Purpose: Healthcare costs have increased steadily over the past 4 decades. One of the key drivers of cost for pediatric heart transplant (PHTx) recipients is the frequency of cardiac catheterization with endomyocardial biopsy (EMB), the current "gold standard" for evaluating myocardial health. Novel cardiac magnetic resonance imaging (CMR) data may allow for non-invasive screening of PHTx. We sought to conduct a longitudinal cost analysis to compare the cost of CMR versus EMB screening over the lifetime of a PHTx.

Aspiration of gastrointestinal contents has been linked to worse outcomes following lung transplantation but uncertainty exists about underlying mechanisms. We applied high-resolution metabolomics of bronchoalveolar lavage fluid (BALF) in patients with episodic aspiration (defined by bile acids in the BALF) to identify potential metabolic changes associated with aspiration. Paired samples, one with bile acids and another without, from 29 stable lung transplant patients were studied. Liquid chromatography coupled to high-resolution mass spectroscopy was used to interrogate metabolomic contents of these samples. Data were obtained for 7068 ions representing intermediary metabolites, environmental agents and chemicals associated with microbial colonization. A substantial number (2302) differed between bile acid positive and negative samples when analyzed by false discovery rate at q = 0.01. These included pathways associated with microbial metabolism. Hierarchical cluster analysis defined clusters of chemicals associated with bile acid aspiration that were correlated to previously reported biomarkers of lung injury including T cell granzyme B level and the chemoattractants CXCL9 and CXCL10. These data specifically link bile acids presence in lung allografts to inflammatory pathways known to segregate with worsening allograft outcome, and provide additional mechanistic insight into the association between reflux and lung allograft injury.

Purpose In chronic viral infections, CD4 exhaustion correlates with poor containment of virus. We predicted that high levels of CD4 exhaustion would be beneficial in lung transplantation. Methods and Materials A retrospective review was performed on 96 lung transplant recipients from Feb 2006 to April 2010 with at least 1 bronchoscopy or peripheral blood (PB) in the first post transplant year. CD4 exhaustion was measured using the sample closest to the 1-year post transplant date. CD4 cells in bronchoalveolar lavage fluid (BALF) and peripheral blood were assessed by flow cytometry and considered exhausted if PD1hi, CD127lo, and GranzymeB negative. Samples were analyzed for the association between exhausted CD4 cells and survival and developing chronic rejection. We performed univariate Kaplan-Meier analyses between CD4 exhaustion and chronic rejection or death. Chronic rejection was defined as BOS 1 or higher by ISHLT criteria. Results A modest rejection free benefit was associated with lower CD4 exhaustion. There was a statistically significant increased freedom from rejection in the patients with a lower degree of CD4 exhaustion in the BALF (p=.04 by Log Rank). Conclusions We hypothesized that high levels of CD4 exhaustion would be fortuitous as this would serve as a biomarker for anergy toward the lung allograft. Our findings indicate that CD4 exhaustion is in fact a negative predictor of lung function. We predict that high levels of CD4 exhaustion are associated with substantial defects in protective immunity thereby leading to impaired pathogen containment. Our findings are consistent with prior reports showing an association with low humoral immunity and chronic rejection. 1-, 3-, and 5-year Rate of Survival and Chronic Rejection Free in Different Levels of Exhausted CD4 in BALF and PB Survival Rate (%) Chronic Rejection Free (%) Exhausted CD4 Frequency 1-year 3-year 5-year 1-year 3-year 5-year Low in BALF 90.6 77.4 65.8 98.1 81.0 67.5 High in BALF 100 84.7 67.8 93.9 63.6 50.0 Low in PB 91.8 77.0 64.6 95.1 73.5 56.6 High in PB 100 86.2 56.6 100 72.4 67.2

PurposePrior studies have defined lung biomarkers associated with graft injury in lung transplant. We have developed a lung metabolomic profile of bile acid aspiration. We correlated the metabolites of aspiration to other omic measures of lung injury.Methods and MaterialsWe performed metabolomic profiling on 29 recipients who had episodic bile detected in lung lavages. Each patient contributed a lung lavage specimen that was positive and negative for bile acid resulting in 58 total samples. Lavages were tested using C18 liquid chromatography coupled to mass spectroscopy. We used three approaches: Principle component analysis, Principle component regression, and Hierarchical clustering analysis. 252 Bile acid associated features were found at the intersection of these approaches. Cluster analysis developed 6 clusters positively or negatively associated with aspiration. Clusters were evaluated against biomarkers CXCL9, CXCL10, MCP1, FoxP3 and GranzymeB.ResultsBile acid aspiration was associated with a distinct metabolomic profile resolved using 3 bioinformatics approaches with a bias of increased small species in the bile positive samples, suggesting an increase in pulmonary permeability with aspiration. Presence of bile only weakly correlated with the other omic markers of injury (r .17-.26, p .09-.2). Individual bile acid associated clusters showed significant positive and negative correlation with known other markers of injury. [figure 1]ConclusionsIn this discovery phase study there is a strong association between metabolomic features of bile acid aspiration and known biomarkers of injury from other omic platforms. This strengthens the claim that aspiration of gastric contents is dangerous and also provides an avenue for risk stratification in a prospective cohort of patients. Prior studies have defined lung biomarkers associated with graft injury in lung transplant. We have developed a lung metabolomic profile of bile acid aspiration. We correlated the metabolites of aspiration to other omic measures of lung injury. We performed metabolomic profiling on 29 recipients who had episodic bile detected in lung lavages. Each patient contributed a lung lavage specimen that was positive and negative for bile acid resulting in 58 total samples. Lavages were tested using C18 liquid chromatography coupled to mass spectroscopy. We used three approaches: Principle component analysis, Principle component regression, and Hierarchical clustering analysis. 252 Bile acid associated features were found at the intersection of these approaches. Cluster analysis developed 6 clusters positively or negatively associated with aspiration. Clusters were evaluated against biomarkers CXCL9, CXCL10, MCP1, FoxP3 and GranzymeB. Bile acid aspiration was associated with a distinct metabolomic profile resolved using 3 bioinformatics approaches with a bias of increased small species in the bile positive samples, suggesting an increase in pulmonary permeability with aspiration. Presence of bile only weakly correlated with the other omic markers of injury (r .17-.26, p .09-.2). Individual bile acid associated clusters showed significant positive and negative correlation with known other markers of injury. [figure 1] In this discovery phase study there is a strong association between metabolomic features of bile acid aspiration and known biomarkers of injury from other omic platforms. This strengthens the claim that aspiration of gastric contents is dangerous and also provides an avenue for risk stratification in a prospective cohort of patients.

Emerging data show that repetitive injury and immune activation triggered by GERD and subsequent aspiration of gastric contents into the lung is a trigger for the development of bronchiolitis obliterans syndrome (BOS). Methods to detect and quantify GERD and aspiration have been described including ambulatory pH monitoring and direct measurement of bile acid aspiration (BAA) in the bronchoalveolar lavage fluid (BALF) which predict subsequent BOS. It is unclear if one episode of BAA unmasks a group of patients with repetitive continuous aspiration or if BAA is episodic. Further it is unknown if BAA correlates with less invasive 24-hour pH probe esophageal monitoring. We compared direct dectection of bile acids in the BALF to esophageal pH testing.