Levels of peripheral blood routine, biochemical and coagulation parameters in patients with hemorrhagic fever with renal syndrome and their relationship with prognosis: an observational cohort study.

BACKGROUND: Hantaan virus (HTNV), Seoul virus (SEOV) and Puumala virus (PUUV) are major serotypes of the Hantavirus, which can cause hemorrhagic fever with renal syndrome (HFRS). The pathophysiology of HFRS in humans is complex and the determinants associated with mortality, especially the coagulation and fibrinolysis disorders, are still not been fully elucidated. Severe patients usually manifest multiple complications except for acute kidney injury (AKI). The aim of this study was to observe the levels of peripheral blood routine, biochemical and coagulation parameters during the early stage, so as to find independent risk factors closely related to the prognosis, which may provide theoretical basis for targeted treatment and evaluation. METHODS: A total of 395 HFRS patients from December 2015 to December 2018 were retrospectively enrolled. According to prognosis, they were divided into a survival group (n = 368) and a death group (n = 27). The peripheral blood routine, biochemical and coagulation parameters were compared between the two groups on admission. The relationship between the parameters mentioned above and prognosis was analyzed, and the dynamic changes of the coagulation and fibrinolysis parameters during the first week after admission were further observed. RESULTS: In addition to AKI, liver injury was also common among the enrolled patients. Patients in the death group manifested higher levels of white blood cell counts (WBC) on admission. 27.30% (107/392) of the patients enrolled presented with disseminated intravascular coagulation (DIC) on admission and DIC is more common in the death group; The death patients manifested longer prothrombin time (PT) and activated partial thromboplastin time (APTT), higher D-dimer and fibrinogen degradation product (FDP), and lower levels of platelets (PLT) and fibrinogen (Fib) compared with those of the survival patients. The proportion of D-dimer and FDP abnormalities are higher than PT, APTT and Fib. Prolonged PT, low level of Fib and elevated total bilirubin (TBIL) on admission were considered as independent risk factors for prognosis (death). CONCLUSIONS: Detection of PT, Fib and TBIL on admission is necessary, which might be benefit to early predicting prognosis. It is also important to pay attention to the dynamic coagulation disorders and hyperfibrinolysis during the early stage in the severe HFRS patients.

Lung ultrasonography versus chest CT for assessing peripheric pulmonary lesions in hemorrhagic fever with renal syndrome: a prospective comparative study in China.

OBJECTIVES: To compare the performances of lung ultrasonography (LUS) versus chest CT for assessing peripheric pulmonary lesions in hemorrhagic fever with renal syndrome (HFRS). METHODS: Paired LUS and chest CT scan were prospectively performed and compared when in diagnosing five pathologies including region with alveolar-interstitial pattern (RAIP), alveolar-interstitial syndrome (AIS), lung consolidation, pleural effusion (PE), and pericardial effusion, in each patient with HFRS. RESULTS: Forty-four patients (aged 39.9 ± 15.0 years, 35 males) were included, from which 68 paired LUS and chest CT imaging data of 816 lung regions were obtained and analyzed. Compared with chest CT, LUS showed high sensitivity (92.19-100%) and negative predictive value (95.9-100%), but relatively low specificity (39.47-97.21%) and positive predictive value (37.5-76.47%) for diagnosing the above pathologies. McNemer's test showed LUS detected more positive findings than chest CT (all p ≤ 0.002). There was a strong correlation between LUS and chest CT scores (rs = 0.7141, p < 0.0001) and both scores correlated with the disease severity, hospital days, and partial laboratory profiles in HFRS patients. CONCLUSIONS: LUS was comparable with chest CT for diagnosing peripheric pulmonary lesions and clinical assessment in patients with HFRS. Given the high sensitivity and negative predictive value compared with chest CT, LUS can be used as an excellent rule-out tool in HFRS, while its use in rule-in still requires more evidence. Considering the obvious advantages of LUS being a bedside, less expansive, and non-radiating exam, future multi-center randomized LUS versus chest CT studies may help to guide the preferred method. KEY POINTS: • LUS could detect more positive findings than chest CT in assessing peripheric pulmonary lesions in patients with hemorrhagic fever with renal syndrome (HFRS). • Compared with chest CT, LUS showed high sensitivity but relatively low specificity when diagnosing the peripheric pulmonary lesions caused by HFRS. • Both LUS and chest CT scores correlated with the disease severity, hospital days, and partial laboratory profiles in HFRS.

Predictive value of pentraxin-3 on disease severity and mortality risk in patients with hemorrhagic fever with renal syndrome.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus is characterized by systemic immunopathological injury. Pentraxin-3 is an acute-phase reactant involved in the processes of inflammation and infection. This study aimed to investigate the levels of plasma pentraxin-3 and evaluate its predictive value on disease severity and mortality risk in patients with HFRS. METHODS: This was a prospective real-world observational study. The concentrations of plasma pentraxin-3 were measured by enzyme linked immunosorbent assay (ELISA) in 105 HFRS patients and 27 healthy controls. We analyzed the clinical relevance between pentraxin-3 and clinical subtyping, hospital stay and conventional laboratory parameters of HFRS patients. Considering the prognosis (death) as the primary endpoint, the levels of pentraxin-3 between survivors and non-survivors were compared, and its association with mortality was assessed by Kaplan-Meier survival analysis. The predictive potency of pentraxin-3 for mortality risk in HFRS patients was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: The levels of pentraxin-3 during the acute phase were increased with the aggravation of the disease, and showed the highest expression in critical-type patients (P < 0.05). Pentraxin-3 demonstrated significant correlations with conventional laboratory parameters (WBC, PLT, AST, ALB, APTT, Fib) and the length of hospital stay. Compared with the survivors, non-survivors showed higher levels of pentraxin-3 and worse expressions of conventional laboratory parameters during the acute phase. The Kaplan-Meier survival curves showed that high levels of pentraxin-3 during the acute phase were significantly associated with the death in HFRS patients. Pentraxin-3 demonstrated significant predictive value for the mortality risk of HFRS patients, with the area under ROC curve (AUC) of 0.753 (95%CI: 0.593 ~ 0.914, P = 0.003). CONCLUSIONS: The detection of plasma pentraxin-3 might be beneficial to the evaluation of disease severity and to the prediction of mortality risk in HFRS patients.

aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis. METHODS: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686). RESULTS: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%. CONCLUSIONS: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide. LAY SUMMARY: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.

Effect of 48-week pegylated interferon α-2a or nucleos(t)ide analogue therapy on renal function in Chinese patients with chronic hepatitis B.

BACKGROUND: Controversy remains as to whether antiviral agents contribute to renal dysfunction in patients with chronic hepatitis B virus (HBV) infection. Thus, the aim of study was to analyze the changes in renal function of chronic hepatitis B (CHB) patients in response to anti-HBV therapy and the association with treatments. METHOD: We performed a retrospective observational cohort study to investigate factors associated with renal function in 249 Chinese CHB patients who were treated with pegylated interferon α-2a (PEG-IFN-α-2a) or nucleos(t)ide analogues for 48 weeks. Changes of estimated glomerular filtration rate (eGFR), which was computed with both the Chronic Kidney Disease Epidemiology Collaboration and the Modification of Diet in Renal Disease formulas, were tested by repeated measures One-way analysis of variance within groups. A linear mixed effects model for repeated measures was also used to evaluate the association between baseline information and eGFR changes over time in all enrolled patients. The model considered the baseline age, sex, HBV DNA, aminotransferase, blood urea nitrogen, treatment group, time, and group-by-time interaction as fixed effects and incorporated random effects for individual subjects. RESULTS: The eGFR increased in patients given PEG-IFN-α-2a, decreased in patients given adefovir, but remained stable in patients given entecavir. Age and blood urea nitrogen were significant negative predictive factors for eGFR changes. CONCLUSION: In real-life study, PEG-IFN-α-2a therapy in CHB patients increased eGFR, thus may associate with renoprotective effects when compared with adefovir or entecavir therapies.

HMGB-1 as a novel predictor of disease severity and prognosis in patients with hemorrhagic fever with renal syndrome.

OBJECTIVE: To examine the predictive capacity of the high mobility group box protein-1 (HMGB-1) for disease severity and prognosis of hemorrhagic fever with renal syndrome (HFRS). METHODS: One hundred and five HFRS patients and 28 controls were studied. The concentrations of HMGB-1 in the blood were measured with a commercially available ELISA. The levels of white blood cells (WBC), platelets (PLT), hematocrit (HCT), albumin (ALB), blood urea nitrogen (BUN), serum creatinine (Scr), and uric acid (UA) were routinely tested in the same time frame. RESULTS: The levels of HMGB-1 increased with the severity of the disease (P < 0.001). HMGB-1 was positively correlated with WBC and BUN and negatively correlated with PLT, ALB, and UA (P < 0.001). HMGB-1 showed statistical significance for predicting prognosis (AUC = 0.800, P < 0.001). The sensitivity and specificity of HMGB-1, WBC, PLT, and ALB used in combination for predicting outcome were better than those of single analyses (AUC = 0.892, P < 0.001). CONCLUSIONS: HMGB-1 can be considered a novel biomarker for severity and outcome in patients with HFRS. The use of HMGB-1, WBC, PLT, and ALB in combination to predict the outcome in patients with HFRS exhibited an acceptable level of diagnostic capability.

Imbalance of regulatory T cells and T helper type 17 cells in patients with chronic hepatitis C.

Pegylated interferon and ribavirin combination therapy is known to be effective in suppressing viral replication in 50-60% of hepatitis C virus (HCV)-infected patients. However, HCV-infected patients often exhibit varied responses to therapy. Therefore, the identification of immunological markers associated with the clinical outcomes of antiviral treatment is critical for improvement of therapeutic options. In this study, we aimed to investigate the ratio of CD4(+) CD25(+) FoxP3(+) regulatory T (Treg) cells to interleukin-17A (IL-17A) -producing T helper type 17 (Th17) cells, and its association with clinical outcomes in response to anti-HCV treatment. In all, 114 patients with HCV infection received pegylated interferon-α2a and ribavirin therapy for 48 weeks, and the frequency of Treg cells and Th17 cells as well as the levels of secreted cytokines were longitudinally analysed by flow cytometry and ELISA. Treg cell proportions and IL-10 production were significantly elevated in HCV-infected patients, especially for HCV genotype 1b. However, the frequency of Th17 cells as well as the secretion of IL-17, IL-22 and IL-23 did not reveal notable difference between HCV infections and healthy individuals. Inhibition of HCV replication was accompanied by a reduction in Treg cells, but little influence on Th17 cells, which led to a significant decrease in Treg : Th17 ratios. Skewed Treg : Th17 ratios existed in chronic hepatitis C. HCV RNA load is closely associated with Treg : Th17 ratios during pegylated interferon-α2a and ribavirin treatment in HCV-infected patients. The imbalance of Treg cells to Th17 cells might play an important role in persistent HCV infection.

Role of A20 in interferon-α-mediated functional restoration of myeloid dendritic cells in patients with chronic hepatitis C.

Hepatitis C virus (HCV) infection is a global health problem characterized by a high rate of chronic infection, which may in part be due to a defect in myeloid dendritic cells (mDCs). This defect appears to be remedied by treatment with interferon-α (IFN-α) -based antiviral therapies; however, the molecular mechanisms underlying mDC dysfunction in HCV infection and restoration by IFN-α treatment are unclear. The ubiquitin-editing protein A20 plays a crucial role in controlling the maturation, cytokine production and immunostimulatory function of mDCs. We propose that the expression of A20 correlates with the function of mDCs during HCV infection and IFN-α therapy. In this study, we observed that A20 expression in mDCs isolated from chronically HCV-infected subjects was significantly higher than healthy subjects or subjects achieving sustained virological responses (SVR) following antiviral treatment. Notably, A20 expression in mDCs from HCV patients during IFN-α treatment was significantly lower than for untreated patients, SVR patients, or healthy subjects. Besides, A20 expression in mDCs stimulated by polyI:C differed between HCV patients and healthy subjects, and this difference could be abrogated by the treatment with IFN-α in vitro. Additionally, A20 expression by polyI:C-activated mDCs, with or without IFN-α treatment, negatively correlated with the expression of HLA-DR, CD86 and CCR7, and the secretion of interleukin-12 (IL-12), but positively associated with the production of IL-10. Importantly, silencing A20 expression using small interfering RNAs increased the production of IL-12 in mDCs of chronically HCV-infected individuals. These findings suggest that A20 plays a crucial role in negative regulation of innate immune responses during chronic viral infection.

The Role of Long Noncoding RNA Negative Regulator of Interferon Response in the Regulation of Hantaan Virus Infection.

Hantaan virus (HTNV) is prevalent in Eurasia. It causes hemorrhagic fever with renal syndrome (HFRS). Long noncoding RNAs (lncRNAs) play key roles in regulating innate immunity. Among these, lncRNA negative regulator of interferon response (NRIR) was reported as an inhibitor of several interferon (IFN)-stimulated genes. Our results showed that: NRIR expression was upregulated by HTNV infection in a type I IFN-dependent manner. The expression of NRIR in CD14+ monocytes from HFRS patients in acute phase was significantly higher than that in convalescent phase and healthy controls. HTNV infection in some HTNV-compatible cells was promoted by NRIR. NRIR negatively regulated innate immunity, especially IFITM3 expression. Localized in the nucleus, NRIR bound with HNRNPC, and knockdown of HNRNPC significantly weakened the effect of NRIR in promoting HTNV infection and restored IFITM3 expression. These results indicated that NRIR regulates the innate immune response against HTNV infection possibly through its interaction with HNRNPC and its influence on IFITM3.

Development and validation of a novel death risk stratification scale in patients with hemorrhagic fever with renal syndrome: a 14-year ambispective cohort study.

OBJECTIVES: To develop and validate a simple and effective death risk stratification scale for hemorrhagic fever with renal syndrome (HFRS). METHODS: In this ambispective cohort study, we investigated the epidemiological and clinical data of 2245 patients with HFRS (1873 enrolled retrospectively and constituting the training cohort, 372 prospectively recruited as the validation cohort) from September 2008 to December 2021, and identified independent risk factors for 30-day death of HFRS. Using logistic regression analysis, a nomogram prediction model was established and was further simplified into a novel scoring scale. Calibration plot, receiver operating characteristic curve, net reclassification index, integrated discrimination index, and decision curve analysis were used to assess the calibration, discrimination, precision, and clinical utility in both training and validation cohorts. RESULTS: Of 2245 patients with HFRS, 132 (5.9%) died during hospitalization. The nomogram prediction model and scoring scale were developed using six predictors: comorbid hypertension, hypotensive shock, hypoxemia, neutrophils, aspartate aminotransferase, and activated partial thromboplastin time. Both the scale and nomogram were well calibrated (near-diagonal calibration curves) and demonstrated significant predictive values (areas under receiver operating characteristic curves >0.9, sensitivity and specificity >90% in the training cohort and >84% in the validation cohort). The simplified scoring scale demonstrated equivalent discriminative ability to the nomogram, with net reclassification index and integrated discrimination index of 0.022 and 0.007 in the training cohort, 0.126 and 0.022 in the validation cohort. Decision curve analysis graphically represented significant clinical utility and comparable net benefits of the nomogram and scoring scale across a range of threshold probabilities. DISCUSSION: This evidence-based, factor-weighted, accurate score could help clinicians swiftly stratify HFRS mortality risk and facilitate the implementation of patient triage and tiered medical services during epidemic peaks.

T-cell immunoglobulin and mucin 1 (TIM-1) mediates infection of Hantaan virus in Jurkat T cells.

Hantaan virus (HTNV) is a major public health concern due to its ability to cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia. Symptoms of HFRS include fever, hemorrhage, immune dysfunction and renal impairment, and severe cases can be fatal. T cell-mediated adaptive immune responses play a pivotal role in countering HTNV infection. However, our understanding of HTNV and T cell interactions in the disease progression is limited. In this study, we found that human CD4+ T cells can be directly infected with HTNV, thereby facilitating viral replication and production. Additionally, T-cell immunoglobulin and mucin 1 (TIM-1) participated in the process of HTNV infection of Jurkat T cells, and further observed that HTNV enters Jurkat T cells via the clathrin-dependent endocytosis pathway. These findings not only affirm the susceptibility of human CD4+ T lymphocytes to HTNV but also shed light on the viral tropism. Our research elucidates a mode of the interaction between the virus infection process and the immune system. Critically, this study provides new insights into the pathogenesis of HTNV and the implications for antiviral research.

Clinical Characteristics and Fatality Risk Factors for Patients with Listeria monocytogenes Infection: A 12-Year Hospital-Based Study in Xi'an, China.

INTRODUCTION: Listeriosis is a severe food-borne disease caused by Listeria monocytogenes infection. The data of listeriosis in Xi'an population are limited. The aim of this study is to evaluate the clinical features and fatality risk factors for listeriosis in three tertiary-care hospitals in Xi'an, China METHODS: The characteristics of demographic data, underlying diseases, clinical manifestations, laboratory indicators, cranial imaging examination, antibiotics therapeutic schemes, and clinical outcomes were collected between 2011 and 2023. Logistic regression analysis was performed. RESULTS: Seventy-one etiologically confirmed listeriosis patients were enrolled, including 12 neonatal and 59 non-neonatal cases. The majority of neonatal listeriosis presented as preterm (50%) and fetal distress (75%). The main clinical manifestations of non-neonatal listeriosis included fever (88%), headache (32%), disorder of consciousness (25%), vomiting (17%), abdominal pain (12%), and convulsions (8%). The fatality rate in neonatal cases was higher than in non-neonatal listeriosis (42 vs. 17%). Although no deaths were reported in maternal listeriosis, only two of 23 patients had an uneventful obstetrical outcome. Five maternal listeriosis delivered culture-positive neonates, three of whom decreased within 1 week post-gestation due to severe complications. Twenty-eight cases were neurolisteriosis and 43 cases were bacteremia. Neurolisteriosis had a higher fatality rate compared with bacteremia listeriosis (36 vs. 12%). The main neuroradiological images were cerebral edema/hydrocephalus, intracranial infection, and cerebral hernia. Listeria monocytogenes showed extremely low resistance to ampicillin (two isolates) and penicillin (one isolate). The fatality risk factors were the involvement of the central nervous system, hyperbilirubinemia, and hyponatremia for all enrolled subjects. Hyperuricemia contributed to the elevation of fatality risk in non-neonatal listeriosis. CONCLUSIONS: When the patients suffered with symptoms of fever and central nervous system infection, they should be alert to the possibility of listeriosis. Early administration of ampicillin- or penicillin-based therapy might be beneficial for recovery of listeriosis.

PP19128R, a Multiepitope Vaccine Designed to Prevent Latent Tuberculosis Infection, Induced Immune Responses In Silico and In Vitro Assays.

Background: Latent tuberculosis infection (LTBI) is the primary source of active tuberculosis (ATB), but a preventive vaccine against LTBI is lacking. Methods: In this study, dominant helper T lymphocyte (HTL), cytotoxic T lymphocyte (CTL), and B-cell epitopes were identified from nine antigens related to LTBI and regions of difference (RDs). These epitopes were used to construct a novel multiepitope vaccine (MEV) based on their antigenicity, immunogenicity, sensitization, and toxicity. The immunological characteristics of the MEV were analyzed with immunoinformatics technology and verified by enzyme-linked immunospot assay and Th1/Th2/Th17 cytokine assay in vitro. Results: A novel MEV, designated PP19128R, containing 19 HTL epitopes, 12 CTL epitopes, 8 B-cell epitopes, toll-like receptor (TLR) agonists, and helper peptides, was successfully constructed. Bioinformatics analysis showed that the antigenicity, immunogenicity, and solubility of PP19128R were 0.8067, 9.29811, and 0.900675, respectively. The global population coverage of PP19128R in HLA class I and II alleles reached 82.24% and 93.71%, respectively. The binding energies of the PP19128R-TLR2 and PP19128R-TLR4 complexes were -1324.77 kcal/mol and -1278 kcal/mol, respectively. In vitro experiments showed that the PP19128R vaccine significantly increased the number of interferon gamma-positive (IFN-γ+) T lymphocytes and the levels of cytokines, such as IFN-γ, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10. Furthermore, positive correlations were observed between PP19128R-specific cytokines in ATB patients and individuals with LTBI. Conclusions: The PP19128R vaccine is a promising MEV with excellent antigenicity and immunogenicity and no toxicity or sensitization that can induce robust immune responses in silico and in vitro. This study provides a vaccine candidate for the prevention of LTBI in the future.

Developing a multiepitope vaccine for the prevention of SARS-CoV-2 and monkeypox virus co-infection: A reverse vaccinology analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and monkeypox virus (MPXV) severely threaten human health; however, currently, no vaccine can prevent a co-infection with both viruses. METHODS: Five antigens were selected to predict dominant T and B cell epitopes screened for immunogenicity, antigenicity, toxicity, and sensitization. After screening, all antigens joined in the construction of a novel multiepitope vaccine. The physicochemical and immunological characteristics, and secondary and tertiary structures of the vaccine were predicted and analyzed using bio- and immunoinformatics. Finally, codon optimization and cloning in-silico were performed. RESULTS: A new multiepitope vaccine, named S7M8, was constructed based on four helper T lymphocyte (HTL) epitopes, six cytotoxic T lymphocyte (CTL) epitopes, five B cell epitopes, as well as Toll-like receptor (TLR) agonists. The antigenicity and immunogenicity scores of the S7M8 vaccine were 0.907374 and 0.6552, respectively. The S7M8 vaccine was comprised of 26.96% α-helices, the optimized Z-value of the tertiary structure was -5.92, and the favored area after majorization in the Ramachandran plot was 84.54%. Molecular docking showed that the S7M8 vaccine could tightly bind to TLR2 (-1100.6 kcal/mol) and TLR4 (-950.3 kcal/mol). In addition, the immune stimulation prediction indicated that the S7M8 vaccine could activate T and B lymphocytes to produce high levels of Th1 cytokines and antibodies. CONCLUSION: S7M8 is a promising biomarker with good antigenicity, immunogenicity, non-toxicity, and non-sensitization. The S7M8 vaccine can trigger significantly high levels of Th1 cytokines and antibodies and may be a potentially powerful tool in preventing SARS-CoV-2 and MPXV.

High levels of exfoliated fragments following glycocalyx destruction in hemorrhagic fever with the renal syndrome are associated with mortality risk.

Background: The glycocalyx is a gel-like structure that covers the luminal side of vascular endothelial cells. It plays an important role in maintaining the integrity of the vascular endothelial barrier structure. However, the presence or absence of glycocalyx destruction in hemorrhagic fever with renal syndrome (HFRS) and its specific mechanism and role is still unclear. Methods: In this study, we detected the levels of exfoliated glycocalyx fragments, namely, heparan sulfate (HS), hyaluronic acid (HA), and chondroitin sulfate (CS), in HFRS patients and investigated their clinical application value on the evaluation of disease severity and prognosis prediction. Results: The expression of exfoliated glycocalyx fragments in plasma was significantly increased during the acute stage of HFRS. The levels of HS, HA, and CS in HFRS patients during the acute stage were significantly higher than in healthy controls and convalescent stages of the same type. HS and CS during the acute stage gradually increased with the aggravation of HFRS, and both fragments showed a significant association with disease severity. In addition, exfoliated glycocalyx fragments (especially HS and CS) showed a significant correlation with conventional laboratory parameters and hospitalization days. High levels of HS and CS during the acute phase were significantly associated with patient mortality and demonstrated an obvious predictive value for the mortality risk of HFRS. Conclusion: Glycocalyx destruction and shedding may be closely associated with endothelial hyperpermeability and microvascular leakage in HFRS. The dynamic detection of the exfoliated glycocalyx fragments may be beneficial for the evaluation of disease severity and prognosis prediction in HFRS.

Alfosbuvir plus Daclatasvir for Treatment of Chronic Hepatitis C Virus Infection in China.

INTRODUCTION: A pan-genotypic and effective treatment regimen for patients with chronic hepatitis C virus (HCV) infection remains an unmet medical need in China. Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. We conducted a phase 3 study to evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV infection. METHODS: All patients received 600 mg alfosbuvir tablets plus 60 mg daclatasvir tablets once daily for 12 weeks. The primary endpoint was sustained virological response 12 weeks after the end of treatment (SVR12). A follow-up visit was done at week 4 and 12, and those who achieved SVR12 were followed up at post-treatment week 24. RESULTS: Of the 326 patients who received at least one dose of the study drug, 320 (98.2% [95% confidence interval (CI): 96.5%-99.5%]) achieved sustained virological response at post-treatment week 12 (SVR12), which was superior to the historical SVR12 rate of 88% (p < 0.0001). The SVR12 rates were similar regardless of most baseline characteristics. The most common adverse event (AE) (≥ 10%) was hypercholesterolemia. Serious adverse events (SAEs) were reported in 25 (7.7%) patients, none of which was judged to be related to the study drug. The majority of AEs were mild to moderate in severity. CONCLUSIONS: Alfosbuvir plus daclatasvir for 12 weeks was highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3, or 6, suggesting that this regimen could be a promising option for HCV treatment in China irrespective of genotype. TRIAL REGISTRATION: ClinicalTrial.gov identifier, NCT04070235.

A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus.

BACKGROUND & AIMS: T-helper (Th)17 cells that secrete interleukin (IL)-22 have immunomodulatory and protective properties in the liver and other tissues. IL-22 induces expression of proinflammatory genes but is also mitogenic and antiapoptotic in hepatocytes. Therefore, it could have multiple functions in the immune response to hepatitis B virus (HBV). METHODS: We examined the role of IL-22 in regulating liver inflammation in HBV transgenic mice and measured levels of IL-22 in HBV-infected patients. RESULTS: In HBV transgenic mice, injection of a single dose of IL-22 increased hepatic expression of proinflammatory genes but did not directly inhibit virus replication. When splenocytes from HBV-immunized mice were transferred into HBV transgenic mice, the severity of the subsequent liver damage was ameliorated by neutralization of IL-22. In this model, IL-22 depletion did not affect interferon gamma-mediated noncytopathic inhibition of virus replication initiated by HBV-specific cytotoxic T cells, but it significantly inhibited recruitment of antigen-nonspecific inflammatory cells into the liver. In patients with acute HBV infections, the percentage of Th17 cells in peripheral blood and concentration of IL-22 in serum were significantly increased. CONCLUSIONS: IL-22 appears to be an important mediator of the inflammatory response following recognition of HBV by T cells in the liver. These findings might be relevant to the development of cytokine-based therapies for patients with HBV infection.

The Comparison of Inflammatory Cytokines (IL-6 and IL-18) and Immune Cells in Japanese Encephalitis Patients With Different Progression.

Background: Japanese encephalitis virus (JEV) is the main cause of viral encephalitis in Asia. Nowadays, no effective and specific therapy for JE patients is available except supportive treatment. The fatality rate of JE patients is still about 30%, and more than half of survivors suffered from various neuropsychiatric sequelae. Thus, more attention should be paid to JE. Methods: In this study, a retrospective cohort of JE patients was collected and the general features of JE patients admitted into the Department of Infectious Diseases were analyzed. Meanwhile, the dynamic change of plasma cytokines and immune cells in JE patients with divergent prognosis was detected and analyzed. Results: We found a mounted proportion of adult/old patients in JE cases. The level of IL-6 and IL-18 increased in JE patients especially in fatal individuals. There was a continuous decreased percentage of CD4+ T and B cells in severe JE patients with fatal outcome compared with the surviving JE patients. Conclusions: The consistent high level of IL-6 and IL-18 in the plasma and low proportion of CD4+ T and B cells in the PBMCs might be the indicators of poor prognosis.

Tenofovir is superior to entecavir in reducing HCC for patients with HBV-related compensated cirrhosis at high HCC risk scores.

Background: Both tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are known to reduce the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to compare the difference in HCC risk reduction between TDF and ETV in treatment-naïve patients with CHB-related compensated cirrhosis. Methods: Patients with compensated cirrhosis initially treated with TDF or ETV at nine Chinese hospitals between June 2014 and March 2021 were enrolled in this retrospective study. The cumulative HCC incidence rates for the two drugs were compared for the entire cohort, and a subgroup analysis was performed according to the HCC risk scores. Propensity score matching (PSM) was used to control confounding biases. Results: The analysis included 1453 patients (TDF group, n = 188; ETV group, n = 1265). Ninety-five patients developed HCC, with a median follow-up period of 26.1 months. The 3-year HCC incidence was 2.0% in the TDF group and 7.5% in the ETV group (log-rank p = 0.005). TDF treatment was associated with a lower risk of HCC than ETV treatment [hazard ratio (HR) = 0.222, 95% confidence interval (CI), 0.070-0.702, p = 0.010] but was similar after PSM (HR = 0.483, 95% CI, 0.144-1.626, p = 0.240; log-rank p = 0.230). However, subgroup analysis showed that the cumulative HCC incidence was lower in the TDF group than in the ETV group among patients with a modified PAGE-B score (mPAGE-B) ⩾9, either before or after PSM (log-rank p = 0.048 and p = 0.023, respectively). Conclusion: Among patients with an mPAGE-B score ⩾9, TDF is associated with a lower HCC incidence than ETV in patients with CHB-related compensated cirrhosis.