Outcomes of Liver Transplant Recipients Hospitalized With COVID-19: A Nationwide Analysis From the United States.

Introduction: Currently available data regarding the impact of liver transplantation on the outcomes of patients hospitalized with COVID-19 is conflicting. This study aims to compare the outcomes and resource utilization between patients with and without a history of liver transplant hospitalized with COVID-19. Methods and materials: This is a retrospective study using the National Inpatient Sample. All adults hospitalized with COVID-19 in the year 2020 were included. Mortality was the primary outcome, while endotracheal intubation, length of hospital stay, and total hospital charges were the secondary outcomes. Results: Out of 1,050,720 adults admitted with COVID-19 as the primary diagnosis, 1,455 had a secondary diagnosis of liver transplant. Mortality was not significantly increased in transplant recipients (OR adjusted = 0.69, 95% CI: 0.46-1.03, P = 0.07). Intubation rates and total hospital charges did not differ significantly between liver transplant recipients and patients without a history of liver transplant receipt. LOS was shorter by a coefficient of almost two days in patients with a history of LT (P < 0.001). Conclusion: Liver transplant recipients do not appear to be at increased risk of severe COVID-19 and COVID-19 mortality.

Impact of Renal Replacement Therapy on Rejection among Liver Transplant Recipients.

Introduction: Renal dysfunction in liver transplant recipients is associated with an increased risk of morbidity and mortality, with an even higher risk among patients requiring renal replacement therapy. There is limited data evaluating rejection outcomes in patients requiring renal replacement therapy after liver transplant. Program evaluation aims: To evaluate the incidence of biopsy-proven acute rejection, recipient and graft survival, infection, renal dysfunction, and immunosuppression practices. Design: This was a single-center, retrospective, cohort study. To be eligible, patients were deceased donor liver transplant recipients ≥18 year of age transplanted between January 2017 and August 2019 who received steroid-only induction and tacrolimus as part of their initial immunosuppression regimen. Results: Recipients that required renal replacement therapy (N = 86) were compared to those who received no renal replacement therapy (N = 158). Biopsy-proven acute rejection at 1-year posttransplant was significantly higher among those requiring renal replacement therapy (36% vs 13%, P < .001). Patient survival at 12 months was 77% for those requiring renal replacement therapy and 94% for those not requiring renal replacement therapy (P < .001). Infection (HR 3.8, 95% CI 1.6-8.8; P < .001), but not rejection (HR 0.7, 95% CI 0.3-1.7; P = .5) was an independent predictor of mortality. The use of renal replacement therapy after liver transplant necessitated careful titration of immunosuppression to balance the detrimental risks of infection versus rejection in this high-risk population.

Functional Imaging of Liver Cancer (FLIC): Study protocol of a phase 2 trial of 18F-DCFPyL PET/CT imaging for patients with hepatocellular carcinoma.

BACKGROUND: While prostate specific membrane antigen (PSMA) is overexpressed in high-grade prostate cancers, it is also expressed in tumor neovasculature and other malignancies, including hepatocellular carcinoma (HCC). Importantly, no functional imaging for HCC is clinically available, making diagnosis and surveillance following local therapies particularly challenging. 18F-DCFPyL binds with high affinity to PSMA yet clears rapidly from the blood pool. PET imaging with 18F-DCFPyL may represent a new tool for staging, surveillance and assessment of treatment response in HCC. The purpose of this Functional Imaging Liver Cancer (FLIC) trial is to assess the ability of 18F-DCFPyL-PET/CT to detect sites of HCC. METHODS: This is a phase II multi-site prospective imaging trial with a plan to enroll 50 subjects with suspected HCC on standard of care CT or MRI and eligible for standard local treatment. Participants will undergo a baseline 18F-DCFPyL-PET/CT, prior to therapy. Subjects will also be scanned with 18F-FDG-PET/CT within 2 weeks of 18F-DCFPyL-PET/CT. Participants will undergo histopathologic assessment and standard of care local treatment for HCC within a multidisciplinary team context. Participants with histopathologic confirmation of HCC and a positive baseline 18F-DCFPyL-PET/CT will undergo a post-treatment 18F-DCFPyL-PET/CT during the first routine follow-up, typically within 4-8 weeks. Subjects with negative baseline 18F-DCFPyL-PET/CT will not be re-scanned after treatment but will remain in follow-up. Participants will be followed for 5-years to assess for progression-free-survival. The primary endpoint is the positive predictive value of 18F-DCFPyL-PET for HCC as confirmed by histopathology. Secondary endpoints include comparison of 18F-DCFPyL-PET/CT with CT, MRI, and 18F-FDG-PET/CT, and evaluation of the value of 18F-DCFPyL-PET/CT in assessing treatment response following local treatment. Exploratory endpoints include next generation sequencing of tumors, and analysis of extracellular vesicles to identify biomarkers associated with response to therapy. DISCUSSION: This is a prospective imaging trial designed to evaluate whether PSMA-PET/CT imaging with 18F-DCFPyL can detect tumor sites, assess local treatment response in HCC patients, and to eventually determine whether PSMA-PET/CT could improve outcomes of patients with HCC receiving standard of care local therapy. Importantly, this trial may help determine whether PSMA-selective radiopharmaceutical therapies may be beneficial for patients with HCC. CLINICAL TRIAL REGISTRATION: NIH IND#133631. Submission date: 04-07-2021. Safe-to-proceed letter issued by FDA: 05.07.2021. NIH IRB #00080. ClinicalTrials.gov Identifier NCT05009979. Date of Registry: 08-18-2021. Protocol version date: 01-07-2022.

Early Liver Transplantation for Severe Alcohol-Associated Hepatitis and a History of Prior Liver Decompensation.

INTRODUCTION: In the published studies of early liver transplantation (LT) for alcohol-associated hepatitis (AH), patients with a prior liver decompensation are excluded. The appropriateness of this criteria is unknown. METHODS: Among 6 American Consortium of Early Liver Transplantation for Alcohol-Associated Hepatitis sites, we included consecutive early LT for clinically diagnosed AH between 2007 and 2020. Patients were stratified as first vs prior history of liver decompensation, with the latter defined as a diagnosis of ascites, hepatic encephalopathy, variceal bleeding, or jaundice, and evidence of alcohol use after this event. Adjusted Cox regression assessed the association of first (vs prior) decompensation with post-LT mortality and harmful (i.e., any binge and/or frequent) alcohol use. RESULTS: A total of 241 LT recipients (210 first vs 31 prior decompensation) were included: median age 43 vs 38 years ( P = 0.23), Model for End-Stage Liver Disease Sodium score of 39 vs 39 ( P = 0.98), and follow-up after LT 2.3 vs 1.7 years ( P = 0.08). Unadjusted 1- and 3-year survival among first vs prior decompensation was 93% (95% confidence interval [CI] 89%-96%) vs 86% (95% CI 66%-94%) and 85% (95% CI 79%-90%) vs 78% (95% CI 57%-89%). Prior (vs first) decompensation was associated with higher adjusted post-LT mortality (adjusted hazard ratio 2.72, 95% CI 1.61-4.59) and harmful alcohol use (adjusted hazard ratio 1.77, 95% CI 1.07-2.94). DISCUSSION: Prior liver decompensation was associated with higher risk of post-LT mortality and harmful alcohol use. These results are a preliminary safety signal and validate first decompensation as a criterion for consideration in early LT for AH patients. However, the high 3-year survival suggests a survival benefit for early LT and the need for larger studies to refine this criterion. These results suggest that prior liver decompensation is a risk factor, but not an absolute contraindication to early LT.

Clinical Practice Issues for Liver Transplantation in COVID-19 Recovered Recipients.

The ongoing burden of COVID-19 in persons with end stage liver failure necessitates the development of sound and rational policies for organ transplantation in this population. Following our initial experience with two COVID-19 recovered recipients who died shortly after transplant, we adjusted our center policies, re-evaluated outcomes, and retrospectively analyzed the clinical course of the subsequent seven COVID-19 recovered recipients. There were two early deaths and 5 successful outcomes. Both deceased patients shared common characteristics in that they had positive SARS-CoV2 PCR tests proximal to transplant (7-17 days), had acute on chronic liver failure, and suffered thromboembolic phenomena. After a careful review of clinical and virological outcome predictors, we instituted policy changes to avoid transplantation in these circumstances. We believe that our series offers useful insights into the unique challenges that confront transplant centers in the COVID-19 era and could guide future discussions regarding this important area.

Transplant in acute alcoholic hepatitis: a relative contraindication.

PURPOSE OF REVIEW: The aim of this review is to provide a critical analysis of liver transplantation for alcoholic hepatitis, with an emphasis on barriers to long-term success in current implementation strategies across the United States. RECENT FINDINGS: Alcohol-associated liver disease is the most rapidly increasing indication for liver transplantation in the USA. Its most severe form, acute alcoholic hepatitis, has a rising incidence particularly in the young, and is associated with a high mortality risk. Although excellent outcomes following liver transplantation for alcoholic hepatitis can be achieved, several barriers limit its routine use. These constraints include risk of allograft dysfunction, the recognition of alcohol use disorder as a multisystem disease and ethical considerations. SUMMARY: Although liver transplantation is an important option in a carefully selected group of candidates, it should not be considered the standard of care in this condition. Consistency, transparency and consensus are necessary to formulate and implement policy changes at the national level. Following liver transplantation, wraparound services are important for relapse prevention, and to ensure long-term success and survival in this challenging group of patients.

Passenger Lymphocyte Syndrome: A Rare Case of Anemia After Liver Transplant.

Passenger lymphocyte syndrome is a rare presentation of posttransplant anemia caused by donor antibodies that target recipient red blood cells. We present a classic case of passenger lymphocyte syndrome in a liver transplant recipient who developed anemia due to immune-mediated hemolysis. He presented 3 weeks posttransplant with shortness of breath and fatigue and was found to have severe anemia with a significant reduction in hemoglobin levels. Evaluation revealed antibody-mediated hemolysis consistent with the diagnosis of passenger lymphocyte syndrome. For these patients, treatment is mainly supportive; however, steroid treatment can be considered. Although rare, passenger lymphocyte syndrome should be part of the differential diagnosis when evaluating posttransplant anemia.

Patterns of Alcohol Use After Early Liver Transplantation for Alcoholic Hepatitis.

BACKGROUND & AIMS: Early liver transplantation (LT) for alcoholic hepatitis (AH) is lifesaving but concerns regarding return to harmful alcohol use remain. We sought to identify distinct patterns of alcohol use post-LT to inform pre-LT candidate selection and post-LT addiction care. METHODS: Detailed post-LT alcohol use data was gathered retrospectively from consecutive patients with severe AH at 11 ACCELERATE-AH sites from 2006-2018. Latent class analysis identified longitudinal patterns of alcohol use post-LT. Logistic and Cox regression evaluated associations between patterns of alcohol use with pre-LT variables and post-LT survival. A microsimulation model estimated the effect of selection criteria on overall outcomes. RESULTS: Of 153 LT recipients, 1-, 3-, and 5-year survival were 95%, 88% and 82%. Of 146 LT recipients surviving to home discharge, 4 distinct longitudinal patterns of post-LT alcohol use were identified: Pattern 1 [abstinent](n = 103; 71%), pattern 2 [late/non-heavy](n = 9; 6.2%), pattern 3 [early/non-heavy](n = 22; 15%), pattern 4 [early/heavy](n = 12; 8.2%). One-year survival was similar among the 4 patterns (100%), but patients with early post-LT alcohol use had lower 5-year survival (62% and 53%) compared to abstinent and late/non-heavy patterns (95% and 100%). Early alcohol use patterns were associated with younger age, multiple prior rehabilitation attempts, and overt encephalopathy. In simulation models, the pattern of post-LT alcohol use changed the average life-expectancy after early LT for AH. CONCLUSIONS: A significant majority of LT recipients for AH maintain longer-term abstinence, but there are distinct patterns of alcohol use associated with higher risk of 3- and 5-year mortality. Pre-LT characteristics are associated with post-LT alcohol use patterns and may inform candidate selection and post-LT addiction care.

Accuracy of Milan, University of California San Francisco, and Up-To-7 Criteria in Predicting Tumor Recurrence Following Deceased-Donor Liver Transplant in Patients With Hepatocellular Carcinoma.

OBJECTIVES: We aimed to investigate the accuracy of the Milan, University of California San Francisco, and Up-to-7 criteria in predicting tumor recurrence after liver transplant for hepatocellular carcinoma. MATERIALS AND METHODS: For this study, 165 patients with deceased-donor liver transplant for hepatocellular carcinoma were evaluated. The Milan, University of California San Francisco, and Up-to-7 criteria were calculated based on explant pathology. RESULTS: Tumor recurrence rate after liver transplant was 14.6%. Of 165 patients, 115 (70%) were within Milan, 131 (79%) were within University of California San Francisco, and 135 (82%) were within Up-to-7 criteria. The odds ratio of tumor recurrence in patients outside versus within criteria for Milan, University of California San Francisco, and Up-to-7 was 3.6 (95% confidence interval, 1.5-9.1; P = .005), 7.5 (95% confidence interval, 2.5-19.3; P < .001), and 7.5 (95% confidence interval, 2.9-19.6; P < .001) times higher, respectively. The sensitivity of being outside of Milan in predicting tumor recurrence was comparable to University of California San Francisco and Up-to-7 criteria (56.5%, 56.5%, and 52.2%, respectively). Specificity was highest in Up-to-7 (87.3%) versus 85.2% for University of California San Francisco and 73.9% for Milan criteria. The area under the curve for Milan, University of California San Francisco, and Up-to-7 criteria was 0.63, 0.65, and 0.63. CONCLUSIONS: Application of standard criteria has significantly improved prediction of hepatocellular carcinoma recurrence. However, these criteria are inadequate, supporting the importance of other factors, including tumor biology. Research is ongoing in discovering novel biomarkers as predictors of tumor recurrence.

Exploring opportunities to prevent cirrhosis admissions in the emergency department: A multicenter multidisciplinary survey.

Patients with cirrhosis have high admission and readmission rates, and it is estimated that a quarter are potentially preventable. Little data are available regarding nonmedical factors impacting triage decisions in this patient population. This study sought to explore such factors as well as to determine provider perspectives on low-acuity clinical presentations to the emergency department, including ascites and hepatic encephalopathy. A survey was distributed in four liver transplant centers to both emergency medicine and hepatology providers, who included attending physicians, house staff, and advanced practitioners; 196 surveys were returned (estimated response rate 50.6%). Emergency medicine providers identified several influential nonmedical factors impacting inpatient triage decisions, including input from a hepatologist (77.7%), inadequate patient access to outpatient specialty care (68.6%), and patient need for diagnostic testing for a procedure (65.6%). When given patient-based scenarios of low-acuity cases, such as ascites requiring paracentesis, only 7.0% believed patients should be hospitalized while 48.9% said these patients would be hospitalized at their institution (P < 0.0001). For mild hepatic encephalopathy, the comparable numbers were 19.5% and 55.2%, respectively (P < 0.001). Several perceived barriers were cited for this discrepancy, including limited resources both in the outpatient setting and emergency department. Most providers believed that an emergency department observation unit protocol would influence triage toward an emergency department observation unit visit instead of inpatient admission for both ascites requiring large volume paracentesis (83.2%) and mild hepatic encephalopathy (79.4%). Conclusion: Many nonmedical factors that influence inpatient triage for patients with cirrhosis could be targeted for quality improvement initiatives. In some scenarios, providers are limited by resource availability, which results in triage to an inpatient admission even when they believe this is not the most appropriate disposition. (Hepatology Communications 2018;2:237-244).

Microvascular Invasion in Hepatocellular Carcinoma and Liver Transplant.

OBJECTIVES: Curative therapy for hepatocellular carcinoma is liver transplant. To date, the Milan Criteria remain the best pretransplant clinical surrogate for tumor behavior and overall prognosis. Microvascular invasion portends a poor prognosis; however, it is often undetectable before transplant. Furthermore, its pretransplant indicators are not well established. In this study, we investigated the presurgical and pathologic predictors of microvascular invasion in patients with hepatocellular carcinoma. MATERIALS AND METHODS: Between August 2000 and August 2013, 156 liver transplants were performed for hepatocellular carcinoma at the Johns Hopkins Medical Center. Information on clinical characteristics and pathology data, including microvascular invasion, were available for 107 patients on liver explants. Logistic regression was used to assess the effects of Milan Criteria, alpha-fetoprotein, tumor differentiation, and multilobar involvement on the presence of microvascular invasion on explant pathology. RESULTS: In 107 patients, 24 (22%) had microvascular invasion on pathology. In patients with microvascular invasion, 41% were outside of Milan Criteria versus 19.3% of patients within but without microvascular invasion. In patients with microvascular invasion, the rate of poor differentiation and alpha-fetoprotein level > 1000 ng/mL were more common than in patients without microvascular invasion; however, on univariate and multivariable analyses, Milan Criteria, alphafetoprotein level, multilobar involvement, and differentiation did not reach statistical significance in predicting microvascular invasion on pathology. CONCLUSIONS: In this study, potential predictors of microvascular invasion, including Milan Criteria, alphafetoprotein level, tumor differentiation, and multilobar involvement, were not predictive. Preoperative prediction of microvascular invasion remains a challenge, suggesting the need for future studies.

Diagnostic and therapeutic utility of SpyGlass(®) peroral cholangioscopy in intraductal biliary disease: single-center, retrospective, cohort study.

BACKGROUND AND AIM: SpyGlass® cholangiopancreatoscopy system has shown early success in aiding diagnosis and management of pancreaticobiliary diseases. We aimed to assess the technical success, clinical success, diagnostic yield, therapeutic yield, and safety of the SpyGlass® system at a single institution. METHODS: A retrospective, single-center review of consecutive patients who underwent endoscopic retrograde cholangiopancreatography with SpyGlass® between January 2008 and August 2013 for a variety of indications. Technical success was defined as the procedure being completed as planned. Clinical success was defined as a successful outcome using diagnostic, clinical, laboratory, or imaging evidence. RESULTS: SpyGlass® cholangioscopy was carried out in 88 patients (49 females, mean age 56.9 ± 15.5 years). Indications were diagnostic in 67 and therapeutic in 21. Overall, technical success was seen in 87.5% and clinical success in 77.3%. Thirty-nine patients with indeterminate biliary stricture had technical and clinical success rates of 92.3% and 74.4%, respectively. In this subgroup, malignancy was ultimately diagnosed in 13 with 12 patients diagnosed by SpyGlass® and confirmed by surgical specimens in 12/12 cases; positive predictive value 100%). In the 23 remaining patients with indeterminate biliary strictures, one was later found to have malignancy (negative predictive value 95.8%) after 1 year of follow up. In the 13 therapeutic cases of stone removal, technical and clinical success was seen in 77.0% for both. Overall, adverse events were seen in 15.9%. CONCLUSIONS: SpyGlass® demonstrated acceptable technical and clinical success rates in both diagnostic and therapeutic procedures. In particular, it allows for an accurate rate of diagnosis of indeterminate biliary strictures.

An IL-2 paradox: blocking CD25 on T cells induces IL-2-driven activation of CD56(bright) NK cells.

Daclizumab (Dac), an Ab against the IL-2R alpha-chain, inhibits brain inflammation in patients with multiple sclerosis, while expanding CD56(bright) immunoregulatory NK cells in vivo. We hypothesized that this unexpected expansion is paradoxically IL-2 driven; caused by the increased availability of T cell-derived IL-2 for NK cell signaling. To this end, we performed ex vivo functional analyses of CD56(bright) NK cells and T cells from patients in clinical trials with Dac. We developed in vitro models to investigate mechanisms for ex vivo observations. We observed that Dac treatment caused decreased numbers and proliferation of FoxP3(+) T regulatory cells (Tregs), a model T cell population known to be dependent on IL-2 for proliferation and survival. As anticipated, Dac therapy inhibited IL-2 signaling in all T cells; however, we also observed functional adaptation of T cells to low IL-2 signal in vivo, characterized by the concomitant enhancement of IL-7 signaling on all T cells and parallel increase of CD127 expression by Tregs. In contrast, IL-2 signaling on CD56(bright) NK cells was not inhibited by Dac and their in vivo proliferation and cytotoxicity actually increased. Mechanistic studies indicated that the activation of CD56(bright) NK cells was likely IL-2 driven, as low doses of IL-2, but not IL-15, mimicked this activation in vitro. Our study provides insight into the role that IL-2 and CD25 play in functional regulation of two important immunoregulatory cell populations in humans: FoxP3(+) Tregs and CD56(bright) NK cells.