G.L. Snow

Mixed cellular and antibody-mediated rejection in heart transplantation: In-depth pathologic and clinical observations

BACKGROUNDnLittle is known about mixed cellular and antibody-mediated rejection (MR) in heart transplantation. It remains unclear whether cardiac MR has distinctive pathologic and clinical features beyond those of simultaneous cellular rejection (CR) and antibody-mediated rejection (AMR). In this study we systematically explore the pathologic and clinical characteristics of MR in heart transplantation.nnnMETHODSnThe UTAH Cardiac Transplant Program database was queried for transplant recipients who survived long enough to have at least one endomyocardial biopsy (EMB) between 1985 and 2014. Only EMBs with both CR and AMR scores documented were included. In addition to detailed pathologic analyses, we also examined the incidence and prevalence of MR, the likelihood to transition from and to MR, and mortality associated with MR.nnnRESULTSnPatients (n = 1,207) with a total of 28,484 EMBs met the study inclusion criteria. The overall prevalence of MR was 7.8% and it was nearly twice as frequent within the first year post-transplant. Mild MR was by far the most common occurrence and was typically preceded by an immune active state. When CR increased in severity, AMR tended to follow, but the reverse was not true. On pathology, individual features of CR and AMR were more easily separated in cases of mild MR, whereas they substantially overlapped in more severe cases. MR was associated with a significant cardiovascular death risk that was incremental with severity.nnnCONCLUSIONSnMR is not common, usually occurs early after transplant, and is associated with worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity.

INHIBITION OF ANGIOTENSIN SIGNALING REDUCES INCIDENCE OF ANTIBODY MEDIATED ALLOGRAFT REJECTION.

Methods: Among consecutive patients transplanted in our program between 2002 and 2007 we identified those who were started on ACE-I or ARB within 30 days of transplant and those who were not. We evaluated the incidence of cellular and antibody mediated rejection (AMR) in the first year after transplant in the two groups. AMR episode was defined as deposits of complement (C3d or C4d) and immunoglobulin detected by immunofluorescence on 3 endomyocardial biopsies.

Responsiveness to Change of Functional Limitation Reporting: Cross-sectional Study Using the Intermountain ROMS Scale in Outpatient Rehabilitation

Background The Centers for Medicare and Medicaid Services (CMS) require physical therapists document patients’ functional limitations. The process is not standardized. A systematic approach to determine a patients functional limitations and responsiveness to change is needed. Objective The purpose of this study is to compare patient‐reported outcomes (PROs) responsiveness to change using 7‐level severity/complexity modifier scale proposed by Medicare to a derived scale implemented by Intermountain Healthcares Rehabilitation Outcomes Management System (ROMS). Design This was a retrospective, observational cohort design. Methods 165,183 PROs prior to July 1, 2013, were compared to 46,334 records from July 1, 2013, to December 31, 2015. Histograms and ribbon plots illustrate distribution and change of patients’ scores. ROMS raw score ranges were calculated and compared to CMS’ severity/complexity levels based on score percentage. Distribution of the population was compared based on the 2 methods. Sensitivity and specificity were compared for responsiveness to change based on minimal clinically important difference (MCID). Results Histograms demonstrated few patient scores placed in CMS scale levels at the extremes, whereas the majority of scores placed in 2 middle levels (CJ, CK). ROMS distributed scores more evenly across levels. Ribbon plots illustrated advantage of ROMS’ using narrower score ranges. Greater chance for patients to change levels was observed with ROMS when an MCID was achieved. ROMS narrower scale levels resulted in greater sensitivity and good specificity. Limitations Geographic representation for the United States was limited. Without patients’ global rating of change, a reference standard to gauge validation of improvement could not be provided. Conclusions ROMS provides a standard approach to identify accurately functional limitation modifier levels and to detect improvement more accurately than a straight across transposition using the CMS scale.

Fibrin on Endomyocardial Biopsy: A Significant Predictor of Cardiovascular Mortality beyond pAMR Score

Purpose Endothelial activation (EA) is the hallmark lesion of antibody-mediated rejection (AMR). Mediators of EA trigger a cascade of additional endothelial injury leading to plasma protein leakage and fibrin accumulation. We hypothesized that interstitial fibrin on endomyocardial biopsy (EMB) would correlate with AMR severity and worse outcomes. Methods and Materials The AMR scores of patients transplanted in the UTAH Cardiac Transplant Program between 1986 and 2012 were classified according to the new ISHLT nomenclature. A semiquantitative scale (0-5) was used to record the presence of fibrin in the interstitium (FInt) and vessels (FVasc) (0, no fibrin; 5, diffuse fibrin). Cox proportional hazard models were fit with cardiovascular (CV) death or retransplant as the outcome. The pAMR value was included as a categorical variable and the fibrin variables were included in separate models as additive continuous variables. Both pAMR and fibrin were measured from last biopsy and varied over the time of the study. Results 11,550 biopsies from 983 patients were analyzed. Across all pAMR values, the presence of any fibrin increased the risk of CV mortality (OR 2.8, p=0.002). On further analysis, for each one unit increase in the FInt score, an additional 20% increase in CV mortality, above that due to pAMR alone, was observed (p=0.005). In contrast, the severity of the Fvasc score did not further increase the risk of CV death beyond that due to pAMR score (p=0.359). Conclusions The presence of interstitial fibrin on EMB confers an incremental risk of CV mortality in heart transplant recipients above that due to pAMR severity alone. This may be related to a more severe and chronic form of AMR in certain patients. Whether fibrin should be required as part of the pAMR grading system warrants serious consideration. Odds ratio for CV mortality stratified by pAMR score and fibrin deposition Interstitial Fibrin 0 1 2 3 4 5 pAMR0 1.00 1.20 1.45 1.74 2.09 2.52 pAMR1 2.37 2.85 3.43 4.12 4.96 5.97 pAMR2 3.21 3.86 4.64 5.58 6.71 8.08 pAMR3 61.51 73.99 88.99 107.03 128.73 154.83

508 Microvessel Density in Cardiac Allograft Biopsies in Patients with Clinically Significant Coronary Allograft Vasculopathy Treated with Sirolimus

ROC Area 0.64 vs 0.75 0.71 vs 0.78 0.93 vs 0.96 0.75 vs 0.78 0.88 vs 0.92 0.86 vs 0.87 Sensitivity 0.56 vs 0.94 0.66 vs 0.62 0.90 vs 1.00 0.65 vs 0.79 0.71 vs 1.00 0.87 vs 0.87 Specificity 0.71 vs 0.54 0.68 vs 0.86 0.82 vs 0.86 0.75 vs 0.68 0.90 vs 0.72 0.74 vs 0.75 PPV 0.31 vs 0.32 0.78 vs 0.88 0.24 vs 0.30 0.56 vs 0.55 0.23 vs 0.13 0.43 vs 0.43 NPV 0.88 vs 0.97 0.54 vs 0.57 0.99 vs 1.00 0.81 vs 0.87 0.99 vs 1.00 0.96 vs 0.96 Prevalence 0.19 0.63 0.06 0.33 0.04 0.18 Cutoff Value 0.13 vs 0.12 0.45 vs 0.70 0.02 vs 0.05 0.35 vs 0.29 0.03 vs 0.02 0.12 vs 0.11 ROC: Receiver Operating Characteristic; PPV: Positive Predictive Value; NPV: Negative Predictive Value