Tertiary Transplant Research Articles

Autoimmune hepatitis in young Somalian men – experience from a German tertiary care center

Background: Autoimmune hepatitis (AIH) is a rare liver disease predominantly affecting women. Data on AIH in African patients is rare. A previous study from the UK reported an unusual form of AIH in Somalian patients. Methods: To examine whether this form of AIH can also be found in Germany, we screened the database of a major tertiary liver transplantation center. Results and conclusions: Among 17 Somalian patients presenting to our hospital between 2008 and 2021 three male patients were admitted with liver disease. All three of them were diagnosed with AIH. Here, we present the clinical courses highlighting diagnostic challenges and the particular severity of liver disease. These cases emphasize the need to consider AIH as an important differential diagnosis in Somalian patients presenting with new onset of hepatopathy.

The Majority of Patients Who Undergo ERCP When Large Duct Obstruction Is Evident on Liver Biopsy Have Biliary Findings Amenable to Endoscopic Intervention.

(1) Background: Abnormal liver function tests are commonly encountered in clinical practice, often leading to additional workup to determine the underlying etiology of these abnormal laboratory studies. As part of this evaluation, if less invasive imaging studies are performed and are without evidence of biliary obstruction, liver biopsy may be performed, and the finding of large duct obstruction on liver biopsy is commonly encountered. The utility of endoscopic retrograde cholangiopancreatography (ERCP) for evaluation and management of possible biliary obstruction in patients with large duct obstruction on liver biopsy has not been studied to date. (2) Methods: To assess the utility of ERCP in patients with large bile duct obstruction on liver biopsy, we retrospectively evaluated patients with large duct obstruction on liver biopsy from 2010-2019 at our tertiary care and transplant center. Demographic and clinical characteristics were evaluated for all patients, with sub-group analysis for patients who underwent ERCP and those who had intervenable findings at the time of ERCP. Descriptive statistics with proportions, means, and standard deviations were performed for demographics and clinical variables using absolute standardized difference. (3) Results: During the study period, 189 liver biopsies with evidence of large duct obstruction were performed. After exclusion criteria were applied, 166 unique patients were eligible for the study. Ninety-one patients with evidence of large duct obstruction on liver biopsy underwent ERCP and 75 did not. Of the 91 patients who underwent ERCP, 76 patients (84%) had an intervenable finding at ERCP. Patients who underwent ERCP were overall more likely to have had a liver transplant (65% ASD 0.63), have previously undergone cholecystectomy (80%, ASD 0.56), and be immunocompromised (80%, ASD 0.56). (4) Conclusions: ERCP is high yield when large duct obstruction is apparent on liver biopsy, with the majority of patients (84%) who undergo ERCP in this clinical context having a biliary finding necessitating therapeutic endoscopic intervention.

Negative impact of the pandemic on hospital admissions, morbidity and early mortality for acute cirrhosis decompensation

IntroductionThe global pandemic has diverted resources away from management of chronic diseases, including cirrhosis. While there is increasing knowledge on COVID-19 infection in liver cirrhosis, little is described on the...

Study on the clinical and etiological profile of hepatocellular carcinoma in a tertiary care centre in south India: a prospective observational study

Background: Hepatocellular carcinoma (HCC) is the most common primary malignant tumour of the liver occurring in patients with underlying chronic liver disease with high morbidity and mortality with various clinical presentations. This study was conducted to analyse the clinical and etiological profiles of HCC patients in tertiary care liver transplant centre.Methods: This prospective cross-sectional study was conducted in the department of medical gastroenterology, government Stanley medical college, for one year, with a sample size of 75 patients. Clinical details, demography, laboratory parameters and imaging findings are entered in pre-structured proforma. Results: Among 75 patients, 69 were males (92%). The mean age of patients was 45.5±10 years. Abdominal pain in 56 (80%) and abdominal distension in 31 patients (44.2%%) was the most common symptom, with underlying cirrhosis in a majority (70.6%). The etiologies include hepatitis B in 25 (33.3%), ethanol in 20 (26.6%), hepatitis C in 8 (10.6%), NAFLD in 8 (10.6%) and cryptogenic in 11 (14.6%) patients. AFP levels >400 ng/ml were observed in 37 cases (49.3%) with a mean value of 6129 ng/ml with normal in 12 (16%) cases. On imaging, multifocal lesions were seen in 24(32%) patients and vascular invasion in 30 (40%) patients. Most of the patients belong to BCLC stage C (54.6%), followed by stage B (30.6%) and stage A (12%) and two patients (2.6%) in stage D. Patients were managed according to institutional protocol with either hepatectomy, TACE, systemic chemotherapy or combination of these modalities.Conclusions: In our study, HBV (33%) and alcohol (27%) were the most common etiologies, with the majority having underlying cirrhosis.

ETV6 Represses TNF during Stress Hematopoiesis and Regulates HSC Self Renewal

INTRO: ETS Variant Transcription Factor 6 (ETV6), formerly known as Translocation ETS Leukemia (TEL), functions primarily as a transcriptional repressor and is highly expressed in mouse and human HSPCs where it is essential for the development and maintenance of adult hematopoiesis. Nevertheless, it has remained poorly understood how ETV6 regulates the HSC compartment. In 2015, our group and others identified heterozygous pathogenic germline ETV6 variants in families with autosomal dominant thrombocytopenia and predisposition to hematologic malignancies (most often B-acute lymphoblastic leukemia), a condition now known as thrombocytopenia 5 (T5). METHODS: To elucidate the mechanisms by which germline ETV6 variants impact hematopoiesis and promote leukemogenesis, we generated a knock-in mouse model harboring Etv6 R355X, the murine equivalent of a human T5-associated variant (R359X). We used complementary in vitro and in vivo assays to comprehensively characterize the numbers and functions of Etv6R355X/+ and Etv6+/+ hematopoietic progenitors. RESULTS:Etv6R355X/+ mice display several of the cardinal features of T5, including abnormally rounded platelets with increased area compared to platelets from wild-type Etv6+/+ littermates. Further, Etv6R355X/+ platelets exhibit significantly delayed and incomplete clot formation as measured through clot retraction assays. Together, these findings indicate that this novel model will serve as a viable means to study the human disease. We observe that 3-month-old Etv6R355X/+mice maintain normal frequencies and numbers of lineage-sca1+cKit+ (LSK) cells in the bone marrow (BM); however, at 12 months of age, they exhibit a significant decrease in frequency in this compartment. At each of these timepoints, there are variable shifts in the proportions and/or numbers of certain HSC subpopulations. To examine whether the Etv6R355X/+mutation impacts HSC function, we carried out in vitrosEtv6R355X/+BM cells generate more colonies than wild-type cells in the first two rounds of plating, but significantly fewer or no colonies by the fourth plating. Similarly, Etv6R355X/+LSK cells exhibit significantly impaired engraftment when challenged via competitive transplantation, with near complete failure to reconstitute irradiated recipients by the tertiary transplant. Etv6R355X/+LSKs home to the bone marrow comparably to Etv6+/+cells, indicating that homing does not account for the defect in repopulation capacity. To investigate how ETV6 functions in HSCs, we performed RNA-seq of Etv6R355X/+LSKs and flow cytometry-purified HSPC subpopulations from 12-month-old mice, which revealed upregulation of genes associated with an active stem cell phenotype, downregulation of genes supporting stem cell quiescence, and upregulated expression of Tnf with enrichment for the Hallmark TNFa Signaling via NFKB geneset. Subsequent experiments using CUT&RUN of Etv6+/+LSK cells revealed several known and novel ETV6 target genes, including Tnf, a cytokine implicated in regulating stress hematopoiesis. The sites bound by ETV6 at the Tnf locus aligned with ATAC-seq peaks generated from HPC5 cells, a mouse bone marrow progenitor cell line, suggesting that this is a region of open chromatin and active transcriptional regulation. Corroborating these findings, examination of Etv6R355X/+HSPCs at 6 weeks post-transplant revealed increased cell cycling and intracellular TNF production. CONCLUSION: From these studies, we conclude that ETV6 regulates HSC maintenance. Further, it binds to a regulatory sequence within the Tnf locus, whereby it represses TNF expression. The loss or reduction of this repression in Etv6R355X/+HSCs is associated with increased cell cycling under conditions of hematopoietic stress and a loss of self-renewal capacity. Studies are ongoing to determine how these changes promote leukemogenesis and contribute to the other features of T5.

Comparing Outcomes of Outpatient Vs. Inpatient High-Dose Melphalan Based Conditioning Regimens Followed By Autologous Hematopoietic Cell Transplantation in Myeloma

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy and high-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) plays a pivotal role in consolidation of response after initial anti-myeloma therapy. High-dose therapy has been historically applied in the inpatient setting, but some centers have shifted autologous HCT to outpatient setting due to various reasons including health care cost. Here, we compared the survival outcomes of high-dose melphalan followed by autologous HCT at a tertiary referral transplant center since its inception of formal outpatient HCT program. Methods: Clinical transplant data on MM patients who underwent high-dose melphalan at Moffitt Cancer Center (MCC) between 2013 and 2021 were retrospectively reviewed. BMT Research Analysis Information Network (BRAIN) database was used for querying the data. The study population consists of those MM patient who received their first autologous HCT with high-dose melphalan based conditioning regimens. HCT outcomes were compared based on the location of transplant (inpatient vs. outpatient) with the outpatient BMT program officially launching in 2013. Autologous HCT was prescribed as an outpatient by default unless there were reasons such as renal failure requiring dialysis, cardiovascular complications requiring inpatient monitoring, psychosocial concerns, patient refusal for outpatient, or physician discretion. HCT for amyloidosis was excluded from this study. Outpatient HCT team consists of a dedicated transplant faculty member and an advanced practice professional who make daily round on outpatient HCT. Patients are seen in the outpatient BMT treatment center during the day and the arrangements have been made to directly admit to inpatient BMT unit when clinical indications arise. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier method and compared with log-rank testing. Cumulative incidence function was compared with Gray's test. Results: There were 1349 MM patients who underwent autologous HCT with high-dose melphalan-based regimen at MCC from 2013 to 2021. There were 670 patients in the inpatient group and 679 in the outpatient. The number of autologous HCT performed in the outpatient setting has increased overtime and surpassed the inpatient in 2018 with 74.6% of HCT performed as outpatient in 2021. Median age for both groups were 63 years and the median KPS of 90. Median HCT-CI was 3 for both groups. Median serum creatinine was 0.9 (range, 0.4-11.9) for inpatient, and 0.8 (range, 0.4-3.8) for outpatient. Within 30 days from HCT, 57.1% of outpatient MM HCT recipients were admitted to the hospital. Median length of stay for inpatient group was 14 days. Univariate analysis showed that the 5-year OS for outpatient vs. inpatient HCT was 80.6% (95% confidence interval (CI): 76.0-84.3) and 71.0% (95%CI: 66.6-74.8), respectively (Log rank, p=0.0009, Figure). The 5-year PFS for outpatient vs. inpatient HCT was 58.0% (95%CI: 52.6-63.0) and 50.7% (95%CI: 46.2-55.1), respectively (Log rank, p=0.012). The 5-year cumulative incidence of relapse for outpatient vs. inpatient HCT was 34.6% (95%CI: 29.7-39.5) and 39.8% (95%CI: 35.6-44.1), respectively (Gray's test, p=0.046). The 5-year cumulative incidence of nonrelapse mortality (NRM) for outpatient vs. inpatient was 7.3% (95%CI: 4.9-10.3) and 9.3% (95%CI: 6.9-12.1), respectively (Gray's test, p=0.25). Additional multivariate analysis will be provided at the presentation. Conclusions: Since the inception, the volume of outpatient HCT has steadily increased at our institution. In our retrospective analysis, outpatient MM HCT patients had better OS, PFS, with decreased risk of MM relapse compared to inpatient group. However, NRM was similar between the group. These survival differences may be due to patient selection and early period for inpatient HCT. Outpatient HCT is safe and appropriate transplant modality in the majority of MM patients who are candidate for such intervention. Further analysis to evaluate disease related prognostic factors is planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real World Favourable Experience of Haematopoietic Stem Cell Transplantation during Acute Coronavirus Disease 2019 in a Highly-Vaccinated Asian Population

Background Patients with high-risk haematological malignancies often progress and succumb to their disease without a timely haematopoietic stem cell transplantation (HCT). However, in patients undergoing HCT following acute Coronavirus disease 2019 (COVID-19) infection, there is a significant morbidity and mortality risk. Few recent reports suggest that allogeneic and autologous HCT may be feasible in patients who have recovered from COVID-19, but there is little data on the optimal timing and safety of HCT following the infection. High rates of COVID-19 community transmission were observed in a highly-vaccinated population of Singapore between September 2021 and April 2022, affecting many HCT recipients. In this study at the largest tertiary transplant centre in Singapore, we analyzed the outcome of patients who underwent HCT following COVID-19 infection in the preceding 120 days or with active COVID-19 infection during transplant. Methods We conducted a retrospective analysis of consecutive patients admitted to Singapore General Hospital for planned HCT from September 2021 and April 2022. Written informed consent was obtained, and patients were followed up for transplant-related outcomes. The date of diagnosis of COVID-19 was based on the first positive SARS-CoV-2 PCR nasopharyngeal swab. Patients who were diagnosed with COVID-19 within 120 days prior to stem cell infusion were included in the study. Results We studied 10 allogeneic and 1 autologous HCT patients, with acute myeloid leukaemia (n=3), acute lymphoblastic leukaemia (n=2), chronic myeloid leukaemia (n=2), myelofibrosis (n=1), severe aplastic anaemia (n=1), Hodgkin lymphoma (n=1) and multiple myeloma (n=1). Median interval between diagnosis of COVID-19 to HCT infusion was 53 days (range 1-118). 6 were tested negative by PCR and 2 were prolonged low-level viral shedders detectable by PCR, prior to HCT. 3 patients were diagnosed with COVID-19 immediately prior to HCT infusion, at Days -1, -3 and -5 respectively. Median duration of COVID-19 infection defined by time to negative PCR was 20 days. All allogeneic HCT patients had 2 doses of COVID-19 mRNA vaccines (Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273) prior to infection, and the autologous HCT patient was unvaccinated. Median receptor binding domain IgG serology titre (Abbott assay) in vaccinated patients was 1301 AU/ml at the time of COVID-19 diagnosis. COVID-19 disease severity by WHO guidelines was mild in 9, moderate in 1 and critical in 1 patient. 8 patients received antivirals; 5 of them had concurrent monoclonal antibodies (sotrovimab, n=4; casirivimab-imdevimab, n=1). Median age at HCT was 53 years (range 26-70); 64% of patients had low-risk HCT-comorbidity index, 45% were male, and 55% were of high-risk by the disease risk index. Allogeneic HCT patients received peripheral blood stem cells from matched siblings donors (MSD, n=3), matched unrelated donors (MUD, n=2) or haploidentical donors (n=5). 50% of patients received myeloablative conditioning regimen (n=5); and prophylaxis for graft-versus-host disease (GvHD) included calcineurin inhibitors and/or mycophenolate mofetil. Haploidentical transplant patients received post-transplant cyclophosphamide (PTCy, n=3) or ex-vivo TCRalpha-beta depleted grafts (n=2). A relapsed AML patient received haploidentical TCRalpha-beta depleted graft without conditioning regimen. A median of 5.5 x 10^6 CD34+ cells/kg (range 2.9-10.1) was infused. Median time to neutrophil and platelet engraftment were 10 days (range 10-17) and 12 days (range 10-20) respectively, in both MSD and MUD recipients (Table 1), comparable to that of non-COVID-19 cohorts. 2 patients died of non-relapse pulmonary complications on D+43 and D+50 post HCT respectively. 2 out of 10 allogeneic HCT patients developed grade II acute GvHD of skin, but none grade III-IV acute GvHD. Median follow up was 103 days (range 43-208), and GvHD-free/relapse-free survival (GRFS) among surviving patients at D+100 was 78%. There was no evidence of COVID-19 reinfection or late complications, or increase in viral reactivation of CMV, EBV and HHV6. Discussion Our study suggests that timely HCT can be safely performed with favourable outcome for patients with haematological malignancies, following acute COVID-19 infection in a fully-vaccinated cohort. Immunization, viral therapeutics and a careful disease risk-benefit assessment play a crucial role. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Re-Sensitization of Allogeneic T Cell Resistant Murine AML with Pegylated IFN-Gamma

Background: The prognosis of AML relapsing after allogeneic hematopoietic stem cell transplant (alloHSCT) is dismal with very few salvage therapy options. Knowing the biological changes that occur at relapse could lead to potential treatment strategies. Using murine AML cells (Dnmt3aR878H/FLT3-ITD model, kind gift from Dr. Ley's lab), we generated allogeneic T cell resistant murine AML cells (alloTr AML1) via sequential MHC-mismatched alloHSCTs. As shown in Figure 1A, mice injected with the AML1 tumor and allogeneic T cells displayed a significantly decreased median survival time (MST) from >250 days (undefined) to 26 days during progression from the primary alloHSCT to the tertiary alloHSCT, respectively (P<0.0001, 1° HSCT vs. 3° HSCT). Genomic analysis using WES showed no mutations in MHC I, MHC II or genes associated in immune functions in the alloTr AML1 cells. Preliminary transcriptome analysis of the alloTr AML1 after the tertiary transplant shows downregulation of genes mediating cell-cycle regulation and activation of T cells, including regulation of IFN-gamma (IFNg) production pathways. Our group previously showed that human AML cells relapsing after alloHSCT downregulated MHC class II and that IFNg could re-induce MHC-II expression and restore allogeneic T cell-mediated cytotoxicity (Christopher et al, NEJM, 2019). Since native IFNg has a very short terminal half-life of approximately 1h in vivo, it necessitates frequent administration to maintain sustained therapeutic levels. Our collaborators at Bolder Biotech have generated site-specific PEGylated IFNg that exhibits a terminal half-life of 26h in rats and can be detected in the plasma for at least 6 days after a single injection (Fam et al, J Interferon & Cytokine Research, 2014). Here, we evaluated if PEGylated murine (PEG-muIFNg) from Bolder Biotech could re-sensitize alloTr AML1 cells to T cell killing after allo-HSCT. Method: Lethally irradiated B6 recipients were reconstituted with 129 SVJ bone marrow (BM) alone on day 0. On day 10 after alloHSCT, mice were injected with 1.5E6 alloTr AML cells and divided into the following groups: (1) untreated controls (BM only), (2) PEG-muIFNg only, (3) 5 x 106 allogeneic 129 SVJ T cells (allo-T) only on day 10 or (4) 5 x 106allogeneic 129 SVJ T cells on day 10 plus PEG-muIFNg. Two doses of PEG-muIFNg (15 ug or 3.8 ug per injection) were tested in these experiments and treatment was started on day 10 post-alloHSCT at the time of allo-T injection. A total of 6 PEG-muIFNg doses were given (3 doses/week x 2 weeks). Mice were monitored for survival and graft-versus-host disease (GVHD). AML1 tumor burden was assessed by FACS for GFP. Results: The untreated BM only controls died of AML within 18 days of tumor injection (Figure 1B). Treatment with PEG-muIFNg alone, slightly extended the median survival time (MST) of mice in a dose dependent manner with 15 ug PEG-muIFNg dosing providing a MST of 38 days while the 3.8ug dose level exhibited a MST of 32 days. Recipients treated with 5 x 106 allo-T cells alone succumbed to leukemia similar to the untreated controls (MST = 26 days), confirming that these cells were resistant to allo-T cell killing. However, mice treated with allo-T + 15 ug PEG-muIFNgexhibited prolonged survival (MST = 49 days) compared to the T cell only (MST= 26 days; p=0.0001) and the 15 ug PEG-muIFNg only controls (MST =38 days; p=0.0001). The 15 ug dose level provided greater graft-versus-leukemia (GVL) activity (only 9/15 mice relapsed vs. 13/15 with 3.8 ug dosing) but was associated with slightly higher GVHD (6/15 mice developed lethal GVHD). In contrast, the 3.8 ug dose had fewer GVHD related deaths (2/15) but provided slightly less GVL activity (13/15 mice succumbed to AML). Conclusion: Treatment with PEG-muIFNg beginning 10 days after allo-HSCT can re-sensitize the alloTr AML1 tumors to allogeneic T cell-mediated killing and provide a significant survival advantage. Ongoing studies are also examining the candidate IFNg signaling pathway genes dysregulated in our model to determine if they are upregulated after PEG-muIFNg treatment. Furthermore, future studies will explore if extending PEG-muIFNgtreatment at the 3.8 ug concentration beyond 2 weeks can enhance GVL activity while limiting lethal GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Good outcomes of living donor liver transplant in primary sclerosing cholangitis: an experience from North India.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. In the absence of effective medical therapy, liver transplant is the definitive treatment for advanced stage. However, recurrence of PSC after liver transplant is of concern which can lead to graft failure and may require retransplant. There are limited data on outcomes of living donor liver transplant (LDLT) in PSC. Also, in LDLT as donors are genetically related there can be an increased risk of recurrence. We conducted this retrospective study to analyze the outcomes of LDLT in PSC at a tertiary liver transplant center in north India. We conducted a retrospective analysis of 3213 transplant recipients who underwent LDLT from January 2006 to May 2021. Of these 26 (0.80%) patients had PSC as indication for liver transplantation (PSC = 24, PSC-AIH overlap = 2). Data analysis was done to look for baseline demographics, clinical details, transplant outcomes, PSC recurrence, and survival. Mean age of study group was 42 (± 13.8) years and 19patients (73.1%) were males. All patients had decompensated cirrhosis at the time of transplant. Mean CTP score and MELD score were 9.5 (± 1.8) and 18.9 (± 7.1), respectively. Sixteen patients received modified right lobe graft, seven extended right lobe graft and five patients received left lateral graft. Median graft weight and mean graft to recipient weight ratio (GRWR) were 633.5 (IQR 473.5-633.5) grams and 1.23 (± 0.42), respectively. Most common biliary anastomosis was hepaticojejunostomy, done in 19 (73.1%) while duct to duct anastomosis was performed in 7 (26.9%) patients. Median follow-up was 96 (36-123) months. One patient had ulcerative colitis and none had cholangiocarcinoma. Two (7.7%) patients had bile leak during early post-transplant period. Three (11.1%) patients developed graft rejection and were managed successfully with steroid pulses. Three patients died during early post-transplant period while seven deaths occurred during long-term follow-up including one death due to COVID-19. Five (21.73%) patients had recurrence of PSC of which two patients had graft loss including one after retransplantation. The one year graft and patient survival rate was 88.5%. LDLT can be performed in PSC with good long-term outcomes with a risk of PSC recurrence in about one-fifth patients.

Humoral response after athird and fourth dose of mRNA-based SARS-CoV-2 vaccine in previously seronegative kidney transplant recipients.

Growing evidence shows diminished response to mRNA-based SARS-CoV‑2 vaccination in kidney transplant recipients. We aimed to investigate the seroconversion rate after a3rd and 4th dose of mRNA vaccination in kidney transplant recipients without prior antibody response to two or three vaccination doses.This retrospective study included 324 prevalent kidney transplant recipients of asingle tertiary transplantation center of which 157 remained seronegative, defined as anti-spike-RBD-IgG antibody titer < 7.1 BAU/ml, after two doses of mRNA-based SARS-CoV‑2 vaccination. Maintenance immunosuppression was not changed. The median patient age was 60.6 years (IQR 51.4-68.1 years), 66.9% were male. Positivity for anti-spike-RBD-IgG (≥ 7.1 BAU/ml) was measured 4-5weeks after administration of a3rd and 4th vaccine dose.Seroconversion rates were 63.9% after a3rd dose and 29.3% after a4th dose of vaccine. Cumulative prevalence of seropositivity was 51.5% after 2 doses, 80.5% after 3 doses and 84.2% after 4 doses.In conclusion, seroconversion can be achieved in the majority of the kidney transplant recipients by administrating three or four doses of mRNA vaccine without changing maintenance immunosuppression.

Seroprevalence and Management of Strongyloides stercoralis at a Large Tertiary Kidney Transplant Centre in London, United Kingdom

Seroprevalence and Management of Strongyloides stercoralis at a Large Tertiary Kidney Transplant Centre in London, United Kingdom

S1437 Harnessing EHR to Improve Care of Patients With Cirrhosis

Introduction: There is an increasing prevalence of patients with decompensated cirrhosis. These patients have a high rate of admission, with over one third readmitted within thirty days. Ultimately, the burden of this chronic illness impedes patients’ quality of life and has an enormous economic impact on the healthcare system. Due to their complex care it is challenging to transition care from inpatient to outpatient management, and if they are being managed by a non-hepatology service, it is likely that not all treatment guidelines are followed. Recent evidence suggests utilization of electronic health records (EHR) leads to improved guideline directed care and coordination. The aim of this project was to utilize the electronic health record (EHR) to improve the coordination, efficiency, and quality of inpatient cirrhosis management. Methods: This project took place in a single tertiary liver transplant center. A group of stakeholders was formed from internal medicine residents, the hepatology and transplant team, and informatics team. Based on patients being managed, ideas were generated that were subsequently plotted on an impact effort matrix. This helped the team determine direction of EHR intervention. Results: The “Liver Accordion” (Figure) was designed to eliminate steps of the workflow and compile necessary temporal information related to patients with cirrhosis or those transplanted for cirrhosis in one view. For example, a patient with a history of decompensated cirrhosis with history of hepatic encephalopathy and an acute kidney injury. The flow sheet would compile the number of recorded bowel movements and the amount of lactulose ordered and received, amount of albumin given, and if their beta blocker and diuretics were held. It also aims to coordinate inpatient care cognizant of their overall care by pulling information regarding patient’s last hepatology appointment, endoscopy screening, or hepatocellular carcinoma screening in a separate tab linked below. Conclusion: The objective of our solution was to develop and implement a temporal data view in the institution’s EHR to allow clinicians to quickly formulate a clinical picture of the patient and thereby track and manage patient’s disease. This will improve care coordination and workflow. Moreover, if adopted by hospitalist teams not trained in managing cirrhosis, patients will not miss recommended treatment. This project offers a novel EHR tool that can be easily adopted and implemented to change clinical practice.Figure 1.: Example of Liver Accordion in a patient being managed for hepatic encephalopathy

Cardiac evaluation for end-stage kidney disease patients on the transplant waitlist: a single-center cohort study.

BackgroundCardiac evaluation before deceased donor kidney transplant (DDKT) remains a matter of debate. Data on Asian countries and countries with prolonged waiting times are lacking. This study aimed to assess the outcomes of patients referred for DDKT after a cardiac evaluation at an Asian tertiary transplant center.MethodsThis single-center retrospective review analyzed patients who were referred for waitlist placement and underwent cardiac stress testing between January 2009 and December 2015. Patients with cardiac symptoms were excluded. The primary outcome was three-point major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.ResultsOf 468 patients referred for DDKT, 198 who underwent cardiac stress testing (myocardial perfusion studies in 159 patients and stress echocardiography in 39 patients) were analyzed. MACE occurred in 20.7% of the patients over a median follow-up of 4.6 years. Cardiac stress tests were positive for ischemia in 19.7% of the patients. Coronary angiography was performed in 63 patients, including 29 patients with diabetic kidney disease and negative cardiac stress tests. Significant coronary artery disease (CAD) was detected in 27 patients (42.8%), of whom 18 underwent revascularization. MACE was associated with significant CAD on coronary angiography in the multivariable analysis. Cardiac stress test results were not associated with MACE. Amongst diabetic patients who had negative cardiac stress tests, 37.9% had significant CAD on coronary angiography.ConclusionsThe cardiovascular disease burden is significant amongst DDKT waitlist candidates. Pretransplant cardiac screening may identify patients with significant CAD at higher risk of MACE.

Accuracy of Ultrasound Elastography and Fibrosis-4 Index (FIB-4) in Ruling Out Cirrhosis in Obese Non-Alcoholic Fatty Liver Disease (NAFLD) Patients.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of advanced liver disease in the USA. Liver biopsy, the gold standard diagnostic test for evaluating liver fibrosis, is associated with significant risk and expense. The accuracy of ultrasound elastography and Fibrosis-4 index (FIB-4) in the obese NAFLD population is unknown. We aimed to compare the accuracy of ultrasound elastography and FIB-4 to liver biopsy in ruling out cirrhosis in NAFLD patients at a tertiary, transplant referral center in the US.Methods: We retrospectively evaluated 93 patients with a mean age of 53 years (SD: 13 years) who underwent liver ultrasound elastography and liver biopsy, and additionally calculated their FIB-4 at the time of biopsy. We compared the liver stiffness measurement (LSM) obtained from ultrasound elastography and FIB-4 with the pathology results for ruling out cirrhosis.Results: 85% of the patients were white, 53% were female, average BMI was 34.7 (SD: 6.7), 52% had diabetes, and 53% had hypertension. For biopsy-proven cirrhosis (prevalence 15%), a cut-off value of 12.5 kilopascals (kPa) for F4 had a sensitivity of 92% and a specificity of 54%. Values below this threshold excluded cirrhosis with 98% certainty. Compared to FIB-4, ultrasound elastography showed higher accuracy in ruling out cirrhosis (92% vs. 80% sensitivity, 98% vs. 95% negative predictive value (NPV), respectively).Conclusion: To our knowledge, this is the first study in a tertiary transplant referral center in the USA to show that ultrasound elastography was superior to FIB-4 and can be used as a reliable screening test to rule out cirrhosis in obese NAFLD patients at a 12.5 kPa cut-off. Therefore, helping to avoid the risk and expense associated with liver biopsy.

Outcomes of incoming and outgoing second opinions from a UK liver transplant centre

ObjectiveSecond transplant centre opinions (STCOs) for patients declined for liver transplantation are infrequent. We aimed to identify STCOs outcomes from a tertiary transplant centre.DesignReferrals between 2012 and 2020 to Birmingham...

Echocardiographic assessment of cardiovascular function and clinical outcomes in liver transplant recipients.

Cardiovascular disease contributes to a high rate of morbidity and mortality after liver transplantation (LT). However, the progression of cardiac function and cardiac remodeling in LT recipients remains poorly understood. This study sought to evaluate the progression of cardiac function and structure in LT recipients and identify independent predictors of prognosis using echocardiography. From 2009 to 2019, 178 adult LT recipients at a tertiary academic transplant center were retrospectively studied. Transthoracic echocardiograms 1-year pre- and post-LT were assessed. Primary outcomes were progression of systolic and diastolic function. Secondary outcomes included left ventricular remodeling, all-cause mortality, and heart failure readmission post-LT. Subgroup analyzes were performed for etiology of native liver disease. A multivariable model was constructed to examine independent predictors of outcomes. Systolic function significantly worsened, with reduction in stroke volume (45-37ml/m2 , p<.001), left ventricular ejection fraction (LVEF) (65%-62%, p<.001) and cardiac index (3.00-2.60 L/min/m2 , p<.001). Conversely, there were significant improvements in diastolic indices, including tricuspid regurgitation Vmax (228-215cm/s, p=.017), left atrial volume index (LAVI) (32-26ml/m2 , p<.001) and right ventricular systolic pressure (RVSP) (31-28mmHg, p=.001). Additionally, patients had increased relative wall thickness (RWT) (p<.001) and decreased left ventricular end-diastolic dimension/body surface area (p<.001) post-LT. The independent predictors for all-cause mortality and heart failure were increased pre-LT mitral annular early diastolic velocity (HR 1.11, CI 1.02-1.22, p=.018), LAVI (HR 1.06, CI 1.02-1.11, p=.007) and decreased LVEF (HR .89, CI .82-.97, p=.006). The effect of non-alcoholic steatohepatitis on cardiovascular outcomes post-LT was largely comparable to that of Hepatitis B. This study showed reduced systolic and improved diastolic function in LT recipients and highlighted the utility of pre-LT echocardiogram in the prognostication and risk stratification of LT candidates.

Elimination of Herpes Simplex Virus-2 and Epstein-Barr Virus With Seraph 100 Microbind Affinity Blood Filter and Therapeutic Plasma Exchange: An Explorative Study in a Patient With Acute Liver Failure

OBJECTIVES:Herpes simplex virus (HSV)-2 is a rare cause of hepatitis that can lead to acute liver failure (ALF) and often death. The earlier the initiation of acyclovir treatment the better the survival. With regard to ALF, controlled randomized data support the use of therapeutic plasma exchange (TPE) both as bridge to recovery or transplantation—possibly by modulating the systemic inflammatory response and by replacing coagulation factors. Seraph 100 Microbind Affinity Blood Filter (Seraph; Ex Thera Medical, Martinez, CA), a novel extracorporeal adsorption device, removes living pathogens by binding to a heparin-coated surface was shown to efficiently clear HSV-2 particles in vitro. Here, we tested the combination of Seraph with TPE to reduce a massive HSV-2 viral load to reach a situation in that liver transplantation would be feasible.DESIGN:Explorative study.SETTING:Academic tertiary care transplant center.PATIENT:Single patient with HSV-2–induced ALF.INTERVENTIONS:TPE + Seraph 100 Microbind Affinity Blood Filter.MEASUREMENTS AND MAIN RESULTS:We report Seraph clearance data of HSV-2 and of Epstein-Barr virus (EBV) in vivo as well as total viral elimination by TPE. Genome copies/mL of HSV-2 and EBV in EDTA plasma were measured by polymerase chain reaction every 60 minutes over 6 hours after starting Seraph both systemically and post adsorber. Also, HSV-2 and EBV were quantified before and after TPE and in the removed apheresis plasma. We found a total elimination of 1.81 × e11 HSV-2 copies and 2.11 × e6 EBV copies with a single TPE (exchange volume of 5L; 1.5× calculated plasma volume). Whole blood clearance of HSV-2 in the first 6 hours of treatment was 6.64 mL/min (4.98–12.92 mL/min). Despite much lower baseline viremia, clearance of EBV was higher 36.62 mL/min (22.67–53.48 mL/min).CONCLUSIONS:TPE was able to remove circulating HSV-2 copies by 25% and EBV copies by 40% from the blood. On the other hand, clearance of HSV-2 by Seraph was clinically irrelevant, but Seraph seemed to be far more effective of removing EBV, implicating a possible use in EBV-associated pathologies, but this requires further study.

Education and Psychosocial Factors Predict Odds of Death After Transfer to Adult health Care in Pediatric Liver Transplant Patients.

To analyze demographic, psychosocial, and clinical factors in pediatric liver transplant recipients for their association with death or loss to follow up in adulthood. We aimed to better understand known health disparities in transplant outcomes and identify potentially modifiable risk factors prior to transfer. A retrospective cohort study of children who underwent liver transplantation at a large tertiary transplant center and were transferred to adult care between 2000 and 2015. During the study period, 101 qualifying patients were transferred. Ninety-three individuals followed with an adult provider, while 8 were lost to follow up. In total 23 of 93 patients died after transfer (24.7%). Several childhood factors were associated with adult death: Black race [odds ratio (OR) 6.59, P < 0.001]; psychiatric illness or substance use (OR 2.81, P = 0.04); failure to graduate high school before transfer (OR 9.59, P < 0.001); posttransplant tacrolimus medication-level variability index >2.5 (OR 5.36, P = 0.04); provider documentation of medication nonadherence (OR 4.72, P = 0.02); acute cellular rejection (OR 4.44, P = 0.03); the presence of diabetes mellitus (OR 5.71, P = 0.001), and chronic kidney disease (OR 2.82, P = 0.04). Failure to graduate HS was associated with loss to follow up ( P < 0.001). On multivariate analysis, Black race, substance use, diabetes, and failure to graduate HS retained association with adult death (each P < 0.05). Complex, intertwined patient characteristics are associated with increased odds of death in pediatric liver transplant recipients transferred to adult care. Early recognition of high-risk patients and intervention for modifiable factors, such as improved HS graduation and substance use prevention, may improve long-term outcomes.

Pulmonary complications of portal hypertension: The overlooked decompensation.

The systemic nature of cirrhosis and portal hypertension has long been recognized, and the amount of data characterizing the interplay between each system is becoming ever so complex. Lung involvement was among the first described associated entities in cirrhosis, with reports dating back to the late nineteenth century. However, it appears that throughout the years, interest in the pulmonary complications of portal hypertension has generally faded, especially in contrast to other decompensating events, as expertise in this field has primarily been concentrated in highly experienced tertiary care facilities and liver transplantation centers. Despite affecting up to 10%-15% of patients with advanced liver disease and having a proven prognostic impact, hepato-pulmonary syndrome, porto-pulmonary hypertension, and hepatic hydrothorax are frequently misdiagnosed, mistreated, or misinterpreted. This lack of precision might adversely impact patient care, referral to expert centers, and, ultimately, liver disease-related mortality and successful transplantation odds. The present minireview aims to increase awareness of the pulmonary complications of chronic liver disease by providing a brief overview of each of the three entities. The paper focuses on the essential theoretical aspects, addressing the most critical knowledge gaps on the one hand and, on the other hand, critically discussing one key issue for each complication.

Human immunodeficiency virus and solid organ transplantation: a 15-year retrospective audit at a tertiary Australian transplant centre.

The incidence of end-stage organ disease in people living with human immunodeficiency virus (HIV) (PLWH) is increasing, as people live longer due to potent, tolerable antiretroviral therapy (ART). Consequently, the number of PLWH who would benefit from solid organ transplant (SOT) is rising. The SOT experience in PLWH in Australia remains limited. Aim To retrospectively review the outcomes for SOT in PLWH at our service, in Victoria, Australia. A retrospective cohort study of PLWH undergoing SOT over a 15-year period was performed. Adult PLWH age >18 years were eligible and identified from the Victorian HIV Service database. Descriptive statistics were used to summarise baseline demographics and clinical data, and outcomes following SOT. Nine virologically suppressed PLWH underwent SOT from HIV-negative donors (five kidneys, two livers and two bilateral sequential lung transplants). All patients were male, with a median age of 57.3 years (interquartile range (IQR)=54.3-60.1) and CD4 count of 485 (IQR=342-835) at transplantation, and comorbidities were common at baseline. After a median follow up of 3.9 years (IQR=2.7-7.6), 8 (89%) patents were alive, 7 (78%) had functioning grafts, although 5 (56%) experienced organ rejection. Infections were common. Two patients required modification to their ART due to significant drug-drug interactions prior to transplant, while 5 (56%) had modifications post-SOT. No patients experienced HIV virologic failure. PLWH with end-stage organ disease experience good clinical and functional outcomes and should be considered for SOT where indicated. However, multidisciplinary planning and care is essential to optimise care in this patient group.