement therapy?

Lung transplantation may be a final destination therapy in lung failure, but limited donor organ availability creates a need for alternative management, including artificial lung technology. This invited review discusses ongoing developments and future research pathways for respiratory assist devices and tissue engineering to treat advanced and refractory lung disease. An overview is also given on the aftermath of the coronavirus disease 2019 pandemic and lessons learned as the world comes out of this situation. The first order of business in the future of lung support is solving the problems with existing mechanical devices. Interestingly, challenges identified during the early days of development persist today. These challenges include device-related infection, bleeding, thrombosis, cost, and patient quality of life. The main approaches of the future directions are to repair, restore, replace, or regenerate the lungs. Engineering improvements to hollow fiber membrane gas exchangers are enabling longer term wearable systems and can be used to bridge lung failure patients to transplantation. Progress in the development of microchannel-based devices has provided the concept of biomimetic devices that may even enable intracorporeal implantation. Tissue engineering and cell-based technologies have provided the concept of bioartificial lungs with properties similar to the native organ. Recent progress in artificial lung technologies includes continued advances in both engineering and biology. The final goal is to achieve a truly implantable and durable artificial lung that is applicable to destination therapy.

Outcomes after lung transplantation for patients with occupational lung diseases.

Occupational lung diseases (OLD) including silicosis, asbestosis, and pneumoconiosis progress to end stage lung disease requiring lung transplantation (LT). Prognosis and treatment of OLDs are poorly understood and a paucity of data exists regarding LT outcomes. Additionally, transplant operative complexity for patients with OLD is high. A single center retrospective review of all single and bilateral LT recipients between May 2005 and Oct 2016 was performed. Patients were grouped by OLD, and nearest neighbor matching was performed at a ratio of 1:3 cases to controls. Thirty cases were matched to 88 controls. Seventeen patients (57%) with OLD required intraoperative support with either extra-corporeal membrane oxygenation (ECMO) or cardiopulmonary bypass (P = 0.02), and 5 (17%) required delayed chest closure (P = 0.05) which was more frequent than matched controls. In addition, operative time was significantly longer in patients with OLD (P = 0.03). Despite these factors, there were no significant differences in immediate post-operative outcomes including mechanical ventilator support, post-operative ECMO, and tracheostomy. Chronic lung allograft dysfunction and long-term survival were also similar between cases and controls. OLDs should not preclude LT. The operation should be performed at experienced centers.

Increasing tacrolimus time-in-therapeutic range is associated with superior one-year outcomes in lung transplant recipients.

Calcineurin inhibitors (CNIs) are the backbone of traditional immunosuppressive regimens for lung transplant recipients (LTR). The CNIs are both narrow therapeutic index drugs with significant interpatient and intrapatient variability that require therapeutic drug monitoring to ensure safety and effectiveness. We hypothesized that tacrolimus time-in-therapeutic range (TTR) affects acute and chronic rejection rates in LTRs. This was a single-center, observational, cross-sectional study of 292 adult LTRs. Subjects who received tacrolimus posttransplant for the first year were included. TTR was calculated at 1 year using protocol goal ranges (12-15 mg/mL months 0-6; 10-12 mg/mL for months 7-12). The primary outcome was acute cellular rejection (ACR) burden at 1 year. Chronic lung allograft dysfunction (CLAD), mortality, and infection rate were assessed as secondary outcomes at 1 year. Primary and secondary outcomes were assessed using logistic regression. Increasing TTR by 10% was associated with a significantly lower likelihood of high-burden ACR at 1 year on univariable (OR 0.46, 95% CI 0.40-0.54, P < .001) and multivariable (OR 0.64, 95% CI 0.47-0.86, P = .003) assessment, controlling for age and induction agent. Increasing TTR by 10% was also associated with lower rates of CLAD (P < .001) and mortality (P < .001) at 1 year. Prospective studies confirming these findings appear warranted.

Extracorporeal Support During Bilateral Sequential Lung Transplantation in Patients With Pulmonary Hypertension: Risk Factors and Outcomes.

OBJECTIVE: To identify preoperative predictors of extracorporeal support in patients with pulmonary hypertension (PH) undergoing bilateral sequential lung transplantation (LTx), and to examine outcomes associated with the use of extracorporeal support. DESIGN: Retrospective, observational study. SETTING: Single organ transplantation and tertiary care university medical center. PARTICIPANTS: Adults with PH (preoperative mean pulmonary artery pressure (mPAP)≥25 mmHg) who underwent primary bilateral sequential LTx during 2007 to 2013. MEASUREMENTS AND MAIN RESULTS: Of 262 patients with PH undergoing LTx, extracorporeal support was initiated intraoperatively in 149 (57%). Preoperative severe right ventricle (RV) dysfunction and moderate or severe tricuspid regurgitation (TR) were associated with extracorporeal support. In the remaining 208 patients without those factors, increasing preoperative oxygen requirement (odds ratio [OR] 1.30 per 1 L/min, 95% confidence intervals [CI] 1.11-1.52, p = 0.001), presence of RV dilation (OR 2.77, 95% CI 1.28-6.02, p = 0.010), and mPAP (OR 1.33 per 5-mmHg increase in mPAP, 95% CI 1.04-1.70, p = 0.021) were associated independently with extracorporeal support in the multivariable model. Analysis of 49 propensity-matched pairs showed longer intensive care unit (5 v 14 days, p = 0.006) and hospital stays (27 v 39 days, p = 0.016) and increased need for tracheostomy (16% v 41%, p = 0.017) in patients exposed to extracorporeal support but no differences in 30-day mortality, stroke, myocardial infarction, or dialysis. CONCLUSIONS: Severity of RV dysfunction, TR, RV dilatation, increasing oxygen requirement, and increasing mPAP showed significant associations with the need for extracorporeal support during LTX in patients with PH. Extracorporeal support was associated with increased length of stay and tracheostomy but not with mortality or other complications. © 2016 Elsevier Inc. All rights reserved.

Optimal lung inflation techniques in a rat lung transplantation model: a revisit.

BACKGROUND: Most of the experimental work assessing optimal lung inflation during lung graft preservation was performed in the late 1990s. Since that time, lung preservation before transplantation has been more standardized, and the optimal lung inflation techniques used during lung preservation in the current clinical setting remain undefined. Nonetheless, lung inflation during storage may play a pivotal role in optimal lung preservation. MATERIALS AND METHODS: Lewis rat lungs were perfused with and stored in cold, low-potassium dextran solution (Perfadex, Vitrolife, Göteborg, Sweden) for 6 hours at different levels of lung inflation (25, 50, 75, or 100% of vital capacity [VC]). Orthotopic left lung transplantation using cuff techniques was performed in syngeneic Lewis rats. Posttransplant allograft function, expression of proinflammatory mediators, and expression of lung surfactants were evaluated. RESULTS: Lungs inflated to 75 or 100% VC showed a significantly better oxygenation in blood gas analysis than lungs inflated to 25 or 50% VC. The levels of mRNAs for tumor necrosis factor-α, pro-interleukin-1ß, intracellular adhesion molecule 1 were attenuated in lungs inflated to 75 or 100% VC as compared with deflated lungs, suggesting reduced ischemia/reperfusion injury. In addition, transmission electron microscopy demonstrated better preserved lung surfactants in the alveolar space in the lungs inflated to 75 or 100% VC. CONCLUSIONS: Inflating lungs to 75 or 100% VC during preservation may be beneficial and result in better posttransplant allograft function through attenuated reperfusion injury and better preserved lung surfactants.

The effect of donor-recipient sex matches on lung transplant survival: An analysis of the United Network for Organ Sharing database.

Objective: To investigate the impact of donor-recipient (DR) sex matches on survival after lung transplantation while controlling for size difference in the United Network of Organ Sharing (UNOS) database. Methods: We performed a retrospective study of 27,423 lung transplant recipients who were reported in the UNOS database (January 2005-March 2020). Patients were divided into groups based on their respective DR sex match: male to male (MM), male to female (MF), female to female, (FF), and female to male (FM). Kaplan-Meier curve and Cox regression with log-rank tests were used to assess 1-, 3-, 5-, and 10-year survival. We also modeled survival for each group after controlling for size-related variables via the Cox regression. Results: Kaplan-Meier curves showed overall significance at 1-, 3-, 5-, and 10-year end points (P < .0001). Estimated median survival time based on Kaplan-Meier analysis were 6.41 ± 0.15, 6.13 ± 0.18, 5.86 ± 0.10, and 5.37 ± 0.17 years for FF, MF, MM, and FM, respectively (P < .0001). After we controlled for size differences, FF had statistically significantly longer 5- and 10-year survival than all other cohorts. MF also had statistically significantly longer 5- and 10-year survival than FM. Conclusions: When variables associated with size were controlled for, FF had improved survival than other DR groups. A female recipient may experience longer survival with a female donor's lungs versus a male donor's lungs of similar size.

A Single-center Experience With >200 Lung Transplant Recipients With COVID-19 Infection.

Background: Although COVID-19 is no longer a declared global health emergency, data remain limited on the impact of COVID-19 in lung transplant recipients. Methods: We identified lung transplant recipients who were diagnosed with COVID-19 from March 2020 through August 2022 in our institutional database and investigated clinical outcomes. We then analyzed outcomes based on date of COVID-19 diagnosis (first wave March 2020-October 2020; second wave November 2020-2021; third wave December 2021-September 2022) and compared these results. Results: Of the 210 lung transplant recipients (median age 67; 67% men) enrolled, 140 (67%) required hospital admission. Among admitted recipients, 35 (25%) were intubated and 7 (5%) were placed on extracorporeal membrane oxygenation. Overall survival was 67.1% at 1 y and 59.0% at 2 y post-COVID-19 diagnosis. COVID-19 led to mortality in all 5 patients diagnosed during their index admission for lung transplantation. Although overall survival was significantly better in recipients with COVID-19 during the third wave, in-hospital mortality remained high (first wave 28%, second wave 38%, and 28% third wave). Vaccination (partially vaccinated versus none and fully vaccinated versus none) was the only significant protective factor for hospital admission, and age 70 y and older and partially vaccinated (versus none or fully vaccinated) were independent risk factors for in-hospital mortality. Conclusions: Overall survival after COVID-19 infection in lung transplant recipients continues to improve; however, in-hospital mortality remains remarkably high. Vaccination appears to have been impactful in preventing hospital admission, but its impact on in-hospital mortality is still unclear. Further research is needed to better identify lung transplant recipients at high risk for mortality from COVID-19.