Viruses and miRNAs: More Friends than Foes

There is evidence that eukaryotic miRNAs (hereafter called host miRNAs) play a role in the replication and propagation of viruses. Expression or targeting of host miRNAs can be involved in cellular antiviral responses. Most times host miRNAs play a role in viral life-cycles and promote infection through complex regulatory pathways. miRNAs can also be encoded by a viral genome and be expressed in the host cell. Viral miRNAs can share common sequences with host miRNAs or have totally different sequences. They can regulate a variety of biological processes involved in viral infection, including apoptosis, evasion of the immune response, or modulation of viral life-cycle phases. Overall, virus/miRNA pathway interaction is defined by a plethora of complex mechanisms, though not yet fully understood. This article review summarizes recent advances and novel biological concepts related to the understanding of miRNA expression, control and function during viral infections. The article also discusses potential therapeutic applications of this particular host–pathogen interaction

Evidence for Alloimmune Sinusoidal Injury in De Novo Nodular Regenerative Hyperplasia After Liver Transplantation

Posttransplant nodular regenerative hyperplasia (NRH) mostly remains unexplained. Microvascular injury due to antibody-mediated rejection (AMR) is suspected, but lack of donor specific antibody (DSA) testing makes it difficult to prove. Centered around a 1-year period of routine DSA testing, concomitant protocol, and indicated posttransplant liver biopsies (LB), recipients with NRH (n = 18) were compared with a matched control group (n = 36). All index, previous, and subsequent LB were reviewed. Both groups were similar in terms of demographics, timing of index LB, and DSA. In the index LB, the NRH group had higher sinusoidal C4d positivity (p = 0.029) and perisinusoidal fibrosis (p = 0.034), both independently associated with NRH (p = 0.038 and 0.050, respectively). Features of possible chronic AMR were detected in 28.5% of the NRH group without a known cause and 0% of the control group (p = 0.009). The NRH group had more preceding indicated LB with increased incidence of rejection and biliary obstruction pattern. In the follow-up histology, overall, sinusoidal and portal C4d positivity, sinusoidal microvasculitis, and perisinusoidal fibrosis were also higher (all p 0.050). In conclusion, we provide evidence towards the hypothesis that some cases of posttransplant NRH are related to preceding active and persistent AMR. Large multicenter studies with protocol DSA testing are required to confirm

Impact of acute-on-chronic liver failure on 90-day mortality following a first liver transplantation

International audienceBACKGROUND:Acute-on-chronic liver failure (ACLF) is associated with a significant short-term mortality rate (23%-74%), depending on the number of organ failures. Some patients present with ACLF at the time of liver transplantation (LT). The aim of this study was to assess whether ACLF was also a prognostic factor after LT and, if applicable, to construct a score that could predict 90-day mortality.METHODS:Three hundred and fifty cirrhotic patients, who underwent LT between January 2008 and December 2013, were enrolled. We used ACLF grades according to EASL-CLIF consortium criteria to categorize the cirrhotic patients. A propensity score was applied with an Inverse Probability Treatment Weighting in a Cox model. A predictive score of early mortality after LT was generated.RESULTS:One hundred and forty patients (40%) met the criteria for ACLF. The overall mortality rate at 90 days post-transplant was 10.6% (37/350 patients). ACLF at the time of LT (HR: 5.78 [3.42-9.77], P<.001) was an independent predictor of 90-day mortality. Infection occurring during the month before LT, high recipient age and male recipient, the reason for LT and a female donor were also independent risk factors for early mortality. Using these factors, we have proposed a model to predict 90-day mortality after LT.CONCLUSIONS:LT is feasible in cirrhotic patients with ACLF. However, we have shown that ACLF is a significant and independent predictor of 90-day mortality. We propose a score that can identify candidate cirrhotic patients in whom LT might be associated with futile LT

Invasive pulmonary aspergillosis in cirrhotic patients: analysis of a 10-year clinical experience

Abstract Background Cirrhosis is not recognised as one of the main risk factors of invasive pulmonary aspergillosis (IPA), although its prevalence is increasing. The aim of our study was to identify factors for IPA in such patients with a positive Aspergillus sp. culture in respiratory samples and to evaluate its impact on outcome. Methods We conducted a monocentric retrospective study between January 2005 and December 2015. All cirrhotic patients hospitalised in our liver ICU with a positive Aspergillus sp. respiratory sample were included. These patients were case-matched with cirrhotic patients without positive Aspergillus respiratory sample. Finally, the patients were classified as having putative aspergillosis or colonisation according to the criteria described previously. Results In total, 986 cirrhotic patients were admitted to ICU during the study period. Among these, sixty patients had a positive Aspergillus sp. respiratory sample. Chronic obstructive pulmonary disease (COPD) comorbidity and organ supports were significantly associated with Aspergillus colonisation. Seventeen patients (28%) were diagnosed as proven or putative IPA and 43 were considered as colonised by Aspergillus sp. The median delay between ICU admission and an IPA diagnosis was 2 [2–24] days. Only COPD was predictive of the presence of IPA (OR 6.44; 95% CI 1.43–28.92; p = 0.0151) in patients with a positive Aspergillus sp. culture. The probability of in-hospital mortality was 71% in the IPA group versus 19% in the colonisation group (p = 0.0001). Conclusion Patients with cirrhosis can be at risk of IPA, especially with COPD. Antifungal agents should be given as soon as possible mainly in cirrhotic patients with COPD

Liver transplantation in elderly patients: a systematic review and first meta-analysis

BACKGROUND: Elderly recipients are frequently discussed by the scientific community but objective indication for this parameter has been provided. The aim of this study was to synthesize the available evidence on liver transplantation for elderly patients to assess graft and patient survival. METHODS: A literature search of the Medline, EMBASE, and Scopus databases was carried out from January 2000 to August 2018. Clinical studies comparing the outcomes of liver transplantation in adult younger (65 years) populations were analyzed. The primary outcomes were patient mortality and graft loss rates. This review was registered (Number CRD42017058261) as required in the international prospective register for systematic review protocols (PROSPERO). RESULTS: Twenty-two studies were included involving a total of 242,487 patients (elderly: 23,660 and young: 218,827) were included in this study. In the meta-analysis, the elderly group had patient mortality (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 0.97-1.63; P = 0.09; I2 = 48%) and graft (HR: 1.09; 95% CI: 0.81-1.47; P = 0.59; I2 = 12%) loss rates comparable to those in the young group. CONCLUSIONS: Elderly patients have similar long-term survival and graft loss rates as young patients. Liver transplantation is an acceptable and safe curative option for elderly transplant candidates

HLA-DP diversity is associated with improved response to SARS-Cov-2 vaccine in hematopoietic stem cell transplant recipients

Summary: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients show lower humoral vaccine responsiveness than immunocompetent individuals. HLA diversity, measured by the HLA evolutionary divergence (HED) metrics, reflects the diversity of the antigenic repertoire presented to T cells, and has been shown to predict response to cancer immunotherapy. We retrospectively investigated the association of HED with humoral response to SARS-CoV-2 vaccine in allo-HSCT recipients. HED was calculated as pairwise genetic distance between alleles at HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 loci in recipients and their donors. Low anti-spike IgG levels (<30 BAU/mL) were associated with short time from allo-SCT and low donor DPB1-HED, mostly related to donor DPB1 homozygosity. The diversity of donor HLA-DP molecules, assessed by heterozygosity or sequence divergence, may thus impact the efficacy of donor-derived CD4 T cells to sustain vaccine-mediated antibody response in allo-HSCT recipients

External validation of the Donor Risk Index and the Eurotransplant Donor Risk Index on the French liver transplantation registry

International audienceBACKGROUND & AIMS:A major limitation to liver transplantation is organ shortage leading to the use of non-optimal liver grafts. The Donor Risk Index has been validated and recommended to select donors/organs. The Eurotransplant Donor Risk Index was derived from the Donor Risk Index. The objective of our study was to perform an external validation of both Donor Risk Index and Eurotransplant-Donor Risk Index against the French liver transplantation Cristal registry according to recommendations of the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis.METHODS:Liver transplantations performed in France between 2009 and 2013 were used to perform the validation study for the Donor Risk Index and the Eurotransplant-Donor Risk Index respectively. We applied on the French data the models used to construct the Donor Risk Index and the Eurotransplant-Donor Risk Index respectively.RESULTS:Neither the Donor Risk Index nor the Eurotransplant-Donor Risk Index were validated against this dataset. Discrimination and calibration of these scores were not preserved according to our data. Important donor and candidates differences between our dataset and the Organ Procurement and Transplantation Network or the Eurotransplant datasets may explain why the Donor Risk Index and the Eurotransplant-Donor Risk Index appeared unadapted to the French transplant registry.CONCLUSION:Neither of these risk indexes were suitable to optimize the French liver allocation system. Thus, our next step will be to propose a general adaptive model for a Donor Risk Index

Caractéristiques et mécanismes de la compartimentation des variants du virus de l'hépatite C

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Distinct hepatitis C virus core and F protein quasispecies in tumoral and nontumoral hepatocytes isolated via microdissection

International audienceHepatitis C virus (HCV) genetic variability may be involved in liver carcinogenesis. We investigated HCV core and corresponding putative F protein genetic variability in hepatocellular carcinoma (HCC) and cirrhotic nodules. Hepatocyte clusters from 7 patients with HCC and HCV1b-related cirrhosis were isolated via microdissection of HCC tissues and 2 nontumoral cirrhotic nodules. The HCV core complementary DNA was cloned and sequenced from each liver compartment and from the serum of 2 patients. Nucleotide diversity and synonymous and nonsynonymous substitutions were analyzed within and between compartments via phylogenetic analysis and Mantel's test. Liver HCV RNA accumulation was lower in HCC. Increased quasispecies diversity and complexity was observed with HCC in 6 of 7 patients. Mantel's test demonstrated marked compartmentalization of quasispecies between HCC and cirrhotic nodules in all 7 patients and also between the 2 nontumoral nodules in 5 of them. Synonymous-nonsynonymous substitution analysis indicated low selection against tumoral core quasispecies in all patients and a more selective pressure against F protein quasispecies in all compartments. In the 2 subjects analyzed, HCC and nontumoral hepatocyte quasispecies were only minor or undetected in serum. Conclusion: In tumoral hepatocytes, low-replicating hepatitis C quasispecies are compartmentalized and more diversified and are subjected to low selective pressure. Our study supports the importance of core genetic variability in hepatocellular carcinogenesis. (HEPATOLOGY 2007.