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INTRODUCTION: Dengue is one of the most important mosquito-borne infections. Severe cases are more frequently observed in adults. However, in 2008, the State of Rio de Janeiro, Brazil, experienced a severe dengue epidemic that primarily affected children and caused many cases of dengue hemorrhagic fever (DHF) and death. METHODS: A cross-sectional analytical study was conducted to examine laboratory diagnosis and clinical epidemiologic factors for confirmed dengue cases in patients aged less than 16 years, from January to June 2008, at a municipal hospital in the City of Rio de Janeiro, Brazil. Variables associated with severe outcomes and P values less than .05 were evaluated by means of a logistic regression model. RESULTS: Of the 419 dengue cases studied, 296 were classified as DHF and 123 as classical dengue. Six patients who had DHF died. In multivariate analysis, some laboratory and clinical variables were independently associated with DHF: age 5 years or older (odds ratio [OR], 4.94; 95% confidence interval [CI], 1.30-18.71), abdominal pain (OR, 8.59; 95% CI, 3.17-23.27), hepatomegaly (OR, 15.87; 95% CI, 5.38-46.85), and positive tourniquet test (OR, 10.84; 95% CI, 3.96-29.71). Hypoalbuminemia occurred more frequently than hemoconcentration in DHF cases, and high aminotransferase levels were associated with severity. CONCLUSIONS: Age greater than 5 years, abdominal pain, painful hepatomegaly, and positive tourniquet test were predictors of DHF. The high frequency of hepatic impairment suggests that acetaminophen should be avoided in severe cases of dengue.
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Dengue Grave/epidemiologia , Adolescente , Brasil/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fatores de RiscoRESUMO
Abstract INTRODUCTION: Dengue is one of the most important mosquito-borne infections. Severe cases are more frequently observed in adults. However, in 2008, the State of Rio de Janeiro, Brazil, experienced a severe dengue epidemic that primarily affected children and caused many cases of dengue hemorrhagic fever (DHF) and death. METHODS: A cross-sectional analytical study was conducted to examine laboratory diagnosis and clinical epidemiologic factors for confirmed dengue cases in patients aged less than 16 years, from January to June 2008, at a municipal hospital in the City of Rio de Janeiro, Brazil. Variables associated with severe outcomes and P values less than .05 were evaluated by means of a logistic regression model. RESULTS: Of the 419 dengue cases studied, 296 were classified as DHF and 123 as classical dengue. Six patients who had DHF died. In multivariate analysis, some laboratory and clinical variables were independently associated with DHF: age 5 years or older (odds ratio [OR], 4.94; 95% confidence interval [CI], 1.30-18.71), abdominal pain (OR, 8.59; 95% CI, 3.17-23.27), hepatomegaly (OR, 15.87; 95% CI, 5.38-46.85), and positive tourniquet test (OR, 10.84; 95% CI, 3.96-29.71). Hypoalbuminemia occurred more frequently than hemoconcentration in DHF cases, and high aminotransferase levels were associated with severity. CONCLUSIONS: Age greater than 5 years, abdominal pain, painful hepatomegaly, and positive tourniquet test were predictors of DHF. The high frequency of hepatic impairment suggests that acetaminophen should be avoided in severe cases of dengue.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Dengue Grave/epidemiologia , Brasil/epidemiologia , Estudos Transversais , Fatores de RiscoRESUMO
Dengue is an acute febrile illness with a wide spectrum of signs and symptoms ranging from mild to severe forms characterized by plasma leakage that can be fatal. NK cells are one of the main effectors in early infection and may play an important role in dengue pathogenesis. We investigated NK cell involvement during dengue infection. A higher frequency of NK cell subsets and TRAIL+NK cells was found in mild DF cases when compared to that in severe cases or healthy donors. NK activation markers such as CD107a and TLR3 were upregulated in patients' cells compared to those in healthy donors. In addition, IL12 related to NK cell activation were upregulated in mild DF cases. In vitro PBMC culture models show that DENV-stimulated and IFNα-stimulated NK cells were able to express TRAIL, suggesting an indirect activation of cells, regarding TRAIL expression. Type I IFN receptor blockage on DENV-stimulated PBMCs showed TRAIL expression on NK cells is partially IFNα dependent. In addition, during PBMC stimulation, TRAIL expression on NK cells was inversely correlated with DENV-positive monocytes. Therefore, we observed DENV-induced activation of NK cell populations. A higher activation of NK cells would promote limited viral spread, resulting in decreased inflammatory response, contributing to protection against dengue severity.
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Vírus da Dengue/patogenicidade , Células Matadoras Naturais/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Adulto , Dengue/imunologia , Dengue/metabolismo , Vírus da Dengue/imunologia , Feminino , Humanos , Interferon-alfa/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismoRESUMO
Outbreaks of the Zika, dengue, and chikungunya viruses, especially in the Americas, pose a global threat due to their rapid spread and difficulty controlling the vector. Extreme phenotypes are often observed, from asymptomatic to severe clinical manifestations, which are well-studied in dengue. Host variations are also important contributors to disease outcomes, and many case-control studies have associated single nucleotide polymorphisms (SNPs) with severe dengue. Here, we found that the TC genotype and T-carriers for SNP rs1285933 in the C-type lectin superfamily member 5 (CLEC5A) gene was associated with severe dengue in a Northern Brazilian population (OR=2.75 and p-value=0.01, OR=2.11 and p-value=0.04, respectively). We also tested the functional effect of the CLEC5A protein and found that it is upregulated on the surface of human monocytes after in vitro dengue infection. CLEC5A was correlated with viral load inside the monocytes (Spearman r=0.55, p=0.008) and TNF production in culture supernatants (Spearman r=0.72, p=0.03). Analysis of mRNA in blood samples from DENV4-infected patients exhibiting mild symptoms showed that CLEC5A mRNA expression is correlated with TNF (r=0.67, p=0.0001) and other immune mediators. Monocytes from rs1285933 TT/TC individuals showed lower CLEC5A expression compared to CC genotypes. However, in these cells, CLEC5A was not correlated with TNF production. In summary, we confirmed that CLEC5A is genetically associated with dengue severity outcome, playing a central role during the immune response triggered by a dengue viral infection, and rs1285933 is a relevant SNP that is able to regulate signaling pathways after interactions between the dengue virus and CLEC5A receptors.
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Vírus da Dengue/fisiologia , Dengue/genética , Genótipo , Lectinas Tipo C/genética , Monócitos/fisiologia , Receptores de Superfície Celular/genética , Aedes , Animais , Doenças Assintomáticas , Brasil , Células Cultivadas , Progressão da Doença , Vetores de Doenças , Estudos de Associação Genética , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Humanos , Lectinas Tipo C/metabolismo , Monócitos/virologia , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Carga ViralRESUMO
The increase in severe dengue (SD) cases has caused great impact on public health and has concerned authorities of countries where the disease is endemic and epidemics reach high proportions. The recognition of progression signs of this severe disease during the initial febrile phase can be difficult, since the symptoms are often indistinguishable from other febrile diseases. The aim of this study was to evaluate the clinical manifestations and laboratory findings in patients from two dengue outbreaks and their association with the disease. The study was conducted in patients (n = 153) with signs and symptoms consistent with dengue occurred during two distinct epidemics, 2010 and 2013, in the city of Campos dos Goytacazes, Rio de Janeiro, Brazil. According to the 2009 World Health Organization criteria, patients were classified as dengue without warning signs ([DwoWS] 60.6%, 57/94), dengue with warning signs ([DwWS] 30.9%, 29/94), and SD (4.25%, 4/94). Patients with DwWS/SD presented lower platelet and leukocyte counts and higher transaminase levels when compared with the DwoWS ones. Interestingly, patients from the epidemic of 2010 caused by dengue virus 2 (DENV-2) had lower platelet counts than patients of the 2013 epidemic caused by DENV-4. Furthermore, plasma leakage, gastrointestinal bleeding, and pleural effusion, hallmarks for a more severe disease, were also more frequently observed in those cases. Although previous studies may have extensively reported the wide range of the clinical aspects of dengue, the characterization of DENV-4 is desirable considering the burden of the disease during epidemics, especially for the health units and hospitals performing patient's management.
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Vírus da Dengue/classificação , Dengue/patologia , Dengue/virologia , Brasil/epidemiologia , Dengue/epidemiologia , Vírus da Dengue/genética , Vírus da Dengue/patogenicidade , Epidemias , Humanos , SorogrupoRESUMO
BACKGROUND: Dengue fever may present hemorrhages and cavitary effusions as result of exacerbated immune responses. We investigated hydro-alcoholic extracts from leaves (UGL) and bark (UGB) of the medicinal species Uncaria guinanensis with respect to antiviral effects in Dengue virus (DENV) infection and in immunological parameters associated with in vivo physiopathological features. METHODS: Chemical profiles from UGB or UGL were compared in thin layer chromatography and 1H nuclear magnetic resonance using flavonoid compounds and a pentacyclic oxindole alkaloid-enriched fraction as references. DENV-2-infected hepatocytes (Huh-7) were treated with extracts. Cell viability, DENV antigens and immunological factors were detected by enzyme-linked immunosorbent assay (ELISA) or flow cytometry. FINDINGS: The UGL mainly differed from UGB by selectively containing the flavonoid kaempferitrin. UGB and UGL improved hepatocyte viability. Both extracts reduced intracellular viral antigen and inhibited the secretion of viral non-structural protein (NS1), which is indicative of viral replication. Reduction in secretion of macrophage migration inhibitory factor was achieved by UGB, of interleukin-6 by UGL, and of interleukin-8 by both UGB and UGL. MAIN. CONCLUSIONS: The U. guianensis extracts presented, antiviral and immunomodulatory effects for DENV and possibly a hepatocyte-protective activity. Further studies may be performed to consider these products as potential candidates for the development of an herbal product for the future treatment of dengue.
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Antivirais/farmacologia , Quimiocinas/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Vírus da Dengue/efeitos dos fármacos , Dengue/virologia , Extratos Vegetais/farmacologia , Uncaria/química , Antígenos Virais/efeitos dos fármacos , Antígenos Virais/imunologia , Sobrevivência Celular/efeitos dos fármacos , Quimiocinas/imunologia , Citocinas/imunologia , Dengue/imunologia , Dengue/fisiopatologia , Vírus da Dengue/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , HumanosRESUMO
ABSTRACT BACKGROUND Dengue fever may present hemorrhages and cavitary effusions as result of exacerbated immune responses. We investigated hydro-alcoholic extracts from leaves (UGL) and bark (UGB) of the medicinal species Uncaria guinanensis with respect to antiviral effects in Dengue virus (DENV) infection and in immunological parameters associated with in vivo physiopathological features. METHODS Chemical profiles from UGB or UGL were compared in thin layer chromatography and 1H nuclear magnetic resonance using flavonoid compounds and a pentacyclic oxindole alkaloid-enriched fraction as references. DENV-2-infected hepatocytes (Huh-7) were treated with extracts. Cell viability, DENV antigens and immunological factors were detected by enzyme-linked immunosorbent assay (ELISA) or flow cytometry. FINDINGS The UGL mainly differed from UGB by selectively containing the flavonoid kaempferitrin. UGB and UGL improved hepatocyte viability. Both extracts reduced intracellular viral antigen and inhibited the secretion of viral non-structural protein (NS1), which is indicative of viral replication. Reduction in secretion of macrophage migration inhibitory factor was achieved by UGB, of interleukin-6 by UGL, and of interleukin-8 by both UGB and UGL. MAIN CONCLUSIONS The U. guianensis extracts presented, antiviral and immunomodulatory effects for DENV and possibly a hepatocyte-protective activity. Further studies may be performed to consider these products as potential candidates for the development of an herbal product for the future treatment of dengue.
Assuntos
Humanos , Antivirais/farmacologia , Extratos Vegetais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Quimiocinas/efeitos dos fármacos , Quimiocinas/imunologia , Uncaria/química , Dengue/fisiopatologia , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/imunologia , Antígenos Virais/efeitos dos fármacos , Antígenos Virais/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de FluxoRESUMO
ABSTRACT Dengue is the most important viral infection transmitted among humans by arthropod-borne. There are currently no vaccines or specific therapeutical treatment. Therefore, immunomodulatory compounds from plants have been widely examined for their antiviral effects. Cissampelos sympodialis Eichler, Menispermaceae, has scientifically proven to present immunomodulatory activities. Here we assessed the antiviral activity of leaf hydroalcoholic extract, warifteine or methylwarifteine from C. sympodialis in an in vitro dengue virus infection model. The results demonstrated that leaf hydroalcoholic extract or warifteine/methylwarifteine treatment did not reduce dengue virus-Ag+ hepatocyte (Huh-7 cell) rates in present experimental conditions. However, we assessed the potential antiviral effect of leaf hydroalcoholic extract or warifteine/methylwarifteine on dengue virus-infection by the production of inflammatory molecules, TNF-α, MIF, IL-8 and PGE2. Dengue virus infection enhanced TNF-α, MIF, IL-8 and PGE2 production in infected Huh-7 cells and leaf hydroalcoholic extract but not warifteine/methylwarifteine treatments, significantly reduced these molecules in infected cells. In dengue virus-infected Huh-7 cells, non-structural protein-1 is produced and leaf hydroalcoholic extract significantly inhibited it independently of alkaloids. Our findings imply that leaf hydroalcoholic extract may attenuate dengue virus infection in Huh-7 cells by inhibiting the enhanced of pro-inflammatory mediators and non-structural protein-1 production induce by dengue virus independently of warifteine/methywarifteine its major compound.
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BACKGROUND: Dengue is a major problem in Brazil. Epidemiological and clinical aspects were characterized in patients from two epidemics which occurred in Mato Grosso do Sul, Brazil. METHODS: Dengue cases were classified according to the 2009 WHO criteria, tested by serological and molecular biology tests and analysed for nonstructural protein 1 (NS1) antigenemia. RESULTS: Dengue was confirmed in 78.7% (48/61) and 75.6% (118/156) of the cases studied in 2010 and 2013, respectively. DENV-1 and DENV-2 were the serotypes involved in the 2010 epidemic and DENV-4 in the 2013 one. Most of the cases were classified as dengue without warning; however, severe dengue was observed in 18.7% (9/48) of the cases in 2010 and less observed in DENV-4 cases. NS1 levels were higher in patients with dengue with warning signs and severe dengue in 2010. Circulating aspartate aminotransferase (AST) and alanine transferase (ALT) were altered in all groups, independently of the infecting serotype or epidemic. Patients with DENV-1 and DENV-2 presented significant lower monocyte counts when compared to patients with DENV-4. An inverse correlation was found between platelet count, leucocytes, monocytes and NS1 levels. CONCLUSIONS: Epidemics caused by the prevalence of distinct DENV serotypes had different impacts and clinical characteristics in a same scenario and, despite the occurrence of secondary infections, the DENV-4 emergence was not associated with severe cases.
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Antígenos/sangue , Vírus da Dengue , Dengue/epidemiologia , Epidemias , Leucócitos/metabolismo , Sorogrupo , Proteínas não Estruturais Virais/sangue , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Contagem de Células Sanguíneas , Brasil/epidemiologia , Dengue/sangue , Dengue/virologia , Vírus da Dengue/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Prevalência , Sorotipagem , Dengue Grave/sangue , Dengue Grave/virologiaRESUMO
BACKGROUND/AIMS: Severe dengue fever is a result of exacerbated immune responses and no specific treatments are available. We evaluated the antiviral and immunomodulatory effects of Norantea brasiliensis Choisy. METHODS: Human adherent monocytes infected in vitro with dengue virus (DENV)-2 were incubated with the crude ethanol extract from leaves (NB1) or 3 derived fractions: dichloromethane (NB3), ethyl acetate (NB5), and butanolic (NB6) partitions. The antiviral and immunomodulatory activities were determined by intracellular detection of DENV antigen within monocytes and by secreted NS1 viral protein and cytokines. RESULTS: The crude extract alone exhibited both antiviral activities (intracellular and secreted antigens) and all fractions derived from this extract modulated NS1 production. Regarding the immunomodulatory effect, among the secreted factors, TNF-α was inhibited by NB3 and NB6; IL-6 was inhibited by NB1, NB3, and NB6; IL-10 by NB1 and NB3; and IFN-α by NB6. The crude extract (NB1) presented the best antiviral effect, whereas the dichloromethane fraction (NB3) presented an immunomodulatory effect in the inflammatory and anti-inflammatory cytokines. CONCLUSION: During in vitro DENV infection, N. brasiliensis Choisy exerts both antiviral and immunomodulatory effects that are likely associated, considering that less viral load may lead to less immunostimulation.