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1.
Viruses ; 13(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34452405

RESUMO

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.


Assuntos
Antivirais/uso terapêutico , Dengue/tratamento farmacológico , Transcriptoma , Adenosina Trifosfatases/antagonistas & inibidores , Antagonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/uso terapêutico , Antivirais/farmacologia , Encéfalo/metabolismo , Simulação por Computador , Dengue/sangue , Dengue/genética , Dengue/metabolismo , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Humanos , Fígado/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , NF-kappa B/metabolismo , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Dengue Grave/sangue , Dengue Grave/tratamento farmacológico , Dengue Grave/genética , Dengue Grave/metabolismo , Baço/metabolismo
2.
Sci Rep ; 10(1): 14923, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913345

RESUMO

The complement system may be crucial during dengue virus infection and progression to severe dengue. This study investigates the role of MBL2 genetic variants and levels of MBL in serum and complement proteins in Vietnamese dengue patients. MBL2 genotypes (- 550L/H, MBL2 codon 54), MBL2 diplotypes (XA/XO, YA/XO) and MBL2 haplotypes (LXPB, HXPA, XO) were associated with dengue in the study population. The levels of complement factors C2, C5, and C5a were higher in dengue and dengue with warning signs (DWS) patients compared to those in healthy controls, while factor D levels were decreased in dengue and DWS patients compared to the levels determined in healthy controls. C2 and C5a levels were associated with the levels of AST and ALT and with WBC counts. C9 levels were negatively correlated with ALT levels and WBC counts, and factor D levels were associated with AST and ALT levels and with platelet counts. In conclusions, MBL2 polymorphisms are associated with dengue in the Vietnamese study population. The levels of the complement proteins C2, C4b, C5, C5a, C9, factor D and factor I are modulated in dengue patients during the clinical course of dengue.


Assuntos
Biomarcadores/análise , Vírus da Dengue/isolamento & purificação , Fatores Imunológicos/sangue , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/genética , Polimorfismo Genético , Dengue Grave/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Complemento C2/análise , Complemento C5/análise , Complemento C5a/análise , Progressão da Doença , Feminino , Seguimentos , Regulação da Expressão Gênica , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Dengue Grave/sangue , Dengue Grave/genética , Dengue Grave/virologia , Índice de Gravidade de Doença , Vietnã/epidemiologia , Adulto Jovem
3.
PLoS One ; 15(8): e0237141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764789

RESUMO

Severe dengue can be lethal caused by manifestations such as severe bleeding, fluid accumulation and organ impairment. This study aimed to investigate the role of dengue non-structural 1 (NS1) protein and host factors contributing to severe dengue. Electrical cell-substrate impedance sensing system was used to investigate the changes in barrier function of microvascular endothelial cells treated NS1 protein and serum samples from patients with different disease severity. Cytokines and metabolites profiles were assessed using a multiplex cytokine assay and liquid chromatography mass spectrometry respectively. The findings showed that NS1 was able to induce the loss of barrier function in microvascular endothelium in a dose dependent manner, however, the level of NS1 in serum samples did not correlate with the extent of vascular leakage induced. Further assessment of host factors revealed that cytokines such as CCL2, CCL5, CCL20 and CXCL1, as well as adhesion molecule ICAM-1, that are involved in leukocytes infiltration were expressed higher in dengue patients in comparison to healthy individuals. In addition, metabolomics study revealed the presence of deregulated metabolites involved in the phospholipid metabolism pathway in patients with severe manifestations. In conclusion, disease severity in dengue virus infection did not correlate directly with NS1 level, but instead with host factors that are involved in the regulation of junctional integrity and phospholipid metabolism. However, as the studied population was relatively small in this study, these exploratory findings should be confirmed by expanding the sample size using an independent cohort to further establish the significance of this study.


Assuntos
Citocinas/sangue , Vírus da Dengue/imunologia , Interações Hospedeiro-Patógeno/imunologia , Dengue Grave/sangue , Proteínas não Estruturais Virais/sangue , Linhagem Celular , Citocinas/imunologia , Citocinas/metabolismo , Vírus da Dengue/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Fosfolipídeos/metabolismo , Cultura Primária de Células , Dengue Grave/imunologia , Dengue Grave/metabolismo , Dengue Grave/patologia , Proteínas não Estruturais Virais/imunologia
4.
Sci Rep ; 10(1): 11856, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678248

RESUMO

Dengue induces a spectrum of severity in humans from the milder dengue fever to severe disease, or dengue hemorrhagic fever (DHF). Chymase is a candidate biomarker that may aid dengue prognosis. This prospective study aimed to identify whether warning signs of severe dengue, including hypovolemia and fluid accumulation, were associated with elevated chymase. Serum chymase levels were quantified prospectively and longitudinally in hospitalized pediatric dengue patients in Sri Lanka. Warning signs were determined based on daily clinical assessments, laboratory tests and ultrasound findings. Chymase was significantly elevated during the acute phase of disease in DHF or Severe dengue, defined by either the 1997 or 2009 WHO diagnosis guidelines, and persisted longer in the most severe patients. Chymase levels were higher in patients with narrow pulse pressure and clinical warning signs such as severe leakage, fluid accumulation, pleural effusion, gall-bladder wall thickening and rapid haematocrit rise concurrent with thrombocytopenia. No association between chymase and liver enlargement was observed. This study confirms that serum chymase levels are associated with DHF/Severe dengue disease in hospitalized pediatric patients. Chymase levels correlate with warning signs of vascular dysfunction highlighting the possible functional role of chymase in vascular leakage during dengue.


Assuntos
Quimases/sangue , Vírus da Dengue/patogenicidade , Hipovolemia/diagnóstico , Derrame Pleural/diagnóstico , RNA Viral/sangue , Dengue Grave/diagnóstico , Trombocitopenia/diagnóstico , Biomarcadores/sangue , Criança , Pré-Escolar , Vírus da Dengue/genética , Vírus da Dengue/isolamento & purificação , Feminino , Hospitalização , Humanos , Hipovolemia/sangue , Hipovolemia/patologia , Hipovolemia/virologia , Estudos Longitudinais , Masculino , Derrame Pleural/sangue , Derrame Pleural/patologia , Derrame Pleural/virologia , Prognóstico , Estudos Prospectivos , Dengue Grave/sangue , Dengue Grave/patologia , Dengue Grave/virologia , Índice de Gravidade de Doença , Sri Lanka , Trombocitopenia/sangue , Trombocitopenia/patologia , Trombocitopenia/virologia , Carga Viral
5.
Arch Virol ; 165(9): 2029-2035, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32617762

RESUMO

Only a minority of dengue infections lead to plasma leakage (critical phase [CP]). Early identification of the risk for CP is helpful for triage of patients. This study aimed to identify early clinical predictors of CP that will aid in patient triage during early illness. A retrospective, case-record-based analysis was performed on all microbiologically confirmed (NS1-antigen- or dengue-IgM-antibody-positive), dengue patients (n = 697), admitted to our unit from 01.01.2017 to 30.06.2017. Bivariate analysis was performed to identify clinical and laboratory parameters that predicted CP. Stepwise multivariate logistic regression with backward elimination (p < 0.05) was used to identify independent risk factors for CP. CP developed in 226 (32.4%) patients. Mortality was 1.0%. Predictors for CP (p < 0.05) within the first three days included age category 41-50 years (OR = 1.96), females (OR = 2.09), diabetes (OR = 1.30), persistent vomiting (OR = 2.18), platelet count < 120,000/mm-3 (OR = 1.91) and AST > 60 IU/L (OR = 3.72). On multivariate analysis, other variables except diabetes remained significant. Elevated transaminase levels remained the strongest independent predictor of CP (OR 2.83). The absence of all five risk factors excluded CP (negative predictive value: 97.2%). Age 41-50 years, female gender, persistent vomiting, thrombocytopenia, and elevated transaminases were early predictors of CP in dengue fever. The absence of these can be used to identify patients who may not require hospital admission. Elevated transaminase was the strongest predictor of CP during early illness.


Assuntos
Vírus da Dengue/isolamento & purificação , Dengue Grave/virologia , Adolescente , Adulto , Idoso , Vírus da Dengue/classificação , Vírus da Dengue/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Retrospectivos , Dengue Grave/sangue , Dengue Grave/diagnóstico , Adulto Jovem
6.
BMC Med ; 18(1): 35, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32063229

RESUMO

BACKGROUND: Dengue infection can cause a wide spectrum of clinical outcomes. The severe clinical manifestations occur sufficiently late in the disease course, during day 4-6 of illness, to allow a window of opportunity for risk stratification. Markers of inflammation may be useful biomarkers. We investigated the value of C-reactive protein (CRP) measured early on illness days 1-3 to predict dengue disease outcome and the difference in CRP levels between dengue and other febrile illnesses (OFI). METHOD: We performed a nested case-control study using the clinical data and samples collected from the IDAMS-consortium multi-country study. This was a prospective multi-center observational study that enrolled almost 8000 participants presenting with a dengue-like illness to outpatient facilities in 8 countries across Asia and Latin America. Predefined severity definitions of severe and intermediate dengue were used as the primary outcomes. A total of 281 cases with severe/intermediate dengue were compared to 836 uncomplicated dengue patients as controls (ratio 1:3), and also 394 patients with OFI. RESULTS: In patients with confirmed dengue, median (interquartile range) of CRP level within the first 3 days was 30.2 mg/L (12.4-61.2 mg/L) (uncomplicated dengue, 28.6 (10.5-58.9); severe or intermediate dengue, 34.0 (17.4-71.8)). Higher CRP levels in the first 3 days of illness were associated with a higher risk of severe or intermediate outcome (OR 1.17, 95% CI 1.07-1.29), especially in children. Higher CRP levels, exceeding 30 mg/L, also associated with hospitalization (OR 1.37, 95% CI 1.14-1.64) and longer fever clearance time (HR 0.84, 95% CI 0.76-0.93), especially in adults. CRP levels in patients with dengue were higher than patients with potential viral infection but lower than patients with potential bacterial infection, resulting in a quadratic association between dengue diagnosis and CRP, with levels of approximately 30 mg/L associated with the highest risk of having dengue. CRP had a positive correlation with total white cell count and neutrophils and negative correlation with lymphocytes, but did not correlate with liver transaminases, albumin, or platelet nadir. CONCLUSIONS: In summary, CRP measured in the first 3 days of illness could be a useful biomarker for early dengue risk prediction and may assist differentiating dengue from other febrile illnesses.


Assuntos
Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Dengue Grave/diagnóstico , Adolescente , Adulto , Proteína C-Reativa/análise , Estudos de Casos e Controles , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Dengue Grave/sangue , Adulto Jovem
7.
Transfus Med ; 30(1): 46-50, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31854052

RESUMO

OBJECTIVE: The aim of this study was to assess abnormality of coagulation and anticoagulation parameters in dengue fever patients and the impact of these tests on the management of patients. BACKGROUND: Dengue fever is endemic in Pakistan with seasonal rise in cases. Morbidities and mortalities are proportionately reported to be increasing and associated with disseminated intravascular coagulation resulting in haemorrhagic or thrombotic manifestations in patients having deranged coagulation profiles. METHODS/MATERIALS: This observational and descriptive study was conducted on confirmed Dengue patients at the National Institute of Blood Diseases during the years 2013 to 2016. Patients of all age groups were included in this study. Results were analysed by SPSS version 23. RESULTS: A total of 200 patients were selected with the mean age being 28.68 years (±13.28) and male predominance (147/200). The mean platelet count, haemoglobin and haematocrit at base line for bleeders and non-bleeders showed significant results, where platelet count at baseline for bleeders was 24 000, whereas for non-bleeders it was 29 000 and it showed significant correlation with bleeding (P-value .027). Platelets were transfused to 76 (38%) patients. However, none of the specialised haemostasis parameters beside the platelet count correlated with bleeding, requiring platelet transfusions. CONCLUSION: Our study showed a significant association of platelet counts, haemoglobin and haematocrit with bleeding. It can be concluded that coagulation and anticoagulation profiles will not benefit the management of dengue patients and in countries like Pakistan, it will only add to the economic burden on the patients.


Assuntos
Coagulação Sanguínea , Coagulação Intravascular Disseminada , Hemorragia , Transfusão de Plaquetas , Dengue Grave , Adolescente , Adulto , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/epidemiologia , Coagulação Intravascular Disseminada/terapia , Feminino , Hemorragia/sangue , Hemorragia/epidemiologia , Hemorragia/terapia , Humanos , Masculino , Paquistão/epidemiologia , Dengue Grave/sangue , Dengue Grave/epidemiologia , Dengue Grave/terapia
8.
Rev Soc Bras Med Trop ; 52: e20180353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31778418

RESUMO

INTRODUCTION: Dengue is an important mosquito-borne disease in tropical and subtropical regions. Adhesion molecules have not been systematically characterized in the renal tissue of patients with severe dengue (SD). The objective of this study was to detect viral antigens in samples from patients that evolved with SD, correlating with the expression of ICAM-1, VCAM-1, VE-cadherin, and E-selectin to contribute to a better understanding of the pathophysiology of SD. METHODS: Kidney specimens from patients with SD were selected according to clinical and laboratorial data and submitted to histological and immunohistochemistry analysis. A semiquantitative evaluation was performed considering positive immunostaining in 20 glomeruli. RESULTS: Viral antigens were mainly detected in distal tubules. The intense immunostaining of VCAM-1 and ICAM-1 was observed. The expression of E-selectin was discrete, and VE-cadherin expression varied from mild to moderate. VCAM-1 was slightly intense in the glomerular capsule; the expression of ICAM-1 was diffuse. E-selectin was diffuse, and VE-cadherin varied from mild to moderate. The most frequent histological findings were glomerular congestion, mild glomerulitis, acute renal injury, and glomerular atrophy. CONCLUSIONS: The results appear to demonstrate an imbalance between vascular endothelial permeability regulating events in renal lesions in SD. The increase in the expression of ICAM-1 and VCAM-1 is an in-situ indicator of higher permeability with a consequent influx of cells favoring the inflammation of the endothelium. These molecules are important in the pathophysiology of the disease and provide the possibility of developing new markers for the evaluation, clinical follow-up, and therapeutic response of patients with SD.


Assuntos
Selectina E/fisiologia , Endotélio/fisiopatologia , Molécula 1 de Adesão Intercelular/fisiologia , Dengue Grave/sangue , Dengue Grave/fisiopatologia , Molécula 1 de Adesão de Célula Vascular/fisiologia , Adolescente , Adulto , Antígenos CD/sangue , Antígenos CD/fisiologia , Antígenos Virais/sangue , Biomarcadores/sangue , Caderinas/sangue , Caderinas/fisiologia , Criança , Pré-Escolar , Progressão da Doença , Selectina E/sangue , Feminino , Humanos , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Regulação para Cima , Molécula 1 de Adesão de Célula Vascular/sangue , Adulto Jovem
9.
PLoS One ; 14(10): e0219117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31665142

RESUMO

Dengue infection (DI) is the most important arboviral infection in the world. The majority of immunocompetent patients will have asymptomatic or mild infections, but the degree of dengue severity in kidney transplant recipients (KTx) is unknown. In this study, we report the clinical profile and outcomes of 39 dengue cases in KTx. From a total of 1,186 KTx outpatients in follow-up we reviewed clinical and laboratory records of 60 (5%) patients admitted with suspected DI initially screened by NS-1, IgM, and when possible, multiplex nested PCR. The prevalence of DI in KTx was 3% (39/1,118), with symptoms leading to hospital admission being fever, myalgia, malaise, and headache. Laboratory tests showed leucopenia, thrombocytopenia, and liver enzyme elevation. DI was confirmed by positivity of NS-1 (33%), IgM (69%), and/or RT-PCR (59%). Twenty-three patients (59%) had dengue with warning signs, and 15% had severe dengue, 2 of them with a fatal course. Acute graft dysfunction occurred in 59% (mean nadir serum creatinine: 2.9 ± 2.6mg/dL), 4 of them requiring dialysis. CMV coinfection diagnosed in 19% of the cases and patients was associated with worse clinical presentation. Our results suggest that KTx with DI presented initial physical and laboratorial profile similar to the general population. However, DI in KTx seems to have a higher risk for graft dysfunction, severe dengue, and death. Because CMV coinfection aggravates the DI clinical presentation and recovery, it must be evaluated in all cases.


Assuntos
Anticorpos Antivirais/sangue , Infecções por Citomegalovirus/sangue , Citomegalovirus , Vírus da Dengue , Imunoglobulina M/sangue , Transplante de Rim , Dengue Grave/sangue , Adulto , Coinfecção , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Dengue Grave/epidemiologia , Dengue Grave/terapia
10.
BMC Res Notes ; 12(1): 604, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547852

RESUMO

OBJECTIVE: Objective of the study is to evaluate the on-admission day symptoms and signs, clinical, hematological parameters and liver transaminases of the dengue NS1 positive patients who got admitted on different clinical phases [Febrile phase (day 1-3) and Critical phase(day 4-5)] of dengue at medical wards of Jaffna Teaching Hospital. RESULTS: Blood samples were collected from 150 suspected dengue patients from day 1 to 5 of the illness. Seventy-eight patients were positive for dengue NS1, according to the WHO proposed dengue clinical phase framework 37 patients were from febrile phase and 41 patients from critical phase. Patients who admitted on critical phase framework suffered from leukopenia and thrombocytopenia. Nine patients had the evidence of leakage with fever and the leakers had significant rise in hemoglobin, hematocrit and liver transaminase levels which are considered as severe form of the disease.


Assuntos
Vírus da Dengue/patogenicidade , Febre/diagnóstico , Hospitais de Ensino , Leucopenia/diagnóstico , Dengue Grave/diagnóstico , Trombocitopenia/diagnóstico , Proteínas não Estruturais Virais/sangue , Adolescente , Adulto , Vírus da Dengue/imunologia , Progressão da Doença , Feminino , Febre/sangue , Febre/imunologia , Febre/virologia , Hospitalização , Humanos , Leucopenia/sangue , Leucopenia/imunologia , Leucopenia/virologia , Fígado/patologia , Fígado/virologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Dengue Grave/sangue , Dengue Grave/imunologia , Dengue Grave/virologia , Sri Lanka , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombocitopenia/virologia , Transaminases/sangue , Proteínas não Estruturais Virais/imunologia
11.
Viruses ; 11(9)2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505806

RESUMO

Hantavirus and dengue virus (DENV) infections are caused by RNA viruses which infect immune systems' cells including monocytes, macrophages and dendritic cells and occur year-round in Barbados. A retrospective serological study (2008-2015) was conducted on hantavirus and dengue patient sera confirmed by IgM and IgG ELISA, NS1 and RT-PCR using Limulus amoebocyte lysate (LAL) kinetic turbidimetric method to determine serum endotoxin levels. Hantavirus patients were categorized into two groups, namely (a) hospitalized and (b) non-hospitalized. Dengue patients were categorized into 3 groups using 2009 WHO dengue guidelines (a) severe dengue (SD), (b) hospitalized non-severe dengue (non-SD) and (c) non-hospitalized non-SD. Statistical analyses were conducted to determine the association of endotoxin levels with hantavirus disease severity based on hospitalization and dengue disease severity. Serum endotoxin levels are associated with hantavirus disease severity and hospitalization and dengue disease severity (p < 0.01). Similar studies have found an association of serum endotoxin levels with dengue disease severity but never with hantavirus infection. Co-detection of hantavirus- and DENV-specific IgM in some patients were observed with elevated serum endotoxin levels. In addition, previous studies observed hantavirus replication in the gut of patients, gastrointestinal tract as a possible entry route of infection and evidence of microbial translocation and its impact on hantavirus disease severity. A significant correlation of serum endotoxin and hantavirus disease severity and hospitalization in hantavirus infected patients is reported for the first time ever. In addition, serum endotoxin levels correlated with dengue disease severity. This study adds further support to the role of endotoxin in both hantavirus and dengue virus infection and disease severity and its role as a possible therapeutic target for viral haemorrhagic fevers (VHFs).


Assuntos
Dengue/sangue , Infecções por Hantavirus/sangue , Lipopolissacarídeos/sangue , Índice de Gravidade de Doença , Anticorpos Antivirais/sangue , Barbados/epidemiologia , Coinfecção/epidemiologia , Coinfecção/imunologia , Coinfecção/virologia , Dengue/epidemiologia , Dengue/imunologia , Vírus da Dengue , Ensaio de Imunoadsorção Enzimática , Feminino , Hantavirus , Infecções por Hantavirus/epidemiologia , Infecções por Hantavirus/imunologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Estudos Retrospectivos , Testes Sorológicos , Dengue Grave/sangue , Dengue Grave/genética
12.
BMC Infect Dis ; 19(1): 680, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370795

RESUMO

BACKGROUND: A major challenge in dengue management in resource limited settings is the confirmation of diagnosis. Clinical features of dengue often overlap with other infections and molecular diagnostic tools are not readily accessible to clinicians at hospitals. In addition, the prediction of plasma leakage in dengue is also difficult. Hematocrit level and ultrasound scans (combined with clinical parameters) are helpful to detect plasma leakage once it has happened, not before. METHODS: Colombo Dengue Study (CDS) is a prospective cohort study of clinically suspected adult dengue patients recruited from the National hospital of Sri Lanka (within the first 3 days of fever) that aimed to a) identify clinical and basic laboratory test parameters to differentiate dengue from non-dengue fever, b) evaluate the comparative efficacy of loop-mediated isothermal amplification (LAMP) for dengue diagnosis (vs. NS1 antigen test and RT-qPCR) and c) identify early associations that are predictive of plasma leakage or severe dengue. The basic laboratory tests considered here included hematological parameters, serum biochemistry and inflammatory markers. RESULTS: Only 70% of clinically suspected patients were confirmed as having dengue by either the NS1 antigen test or RT-qPCR. On a Bayesian latent class model which assumes no "gold standard", LAMP performed equally or better than RT-qPCR and NS1 antigen test respectively. When confirmed dengue patients were compared with others, the earlier group had significantly lower lymphocyte counts and higher aspartate aminotransferase levels (AST) within the first 3 days of fever. Confirmed dengue patients with plasma leakage had a lower mean age and a higher median baseline AST level compared to those without plasma leakage (p < 0.05). CONCLUSION: Clinical suspicion overestimates the true number of dengue patients. RT-LAMP is a potentially useful low-cost diagnostic tool for dengue diagnosis. Confirmed dengue patients had significantly higher AST levels and lower lymphocyte counts in early disease compared to others. In confirmed dengue patients, younger age and a higher AST level in early infection were associated with subsequent plasma leakage.


Assuntos
Aspartato Aminotransferases/sangue , Técnicas de Amplificação de Ácido Nucleico/métodos , Dengue Grave/diagnóstico , Dengue Grave/etiologia , Adulto , Teorema de Bayes , Biomarcadores/sangue , Estudos de Coortes , Dengue/diagnóstico , Vírus da Dengue/genética , Feminino , Febre/virologia , Humanos , Testes Imunológicos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Medição de Risco , Sensibilidade e Especificidade , Dengue Grave/sangue , Sri Lanka
13.
Clin Exp Immunol ; 198(2): 251-260, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31260079

RESUMO

Global incidence of dengue has drastically increased in the last few years. Despite the global morbidity and mortality associated with dengue infection, mechanisms of immune control and viral pathogenesis are poorly explored. Pancytopenias, along with increased oxidative stress, are salient clinical findings in severe dengue patients. Previously, we demonstrated significant differences of circulating immune complexes (CICs) among severe and non-severe dengue patients. Accordingly, here we sought to determine the contributory role of affinity-purified antibody-bound CICs in dengue severity. To characterize intracellular oxidative stress induced by antibody-bound CICs, 5-(and-6)-chloromethyl-2'-7'-dichlorodihydrofluorescein diacetate (DCFDA) was measured by flow cytometry. At the same time, CICs sensitized healthy red blood cells (RBC) and patients' RBC morphology was determined by scanning electron microscopy and flow cytometry analysis. Erythrophagocytosis and ferritin levels were further determined in severe and non-severe dengue patients. Our results showed that the severe patients had high titres of immunoglobulin (Ig)M-bound CICs (P < 0·0001) in their sera, increased intracellular oxidative stress (P < 0·0001), high ferritin levels (P < 0·0001), altered morphology of RBC and finally enhanced erythrophagocytosis. This study shows for the first time that RBC morphology is altered in severe dengue patients. Taken together, this study suggests that the enhanced IgM-bound CICs could contribute to the increased oxidative stress and act directly on RBC destruction of severe dengue patients, and is an important pathophysiological determinant. Hence, IgM-bound CICs can serve as an important laboratory parameter to monitor dengue infection progression.


Assuntos
Complexo Antígeno-Anticorpo , Eritrócitos , Imunoglobulina M , Estresse Oxidativo/imunologia , Dengue Grave , Adulto , Complexo Antígeno-Anticorpo/sangue , Complexo Antígeno-Anticorpo/imunologia , Eritrócitos/imunologia , Eritrócitos/metabolismo , Eritrócitos/patologia , Humanos , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Dengue Grave/sangue , Dengue Grave/imunologia , Dengue Grave/patologia , Índice de Gravidade de Doença
14.
Rev Med Virol ; 29(5): e2056, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31172625

RESUMO

Dengue virus is known to modulate host cell lipid metabolism in order to promote efficient viral replication. Recent studies have focused on circulating lipids as potential biomarkers of dengue severity; however, the results obtained so far lack the consistency to establish a definite relationship between the two. Therefore, in the present study, we investigated serum lipids as potential biomarkers of dengue severity by conducting a meta-analysis of the currently available clinical data. Nine studies that evaluated 1,953 patients were included in the review, many of which were cross-sectional (44.4%) and conducted in Asian countries (55.5%). These studies observed the presence of lipids in serum samples (77%) of patients in the acute phase of the disease (88.8%). Circulating total-cholesterol (P = .001) and LDL (P = .001) levels, but not HDL (P = .07), VLDL (P = .9) and triglyceride (P = .57) levels, were inversely and significantly correlated with dengue severity. Total cholesterol (P ≤ .001) and LDL (P = .001) were also useful in determining the risk of hypovolemic shock in patients with severe dengue. Subgroup analysis showed that factors, such as design (cross-sectional vs cohort), racial-ethnic differences (Asian vs Latin Americans), and age range (children vs adult) influenced the correlation and also contributed to the high level of heterogeneity in the studies. Our meta-analysis demonstrates that total-cholesterol and LDL-cholesterol levels should be explored as routine laboratory markers for dengue severity, as they will help in employing an appropriate patient therapy, and thus optimize the use of available resources.


Assuntos
Biomarcadores , Dengue/sangue , Dengue/diagnóstico , Lipídeos/sangue , Humanos , Prognóstico , Viés de Publicação , Dengue Grave/sangue , Dengue Grave/diagnóstico , Índice de Gravidade de Doença
15.
BMC Pediatr ; 19(1): 87, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935373

RESUMO

BACKGROUND: Series of biochemical and haematological changes occur during the course of dengue infection, which vary depending on the clinical disease. The patterns of change are not well documented and identifying these patterns in children with dengue infection would help to anticipate the progression to different clinical stages thus enabling effective management. METHODS: A prospective follow up study was conducted during the period of July 2013 - April 2014 at Professorial Pediatric unit, Lady Ridgeway Hospital for Children, Colombo, Sri Lanka. Children (5-12 years) admitted within the first 84 h of fever, with a clinical diagnosis of dengue infection were recruited. Children who became positive for dengue IgM were included in the final analysis. Blood was collected on admission for complete blood count, Alanine aminotransferase, Aspartate aminotransferase, albumin, cholesterol and corrected calcium. These tests were repeated at 12 hourly intervals during the hospital stay. RESULTS: Data of 130-subjects were analyzed (Dengue fever /Dengue hemorrhagic fever: 100/30). There was a significant difference in the pattern of white cell counts, platelets and haematocrit in the two clinical groups. Both transaminase rose initially in both dengue fever and dengue hemorrhagic fever and a steep rise were seen between 8th and 9th days in hemorrhagic fever. Both albumin and cholesterol decreased significantly at the time of entering into the critical phase. According to Receiver operating characteristic curve analysis, albumin level crossing 37.5g/L (sensitivity 86.7%, specificity 77.8%) and a 0.38 mmol/L reduction in cholesterol level (sensitivity 77.3%, specificity 71.9%) between day 3 and 4 were the best predictors of entering into critical phase. Calcium levels did not show any distinct pattern. CONCLUSIONS: There is a clear difference in the pattern of change of both hematological and biochemical parameters in dengue fever and dengue hemorrhagic fever. Reduction in albumin and cholesterol levels seen between the completion of day 3 and day 4 were highly valid predictors of entering into critical phase in dengue hemorrhagic fever.


Assuntos
Colesterol/sangue , Dengue/sangue , Albumina Sérica , Dengue Grave/sangue , Transaminases/sangue , Contagem de Células Sanguíneas , Cálcio/sangue , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Humanos , Testes de Função Hepática , Masculino , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade , Sri Lanka
16.
Transfus Med Rev ; 33(1): 35-42, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30471867

RESUMO

The presence of antibodies to Zika virus (ZIKV) and dengue virus (DENV) can be detected in blood donations. Donation-based surveillance provides an alternative strategy to estimate population prevalence by detecting antibodies that are circulating. To estimate population prevalence, we conducted a systematic review of literature on the seroprevalence of ZIKV and DENV antibodies in blood donations. We searched PubMed and Web of Science for studies that reported the seroprevalence of ZIKV and DENV in blood donations. The title and abstract of each study were screened by 2 reviewers simultaneously for possible inclusion, and the full text of selected studies was reviewed to ensure that they met inclusion criteria (used primary data collection, reported evidence of immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies in the blood supply, and included a representative sample of the total population). Immunoglobin test measuring levels of antibodies to IgM and IgG and number of positive cases were extracted from each study. No exclusions were made based on language or country. Our initial search identified 1890 studies after excluding duplicates, of which 76 were assessed for full text eligibility to ensure that they met our final inclusion criteria. There were 14 studies included in our review; 11 examined the seroprevalence of DENV, and 3 examined ZIKV. The highest seroprevalence by IgM was 2.82% for DENV and 0.53% for ZIKV. Our results indicate that the seroprevalence of ZIKV and DENV antibody presence in countries with active transmission is higher than reports by traditional surveillance in some countries. This finding is expected due to the large percentage of asymptomatic cases. The highest seroprevalence was observed for IgG, which can persist over long periods of time compared to IgM. Screening of blood donations may help supplement traditional surveillance measures, especially during outbreak settings.


Assuntos
Doadores de Sangue , Transfusão de Sangue , Estudos Soroepidemiológicos , Dengue Grave/sangue , Dengue Grave/epidemiologia , Infecção por Zika virus/sangue , Infecção por Zika virus/epidemiologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Prevalência
17.
Rev. Soc. Bras. Med. Trop ; 52: e20180353, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1057248

RESUMO

Abstract INTRODUCTION: Dengue is an important mosquito-borne disease in tropical and subtropical regions. Adhesion molecules have not been systematically characterized in the renal tissue of patients with severe dengue (SD). The objective of this study was to detect viral antigens in samples from patients that evolved with SD, correlating with the expression of ICAM-1, VCAM-1, VE-cadherin, and E-selectin to contribute to a better understanding of the pathophysiology of SD. METHODS: Kidney specimens from patients with SD were selected according to clinical and laboratorial data and submitted to histological and immunohistochemistry analysis. A semiquantitative evaluation was performed considering positive immunostaining in 20 glomeruli. RESULTS: Viral antigens were mainly detected in distal tubules. The intense immunostaining of VCAM-1 and ICAM-1 was observed. The expression of E-selectin was discrete, and VE-cadherin expression varied from mild to moderate. VCAM-1 was slightly intense in the glomerular capsule; the expression of ICAM-1 was diffuse. E-selectin was diffuse, and VE-cadherin varied from mild to moderate. The most frequent histological findings were glomerular congestion, mild glomerulitis, acute renal injury, and glomerular atrophy. CONCLUSIONS: The results appear to demonstrate an imbalance between vascular endothelial permeability regulating events in renal lesions in SD. The increase in the expression of ICAM-1 and VCAM-1 is an in-situ indicator of higher permeability with a consequent influx of cells favoring the inflammation of the endothelium. These molecules are important in the pathophysiology of the disease and provide the possibility of developing new markers for the evaluation, clinical follow-up, and therapeutic response of patients with SD.


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Adulto Jovem , Molécula 1 de Adesão Intercelular/fisiologia , Molécula 1 de Adesão de Célula Vascular/fisiologia , Selectina E/fisiologia , Dengue Grave/fisiopatologia , Dengue Grave/sangue , Endotélio/fisiopatologia , Imuno-Histoquímica , Biomarcadores/sangue , Antígenos CD/fisiologia , Antígenos CD/sangue , Caderinas/fisiologia , Caderinas/sangue , Regulação para Cima , Molécula 1 de Adesão Intercelular/sangue , Progressão da Doença , Molécula 1 de Adesão de Célula Vascular/sangue , Selectina E/sangue , Pessoa de Meia-Idade , Antígenos Virais/sangue
18.
Acta Med Indones ; 50(3): 183-184, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30333266

RESUMO

Dengue viral infection remains a major public health problem. As many as 400 million people are infected yearly. Even though the vaccine is available, the use of dengue vaccine is still limited due to some concerns. Among patient infected with dengue viral infection, early recognition of the virus and prompt supportive treatment are important to avoid complication and mortality.The clinical spectrum of dengue viral infection is diverse ranging from undifferentiated fever to dengue shock syndrome characterized by plasma leak and hemoconcentration. No specific antiviral therapy is available. Therefore, anticipation of complication should be performed adequately.The most dangerous complication of dengue infection is shock syndrome. Hypothetically the occurrence of shock is a result of secondary viral infection. The manifestation of increased vascular permeability and low intravascular volume lead to the development of shock. In addition to that, another complex mechanism underlies the occurrence of shock such as endothelial dysfunction that could happened abruptly. No specific method exists to identify this condition as early as possible.During dengue infection, fever can be last between 2 and 7 days. The localized plasma leakage could happen and manifested as a pleural effusion fluid accumulation in abdominal cavity or hemoconcentration. This will only last for 48 hours and will be resolved later spontaneously. Severity of leakage varies among patients and the unanticipated of leakage due to failure to recognize and treat this manifestation related to mortality.Most of the fatal cases of dengue are related to late detection of the illness as shown by massive hemorrhage and severe intravascular volume depletion. The role of dendritic cells is as the initiator of immune response that facilitate virus uptake. On the other hand, the non-neutralize cross reactive antibodies will increase virus uptake and resulted in more viral replication. Some studies showed higher NS1 protein were found in patients with more severe disease. In addition to that antibody to NS1 could bind to the endothelial cells and lead to apoptosis of these cells. Both host and viral factors contribute to the severity of the illness.One of the important factors for dengue viral infection is the capacity of clinicians to identify the risk factors for shock. Studies reported that female, infants, elderly, patients with concomitant diseases are prone to have more severe infection. Virus serotype and genetic susceptibility may also contribute but the evidence is still limited. So, those are not sensitive enough be used in clinical setting.Besides those, after the diagnosis of with dengue infection based on WHO criteria and confirmation by serology detection or viral material in the blood, no specific sign and symptoms are available to determine any potential severity. There were studies performed to monitor the plasma leakage using mean arterial blood pressure (MAP) instead of hematocrit values. Rapid intervention can be administered by monitoring MAP to avoid deleterious consequences.The classification of WHO 1997 or 2009 were not able to detect the plasma leakage earlier. Nainggolan et al presented the resulted of their observation among early dengue infection which was the occurrence of gallbladder wall thickening as a manifestation of plasma leakage. Ultrasonographic measurement is valuable and applicable to detect plasma leakage in earlier phase with positive likelihood ratio 2.14 (95% CI 1.12 - 4.12). Similar report from Indonesia also showed the role of ultrasonography in dengue.


Assuntos
Diagnóstico Precoce , Hemorragia/diagnóstico , Dengue Grave/sangue , Dengue/diagnóstico , Dengue/etiologia , Vírus da Dengue/patogenicidade , Hemorragia/etiologia , Hemorragia/virologia , Humanos , Indonésia , Plasma , Dengue Grave/diagnóstico , Índice de Gravidade de Doença , Ultrassonografia
19.
Br J Nutr ; 120(7): 787-796, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30105961

RESUMO

PUFA might modulate inflammatory responses involved in the development of severe dengue. We aimed to examine whether serum PUFA concentrations in patients diagnosed with dengue fever (DF) were related to the risk of progression to dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). A secondary aim was to assess correlations between fatty acids (FA) and inflammatory biomarkers in patients with DF. We conducted a prospective case-control study nested within a cohort of patients who were diagnosed with DF and followed during the acute episode. We compared the distribution of individual FA (% of total FA) at onset of fever between 109 cases who progressed to DHF/DSS and 235 DF non-progressing controls using unconditional logistic regression. We estimated correlations between baseline FA and cytokine concentrations and compared FA concentrations between the acute episode and >1 year post-convalescence in a subgroup. DHA was positively related to progression to DHF/DSS (multivariable adjusted OR (AOR) for DHA in quintile 5 v. 1=5·34, 95 % CI 2·03, 14·1; P trend=0·007). Dihomo-γ-linolenic acid (DGLA) was inversely associated with progression (AOR for quintile 5 v. 1=0·30, 95 % CI 0·13, 0·69; P trend=0·007). Pentadecanoic acid concentrations were inversely related to DHF/DSS. Correlations of PUFA with cytokines at baseline were low. PUFA were lower during the acute episode than in a disease-free period. In conclusion, serum DHA in patients with DF predicts higher odds of progression to DHF/DSS whereas DGLA and pentadecanoic acid predict lower odds.


Assuntos
Ácidos Graxos/sangue , Febres Hemorrágicas Virais/sangue , Dengue Grave/sangue , Ácido 8,11,14-Eicosatrienoico/sangue , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Citocinas/sangue , Dengue , Progressão da Doença , Ácidos Docosa-Hexaenoicos/sangue , Feminino , Febre , Humanos , Inflamação/sangue , Modelos Logísticos , Masculino , Estado Nutricional , Razão de Chances , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
20.
Sci Rep ; 8(1): 11826, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087415

RESUMO

Dengue fever is a viral condition that has become a recurrent issue for public health in tropical countries, common endemic areas. Although viral structure and composition have been widely studied, the infection phenotype in terms of small molecules remains poorly established. This contribution providing a comprehensive overview of the metabolic implications of the virus-host interaction using a lipidomic-based approach through direct-infusion high-resolution mass spectrometry. Our results provide further evidence that lipids are part of both the immune response upon Dengue virus infection and viral infection maintenance mechanism in the organism. Furthermore, the species described herein provide evidence that such lipids may be part of the mechanism that leads to blood-related complications such as hemorrhagic fever, the severe form of the disease.


Assuntos
Vírus da Dengue/imunologia , Dengue/imunologia , Lipídeos/imunologia , Dengue Grave/imunologia , Adulto , Dengue/sangue , Dengue/virologia , Vírus da Dengue/fisiologia , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Metabolismo dos Lipídeos/imunologia , Lipídeos/sangue , Masculino , Espectrometria de Massas/métodos , Metabolômica/métodos , Fator de Ativação de Plaquetas/imunologia , Fator de Ativação de Plaquetas/metabolismo , Análise de Componente Principal , Dengue Grave/sangue , Dengue Grave/virologia
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