An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial.

BACKGROUND AND AIMS: The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. METHODS: A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. RESULTS: Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. CONCLUSIONS: Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).

Prediction of biochemical nonresolution in patients with chronic drug-induced liver injury: A large multicenter study.

BACKGROUND AND AIMS: To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. APPROACH AND RESULTS: Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. CONCLUSIONS: Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.

Clinical features, microbial spectrum, and antibiotic susceptibility patterns of spontaneous bacterial peritonitis in cirrhotic patients.

BACKGROUND AND AIMS: The microbial spectrum and antimicrobial resistance patterns change over time and vary across regions in patients with spontaneous bacterial peritonitis (SBP). There is an urgent need to clarify the factors associated with in-hospital mortality in these patients. METHODS: In this study, 377 patients with SBP and 794 patients with bacterascites were analyzed for the microbial spectrum, antimicrobial resistance profiles, and laboratory findings. RESULTS: The most common pathogens were Escherichia coli (96, 25.5%), Staphylococcus epidermidis (55, 14.6%), and Enterococcus faecium (42, 11.1%). Multidrug-resistant (MDR) bacteria comprised 49.7% of gram-positive bacteria (GPB) and 48.8% of gram-negative bacteria (GNB). The most sensitive antibiotics were amikacin (91.5%), meropenem (89.8%) and piperacillin/tazobactam (87.6%). Extensively drug-resistant (XDR) (OR=51.457, p < 0.001), neutrophil count (OR=1.088, p < 0.001), and the model for end-stage liver disease (MELD) score (OR=1.124, p < 0.001) were independent predictive factors of in-hospital mortality in patients with SBP. CONCLUSION: MDR represented nearly half of the bacteria isolated from patients with SBP, of which the high prevalence of extended-spectrum ß-lactamase-producing and Carbapenem-resistant bacteria is concerning. The presence of XDR, higher MELD score, and neutrophil count were independent predictive factors associated with higher in-hospital mortality in patients with SBP, indicating that intensive care should be provided to these patients.

The Association Between the Albumin and Viral Negative Conversion Rate in Patients Infected with Novel Coronavirus Disease 2019 (COVID-19).

Purpose: The novel coronavirus disease 2019 (COVID-19) epidemic is the severe global pandemic with large numbers of infected cases and deaths in recent decades. The previous studies were all about the influence of albumin (ALB) for the severity and mortality of in-patients infected with COVID-19. But few studies exist about the influence factors to achieve viral negative conversion. Therefore, this study conducted an exploratory study to investigate the effect of albumin on negative conversion rate. Methods: Among the 190 hospitalized patients with moderate COVID-19 who had a course of disease longer than 30 days, 102 achieved viral negative conversion in 30-45 days and 88 not after 45 days. Taking other variables as concomitant variable, Cox proportional hazard regression model was applied to explore the influence of albumin to negative conversion rate under various factors. Results: By comparing patients who could and could not achieve the finally viral negative conversion, a possible nonlinear relationship between the continuous variables and clinical outcomes was examined by a restricted cubic spline regression model. An association was found between albumin levels and hazard ratio of viral negative conversion rate (P = 0.027). The increase of albumin was accompanied with decreases of hazard ratio of viral negative conversion rate (the value of albumin <38 g/L). But when the value of albumin was higher than 38 g/L, the hazard ratio of viral negative conversion rate approached 1, it means that albumin is not a risk factor for the viral negative conversion rate of COVID-19 disease. Conclusion: For patients with COVID-19, albumin is a common and observed laboratory parameter. It is associated with final viral negative conversion rate although its underlying mechanism and relationship with the viral negative conversion rate still need to be clarified.

Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial.

BACKGROUND: Treatment of chronic drug-induced liver injury (DILI) or herb-induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI. AIMS: To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI. METHODS: This was a randomised open-label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48-week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48-week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety. RESULTS: Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)-like DILI and non-AIH-like subgroups, showed comparable responses. No severe adverse events were observed during the trial. CONCLUSION: This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH-like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT02651350).

Risk Factors for the Incidence and Severity of Acute Kidney Injury After Liver Transplantation.

BACKGROUND/AIMS: To explore risk factors of acute kidney injury (AKI) and its severity after liver transplantation. MATERIALS AND METHODS: This was a retrospective cohort of consecutive adults undergoing orthotopic liver transplantation (OLT) at a referral hospital. Risk factors for AKI from 1week post-liver transplantation and 4-week outcomes were analysed. Further analyses of factors that influenced the severity of AKI were also performed. RESULTS: A total of 204 patients were included. AKI was found in 55.4% of patients in the first week after OLT. Risk factors for AKI were recipient's sex, BMI, preoperative creatinine, preoperative hepatic encephalopathy, cold ischaemia time, duration of surgery, duration of inferior vena clamping, postoperative peak lactate and postoperative peak AST, which were higher in the AKI group. Four weeks after liver transplantation, 20.4% of AKI patients still had abnormal renal function and a mortality rate of 3.6%, and these values were significantly higher than those of patients without AKI (P<0.05). CONCLUSION: Preoperative, intraoperative and postoperative factors can all lead to AKI after OLT.

Multivariate predictive model for asymptomatic spontaneous bacterial peritonitis in patients with liver cirrhosis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a detrimental infection of the ascitic fluid in liver cirrhosis patients, with high mortality and morbidity. Early diagnosis and timely antibiotic administration have successfully decreased the mortality rate to 20%-25%. However, many patients cannot be diagnosed in the early stages due to the absence of classical SBP symptoms. Early diagnosis of asymptomatic SBP remains a great challenge in the clinic. AIM: To establish a multivariate predictive model for early diagnosis of asymptomatic SBP using positive microbial cultures from liver cirrhosis patients with ascites. METHODS: A total of 98 asymptomatic SBP patients and 98 ascites liver cirrhosis patients with negative microbial cultures were included in the case and control groups, respectively. Multiple linear stepwise regression analysis was performed to identify potential indicators for asymptomatic SBP diagnosis. The diagnostic performance of the model was estimated using the receiver operating characteristic curve. RESULTS: Patients in the case group were more likely to have advanced disease stages, cirrhosis related-complications, worsened hematology and ascites, and higher mortality. Based on multivariate analysis, the predictive model was as follows: y (P) = 0.018 + 0.312 × MELD (model of end-stage liver disease) + 0.263 × PMN (ascites polymorphonuclear) + 0.184 × N (blood neutrophil percentage) + 0.233 × HCC (hepatocellular carcinoma) + 0.189 × renal dysfunction. The area under the curve value of the established model was 0.872, revealing its high diagnostic potential. The diagnostic sensitivity was 73.5% (72/98), the specificity was 86.7% (85/98), and the diagnostic efficacy was 80.1%. CONCLUSION: Our predictive model is based on the MELD score, polymorphonuclear cells, blood N, hepatocellular carcinoma, and renal dysfunction. This model may improve the early diagnosis of asymptomatic SBP.

Exploring an Integrative Therapy for Treating COVID-19: A Randomized Controlled Trial.

OBJECTIVES: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. METHODS: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. RESULTS: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). CONCLUSIONS: Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).

Population Pharmacokinetics of Voriconazole and Optimization of Dosage Regimens Based on Monte Carlo Simulation in Patients With Liver Cirrhosis.

Because voriconazole metabolism is highly influenced by liver function, the dose regimen of voriconazole should be carefully assessed in patients with liver cirrhosis. We aimed to identify significant factors associated with plasma concentrations. Blood samples were collected from patients with liver cirrhosis who received voriconazole, and voriconazole concentrations were determined. One-compartment model with first-order absorption and elimination appropriately characterized the in vivo process of voriconazole. The typical population value of voriconazole clearance (CL) was 1.45 L/h and the volume of distribution (V) was 132.12 L. The covariate analysis identified that CYP2C19 gene phenotype and Child-Pugh classification were strongly associated with CL and body weight had a significant influence on V. The results of the Monte Carlo simulation suggested that CYP2C19 gene phenotype was a critical factor for determining voriconazole dosage in patients with liver cirrhosis. The extensive metabolizer patients with Aspergillus fumigatus infections could be treated effectively with a recommended dose of 75 mg twice daily in mild to moderate liver cirrhosis and 100 mg once daily in moderate severe liver cirrhosis. However, the recommended dosage for Candida albicans infections patients was not achieved in present study.