Cytomegalovirus-associated pseudomembranous colitis in a kidney transplant recipient.

Pseudomembranous colitis (PMC) is classically associated with Clostridium difficile infection. We report a rare case of cytomegalovirus (CMV)-associated PMC in a 52-year-old female patient who had undergone kidney transplantation more than 20 years ago and was on low dose prednisolone and ciclosporin. She presented with an acute history of fever, lethargy, vomiting and diarrhoea on admission. Computed tomography of the abdomen showed extensive colitis, and colonoscopy revealed extensive pseudomembrane formation. Multiple tests for Clostridium difficile and other common microbiological causes of colitis were negative. CMV DNAemia and colonic biopsies confirmed the diagnosis of CMV colitis. The patient responded to prompt CMV treatment, as demonstrated by clinical, endoscopic, and histological response. While CMV is a common pathogen in the solid organ transplant population that is familiar to most transplant physicians, it may present atypically as PMC. Here, we review the literature on CMV-associated PMC and its relevance to solid organ transplant recipients. To our knowledge, this is the first reported case of CMV-associated PMC in a kidney transplant recipient.

Description of parallel and sequential configurations for concurrent therapeutic plasma exchange and continuous kidney replacement therapy in adults.

Therapeutic plasma exchange (TPE) and continuous kidney replacement therapy (CKRT) are extracorporeal therapeutic procedures often implemented in management of patients. Critically ill patients may be afflicted with disease processes that require both TPE and CKRT. Performing TPE discontinuous with CKRT is technically easier, however, it disrupts CKRT and may compromise with CKRT efficiency or hemofilter life. Concurrent TPE with CKRT offers several advantages including simultaneous control of disease process and correction of electrolyte, fluid, and acid-base disturbances that may accompany TPE. Additionally, TPE may be performed by either centrifugation method or membrane plasma separation method. The technical specifications of these methods may influence the methodology of concurrent connections. This report describes and reviews two different approaches to circuit arrangements when establishing concurrent TPE and CKRT.

Immunosuppressive Drug-Resistant Armored T-Cell Receptor T Cells for Immune Therapy of HCC in Liver Transplant Patients.

BACKGROUND AND AIMS: HBV-specific T-cell receptor (HBV-TCR) engineered T cells have the potential for treating HCC relapses after liver transplantation, but their efficacy can be hampered by the concomitant immunosuppressive treatment required to prevent graft rejection. Our aim is to molecularly engineer TCR-T cells that could retain their polyfunctionality in such patients while minimizing the associated risk of organ rejection. APPROACH AND RESULTS: We first analyzed how immunosuppressive drugs can interfere with the in vivo function of TCR-T cells in liver transplanted patients with HBV-HCC recurrence receiving HBV-TCR T cells and in vitro in the presence of clinically relevant concentrations of immunosuppressive tacrolimus (TAC) and mycophenolate mofetil (MMF). Immunosuppressive Drug Resistant Armored TCR-T cells of desired specificity (HBV or Epstein-Barr virus) were then engineered by concomitantly electroporating mRNA encoding specific TCRs and mutated variants of calcineurin B (CnB) and inosine-5'-monophosphate dehydrogenase (IMPDH), and their function was assessed through intracellular cytokine staining and cytotoxicity assays in the presence of TAC and MMF. Liver transplanted HBV-HCC patients receiving different immunosuppressant drugs exhibited varying levels of activated (CD39+ Ki67+ ) peripheral blood mononuclear cells after HBV-TCR T-cell infusions that positively correlate with clinical efficacy. In vitro experiments with TAC and MMF showed a potent inhibition of TCR-T cell polyfunctionality. This inhibition can be effectively negated by the transient overexpression of mutated variants of CnB and IMPDH. Importantly, the resistance only lasted for 3-5 days, after which sensitivity was restored. CONCLUSIONS: We engineered TCR-T cells of desired specificities that transiently escape the immunosuppressive effects of TAC and MMF. This finding has important clinical applications for the treatment of HBV-HCC relapses and other pathologies occurring in organ transplanted patients.

Waitlisted Transplant Candidates' Attitudes and Concerns Toward Transplantation During COVID-19.

BACKGROUND In solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients, coronavirus disease 2019 (COVID-19) can contribute to a severe clinical course and an increased risk of death. Thus, patients awaiting a SOT or HSCT face the dilemma of choosing between a life-saving treatment that presents a significant threat of COVID-19 and the risk of waitlist dropout, progression of disease, or mortality. The lack of established literature on COVID-19 complicates the issue as patients, particularly those with inadequate health literacy, may not have the resources needed to navigate these decisions. MATERIAL AND METHODS We conducted a standardized phone survey of patients awaiting SOT or HSCT to assess the prevalence of inadequate health literacy and attitudes toward transplant during the COVID-19 pandemic. RESULTS Seventy-one patients completed the survey, with a response rate of 84.5%. Regardless of health literacy, most waitlisted candidates recognized that the current pandemic is a serious situation affecting their care and that COVID-19 poses a significant risk to their health. Despite the increased risks, most patients reported they would choose immediate transplantation if there was no foreseeable end to the pandemic, and especially if the medical urgency did not permit further delay. There were no differences in responses across the patient waitlist groups for heart, kidney, liver, and stem cell transplant. CONCLUSIONS These findings can help transplant centers decide how transplantation services should proceed during this pandemic and can be used to educate patients and guide discussions about informed consent for transplant during the COVID-19 pandemic.

Practical Considerations for Solid Organ Transplantation During the COVID-19 Global Outbreak: The Experience from Singapore.

The current coronavirus disease 2019 (COVID-19) pandemic has not only caused global social disruptions but has also put tremendous strain on healthcare systems worldwide. With all attention and significant effort diverted to containing and managing the COVID-19 outbreak (and understandably so), essential medical services such as transplant services are likely to be affected. Closure of transplant programs in an outbreak caused by a highly transmissible novel pathogen may be inevitable owing to patient safety. Yet program closure is not without harm; patients on the transplant waitlist may die before the program reopens. By adopting a tiered approach based on outbreak disease alert levels, and having hospital guidelines based on the best available evidence, life-saving transplants can still be safely performed. We performed a lung transplant and a liver transplant successfully during the COVID-19 era. We present our guidelines and experience on managing the transplant service as well as the selection and management of donors and recipients. We also discuss clinical dilemmas in the management COVID-19 in the posttransplant recipient.

Repeat liver resection versus salvage liver transplant for recurrent hepatocellular carcinoma: A propensity score-adjusted and -matched comparison analysis.

BACKGROUNDS/AIMS: Repeat liver resection (RLR) and salvage liver transplantation (SLT) are viable treatment options for recurrent hepatocellular carcinoma (HCC). With possibly superior survival outcomes than RLR, SLT is however, limited by liver graft availability and poses increased perioperative morbidity. In this study, we seek to compare the outcomes of RLR and SLT for patients with recurrent HCC. METHODS: Between 1999 and 2018, 94 and 16 consecutive patients who underwent RLR and SLT respectively were identified. Further retrospective subgroup analysis was conducted, comparing 16 RLR with 16 SLT patients via propensity-score matching. RESULTS: After propensity-score adjusted analyses, SLT demonstrated inferior short-term perioperative outcomes than RLR, with increased major morbidity (57.8% vs 5.4 %, p=0.0001), reoperations (39.1% vs 0, p<0.0001), renal insufficiency (30.1% vs 3%, p=0.0071), bleeding (19.8% vs 2.2%, p=0.0289), prolonged intensive care unit stay (median=4 vs 0 days, p<0.0001) and hospital stay (median=19.8 vs 7.1days, p<0.001). However, SLT showed significantly lower recurrence rate (15.4% versus 70.3%, p=0.0005) and 5-year cumulative incidence of recurrences (19.4% versus 68.4%, p=0.005). Propensity-matched subgroup analysis showed concordant findings. CONCLUSIONS: While SLT offers potentially reduced risks of recurrence and trended towards improved long-term survival outcomes relative to RLR, it has poorer short-term perioperative outcomes. Patient selection is prudent amidst organ shortages to maximise allocated resources and optimise patient outcomes.

Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3rd cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival.

Outcomes of salvage liver transplant for recurrent hepatocellular carcinoma: A comparison with primary liver transplant.

BACKGROUNDS/AIMS: Salvage liver transplantation (SLT) is a therapeutic strategy for recurrent hepatocellular carcinoma (HCC). However, it remains controversial with compromised survival outcomes and increased perioperative morbidity compared to primary liver transplant (PLT). In the present work, we describe our institution's experience on SLT by comparing outcomes of SLT to PLT for HCCs. METHODS: Retrospective analysis was conducted for 49 transplant patients from 2006-2017. A comparative analysis was carried out between 14 SLT patients and 35 PLT patients. RESULTS: SLT patients demonstrated significantly shorter time to recurrence than PLT patients (median=5.5 versus 23 months, p<0.001) with a trend towards increased perioperative major morbidity (42.9% versus 37%, p=0.711), inferior 5-year overall survival (61% versus 75%, p=0.345) and inferior 5-year recurrence-free survival (57% versus 72%, p=0.263). However, overall survival from the point of primary resection over a 10-year period showed no statistical difference between the 2 groups (SLT=60% versus PLT=61%, p=0.685). CONCLUSIONS: SLT is a viable treatment strategy for HCCs. However, it exhibited poorer short-term perioperative and oncologic outcomes than PLT. SLT requires better patient selection with liver donor grafts for optimization of resource allocation in this era of organ shortage. Considering the worldwide shortages in liver grafts, it is hypothesized that optimization of a salvage transplant strategy may improve resource allocation and reap optimal patient outcomes.

Understanding the hepatitis B core positive liver donor.

The increasing number of patients on the Singapore national liver transplant waiting list and the lack of donor livers have necessitated a review of the limited use of marginal donor liver grafts. Some grafts are of good quality but are considered marginal due to positive donor antibody to hepatitis B virus core protein serology, and negative hepatitis B surface antigen (HBsAg) and hepatitis B DNA. The fear is of viral reactivation during periods of intense immunosuppression. This is made possible by the ability of the hepatitis B virion to reside in a dormant state within the hepatocyte nucleus despite HBsAg clearance, i.e. the occult hepatitis B infection (OBI). In truth, appropriate selection of recipients and effective post-transplantation immunoprophylaxis significantly reduce the risk of hepatitis B viral reactivation. This article explains the confusion surrounding OBI and reviews current recommendations on how to manage such donor liver grafts.

Hepatitis B: encouraging the use of interferon.

PURPOSE OF REVIEW: Hepatitis B is a major cause of hepatocellular carcinoma and liver cirrhosis. Interferon (IFN)-based therapies provide the highest likelihood of achieving off-treatment virological and serological control although their use is often avoided because of the side-effect profile. We review recent developments regarding the use of IFN in the treatment of chronic hepatitis B, including proposed strategies to enhance efficacy while limiting treatment exposure for patients who are unlikely to achieve acceptable treatment endpoints. RECENT FINDINGS: The utility of host genetics (human leukocyte antigen associations and interleukin 28B) is yet to be defined. In hepatitis B e antigen (HBeAg)-positive disease, add-on IFN therapy to patients on entecavir may allow curtailment of nucleos(t)ide analogue treatment. In HBeAg-negative disease, an on-treatment stopping rule that measures decline of hepatitis B surface antigen and hepatitis B virus DNA at 12 and 24 weeks may identify up to two-thirds of poor responders. Prolonging IFN therapy to 96 weeks in patients with HBeAg-negative disease may improve virological and serological response rates. The combination of telbivudine and IFN therapy is contraindicated because of high rates of peripheral neuropathy. SUMMARY: These findings need to be confirmed in larger trials before they can be instituted into routine clinical practice.

Change in model for end-stage liver disease score at two weeks, as an indicator of mortality or liver transplantation at 60 days in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterised by a sudden deterioration of underlying chronic liver disease, resulting in increased rates of mortality and liver transplantation. Early prognostication can benefit optimal allocation of resources. METHODS: ACLF was defined as per the disease criteria of the Asian Pacific Association for the Study of the Liver. Inpatient discharge summaries from between January 2001 and April 2013 were reviewed. The primary outcome was mortality or liver transplantation within 60 days from onset of ACLF. Absolute 'model for end-stage liver disease' (MELD) score and change in MELD at Weeks 1, 2 and 4 were reviewed in order to identify the earliest point for prediction of mortality or liver transplantation. RESULTS: Clinical data were collected on 53 subjects who fulfilled the inclusion and exclusion criteria. At 60 days from presentation, 20 patients (37.7%) died and 4 (7.5%) underwent liver transplantation. Increased MELD of ≥2 after 2 weeks was 75.0% sensitive and 75.9% specific for predicting mortality or liver transplantation. If the MELD score did not increase at 2 weeks, predictive chance of survival was 93.8% over the next 60 days. MELD change at 1 week showed poor sensitivity and specificity. Change at 4 weeks was too late for intervention. CONCLUSION: Change in MELD score at 2 weeks provides an early opportunity for prognostication in ACLF. A MELD score that does not deteriorate by Week 2 would predict 93.8% chance of survival for the next 60 days. This finding warrants further validation in larger cohort studies.