Time since liver transplant and immunosuppression withdrawal outcomes: Systematic review and individual patient data meta-analysis.

BACKGROUND & AIMS: Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term "pre-withdrawal time". To clarify the impact of pre-withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta-analysis. METHODS: We systematically interrogated the literature for LT recipient ISW studies reporting pre-withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre-withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time-response curves were calculated using random-effects meta-analyses. RESULTS: We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study-level risk of bias was heterogeneous. Mean pre-withdrawal time was greater by 427 days [95% confidence interval (CI) 67-788] in OT compared to non-OT patients. This increase was potentiated to 799 days (95% CI 369-1229) or 1074 days (95% CI 685-1463) when restricting analysis to adult or European study participants. In time-response meta-analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4-10%) per year after LT (GRADE low- and moderate-certainty of evidence, respectively). CONCLUSIONS: Our data support the impact of pre-withdrawal time in ISW decision-making for adult and European LT recipients. PROSPERO REGISTRATION: CRD42021272995.

[Gastroenterology and hepatology: what's new in 2023]. / Gastroentérologie et hépatologie: ce qui a changé en 2023.

2023 has been marked by numerous advancements in the fields of hepatology, liver transplantation, gastroenterology, and interventional endoscopy. These developments hold the promise of changing our daily practice while enhancing the diagnosis and treatment of various hepatic and gastroenterological conditions. Additionally, the European Association for the Study of the Liver (EASL) has issued recommendations for the management of hepatitis delta, acute-on-chronic liver failure, liver diseases of pregnancy, and intrahepatic cholangiocarcinoma. Risankizumab was approved by Swiss Authorities for patients with Crohn's disease and dupilumab was approved for patients with eosinophilic esophagitis. The European Society of Gastrointestinal Endoscopy (ESGE) has revised its recommendations regarding Barrett's esophagus.

2023 a été marquée par de nombreuses avancées dans le domaine de l'hépatologie, de la transplantation hépatique, de la gastroentérologie et de l'endoscopie interventionnelle. Ces développements promettent de changer notre pratique quotidienne dans le but d'améliorer le diagnostic et le traitement de nombreuses affections hépatiques et gastroentérologiques. En outre, la Société européenne d'hépatologie (EASL) a émis des recommandations pour la prise en charge de l'hépatite delta, de l'insuffisance hépatique aiguë sur chronique, des complications hépatiques de la grossesse et du cholangiocarcinome intrahépatique. Le risankizumab a été approuvé par Swissmedic pour le traitement de la maladie de Crohn et le dupilumab pour les patients avec œsophagite à éosinophiles. La Société européenne d'endoscopie a mis à jour ses recommandations concernant l'œsophage de Barrett.

[Short telomere syndrome in adults: a rare entity that should be evoked]. / Syndrome des télomères courts chez l'adulte†: une entité rare qu'il faut savoir évoquer.

Short telomere syndrome (STS) is a group of rare, often underrecognized, diseases caused by defects in telomere-maintenance genes, leading to abnormal telomere shortening and associated with diverse multi-organ manifestations. In pediatric patients, STS typically presents with mucocutaneous or gastrointestinal lesions, bone marrow failure and neoplasia. In adulthood, aplastic bone marrow disease, liver disease and pulmonary fibrosis are classic clinical manifestations. At present, medical treatment options for STS remain limited. Danazol, a synthetic androgenic hormone, can slow down telomere shortening and thus limit the progression of the disease. Finally, hematopoietic, hepatic and pulmonary transplantation, sometimes combined, may be discussed in a multidisciplinary setting in certain situations.

Le syndrome des télomères courts (STC) est un groupe de maladies rares dues à un défaut dans les gènes de maintenance des télomères, provoquant leur raccourcissement anormal et des manifestations cliniques multiorganiques. Dans l'enfance, le STC se présente par des lésions mucocutanées et gastro-intestinales, une insuffisance médullaire et des néoplasies. À l'âge adulte, une atteinte médullaire aplasiante, hépatique, et une fibrose pulmonaire sont des manifestations cliniques classiques. Les options thérapeutiques pour le STC restent limitées. Le danazol, une hormone androgène synthétique, permet, parfois, de freiner le raccourcissement télomérique et de limiter la progression de la maladie. Finalement, les transplantations hématopoïétique, hépatique et pulmonaire sont discutées dans certaines situations de manière multidisciplinaire.

Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: A scoping review.

Indefinite allograft acceptance after immunosuppression withdrawal (ISW), also known as operational tolerance (OT), can occur spontaneously after liver transplantation (LT), but reliable and reproducible prognosis of OT versus non-OT outcomes remains elusive. To prime this, systematic extraction of OT-predictive factors from the literature is crucial. We provide the first comprehensive identification and synthesis of clinical parameters and biomarkers predicting spontaneous OT in non-autoimmune/non-replicative viral LT recipients selected for ISW. We searched Embase, Medline, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform for articles, conference abstracts, and ongoing trials. We contacted principal investigators of stand-alone abstracts and ongoing trials for unpublished data and screened citations and references of eligible articles. Twenty-three articles reporting on 11 completed ISW studies, 13 abstracts, and five trial registry entries were included. Longer time between LT and ISW was the only clinical parameter that may increase the incidence of OT. Prognostic biomarkers conspicuously differed between pediatric and adult ISW candidates. These included allograft gene expression patterns and peripheral blood immune exhaustion markers for adults, and histological allograft scores for children. Our results will foster cross-validation efforts to facilitate safe and harmonized candidate selection for successful ISW.

Non-invasive alloimmune risk stratification of long-term liver transplant recipients.

BACKGROUND & AIMS: Management of long-term immunosuppression following liver transplantation (LT) remains empirical. Surveillance liver biopsies in combination with transcriptional profiling could overcome this challenge by identifying recipients with active alloimmune-mediated liver damage despite normal liver tests, but this approach lacks applicability. Our aim was to investigate the utility of non-invasive tools for the stratification of stable long-term survivors of LT, according to their immunological risk and need for immunosuppression. METHODS: We conducted a cross-sectional multicentre study of 190 adult LT recipients assessed to determine their eligibility to participate in an immunosuppression withdrawal trial. Patients had stable liver allograft function and had been transplanted for non-autoimmune non-replicative viral liver disease >3 years before inclusion. We performed histological, immunogenetic and serological studies and measured the intrahepatic transcript levels of an 11-gene classifier highly specific for T cell-mediated rejection (TCMR). RESULTS: In this cohort, 35.8% of patients harboured clinically silent fibro-inflammatory liver lesions (13.7% had mild damage and 22.1% had moderate-to-severe damage). The severity of liver allograft damage was positively associated with TCMR-related transcripts, class II donor-specific antibodies (DSAs), ALT, AST, and liver stiffness measurement (LSM), and negatively correlated with serum creatinine and tacrolimus trough levels. Liver biopsies were stratified according to their TCMR transcript levels using a cut-off derived from biopsies with clinically significant TCMR. Two multivariable prediction models, integrating ALT+LSM or ALT+class II DSAs, had a high discriminative capacity for classifying patients with or without alloimmune damage. The latter model performed well in an independent cohort of 156 liver biopsies obtained from paediatric liver recipients with similar inclusion/exclusion criteria. CONCLUSION: ALT, class II DSAs and LSM are valuable tools to non-invasively identify stable LT recipients without significant underlying alloimmunity who could benefit from minimisation of immunosuppression. LAY SUMMARY: A large proportion of liver transplant patients with normal liver tests have inflammatory liver lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate.

[Autoimmune hepatitis: 2021 update]. / Hépatite autoimmune : mise au point 2021.

Autoimmune hepatitis is a rare disease which can present as acute or chronic forms and can be difficult to diagnose due to its variable clinical presentation. The disease arises in genetically susceptible individuals and several triggers have been identified. The diagnosis is based on the presence of autoantibodies, elevated transaminases and serum immunoglobulin G levels as well as a compatible histology. First-line immunosuppressive treatment strategies lead to clinical remission in most patients. In case of non-response, second-line therapies can be used and in case of hepatocellular insufficiency, liver transplantation remains an excellent option.

L'hépatite autoimmune est une maladie rare, pouvant se présenter sous forme aiguë ou chronique et dont le diagnostic peut être difficile à poser en raison d'une présentation clinique variable. La maladie se développe chez des personnes génétiquement prédisposées et plusieurs événements déclencheurs ont été identifiés. Le diagnostic repose sur la présence d'autoanticorps spécifiques, d'une élévation des transaminases et des immunoglobulines G, ainsi que sur une histologie compatible. Les traitements de première ligne, immunosuppresseurs, permettent dans la plupart des cas d'obtenir une rémission clinique. En cas de non-réponse, des traitements de deuxième ligne sont disponibles et lors d'insuffisance hépatocellulaire, la transplantation hépatique reste une excellente option.

Real-life food-safety behavior and incidence of foodborne infections in solid organ transplant recipients.

Food-safety measures are recommended in solid organ transplant (SOT) recipients. However, the actual adherence of patients in a real-life setting and the impact on the incidence of foodborne infections remain largely unexplored. We performed a survey among SOT recipients followed at our institution, aiming to evaluate their food-safety behavior. We assessed the incidence of microbiologically proven foodborne infections by chart review. One hundred ninety-seven SOT recipients (kidney = 117, lung = 35, liver = 29, and heart = 16) participated in the survey. Overall, 17.7% of the participants observed all food-safety recommendations (22.0% avoided food at risk of contamination while 67.9% applied hygiene recommendations). Patients within the first year after transplantation (odds ratio [OR] 5.42; P = .001) and females (OR 4.67; P = .001) followed food-safety recommendations more closely. Although the majority of SOT recipients felt concerned and actively sought information on food safety (68%-70%), only 27% were able to recognize all risks of foodborne infection in hypothetical scenarios. Incidence of proven foodborne infections was 17.9% (95% confidence interval 9.9%-30.9%) 5 years after transplantation. Importantly, foodborne infections occurred exclusively among patients not following food-safety recommendations. In summary, most SOT recipients eat foods that make them at risk of foodborne infections. Our results indicate that there is room for improvement in patient education, particularly later after transplantation, and reinforce current food-safety recommendations.

Management of allergy transfer upon solid organ transplantation.

Allergy transfer upon solid organ transplantation has been reported in the literature, although only few data are available as to the frequency, significance, and management of these cases. Based on a review of 577 consecutive deceased donors from the Swisstransplant Donor-Registry, 3 cases (0.5%) of fatal anaphylaxis were identified, 2 because of peanut and 1 of wasp allergy. The sera of all 3 donors and their 10 paired recipients, prospectively collected before and after transplantation for the Swiss Transplant Cohort Study, were retrospectively processed using a commercial protein microarray fluorescent test. As early as 5 days posttransplantation, newly acquired peanut-specific IgE were transiently detected from 1 donor to 3 recipients, of whom 1 liver and lung recipients developed grade III anaphylaxis. Yet, to define how allergy testing should be performed in transplant recipients and to better understand the impact of immunosuppressive therapy on IgE sensitization, we prospectively studied 5 atopic living-donor kidney recipients. All pollen-specific IgE and >90% of skin prick tests remained positive 7 days and 3 months after transplantation, indicating that early diagnosis of donor-derived IgE sensitization is possible. Importantly, we propose recommendations with respect to safety for recipients undergoing solid-organ transplantation from donors with a history of fatal anaphylaxis.

Donor-specific antibodies in liver transplantation.

Despite unique immunoregulatory properties pointing toward tolerance, the liver allograft can be negatively impacted by humoral alloreactivity, with immediate as well as long-term harmful consequences. With regard to the unmet need of long-term outcomes improvement after liver transplantation, donor-specific antibodies have recently been the matter of intense study in this context. We review here recent advances regarding the understanding of the impact of preformed as well as de novo anti-human leukocyte antigen donor-specific antibodies in liver transplantation and discuss potential strategies to overcome this problem.

Late hepatitis B reactivation following direct-acting antiviral-based treatment of recurrent hepatitis C in an anti-HBc-positive liver transplant recipient.

Direct-acting antivirals (DAAs) have changed the landscape of hepatitis C virus (HCV) treatment, but chronic hepatitis C (CHC) remains a leading indication for liver transplantation (LT). Hepatitis B virus (HBV) reactivation has been reported in HBV-HCV-coinfected patients treated with DAAs. We report on a case of late HBV reactivation after DAA-based treatment of recurrent hepatitis C in an antibody against hepatitis B core antigen (anti-HBc)-positive LT recipient. (Hepatology 2018;67:791-793).