Impact of nonalcoholic fatty liver disease status change on antiviral efficacy of nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B.

Data on the dynamic changes in chronic hepatitis B (CHB) patients with nonalcoholic fatty liver disease (NAFLD) during antiviral therapy are scarce. We aimed to investigate the evolution of NAFLD status change in CHB patients treated with nucleos(t)ide analogues (NAs) and its influence on therapeutic outcomes. This retrospective study included 164 HBeAg-positive CHB patients from a randomized controlled trial who were treated with NAs for 104 weeks and underwent paired liver biopsies. Histological evaluation was performed at baseline and Week 104. The patients were divided into four groups according to NAFLD status changes. From baseline to Week 104, the overall percentage of CHB patients with concurrent NAFLD increased from 17.1% to 26.2% (p = 0.044). Among them, 7 of 28 patients (25.0%) with NAFLD at baseline showed NAFLD remission at week 104, while 22 of 136 patients (16.2%) without NAFLD at baseline developed new-onset NAFLD. In subgroup analyses, the new-onset and sustained NAFLD groups showed significantly lower rates of biochemical response at week 104 as compared to the sustained non-NAFLD group (77.3% and 57.1% vs. 93.9%, respectively; all p < 0.05), as well as fibrosis improvement (31.8% and 42.9% vs. 69.3%, respectively; all p < 0.05). NAFLD status changes did not influence the virological response, HBeAg seroconversion, and necroinflammation improvement (all p > 0.05). In HBeAg-positive CHB patients receiving NAs therapy, new-onset and sustained NAFLD may counteract the benefits of antiviral therapy, reducing the rate of biochemical response and fibrosis improvement.

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.

Combining Hepatitis B Virus RNA and Hepatitis B Core-Related Antigen: Guidance for Safely Stopping Nucleos(t)ide Analogues in Hepatitis B e Antigen-Positive Patients With Chronic Hepatitis B.

BACKGROUND: Safe nucleos(t)ide analogue discontinuation in chronic hepatitis B (CHB) is an unmet need. We aimed to investigate whether combining hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) could perform satisfactorily in predicting off-treatment outcomes. METHODS: The evaluation cohort included 127 hepatitis B e antigen (HBeAg)-positive patients from a multicenter prospective trial who stopped telbivudine-based therapy after achieving HBeAg seroconversion and HBV DNA < 50 IU/mL for > 48 weeks. As validation, 59 patients treated with entecavir or tenofovir before discontinuation were analyzed. RESULTS: At the end of treatment (EOT), HBV RNA and HBcrAg were significant independent predictors of the clinical relapse risk. In the evaluation cohort, no clinical relapse occurred among patients with negative HBV RNA and HBcrAg < 4 log10 U/mL at EOT (low-risk group), whereas 46.8% patients with positive HBV RNA and HBcrAg ≥ 4 log10 U/mL (high-risk group) experienced clinical relapse during 4-year posttreatment follow-up (P < .001); the corresponding incidences in the validation cohort were 0% and 69.4% (P < .001), respectively. More patients in the low-risk group achieved HBsAg loss than the other patients after treatment cessation (16.1% vs 1.3%, P = .002). CONCLUSIONS: Combining HBV RNA and HBcrAg performed satisfactorily in predicting clinical relapse and HBsAg loss after treatment cessation in HBeAg-positive patients with CHB.The combination of hepatitis B virus RNA and hepatitis B core-related antigen performed satisfactorily in predicting clinical relapse and hepatitis B surface antigen loss after stopping nucleos(t)ide analogue treatment among noncirrhotic hepatitis B e antigen-positive patients with chronic hepatitis B and could be used to guide safe discontinuation.

Association Between Negative Results From Tests for HBV DNA and RNA and Durability of Response After Discontinuation of Nucles(t)ide Analogue Therapy.

BACKGROUND & AIMS: There is no satisfactory way to identify patients who will maintain a response after discontinuation of nuleos(t)ide analogue therapy for chronic hepatitis B virus (HBV) infection. We investigated whether patients with negative results from tests for HBV DNA and HBV RNA (double negative) at the end of treatment maintain a long-term response to treatment. METHODS: We performed a post-hoc analysis of data from a 2-year multi-center randomized controlled trial, and its long-term extension trials, on 130 patients with chronic HBV infection who were positive for the HB e antigen (HBeAg-positive; mean age, 30.8 ± 6.9 years; 72.3% male) and received telbivudine with or without adefovir and stopped therapy after they had HBeAg seroconversion and levels of HBV DNA <300 copies/mL for at least 48 weeks (evaluation cohort). Clinical and laboratory assessments were made every 12 or 16 weeks until clinical relapse (defined as HBV DNA > 2000 IU/mL and level of alanine aminotransferase more than 2-fold the upper limit of normal) or until 4 years off treatment. We validated our findings in a cohort of 40 HBeAg-positive patients (36.5 ± 9.4 years old; 72.5% male) treated with entecavir or tenofovir, and followed after discontinuation for up to 5.5 years. Patients were considered to be negative for HBV DNA if it was not detected in the COBAS Taqman assay. Patients were considered to be negative for HBV RNA if it was not detected by quantitative real-time PCR with 2 different pairs of primers. RESULTS: After 4 years off treatment, in the evaluation cohort, 30.8% of patients had a clinical relapse, 54.7% had virologic relapse (HBV DNA >2000 IU/mL in 2 tests), and 16.8% had reappearance of HBeAg in 2 tests (reversion). A significantly lower proportion of double negative patients had a clinical relapse 4 years later (2/35; 8.0%) than of patients who tested positive for either HBV DNA or RNA (32/102; 31.4%; P = .018). In the validation cohort, after 5.5 years of follow up, a lower proportion of double negative patients had clinical relapse (2/13; 15.4%) than of patients who tested positive for either HBV DNA or RNA at the end of treatment (9/27; 33.3%; P = .286) CONCLUSIONS: In an analysis of data from 2 independent cohorts, we associated negative results from tests for HBV DNA and RNA (double negative) at the end of treatment with continued response 4 or more years after discontinuation of therapy in HBeAg-positive patients. These results might be used to identify the best candidates for discontinuation of nuleos(t)ide analogue therapy.

Study on expression of plasma sCD138 in patients with hemorrhagic fever with renal syndrome.

BACKGROUND: Until now, there is non-specific treatment, and exploring early and novel biomarkers to determine the disease severity and prognosis of hemorrhagic fever with renal syndrome (HFRS) would be of importance for clinician to take systematic and timely intervention. This study observed the expression of plasma sCD138, a soluble component shedding from the glycocalyx (GCX) to the circulating blood, and evaluated its predictive value on disease severity and prognosis of HFRS. METHODS: One hundred and seventy-six patients with HFRS who were treated at our center between January 2011 and December 2013 were randomly enrolled in this study. The patients were divided into a mild-type group, a moderate-type group, a severe-type group and a critical-type group according to the HFRS criteria for clinical classification. Thirty-five blood samples from healthy subjects were obtained as the controls. The concentrations of sCD138 were detected using enzyme linked immunosorbent assay (ELISA). The levels of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cells (WBC), platelets (PLT), glucose (GLU), blood urea nitrogen (BUN) and serum creatinine (Scr) in the samples were routinely tested. The levels of sCD138 among the different types were compared; the correlation among sCD138 and the laboratory parameters mentioned above were analyzed. The predictive effectiveness for prognosis of sCD138 was evaluated using the receiver operating characteristic (ROC) curve analysis. RESULTS: Except for the mild-type, the levels of sCD138 in the moderate-, severe- and critical-type patients during the acute stage were significantly higher than that of the convalescent stage and the control (P<0.05). With the aggravation of the disease, the levels of sCD138 during the acute stage had an increasing tendency, while demonstrated no significant difference among the moderate-, severe- and critical-type patients (P>0.05). sCD138 was negatively correlated with Fib, PLT and ALB, and was positively correlated with WBC and AST (P<0.05). sCD138 demonstrated predictive effectiveness for prognosis with the area under the curve (AUC) of 0.778 (P<0.001). CONCLUSION: Dynamic detection of plasma sCD138 might be benefit to evaluating the disease severity and prognosis of the patients with HFRS.

Association of baseline vitamin D level with genetic determinants and virologic response in patients with chronic hepatitis B.

AIM: The role of vitamin D in individuals with chronic hepatitis B (CHB) is unclear. We aimed to explore the association of baseline vitamin D level with genetic determinants and week-104 treatment outcome in CHB patients. METHODS: Baseline serum 25-hydroxycholecalciferol (25(OH)D) levels and genetic polymorphism within GC, DHCR7, and CYP2R1 were determined in stored serum of 560 patients who were enrolled into a multicenter, randomized, controlled study and completed 104 weeks of telbivudine monotherapy or telbivudine-based optimized therapy. Virologic response was defined as hepatitis B virus DNA <300 copies/mL (52 IU/mL) at week 104. RESULTS: The mean 25(OH)D value was 29.64 ng/mL. The percentage of patients with vitamin D insufficiency (<30 ng/mL) and vitamin D deficiency (<20 ng/mL) were 55.0% and 20.9%, respectively. Gender, season, latitude, and GC rs2282679 polymorphism were independent factors of vitamin D status. Patients with sufficient vitamin D (≥30 ng/mL) achieved a higher virologic response rate than those with vitamin D insufficiency (81.7% vs. 67.2%, P < 0.001). The area under the curve of 25(OH)D to predict virologic response was 0.65 (P < 0.001; 95% confidence interval, 0.62-0.67). On multivariate analysis, 25(OH)D level was an independent predictor of virologic response, but not associated with hepatitis B envelope antigen (HBeAg) seroconversion or alanine aminotransferase (ALT) normalization. CONCLUSIONS: Vitamin D insufficiency was highly prevalent in treatment-naïve CHB patients in mainland China. Latitude and genetic determinants affect vitamin D status. Baseline vitamin D level can predict week-104 virologic response, but not HBeAg seroconversion or ALT normalization.

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.

Hantavirus infection: a global zoonotic challenge.

Hantaviruses are comprised of tri-segmented negative sense single-stranded RNA, and are members of the Bunyaviridae family. Hantaviruses are distributed worldwide and are important zoonotic pathogens that can have severe adverse effects in humans. They are naturally maintained in specific reservoir hosts without inducing symptomatic infection. In humans, however, hantaviruses often cause two acute febrile diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). In this paper, we review the epidemiology and epizootiology of hantavirus infections worldwide.

Notch Signaling Contributes to Liver Inflammation by Regulation of Interleukin-22-Producing Cells in Hepatitis B Virus Infection.

The mechanism of hepatitis B virus (HBV) induced liver inflammation is not fully elucidated. Notch signaling augmented interleukin (IL)-22 secretion in CD4+ T cells, and Notch-IL-22 axis fine-tuned inflammatory response. We previously demonstrated a proinflammatory role of IL-22 in HBV infection. Thus, in this study, we analyzed the role of Notch in development of IL-22-producing cells in HBV infection by inhibition of Notch signaling using γ-secretase inhibitor DAPT in both hydrodynamic induced HBV-infected mouse model and in peripheral blood cells isolated from patients with HBV infection. mRNA expressions of Notch1 and Notch2 were significantly increased in livers and CD4+ T cells upon HBV infection. Inhibition of Notch signaling in vivo leaded to the reduction in NKp46+ innate lymphoid cells 22 (ILC22) and lymphoid tissue inducer 4 (LTi4) cells in the liver. This process was accompanied by downregulating the expressions of IL-22 and related proinflammatory cytokines and chemokines in the liver, as well as blocking the recruitment of antigen-non-specific inflammatory cells into the liver and subsequent liver injury, but did not affect HBV antigens production and IL-22 secretion in the serum. Furthermore, IL-22 production in HBV non-specific cultured CD4+ T cells, but not HBV-specific CD4+ T cells, was reduced in response to in vitro inhibition of Notch signaling. In conclusion, Notch siganling appears to be an important mediator of the liver inflammation by modulating hepatic ILC22. The potential proinflammatory effect of Notch-mediated ILC22 may be significant for the development of new therapeutic approaches for treatment of hepatitis B.

Changes in Plasma Adiponectin Concentrations in Patients With Hemorrhagic Fever With Renal Syndrome: An Observational Prospective Study.

The objective is to observe the changes in plasma adiponectin (APN) and its predictive capacity for disease severity and prognosis of hemorrhagic fever with renal syndrome (HFRS).One hundred and five patients who were treated at our center between October 2011 and December 2012 were randomly enrolled in this study. The patients were divided into a mild-type group, a moderate-type group, a severe-type group, and a critical-type group according to the HFRS criteria for clinical classification. Ninety-three plasma samples from the patients in the acute stage and 78 samples from the patients in the convalescent stage were obtained, and 28 samples from healthy subjects were obtained as controls. The concentrations of APN were detected using the enzyme-linked immunosorbent assay. The levels of white blood cells, platelets, hematocrit, albumin, blood urea nitrogen, serum creatinine, and uric acid in the samples were routinely tested. The levels of APN among the different types were compared; the correlation between APN and the laboratory parameters was analyzed. The predictive effectiveness for prognosis of APN and the laboratory parameters as mentioned above were evaluated using the receiver operating characteristic curve analysis.The levels of APN in the mild- and moderate-type patients in the acute stage were significantly higher than the severe-type and control (P < 0.05) and decreased with the severity of the disease, while there were no obvious difference among severe-, critical-type and control groups. The levels of APN in patients in the convalescent stage were higher than the control group (P < 0.05), and the APN levels of the critical-type group were higher compared with the mild-type groups (P < 0.05). Adiponectin was negatively correlated with white blood cells and hematocrit and positively correlated with platelets, albumin, and uric acid (P < 0.001). Adiponectin showed no statistical significance for predicting prognosis, with the area under the curve equal to 0.609 (95% CI: 0.237-0.745, P = 0.215).Adiponectin can be considered as a novel biomarker for disease severity in patients with HFRS, while it seems to have no predictive capacity for prognosis of HFRS.

Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues.

OBJECTIVE: The investigation regarding the clinical significance of quantitative hepatitis B core antibody (anti-HBc) during chronic hepatitis B (CHB) treatment is limited. The aim of this study was to determine the performance of anti-HBc as a predictor for hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive CHB patients treated with peginterferon (Peg-IFN) or nucleos(t)ide analogues (NUCs), respectively. DESIGN: This was a retrospective cohort study consisting of 231 and 560 patients enrolled in two phase IV, multicentre, randomised, controlled trials treated with Peg-IFN or NUC-based therapy for up to 2 years, respectively. Quantitative anti-HBc evaluation was conducted for all the available samples in the two trials by using a newly developed double-sandwich anti-HBc immunoassay. RESULTS: At the end of trials, 99 (42.9%) and 137 (24.5%) patients achieved HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. We defined 4.4 log10 IU/mL, with a maximum sum of sensitivity and specificity, as the optimal cut-off value of baseline anti-HBc level to predict HBeAg seroconversion for both Peg-IFN and NUC. Patients with baseline anti-HBc ≥4.4 log10 IU/mL and baseline HBV DNA <9 log10 copies/mL had 65.8% (50/76) and 37.1% (52/140) rates of HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. In pooled analysis, other than treatment strategy, the baseline anti-HBc level was the best independent predictor for HBeAg seroconversion (OR 2.178; 95% CI 1.577 to 3.009; p<0.001). CONCLUSIONS: Baseline anti-HBc titre is a useful predictor of Peg-IFN and NUC therapy efficacy in HBeAg-positive CHB patients, which could be used for optimising the antiviral therapy of CHB.

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.

Tetraspanin CD63 is a regulator of HIV-1 replication.

Macrophages and CD4(+) T-cells are the major reservoirs for HIV-1 infection. CD63 is a tetraspanin transmembrane protein, which has been shown to play an essential role during HIV-1 replication in macrophages. In this study, we further confirm the requirement of CD63 in HIV-1 replication events in primary human CD4(+) T-cells, dendritic cells, and a CD4(+) cell line. Most interestingly, we also show the evidences for the co-localization and internalization of CD63 and HIV-1 major receptor CD4 in primary human macrophages and CD4(+) cell line by confocal microscopy and Co-Immunoprecipitation assay. Analysis revealed that CD63-depleted CD4(+) T-cells, dendritic cells, and a cell line showed significant decrease in HIV-1 production. Further analysis showed that CD63 down regulation reduced production of the early HIV protein Tat, and affected HIV protein Gag by CD63-Gag interaction. In agreement, CD63 silencing also inhibited production of the late protein p24. Furthermore, we revealed that CD63 silencing has no effect on HIV-1 replication with extensive viral challenge (MOI > 0.2). These findings suggest that CD63 plays a dual-role both in early and late HIV-1 life cycle with a range of HIV-1 infection (MOI < 0.2).

Elevated soluble CD163 plasma levels are associated with disease severity in patients with hemorrhagic fever with renal syndrome.

BACKGROUND: Hantaan virus is a major zoonotic pathogen that causesing hemorrhagic fever with renal syndrome (HFRS). Although HFRS pathogenesis has not been entirely elucidated, the importance of host-related immune responses in HFRS pathogenesis has been widely recognized. CD163, a monocyte and macrophage-specific scavenger receptor that plays a vital function in the hosts can reduce inflammation, is shed during activation as soluble CD163 (sCD163). The aim of this study was to investigate the pathological significance of sCD163 in patients with HFRS. METHODS: Blood samples were collected from 81 hospitalized patients in Tangdu Hospital from October 2011 to January 2014 and from 15 healthy controls. The sCD163 plasma levels were measured using a sandwich ELISA, and the relationship between sCD163 and disease severity was analyzed. Furthermore, CD163 expression in 3 monocytes subset was analyzed by flow cytometry. RESULTS: The results demonstrated that sCD163 plasma levels during the HFRS acute phase were significantly higher in patients than during the convalescent stage and the levels in the healthy controls (P<0.0001). The sCD163 plasma levels in the severe/critical group were higher than those in the mild/moderate group during the acute (P<0.0001). A Spearman correlation analysis indicated that the sCD163 levels were positively correlated with white blood cell, serum creatine, blood urea nitrogen levels, while they were negatively correlated with blood platelet levels in the HFRS patients. The monocyte subsets were significantly altered during the acute stage. Though the CD163 expression levels within the monocyte subsets were increased during the acute stage, the highest CD163 expression level was observed in the CD14++CD16+ monocytes when compared with the other monocyte subsets. CONCLUSION: sCD163 may be correlated with disease severity and the disease progression in HFRS patients; however, the underlying mechanisms should be explored further.

[Clinical characteristics of pediatric hemorrhagic fever with renal syndrome].

OBJECTIVE: To study the clinical characteristics of pediatric hemorrhagic fever with renal syndrome (HFRS), and to improve its understanding so as to reduce the misdiagnosis. METHODS: A retrospective analysis was performed on the clinical data of 26 children with HFRS between January 2009 and December 2012. RESULTS: The age of disease onset was mainly distributed between 7 and 14 years (23 cases, 88%), and the male-to-female ratio was 1.89:l. The clinical manifestations of pediatric HFRS varied. The early symptoms resembled those of a cold, and in the course of HFRS, most patients developed digestive symptoms such as vomiting and abdominal pain. The laboratory examinations usually implicated platelet changes, and the imaging examinations revealed polyserous effusions. The prominent complication was myocardial injury. CONCLUSIONS: Pediatric HFRS mainly occurs in school-age children, more commonly in males. HFRS does not have typical clinical manifestations or symptoms, so it should be distinguished from cold or appendicitis at the early stage. When applying the fluid replacement therapy, the cardiac function should be carefully monitored in case of heart failure.

A randomized, open-label clinical study of combined pegylated interferon Alfa-2a (40KD) and entecavir treatment for hepatitis B "e" antigen-positive chronic hepatitis B.

BACKGROUND: Treatment with pegylated interferon (peg-IFN) alfa-2a (40KD) results in hepatitis B "e" antigen (HBeAg) seroconversion 6 months after treatment in up to 36% of HBeAg-positive chronic hepatitis B patients. This study explored the efficacy of a novel combination of peg-IFN alfa-2a and entecavir (ETV), a potent nucleoside analogue. METHODS: In total, 218 treatment-naive Chinese HBeAg-positive patients were randomized to peg-IFN alfa-2a (180 µg/week) for 48 weeks, either as monotherapy (n = 72), or with 24 weeks of ETV (0.5 mg/daily) added at week 13 (ETV add-on, n = 73), or pretreatment with a 24-week course of ETV, starting peg-IFN alfa-2a at week 21 (ETV pretreatment, n = 73). The primary endpoint was reduction in quantitative HBeAg from baseline to 24 weeks posttreatment. RESULTS: Significant reductions in HBeAg from baseline were achieved in all treatment groups 24 weeks posttreatment; reductions were comparable across treatment arms (shown as log10 Paul Ehrlich international units [PEIU]/mL): monotherapy: -1.4 (SD, 1.8); ETV add-on: -1.6 (SD, 1.8); ETV pretreatment: -1.3 (SD, 1.7). Rates of HBeAg seroconversion were similar across treatment groups posttreatment (monotherapy: 22 [31%]; ETV add-on: 18 [25%]; ETV pretreatment: 19 [26%]). Significantly greater reductions of hepatitis B virus DNA were achieved with ETV add-on while on treatment, but were not sustained posttreatment. Safety profiles were comparable between treatment groups; adverse events were experienced by 62 (86%) monotherapy, 65 (89%) ETV add-on, and 58 (81%) ETV pretreatment patients. CONCLUSIONS: Neither ETV add-on nor ETV pretreatment demonstrated superiority compared with 48 weeks of peg-IFN alfa-2a monotherapy. The optimal treatment strategy using nucleos(t)ide analogues and peg-IFN alfa-2a remains to be determined. Clinical Trials Registration. NCT00614471.

A fusion DNA vaccine encoding middle version of HBV envelope protein fused to interleukin-21 did not enhance HBV-specific immune response in mice.

DNA vaccination can generate both humoral and cellular immunity, resulting in potential prophylactic and therapeutic vaccines in variety of conditions, including hepatitis B virus (HBV) infection. Fusion of cytokine gene is one of the ways to increase the immunogenicity of DNA vaccine. Interleukin (IL)-21 has been demonstrated to play an immunomodulatory role in HBV infection. Thus, we aimed to investigate the ability of IL-21 in the regulation of middle version of HBV envelop protein (MS) DNA vaccine. Fusion plasmid encoding IL-21 linked with MS was constructed. Normal and HBV transgenic mice were immunized by plasmid. pcDNA-IL-21/S2S induced a comparable level of anti-HBs antibody and HBsAg-specific CD8+ T-cell response with pcDNA-S2S. Furthermore, the level of circulating HBsAg was decreased by induction of anti-HBs antibody and HBsAg-specific CD8+ T-cell response to both pcDNA-IL-21/S2S and pcDNA-S2S vaccination in HBV transgenic mice. Thus, immunization with DNA vaccine encoding HBV MS protein induced both T- and B-cell response by targeting the specific antigen. Furthermore, it was also revealed that MS DNA vaccination could break immune tolerance in HBV transgenic mice. But IL-21 did not strengthen immune response induced by HBV DNA immunization. Our study suggested that MS-expressing plasmid may be useful for both preventive and therapeutic methods in HBV infection. However, IL-21 does not improve the immunogenicity and efficacy of MS DNA vaccination, and thus may not be used as a therapeutic marker for chronic hepatitis B.

Early indicators of severity and construction of a risk model for prognosis based upon laboratory parameters in patients with hemorrhagic fever with renal syndrome.

BACKGROUND: The objective of this study was to explore the role of laboratory parameters as early indicators of severity and as effective predictors of prognosis in patients with hemorrhagic fever with renal syndrome (HFRS). METHODS: A total of 356 patients were enrolled in this study and were divided into mild, moderate, severe and critical types according to the clinical classification of HFRS. The levels of 12 routinely tested laboratory parameters during the acute stage among the four types were compared. The predictive values of the laboratory parameters for prognosis were analyzed, and a risk model for prognosis based upon the parameters was constructed. RESULTS: The levels of white blood counts (WBC), platelets (PLT), aspartate aminotransferase (AST), albumin (ALB), blood urea nitrogen (BUN), serum creatinine (Scr), prothrombin time (PT) and activated partial thromboplastin time (APTT) demonstrated significant differences among the four types (p<0.001); WBC, AST, PT and fibrinogen (Fib) were major independent risk factors for death; WBC, AST, PT and Fib used in combination were better for predicting prognosis than single parameters used alone (p<0.001). CONCLUSIONS: Some routinely tested laboratory parameters can be beneficial as early indicators of severity of HFRS. Using a combination of WBC, AST, PT and Fib to predict the outcome in patients with HFRS exhibited acceptable diagnostic capability.

Clinical characteristics and outcomes in critical patients with hemorrhagic fever with renal syndrome.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) has become an important public health concern because of the high incidence and mortality rates, and limited treatment and vaccination. Until now, clinical studies on characteristics and outcomes in critical patients with HFRS have been limited. The aim of this study was to observe the clinical characteristics and cumulative proportions surviving and explore the predictive effects and risk factors for prognosis. METHODS: A detailed retrospective analysis of clinical records for critical HFRS patients was conducted. The patients enrolled were treated in the centre for infectious diseases, Tangdu Hospital, between January 2008 and August 2012. The clinical characteristics between the survivors and non-survivors were compared by Student's t-test or Chi-square test. The risk clinical factors for prognosis were explored by logistic regression analysis. The predictive effects of prognosis in clinical and laboratory parameters were analyzed by receiver operating characteristic (ROC) curves. The cumulative proportions surviving at certain intervals in the critical patients were observed by Kaplan-Meier survival analysis. RESULTS: Of the 75 patients enrolled, the cumulative proportion surviving was 70.7% at the second week interval, with a 28-day mortality rate of 36.3%. The non-survivors tended to have higher frequencies of agitation, dyspnea, conjunctival hemorrhage, coma, cardiac failure, acute respiratory distress syndrome (ARDS) and encephalopathy (P < .05). ARDS, conjunctival hemorrhage and coma were risk factors for death in the critical patients with HFRS. The non-survivors were found to have lower serum creatinine (Scr) levels (P < .001) and higher incidences of prolonged prothrombin time (PT) (P = .006), activated partial thromboplastin time (APTT) (P = .003) and elevated white blood cells (WBC) levels (P = .005), and the laboratory parameters mentioned above reached statistical significance for predicting prognosis (P < .05). CONCLUSION: The high fatality in critical patients with HFRS underscores the importance of clinicians' alertness to the occurrence of potentially fatal complications and changes in biochemical status to ensure that timely and systematically supportive treatment can be initiated when necessary.

Involvement of the Akt/NF-κB pathways in the HTNV-mediated increase of IL-6, CCL5, ICAM-1, and VCAM-1 in HUVECs.

BACKGROUND: Hantaan virus (HTNV) infection causes a severe form of HFRS(hemorrhagic fever with renal syndrome)in Asia. Although HTNV has been isolated for nearly forty years, the pathogenesis of HFRS is still unknown, and little is known regarding the signaling pathway that is activated by the virus. METHODOLOGY/PRINCIPAL FINDINGS: Cardamonin was selected as a NF-κB inhibitor, and indirect immunofluorescence assays were used to detect the effect of cardamonin on HTNV-infected HUVECs. The effect of cardamonin on the HTNV-induced phosphorylation of Akt and DNA-binding activity of NF-κB were determined using Western blot analysis and electrophoretic mobility shift assays (EMSAs), respectively. Then, flow cytometric and quantitative real-time PCR analyses were performed to quantify the expression levels of the adhesion molecules ICAM-1 and VCAM-1, and the concentrations of IL-6, IL-8, and CCL5 in HUVEC supernatants were examined using ELISA. The results showed that cardamonin did not effect the proliferation of HUVECs or the replication of HTNV in HUVECs. Instead, cardamonin inhibited the phosphorylation of Akt and nuclear transduction of NF-κB and further reduced the expression of the adhesion molecules ICAM-1 and VCAM-1 in HTNV-infected HUVECs. Cardamonin also inhibited the secretion of IL-6 and CCL5, but not IL-8. CONCLUSION/SIGNIFICANCE: HTNV replication may not be dependent upon the ability of the virus to activate NF-κB in HUVECs. The Akt/NF-κB pathways may be involved in the pathogenesis of HFRS; therefore, cardamonin may serve as a potential beneficial agent for HFRS therapy.