During the 2009 H1N1 influenza pandemic, public health nurses (PHNs) were called upon to protect their communities against a deadly influenza virus. Currently, there appears to be no literature that describes the experience of Canadian PHNs responding to the first influenza pandemic of the 21st century. A qualitative research study was conducted and the data were analyzed by using content analysis. Thirteen nurses were interviewed from an Urban, Rural and Northern health region in Manitoba. Focus groups were conducted for the Urban and Rural nurses while Northern nurses were interviewed by telephone. Communication and dissemination of information, personal and professional challenges, personal face of the pandemic, regional support and lessons learned were themes generated from the data analysis. Communication and information flow was a major theme that impacted the overall PHNs’ response experience. Practice, administration, research and education implications and the limitations of the study are presented in the study.

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Made available in DSpace on 2016-03-10T13:20:27Z (GMT). No. of bitstreams: 2 paola_silva_ioc_dout_2015.pdf: 5954809 bytes, checksum: 02b143793e3dbd017a0d95c668d3108c (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2016-01-13 / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / A primeira detecção do vírus Influenza A (H1N1)pdm09 no Brasil aconteceu em maio de 2009, e foi seguida de uma extensa disseminação por toda a população brasileira, com grande impacto em morbidade e mortalidade. Para entender a dinâmica molecular do Influenza A (H1N1)pdm09 no país, a presente tese reuniu sete trabalhos que abordaram a análise filogenética deste agente viral durante e após o período pandêmico (2009 a 2014) e buscou indentificar polimorfismos virais associados à virulência e à resistência ao antiviral Oseltamivir (OST). Para isso, as metodologias realizadas foram o sequenciamento dos genes de hemaglutinina (HA) e neuraminidase (NA) utilizando a metodologia de Sanger e a metodologia de pirosequenciamento para detectar polimorfismos de base única (SNPs). Nossos resultados revelaram a circulação de nove grupos filogenéticos ao longo dos cinco anos do estudo, indicando uma substituição temporal dos grupos e ocasionalmente uma estratificação geográfica. No entanto, nenhum dos grupos filogenéticos identificados foram associados com um pior prognóstico da infecção por influenza. Ao contrário do que foi observado em estudos anteriores, as mutações K-15E e Q310H no gene HA não se associaram ao aumento de virulência, mesmo na infecção de indivíduos imunocomprometidos. Por outro lado, polimorfismos no resíduo 222 da HA, que caracterizaram a presença de quasispecies virais, mostraram uma forte associação com a gravidade da infecção, especialmente em gestantes. Nesta tese, também realizamos a vigilância de marcadores de resistência no gene NA. Entre as amostras analisadas encontramos sete vírus com a mutação H275Y e dois com S247N, esses marcadores estão relacionados com a diminuição de sensibilidade ao antiviral OST Entre as amostras resistentes, a grande maioria foi detectada na região Sul do Brasil, em pacientes que não receberam OST. Isto sugere uma possível transmissão sustentada do vírus resistentes no país. Embora variantes H275Y resistentes apresentem baixa aptidão viral, a propagação deste vírus pode ocorrer com o ganho de mutações permissivas nos genes HA ou NA. No Brasil, o vírus que circulam desde 2011 apresentaram mutações V241I e N369K no gene NA, que foram, teoricamente, associadas a uma maior aptidão viral da variante resistente. Diante disso, cinco anos após a pandemia observamos que o vírus A (H1N1)pdm09 está estabelecido na população humana com várias substituições genéticas quando comparado com a sequencia da cepa vacinal A/California/07/2009. A maioria destas substituições parecem não ocasionar uma maior gravidade da infecção, e esta pode ser atribuída a outros fatores, tais como fatores genéticos do hospedeiro. Por fim, considerando o risco de surgimento e disseminação de vírus resistentes é importante reforçar o monitoramento viral e também realizar estudos para novas drogas antivirais / The Influenza A (H1N1)pdm09 virus was first detecte d in May 2009 in Brazil and later resulted in an extensive spread throughout the Brazilian pop ulation with a severe impact on morbidity and mortality. To understand the molecular dynamic of ( H1N1)pdm09 virus in Brazil this thesis grouped seven papers which approached the phylogenetic reco nstruction of the virus during and after the pandemic period (2009 to 2014) and the genomic iden tification of viral polymorphisms associated with virulence or antiviral resistance to Oseltamivir (O ST). For this, we performed genome sequencing, focusing especially on the hemagglutinin (HA) and n euraminidase (NA) genes using conventional Sanger sequencing and PyroMark 96ID to detect singl e nucleotide polymorphisms (SNPs). Our results showed that in Brazil nine (H1N1)pdm09 phylogenetic groups circulated along the five years of the study, indicating a temporal repl acement of groups and ocasionally a geographic stratification. However, no phylogenetic group seem ed to be associated with a worse clinical outcome. The increased virulence observed in previous studie s with a 2009 group bearing the genetic markers K-15E and Q310H was not confirmed in our analyses, even evaluating an immunocompromised population. On the other hand, polymorphysms at pos ition 222 of HA gene, which characterized the presence of viral quasispecies, showed an associati on with increased virulence in brazilian samples, especially in pregnant women. In this study we also performed surveillance of resistance markers at the NA gene. From the analysed samples we found sev en viruses with H275Y and two with S247N mutation, that diminish the sensibility to oseltami vir (OST). Among the resistant samples, the large majority was detected in the Southern region of Bra zil in patients that did not receive OST. This suggests a possible sustained transmission of resis tant virus in the country. Although resistant H275Y variants have low viral fitness, the spread of this virus can occur with the gain of permissive mutati ons in the HA or NA genes. In Brazil, viruses circulati ng since 2011 presented mutations V241I and N369K in the NA gene, which were theoretically associated with greater viral fitness. Five years after the pandemic we observed that A (H 1N1)pdm09 is established in the population with genetic substitutions in all gene s egments when compared to the vaccine strain A/California/07/2009. We demonstrated that the majo rity of those substitutions did not increase the severity of infection. The worst clinical outcomes may be attributed to other factors, such as genetic host factors. Finally, considering the risk of emer gence and spread of resistant viruses it is importa nt to strengthen viral surveillance and also carry out studies for new antiviral drugs

Tese (doutorado)—Universidade de Brasília, Instituto de Ciências Biológicas, Programa de Pós-Graduação em Biologia Animal, 2016. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2016-09-15T21:04:04Z No. of bitstreams: 1 2016_AnaCarolinaArcanjoSilva.pdf: 5455901 bytes, checksum: fe4633e3d83f5d329ef96a0881076c7a (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2016-11-08T12:16:49Z (GMT) No. of bitstreams: 1 2016_AnaCarolinaArcanjoSilva.pdf: 5455901 bytes, checksum: fe4633e3d83f5d329ef96a0881076c7a (MD5) / Made available in DSpace on 2016-11-08T12:16:49Z (GMT). No. of bitstreams: 1 2016_AnaCarolinaArcanjoSilva.pdf: 5455901 bytes, checksum: fe4633e3d83f5d329ef96a0881076c7a (MD5) / O estado da arte do conhecimento sobre as relações entre variabilidade genética e a dinâmica das populações humanas é reflexo de anos de descrições de frequências alélicas e genotípicas. Os padrões de variação de marcadores genéticos em regiões codificadoras e nãocodificadoras não são necessariamente os mesmos, uma vez que mutações em regiões codificadoras podem ter impactos significativos na sobrevivência de um indivíduo. Esse trabalho tem por principal objetivo explorar a variabilidade genética humana sob duas perspectivas. Na saúde refere-se à variabilidade genética acessada por marcadores genéticos neutros, que caracterizam as relações de variabilidade entre os grupos populacionais de uma forma não-enviesada. Para isso, utilizou-se um painel de 100 inserções Alu em um conjunto de 1125 amostras de populações mundiais. O painel evidenciou grande desequilíbrio de ligação nas populações brasileiras e na população de Utah, fruto da miscigenação recente (250 anos) durante a formação dessas populações. A miscigenação detectada pelo painel distorce as relações entre os grupos populacionais, uma vez que Kalunga forma um grupo à parte dentro do grupo africano (devido à miscigenação europeia) e Brasília se assemelha mais ao grupo do Oriente Médio do que ao europeu (devido à miscigenação africana). Além disso, o painel evidenciou que os grupos populacionais não podem ser considerados homogêneos, apesar de pelo menos uma população de cada grupo não apresentar diferenciação populacional às outras populações do seu grupo. Na doença, a variabilidade genética de genes e regiões gênicas foram avaliadas usando como exemplo a susceptibilidade de indivíduos a formas severas da infecção pelo vírus da influenza H1N1, a partir de uma busca da variabilidade genética global acessada por meio do 1000 Genomes Project. A variabilidade genética para marcadores associados à susceptibilidade a formas severas da infecção pelo vírus da influenza é pequena, ocorrendo principalmente em regiões intergênicas e que, a priori, não afetam a expressão dos genes. No entanto, mutações que já haviam apresentado associação a quadros severos da infecção alcançaram maiores frequências nas populações que tiveram maiores taxas de mortalidade durante a pandemia de H1N1/2009, que estão também relacionadas à ancestralidade compartilhada dessas populações. Portanto, os marcadores genéticos neutros foram suficientes para a diferenciação de grupos de amostras quanto à ancestralidade geográfica, onde as populações miscigenadas tenderam a se agrupar a populações que representassem o grupo com maior contribuição genética daquela população. Já os marcadores genéticos associados à susceptibilidade à infecção pelo vírus da influenza, permitiram identificar poucos grupos, normalmente também congruentes com a ancestralidade genética das amostras. Dessa forma, entender a ancestralidade genética de um grupo populacional facilitaria entender a susceptibilidade a doenças infecciosas, isto é, as duas classes de marcadores se complementam na busca de um melhor entendimento da transição entre a saúde e a doença. ________________________________________________________________________________________________ ABSTRACT / The state of the art of the knowledge about the relationship between genetic variability and the dynamics of human populations is a result of yeas of describing allelic and genotypic frequencies. The patterns of variation for genetic markers in coding and non-coding regions are not the same, since mutations in coding regions might have significant impact in one’s ability to survive. The main goal for this work is to explore the human genetic variability under two different perspectives. In health, it refers to the genetic variability that is accessed by neutral genetic markers, which describe the variability relationships among population groups in an unbiased way. To achieve that, a panel of 100 Alu insertions was used in a set of 1125 worldwide samples, including 160 samples from two admixed Brazilian populations, Brasília and Kalunga. The insertion panel showed a tenfold increase in the number of linked loci to each locus in Brasilia, Kalunga and Utah when compared to African, European, Asian and Indian populations. Which is mainly due to the recent admixture of different populations in the making of those populations (250 years). Kalunga clusters with the African populations, but still shows differentiation due to being admixed, Brasilia clusters with both the European and the Middle- Eastern groups, being the last one more genetically similar to Brasilia than the first due to an African genetic component. The population groups cannot be considered homogeneous, despite at least one population of each group not showing population differentiation to the other populations of its group. In health, the genetic variability of genes and coding regions were evaluated using as a model the susceptibility of an individual to severe forms of H1N1 influenza virus infection, by searching a global genetic variability that exists in the 1000 Genome Project database. The genetic variability of genetic markers that are associated to susceptibility to severe forms of influenza infection is small, occurring mainly in intergenic regions that, a priori, do not affect gene expression. However, mutations that have been associated to severe forms of infection have reached larger frequencies in populations that had larger mortality rates during the H1N1/2009 pandemic. Therefore, the neutral genetic markers were sufficient to the clustering of samples related to their geographic region. An exception to that were the admixed Brazilian populations that clustered with the groups that had contributed most to their genetic composition. The genetic markers related to susceptibility to influenza virus infection, on the other hand, could tell apart few groups, usually coincidental to their genetic ancestry. In this way, understanding the genetic ancestry of a population group would make it easier to understand the susceptibility to infectious diseases, that is to say that both classes of genetic markers complete each other in the search for a better understanding of the transition between health and sickness.

Tese (doutorado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2015. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2016-03-02T12:17:34Z No. of bitstreams: 1 2015_LigiaMariaCantarinodaCosta.pdf: 12146458 bytes, checksum: 8583d5014227cbcc6cb3e5156afe26a8 (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2016-03-02T18:04:22Z (GMT) No. of bitstreams: 1 2015_LigiaMariaCantarinodaCosta.pdf: 12146458 bytes, checksum: 8583d5014227cbcc6cb3e5156afe26a8 (MD5) / Made available in DSpace on 2016-03-02T18:04:22Z (GMT). No. of bitstreams: 1 2015_LigiaMariaCantarinodaCosta.pdf: 12146458 bytes, checksum: 8583d5014227cbcc6cb3e5156afe26a8 (MD5) / Influenza é virose respiratória de alta transmissibilidade e de impacto na população mundial. A Organização Mundial da Saúde estima que epidemias anuais resultem em cerca de 3 a 5 milhões de casos de doença grave e de 250 mil a 500 mil mortes em todo o mundo. O objetivo geral do estudo foi avaliar a o sistema de vigilância epidemiológica de influenza no Brasil. Eram os objetivos específicos: descrever a estrutura sanitária brasileira frente a episódios pandêmicos de influenza; descrever a implantação e estruturação da vigilância de influenza no Brasil; discutir princípios éticos na vigilância de influenza; descrever os dados e a qualidade do seu registro nos bancos de dados do sistema de vigilância epidemiológica da influenza; descrever os atributos do sistema de vigilância epidemiológica de influenza. Foi realizada revisão de literatura e, para avaliar os atributos qualitativos, quantitativos, utilidade do sistema e desempenho da definição de caso foi utilizada a metodologia do Updated Guidelines for Evaluating Public Health Systems do Centers for Disease Control and Prevention (CDC). A população de estudo correspondeu aos casos registrados de síndrome gripal no Sistema de Informação Epidemiológica da Gripe (Sivep-Gripe), de 2010 a 2013, com base de dados secundários, não nominais. O sistema de vigilância deve ser melhorado em relação à qualidade dos dados, clareza metodológica e completitude. Foi considerado parcialmente útil, simples, de fácil entendimento, oportuno e flexível. No entanto, possui baixa aceitabilidade, baixo valor preditivo positivo e representatividade insatisfatória. O estudo demonstrou que há necessidade de reflexão ética sobre as práticas em vigilância em saúde, observando a interdependência entre vigilância e pesquisa em saúde. É evidenciada a importância da vigilância da influenza de avaliações constantes, para identificar e corrigir problemas e melhorar o desempenho do sistema de vigilância, num processo contínuo de aperfeiçoamento. / Influenza is a highly transmissible viral respiratory infection with significant impact on world population. The World Health Organization estimates that current epidemics result in approximately 3 to 5 million cases of severe illness and 250 thousand to 500 thousand deaths worldwide. The overall objective of the study was to evaluate the epidemiological surveillance system of influenza in Brazil. The specific objectives were: to describe the Brazilian health structure against the pandemic episodes of influenza; to describe the implementation and structuring of influenza surveillance in Brazil; to discuss ethical principles in influenza surveillance; to describe the data and the quality of the records in the databases of the influenza epidemiological surveillance system; to describe the attributes of the influenza epidemiological surveillance system. Literature review was performed and in order to assess the qualitative and quantitative attributes, the system usefulness and the performance of the case definition the methodology used was based on the Updated Guidelines for Evaluating Public Health of Systems Centers of the Disease Control and Prevention (CDC). The population of the study corresponded to recorded cases of flu-like illness in Brazil’s Influenza Epidemiological Information System (Sivep-Gripe), from 2010 to 2013, with secondary databases and without patient names. The surveillance system should be improved in relation to data quality, methodological clarity and completeness. It was considered partially useful, simple, of easy comprehension, timely and flexible. However, it has low acceptability, low positive predictive value and unsatisfactory representation. The study demonstrated that there is a need for ethical reflection on health surveillance practices, noting the interdependence between surveillance and health research. It is evidenced the importance of influenza surveillance and that ongoing assessments should be conducted to identify and correct problems and to improve the performance of the surveillance system in a continuous process of improvement.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-10-04T22:23:59Z No. of bitstreams: 1 DalilaNascimentoManso_DISSERT.pdf: 1914411 bytes, checksum: 966fc442e252d656c3946bff697a75f5 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-10-13T21:33:08Z (GMT) No. of bitstreams: 1 DalilaNascimentoManso_DISSERT.pdf: 1914411 bytes, checksum: 966fc442e252d656c3946bff697a75f5 (MD5) / Made available in DSpace on 2017-10-13T21:33:08Z (GMT). No. of bitstreams: 1 DalilaNascimentoManso_DISSERT.pdf: 1914411 bytes, checksum: 966fc442e252d656c3946bff697a75f5 (MD5) Previous issue date: 2017-04-19 / A mais recente pandemia do v?rus influenza ocorreu no ano de 2009, causada pela cepa do influenza A (H1N1), e popularmente conhecida como gripe A ou gripe su?na, gerou preocupa??o aos ?rg?os mundiais de sa?de. Com um quadro sintom?tico que inclui febre, tosse, inflama??o na garganta na maioria dos casos, alguns pacientes, principalmente imunossuprimidos que podem apresentar complica??es que evoluem ao ?bito. A transmiss?o do v?rus ocorre atrav?s do contato entre pessoa a pessoa e seu mecanismo de infec??o se d? a partir das duas glicoprote?nas de superf?cie, a hemaglutinina e a neuraminidase. A hemaglutinina atua se ligando aos receptores do ?cido si?lico favorecendo a entrada do v?rus nas c?lulas-alvo e a neuraminidase cliva as c?lulas do receptor de res?duos do ?cido si?lico, onde as novas part?culas virais est?o se ligando. Atrav?s dessa quebra haver? libera??o das novas part?culas virais, que atrav?s da hemaglutinina invadir?o novas c?lulas. Baseado nisso, f?rmacos foram desenvolvidos com intuito de inibir a a??o da neuraminidase, os chamados inibidores da neuraminidase que interferem na libera??o dessas novas part?culas virais evitando a dissemina??o da infec??o no trato respirat?rio. Dentre estes inibidores o oseltamivir ? o f?rmaco de escolha para profilaxia e tratamento da gripe A; por?m, relatos de resist?ncia a esse f?rmaco foram descritos, o que causou preocupa??o nos profissionais da sa?de e governantes. A muta??o mais encontrada ? a HIS275TIR, onde a histidina ? substitu?da por uma tirosina, promovendo uma s?rie de altera??es conformacionais que diminuem a afinidade do f?rmaco pelo v?rus originando a resist?ncia. A partir da obten??o de dados cristalogr?ficos e simula??o computacional, calculamos a energia de intera??o da neuraminidase selvagem e com a presen?a da muta??o HIS275TIR ligadas ao oseltamivir utilizando a Teoria Funcional da Densidade (DFT) e do M?todo de Fracionamento Molecular com Capas Conjugadas (MFCC). Obtivemos 115 res?duos de intera??o para a neuraminidase selvagem (cristal 4B7R) e 109 res?duos de intera??o para o cristal com a neuraminidase mutante (3CL0). Os resultados foram avaliados de acordo com a relev?ncia dos valores energ?ticos para energias repulsivas e energias atrativas. Os c?lculos energ?ticos realizados confirmaram a redu??o da afinidade da cepa contendo a muta??o HIS275TIR e destacaram a import?ncia energ?tica do s?tio ativo da neuraminidase mostrando que os principais res?duos energ?ticos s?o encontrados nele tornando um alvo para obten??o de novos f?rmacos devido a sua conserva??o. As altera??es causadas pela substitui??o do amino?cido histidina por uma tirosina levaram a uma s?rie de mudan?as conformacionais nos amino?cidos vizinhos que provocaram altera??es eletrost?ticas resultando na resist?ncia ao f?rmaco. A partir desse estudo ser? poss?vel conhecer melhor as intera??es moleculares da neuraminidase mutante e posteriormente projetar novos designs de f?rmacos para serem elaborados e se tornarem mais eficientes na intera??o com as cepas mutantes desse v?rus. / The latest influenza pandemic occurred in the year 2009, caused by the strain of influenza A (H1N1), and popularly known as influenza A or swine flu, generated concern to the global health agencies. With a symptomatic picture that includes fever, cough, throat inflammation in most cases, some patients, mainly immunosuppressed, that can to present complications that evolve to death. Transmission of the virus takes place through contact between person to person and its mechanism of infection occurs from the two surface glycoproteins, hemagglutinin and neuraminidase. The hemagglutinin acts by binding to the sialic acid receptors favoring the entry of the virus into the target cells and the neuraminidase cleaves the receptor cells of sialic acid residues, where the new viral particles are binding. Through this breakdown there will be release of the new particles that through hemagglutinin will attack new cells. Based on these, drugs were developed in an attempt to inhibit the action of neuraminidase, so called neuraminidase inhibitors that interfere in the release of these new viral particles avoiding the spread of infection in the respiratory tract. Among the inhibitors, oseltamivir is the drug of choice for prophylaxis and treatment of influenza A, but reports of resistance to this drug have been described, which has caused concern in health professionals and rulers. The HIS275TIR mutation is most commonly found, where histidine is replaced by a tyrosine, promoting a series of conformational changes that decrease the affinity of the drug for the virus causing resistance. Based on crystallographic data and computational simulation, we calculated the interaction energy of the wild neuraminidase and the presence of the HIS275TIR mutation bonded to oseltamivir using the Functional Density Theory (DFT) and the Molecular Fractionation with Conjugated Caps (MFCC). We obtained 115 interaction residues for the wild neuraminidase (4B7R crystal) and 109 interaction residues for the crystal with the mutant neuraminidase (3CL0). The results were evaluated according to the relevance of the energy values for repulsive energies and attractive energies. The energetic calculations confirmed the reduction of the affinity of the strain containing the HIS275TIR mutation and highlighted the energy importance of the active site of the neuraminidase, showing that the main energy residues are found in it becoming a target for obtaining new drugs due to its conservation. The changes caused by the substitution of the amino acid histidine for a tyrosine led to a series of conformational changes in the neighboring amino acids that provoked electrostatic changes resulting in the resistance to the drug. From this study, it will be possible to know better the molecular interactions of the mutant neuraminidase and subsequently to project new drugs designs to be elaborated and become more efficient in the interaction with the mutant strains of this virus.

INTRODUÃÃO - A gripe à uma doenÃa infecciosa aguda de origem viral, de distribuiÃÃo universal, que acomete o trato respiratÃrio. Segundo estatÃsticas da OrganizaÃÃo Mundial da SaÃde (OMS), cerca de 5 a 15% da populaÃÃo mundial se infecta com o vÃrus da influenza anualmente. Em marÃo de 2009, com mudanÃa no padrÃo da ocorrÃncia da influenza no MÃxico, o vÃrus da influenza A (H1N1), um quÃdruplo recombinante nunca antes visto, foi identificado atravÃs da anÃlise de amostras de secreÃÃo de nasofaringe de crianÃas americanas sintomÃticas, confirmando o vÃnculo epidemiolÃgico com os casos no MÃxico (CDC/Atlanta, 2009) e em meses seguintes, com a transmissÃo sustentada de pessoa para pessoa e acometimento de vÃrios paÃses e naÃÃes, foi deflagrada uma nova pandemia. OBJETIVOS - Os objetivos deste estudo foram descrever a evoluÃÃo temporal, caracterizar os padrÃes de morbi-mortalidade e identificar os fatores associados à ocorrÃncia de gravidade e Ãbitos nas diferentes fases da pandemia de Influenza A (H1N1) 2009 no CearÃ. MÃTODOS - Trata-se de estudo descritivo, retrospectivo, dos casos notificados e confirmados de influenza pandÃmica (H1N1) 2009, no Estado do CearÃ, nos anos de 2009 e 2010. RESULTADOS E DISCUSSÃO - A pandemia deu-se em trÃs pequenas ondas, uma na fase de contenÃÃo, caracterizada por casos leves, com resoluÃÃo rÃpida. As duas segundas ondas, na fase de mitigaÃÃo, com casos com maior gravidade, maior taxa de hospitalizaÃÃo, a totalidade de pacientes que necessitaram de cuidados intensivos (UTI) e todos os pacientes que evoluÃram para Ãbito. Foram notificados 615 casos, destes 144 foram confirmados. 55,5% eram do sexo feminino, 30% eram pardos, 72,5% dos casos graves possuÃam alguma comorbidade e 40 pacientes necessitaram de hospitalizaÃÃo. A letalidade hospitalar foi de 20% e a letalidade em UTI foi de 66%. Foram significantes para evoluÃÃo para cura ou Ãbito aspectos relacionados à procura por assistÃncia mÃdica, atraso no inÃcio da terapia antiviral, obesidade, ter baixa escolaridade, uso de ventilaÃÃo mecÃnica e ser hospitalizado em hospitais com atendimento especializado. CONCLUSÃO - A anÃlise dos dados do presente estudo permitiu conhecimento aprofundado acerca do padrÃo de morbi-mortalidade causado pela pandemia de influenza A (H1N1) 2009 no Estado do CearÃ. O estudo sugere que a pandemia de influenza A (H1N1) 2009 nesta regiÃo do Brasil teve magnitude menor se comparado a outros estados de outras regiÃes do paÃs, com baixa incidÃncia, porÃm altas taxas de letalidade em pacientes internados em UTI. / NTRODUCTION - Influenza is an acute infectious disease of viral origin, universal distribution, which affects the respiratory tract. According to statistics from the World Health Organization (WHO), about 5-15% of the world population is infected with influenza virus annually. In March 2009, with change in the pattern of occurrence of influenza in Mexico, influenza virus A (H1N1), a quadruple recombinant never seen before, was identified by analyzing samples of nasopharyngeal secretions from symptomatic American children, confirming the epidemiological link with the cases in Mexico (CDC / Atlanta, 2009) and months, with sustained transmission from person to person and involvement of various countries and nations, was sparked a new pandemic. OBJECTIVES - The objectives of this study were to describe the temporal evolution, characterize the patterns of morbidity and mortality in different periods and to identify factors associated with the occurrence and severity of deaths in different phases of pandemic Influenza A (H1N1) 2009 in CearÃ. METHODS - This study is a descriptive, retrospective study of cases reported and confirmed pandemic influenza (H1N1) 2009 in the state of CearÃ, in the years 2009 and 2010. RESULTS AND DISCUSSION - The pandemic occurred in three small waves, one at retention phase, characterized by mild, with rapid resolution. The second two waves, the mitigation phase, with more severe cases, higher rates of hospitalization, all patients who required intensive care (ICU) and all patients who died. 615 cases were reported, 144 of these were confirmed. 55.5% were female, 30% were mixed race, 72.5% of the cases had some serious comorbidity and 40 patients required hospitalization. Hospital mortality was 20%, and mortality in the ICU was 66%. Were significant for evolution to cure or death issues related to the demand for medical care, delay in initiation of antiviral therapy, obesity, low education, use of mechanical ventilation and be hospitalized in hospitals with specialized care. CONCLUSION - The data analysis of this study allowed in-depth knowledge about the pattern of morbidity and mortality caused by pandemic influenza A (H1N1) 2009 in the state of CearÃ. The study suggests that pandemic influenza A (H1N1) 2009 in this region of Brazil was magnitude lower compared to other states in other regions of the country with low incidence but high mortality rates in ICU patients.

The 2009 Influenza A (H1N1) virus quickly became a pandemic and a threat to the health of many across the globe. H1N1 was able to preferentially bind to pneumocytes in the lower lung, resulting in atelectasis, surfactant disruption, and eventual acute respiratory distress syndrome (ARDS). Management of ARDS during this time included non-ventilatory and ventilatory techniques such as conservative fluid management, prone positioning, differing PEEP levels, and Extracorporeal Membrane Oxygenation (ECMO). High cost, unequal global access to ECMO centers, and complication rates present challenges to future ECMO expansion. Despite this, the available information supports the use of ECMO for H1N1-associated ARDS. Future studies and simulations should be conducted to expand the knowledge base on using ECMO as a treatment for pandemic influenza-associated ARDS, with particular attention on bridging gaps in access for the most vulnerable and affected populations.

L'absentéisme scolaire a été un indicateur de surveillance de l'influenza pour la première fois au Québec lors de la deuxième vague de la pandémie de grippe A (H1N1). Cette étude avait pour objectif de décrire les données ainsi recueillies, et de comparer cet indicateur par rapport à ceux existants. Toutes les écoles devaient effectuer un signalement quotidien et durant 7 jours, lorsque le taux d'absentéisme pour syndrome d'allure grippale (SAG) atteignait 10%. La courbe de distribution hebdomadaire des écoles affectées a été comparée aux courbes des données de laboratoire et des données d'hospitalisations chez les jeunes d'âge scolaire et dans la population générale. Au total 35,6% d'écoles ont effectué un signalement, avec un maximum de signalements durant la semaine CDC 44. Le pic de l'absentéisme scolaire a été observé la même semaine que celui des tests de laboratoire positifs et une semaine avant celui des hospitalisations des jeunes de 5-17 ans. L'absentéisme scolaire s'est avéré être un indicateur utile de la progression de la pandémie. Cependant le caractère précoce de cet indicateur reste à évaluer.

Les inhibiteurs de la neuraminidase (INAs) jouent un rôle central dans le contrôle des infections grippales, tant dans le cas des épidémies et des pandémies comme chez les patients immunosuprimés et d'autres patients à risque. Cependant, le développement et la dissémination de la résistance compromettent l'utilité à long terme de cette intervention. En fait, le problème de la résistance aux INAs a été mis en évidence pendant les épidémies de grippe annuelles de 2007-09, avec la dissémination globale d’une variante de la souche A(H1N1) saisonnière résistante à l'oseltamivir. Dans ce cas, les observations préliminaires ont spéculé avec l'existence d'un ensemble de mutations “permissives” qui auraient facilité cette transmission mondiale. Heureusement, l'émergence et la propagation mondiale de la souche pandémique en 2009 a mené au remplacement de la souche saisonnière A/Brisbane/59/2007 (H1N1) résistante à l'oseltamivir, par le virus A(H1N1)pdm09 naturellement sensible aux INA, et, par conséquent, l'oseltamivir a récupéré son utilité clinique. En fait, la plupart des virus A(H1N1)pdm09, A(H3N2) et B circulants à ce jour restent sensibles à l'oseltamivir, avec seulement 1-2% de souches résistantes. Néanmoins, le nombre croissant de souches résistantes récemment détectées en l’absence de traitement fait craindre que ce problème puisse encore augmenter. À cet égard, l'impact de l'émergence et la dissémination de la résistance sur le choix limité des antiviraux actuellement disponibles renforce la nécessité d’une meilleure compréhension des mécanismes sous-jacents à ce phénomène ainsi que de nouvelles approches thérapeutiques. Les différentes études présentées dans le cadre de cette thèse convergent vers l'objectif général de mieux décrire les mécanismes de développement de la résistance aux INAs dans les virus de la grippe. En outre, nous prévoyons que les thérapies combinées pourraient induire une meilleure réponse virologique et immunologique par rapport à la monothérapie antivirale. À la fin, nous nous attendons à ce que notre travail ait un impact sur la gestion des infections grippales en guidant la surveillance mondiale des marqueurs potentiels de résistance, ainsi qu’en proposant des traitements novateurs qui minimisent le développement de souches résistantes. / Neuraminidase inhibitors (NAIs) play a central role in the control of influenza infections, with important implications in the management of outbreaks and pandemics as well as in immunocompromised and other at risk patients, with both prophylactic and therapeutic indications. However, the development and dissemination of antiviral drug resistance represents a major limitation that compromises the long-term usefulness of this intervention. Actually, the problem of resistance to NAIs was highlighted by the worldwide dissemination of the oseltamivir-resistant seasonal A(H1N1) neuraminidase H274Y variant during the 2007-09 annual influenza epidemics. In that case, preliminary observations speculated with the existence of a set of “permissive” mutations that could have facilitated this global transmission. Fortunately, the antigenic shift that enabled the emergence of and global spread of the 2009 pandemic strain meant the replacement of the oseltamivir-resistant seasonal A/Brisbane/59/2007 (H1N1) virus by the naturally NAI-susceptible A(H1N1)pdm09 virus, and, consequently, oseltamivir recovered its clinical utility. In fact, most of the circulating A(H1N1)pdm09, A(H3N2) and B viruses remain susceptible to oseltamivir with only 1-2% of tested strains exhibiting phenotypic or genotypic evidence of resistance. Nevertheless, the growing number of resistant strains recently detected in the absence of therapy raises concern that this problem could increase. In that regard, the impact of the emergence and dissemination of resistance on the limited choice of antivirals currently available underscores a better understanding of the mechanisms underlying this phenomenon as well as the necessity for innovative therapeutic approaches. The different studies presented in this thesis converge to the general objective of better describing the mechanisms underlying the development of resistance to NAIs in influenza viruses. Also, we anticipate that combination therapies will induce better virological and immunological responses compared to antiviral monotherapy. In the end, we expect that our work will have an impact on the management of influenza infections by guiding the global surveillance of potential drug resistance markers, as well as proposing innovative ways to improve the clinical outcome and minimizing the development of drug-resistant strains.