Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a transcriptional program with potent antiviral activity, driven by E74-like ETS transcription factor 1 (ELF1). Using microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses after multi-cycle replication. Elf1 deficiency results in enhanced susceptibility to influenza A virus infections in mice. ELF1 does not feed-forward to induce interferons, and ELF1’s antiviral effect is not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNA-seq revealed that the ELF1 transcriptional program is distinct from interferon signatures. Thus, ELF1 provides an additional layer of the innate host response, independent from the action of type I interferons. After decades of research on the innate immune system, we still struggle to understand exactly how this first line of defense protects cells against viral infections. Our gap in knowledge stems, on one hand, from the sheer number of effector genes, few of which have been characterized in mechanistic detail. On the other hand, our understanding of innate gene transcription is constantly evolving. We know that different regulatory mechanisms greatly influence the quality, magnitude, and timing of gene expression, all of which may contribute to the antiviral power of the innate response. Deciphering these regulatory mechanisms is indispensable for harnessing the power of innate immunity in novel antiviral therapies. Here, we report a novel transcriptional program as part of the cell-intrinsic immune system, raised by E74-like ETS transcription factor 1 (ELF1). ELF1 potently restricts multi-cycle propagation of all viruses tested in our study. Reduced levels of ELF1 significantly diminish host defenses against influenza A virus in vitro and in vivo, suggesting a critical but previously overlooked role of this ETS transcription factor. The ELF1 program is complex and comprises over 300 potentially antiviral genes, which are almost entirely distinct from those known to be induced by interferon. Taken together, our data provide evidence for a program of antiviral protection that expands the previously known arsenal of the innate immune response.

Background: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an established procedure to treat portal hypertension with hepatic encephalopathy (HE) as a common complication. There is lack of evidence concerning HE prophylaxis after TIPS. Methods: N = 233 patients receiving TIPS between 2011 and 2018 at a German tertiary care center were included. Of them, 21% (n = 49) had a history of HE. The follow-up period was 12 months. The risk factors of post-TIPS HE were analyzed via multivariate analysis. The efficacy of prophylactic medication regimens was studied. The results show that 35.6% (n = 83) received no medication (NM), 36.5% (n = 85) received lactulose monoprophylaxis (LM), 2.6% (n = 6) rifaximin monoprophylaxis (RM) and 25.3% (n = 59) lactulose and rifaximin (LR) of which 64.4% received l-ornithin-l-aspartate (LOLA) additionally (LR + LOLA) and 36.6% did not (LRonly). Results: Multivariate analysis revealed higher age (p = 0.003) and HE episodes prior to TIPS (p = 0.004) as risk factors for HE after TIPS. LM has no prophylactic effect. LR prevents HE recurrence at 1, 3 and 12 months after TIPS (p = 0.003, p = 0.003, p = 0.006) but does not prevent HE in patients with no history of HE (p = 0.234, p = 0.483, p = 0.121). LR prevents HE recurrence compared with LM/NM (25.0% vs. 64.7%, p = 0.007) within 12 months after TIPS, whereas de novo occurrence is unaffected (p = 0.098). The additional administration of LOLA to LR has no benefit (LRonly: 25.0%, LR + LOLA: 29.7%, p = 0.780). Conclusions: Higher age and previous HE are risk factors post-TIPS HE. In patients with HE prior to TIPS, effective prophylaxis of HE is feasible via combination of lactulose and rifaximin with no additional benefit from LOLA.

Purpose: To evaluate predictive parameters for the development of Hepatic Encephalopathy (HE) after Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement and for success of shunt modification in the management of shunt-induced HE. Methods: A retrospective analysis of all patients with TIPS (n = 344) has been performed since 2011 in our university liver center. n = 45 patients with HE after TIPS were compared to n = 48 patients without HE after TIPS (case-control-matching). Of n = 45 patients with TIPS-induced HE, n = 20 patients received a reduction stent (n = 18) or TIPS occlusion (n = 2) and were differentiated into responders (improvement by at least one HE grade according to the West Haven classification) and non-responders (no improvement). Results: Older patient age, increased serum creatinine and elevated International Normalized Ratio (INR) immediately after TIPS placement were independent predictors for the development of HE. In 11/20 patients (responders, 55%) undergoing shunt modification, the HE grade was improved compared with nine non-responders (45%), with no relevant recurrence of refractory ascites or variceal bleeding. A high HE grade after TIPS insertion was the only positive predictor of treatment response (p = 0.019). A total of 10/11 responders (91%) survived the 6 months follow-up after modification but only 6/9 non-responders (67%) survived. Discussion: Older patient age as well as an increased serum creatinine and INR after TIPS are potential predictors for the development of HE. TIPS reduction for the treatment of TIPS-induced HE is safe, with particular benefit for patients with pronounced HE.

The Freiburg index of post-TIPS survival (FIPS) defines a high-risk group of patients with significantly reduced survival following transjugular intrahepatic portosystemic shunt (TIPS) implantation. However, the clinical hallmarks responsible for these patients' unfavorable outcome remain to be identified. Therefore, the present study aimed to characterize the clinical course after TIPS implantation according to the FIPS. A total of 1,359 patients with cirrhosis allocated to TIPS implantation for treatment of recurrent or refractory ascites or secondary prophylaxis of variceal bleeding from eight tertiary centers were retrospectively included. The patients' clinical course following TIPS placement was analyzed, stratified according to the FIPS. The primary study outcome was further decompensation within 90 days after TIPS; secondary outcomes were acute-on-chronic liver failure (ACLF) within 90 days and 1-year transplant-free survival. Further decompensation after TIPS implantation was significantly more frequent in FIPS high-risk patients compared to low-risk patients (cumulative incidence function 0.58 vs. 0.38, p <0.001). Moreover, FIPS high-risk patients developed ACLF significantly more often (0.18 vs. 0.08; p = 0.008). Uni- and multivariable competing risk regression analyses confirmed that high-risk FIPS independently predicted further decompensation (subdistribution hazard ratio 1.974; 95% CI 1.531-2.544; p <0.001) and ACLF (subdistribution hazard ratio 2.586; 95% CI 1.449-4.616; p = 0.001) after TIPS. Importantly, further decompensation and ACLF after TIPS were associated with significantly reduced transplant-free survival. The present study reveals that the FIPS predicts development of further decompensation and ACLF after TIPS implantation. These events are responsible for impaired transplant-free survival in FIPS high-risk patients. These results pave the way for the development of tailored clinical management strategies. Prognostication after transjugular intrahepatic portosystemic shunt (TIPS) implantation is challenging. Several clinical scores have been proposed in this context, such as the Freiburg index of post-TIPS survival (FIPS). The FIPS can identify a high-risk group of patients with significantly reduced survival after TIPS. However, to understand the reasons for these patients' unfavorable outcome, their clinical course after TIPS needs to be characterized. This study reveals that the FIPS predicts development of further decompensation and acute-on-chronic liver failure after TIPS implantation, which are responsible for the poor prognosis of FIPS high-risk patients. Therefore, the present results may be useful for tailored decision making in patients allocated to TIPS implantation.

Background and aims: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an established procedure to treat portal hypertension. Impact of administration of aspirin on transplant-free survival after TIPS remains unknown. Methods: A multicenter retrospective analysis including patients with TIPS implantation between 2011 and 2018 at three tertiary German Liver Centers was performed. N = 583 patients were included. Survival analysis was performed in a matched cohort after propensity score matching. Patients were grouped according to whether aspirin was (PSM-aspirin-cohort) or was not (PSM-no-aspirin-cohort) administered after TIPS. Primary endpoint of the study was transplant-free survival at 12 months after TIPS. Results: Aspirin improved transplant-free survival 12 months after TIPS with 90.7% transplant-free survival compared to 80.0% (p = 0.001) after PSM. Separated by TIPS indication, aspirin did improve transplant-free survival in patients with refractory ascites significantly (89.6% vs. 70.6% transplant-free survival, p < 0.001), while no significant effect was observed in patients with refractory variceal bleeding (91.1% vs. 92.2% transplant-free survival, p = 0.797). Conclusion: This retrospective multicenter study provides first data indicating a beneficial effect of aspirin on transplant-free survival after TIPS implantation in patients with refractory ascites.

Transjugular intrahepatic portosystemic shunt (TIPS) is the most effective measure to treat complications of portal hypertension. However, liver function may deteriorate after TIPS. Predictors of liver function and outcome after TIPS are therefore important for management of TIPS patients. The study aimed to evaluate the impact of liver volume on transplant-free survival (TFS) after TIPS, as well as the evolution of liver volume and its relationship with liver function after TIPS. A retrospective analysis of all consecutive patients who underwent TIPS in a tertiary care university liver center between 2012 and 2017 (n = 216) was performed; n = 72 patients with complete prior and follow-up (FU) computed tomography (CT) imaging studies were included in the study. Volumetry of the liver was performed by a semi-automatic 9-lobe image segmentation algorithm at baseline and FU (FU 1: 90–180 d; FU 2: 180–365 d; FU 3: 365–545 d; FU 4: 545–730 d; FU 5: >730 d). Output variables were total liver volume (TLV, cm³), left liver volume (LLV, cm³), right liver volume (RLV, cm³) and TLV/body weight ratio. CT derived liver volumes were correlated with liver function tests, portosystemic pressure gradient (PPG) measurements and survival. To assess predictors of liver volume change over time we fitted linear mixed models. Kaplan–Meier analysis was performed and validated by matched pair analysis followed by Cox regression to determine independent prognostic factors for survival. The median TLV at baseline was 1507.5 cm³ (773.7–3686.0 cm³). Livers with higher baseline liver volumes and larger TLV/weight ratios retained their volume after an initial loss while smaller livers continuously lost volume after TIPS. At the first follow-up period (90–180 d post-TIPS) lower liver volumes and TLV/weight ratios were associated with higher bilirubin levels. Within the final multivariable model containing time (days since TIPS), baseline INR and baseline TLV, the average loss of liver volume was 0.74 mL per day after TIPS. Twelve-month overall transplant-free survival was 89% and median overall TFS was 33 months. The median TFS for a baseline TLV/body weight ratio > 20 was significantly higher compared with ≤20 (40.0 vs. 27.0 months, p = 0.010) while there were no differences regarding the indication for TIPS or etiology of liver disease in the matched pair analysis. Lower TLV/weight ratios before TIPS were associated with shorter TFS and should therefore be critically considered when selecting patients for TIPS. In addition, this study provides first evidence of an effect of TIPS on subsequent liver volume change and associated liver function.