ABSTRACT
Background: Lung transplant patients are vulnerable to various forms of allograft injury, whether from acute rejection (AR) (encompassing acute cellular rejection [ACR] and antibody-mediated rejection [AMR]), chronic lung allograft dysfunction (CLAD), or infection (INFXN). Previous research indicates that donor-derived cell-free DNA (dd-cfDNA) is a promising noninvasive biomarker for the detection of AR and allograft injury. Our aim was to validate a clinical plasma dd-cfDNA assay for detection of AR and other allograft injury and to confirm and expand on dd-cfDNA and allograft injury associations observed in previous studies. Methods: We measured dd-cfDNA fraction using a novel single-nucleotide polymorphism-based assay in prospectively collected plasma samples paired with clinical-pathologic diagnoses. dd-cfDNA fraction was compared across clinical-pathologic cohorts: stable, ACR, AMR, isolated lymphocytic bronchiolitis, CLAD/neutrophilic-responsive allograft dysfunction (NRAD), and INFXN. Performance characteristics were calculated for AR and combined allograft injury (AR + CLAD/NRAD + INFXN) versus the stable cohort. Results: The study included 195 samples from 103 patients. Median dd-cfDNA fraction was significantly higher for ACR (1.43%, interquartile range [IQR]: 0.67%-2.32%, P = 5 × 10-6), AMR (2.50%, IQR: 2.06%-3.79%, P = 2 × 10-5), INFXN (0.74%, IQR: 0.46%-1.38%, P = 0.02), and CLAD/NRAD (1.60%, IQR: 0.57%-2.60%, P = 1.4 × 10-4) versus the stable cohort. Area under the receiver operator characteristic curve for AR versus stable was 0.91 (95% confidence interval [CI]: 0.83-0.98). Using a ≥1% dd-cfDNA fraction threshold, sensitivity for AR was 89.1% (95% CI: 76.2%-100.0%), specificity 82.9% (95% CI: 73.3%-92.4%), positive predictive value, 51.9% (95% CI: 37.5%-66.3%), and negative predictive value, 97.3% (95% CI: 94.3%-100%). For combined allograft injury area under the receiver operator characteristic curve was 0.76 (95% CI: 0.66-0.85), sensitivity 59.9% (95% CI: 46.0%-73.9%), specificity 83.9% (95% CI: 74.1%-93.7%), positive predictive value, 43.6% (95% CI: 27.6%-59.6%), and negative predictive value, 91.0% (95% CI: 87.9%-94.0%). Conclusions: These results indicate that our dd-cfDNA assay detects AR and other allograft injury. dd-cfDNA monitoring, accompanied by standard clinical assessments, represents a valuable precision tool to support lung transplant health and is appropriate for further assessment in a prospective randomized-controlled study.
ABSTRACT
INTRODUCTION: The short-term return visit rate among patients discharged from emergency departments (ED) is a quality metric and target for interventions. The ability to accurately identify which patients are more likely to revisit the ED could allow EDs and health systems to develop more focused interventions, but efforts to reduce revisits have not yet found success. Whether patients with a high number of ED visits are at increased risk of a return visit remains underexplored. METHODS: This was a population-based, retrospective, cohort study using administrative data from a large physician partnership. We included patients discharged from EDs from 80 hospitals in seven states from July 2014 - June 2016. We performed multivariable logistic regression of short-term return visits on patient, visit, hospital, and community characteristics. The primary outcome was the proportion of patients who had a return visit within 14 days of an index ED visit. RESULTS: Among 6,699,717 index visits, the overall risk of 14-day revisit was 12.6%. Frequent visitors accounted for 18.7% of all visits and 40.2% of all 14-day revisits. Frequent visitor status was associated with the highest odds of a revisit (odds ratio [OR] 3.06; 95% confidence interval [CI], 3.041 - 3.073). Other predictors of revisits were cellulitis (OR 2.131; 95% CI, 2.106 - 2.156), alcohol-related disorders (OR 1.579; 95%CI, 1.548 - 1.610), congestive heart failure (OR 1.175; 95% CI, 1.126 - 1.226), and public insurance (Medicaid OR 1.514; 95% CI, 1.501 - 1.528; Medicare OR 1.601; 95% CI, 1.583 - 1.620). CONCLUSION: Previous ED use - even a single previous visit - was a stronger predictor of a return visit than any other patient, hospital, or community characteristic. Clinicians should consider previous ED use when considering treatment decisions and risk of return visit, as should stakeholders targeting patients at risk of a return visit.
