Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Nov. 17, 2008). Includes bibliographical references.

Andes virus (ANDV) is a highly pathogenic New World hantavirus found in Chile and Argentina that causes Hantavirus Pulmonary Syndrome (HPS). A significantly high case fatality rate, the potential for human-to-human transmission, and the lack of licensed vaccines or effective treatments for the disease suggest an urgent need for the development of such measures. Many vaccine platforms have been recently described using reverse genetics systems to generate attenuated virus strains, as well as recombinant viruses expressing foreign proteins. This study attempted to generate and characterize vaccines based on an ANDV infectious clone system, as well as a recombinant vesicular stomatitis virus (VSV) vector expressing the ANDV glycoprotein precursor (VSVΔG/ANDVGPC), to test their efficacy in the only lethal disease animal model of HPS. Although an ANDV infectious clone system was not successfully established, precluding its use as a possible vaccine candidate, the first New World hantavirus minigenome system was described. In addition, Syrian hamsters immunized with a single dose of the recombinant VSVΔG/ANDVGPC vaccine were fully protected against disease when challenged at 28, 14, 7, or 3 days post-immunization with a lethal dose of ANDV; however, the mechanism of protection seems to differ, depending on the time point of immunization. At 28 days post-immunization, a lack of detectable ANDV RNA in tissue samples as well as a lack of seroconversion against the ANDV nucleoprotein (N) in nearly all hamsters suggested mostly sterile immunity. The vaccine was able to generate high levels of neutralizing anti-ANDV GN/GC antibodies that seem to play a role as a mechanism of vaccine protection. Administration of the vaccine at 7 and 3 days before challenge also resulted in full protection, but the lack of a neutralizing humoral immune response and the up-regulation of hamster cytokines involved in innate pathways suggested a possible role of innate responses in protection. The role of innate immunity was supported by the fact that administration of the vaccine 24 hours post-challenge was successful in protecting 90% of hamsters. Overall, the data suggests the potential for the use of the VSV platform as a fast-acting and effective prophylaxis/post-exposure treatment against lethal hantavirus infections.

Andes virus (ANDV) is a highly pathogenic New World hantavirus found in Chile and Argentina that causes Hantavirus Pulmonary Syndrome (HPS). A significantly high case fatality rate, the potential for human-to-human transmission, and the lack of licensed vaccines or effective treatments for the disease suggest an urgent need for the development of such measures. Many vaccine platforms have been recently described using reverse genetics systems to generate attenuated virus strains, as well as recombinant viruses expressing foreign proteins. This study attempted to generate and characterize vaccines based on an ANDV infectious clone system, as well as a recombinant vesicular stomatitis virus (VSV) vector expressing the ANDV glycoprotein precursor (VSVΔG/ANDVGPC), to test their efficacy in the only lethal disease animal model of HPS. Although an ANDV infectious clone system was not successfully established, precluding its use as a possible vaccine candidate, the first New World hantavirus minigenome system was described. In addition, Syrian hamsters immunized with a single dose of the recombinant VSVΔG/ANDVGPC vaccine were fully protected against disease when challenged at 28, 14, 7, or 3 days post-immunization with a lethal dose of ANDV; however, the mechanism of protection seems to differ, depending on the time point of immunization. At 28 days post-immunization, a lack of detectable ANDV RNA in tissue samples as well as a lack of seroconversion against the ANDV nucleoprotein (N) in nearly all hamsters suggested mostly sterile immunity. The vaccine was able to generate high levels of neutralizing anti-ANDV GN/GC antibodies that seem to play a role as a mechanism of vaccine protection. Administration of the vaccine at 7 and 3 days before challenge also resulted in full protection, but the lack of a neutralizing humoral immune response and the up-regulation of hamster cytokines involved in innate pathways suggested a possible role of innate responses in protection. The role of innate immunity was supported by the fact that administration of the vaccine 24 hours post-challenge was successful in protecting 90% of hamsters. Overall, the data suggests the potential for the use of the VSV platform as a fast-acting and effective prophylaxis/post-exposure treatment against lethal hantavirus infections.

As hantaviroses são zoonoses de roedores silvestres que causam doenças humanas graves: febre hemorrágica com síndrome renal na Ásia e Europa, com letalidade de 10 a 12% e no continente americano causam a Síndrome Pulmonar e Cardiovascular por Hantavirus (SPCVH), letalidade de 59%. Os Hantavirus (família Bunyaviridae) são vírus envelopados que medem aproximadamente 120 nm, possuem RNA de fita simples e polaridade negativa, dividida em 3 segmentos (L, M e S) que se replicam no citoplasma. A infecção humana relaciona-se à inalação de aerossóis de excretas de roedores infectados com Hantavirus, embora existam relatos de transmissão interpessoal na América do Sul. No Estado de São Paulo, os roedores infectados mais encontrados foram o “rato do rabo peludo" (Bolomys lasiurus), o “rato da mata" (Akodon cursor) e o “ratinho do arroz" (Oligoryzomys negrips). Desde os 3 primeiros casos de hantavirose descritos no Brasil (1993) com indivíduos moradores da área rural de Juquitiba, SP, evidenciando o primeiro surto conhecido de SPCVH, mais de uma centena de casos da SPCVH foram notificados, causando 60 óbitos (letalidade de 46%). Na região de Ribeirão Preto, ocorreram quatorze casos de SPCVH de 1998 a 2001, com letalidade de 64,2%, o que motivou este trabalho. Um primeiro objetivo deste trabalho foi estudar aspectos clínicos e epidemiológicos dos casos de hantavirose ocorridos na região de Ribeirão Preto, de 1998 a 2001, para conhecer o comportamento das hantaviroses nesta região. Analisando e acompanhando prontuários de 14 pacientes com SPCVH, observou-se febre (100% dos casos), estertores pulmonares, dispnéia e tosse (64,2%), taquicardia acompanhada de hipotensão (64,2%), cefaléia e sintomas digestivos (57%), adinamia e indisposição geral (50%), fenômenos hemorrágicos (28,5%), mialgia (21,4%) e convulsão (7,5%). No perfil laboratorial, a plaquetopenia <130000/mm3 (100%), hematócrito >55%, (78,6%); leucocitose >15000/mm3 (64,2%), neutrofilia >7000/ mm3 e bastonetes >600 cels/mm3 (64,2%), creatinina sérica >1,5mg/100ml (63,6%) e PO2 <70 mmHg (54,5%). O diagnóstico laboratorial das hantaviroses foi feito por ELISA para IgM e IgG anti Sin Nombre após a alta. Houve diferença significativa entre casos fatais e sobreviventes, quanto à época de suspeita diagnóstica de hantavirose (p=0,0152) e quanto ao uso de hidratação parenteral (p=0,0152): nos sobreviventes, a suspeita diagnóstica de SPCVH foi feita entre o 1º e o 2º dia de internação e, nos casos fatais, a suspeita foi feita apenas na necropsia. Existe uma correlação significativa entre o volume de infusão endovenosa de líquidos &#61619; 2500 ml, nas primeiras 24h de tratamento, e a evolução dos casos para o óbito. A oxigenação precoce, ventilação mecânica, assim como o uso de aminas vasoativas e o de corticosteróides não tiveram associação com sobrevida e a presença de choque não teve associação com óbito. O segundo objetivo foi estudar a prevalência de anticorpos para Hantavirus na população de Jardinópolis, na região de Ribeirão Preto, SP. Em estudo prévio entre cidades da região de Ribeirão Preto, obteve-se maior índice de prevalência sorológica (4,5%) para Hantavirus naquele município. Através de coleta aleatória em parte da área rural e em toda a área urbana, obtivemos 818 amostras de sangue de moradores entre 15 e 70 anos, por digitopuntura em papel de filtro, dos quais coletamos dados relevantes como idade, sexo, cor, procedência, atividade profissional, endereço, telefone; moléstia atual, medicamentos em uso, pneumonia grave pregressa, tipo de moradia, número de moradores na casa, esgoto, coleta de lixo, celeiro, contato com roedores. Essas amostras foram processadas nas diluições 1/50, 1/100, 1/400 e 1/1600 e submetidas ao ELISA indireto para detecção de IgG para Hantavirus Andes. Os resultados foram analisados pelo teste de Fisher e teste do Qui-quadrado, utilizando o programa InStat 3.0 (GraphPad Software Inc, USA) e para &#945; de 5%, com intervalo de confiança de 95%. A positividade geral foi de 14,3% com ELISA à diluição 1/50, na zona urbana foi de 15,3% e na zona rural de 6,5%, demonstrando alta representatividade para a população do município de Jardinópolis. Entre moradores de zona urbana e rural, a positividade para Hantavirus foi significativamente maior para os moradores urbanos (p= 0,0183). E entre as diferentes faixas etárias com a das restantes, observou-se diminuição significativa para a faixa etária de 21 a 30 anos (p= 0,0117) e aumentada para a de 31 a 40 anos (p= 0,0036). Não houve diferença significativa de positividade para Hantavirus observada nos homens e nas mulheres (p= 0,0892), nem para indivíduos com atividade profissional urbana e rural (p=0,8799), nem com os indivíduos que referiram pneumonia grave (p= 0,6096) e da mesma forma nos indivíduos que declararam contato com roedores (p= 0,4842). Assim como não houve associação entre títulos de 100 e 400 para as mesmas características analisadas. / The hantaviruses are zoonoses of wild rodents that cause serious human diseases: hemorrhagic fever with renal syndrome in Asia and Europe (10 to 12% lethality rates) and Pulmonary and Cardiovascular Syndrome in the American continent (HPCVS - 59% lethality rate). Hantaviruses (family Bunyaviridae) are enclosing viruses that measure 120 nm approximately, they possess RNA of simple ribbon and negative sense, divided in 3 segments (L, M and S) that are replication in the cytoplasm. The human infection links to the inhalation of aerosols of Hantavirus infected rodents excretes, although reports of person-to-person transmission exist in South America. In the State of São Paulo the infected rodents found were the Bolomys lasiurus, the Akodon cursor and the Oligoryzomys negrips. From the first 3 cases of hantaviruses described in Brazil (1993) with individuals inhabitants of the rural area of Juquitiba, SP, evidencing the first well-known supplies of HPCVS, more than a hundred cases have been notified in Brazil, causing 60 deaths (of 46% lethality rate). There have been fourteen cases of HPCVS since1998 to 2001 with of 64,2% letality rate, in the Ribeirão Preto area what motivated this work. One of the objectives was clinical and epidemic aspects studies of the cases of hantaviruses that happened in the Area of Ribeirão Preto, from 1998 to 2001, to know the behavior of the hantavirusess in this area. Analyzing and accompanying patient medical records of 14 patients with HPCVS, fever was observed (100% of the cases), disnea and coughs (64,2%), accompanied of arterial hipotension, tachicardia (64,2%), migraine and digestive symptoms (57%); adynamic and general weakness (50%), hemorrhagic phenomenons (28,5%), mialgia (21,4%) and convulsion (7,5%). In the laboratorial profile the platelets count <130000/mm3 (100%), hematocrit> 55%, (78,6%); leucocytosis > 15000/mm3 (64,2%), neutrofilia >7000 / mm3 and small sticks> 600 cels / mm3 (64,2%), creatinine serical level > 1,5mg/100ml (63,6%) and PO2 <70 mmHg (54,5%). The diagnosis laboratorial of the hantaviruses was made by ELISA for IgM and IgG anti Sin Nombre after the discharge. There was significant difference among fatal and surviving cases, as the hantaviruses diagnosis suspicious (p=0,0152) and parenteral hydratation (p=0,0152): in the survivors, the HPCVS diagnosis suspicious was made between the 1st and the 2nd day of internment and the fatal cases, the suspicion was just made to the necropsies. Among infusion of liquid EV ³ over 2500 ml in the first 24 hours of treatment and evolution for the death. The precocious oxygen support, mechanics ventilation, as well as the use of vasoatives amines and the one of corticosteróides, did not have association with survival and the shock presence did not have association with death. The second objective was to antibodies for Hantavirus prevalence studies in the Area of Ribeirão Preto, in the population of Jardinópolis, SP. In the previous study among cities in that area it was obtained larger index of serologic prevalence (4,5%) for Hantavirus, it was in the Jardinópolis county Through ramdomised collection partly of the rural area and whole urban area, we obtained 818 samples of blood, inhabitants between 15 and 70 years, for digital puncture in filter paper and important data as age, gender, color, origin, professional activity, address, telephone; current disease, medications in use, pneumonia serious, dwelling type, number of inhabitants in the house, sewer, collects of garbage, barn, contact with rodents. These samples were processed, in the dilutions 1/50, 1/100, 1/400 and 1/1600. and submitted to indirect ELISA for detection of IgG for Hantavirus Los Andes. The results were analyzed by Fisher and Qui-square tests, using the InStat 3.0 program (GraphPad.Software Inc, USA) and for the one of 5%, with interval of trust of 95%. The general positivity rated 14,3% with ELISA (at title 50), urban zone (15,3%) and in rural zone 6,5% and they demonstrated high rates for the population of the Jardinópolis county. Comparing the positivity rates for Hantavirus between urban and rural zone inhabitants was significantly larger for the urban inhabitants (p = 0,0183). Significant increase was observed for the age group of 21 to 30 years (p = 0,0117) and for the one of 31 to 40 years (p = 0,0036) among different age groups. There was not significant difference of positivist for Hantavirus between men and women (p = 0,0892); nor for individuals with urban and rural professional activity (p=0,8799), neither for the individuals that referred serious pneumonia (p = 0,6096) as well as in the individuals that declared contact with rodents (p = 0,4842). There was not association among titles of 100 and 400 for Hantavirus with gender, local of habitation, contact with rodents and pneumonia serious.

acase@tulane.edu / 1 / Catherine Arnold

Hantaviruses are members of the Bunyaviridae family of viruses. Pathogenic hantaviruses are the etiologic agents of hemorrhagic fever with renal syndrome (HFRS), a disease principally endemic in the Old World, and hantavirus pulmonary syndrome (HPS), a disease primarily restricted to the Americas. Maporal virus (MPRLV), a recently isolated hantavirus, has been found to cause disease in hamsters that resembles HPS in humans. However, the virus has not been linked to human cases of HPS. Considerable evidence suggests that β-integrin usage mediating infection may serve to distinguish hantaviruses pathogenic to humans from nonpathogenic, but this receptor usage pattern information is not yet available for MPRLV. Although ribavirin has been shown to be effective in treating HFRS, it lacks specificity and has toxicity. Moreover, there are no effective antivirals for the treatment of HPS. Considering the above, we have investigated MPRLV 1) β-integrin-mediated mechanism of entry, 2) genetic determinants of pathogenicity, and 3) susceptibility to the promising antiviral, favipiravir (T-705). Using antibodies targeting specific integrin chains, we found infection of Vero E6 cells with MPRLV to be dependent on β3-integrins, similar to that reported for other pathogenic hantaviruses such as Dobrava virus (DOBV) included in our studies. β1-integrin chain-specific antibodies and fibronectin did not block MPRLV or DOBV infectivity as observed with the nonpathogenic Prospect Hill Virus (PHV). Phylogenic analysis of characteristic degron sequences and ITAM motifs in the G1 cytoplasmic tails of MPRLV and other hantaviruses emphasizes the close genetic proximity of MPRLV to other HPS-causing hantaviruses. Favipiravir, a pyrazine derivative reported to be active against related bunyaviruses, was found to be active against MPRLV, DOBV, and PHV (EC50 = 65 - 93 µM) with therapeutic indexes of 74, 52, and 58, respectively. The data presented suggests that MPRLV may be pathogenic to humans and that it and other hantaviruses tested are sensitive to favipiravir in cell culture.

OLIVEIRA, Augusto César Aragão. Identificação etiológica de quadros dengue-símile no Ceará, no ano de 2008. 2011. 99 f. Dissertação (Mestrado em Patologia) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2011. / Submitted by denise santos (denise.santos@ufc.br) on 2013-12-03T12:07:15Z No. of bitstreams: 1 2011_dis_acaoliveira.pdf: 1624844 bytes, checksum: 97ea83bb9fc0470693f6835afdbfb072 (MD5) / Approved for entry into archive by denise santos(denise.santos@ufc.br) on 2013-12-03T12:08:09Z (GMT) No. of bitstreams: 1 2011_dis_acaoliveira.pdf: 1624844 bytes, checksum: 97ea83bb9fc0470693f6835afdbfb072 (MD5) / Made available in DSpace on 2013-12-03T12:08:09Z (GMT). No. of bitstreams: 1 2011_dis_acaoliveira.pdf: 1624844 bytes, checksum: 97ea83bb9fc0470693f6835afdbfb072 (MD5) Previous issue date: 2011 / 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 Saúde Pública do Ceará (LACEN-CE), Brazil, in 2008. In the present study, the serum samples from these patients were evaluated for dengue infection by IgM-ELISA (PanBio Diagnostics®) and RT-PCR, following Lanciotti et alli protocol (1992). Negative samples to dengue infection were tested to leptospirosis by IgM-ELISA (PanBio Diagnostics®). 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 Ceará, 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. / A dengue é a arbovirose mais importante no mundo, causando mais de 100 milhões de casos de dengue clássico (DC) e mais de 250 mil casos de febre hemorrágica da dengue (FHD), anualmente. A infecção com o vírus dengue (DENV), família Flaviviridae, causa um amplo espectro de manifestações clínicas que variam desde formas assintomáticas a quadros graves, potencialmente fatais, como os casos hemorrágicos e/ou de choque hipovolêmico. Na maioria das vezes, a doença se apresenta com sintomas inespecíficos. Dessa forma, torna-se difícil diferenciar a dengue de outros casos febris de natureza infecciosa como leptospirose, febre amarela e outras arboviroses, apenas com base nas manifestações clínicas iniciais. Diante disso, o objetivo deste estudo foi identificar a etiologia de 82 pacientes com quadro clínico semelhante ao de dengue e com resultado negativo no isolamento viral (IV) para o DENV. O IV foi realizado pelo Laboratório Central de Saúde Pública do Ceará (LACEN-CE), em 2008. Neste estudo, as amostras desses pacientes foram avaliadas para dengue por meio da detecção de anticorpos específicos contra o vírus pela técnica de IgM-ELISA (PanBio Diagnostics®) e pela reação em cadeia da polimerase após transcrição reversa (RT-PCR). As amostras negativas para dengue foram testadas para a detecção de anticorpos IgM específicos contra bactérias do gênero Leptospira por ELISA (PanBio Diagnostics®). Foram testadas também amostras de 73 pacientes quanto a infecção por hantavirus, através da detecção de anticorpos específicos (IgM e IgG) contra antígenos de hantavírus 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 também no RT-PCR. Das 47 amostras dengue-negativas, apenas 43 foram testadas para infecção por Leptospira devido ao volume insuficiente das amostras. Seis pacientes (6/82; 7,32%) foram positivos IgM-ELISA para leptospirose. Três pacientes foram positivos para hantavírus, entretanto apenas 1 (1/82; 1,22%) foi positivo no IgM-ELISA e 2, no IgG-ELISA. A infecção dos 35 (42,68%) pacientes negativos em todos os testes de detecção de infecção aguda foi classficada como síndrome febril indiferenciada (SFI). Esta é a primeira evidência de infecção por hantavírus no Estado do Ceará. Essas doenças podem causar infecção clinicamente indistinguível da dengue e, portanto, deveriam ser incluídas no diagnóstico diferencial no contexto dessas síndromes febris.

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Saúde Coletiva, 2017. / Texto parcialmente liberado pelo autor. Conteúdo restrito: Capítulo 4. / Submitted by Raquel Almeida (raquel.df13@gmail.com) on 2017-12-07T17:12:22Z No. of bitstreams: 1 2017_LidsyXimenesFonseca_PARCIAL.pdf: 1031893 bytes, checksum: 4db854573bd31b44ca869b4b037b0d1f (MD5) / Approved for entry into archive by Raquel Viana (raquelviana@bce.unb.br) on 2018-02-08T21:02:06Z (GMT) No. of bitstreams: 1 2017_LidsyXimenesFonseca_PARCIAL.pdf: 1031893 bytes, checksum: 4db854573bd31b44ca869b4b037b0d1f (MD5) / Made available in DSpace on 2018-02-08T21:02:06Z (GMT). No. of bitstreams: 1 2017_LidsyXimenesFonseca_PARCIAL.pdf: 1031893 bytes, checksum: 4db854573bd31b44ca869b4b037b0d1f (MD5) Previous issue date: 2018-02-08 / Introdução: A hantavirose é uma importante doença zoonótica transmitida por roedores silvestres. A doença tem início súbito e pode levar à morte rapidamente. A descrição e os fatores associados à sua letalidade no Brasil e regiões ainda é pouco conhecida. Objetivo: Descrever as características e distribuição dos casos óbitos por hantavirose e analisar fatores associados ao óbito no Brasil, no período de 2007 a 2015. Método: Trata-se de um estudo descritivo dos casos e óbitos por hantavirose e um estudo do tipo caso-controle para determinar os fatores associados ao óbito por hantavirose, ambos com uso de dados secundários do Sistema de Informação de Agravos de Notificação (SINAN). Resultados: No período de estudo foram selecionados 1060 casos destes, 410 óbitos. A taxa de letalidade por hantavirose (TLH) no período de estudo foi de 39,0%, variando segundo mês (28,6% em novembro a 50,7% em dezembro), sexo (37,4% em homens e 42,6% em mulheres), idade (50% em pessoas <10 anos e 44,4% em pessoas com 60 ou mais anos) e regiões (46,2% no Norte, 32,9% no Sul). A maioria dos indivíduos que morreu morava em zona urbana (58,3%) foi infectada na zona rural (70,2%) e tinha o local de trabalho como o principal ambiente provável de infecção (39,0%). Na análise ajustada, foram identificadas como tendo maiores chances de óbito por hantavirose as mulheres (OR: 1,43 - IC95% 1,01 a 1,99) comparadas aos homens, os indivíduos adultos com escolaridade não informada (OR: 3,86 – IC95% 1,72 a 8,66) e com ensino fundamental (OR: 3,88 - IC95% 1,51 a 9,96) comparados aos que tinham ensino superior completo ou incompleto; os moradores da zona urbana (OR: 1,56 – IC95%. 1,15 a 2,12) em relação aos que moravam na zona rural; e aqueles indivíduos que apresentaram choque e/ou hipotensão (OR: 3,37 - IC95% 2,51 a 4,51) ou sinais e sintomas respiratórios (OR: 3,76 – IC95%: 1,93 a 7,33) em comparação aos que não apresentaram tais características. Em relação à oportunidade de atendimento, o fato dos indivíduos demorarem mais de 4 dias para buscar atendimento médico, foi considerado um fator protetor contra o óbito. Conclusão: A alta TLH em certos grupos populacionais, épocas do ano e regiões do Brasil, além de algumas características clínicas do indivíduo podem indicar falhas no acesso aos serviços de saúde, além de baixa suspeição clínica e possível demora na adoção do manejo adequado dos casos. Particularmente, a busca precoce de atenção e a presença de certos sinais clínicos (choque, hipotensão e/ou sinais respiratórios) aparentemente são marcadores importantes da evolução rápida da doença e maior gravidade. Esses resultados podem auxiliar na definição de grupos mais vulneráveis ao óbito por hantavirose e no direcionamento de ações específicas para a prevenção deste desfecho. / Introduction: Hantavirus is an important zoonotic disease transmitted by wild rodents. The disease has a sudden onset and can lead to death quickly. The description and factors associated with its lethality in Brazil and regions is still poorly understood. Objective: To describe the characteristics and distribution of cases of death due to hantavirosis and to analyze factors associated with death in Brazil, from 2007 to 2015. Method: This is a descriptive study of cases and deaths due to hantavirosis and a casecontrol study to determine the factors associated with death due to hantavirus, both using secondary data from the SINAN. Results: During the study period, 1060 cases were selected, 410 deaths. The rate of lethality due to hantavirus (TLH) in the study period was 39.0%, varying according to month (28.6% in November to 50.7% in December), sex (37.4% in men and 42, 6% in women), age (50% in people <10 years and 44.4% in people aged 60 years and over) and regions (46.2% in the North, 32.9% in the South). Most of the individuals who died lived in urban areas (58.3%) were infected in the rural area (70.2%) and had the workplace as the main probable infection environment (39.0%). In the adjusted analysis, women (OR: 1.43 - 95% CI 1.01 to 1.99) were identified as having a higher chance of death due to hantavirosis compared to men, adult individuals with unreported schooling (OR: 3.86 - IC95% 1.72 to 8.66) and with elementary education (OR: 3.88 - 95% CI 1.51 to 9.96) compared to those who had completed or incomplete higher education; (OR: 1.56 - 95% CI 1.15 to 2.12) compared to those living in the rural area; and those individuals who presented shock and / or hypotension (OR: 3.37 - 95% CI 2.51 to 4.51) or respiratory signs and symptoms (OR: 3.76 - 95% CI: 1.93 to 7.33) compared to those who did not. Regarding the opportunity for care, the fact that individuals took more than 4 days to seek medical attention was considered a protective factor against death. Conclusion: High TLH in certain population groups, times of the year and regions of Brazil, as well as some clinical characteristics of the individual may indicate faults in access to health services, as well as low clinical suspicion and possible delay in adopting appropriate case management . Particularly, early attention seeking and the presence of certain clinical signs (shock, hypotension and / or respiratory signs) appear to be important markers of rapid disease progression and increased severity. These results may help in the definition of groups more vulnerable to death due to hantavirus and in directing specific actions to prevent this outcome.

As hantaviroses são zoonoses de roedores silvestres que causam doenças humanas graves: febre hemorrágica com síndrome renal na Ásia e Europa, com letalidade de 10 a 12% e no continente americano causam a Síndrome Pulmonar e Cardiovascular por Hantavirus (SPCVH), letalidade de 59%. Os Hantavirus (família Bunyaviridae) são vírus envelopados que medem aproximadamente 120 nm, possuem RNA de fita simples e polaridade negativa, dividida em 3 segmentos (L, M e S) que se replicam no citoplasma. A infecção humana relaciona-se à inalação de aerossóis de excretas de roedores infectados com Hantavirus, embora existam relatos de transmissão interpessoal na América do Sul. No Estado de São Paulo, os roedores infectados mais encontrados foram o “rato do rabo peludo” (Bolomys lasiurus), o “rato da mata” (Akodon cursor) e o “ratinho do arroz” (Oligoryzomys negrips). Desde os 3 primeiros casos de hantavirose descritos no Brasil (1993) com indivíduos moradores da área rural de Juquitiba, SP, evidenciando o primeiro surto conhecido de SPCVH, mais de uma centena de casos da SPCVH foram notificados, causando 60 óbitos (letalidade de 46%). Na região de Ribeirão Preto, ocorreram quatorze casos de SPCVH de 1998 a 2001, com letalidade de 64,2%, o que motivou este trabalho. Um primeiro objetivo deste trabalho foi estudar aspectos clínicos e epidemiológicos dos casos de hantavirose ocorridos na região de Ribeirão Preto, de 1998 a 2001, para conhecer o comportamento das hantaviroses nesta região. Analisando e acompanhando prontuários de 14 pacientes com SPCVH, observou-se febre (100% dos casos), estertores pulmonares, dispnéia e tosse (64,2%), taquicardia acompanhada de hipotensão (64,2%), cefaléia e sintomas digestivos (57%), adinamia e indisposição geral (50%), fenômenos hemorrágicos (28,5%), mialgia (21,4%) e convulsão (7,5%). No perfil laboratorial, a plaquetopenia <130000/mm3 (100%), hematócrito >55%, (78,6%); leucocitose >15000/mm3 (64,2%), neutrofilia >7000/ mm3 e bastonetes >600 cels/mm3 (64,2%), creatinina sérica >1,5mg/100ml (63,6%) e PO2 <70 mmHg (54,5%). O diagnóstico laboratorial das hantaviroses foi feito por ELISA para IgM e IgG anti Sin Nombre após a alta. Houve diferença significativa entre casos fatais e sobreviventes, quanto à época de suspeita diagnóstica de hantavirose (p=0,0152) e quanto ao uso de hidratação parenteral (p=0,0152): nos sobreviventes, a suspeita diagnóstica de SPCVH foi feita entre o 1º e o 2º dia de internação e, nos casos fatais, a suspeita foi feita apenas na necropsia. Existe uma correlação significativa entre o volume de infusão endovenosa de líquidos &#61619; 2500 ml, nas primeiras 24h de tratamento, e a evolução dos casos para o óbito. A oxigenação precoce, ventilação mecânica, assim como o uso de aminas vasoativas e o de corticosteróides não tiveram associação com sobrevida e a presença de choque não teve associação com óbito. O segundo objetivo foi estudar a prevalência de anticorpos para Hantavirus na população de Jardinópolis, na região de Ribeirão Preto, SP. Em estudo prévio entre cidades da região de Ribeirão Preto, obteve-se maior índice de prevalência sorológica (4,5%) para Hantavirus naquele município. Através de coleta aleatória em parte da área rural e em toda a área urbana, obtivemos 818 amostras de sangue de moradores entre 15 e 70 anos, por digitopuntura em papel de filtro, dos quais coletamos dados relevantes como idade, sexo, cor, procedência, atividade profissional, endereço, telefone; moléstia atual, medicamentos em uso, pneumonia grave pregressa, tipo de moradia, número de moradores na casa, esgoto, coleta de lixo, celeiro, contato com roedores. Essas amostras foram processadas nas diluições 1/50, 1/100, 1/400 e 1/1600 e submetidas ao ELISA indireto para detecção de IgG para Hantavirus Andes. Os resultados foram analisados pelo teste de Fisher e teste do Qui-quadrado, utilizando o programa InStat 3.0 (GraphPad Software Inc, USA) e para &#945; de 5%, com intervalo de confiança de 95%. A positividade geral foi de 14,3% com ELISA à diluição 1/50, na zona urbana foi de 15,3% e na zona rural de 6,5%, demonstrando alta representatividade para a população do município de Jardinópolis. Entre moradores de zona urbana e rural, a positividade para Hantavirus foi significativamente maior para os moradores urbanos (p= 0,0183). E entre as diferentes faixas etárias com a das restantes, observou-se diminuição significativa para a faixa etária de 21 a 30 anos (p= 0,0117) e aumentada para a de 31 a 40 anos (p= 0,0036). Não houve diferença significativa de positividade para Hantavirus observada nos homens e nas mulheres (p= 0,0892), nem para indivíduos com atividade profissional urbana e rural (p=0,8799), nem com os indivíduos que referiram pneumonia grave (p= 0,6096) e da mesma forma nos indivíduos que declararam contato com roedores (p= 0,4842). Assim como não houve associação entre títulos de 100 e 400 para as mesmas características analisadas. / The hantaviruses are zoonoses of wild rodents that cause serious human diseases: hemorrhagic fever with renal syndrome in Asia and Europe (10 to 12% lethality rates) and Pulmonary and Cardiovascular Syndrome in the American continent (HPCVS - 59% lethality rate). Hantaviruses (family Bunyaviridae) are enclosing viruses that measure 120 nm approximately, they possess RNA of simple ribbon and negative sense, divided in 3 segments (L, M and S) that are replication in the cytoplasm. The human infection links to the inhalation of aerosols of Hantavirus infected rodents excretes, although reports of person-to-person transmission exist in South America. In the State of São Paulo the infected rodents found were the Bolomys lasiurus, the Akodon cursor and the Oligoryzomys negrips. From the first 3 cases of hantaviruses described in Brazil (1993) with individuals inhabitants of the rural area of Juquitiba, SP, evidencing the first well-known supplies of HPCVS, more than a hundred cases have been notified in Brazil, causing 60 deaths (of 46% lethality rate). There have been fourteen cases of HPCVS since1998 to 2001 with of 64,2% letality rate, in the Ribeirão Preto area what motivated this work. One of the objectives was clinical and epidemic aspects studies of the cases of hantaviruses that happened in the Area of Ribeirão Preto, from 1998 to 2001, to know the behavior of the hantavirusess in this area. Analyzing and accompanying patient medical records of 14 patients with HPCVS, fever was observed (100% of the cases), disnea and coughs (64,2%), accompanied of arterial hipotension, tachicardia (64,2%), migraine and digestive symptoms (57%); adynamic and general weakness (50%), hemorrhagic phenomenons (28,5%), mialgia (21,4%) and convulsion (7,5%). In the laboratorial profile the platelets count <130000/mm3 (100%), hematocrit> 55%, (78,6%); leucocytosis > 15000/mm3 (64,2%), neutrofilia >7000 / mm3 and small sticks> 600 cels / mm3 (64,2%), creatinine serical level > 1,5mg/100ml (63,6%) and PO2 <70 mmHg (54,5%). The diagnosis laboratorial of the hantaviruses was made by ELISA for IgM and IgG anti Sin Nombre after the discharge. There was significant difference among fatal and surviving cases, as the hantaviruses diagnosis suspicious (p=0,0152) and parenteral hydratation (p=0,0152): in the survivors, the HPCVS diagnosis suspicious was made between the 1st and the 2nd day of internment and the fatal cases, the suspicion was just made to the necropsies. Among infusion of liquid EV ³ over 2500 ml in the first 24 hours of treatment and evolution for the death. The precocious oxygen support, mechanics ventilation, as well as the use of vasoatives amines and the one of corticosteróides, did not have association with survival and the shock presence did not have association with death. The second objective was to antibodies for Hantavirus prevalence studies in the Area of Ribeirão Preto, in the population of Jardinópolis, SP. In the previous study among cities in that area it was obtained larger index of serologic prevalence (4,5%) for Hantavirus, it was in the Jardinópolis county Through ramdomised collection partly of the rural area and whole urban area, we obtained 818 samples of blood, inhabitants between 15 and 70 years, for digital puncture in filter paper and important data as age, gender, color, origin, professional activity, address, telephone; current disease, medications in use, pneumonia serious, dwelling type, number of inhabitants in the house, sewer, collects of garbage, barn, contact with rodents. These samples were processed, in the dilutions 1/50, 1/100, 1/400 and 1/1600. and submitted to indirect ELISA for detection of IgG for Hantavirus Los Andes. The results were analyzed by Fisher and Qui-square tests, using the InStat 3.0 program (GraphPad.Software Inc, USA) and for the one of 5%, with interval of trust of 95%. The general positivity rated 14,3% with ELISA (at title 50), urban zone (15,3%) and in rural zone 6,5% and they demonstrated high rates for the population of the Jardinópolis county. Comparing the positivity rates for Hantavirus between urban and rural zone inhabitants was significantly larger for the urban inhabitants (p = 0,0183). Significant increase was observed for the age group of 21 to 30 years (p = 0,0117) and for the one of 31 to 40 years (p = 0,0036) among different age groups. There was not significant difference of positivist for Hantavirus between men and women (p = 0,0892); nor for individuals with urban and rural professional activity (p=0,8799), neither for the individuals that referred serious pneumonia (p = 0,6096) as well as in the individuals that declared contact with rodents (p = 0,4842). There was not association among titles of 100 and 400 for Hantavirus with gender, local of habitation, contact with rodents and pneumonia serious.

Submitted by Cláudia Bueno (claudiamoura18@gmail.com) on 2015-11-04T16:01:17Z No. of bitstreams: 2 Dissertação - Hélio Ranes de Menezes Filho - 2015.pdf: 2092890 bytes, checksum: f6dbc2938f19e7ee61d8ef683a9cb489 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-11-05T10:14:32Z (GMT) No. of bitstreams: 2 Dissertação - Hélio Ranes de Menezes Filho - 2015.pdf: 2092890 bytes, checksum: f6dbc2938f19e7ee61d8ef683a9cb489 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-11-05T10:14:32Z (GMT). No. of bitstreams: 2 Dissertação - Hélio Ranes de Menezes Filho - 2015.pdf: 2092890 bytes, checksum: f6dbc2938f19e7ee61d8ef683a9cb489 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-01-26 / The Hantaviruses are acute viral zoonosis, caused by a virus from the Bunyaviridae family, genus Hantavirus, having the rodents as reservoir. It is considered an emergent disease in several regions of the world. There are few studies in Brazil in areas of cerrado biome and even fewer studies directed to understand how behaves the aggravation in municipalities in Goias. They can present two clinical instances: the Hemorrhagic Fever with Renal Syndrome – HFRS, known since 1930 and endemic in Europe and Asia and Hantavirus Cardiopulmonary Syndrome – HCPS, described for the first time in the USA in 1933, that associates cardiogenic shock and vascular involvement that follow serious pneumopathy, and that is restrict to Americas. Although the disease is registered in all regions of Brazil, the South, the Southeast and the Middle-West concentrate major percentage of confirmed cases. Objective: To describe the clinic and epidemiologic aspects of patients with diagnosis of Hantavirus infection in the state of Goias from 2007 to 2013. Material and Methods: It was made a descriptive epidemiologic study with data from the State of Goias between 2007 and 2013. The data were obtained from Hantavirus infection investigation file contained in the System of Information of Aggravation and Notification (SINAN-NET) between 2007 and 2013. The analyzed data were social-demographic, clinical and epidemiological, besides mortality rate. All the data were analyzed in the set period of seven years and also what is the behavior of the disease each year. Results: 1171 suspect cases of Hantavirus infection were notified in the State of Goias, and 73 cases were confirmed (6,2%), being the average of 10,4 confirmed cases a year. The average age of the confirmed cases of the disease was 35,4 years old ( 13,2 years old) , with the minimum of 12 and the maximum of 71 years old (Median 33,5 years old); and more frequently among males, with 68,5% of the cases (p<0,05). Related to education, the highest frequency was cases with elementary or high school. The brown race (self-reported) had higher frequency, followed by the white race. The total mortality rate in the period was 57,5%. There was no association between the frequency of confirmed cases of the disease and the seasonality of the regional climate. From the total of 73 confirmed cases, 93,2% (68) were hospitalized and among the first ones, 82,2% (60) with diagnose of clinical form CSBH. The majority of cases had confirmation diagnosed through laboratory. Related to the symptoms and clinical signs, the fever was the most frequent, being present in 95,9% of the cases, followed by dyspnea (86,3%) and dry cough (71,2%). Discussion: There was a higher concentration of cases in the center-south region of the state, highlighting Anapolis and Jatai as the municipalities with higher frequency of the disease, after the capital of the state. The southwest region of the state is characterized by the economic production directed to agriculture and livestock, with advances in the production of grains and soil exploitation, putting the man in frequent contact with rodents, enabling the transmission of the disease. The frequency of Hantavirus infection found in this study was lower than other studies taken in regions of Cerrado Biome. The mortality rate was higher than in other regions of the country. The clinical status shows similar characteristics for the disease. Conclusion: the Hantavirus infection is an emergent infection in the state of Goias, showing frequency with tendency to elevation and with high rates of mortality. The number of notified cases has increased, but it is not reflecting in the increase of the number of confirmed cases. The majority of confirmed cases are hospitalized and the clinical condition identified is similar to the related for the most frequent clinical form, which was the HCPS. / As hantaviroses são zoonoses virais agudas, causadas por vírus da família Bunyaviridae, gênero Hantavirus, tendo os roedores como reservatórios. É considerada uma doença emergente em várias regiões do mundo. Podem apresentar duas formas clínicas: a Febre Hemorrágica com Síndrome Renal – FHSR, conhecida desde 1930 e endêmica na Europa e Ásia e a Síndrome Cardiopulmonar por Hantavírus – SCPH, descrita pela primeira vez nos EUA em 1993, que associa choque cardiogênico e acometimento vascular que acompanham a pneumopatia grave, e que é restrita às Américas. Apesar de a doença ser registrada em todas as regiões brasileiras, o Sul, o Sudeste e o Centro-Oeste concentram maior percentual de casos confirmados. São poucos os estudos feitos no Brasil em regiões do bioma cerrado e mais escassos ainda estudos direcionados a compreender como se comporta o agravo nos municípios goianos. Objetivo: Descrever os aspectos clínicos e epidemiológicos dos pacientes com diagnóstico de hantavirose no Estado de Goiás no período de 2007 a 2013. Material e Métodos: Foi realizado um estudo epidemiológico descritivo com dados do Estado de Goiás, no período de 2007 a 2013, obtidos da ficha de investigação de hantavirose constante do Sistema de Informação de Agravos de Notificação (SINAN- NET). Os dados analisados foram sócio-demográficos, clínicos e epidemiológicos, além da taxa de letalidade. Todos os dados foram analisados no conjunto do período de sete anos e também qual o comportamento da doença em cada ano. Resultados: foram notificados 1171 casos suspeitos de hantavirose no Estado de Goiás, e confirmados 73 casos (6,2%), sendo a média de 10,4 casos confirmados por ano. A idade média dos casos confirmados da doença foi 35,4 anos ( 13,2 anos), com a mínima de 12 anos e máxima de 71 anos (Mediana 33,5 anos); e maior frequência entre o sexo masculino, com 68,5% dos casos (p<0,05). Com relação à escolaridade, a maior frequência foi de casos com ensino fundamental ou médio. A raça parda (auto referida) teve maior frequência, seguida da raça branca. A taxa de letalidade total no período foi de 57,5%. Não houve associação entre a frequência de casos confirmados da doença e a sazonalidade do clima da região. Do total de 73 casos confirmados, 93,2% (68) foram hospitalizados e entre os primeiros, 82,2% (60) com diagnóstico de forma clínica SCPH. A quase totalidade dos casos teve confirmação diagnóstica por meio laboratorial. Em relação aos sinais e sintomas clínicos a febre foi o mais frequente, estando presente em 95,9% dos casos, seguida por dispneia (86,3%) e tosse seca (71,2%). Discussão: houve maior concentração de casos na região centro sul do Estado, destacando-se Anápolis e Jataí como os municípios com maior frequência da doença, depois da capital. A região sudoeste do Estado caracteriza-se por produção econômica voltada para a agricultura e pecuária, com avanços na produção de grãos e exploração do solo, colocando o homem em contato frequente com roedores, possibilitando a transmissão da doença. A frequência da hantavirose encontrada neste estudo foi inferior a outros estudos realizados em regiões do Bioma Cerrado. A taxa de letalidade foi superior a de outras regiões do país. O quadro clínico apresenta características similares para a doença. Conclusão: a hantavirose é uma infecção emergente no Estado de Goiás, apresentando frequência com tendência à elevação e com altas taxas de letalidade. O número de casos notificados tem aumentado, mas sem refletir no aumento do número de casos confirmados. A quase totalidade dos casos confirmados é hospitalizada e o quadro clínico identificado é semelhante ao relatado para a forma clínica mais frequente, que foi a SCPH.