New OPTN/UNOS data demonstrates higher than previously reported waitlist mortality for lung transplant candidates supported with ECMO.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) is not currently incorporated into US allocation models due to the historical lack of complete data in the national US registry which changed in 2016 to include ECMO at the time of waitlist removal and more granular timing and configuration data. METHODS: We studied adult lung transplant candidates from May 1, 2016 to June 1, 2020 with data abstracted from multiple sources in the US Scientific Registry of Transplant Recipients. Waitlist analyses included cumulative incidence functions and Cox proportional hazards models considering ECMO as a time-dependent variable. Post-transplant analyses included Kaplan Meier, Cox proportional hazards models, and observed to expected survival ratios. RESULTS: A total of 867 candidates were on ECMO prior to transplant; 247 were identified using new sources of data. Candidates on ECMO had a 23.9 increased adjusted likelihood of waitlist removal for being too sick or death, but only a 4.08 increased adjusted likelihood of transplant. Candidates bridged with ECMO who underwent lung transplant (N = 587) experienced an increased overall hazard of post-transplant mortality with veno-arterial and veno-venous configurations conferring hazard ratio (HR) = 1.67 (95% CI, 1.16, 2.40), HR = 1.45 (95% CI, 1.15, 1.82), respectively. CONCLUSIONS: We identified an additional 28.5% of candidates bridged with ECMO prior to transplant using new data. This study of the newly identified full cohort of ECMO candidates demonstrates higher utilization of ECMO as well as an underestimation of waitlist mortality risk factors that should inform strategies to provide timely access to transplants for this population.

The lung allocation score and other available models lack predictive accuracy for post-lung transplant survival.

BACKGROUND: Improved predictive models are needed in lung transplantation in the setting of a proposed allocation system that incorporates longer-term post-transplant survival in the United States. Allocation systems require accurate mortality predictions to justly allocate organs. METHODS: Utilizing the United Network for Organ Sharing database (2005-2017), we fit models to predict 1-year mortality based on the Lung Allocation Score (LAS), the Chan, et al, 2019 model, a novel "clinician" model (a priori clinician selection of pre-transplant covariates), and two machine learning models (Least Absolute Shrinkage and Selection Operator; LASSO and Random Forests) for predicting 1-year and 3-year post-transplant mortality. We compared predictive accuracy among models. We evaluated the calibration of models by comparing average predicted probability vs observed outcome per decile. We repeated analyses fit for 3-year mortality, disease category, including donor covariates, and LAS era. RESULTS: The area under the cure for all models was low, ranging from 0.55 to 0.62. All exhibited reasonable negative predictive values (0.87-0.90), but the positive predictive value for was poor (all <0.25). Evaluating LAS calibration found 1-year post-transplant estimates consistently overestimated risk of mortality, with greater differences in higher deciles. LASSO, Random Forests, and clinician models showed no improvement when evaluated by disease category or with the addition of donor covariates and performed worse for 3-year outcomes. CONCLUSIONS: The LAS overestimated patients' risk of post-transplant death, thus underestimating transplant benefit in the sickest candidates. Novel models based on pre-transplant recipient covariates failed to improve prediction. There should be wariness in post-transplant survival predictions from available models.

Ex Vivo Lung Perfusion: A Review of Current and Future Application in Lung Transplantation.

The number of waitlisted lung transplant candidates exceeds the availability of donor organs. Barriers to utilization of donor lungs include suboptimal lung allograft function, long ischemic times due to geographical distance between donor and recipient, and a wide array of other logistical and medical challenges. Ex vivo lung perfusion (EVLP) is a modality that allows donor lungs to be evaluated in a closed circuit outside of the body and extends lung donor assessment prior to final acceptance for transplantation. EVLP was first utilized successfully in 2001 in Lund, Sweden. Since its initial use, EVLP has facilitated hundreds of lung transplants that would not have otherwise happened. EVLP technology continues to evolve and improve, and currently there are multiple commercially available systems, and more under investigation worldwide. Although barriers to universal utilization of EVLP exist, the possibility for more widespread adaptation of this technology abounds. Not only does EVLP have diagnostic capabilities as an organ monitoring device but also the therapeutic potential to improve lung allograft quality when specific issues are encountered. Expanded treatment potential includes the use of immunomodulatory treatment to reduce primary graft dysfunction, as well as targeted antimicrobial therapy to treat infection. In this review, we will highlight the historical development, the current state of utilization/capability, and the future promise of this technology.

Extremes of Age Decrease Survival in Adults After Lung Transplant.

BACKGROUND: Age has been implicated as a factor in the plateau of long-term survival after lung transplant. METHODS: We used data from the Scientific Registry of Transplant Recipients to identify all recipients of lung transplant aged ≥18 years of age between January 1, 2006, and February 19, 2015. A total of 14,253 patients were included in the analysis. Survival was estimated using a nonproportional hazard model and random-survival forest methodology was used to examine risk factors for death. Final selection of model variables was performed using bootstrap aggregation. Age was analyzed as both a continuous and categorical variable (age <30, 30-55, and >55 years). Risk factors for death were obtained for the entire cohort and additional age-specific risk factors were identified for each age category. RESULTS: The median age at transplant was 59 years. There were 1,098 (7.7%) recipients <30 years, 4,201 (29.5%) 30 to 55 years, and 8,954 (62.8%) >55 years of age. Age was the most significant risk factor for death at all time-points following transplant and its impact becomes more prominent as time from transplant increases. Risk factors for death for all patients included extremes of age, higher creatinine, single lung transplant, hospitalization before transplant, and increased bilirubin. Risk factors for death differed by age with social determinants of health disproportionately affecting survival for those in the youngest age category. CONCLUSIONS: The youngest and oldest adult recipients experienced the lowest posttransplant survival through divergent pathways that may present opportunities for intervention to improve survival after lung transplant.

Complement system in lung transplantation.

The complement system is a cascade of multiple proteins that have been known to mediate inflammatory response. This tightly regulated system has been recognized to play a role in adaptive immunity via humoral and cell-mediated processes. There is evidence from animal and human studies that the complement system is involved in various outcomes of solid organ transplantation. Most of the studies have been done in the field of kidney transplantation. In this paper, we review the studies looking at lung transplantation. The complement cascade appears to have a prominent role in mediating lung allograft damage in the setting of ischemia-reperfusion injury, humoral rejection, as well as chronic allograft dysfunction. In this review, we look at the available data regarding the role of complement in these outcomes and propose some ideas about future direction of research in this field.

Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant.

RATIONALE: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. OBJECTIVES: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. METHODS: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. MEASUREMENTS AND MAIN RESULTS: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. CONCLUSIONS: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

An oversized allograft is associated with improved survival after lung transplantation for idiopathic pulmonary arterial hypertension.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is associated with high short-term mortality after bilateral lung transplantation (BLT). Previous studies have suggested that oversized allografts are associated with improved outcomes and that this association was strongest within the first year after transplant. We hypothesized that oversizing the allograft is associated with improved survival after BLT for IPAH. METHODS: All adults in the United Network of Organ Sharing lung transplant registry who underwent first-time BLT for IPAH between October 1989 and April 2010 were studied. Lung size mismatch was assessed by calculating the predicted total lung capacity (pTLC) ratio of the donor to the recipient. The cohort was divided evenly into "undersized" (pTLC ratio less than the median pTLC ratio) and "oversized" (pTLC ratio exceeding the median pTLC ratio). Risk of death after BLT was analyzed using Kaplan-Meier survival and Cox proportional hazards models. RESULTS: The mean pTLC ratio was 0.93 ± 0.10 in the 302 undersized patients compared with 1.24 ± 0.14 in the 302 oversized patients. Cohorts had comparable baseline characteristics. Median survival was 831 days longer in the oversized cohort (2,166 vs. 1,335 days, p = 0.006). In a multivariate model controlling for sex mismatch, recipient factors, acuity, donor factors, and transplant factors, oversizing was associated with decreased hazard for death at 5 years (hazard ratio, 0.73; 95% CI 0.56-0.96, p = 0.02). CONCLUSION: Oversizing the allograft is associated with improved survival after BLT for IPAH. In the setting of donor organ shortages and waiting list mortality, it is not practical to intentionally oversize the allograft. However, the pTLC ratio could provide further refinement in the peri-transplant risk assessment.