HIV-Negative Case of Talaromyces marneffei Pulmonary Infection with Liver Cirrhosis in China: A Case Report and Literature Review.

Background: Talaromyces marneffei (TM) is the third most prevalent opportunistic infection in HIV-positive patients after tuberculosis and cryptococcosis. However, such infection of non-HIV individuals has rarely been reported. Case Presentation: We describe a very rare case of a 52-year-old male who presented with a single space-occupying lesion on the right lung and was eventually diagnosed with pulmonary TM infection. The patient was HIV-negative and had liver cirrhosis with portal vein thrombosis. Lung tissue next-generation sequencing (NGS) revealed TM infection. We successfully treated the patient with voriconazole for 8 weeks and observed lesion absorption via subsequent CT. The patient consumed wild bamboo rats two months before admission. Mutations related to congenital immune deficiency were not detected by whole-exome sequencing. Conclusion: Early and timely diagnosis is critical for improving patient prognosis. NGS plays a vital role in the diagnosis of pulmonary TM infection in patients. To our knowledge, this is the first published case of pulmonary TM infection in an HIV-negative patient with liver cirrhosis.

The clinical courses of HBV-related acute-on-chronic liver failure and a multi-state model to predict disease evolution.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a highly dynamic syndrome. The objective of this study was to delineate the clinical course of patients with HBV-ACLF and to develop a model to estimate the temporal evolution of disease severity. METHODS: We enrolled eligible patients from 2 large, multicenter prospective cohorts. The ACLF grade, organ failures, and outcomes were assessed at multiple time points (days 1/4/7/14/21/28). Probabilities for ACLF transitions between these disease states and to death within 28 days were calculated using a multi-state model that used baseline information and updated ACLF status. The model was validated in independent patients. RESULTS: Among all the 445 patients with HBV-ACLF, 76 represented disease progression, 195 had a stable or fluctuating course, 8 with improvement, and the remaining 166 with resolution within 28-day follow-up. New coagulation (63.64%) or renal failure (45.45%) was frequently observed during early progression. Patients with disease progression had a higher incidence of new episodes of ascites [10 (13.16%) vs. 22 (5.96%), p = 0.027] and HE [13(17.11%) vs. 21 (5.69%), p = 0.001], and a significant increase in white blood cell count. The multi-state model represented dynamic areas under the receiver operating characteristic curves ranging from 0.71 to 0.84 for predicting all ACLF states and death at 4, 7, 14, 21, and 28 days post-enrollment and from 0.73 to 0.94 for predicting death alone, performing better than traditional prognostic scores. CONCLUSIONS: HBV-ACLF is a highly dynamic syndrome with reversibility. The multi-state model is a tool to estimate the temporal evolution of disease severity, which may inform clinical decisions on treatment.

Metabolic biomarkers significantly enhance the prediction of HBV-related ACLF occurrence and outcomes.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality in patients with chronic liver disease. Chronic hepatitis B is the main cause of ACLF (HBV-ACLF) in China and other Asian countries. To improve disease management and survival for patients with ACLF, we aimed to discover novel biomarkers to enhance HBV-ACLF diagnosis and prognostication. METHODS: We performed a metabolomics profiling of 1,024 plasma samples collected from patients with HBV-related chronic liver disease with acute exacerbation at hospital admission in a multi-year and multi-center prospective study (367 ACLF and 657 non-ACLF). The samples were randomly separated into equal halves as a discovery set and a validation set. We identified metabolites associated with 90-day mortality in the ACLF group and the progression to ACLF within 28 days in the non-ACLF group (pre-ACLF) using statistical analysis and machine learning. We developed diagnostic algorithms in the discovery set and used these to assess the findings in the validation set. RESULTS: ACLF significantly altered the plasma metabolome, particularly in membrane lipid metabolism, steroid hormones, oxidative stress pathways, and energy metabolism. Numerous metabolites were significantly associated with 90-day mortality in the ACLF group and/or pre-ACLF in the non-ACLF group. We developed algorithms for the prediction of 90-day mortality in patients with ACLF (area under the curve 0.87 and 0.83 for the discovery set and validation set, respectively) and the diagnosis of pre-ACLF (area under the curve 0.94 and 0.88 for the discovery set and validation set, respectively). To translate our discoveries into practical clinical tests, we developed targeted assays using liquid chromatography-mass spectrometry. CONCLUSIONS: Based on novel metabolite biomarkers, we established tests for HBV-related ACLF with higher accuracy than existing methods. CLINICAL TRIAL NUMBER: NCT02457637 and NCT03641872. IMPACT AND IMPLICATIONS: Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality affecting 25% of patients hospitalized with cirrhosis. Chronic hepatitis B is the main etiology of ACLF in China and other Asian counties. There is currently no effective therapy. Early diagnosis and accurate prognostication are critical for improving clinical outcomes in patients with ACLF. Based on novel metabolite biomarkers, we developed liquid chromatography-mass spectrometry tests with improved accuracy for the early diagnosis and prognostication of HBV-related ACLF. The liquid chromatography-mass spectrometry tests can be implemented in clinical labs and used by physicians to triage patients with HBV-related ACLF to ensure optimized clinical management.

New Algorithm Rules Out Acute-on-chronic Liver Failure Development within 28 Days from Acute Decompensation of Cirrhosis.

Background and Aims: Approximately 10% of patients with acute decompensated (AD) cirrhosis develop acute-on-chronic liver failure (ACLF) within 28 days. Such cases have high mortality and are difficult to predict. Therefore, we aimed to establish and validate an algorithm to identify these patients on hospitalization. Methods: Hospitalized patients with AD who developed ACLF within 28 days were considered pre-ACLF. Organ dysfunction was defined according to the chronic liver failure-sequential organ failure assessment (CLIF-SOFA) criteria, and proven bacterial infection was taken to indicate immune system dysfunction. A retrospective multicenter cohort and prospective one were used to derive and to validate the potential algorithm, respectively. A miss rate of <5% was acceptable for the calculating algorithm to rule out pre-ACLF. Results: In the derivation cohort (n=673), 46 patients developed ACLF within 28 days. Serum total bilirubin, creatinine, international normalized ratio, and present proven bacterial infection at admission were associated with the development of ACLF. AD patients with ≥2 organ dysfunctions had a higher risk for pre-ACLF patients [odds ratio=16.581 95% confidence interval: (4.271-64.363), p<0.001]. In the derivation cohort, 67.5% of patients (454/673) had ≤1 organ dysfunction and two patients (0.4%) were pre-ACLF, with a miss rate of 4.3% (missed/total, 2/46). In the validation cohort, 65.9% of patients (914/1388) had ≤1 organ dysfunction, and four (0.3%) of them were pre-ACLF, with a miss rate of 3.4% (missed/total, 4/117). Conclusions: AD patients with ≤1 organ dysfunction had a significantly lower risk of developing ACLF within 28 days of admission and could be safely ruled out with a pre-ACLF miss rate of <5%.

Complement C3 Facilitates Stratification of Stages of Chronic Hepatitis B and Signifies Development of Acute-on-Chronic Liver Failure in Acute Decompensated Cirrhosis.

INTRODUCTION: Patients with chronic hepatitis B (CHB) have a dynamic disease process and risk of end-stage liver disease. It is critical to unambiguously differentiate the stages of the disease and focus on therapy prior to onset of an irreversible clinical endpoint. METHODS: We retrospectively analyzed a wide range of CHB patients at different stages. The predictive power of serum complement component 3 (C3) levels for the development of acute-on-chronic liver failure (ACLF) in patients with decompensated cirrhosis was established and validated. RESULTS: The decrease in serum C3 levels paralleled the severity of diseases related to hepatitis B virus. Patients with decompensated cirrhosis who developed ACLF had significantly lower serum C3 levels than others on admission (0.50 vs. 0.80 g/L, P < 0.001). Data analysis also revealed that low serum C3 was a significant risk factor for developing ACLF (hazard ratio = 0.32, P < 0.01). The area under the receiver operating characteristic curve (auROC) for serum C3 levels that predicted the development of ACLF in patients with decompensated cirrhosis was 0.90, which had sensitivity and specificity of 88.2% and 88.7%, respectively. A similar result was observed in the validation set (auROC = 0.86 for predicting development of ACLF in patients with decompensated cirrhosis). CONCLUSIONS: Serum C3 levels are valuable in assessing the severity of CHB-related stages. Low C3 levels signifies the development of ACLF in patients with decompensated cirrhosis.

Generally, acute-on-chronic liver failure is a rapidly worsening liver failure syndrome. This disease is intractable and with high mortality. Acute decompensation of the liver is defined as the occurrence of complications of liver disease (i.e., ascites, hepatic encephalopathy, gastrointestinal bleeding, and bacterial infection). Clinically, acute decompensation in hepatitis B virus-related cirrhosis (a result of chronic liver injury by virus) often develops into acute-on-chronic liver failure. In addition, the complement component 3 is a serum protein, which participates in the immune response against virus infection and has been reported to be associated with liver failure. We tried to explore the feature of serum complement component 3 to differentiate the stages of the disease and assess its predictive value for acute-on-chronic liver failure. So, we analyzed the complement component 3 data from a broad range of hepatitis B virus-cirrhosis patients. Through analysis, we found that complement component 3 levels are valuable in assessing the severity of chronic hepatitis B-related stages. Low complement component 3 levels can also signify the development of acute-on-chronic liver failure in patients with decompensated cirrhosis.

Portal vein thrombosis compromises the performance of MELD and MELD-Na scores in patients with cirrhosis.

BACKGROUND AND AIMS: The accuracy of model for end-stage liver disease (MELD) and MELD with sodium (MELD-Na) scores in reflecting the clinical outcomes of patients with cirrhosis and portal vein thrombosis (PVT) remains unclear. This study aimed to evaluate the performance of scores in predicting 90-day mortality in patients with cirrhosis and PVT. METHODS: Post hoc analysis was performed in two prospective cohorts (NCT02457637 and NCT03641872). The correlation between the MELD/MELD-Na score and 90-day liver transplantation (LT)-free mortality was investigated in patients with cirrhosis with and without PVT. RESULTS: In this study, 2826 patients with cirrhosis were included, and 255 (9.02%) had PVT. The cumulative incidence of 90-day LT-free mortality did not significantly differ between patients with and without PVT (log-rank P = 0.0854). MELD [area under the receiver operating curve (AUROC), 0.649 vs. 0.842; P = 0.0036] and MELD-Na scores (AUROC, 0.691 vs. 0.851; P = 0.0108) were compared in patients with and without PVT, regarding the prediction of 90-day LT-free mortality. In MELD < 15 and MELD-Na < 20 subgroups, patients with PVT had a higher 90-day LT-free mortality than those without PVT (7.91% vs. 2.64%, log-rank P = 0.0011; 7.14% vs. 3.43%, log-rank P = 0.0223), whereas in MELD ≥ 15 and MELD-Na ≥ 20 subgroups, no significant difference was observed between patients with and without PVT. CONCLUSIONS: The performance of MELD and MELD-Na scores in predicting 90-day LT-free mortality of patients with cirrhosis was compromised by PVT. MELD < 15 or MELD-Na < 20 may underestimate the 90-day LT-free mortality in patients with PVT.

Prognosis prediction performs better in patients with non-cirrhosis hepatitis B virus-related acute-on-chronic liver failure than those with cirrhosis.

Background: The accurate prediction of the outcome of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is impeded by population heterogeneity. The study aimed to assess the impact of underlying cirrhosis on the performance of clinical prediction models (CPMs). Methods: Using data from two multicenter, prospective cohorts of patients with HBV-ACLF, the discrimination, calibration, and clinical benefit were assessed for CPMs predicting 28-day and 90-day outcomes in patients with cirrhosis and those without, respectively. Results: A total of 919 patients with HBV-ACLF were identified by Chinese Group on the Study of Severe Hepatitis B (COSSH) criteria, including 675 with cirrhosis and 244 without. COSSH-ACLF IIs, COSSH-ACLFs, Chronic Liver Failure-Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLFs), Tongji Prognostic Predictor Model score (TPPMs), Model for End-Stage Liver Disease score (MELDs), and MELD-Sodium score (MELD-Nas) were all strong predictors of short-term mortality in patients with HBV-ACLF. In contrast to a high model discriminative capacity in ACLF without cirrhosis, each prognostic model represents a marked decline of C-index, net reclassification index (NRI), and integrated discrimination improvement (IDI) in predicting either 28-day or 90-day prognosis of patients with cirrhosis. The hazard analysis identified largely overlapping risk factors of poor outcomes in both subgroups, while serum bilirubin was specifically associated with short-term mortality in patients with cirrhosis and blood urea nitrogen in patients without cirrhosis. A subgroup analysis in patients with cirrhosis showed a decline of discrimination of CPMS in those with ascites or infections compared to that in those without. Conclusion: Predicting the short-term outcome of HBV-ACLF by CPMs is optimal in patients without cirrhosis but limited in those with cirrhosis, at least partially due to the complicated ascites or infections.

Role of precipitants in transition of acute decompensation to acute-on-chronic liver failure in patients with HBV-related cirrhosis.

Background & Aims: Pre-acute-on-chronic liver failure (ACLF) is a distinct intermediate stage between acute decompensation (AD) and ACLF. However, identifying patients with pre-ACLF and predicting progression from AD to ACLF is difficult. This study aimed to identify pre-ACLF within 28 days, and to develop and validate a prediction model for ACLF in patients with HBV-related decompensated cirrhosis. Methods: In total, 1,736 patients with HBV-related cirrhosis and AD were enrolled from 2 large-scale, multicenter, prospective cohorts. ACLF occurrence within 28 days, readmission, and 3-month and 1-year outcomes were collected. Results: Among 970 patients with AD without ACLF in the derivation cohort, the 94 (9.6%) patients with pre-ACLF had the highest 3-month and 1-year LT-free mortality (61.6% and 70.9%, respectively), which was comparable to those with ACLF at enrollment (57.1% and 67.1%); the 251 (25.9%) patients with unstable decompensated cirrhosis had mortality rates of 22.4% and 32.1%, respectively; while the 507 (57.9%) patients with stable decompensated cirrhosis had the best outcomes (1-year mortality rate of 2.6%). Through Cox proportional hazard regression, specific precipitants, including hepatitis B flare with HBV reactivation, spontaneous hepatitis B flare with high viral load, superimposed infection on HBV, and bacterial infection, were identified to be significantly associated with ACLF occurrence in the derivation cohort. A model that incorporated precipitants, indicators of systemic inflammation and organ injuries reached a high C-index of 0.90 and 0.86 in derivation and validation cohorts, respectively. The optimal cut-off value (0.22) differentiated high-risk and low-risk patients, with a negative predictive value of 0.95. Conclusions: Three distinct clinical courses of patients with AD are validated in the HBV-etiology population. The precipitants significantly impact on AD-ACLF transition. A model developed by the precipitant-systemic inflammation-organ injury framework could be a useful tool for predicting ACLF occurrence. Clinical trial number: NCT02457637 and NCT03641872. Lay summary: It was previously shown that patients with decompensated cirrhosis could be stratified into 3 groups based on their short-term clinical prognoses. Herein, we showed that this stratification applies to patients who develop cirrhosis as a result of hepatitis B virus infection. We also developed a precipitant-based model (i.e. a model that incorporated information about the exact cause of decompensation) that could predict the likelihood of these patients developing a very severe liver disease called acute-on-chronic liver failure (or ACLF).

Hepatitis B Virus Reactivation Increased the Risk of Developing Hepatic Failure and Mortality in Cirrhosis With Acute Exacerbation.

Background and Aims: Hepatitis B virus (HBV) reactivation is a serious condition and has been extensively described in chemotherapeutic immunosuppressive population. However, little is known about HBV reactivation in immunocompetent patients with chronic hepatitis B (CHB). In this study, we evaluated the prevalence and the clinical significance of HBV reactivation in CHB patients with acute exacerbations. Method: Patients were screened from two prospective multicenter observational cohorts (CATCH-LIFE cohort). A total of 1,020 CHB patients with previous antiviral treatment history were included to assess the prevalence, risk factors, clinical characteristics of HBV reactivation, and its influence on the progression of chronic liver disease. Results: The prevalence of HBV reactivation was 51.9% in CHB patients with acute exacerbations who had antiviral treatment history in our study. Among the 529 patients with HBV reactivation, 70.9% of them were triggered by discontinued antiviral treatment and 5.9% by nucleos(t)ide analogs (NUCs) resistance. The prevalence of antiviral treatment disruption and NUCs resistance in patients with HBV reactivation is much higher than that in the patients without (70.9% vs. 0.2%, and 5.9% vs. 0, respectively, both p < 0.001). Stratified and interaction analysis showed that HBV reactivation was correlated with high short-term mortality in cirrhosis subgroup (HR = 2.1, p < 0.001). Cirrhotic patients with HBV reactivation had a significantly higher proportion of developing hepatic failure (45.0% vs. 20.3%, p < 0.001), acute-on-chronic liver failure (ACLF; 31.4% vs. 21.8%, p = 0.005), and short-term death (14.0% vs. 5.9% for 28-day, and 23.3% vs. 12.4% for 90-day, both p < 0.001) than those without. HBV reactivation is an independent risk factor of 90-day mortality for cirrhosis patients (OR = 1.70, p = 0.005), as well as hepatic encephalopathy, ascites, and bacterial infection. Conclusion: This study clearly demonstrated that there was a high prevalence of HBV reactivation in CHB patients, which was mainly triggered by discontinued antiviral treatment. The HBV reactivation strongly increased the risk of developing hepatic failure, ACLF and short-term death in HBV-related cirrhotic patients, which may suggest that HBV reactivation would be a new challenge in achieving the WHO target of 65% reduction in mortality from hepatitis B by 2030.

Baseline Neutrophil-to-Lymphocyte Ratio Is Independently Associated With 90-Day Transplant-Free Mortality in Patients With Cirrhosis.

Background: Patients with cirrhosis have an increased risk of short-term mortality, however, few studies quantify the association between neutrophil-to-lymphocyte ratio (NLR) and 90-day transplant-free mortality in cirrhotic patients. Methods: We prospectively analyzed 3,970 patients with chronic liver diseases from two multicenter cohorts in China (January 2015 to December 2016 and July 2018 to January 2019). Restricted cubic splines (RCS) were used to analyze the relation of NLR and all-causes 90-day transplant-free mortality in cirrhosis. Results: A total of 2,583 cirrhotic patients were enrolled in our study. Restricted cubic splines showed that the odds ratio (OR) of all causes 90-day transplant-free mortality started to increase rapidly until around NLR 6.5, and then was relatively flat (p for non-linearity <0.001). The risk of 90-day transplant-free mortality in cirrhotic patients with NLR < 6.5 increased with an increment of 23% for every unit increase in NLR (p < 0.001). The patients with NLR < 4.5 had the highest risk (OR: 2.34, 95% CI 1.66-3.28). In multivariable-adjusted stratified analyses, the increase in the incidence of 90-day transplant-free mortality with NLR increasing was consistent (OR >1.0) across all major prespecified subgroups, including infection group (OR: 1.04, 95% CI 1.00-1.09) and non-infection (OR: 1.06, 95% CI 1.02-1.11) group. The trends for NLR and numbers of patients with organ failure varied synchronously and were significantly increased with time from day 7 to day 28. Conclusions: We found a non-linear association between baseline NLR and the adjusted probability of 90-day transplant-free mortality. A certain range of NLR is closely associated with poor short-term prognosis in patients with cirrhosis.

Prevalence and Clinical Significance of Portal Vein Thrombosis in Patients With Cirrhosis and Acute Decompensation.

BACKGROUND & AIMS: Portal vein thrombosis (PVT) is a common and serious complication in patients with cirrhosis. However, little is known about PVT in patients with cirrhosis and acute decompensation (AD). We investigated the prevalence and clinical significance of PVT in nonmalignant patients with cirrhosis and AD. METHODS: We performed a retrospective study of 2 cohorts of patients with acute exacerbation of chronic liver disease who participated in the Chinese AcuTe on CHronic LIver FailurE study, established by the Chinese Chronic Liver Failure Consortium, from January 2015 through December 2016 (n = 2600 patients) and July 2018 through January 2019 (n = 1370 patients). We analyzed data on the prevalence, clinical manifestations, and risk factors of PVT from 2826 patients with cirrhosis, with and without AD. RESULTS: The prevalence of PVT in patients with cirrhosis and AD was 9.36%, which was significantly higher than in patients with cirrhosis without AD (5.24%) (P = .04). Among patients with cirrhosis and AD, 63.37% developed PVT recently (the first detected PVT with no indication of chronic PVT). Compared with patients without PVT, a significantly higher proportion of patients with PVT had variceal bleeding (47.33% vs 19.63%; P < .001) and patients with PVT had a significantly higher median serum level of D-dimer (2.07 vs 1.25; P < .001). Splenectomy and endoscopic sclerotherapy were independent risk factors for PVT in patients with cirrhosis and AD. The 1-year mortality rate did not differ significantly between patients with vs without PVT. CONCLUSIONS: In an analysis of data from 2826 patients with cirrhosis, a significantly higher proportion of those with AD had PVT than those without AD. PVT was associated with increased variceal bleeding, which would increase the risk for AD. Strategies are needed to prevent PVT in patients with cirrhosis, through regular screening, to reduce portal hypertension. ClinicalTrials.gov no: NCT02457637 and NCT03641872.