<b>Introduction:</b> Respiratory Syncytial Virus is the major viral cause of lower respiratory tract disease in young children worldwide, with the greatest burden of disease in infants aged 1-3 months. Consequently, vaccine development has centered on a vaccine to directly protect the infants in this age group. The fundamental problem is that these young infants are poor responders to candidate RSV vaccines. This thesis focuses on the use of mathematical models to explore the merits of vaccination. <b>Methods:</b> Following development and analysis of a simple non-age-structured ODE model, we elaborate this to a Realistic Age Structured model (RAS) capturing the key epidemiological characteristics of RSV and incorporating age-specific vaccination options. The compartmental ODE model was calibrated using agespecific and time series hospitalization data from a rural coastal Kenyan population. The determination of Who Acquires Infection From Whom (WAIFW) matrix was done using social contact data from 1) a synthetic mixing matrix generated from primarily household occupancy data and 2) a diary study that we conducted in the Kilifi Health and Demographic Surveillance System (KHDSS). The vaccine was assumed to elicit partial immunity equivalent to wild type infection and its impact was measured by the ratio of hospitalized RSV cases after to before introduction. of vaccination. Uncertainty and sensitivity analysis were undertaken using Latin Hypercube Sampling (LHS) and partial rank correlation respectively. Given the importance of households in the transmission of respiratory infections, an exploratory household model was developed to capture the transmission dynamics of RSV A and B in a population of households. <b>Results:</b> From the analytical work of the simple ODE model, we have demonstrated that the model has the potential to exhibit a backward bifurcation curve within realistic parameter ranges. Both the diary and the synthetic mixing matrices had similar characteristics i.e. strong assortative mixing in individuals less than 30 years old and strong mixing between children less than 5 years and adults between 20 and 50 years old. When the two matrices were jointly linearly regressed, their elements were well correlated with an R2 ~ 0.6. The RAS model was capable of capturing the age-specific disease and the temporal epidemic nature of RSV in the specified location. Introduction of routine universal vaccination at ages varying from the first month of life to the 10th year of life resulted in optimal long-term benefit at 7 months (for the diary contact model) and 5 months (for the synthetic contact model). The greatest benefit arose under the assumption of age-related mixing with the contact diary data with no great deal of effectiveness lost when the vaccine is delayed between 5 and 12 months of age from birth. Vaccination was also shown to change the temporal dynamics of RSV hospitalizations and also to increase the average age at primary infection. From the sensitivity analysis, we identified the duration of RSV specific maternal antibodies, duration of primary and tertiary infections as the most important parameters in explaining the imprecision observed in predicting both the age specific hospitalizations and the optimal month at vaccination. Results from the household model have demonstrated that the household epidemic profile may be different from the general population with strong interaction of the viruses in the household that do not necessarily reflect at the population level. <b>Conclusion:</b> The synthetic matrix method would be a preferable alternative route in estimating mixing patterns in populations with the required socio-demographic data. Retrospectively, the synthetic mixing data can be used to reconstruct contact patterns in the past and therefore beneficial in assessing the effect of demographic transition in disease transmission. Universal infant vaccination has the potential to significantly reduce the burden of RSV associated disease, even with delayed vaccination between 5 and 12 months. This age class represents the group that is being targeted by vaccines that are currently under development. More accurate data measuring the duration of RSV specific maternal antibodies and the duration of infections are required to reduce the uncertainty in the model predictions.

Orientador: Fátima Pereira de Souza / Banca: Karina Alves de Toledo / Banca: José Roberto Ruggiero / Resumo: O Vírus Sincicial Respiratório Humano (hRSV) foi identificado em 1957 e mesmo após vários anos de investigação, nenhuma vacina foi desenvolvida. Acredita-se que a chave de inibição da ação viral são suas glicoproteínas de membrana, em especial a proteína de fusão (F), que com auxílio da proteína de ligação (G), é responsável pela instalação do hRSV na célula hospedeira. Há evidências experimentais de que compostos como flavonóides e glicosaminoglicanos podem diminuir a infecção viral, sendo então a proteína F um bom alvo para a ação destes compostos. O presente estudo utilizou de ferramentas de bioinformática para verificar as possíveis regiões de interação da proteína F com a Heparina Sulfatada e Flavonóides. Os programas de bioinformática foram utilizados para: modelagem dos compostos, caracterização e previsão da estrutura secundária da proteína, modelagem da estrutura terciária e docking molecular entre o modelo da proteína F e as estruturas tridimensionais dos Flavonóides e da Heparina Sulfatada. Modelos válidos foram obtidos para as estruturas tridimensionais dos flavonóides e para o modelo completo da proteína F. As características da proteína incluem um alto nível de conservação na seqüência de aminoácidos e, especialmente, em seus sítios de ligação. O docking da proteína com a Heparina, e o virtual screening da biblioteca de Flavonóides e a estrutura da proteína, resultaram em sítios de interação com grande potencial de inibição, uma vez que concordam com evidências experimentais descritos na literatura. A Heparina liga-se ao sítio de clivagem II, importante região para obtenção da atividade de fusão da proteína. Os Flavonóides podem se ligar a região hidrofóbica que desestabiliza... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Human Respiratory Syncytial Virus (hRSV) was identified in 1957 and even after several years of research, no vaccine has been developed yet. It is believed that the key to the inhibition of viral action is its membrane glycoproteins, including the Fusion Protein (F), responsible for the installation of the hRSV in the host cell. There are evidences that compounds such as flavonoids and glycosaminoglycans can decrease the viral infection, and F protein can be a good target for the action of these compounds. The present study checked the possible sites of interaction between F protein and heparin and flavonoids, using computational tools. Bioinformatics programs were used for: modeling compounds, characterization and prediction of protein secondary structure, tertiary structure modeling and the docking between the protein model and the structures of flavonoids and sulfated heparin. Valid models were obtained for flavonoids structures and the complete model of F protein. The characteristics of the protein include a high level of conservation in amino acid sequence and especially in its binding sites. The heparin docking and virtual screening of flavonoids resulted in interaction sites with great potential for inhibition, since they agree with other studies and experimental evidence of F protein inhibition. This study shows that compounds such as sulfated heparin and flavonoids interact in important sites of F protein. Heparin binds to the cleavage site II and flavonoids can bind to the hydrophobic site that destabilizes the formation of the six-helix-bundle region. Both regions are important for conformational changes that F protein undergoes to get its fusion activity. Docking showed that molecular interactions are likely to occur and selected the best candidates for a possible inhibitor. These evidences... (Complete abstract click electronic access below) / Mestre

Orientador: Maria Rita Donalísio Cordeiro / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T16:23:15Z (GMT). No. of bitstreams: 1 Freitas_AndreRicardoRibasde_D.pdf: 4270845 bytes, checksum: 09078cb28a971b59a0103ccfbe6a3bee (MD5) Previous issue date: 2014 / Resumo: Introdução e objetivos: As infecções respiratórias estão entre as mais importantes causas de morbimortalidade no mundo. A sua alta incidência tem relevante impacto nos óbitos, como também na sobrecarga do sistema de saúde e absenteísmo no trabalho e escola Todas as faixas etárias são acometidas, porém, as mais afetadas são as crianças e os idosos. Também são particularmente susceptíveis os imunocomprometidos e os portadores de doenças crônicas em geral. Os vírus são os agentes responsáveis pela maior parte das infecções respiratórias, os principais vírus causadores de infecções respiratórias são o influenza A e B e o Vírus Sincicial Respiratório (VSR). Estes vírus têm comportamento biológicos distintos e o conhecimento de como estes vírus afetam a saúde da população é fundamental para embasar as ações de prevenção, profilaxia e tratamento de pacientes permitindo uma alocação adequada de recursos em quantidade e tempo adequados. No Brasil, no ano 2000, para monitorar a ocorrência destes vírus foi implantada a vigilância de síndromes gripais SIVEP-GRIPE, que através de 128 unidades sentinelas distribuídas em todas as regiões do país coletam semanalmente amostras de secreção de nasofaringe por semana de pacientes com síndromes gripais. Neste trabalho estudamos o impacto do influenza na mortalidade no estado de São Paulo, nas diferentes faixas etárias no período entre 2002 e 2011, incluindo o período da pandemia de 2009. Estudamos também a sazonalidade do VSR nas 5 diferentes regiões brasileiras e o impacto deste vírus nas internações por doenças respiratórias entre menores de 5 anos. Metodologia: Para o estudo da mortalidade associada ao influenza utilizamos o método de regressão de Serfling adaptado para dados semanais extraindo da série histórica os períodos de maior circulação viral a partir dos resultados do sistema de vigilância sentinela SIVEP-GRIPE. Comparar a mortalidade associada à pandemia de influenza de 2009, às epidemias prévias anuais de influenza nas diferentes faixas etárias e com diferentes subtipos de vírus influenza circulantes no estado de São Paulo. Para o estudo da sazonalidade do VSR utilizamos análise de Wavelets, análise de Fourier, análise simplificada de estações anuais comparando os resultados nas 5 regiões administrativas do Brasil. Para identificar possíveis correlações temporais entre a circulação dos vírus respiratórios utilizamos métodos de regressão de ranque de Spearman e de regressão parcial. Resultados e conclusões: A mortalidade por pneumonia e influenza associada à pandemia de 2009 no estado de São Paulo foi ligeiramente mais alta que nos outros anos de influenza sazonal, considerando a mortalidade geral, sem distinção de faixa etária. Houve diferenças no risco de morrer entre as faixas etárias. Entre os indivíduos de 5 a 19 anos, a mortalidade associada à pandemia de 2009 foi 2,6 maior (0,6 óbitos/100.000hab) que a de anos não pandêmicos. Na faixa etária de 20 a 59 anos, a mortalidade associada à pandemia de 2009 foi 5,1 maior (2,8 óbitos/100.000hab) que nos anos não pandêmicos. As taxas de mortalidade entre menores de 5 anos foi 0,9 óbitos/100.000hab e na população de mais 60 anos foi 13,1 óbitos/100.000hab, ou seja, foram menores que nos anos não pandêmicos. O método de análise utilizado permitiu a diferenciação entre a mortalidade associada a subtipos virais (A(H3N2), B ou sazonal A(H1N1) e A(H1N1) pdm 2009). Foi possível a comparação entre a mortalidade associada à pandemia de influenza de 2009 em São Paulo, às epidemias anuais de influenza nas diferentes faixas etárias e com diferentes subtipos de vírus influenza circulando. Isto é, o impacto da circulação do vírus pandêmico influenza A(H1N1) foi maior na mortalidade em adultos e jovens, enquanto em maiores de 65 anos foi discreto. Por outro lado, o excesso de mortalidade foi expressivo em maiores de 65 anos, nos anos de circulação do influenza A(H3N2). O modelo de Serfling adaptado a dados semanais com validação por meio de dados da vigilância sentinela de síndromes gripais (SIVEP-GRIPE) mostrou-se confiável para detectar picos de maior circulação viral do Influenza e supostos reflexos na mortalidade em diferentes faixas etárias em período pandêmico, epidêmico e de circulação sazonal do vírus Influenza. Sobre o VSR foi possível identificar padrões sazonais do VSR em todas as regiões administrativas do Brasil utilizando-se dados da vigilância de síndromes gripais (SIVEP-GRIPE). Houve diferenças entre os momentos de maior circulação do vírus em algumas das cinco regiões administrativas do Brasil. Os padrões sazonais de internação por doenças sabidamente relacionadas com o VSR [Pneumonia devida a vírus respiratório sincicial, Bronquite aguda devida a vírus sincicial respiratório, Bronquiolite aguda devida a vírus sincicial respiratório, Bronquiolite (aguda, não especificada),] foram semelhantes aos encontrados pela análise da circulação do VSR por meio de dados da vigilância de síndromes gripais (SIVEP-GRIPE). Houve correlação temporal entre a circulação do VSR e as taxas de internação por doenças do aparelho respiratório em geral (Capítulo-X da CID-10) entre menores de 5 anos, nas cinco regiões administrativas do Brasil. Houve correlação temporal entre as taxas de internação entre menores de 5 anos por doenças sabidamente relacionadas com o VSR [Pneumonia devida a vírus respiratório sincicial, Bronquite aguda devida a vírus sincicial respiratório, Bronquiolite aguda devida a vírus sincicial respiratório, Bronquiolite (aguda, não especificada),] e as taxas de internação por doenças respiratórias em geral nesta faixa etária nas cinco regiões administrativas do Brasil, indicando que este é o principal vírus associado às internações de crianças até 5 anos por doenças respiratórias. De acordo com as evidências encontradas neste estudo, os esquemas de profilaxia contra o VSR hoje utilizados precisam ser revistos e particularizados para cada região do país. Entre as ações a serem revistas estão a disponibilização do palivizumabe, bem como medidas de prevenção à circulação do VSR na comunidade / Abstract: Introduction and Objectives: Respiratory infections are amongst the most important causes of morbidity and mortality worldwide. Its high incidence has significant impact on deaths, but also burdens the health system and leads to absenteeism from work and school All age groups are affected, but the most affected are children and the elderly. Are also particularly susceptible immunocompromised and patients with chronic diseases in general. Viruses are the agents responsible for most respiratory infections, the main cause of respiratory virus infections are influenza A and B and Respiratory Syncytial Virus (RSV). These viruses have distinct biological behavior and knowledge of how these viruses affect people's health is fundamental to support the prevention, prophylaxis and treatment of patients allowing an adequate allocation of resources in quantity and adequate time. In Brazil, in 2000, to monitor the occurrence of these viruses was established surveillance of influenza-like syndromes SIVEP-FLU, which through 128 sentinel units distributed in all regions of the country collect weekly samples of nasopharyngeal secretions of patients per week with influenza-like illness. In this work we study the impact of influenza on mortality in the state of São Paulo , in different age groups between 2002 and 2011 , including the period of the 2009 pandemic. We also studied the seasonality of RSV in 5 different Brazilian regions and the impact of this virus in hospitalizations for respiratory diseases among children under 5 years. Methods: To study the mortality associated with influenza used the regression method of Serfling adapted for extracting weekly data of the time series periods of increased viral movement from the results of sentinel surveillance system SIVEP - FLU . Compare the mortality associated with pandemic 2009 influenza , annual epidemics of influenza prior at different ages and with different subtypes of influenza viruses circulating in the state of São Paulo . To study the seasonality of RSV , we use wavelet analysis , Fourier analysis , simplified analysis of annual seasons comparing the results in five administrative regions of Brazil . To identify possible temporal correlations between the circulation of respiratory viruses use regression methods of Spearman rank and partial regression. Results and Conclusions: The mortality from pneumonia and influenza associated with the 2009 pandemic in the state of São Paulo was slightly higher than in the other years of seasonal influenza, considering the overall mortality, irrespective of age. There were differences in the risk of dying between age groups. Among individuals 5-19 years, the mortality rate associated with the 2009 pandemic was 2.6 higher than that of non-pandemic years. (0.6 deaths /100,000 inhabitants) In the age group 20-59 years, the rate associated with the 2009 pandemic mortality was 5.1 higher than in non-pandemic years. (2.8 deaths /100,000 inhabitants). Mortality rates among children under five years was 0.9 deaths /100,000 inhabitants and in persons over 60 years was 13.1 deaths /100,000 inhabitants, ie were lower than in non- pandemic years . The method of analysis used allowed the differentiation between mortality associated with viral subtypes (A(H3N2), A(H1N1) and B or seasonal A(H1N1) pdm 2009) . It was possible to compare the mortality associated with the 2009 influenza pandemic in Sao Paulo, annual influenza epidemics in different ages and with different subtypes of influenza viruses circulating. That is, the impact of the circulation of influenza A(H1N1) pandemic virus was higher mortality in adults and children, while in adults over 65 years was low . On the other hand, the excess mortality was significant in adults over 65 years ago, in circulating influenza A H3N2. The Serfling model adapted to weekly data validation using data from sentinel surveillance of influenza-like illness (SIVEP - GRIPE) was reliable for detecting peaks of higher viral circulation of influenza and alleged impacts on mortality in different age groups in pandemic period , epidemic and seasonal circulation of influenza viruses . About RSV was possible to identify seasonal patterns of RSV in all administrative regions of Brazil using surveillance data of influenza syndromes (SIVEP -GRIPE). There were differences between the moments of greatest circulation of the virus in some of the five administrative regions of Brazil. Seasonal patterns of hospitalization for known diseases with RSV [ Pneumonia due to respiratory syncytial virus , acute bronchitis due to respiratory syncytial virus , acute bronchiolitis due to respiratory syncytial virus bronchiolitis ( acute , unspecified ) ] were similar to those found by analysis of the movement of data through RSV surveillance of influenza-like syndromes ( SIVEP - GRIPE) . There was a temporal correlation between the circulation of RSV and the rates of hospitalization for respiratory diseases in general (Chapter X of ICD- 10) among children under 5 diseases in the five administrative regions of Brazil . There was a temporal correlation between the rates of hospitalization among children under 5 years for known diseases with RSV [ Pneumonia due to respiratory syncytial virus , acute bronchitis due to respiratory syncytial virus , acute bronchiolitis due to respiratory syncytial virus bronchiolitis ( acute , unspecified ) ] and rates of hospitalization for respiratory diseases in general in this age group in the five administrative regions of Brazil , indicating that this is the main virus associated with hospitalizations of children under 5 years due to respiratory diseases . According to the evidence found in this study , the schemes of prophylaxis against RSV used today need to be reviewed and individualized for each region of the country . Among the actions to be reviewed are the availability of palivizumab , as well as measures to prevent the circulation of RSV in the community / Doutorado / Epidemiologia / Doutor em Saude Coletiva

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Medicine in the field of Clinical Microbiology and Infectious Diseases Johannesburg, 2018. / Background: Respiratory Syncytial Virus (RSV) is a common cause of upper and lower respiratory tract infections (LRTI), primarily in children having severe disease manifestation. In South Africa, RSV is identified in approximately 25-30% of children hospitalized for LRTI. There is a spectrum of RSV-associated LRTI severity. Understanding associations between immune mediators and RSV-LRTI severity could assist clinicians in the triaging for level of care. Several cytokines have been implicated in RSV-LRTI severity. Aim: Study the associations between cytokine levels from plasma and nasopharyngeal aspirate with RSV infection or RSV-associated LRTI severity in hospitalized infants ranging from 0-12 months of age. The correlation between plasma and nasopharyngeal aspirate cytokine concentrations was also evaluated. Methods: Paired plasma and nasopharyngeal aspirate (NPA) samples were collected from polymerase chain reaction confirmed RSV-infected infants without coinfection with other pathogens that we investigated for. Paired samples were also collected from RSV negative-control infants (n=31) who did not have any respiratory symptoms. Control-infants were scheduled for elective surgery; samples were collected before administration of medication and surgical procedure. RSV associated LRTI episodes were grouped into mild (n=89) and severe RSV-LRTI (n=113) using the Respiratory Index of Severity in Children (RISC) Score. Interferon gamma (IFN-γ), interleukins (IL) IL-1α, IL-1β, IL-4, IL5, IL-6, IL-8, IL-9, IL-10, IL-12(p70)IL-13, macrophage inducing protein (MIP-1α), monocyte chemo attractant protein (MCP-1), tumour necrosis alpha (TNF-α), Regulated on activation, normal T cell expressed and secreted (RANTES) and were measured with multiplex immunosorbent assay using Luminex® technology. Cytokine profiles were evaluated for association of RSV-LRTI severity and between RSV LRTI cases and controls. Results: Comparing hospitalized RSV-associated LRTI to control infants, RSV cases had elevated plasma TNF-α (0.7pg/ml vs. 0.5pg/ml; p=0.007), and IL-10 (1.0pg/ml vs. 0.6pg/ml; p=0.02) concentrations, and reduced plasma MIP-1α (12pg/ml vs. 28pg/ml; p=0.008) and IFN-γ (3pg/ml vs. 5pg/ml; p=0.02) levels. Nasopharyngeal aspirate TNF-α (8.0pg/ml vs. 1.0pg/ml; p=0.01), IL-8 (2682pg/ml vs. 184pg/ml; p=0.002), MCP-1 (287pg/ml vs. 66pg/ml; p<0.001), MIP-1α (27pg/ml vs. 6.7pg/ml; p=0.004) concentrations were elevated in RSV-LRTI cases compared to control infants. Infants hospitalized with severe RSV-associated LRTI (RISC score ≥2) were younger than mild cases (3.9 vs. 4.5 months; p=0.01). In RSV cases, severe RSV-LRTI was associated with increased plasma IFN-γ levels (4pg/ml vs. 3pg/ml) and NPA MIP-1α concentrations (88pg/ml vs. 50pg/ml, mean; all other values medians) compared to mild RSV-LRTI. In a multivariate analysis, NPA MIP-1α levels remained associated with RSV-LRTI (p=0.05), but could not predict RSV-LRTI severity. Conclusion: This study observed that during RSV-associated LRTI, immune response was directed at the respiratory tract. Reduced concentrations of plasma IFN-γ and elevated levels of cytokines in the NPA may suggest that the blood of RSV-LRTI cases had reduced number of IFN-γ producing cells. There was no evidence of distinct Th1 or Th2 type immune response and the cytokines associated with RSV-LRTI severity could not predict the outcome of severe RSV-associated LRTI. Key words: Respiratory Syncytial Virus, Lower respiratory tract infections, Severity, Plasma, Nasopharyngeal aspirate, IFN-γ, MIP-1α, Luminex® / LG2018

Les vecteurs permettant la transmission des infections nosocomiales ne sont pas toujours bien identifiés. Les risques représentés par les virus aéroportés dans les milieux de soins doivent être étudié davantage. Ce mémoire présente des méthodologies pour détecter la présence de virus aéroportés et évaluer leur résistance dans cet état. Le virus influenza, le norovirus et le virus respiratoire syncytial y sont à l’étude. Deux techniques d’échantillonnage furent utilisées soit un échantillonnage à sec (NIOSH 251) et un échantillonneur liquide (Coriolis µ®). Les ADNc viraux furent détectés par qPCR. La résistance des norovirus à l’aérosolisation a été démontrée à l’aide d’un virus-modèle, le norovirus murin. La première détection des norovirus dans l’air de milieux de soins y est décrite. La présence du virus influenza dans l’air a aussi été démontrée. Le virus respiratoire syncytial n’a pu être mis en évidence dans l’air. Les virus pathogènes peuvent être aéroportés et représenter un risque infectieux. / The route of transmission of healthcare associated infections is not always well defined. The airborne dissemination of influenza virus, norovirus and respiratory syncytial virus has to be assessed. This thesis presents methodologies to detect airborne viruses and some innovative way to assess their resistance through the airborne route. Two sampling techniques were used, more precisely a dry sampling using a NIOSH 251 impactor and a liquid sampling using a Corriolis µ®. Viral cDNA was detected by real-time PCR. To assess the resistance of norovirus through the air route we used a cultivable experimental model; the murine norovirus. This thesis presents the first detection of airborne norovirus in a healthcare setting. Influenza virus was detected in the air of an emergency department and in the room of influenza positive patient. Respiratory syncytial virus could not be detected in an airborne state. Pathogenic virus can be disseminated through the airborne route and could represent an infectious risk.

No description available.

No description available.

No description available.

No description available.

Thesis (D.P.H.)--University of Michigan.