Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A dengue à a arbovirose mais importante no mundo, causando mais de 100 milhÃes de casos de dengue clÃssico (DC) e mais de 250 mil casos de febre hemorrÃgica da dengue (FHD), anualmente. A infecÃÃo com o vÃrus dengue (DENV), famÃlia Flaviviridae, causa um amplo espectro de manifestaÃÃes clÃnicas que variam desde formas assintomÃticas a quadros graves, potencialmente fatais, como os casos hemorrÃgicos e/ou de choque hipovolÃmico. Na maioria das vezes, a doenÃa se apresenta com sintomas inespecÃficos. Dessa forma, torna-se difÃcil diferenciar a dengue de outros casos febris de natureza infecciosa como leptospirose, febre amarela e outras arboviroses, apenas com base nas manifestaÃÃes clÃnicas iniciais. Diante disso, o objetivo deste estudo foi identificar a etiologia de 82 pacientes com quadro clÃnico semelhante ao de dengue e com resultado negativo no isolamento viral (IV) para o DENV. O IV foi realizado pelo LaboratÃrio Central de SaÃde PÃblica do Cearà (LACEN-CE), em 2008. Neste estudo, as amostras desses pacientes foram avaliadas para dengue por meio da detecÃÃo de anticorpos especÃficos contra o vÃrus pela tÃcnica de IgM-ELISA (PanBio DiagnosticsÂ) e pela reaÃÃo em cadeia da polimerase apÃs transcriÃÃo reversa (RT-PCR). As amostras negativas para dengue foram testadas para a detecÃÃo de anticorpos IgM especÃficos contra bactÃrias do gÃnero Leptospira por ELISA (PanBio DiagnosticsÂ). Foram testadas tambÃm amostras de 73 pacientes quanto a infecÃÃo por hantavirus, atravÃs da detecÃÃo de anticorpos especÃficos (IgM e IgG) contra antÃgenos de hantavÃrus e RT-PCR. Trinta e cinco pacientes (35/82; 42,68%) foram positivos para dengue, sendo que destes, todos foram positivos no IgM-ELISA e 4 foram positivos tambÃm no RT-PCR. Das 47 amostras dengue-negativas, apenas 43 foram testadas para infecÃÃo por Leptospira devido ao volume insuficiente das amostras. Seis pacientes (6/82; 7,32%) foram positivos IgM-ELISA para leptospirose. TrÃs pacientes foram positivos para hantavÃrus, entretanto apenas 1 (1/82; 1,22%) foi positivo no IgM-ELISA e 2, no IgG-ELISA. A infecÃÃo dos 35 (42,68%) pacientes negativos em todos os testes de detecÃÃo de infecÃÃo aguda foi classficada como sÃndrome febril indiferenciada (SFI). Esta à a primeira evidÃncia de infecÃÃo por hantavÃrus no Estado do CearÃ. Essas doenÃas podem causar infecÃÃo clinicamente indistinguÃvel da dengue e, portanto, deveriam ser incluÃdas no diagnÃstico diferencial no contexto dessas sÃndromes febris. / Dengue is the most important arborvirosis in the world, causing approximately 100 millions cases of classical dengue fever (DF) and more than 250.000 of dengue hemorrhagic fever (DHF), annually. The dengue virus (DENV) belongs to the Flaviviridae family and its infection causes a wide clinical spectrum ranging from assymptomatic forms to severe manifestations, potentially fatal, as in hemorrhagic forms or dengue shock syndrome (DSS). Most of times the disease presents inespecific symptoms. Thus, DF is difficult to distinguish from other acute febrile illnesses, including arboviral ones and leptospirosis, based only on clinical criteria. Given this, the aim of this study was to identify the etiology of 82 patients with clinical picture of dengue-like illness, negative in DENV isolation. The virus isolation was done in Laboratorio Central de SaÃde PÃblica do Cearà (LACEN-CE), Brazil, in 2008. In the present study, the serum samples from these patients were evaluated for dengue infection by IgM-ELISA (PanBio DiagnosticsÂ) and RT-PCR, following Lanciotti et alli protocol (1992). Negative samples to dengue infection were tested to leptospirosis by IgM-ELISA (PanBio DiagnosticsÂ). Seventy-three patients were also tested for hantavirus infection by IgM and IgG by ELISA and RT-PCR. Dengue infection was diagnosed in 35 patients (35/82; 42.68%) of which all were positive in IgM-ELISA, and 4 were also positive in RT-PCR. Of 47 (47/82; 57.32%) DENV-negative samples, only 43 were tested to evaluate lesptospiral infection because of insufficient sample volume. Six patients (6/82; 7,32%) were positive to leptospirosis in the IgM-ELISA. Three patients were positives to hantavirus infection, but only 1 (1/82; 1,22%) was positive in the IgM-ELISA and the two others, in the IgG-ELISA. Thirty and five patients (35/82; 42,68%) remained negative em all tests. They were classified as having other febril illness (OFI). To the best of our knowledge, this is the first evidence of hantavirus infection in humans in the state of CearÃ, Brazil. These diseases, including leptospirosis, may cause infection clinically indistinguishable from DF and therefore should be included in the differential diagnosis of febrile illnesses in this setting.

Orientador : Yuri Dimitrov Bozhkov / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Matematica Estatistica e Computação Cientifica / Made available in DSpace on 2018-08-03T22:37:42Z (GMT). No. of bitstreams: 1 Maidana_NorbertoAnibal_D.pdf: 2126127 bytes, checksum: 48ca33a840223ab2f9cb278dcf6afbd2 (MD5) Previous issue date: 2004 / Doutorado / Doutor em Matemática

Made available in DSpace on 2014-06-12T18:28:39Z (GMT). No. of bitstreams: 2 arquivo1132_1.pdf: 904466 bytes, checksum: 86e274a6fb9961122435e3a3629b7199 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2010 / A dengue é uma arbovirose causada por um flavivírus e sua incidência tem aumentado nas últimas décadas, constituindo um grave problema de saúde pública mundial. Em muitos países acomete principalmente crianças, e no Sudeste da Ásia, é uma das principais causas de hospitalização e morte infantil. No Brasil, a dengue se tornou endêmica e observa-se uma mudança na distribuição etária, com aumento da incidência em menores de 15 anos e o predomínio das formas graves da doença. O presente trabalho foi realizado com o objetivo de descrever as principais manifestações clínicas e alterações laboratoriais em crianças menores de 15 anos com dengue internadas no Hospital Lauro Wanderley em João Pessoa, no período de 2007-2009. Foram estudados 136 casos de dengue, utilizando formulários padronizados, preenchidos retrospectivamente a partir das informações contidas nos prontuários dos anos de 2007 e 2008, e prospectivamente durante o acompanhamento dos pacientes em 2009. A distribuição de idade nos 136 pacientes foi de 3 a 12 anos, havendo predomínio do sexo masculino. O tempo médio de internação foi de cinco dias. Os sintomas mais observados foram febre, vômitos, cefaléia, exantema e mialgia. A prova do laço foi realizada em 30 pacientes, sendo positiva em 16 pacientes, e a presença de petéquias foi o sangramento espontâneo mais comum. Entre os sinais de alarme, a dor abdominal foi relatada em 94 pacientes. Das alterações radiológicas, o derrame pleural à direita foi o achado mais frequente e as principais alterações ultrassonográficas foram ascite, derrame pleural e espessamento da vesícula biliar. A Febre Hemorrágica da Dengue foi a forma clínica predominante, mostrando a necessidade de estudos na faixa etária pediátrica e o conhecimento das manifestações mais comuns pelos médicos, evitando a evolução desfavorável da doença

Made available in DSpace on 2014-06-12T23:13:30Z (GMT). No. of bitstreams: 2 arquivo2935_1.pdf: 3041297 bytes, checksum: e1b3b767950f407a70071937d040ae71 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2011 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Neste trabalho, nós descrevemos a preparação e caracterização de um novo compósito híbrido de nanopartículas de ouro-polianilina (AuNpPANI) com grupos terminais SH que, devido a sua habilidade de imobilizar primers específicos para os sorotipos de dengue 1, 2 e 3 (ST1, ST2 e ST3), pode ser utilizado para o desenvolvimento de biossensores. Espectroscopia de impedância eletroquímica (EIE) na faixa de freqüência de 100 mHz a 100 KHz e voltametria cíclica (VC) na faixa de varredura -0,2 a 0,7 V foram realizadas na presença da mistura de 10 mM K3[Fe(CN)6]4-/K4[Fe(CN)6]3- (1:1), utilizada como par redox. Resultados de CV e EIS demonstraram que o AuNpPANI foi capaz de imobilizar ST1, ST2 e ST3, formando os complexos AuNpPANI-ST. As imagens de MEV mostraram a presença de aglomerados AuNpPANI quando a seqüência genômica DEN1 (alvo complementar) é hibridizada com o ST1 da dengue. Voltamogramas cíclicos bem definidos característicos de um processo redox de difusão limitada foram observados no eletrodo de ouro limpo e após este ter sido modificado pela adsorção de AuNpPANI ou AuNpPANI-ST. Em adição, foi observado um notável decréscimo nos picos anódico e catódico. O sistema AuNpPANI-ST(1-3) exibiu uma resposta altamente seletiva para o alvo complementar da dengue e pode ser utilizado para a construção de um biossensor para sorotipos da dengue. O sistema AuNpPANI-ST(1-3) foi capaz de reconhecer o sorotipo da dengue de diferentes pacientes em concentrações de picomolar. Os resultados VC e EIE mostraram evidência inequívoca da interação existente entre os primers específicos para os sorotipos de dengue estudados e o DNA genômico complementar utilizando pequenos volumes e baixas concentrações do analito

Objective: To assess the presence of Dengue, Chikungunya, and Zika in serum samples of patients with acute febrile illness in Piura, Peru and describe the most common clinical features. Results: Dengue was the most common arbovirus detected in 170/496 (34.3%), followed by Zika in 39/496 (7.9%) and Chikungunya in 23/496 (4.6%). Among the 170 samples positive for Dengue, serotype 2 was the most predominant type present in 97/170 (57.1%) of samples, followed by the serotype 3 in 9/170 (5.3%). Headaches, muscle pain, and joint pain were the most common symptoms associated with fever in patients with Dengue and Zika. No symptoms predominance was observed in patients with Chikungunya.Dengue is considered the most frequent arbovirus in Peru and the number of cases has increased dramatically in the last 5 years. However, it is not the only arbovirus that circulates along the northern coast of Peru. It has also been determined the presence of Zika and Chikungunya in our population, which may suggest the circulation of other arboviruses that have not been detected.

Objective: To evaluate the frequency of infection caused by the Oropouche virus (OROV) in 496 patients with acute febrile disease (AFI), whose samples were obtained for the analysis of endemic arboviruses in a previous investigation carried out in 2016. Results: OROV was detected in 26.4% (131/496) of serum samples from patients with AFI. Co-infections with Dengue virus (7.3%), Zika virus (1.8%) and Chikungunya (0.2%) were observed. The most common clinical symptoms reported among the patients with OROV infections were headache 85.5% (112/131), myalgia 80.9% (106/131), arthralgia 72.5% (95/131) and loss of appetite 67.9% (89/131). Headache and myalgia were predominant in all age groups. Both OROV infections and co-infections were more frequent in May, June and July corresponding to the dry season of the region. / Revisión por pares

Objective: To describe the prevalence of dengue virus serotypes, as well as other viral and bacterial pathogens that cause acute febrile illness during an outbreak in Cajamarca in 2016. Results: Dengue virus (DENV) was the most frequent etiologic agent detected in 25.8% of samples (32/124), followed by Rickettsia spp. in 8.1% (10/124), Zika virus in 4.8% (6/124), Chikungunya virus 2.4% (3/124) and Bartonella bacilliformis 1.6% (2/124) cases. No positive cases were detected of Oropouche virus and Leptospira spp. DENV serotypes identification was only achieved in 23% of the total positive for DENV, two samples for DENV-2 and four samples for DENV-4. During the 2016 outbreak in Cajamarca-Peru, it was observed that in a large percentage of positive samples for DENV, the infecting serotype could not be determined by conventional detection assays. This represents a problem for the national surveillance system and for public health due to its epidemiological and clinical implications. Other viral and bacterial pathogens responsible for acute febrile syndrome were less frequently identified. / Revisión por pares

Objective: To describe frequency and clinical characteristics of MAYV infection in Piura, as well as the association of this pathogen with DENV. Results: A total of 86/496 (17.3%) cases of MAYV were detected, of which 54 were MAYV mono-infection and 32 were co-infection with DENV, accounting for 10.9% and 6.4%, respectively. When evaluating monoinfection by MAYV the main groups were 18–39 and 40–59 years old, with 25.9% and 20.4% respectively. Co-infections were more common in the age group 18–39 and those > 60 years old, with 34.4% and 21.9%, respectively. The most frequent clinical presentation were headaches (94.4%, 51/54) followed by arthralgias (77.8%, 42/54). During the 8-month study period the most cases were identified in the months of May (29.1%) and June (50.0%). / National Research Foundation of Korea / Revisión por pares

In recent years, dengue viral infection has become one of the most widely-spread mosquito-borne diseases in the world, with an estimated 50-100 million cases annually, resulting in 500,000 hospitalizations. Due to the nature of the immune response to each of the four serotypes of dengue virus, secondary infections of dengue put patients at higher risk for more severe infection as opposed to primary infections. The current hypothesis for this phenomenon is antibody-dependent enhancement, where strain-specific antibodies from the primary infection enhance infection by a heterologous serotype. To determine the mechanisms responsible for the increase in disease severity, we develop mathematical models of within-host virus-cell interaction, epidemiological models of virus transmission, and a combination of the within-host and between-host models. The main results of this thesis focus on the within-host model. We model the effects of antibody responses against primary and secondary virus strains. We find that secondary infections lead to a reduction of virus removal. This is slightly different than the current antibody-dependent enhancement hypothesis, which suggests that the rate of virus infectivity is higher during secondary infections due to antibody failure to neutralize the virus. We use the results from the within-host model in an epidemiological multi-scale model. We start by constructing a two-strain SIR model and vary the parameters to account for the effect of antibody-dependent enhancement. / Master of Science

Dengue viral infection is a mosquito-borne disease with four distinct strains, where the interactions between these strains have implications on the severity of the disease outcomes. The two competing hypotheses for the increased severity during secondary infections are antibody dependent enhancement and original antigenic sin. Antibody dependent enhancement suggests that long-lived antibodies from primary infection remain during secondary infection but do not neutralize the virus. Original antigenic sin proposes that T cells specific to primary infection dominate cellular immune responses during secondary infections, but are inefficient at clearing cells infected with non-specific strains. To analyze these hypotheses, we developed within-host mathematical models. In previous work, we predicted a decreased non-neutralizing antibody effect during secondary infection. Since this effect accounts for decreased viral clearance and the virus is in quasi-equilibrium with infected cells, we could be accounting for reduced cell killing and the original antigenic sin hypothesis. To further understand these interactions, we develop a model of T cell responses to primary and secondary dengue virus infections that considers the effect of T cell cross-reactivity in disease enhancement. We fit the models to published patient data and show that the overall infected cell killing is similar in dengue heterologous infections, resulting in dengue fever and dengue hemorrhagic fever. The contribution to overall killing, however, is dominated by non-specific T cell responses during the majority of secondary dengue hemorrhagic fever cases. By contrast, more than half of secondary dengue fever cases have predominant strain-specific T cell responses. These results support the hypothesis that cross-reactive T cell responses occur mainly during severe disease cases of heterologous dengue virus infections. Finally, using the results from our within-host models, we develop a multiscale model of dengue viral infection which couples the within-host virus dynamics to the population level dynamics through a system of partial differential equations. We analytically determine the relationship between the model parameters and the characteristics of the solutions, and find thresholds under which infections persist in the population. Furthermore, we develop and implement a full numerical scheme for our model. / Ph. D. / Dengue viral infection is a mosquito-borne disease with four distinct strains, where the interactions between these strains have implications on the severity of the disease outcomes. The two competing hypotheses for the increased severity during secondary infections are antibody dependent enhancement and original antigenic sin. Antibody dependent enhancement suggests that long-lived antibodies from primary infection remain during secondary infection but do not neutralize the virus. Original antigenic sin proposes that T cells specific to primary infection dominate cellular immune responses during secondary infections, but are inefficient at clearing cells infected with non-specific strains. To analyze these hypotheses, we developed within-host mathematical models. In previous work, we predicted a decreased non-neutralizing antibody effect during secondary infection. Since this effect accounts for decreased viral clearance and the virus is in quasi-equilibrium with infected cells, we could be accounting for reduced cell killing and the original antigenic sin hypothesis. To further understand these interactions, we develop a model of T cell responses to primary and secondary dengue virus infections that considers the effect of T cell cross-reactivity in disease enhancement. We fit the models to published patient data and show that the overall infected cell killing is similar in dengue heterologous infections, resulting in dengue fever and dengue hemorrhagic fever. The contribution to overall killing, however, is dominated by non-specific T cell responses during the majority of secondary dengue hemorrhagic fever cases. By contrast, more than half of secondary dengue fever cases have predominant strain-specific T cell responses. These results support the hypothesis that cross-reactive T cell responses occur mainly during severe disease cases of heterologous dengue virus infections. Finally, using the results from our within-host models, we develop a multiscale model of dengue viral infection which couples the within-host virus dynamics to the population level dynamics through a system of partial differential equations. We analytically determine the relationship between the model parameters and the characteristics of the solutions, and find thresholds under which infections persist in the population. Furthermore, we develop and implement a full numerical scheme for our model.