Heme oxygenase-1 inhibits DENV-induced endothelial hyperpermeability and serves as a potential target against dengue hemorrhagic fever.

Dengue virus (DENV) is a cause of vascular endothelial dysfunction and vascular leakage, which are characterized as hallmarks of dengue hemorrhagic fever or dengue shock syndrome, which become a severe global health emergency with substantial morbidity and mortality. Currently, there are still no promising therapeutics to alleviate the dengue-associated vascular hemorrhage in a clinical setting. In the present study, we first observed that heme oxygenase-1 (HO-1) expression level was highly suppressed in severe DENV-infected patients. In contrast, the overexpression of HO-1 could attenuate DENV-induced pathogenesis, including plasma leakage and thrombocytopenia, in an AG129 mouse model. Our data indicate that overexpression of HO-1 or its metabolite biliverdin can maintain endothelial integrity upon DENV infection in vitro and in vivo. We further characterized the positive regulatory effect of HO-1 on the endothelial adhesion factor vascular endothelial-cadherin to decrease DENV-induced endothelial hyperpermeability. Subsequently, we confirmed that two medicinal plant-derived compounds, andrographolide, and celastrol, widely used as a nutritional or medicinal supplement are useful to attenuate DENV-induced plasma leakage through induction of the HO-1 expression in DENV-infected AG129 mice. In conclusion, our findings reveal that induction of the HO-1 signal pathway is a promising option for the treatment of DENV-induced vascular pathologies.

Role of mitogen-activated protein kinase signaling in the pathogenesis of dengue virus infection.

Dengue virus (DENV) infection is a disease that is endemic to many parts of the world, and its increasing prevalence ranks it among the diseases considered to be a significant threat to public health. The clinical manifestations of DENV infection range from mild dengue fever (DF) to more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Increased proinflammatory cytokines and vascular permeability, both of which cause organ injury, are the hallmarks of severe dengue disease. Signs of liver injury were observed in studies using hepatic cell lines, mouse models, and autopsy specimens from DENV-infected patients, and these signs substantiated the effects of inflammatory responses and hepatic cell apoptosis. Mitogen-activated protein kinases (MAPK) are involved in inflammatory responses and cellular stress during viral infections. The roles of MAPK signaling in DENV infection were reviewed, and published data indicate MAPK signaling to be involved in inflammatory responses and hepatic cell apoptosis in both in vitro cultures and in vivo models. Modulation of MAPK signaling ameliorates the inflammatory responses and hepatic cell apoptosis in DENV infection. This accumulation of published data relative to the role of MAPK signaling in inflammatory responses and cell apoptosis in DENV infection is elucidatory, and may help to accelerate the development of novel or repositioned therapies to treat this unpredictable and often debilitating disease.

Evaluation of creatine kinase and liver enzymes in identification of severe dengue.

BACKGROUND: Existing biomarkers such as AST, ALT and hematocrit have been associated with severe dengue but evidence are mixed. Recently, interests in creatine kinase as a dengue biomarker have risen. These biomarkers represent several underlying pathophysiological processes in dengue. Hence, we aimed to assess AST, ALT, CK and hematocrit in identification of severe dengue and to assess the correlational relationship amongst common biomarkers of dengue. METHODS: This was a retrospective cohort study of confirmed dengue patients who were warded in Kuala Lumpur Hospital between December 2014 and January 2015. CK, AST, ALT, hematocrit, platelet count, WBC and serum albumin were taken upon ward admission and repeated at timed intervals. Composite indices based on admission AST and ALT were analyzed. Correlation coefficients and coefficients of determination were computed. RESULTS: Among the 365 cases reviewed, twenty-two (6%) patients had severe dengue. AST and ALT were found to be good at identification of severe dengue. The AST2/ALT composite index was the most accurate (AUC 0.83; 95% CI 0.73 - 0.93). Optimal cutoff was 402 with a sensitivity of 59.1% (95% CI: 36.4 - 79.3%) and specificity of 92.4% (95% CI: 89.1 - 95.0%). Modified cutoff of 653 had a sensitivity of 40.9% (95% CI: 20.7 - 63.7%) and specificity of 97.4% (95% CI: 95.1 - 98.8%). Our analyses also suggested that several underlying biological processes represented by biomarkers tested were unrelated despite occurring in the same disease entity. Also, markers of plasma leakage were discordant and AST was likely hepatic in origin. CONCLUSIONS: The composite index AST2/ALT may be used as a marker for identification of severe dengue based on admission AST and ALT, with two choices of cutoff values, 402 and 653. AST is most likely of liver origin and CK does not provide additional value.

Serum transaminase level changes in dengue fever and its correlation with disease severity.

It was observed that liver enzymes are elevated in dengue fever. In this study our aims were to determine the changes in serum transaminases in dengue fever, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) and to find out the relation of transaminase level changes with the disease severity. This cross sectional, prospective hospital based observational study was carried out in the department of Gastrointestinal Hepatobiliary and Pancreatic diseases and Internal Medicine department of BIRDEM Hospital, Dhaka. Patients are classified into 3 groups depending on clinical & laboratory findings: Group 1 dengue fever (DF), Group 2 dengue hemorrhagic fever & Group 3 dengue shock syndrome. A total of 240 cases were taken in this study who fulfilled the selection criteria. Out of whom 125 male and 115 female patients. DF was 157(65.4%) & DHF was 83(34.6%). Aminotransferases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] were significantly raised in DHF cases compared to those of classical dengue fever (AST 84.5±42.4 in DF vs. 507±106.8 IU/L in DHF and ALT 59.9±31.3 in DF vs. 234±30.6 IU/L in DHF). The rise of AST is far greater than ALT in both DF and DHF. Dengue fever is usually associated with mild to moderate elevations of aminotransferase levels. The increase in aminotransferases, mainly AST has been associated with disease severity and serves as an early indicator of dengue infection.

Matrix metalloproteinase-9 (mmp-9) in children with dengue virus infection.

The purpose of this study was to investigate the role of matrix metalloproteinase-9 (MMP-9) in the pathogenesis of vascular leakage in patients with dengue virus infection. Serum samples from 24 children with serologically confirmed dengue virus infection (dengue fever [DF], 16; dengue hemorrhagic fever [DHF], 8; age, 9.5+/-2.4 years; 67% male] were analyzed for MMP-9 during the febrile and toxic stages and at follow-up. Serum samples obtained from 7 healthy children were used as controls. Serum MMP-9 levels in patients with dengue virus infection were found to be lower at the febrile (227.0+/-186.9 ng/ml) and toxic stages (150.9+/-151.7 ng/ml) than at follow-up (424.5+/-227.8 ng/ml) or in the control group (393.3+/-125.9 ng/ml, P<0.001 by one-way ANOVA). There was no significant difference between MMP-9 levels in patients with DHF and those with DF at any stage of the disease. In conclusion, MMP-9 levels are reduced during the febrile and toxic stages of dengue virus infection.

Differential expression of aldolase, alpha tubulin and thioredoxin peroxidase in peripheral blood mononuclear cells from dengue fever and dengue hemorrhagic fever patients.

We determined the differential expression levels of proteins in peripheral blood mononuclear cells of patients with dengue fever (DF) and dengue hemorrhagic fever (DHF). Proteins were subjected to two-dimensional electrophoresis, mass spectrometry and Western blot analysis. We identified 8 proteins that were 2-fold or more up-regulated in patients compared to healthy control, three of which, aldolase, thioredoxin peroxidase and alpha tubulin, were related to dengue infection. Both thioredoxin peroxidase and alpha tubulin were over-expressed 4.9 and 3.3 times respectively in DHF compared to DF patients while aldolase was up-regulated 2.2 times in DF compared to DHF patients. Alpha tubulin and thioredoxin peroxidase have the potential to be utilized as biomarkers for DHF.

Aminotransferasas séricas en pacientes con Dengue tipo 3 / Aminotransferases serum levels in patients with Dengue type 3

Background: Dengue infections may affect the liver, causing inflammation and compromising its function. Aim: To determine serum aminotransferases in patients with Dengue. Material and methods: One hundred eighty four patients with Dengue confirmed with anti-Dengue IgG and IgM antibodies measured by ELISA, aged 1 month to 79 years, were studied. As controls, 40 patients with acute hepatitis B virus infection aged 11 to 59 years and 40 healthy individuals, aged 14 to 55 years, were also studied. Alanine and aspartate aminotransferases (ALT and AST) were determined using a colorimetric method. Results: Sixty one percent of patients with Dengue had elevated aminotransferase levels. In patients with Dengue and hepatitis B, mean ALT levels were 21.3±8.4 and 29.7±18.8 U/I, respectively. Mean AST values were 37.3±19, 19.6± 16.4 and 4.3±1.7 U/I in patients with Dengue, hepatitis B and controls, respectively. During the year 2001, there was an increase in the number of cases with hemorrhagic fever caused by Dengue and 65 percent had elevation of aminotransferases. Conclusions: An increase in aminotransf erase levels is common in patients with Dengue.

The impact of dengue on liver function as evaluated by aminotransferase levels.

The objective of this study was to evaluate the impact of dengue virus infection on liver function by measuring aminotransferase in blood samples from patients serologically diagnosed by according to two MAC-ELISA protocols. Degrees of liver damage were classified according to aminotransferase levels: grade A--normal enzyme levels; grade B--increased levels of at least one of the enzymes; grade C--increased, with at least one of the enzymes being at levels higher than three times the upper reference values; grade D--acute hepatitis, with aminotransferase levels at least ten times their normal values. Of the 169 serologically confirmed cases of dengue at the dengue referral center in Campos dos Goytacazes in the state of Rio de Janeiro, Brazil, 65.1% had abnormal aminotransferase levels: 81 cases being classified as grade B, 25 as grade C and 3 as grade D. A further 34.9% of cases had normal enzyme levels and were classified as grade A. Liver damage is a common complication of dengue infection and aminotransferase levels are a valuable marker for monitoring these cases.

[Association between glutathione peroxidase levels and clinical manifestations of dengue]. / Correlación entre los niveles de glutatión peroxidasa, un marcador de estrés oxidativo, y la presentación clínica del dengue.

BACKGROUND: Glutathione peroxidase (GP) can be used as a marker of oxidative stress in infectious diseases. AIM: To evaluate the association between the levels of glutathione peroxidase (GP) and the manifestations and complications of dengue. PATIENTS AND METHODS: Between April 2003 and December 2004, 161 patients with dengue were prospectively evaluated. In the first evaluation, within 48 and 96 hours of disease onset, a plasma sample was obtained to measure the GP levels. The association between GP levels, clinical manifestations and complications was evaluated during the follow up. RESULTS: Mean GP values were 1198 U/L (95% confidence interval 1089-1306). Values greater than 1200 U/L were associated with headache, arthralgias and increased heart rate. There was a negative association between GP levels and serum triglycerides. During follow up, patients with GP >1200 U/L had a higher frequency of spontaneous hemorrhages. In a logistic regression analysis arthralgias, fever and increased heart rate, were independently associated with levels >1200 U/L. CONCLUSIONS: GP levels was associated to some of the manifestations of dengue. This finding suggests that the intensity of oxidative stress can influence the clinical presentation of dengue.

The impact of dengue on liver function as evaluated by aminotransferase levels

The objective of this study was to evaluate the impact of dengue virus infection on liver function by measuring aminotransferase in blood samples from patients serologically diagnosed by according to two MAC-ELISA protocols. Degrees of liver damage were classified according to aminotransferase levels: grade A - normal enzyme levels; grade B - increased levels of at least one of the enzymes; grade C - increased, with at least one of the enzymes being at levels higher than three times the upper reference values; grade D - acute hepatitis, with aminotransferase levels at least ten times their normal values. Of the 169 serologically confirmed cases of dengue at the dengue referral center in Campos dos Goytacazes in the state of Rio de Janeiro, Brazil, 65.1 percent had abnormal aminotransferase levels: 81 cases being classified as grade B, 25 as grade C and 3 as grade D. A further 34.9 percent of cases had normal enzyme levels and were classified as grade A. Liver damage is a common complication of dengue infection and aminotransferase levels are a valuable marker for monitoring these cases.

Correlación entre los niveles de glutatión peroxidasa, un marcador de estrés oxidativo, y la presentación clínica del dengue / Association between glutathione peroxidase levels and clinical manifestations of dengue

Background: Glutathione peroxidase (GP) can be used as a marker of oxidative stress in infectious diseases. Aim: To evaluate the association between the levels of glutathione peroxidase (GP) and the manifestations and complications of dengue. Patients and Methods: Between April 2003 and December 2004, 161 patients with dengue were prospectively evaluated. In the first evaluation, within 48 and 96 hours of disease onset, a plasma sample was obtained to measure the GP levels. The association between GP levels, clinical manifestations and complications was evaluated during the follow up. Results: Mean GP values were 1198 U/L (95 percent confidence interval 1089-1306). Values greater than 1200 U/L were associated with headache, arthralgias and increased heart rate. There was a negative association between GP levels and serum triglycerides. During follow up, patients with GP >1200 U/L had a higher frequency of spontaneous hemorrhages. In a logistic regression analysis arthralgias, fever and increased heart rate, were independently associated with levels >1200 U/L. Conclusions: GP levels was associated to some of the manifestations of dengue. This finding suggests that the intensity of oxidative stress can influence the clinical presentation of dengue.

Fulminant hepatitis in dengue haemorrhagic fever.

Dengue virus is estimated to cause over 100 million infections throughout the world annually. While dengue infections can have a wide range of infections, atypical manifestations have been described. These involve the central nervous system, cardiac alterations and hepatitis. Here, we highlight a case of dengue haemorrhagic fever (DHF) with fulminant hepatitis. A 55-year-old male was admitted for 16 days, developing severe thrombocytopenia as low as 6x10(9)/L, haematocrit of 48% with transaminitis: ALT: 3,515 U/L, AST: 12,541 U/L, GGT: 1,094 U/L. Subsequent investigations excluded any occult liver lesions, hepatitis A, B and C, Wilson's disease, Epstein-Barr virus and Cytomegalo virus as possible causes. His dengue PCR was positive. His condition subsequently improved with supportive treatment. Liver injury from dengue virus is mediated by its direct infection of hepatocytes and kupffer cells. While mild to moderate elevations of serum aminotransferases (ALT and AST<5X normal) are common in dengue virus infection, liver failure rarely dominate the clinical picture. Liver dysfunction was commoner in DHF, with case reports indicating that severe hepatic dysfunction (ALT and AST>10X normal) was seen with DHF associated with spontaneous bleeding tendencies. Overall prognosis depends on age and other concomitant co-morbidities. We seek to review the literature on dengue infections with hepatitis and discuss issues pertaining to pathophysiology of liver impairment in dengue, the frequency of transaminitis associated with DHF and the overall prognosis.

[Aminotransferases serum levels in patients with Dengue type 3]. / Aminotransferasas séricas en pacientes con Dengue tipo 3.

BACKGROUND: Dengue infections may affect the liver, causing inflammation and compromising its function. AIM: To determine serum aminotransferases in patients with Dengue. MATERIAL AND METHODS: One hundred eighty four patients with Dengue confirmed with anti-Dengue IgG and IgM antibodies measured by ELISA, aged 1 month to 79 years, were studied. As controls, 40 patients with acute hepatitis B virus infection aged 11 to 59 years and 40 healthy individuals, aged 14 to 55 years, were also studied. Alanine and aspartate aminotransferases (ALT and AST) were determined using a colorimetric method. RESULTS: Sixty one percent of patients with Dengue had elevated aminotransferase levels. In patients with Dengue and hepatitis B, mean ALT levels were 21.3+/-8.4 and 29.7+/-18.8 U/I, respectively. Mean AST values were 37.3+/-19, 19.6+/- 16.4 and 4.3+/-1.7 U/I in patients with Dengue, hepatitis B and controls, respectively. During the year 2001, there was an increase in the number of cases with hemorrhagic fever caused by Dengue and 65% had elevation of aminotransferases. CONCLUSIONS: An increase in aminotransf erase levels is common in patients with Dengue.