Abstract: SARS-CoV-2 infection may affect the liver in healthy individuals but also influences the course of COVID-19 in patients with chronic liver disease (CLD). As described in healthy individuals, a strong SARS-CoV-2-specific adaptive immune response is important for the outcome of COVID-19, however, knowledge on the adaptive immune response in CLD is limited. Here, we review the clinical and immunological features of SARS-CoV-2 infection in individuals with CLD. Acute liver injury occurs in many cases of SARS-CoV-2 infection and may be induced by multiple factors, such as cytokines, direct viral infection or toxic effects of COVID-19 drugs. In individuals with CLD, SARS-CoV-2 infection may have a more severe course and promote decompensation and particularly in patients with cirrhosis. Compared with healthy individuals, the SARS-CoV-2-specific adaptive immune responses is impaired in patients with CLD after both, natural infection and vaccination but improves at least partially after booster vaccination. Following SARS-CoV-2 vaccination, rare cases of acute vaccine-induced liver injury and the development of autoimmune-like hepatitis have been reported. However, the concomitant elevation of liver enzymes is reversible under steroid treatment

Abstract: More than twenty years ago, non-HBV-specific CD8+ T cells were found to contribute to liver immunopathology in chronic HBV infection, while HBV-specific CD8+ T cells were noted to contribute to viral control. The role of HBV-specific CD8+ T cells in viral control and the mechanisms of their failure in persistent infection have been intensively studied during the last two decades, but the exact nature of nonspecific bystander CD8+ T cells that contribute to immunopathology has remained elusive. In this issue of the JCI, Nkongolo et al. report on their application of two methodological advances, liver sampling by fine-needle aspiration (FNA) and single-cell RNA sequencing (scRNA-Seq), to define a liver-resident CD8+ T cell population that was not virus specific but associated with liver damage, thus representing hepatotoxic bystander CD8+ T cells

Abstract: Background & Aims Liver transplant recipients (LTRs) demonstrate a reduced response to COVID-19 mRNA vaccination; however, a detailed understanding of the interplay between humoral and cellular immunity, especially after a third (and fourth) vaccine dose, is lacking. Methods We longitudinally compared the humoral, as well as CD4+ and CD8+ T-cell, responses between LTRs (n = 24) and healthy controls (n = 19) after three (LTRs: n = 9 to 16; healthy controls: n = 9 to 14 per experiment) to four (LTRs: n = 4; healthy controls: n = 4) vaccine doses, including in-depth phenotypical and functional characterization. Results Compared to healthy controls, development of high antibody titers required a third vaccine dose in most LTRs, while spike-specific CD8+ T cells with robust recall capacity plateaued after the second vaccine dose, albeit with a reduced frequency and epitope repertoire compared to healthy controls. This overall attenuated vaccine response was linked to a reduced frequency of spike-reactive follicular T helper cells in LTRs. Conclusion Three doses of a COVID-19 mRNA vaccine induce an overall robust humoral and cellular memory response in most LTRs. Decisions regarding additional booster doses may thus be based on individual vaccine responses as well as evolution of novel variants of concern. Impact and implications Due to immunosuppressive medication, liver transplant recipients (LTR) display reduced antibody titers upon COVID-19 mRNA vaccination, but the impact on long-term immune memory is not clear. Herein, we demonstrate that after three vaccine doses, the majority of LTRs not only exhibit substantial antibody titers, but also a robust memory T-cell response. Additional booster vaccine doses may be of special benefit for a small subset of LTRs with inferior vaccine response and may provide superior protection against evolving novel viral variants. These findings will help physicians to guide LTRs regarding the benefit of booster vaccinations

Abstract: Background C-type natriuretic peptide (CNP) is an endothelium-derived paracrine molecule with an important role in vascular homeostasis. In septic patients, the serum level of the amino-terminal propeptide of CNP (NT-proCNP) shows a strong positive correlation with inflammatory biomarkers and, if elevated, correlates with disease severity and indicates a poor outcome. It is not yet known whether NT-proCNP also correlates with the clinical outcome of patients suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the current study, we aimed to determine possible changes in the NT-proCNP levels of patients with coronavirus disease 2019 (COVID-19), with special regard to disease severity and outcome. Methods In this retrospective analysis, we determined the serum level of NT-proCNP in hospitalized patients with symptoms of upper respiratory tract infection, using their blood samples taken on admission, stored in a biobank. The NT-proCNP levels of 32 SARS-CoV-2 positive and 35 SARS-CoV-2 negative patients were measured to investigate possible correlation with disease outcome. SARS-CoV-2 positive patients were then divided into two groups based on their need for intensive care unit treatment (severe and mild COVID-19). Results The NT-proCNP was significantly different in the study groups (e.g. severe and mild COVID-19 and non-COVID-19 patients), but showed inverse changes compared to previous observations in septic patients: lowest levels were detected in critically ill COVID-19 patients, while highest levels in the non-COVID-19 group. A low level of NT-proCNP on admission was significantly associated with severe disease outcome. Conclusions Low-level NT-proCNP on hospital admission is associated with a severe COVID-19 disease course. The pathomechanism underlying this observation remains to be elucidated, while future studies in larger patient cohorts are necessary to confirm these observations and reveal therapeutic importance. Trial registration DRKS00026655 Registered 26. November 2021

Abstract: Background and aim: Liver cirrhosis in patients treated in the intensive care unit (ICU) is associated with high mortality. Well established scores are useful to allow for assessment of prognosis and support ICU treatment guidance. However, currently used scoring systems often do not reflect the complexity of critically ill patients. Therefore, we tested the newly developed Freiburg index-of post-TIPS survival (FIPS) score in order to assess its potential role for prognostication of cirrhotic patients in the ICU. Methods: A total of 310 patients with liver cirrhosis treated in the ICU between 2010 and 2021 were enrolled in this retrospective observational study. Prognostic factors for mortality and 28-day mortality were assessed. Moreover, using c indices the prognostic discrimination of different prognostic scores was analyzed. Results: The FIPS score allowed to discriminate patients with high ICU mortality and within 28-days after ICU treatment (ICU mortality: 42.2 vs. 59.9%, p = 0.008 and 28-day mortality: 43.3 vs. 74.1%, p 0.001). However, the FIPS score in its current composition showed no superior prognostic discrimination compared to other established scores. Multivariable analyses identified the FIPS score (HR 1.25 [1.04-1.49], p = 0.015) and lactate at admission (HR 1.07 [1.04-1.09], p 0.001) as significant predictors of ICU mortality. Lactate at admission substantially improved patient risk stratification within each FIPS risk groups.

Abstract: Adaptive immune responses play an important role in the clinical course of SARS-CoV-2 infection. While evaluations of the virus-specific defense often focus on the humoral response, cellular immunity is crucial for the successful control of infection, with the early development of cytotoxic T cells being linked to efficient viral clearance. Vaccination against SARS-CoV-2 induces both CD4+ and CD8+ T cell responses and permits protection from severe COVID-19, including infection with the currently circulating variants of concern. Nevertheless, in immunocompromised individuals, first data imply significantly impaired SARS-CoV-2-specific immune responses after both natural infection and vaccination. Hence, these high-risk groups require particular consideration, not only in routine clinical practice, but also in the development of future vaccination strategies. In order to assist physicians in the guidance of immunocompromised patients, concerning the management of infection or the benefit of (booster) vaccinations, this review aims to provide a concise overview of the current knowledge about SARS-CoV-2-specific cellular immune responses in the vulnerable cohorts of cancer patients, people living with HIV (PLWH), and solid organ transplant recipients (SOT). Recent findings regarding the virus-specific cellular immunity in these differently immunocompromised populations might influence clinical decision-making in the future

Abstract: Background: Postembolization syndrome (PES) represents the most frequent complication after transarterial chemoembolization (TACE) in patients with HCC. Given the vague definition as a symptom complex comprising abdominal pain, fever, and nausea, PES is diagnosed in heterogeneous patient cohorts with symptoms ranging from mild pain to severe deterioration of their general condition. This study aimed to evaluate predictive factors and the prognostic impact of PES with regard to different severity grades. Methods: A total of 954 patients treated with TACE for HCC at the University Medical Centres Mainz and Freiburg were included in this study. PES disease severity was graded as mild, moderate, or severe according to a predefined combination of symptoms. Logistic regression models were used to identify independent predictors of PES. The prognostic impact of PES was evaluated by competing risk analyses considering liver transplantation as a competing risk. Results: PES occurred in 616 patients (64.5%), but only 56 patients (5.9%) had severe PES, defined as moderate to severe abdominal pain requiring opioids in combination with fever and nausea. The largest tumor diameter was the strongest independent predictor of PES (OR = 1.21, 95% CI = 1.13-1.28), and severe PES (OR = 1.23, 95% CI = 1.14-1.33, p 0.0001). Presence of liver cirrhosis was protective against PES (OR = 0.48, 95% CI = 0.27-0.84, p = 0.01). Furthermore, PES was independently associated with an impaired disease control rate (OR = 0.33, 95% CI = 0.16-0.69, p = 0.003) and severe PES with poor overall survival (subdistribution HR = 1.53, 95% CI = 0.99-2.36, p = 0.04).brbrConclusions: