Introdução- Em abril de 2009, novo subtipo viral foi identificado, Influenza A(H1N1)pdm09. Em 11 de junho de 2009, a Organização Mundial da Saude anunciou o início de uma pandemia de influenza. Objetivo- Investigar os fatores de risco para óbito por Influenza A(H1N1)pdm09 em pacientes e em gestantes hospitalizados com Doença Respiratória Aguda Grave-DRAG. Nas gestantes, foram analisados também os desfechos gestacionais e neonatais. Metodologia- Foram realizados dois estudos caso-controles, em pacientes e em gestantes hospitalizados com Influenza A(H1N1)pdm09 confirmada laboratorialmente e DRAG. Os casos evoluíram para óbito e os controles para cura. Os casos e controles foram selecionados no Sistema de Informação de Agravos de Notificação-SINANInfluenza- web, sendo sorteados dois controles no estudo dos pacientes, e quatro no das gestantes, pareados por semana epidemiológica da data de internação do caso. O primeiro estudo foi realizado nas regiões Metropolitanas de São Paulo e de Campinas, de 28 de junho a 29 de agosto de 2009. Nas gestantes, o estudo incluiu o Estado de São Paulo, de 09 de junho a 01 de dezembro de 2009. Foram realizadas avaliações dos prontuários hospitalares e entrevistas domiciliares, a partir de formulários padronizados. Foram empregados testes de Mann-Whitney-U ou quiquadrado para comparação das variáveis, e cálculos dos odds ratio brutos-ORb e seus intervalos de confiança-IC95 por cento , para avaliação dos fatores de risco. No primeiro estudo foi definido modelo de regressão logística múltipla para análise dos fatores associados ao óbito. Resultados- No primeiro estudo, foram investigados 193 casos e 386 controles, 73,6 por cento dos casos e 38,1 por cento dos controles tinham alguma condição de risco para complicações relacionadas à influenza. No modelo final, as seguintes variáveis foram fatores de risco para óbito: idade entre 18 a 59 anos, Odds Ratio Ajustado-ORa de 2,31, 95 por cento IC 1,31-4,10, (referência pacientes < 18 anos), presença de pelo menos uma condição de risco (ORa=1,99, 95 por cento IC 1,11-3,57), mais de uma condição de risco (ORa=6,05 95 por cento IC 2,76-13,28), obesidade (ORa=2,73, 95 por cento IC 1,28- 5,83), imunossupressão (ORa=3,43 95 por cento IC 1,28-9,19) e ter tido atendimento prévio à internação (ORa=3,35, 95 por cento IC 1,75-6,40). O tratamento antiviral, quando administrado nas primeiras 48 horas do início dos sintomas foi fator de proteção para óbito, (ORa=0,17, 95 por cento IC 0,08-0,37). Houve benefício também da administração do antiviral entre 48 a 72 horas, (ORa=0,30, 95 por cento IC 0,11-0,81). Em gestantes, foram investigados 48 casos e 185 controles. Foram fatores de risco para óbito: ter tido atendimento prévio à internação, (ORb de 8,03, 95 por cento IC 2,38-27,09) e terceiro trimestre de gestação, (ORb=4,45, 95 por cento IC 1,15-29,25). Tratamento antiviral foi fator de proteção, quando administrado até 48 horas do início dos sintomas (ORb=0,14, 95 por cento IC 0,05-0,37), e de 48 a 72 horas, (ORb=0,13, 95 por cento IC 0,02-0,68). Em relação aos desfechos gestacionais, houve maior proporção de perdas fetais e partos prematuros entre os casos, p=0,001. As gestantes que evoluíram para óbitos tiveram recém nascidos vivos com mais baixo peso e índices inferiores no Apgar do primeiro minuto, p=0,016, quando comparado aos controles que tiveram parto durante a internação, p<0,001. Conclusão: A identificação dos pacientes de maior risco e o tratamento precoce são fatores importantes para a redução da morbimortalidade por influenza. / Introduction - In April 2009, a new viral subtype was identified, influenza A (H1N1)pdm09. On June 11, the World Health Organization announced the beginning of the influenza pandemic. Objective - To investigate the risk factors for death from influenza A(H1N1)pdm09 in hospitalized patients and pregnant women with Severe Acute Respiratory Infections-SARI. In the pregnant women, the gestational and neonatal outcomes were analyzed. Methodology - Two case control studies were performed in hospitalized patients and pregnant women with laboratory confirmed influenza A (H1N1)pdm09 and SARI. The cases died and the controls recovered. The cases and controls were selected from the Information System for Notifiable Diseases-SINAN-Influenza-web. Two controls were randomly selected in the study of patients and four in the pregnant women, matched by epidemiological week of the date of admission of the case. The first study was conducted in the metropolitan regions of São Paulo and Campinas, from June 28th to August 29th, 2009. The study on pregnant women included the State of São Paulo, from June 09th to December 1th, 2009. Evaluations of the medical records and home interviews were conducted using standardized forms. The Mann-Whitney U test or the chi-square tests were performed to compare the variables, in addition to calculations of crude odds ratio- ORc and their 95 per cent confidence intervals for the assessment of the risk factors. In the first study a multiple logistic regression model was used to analyze factors associated with death. Results - In the first study, 193 cases and 386 controls were investigated, 73.6 per cent of cases and 38.1 per cent of controls presented some risk condition for developing influenza-related complications. In the final model, the following variables were risk factors for death: aged between 18 and 59 , Adjusted Odds Ratio-ORa of 2.31, CI95 per cent 1.31-4.10, (reference patients <18 years), the presence of at least one risk condition (ORa=1.99, CI95 per cent 1.11-3.57), more than one risk condition (ORa=6.05 CI95 per cent 2.76-13.28), obesity (ORa=2.73, CI95 per cent 1.28-5.83), immunosuppression (ORa=3.43 CI95 per cent 1.28-9.19) and being attended prior to hospitalization (ORa=3.35, CI95 per cent 1.75-6.40). Antiviral treatment, when administered during the first 48 hours of onset of symptoms, was a protective factor for death, (ORa=0.17, CI95 per cent 0.08-0.37). There were also benefits from antiviral administration between 48 and 72 hours, (ORa=0.30, CI95 per cent 0.11-0.81). In the pregnant women, 48 cases and 185 controls were investigated. The risk factors for death were: being attended prior to hospitalization, (ORc 8.03, CI95 per cent 2.38-27.09) and third trimester of pregnancy, (ORc=4.45, CI95 per cent 1.15-29.25). Antiviral treatment was a protective factor when administered within 48 hours of onset of symptoms (ORc=0.14, CI95 per cent 0.05-0.37) and between 48 and 72 hours, (ORc= 0.13, CI95 per cent 0.02-0.68). In relation to pregnancy outcomes, there was a higher proportion of fetal losses and premature births among cases, p=0.001. The pregnant women who died had live newborns with lower weight and lower Apgar scores in the first minute, p=0.016 compared to controls who gave birth during hospitalization, p<0.001. Conclusion: The identification of high-risk patients and early treatment are important factors in the reduction of morbidity and mortality from influenza.

學校停課在世界各國的流感大流行應對方案中常被列為一項社區緩疫措施，而這項措施亦在2009年H1N1流感大流行中被廣泛地使用。然而，這項緩疫措施經常被質疑是否恰當，原因是因為停課會對教育構成重大的影響，而且過往的流行病學硏究亦表示這項緩疫措施不一定有效。本論文硏究學校停課對2009年H1N1流感大流行在香港首5個月疫情中降低大流行流感傳播的效能。 / 在香港，在該大流行流感病毒於2009年4月在美國被發現後，香港政府實施了控疫措施(containment phase measures)，並開始對該流感大流行進行監測。為了判定大流行是否已在香港內蔓延，衛生防護中心設定了一個報告準則來讓本地醫生報告疑似大流行流感感染個案，並為每個懷疑個案作確診測試及為每個確診個案追溯感染源頭。當大流行流感在6月開始在香港內蔓延時，香港政府實施了緩疫措施(mitigation phase measures)。在緩疫措施底下，帶有流感病症的病人求診於指定流感診所和公共醫院急症室會被測試是否感染大流行流感，而停課措施亦在此時開始實行去減低大流行流感的傳播。停課措施一直維持至7月直至暑假開始，並經修改後於9月開學時繼續實行。在9月，鑑於已不再需要對流感大流行進行監測，對懷疑感染個案進行確診測試的政策止於該月下旬。確診個案中記錄了的病人資料，與及由學校停課和暑假所引起的學期變化，為這課題提供了一個理想硏究的機會。 / 在2009年的5月至9月，一共確診了27,687宗大流行流感個案。在確診個案中，所有個案都記錄了確診者的年歲和確診日期，而88%確診者提供了一個可定位的住宅地址。為了觀察學校停課的緩疫效果，本硏究定義了5個社會經濟年齡級別(socio-economic age classes) (當中包括有小學生和中學生)，並繪製了年齡級別與地域特定的疫情曲線(age-class-and-district-specific epidemic curves)。所有的疫情曲線在大流行流感在6月開始在香港蔓延後均穩步上升，而在屬於小學生和中學生的疫情曲線中能看到一個不尋常的上升出現在9月新學年開始時，意味著中小學生在學校的活動提升了大流行流感在他們之間的傳播。 / 先前，學校停課對減低2009年H1N1流感大流行在香港的傳播已被Wu et. al (2010a)進行了調查。透過使用一個具年齡結構的SIR模型(age-structured SIR model)來分析收集至8月27日的監測數據，該硏究表示流感大流行的傳播在暑假開始時減低了25%。在這研究中，我應用了Wu et. al (2010a)的方法來分析整個監測期間所收集的數據。在發現到該數學模型不能準確地擬合附加的監測數據後，我在該模型添加了兩個傳播特徵(當中包含兒童和成人之間的傳染在學校停課期間增加)去更準確地代表現實中的疫情。我的硏究顯示，學校停課雖然降低了兒童的感染率，但卻增加了成年人的感染率，令整體傳播在暑假開始時只減低了7.6%。這硏究結果表示，在將來的流感大流行中，封閉學校不大可能延遲流感大流行疫情至一個可令疫苗產生作用的程度，而且封閉學校可能會增加成人的感染率，從而有可能導致社會運作出現更混亂的情況。 / School closure is often included in national pandemic influenza response plans as a community mitigation measure and it was widely applied in Pandemic (H1N1) 2009. However, the appropriateness of this intervention is often questioned, as school closure causes major disruption to the education system and past epidemiological studies reveal this intervention is not necessarily effective. The present thesis evaluates the effect of school closure in mitigating transmission of Pandemic (H1N1) 2009 in Hong Kong in the initial 5 months of the pandemic. / In Hong Kong, following identification of the pandemic virus in US in April 2009, the government implemented containment phase measures and began surveillance on the pandemic. The Centre for Health Protection established a reporting criteria for doctors to report suspected cases of pandemic infection for laboratory confirmation, and the source of infection of confirmed cases was traced to determine if the pandemic was spreading locally. When local transmission of the pandemic began in June, the government began mitigation phase measures, in which patients with influenza-like- illness seeking treatment at designated flu clinics and public hospital emergency departments were tested for pandemic infection, and school closure was implemented for pandemic mitigation. The school closure policy lasted until summer holiday commenced in July, and was revised and continued in September when the new school season started. At the end of September, in view of pandemic surveillance was no longer useful, laboratory testing for suspected pandemic cases was halted. Patient demographic data collected from confirmed pandemic cases, together with temporal changes in school session induced by school closure and summer holiday, provided an ideal opportunity for investigation. / From May through September 2009, a total of 27,687 pandemic cases were confirmed, in which the age and confirmation date were recorded in all cases, and 88% provided a locatable residential address. To visualise the mitigative effect of school closure, 5 socio-economic age classes (which include primary and secondary school-aged children) were defined, and age-class-and-district-specific epidemic curves were constructed. All epidemic curves rose steadily after local transmission began in June, and an unusual upsurge in the epidemic curve of primary and secondary school-aged children is observed when schools resumed session in September, suggesting school session facilitated transmission amongst them. / Previously, the effect of school closure in mitigating Pandemic (H1N1) 2009 transmission in Hong Kong was investigated in Wu et al. (2010a). By analysing surveillance data collected as of 27 August with an age-structured susceptible- infectious-recovered (SIR) model, the study reported transmission was reduced by 25% when summer holiday commenced. In this study, I adapted the methodology in Wu et al. (2010a) to analyse data collected in the entire surveillance period. Upon observing the model fitted poorly to the additional data, I added 2 transmission features to the model (which include increased transmission between children and adults during school closure) to better represent the epidemic in reality. My analysis revealed that while school closure reduced incidence in children, it increased incidence in adults, leading to a reduction in overall transmission by only 7.6% when summer holiday started. The findings of this study suggest that school closure in a future influenza pandemic is unlikely to be able to delay the pandemic for vaccine to arrive in time, and that implementing this intervention may increase incidence in adults, which may lead to causing more disruption on the functioning of society. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chau, Kwan Long. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 148-154). / Abstracts also in Chinese. / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Influenza --- p.2 / Chapter 1.2 --- Public health response to pandemic influenza & School closure --- p.8 / Chapter 1.3 --- Pandemic (H1N1) 2009 --- p.13 / Chapter 1.4 --- Hong Kongs response to Pandemic (H1N1) 2009 --- p.17 / Chapter 1.5 --- Data and Research Objective --- p.24 / Chapter Chapter 2 --- Descriptive and Exploratory Analysis of Surveillance Data --- p.31 / Chapter 2.1 --- Introduction --- p.31 / Chapter 2.2 --- Methodology --- p.36 / Chapter 2.3 --- Results --- p.40 / Chapter 2.4 --- Discussion --- p.57 / Chapter Chapter 3 --- Evaluating the effect of School Closure by Modelling --- p.62 / Chapter 3.1 --- Introduction --- p.62 / Chapter 3.2 --- Methodology --- p.90 / Chapter 3.3 --- Results --- p.98 / Chapter 3.4 --- Discussion --- p.105 / Chapter Chapter 4 --- Discussion --- p.108 / Chapter 4.1 --- Study Findings --- p.108 / Chapter 4.2 --- Study Limitations --- p.109 / Chapter 4.3 --- Comments on using school closure in future influenza pandemics --- p.111 / Appendices --- p.116 / Bibliography --- p.148

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

The research presented in this dissertation integrates data and theory to examine three important topics in biology. In the first chapter, I investigate genetic variation at two loci involved in a genetic incompatibility in the genus Xiphophorus. In this genus, hybrids develop a fatal melanoma due to the interaction of an oncogene and its repressor. Using the genetic variation data from each locus, I fit evolutionary models to test for coevolution between the oncogene and the repressor. The results of this study suggest that the evolutionary trajectory of a microsatellite element in the proximal promoter of the repressor locus is affected by the presence of the oncogene. This study significantly advances our understanding of how loci involved in both a genetic incompatibility and a genetically determined cancer evolve. Chapter two addresses the role polyploidy, or whole genome duplication, has played in generating flowering plant diversity. The question of whether polyploidy events facilitate diversification has received considerable attention among plant and evolutionary biologists. To address this question, I estimated the speciation and genome duplication rates for 60 genera of flowering plants. The results suggest that diploids, as opposed to polyploids, generate more species diversity. This study represents the broadest comparative analysis to date of the effect of polyploidy on flowering plant diversity. In the final chapter, I develop a computational method for designing disease surveillance networks. The method is a data-driven, geographic optimization of surveillance sites. Networks constructed using this method are predicted to significantly outperform existing networks, in terms of information quality, efficiency, and robustness. This work involved the coordinated efforts of researchers in biology, epidemiology, and operations research with public health decision makers. Together, the results of this dissertation demonstrate the utility of applying quantitative theory and statistical methods to data in order to address complex, biological processes. / text

Os pacientes com doenças reumáticas crônicas exibem um risco aumentado de contrair infecções. Consequentemente, sua vacinação é indispensável. Há relatos da produção de anticorpos antifosfolípides e tromboses após infecções e vacinação nesta população, exceto em síndrome antifosfolípide (SAF) primária. O objetivo principal deste estudo foi avaliar a curto e longo prazos um painel de anticorpos antifosfolípides após a vacinação contra influenza A/H1N1 (sem adjuvante) em SAF primária e controles saudáveis. Quarenta e cinco pacientes com SAF primária e 33 controles saudáveis foram imunizados e prospectivamente avaliados antes da vacinação e 3 semanas e 6 meses após a vacinação. Os anticorpos antifosfolípides foram determinados por ensaio imunoenzimático (ELISA) e incluíram os anticorpos IgG e IgM a seguir: anticardiolipina (aCL), anti-beta2glicoproteína I (anti-beta2GPI), anti-anexina V, anti-fosfatidilserina e anti-protrombina. O anticorpo anti-Sm foi igualmente determinado por ELISA e o anti-DNA dupla hélice, por imunofluorescência indireta. Avaliamos clinicamente à ocorrência de tromboses arterial e venosa. A frequência pré-vacinação de pelo menos um anticorpo antifosfolípide foi significativamente maior nos pacientes com SAF primária comparados aos controles (58% vs 24%, p = 0,0052). A frequência global de anticorpos antifosfolípides pré-vacinação e 03 semanas e 06 meses após a vacinação permaneceu inalterada tanto em pacientes (p = 0,89) como em controles (p = 0,83). A frequência de cada anticorpo específico nos dois grupos permaneceu estável nas três avaliações (p > 0,05). A frequência de cada anticorpo mantevese invariável nos pacientes tratados com cloroquina (p > 0,05). Em 3 semanas, 2 pacientes com SAF primária deselvolveram um anticorpo antifosfolípide novo porém transitório (aCL IgG e IgM), enquanto que em 6 meses novos anticorpos foram observados em 6 pacientes e nenhum apresentou altos títulos. Anti-Sm e anti-DNA dupla hélice foram negativos e nenhuma nova trombose arterial ou venosa foi observada durante o estudo. Este foi o primeiro estudo a demonstrar que a vacina contra influenza pandêmica em pacientes com SAF primária não induz tromboses e uma produção significante de anticorpos antifosfolípides a curto e longo prazos. (ClinicalTrials.gov, #NCT01151644). / Chronic rheumatic disease patients exhibit an increased risk for infections. Therefore, vaccination is imperative. Antiphospholipid antibodies (aPL) and thrombosis triggering after infections and vaccination in this population were reported, except for primary antiphospholipd syndrome (PAPS). Study\'s main objective was short and long-term evaluation of a panel of antiphospholipid autoantibodies following pandemic influenza A/H1N1 non-adjuvant vaccine in primary antiphospholipid syndrome patients and healthy controls. Forty-five PAPS and 33 healthy controls were immunized with A/H1N1 pandemic influenza vaccine. They were prospectively assessed at pre-vaccination, 3 weeks and 6 months after vaccination. aPL autoantibodies were determined by an enzyme-linked immunosorbent assay (ELISA) and included IgG/IgM: anticardiolipin (aCL), anti-beta2GPI; anti-annexin V, anti-phosphatidyl serine and antiprothrombin antibodies. Anti-Sm was determined by ELISA and anti-dsDNA by indirect immunfluorescence. Arterial and venous thrombosis were also clinically assessed. Pre-vaccination frequency of at least one aPL antibody was significantly higher in PAPS patients versus controls (58% vs. 24%, p=0.0052). The overall frequencies of aPL antibody at pre-vaccination, 3 weeks and 6 months after immunization remained unchanged in patients (p=0.89) and controls (p=0.83). The frequency of each antibody specificity for patients and controls remained stable in the three evaluated period (p > 0.05). The frequency of each antibody kept invariable in PAPS patients under chloroquine treatment (p > 0.05). At 3 weeks, 2 PAPS patients developed a new but transient aPL antibody (aCL IgG and IgM), whereas at 6 months new aPL antibodies were observed in 6 PAPS patients and none had high titer. Anti-Sm and anti-dsDNA autoantibodies were uniformly negative and no new arterial or venous thrombosis were observed throughout the study. This was the first study to demonstrate that pandemic influenza vaccine in PAPS patients does not trigger short and long-term thrombosis or a significant production of aPL related antibodies. (ClinicalTrials.gov, #NCT01151644)

Os pacientes com doenças reumáticas crônicas exibem um risco aumentado de contrair infecções. Consequentemente, sua vacinação é indispensável. Há relatos da produção de anticorpos antifosfolípides e tromboses após infecções e vacinação nesta população, exceto em síndrome antifosfolípide (SAF) primária. O objetivo principal deste estudo foi avaliar a curto e longo prazos um painel de anticorpos antifosfolípides após a vacinação contra influenza A/H1N1 (sem adjuvante) em SAF primária e controles saudáveis. Quarenta e cinco pacientes com SAF primária e 33 controles saudáveis foram imunizados e prospectivamente avaliados antes da vacinação e 3 semanas e 6 meses após a vacinação. Os anticorpos antifosfolípides foram determinados por ensaio imunoenzimático (ELISA) e incluíram os anticorpos IgG e IgM a seguir: anticardiolipina (aCL), anti-beta2glicoproteína I (anti-beta2GPI), anti-anexina V, anti-fosfatidilserina e anti-protrombina. O anticorpo anti-Sm foi igualmente determinado por ELISA e o anti-DNA dupla hélice, por imunofluorescência indireta. Avaliamos clinicamente à ocorrência de tromboses arterial e venosa. A frequência pré-vacinação de pelo menos um anticorpo antifosfolípide foi significativamente maior nos pacientes com SAF primária comparados aos controles (58% vs 24%, p = 0,0052). A frequência global de anticorpos antifosfolípides pré-vacinação e 03 semanas e 06 meses após a vacinação permaneceu inalterada tanto em pacientes (p = 0,89) como em controles (p = 0,83). A frequência de cada anticorpo específico nos dois grupos permaneceu estável nas três avaliações (p > 0,05). A frequência de cada anticorpo mantevese invariável nos pacientes tratados com cloroquina (p > 0,05). Em 3 semanas, 2 pacientes com SAF primária deselvolveram um anticorpo antifosfolípide novo porém transitório (aCL IgG e IgM), enquanto que em 6 meses novos anticorpos foram observados em 6 pacientes e nenhum apresentou altos títulos. Anti-Sm e anti-DNA dupla hélice foram negativos e nenhuma nova trombose arterial ou venosa foi observada durante o estudo. Este foi o primeiro estudo a demonstrar que a vacina contra influenza pandêmica em pacientes com SAF primária não induz tromboses e uma produção significante de anticorpos antifosfolípides a curto e longo prazos. (ClinicalTrials.gov, #NCT01151644). / Chronic rheumatic disease patients exhibit an increased risk for infections. Therefore, vaccination is imperative. Antiphospholipid antibodies (aPL) and thrombosis triggering after infections and vaccination in this population were reported, except for primary antiphospholipd syndrome (PAPS). Study\'s main objective was short and long-term evaluation of a panel of antiphospholipid autoantibodies following pandemic influenza A/H1N1 non-adjuvant vaccine in primary antiphospholipid syndrome patients and healthy controls. Forty-five PAPS and 33 healthy controls were immunized with A/H1N1 pandemic influenza vaccine. They were prospectively assessed at pre-vaccination, 3 weeks and 6 months after vaccination. aPL autoantibodies were determined by an enzyme-linked immunosorbent assay (ELISA) and included IgG/IgM: anticardiolipin (aCL), anti-beta2GPI; anti-annexin V, anti-phosphatidyl serine and antiprothrombin antibodies. Anti-Sm was determined by ELISA and anti-dsDNA by indirect immunfluorescence. Arterial and venous thrombosis were also clinically assessed. Pre-vaccination frequency of at least one aPL antibody was significantly higher in PAPS patients versus controls (58% vs. 24%, p=0.0052). The overall frequencies of aPL antibody at pre-vaccination, 3 weeks and 6 months after immunization remained unchanged in patients (p=0.89) and controls (p=0.83). The frequency of each antibody specificity for patients and controls remained stable in the three evaluated period (p > 0.05). The frequency of each antibody kept invariable in PAPS patients under chloroquine treatment (p > 0.05). At 3 weeks, 2 PAPS patients developed a new but transient aPL antibody (aCL IgG and IgM), whereas at 6 months new aPL antibodies were observed in 6 PAPS patients and none had high titer. Anti-Sm and anti-dsDNA autoantibodies were uniformly negative and no new arterial or venous thrombosis were observed throughout the study. This was the first study to demonstrate that pandemic influenza vaccine in PAPS patients does not trigger short and long-term thrombosis or a significant production of aPL related antibodies. (ClinicalTrials.gov, #NCT01151644)

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Thesis (M.P.H.)--University of Texas Health Science Center at Houston, School of Public Health, 2007. / Source: Masters Abstracts International, Volume: 46-01, page: 0339. Adviser: Cynthia L. Chappell. Includes bibliographical references.

While memory CD4 T cells are critical for effective immunity to pathogens, the mechanisms underlying their generation are poorly defined. Although extensive work has been done to examine the role of antigen (Ag) in shaping memory formation, most studies focus on the requirements during the first few days of the response known as the priming phase. Little is known about whether or not Ag re-encounter by effector T cells (late Ag) alters CD4 memory T cell formation. Since influenza infection produces a large, heterogeneous, protective CD4 memory T cell population, I used this model to examine the role of late Ag in promoting CD4 memory T cell formation. In the experiments presented in this thesis, I demonstrate that late Ag is required to rescue responding CD4 T cells from default apoptosis and to program the transition to long-lived memory. Responding cells that failed to re-encounter Ag had decreased memory marker expression and failed to produce multiple cytokines upon re-stimulation. Ag recognition is required at a defined stage, as short-term Ag presentation provided 6 days after infection is able to restore canonical memory formation even in the absence of viral infection. Finally, I find that memory CD4 T cell formation following cold-adapted influenza vaccination is boosted when Ag is administered at this stage. These findings imply that persistence of viral Ag presentation into the effector phase is the key factor that determines the efficiency of memory generation. They also suggest that administering Ag during the effector stage may improve vaccine efficacy.

Les virus respiratoires induisent de nombreuses et fréquentes pathologies en pédiatrie avec une morbidité importante. Ces virus sont bien connus car étudiés depuis longtemps mais ils sont en évolution constante. L’apparition des antibiotiques, des antiviraux, des soins intensifs, de la vaccination, les connaissances sur l’hygiène ont transformé l’impact de ces virus sur les populations humaines. Nos modes de vie principalement citadins favorisent la diffusion virale locale par le regroupement de presque tous les enfants dans des crèches ou des écoles. De même l’explosion récente des moyens de transport en particulier aérien qui ont reliés physiquement tous les pays du monde entre eux et qui accentuent la diffusion virale mondiale. Faut-il appliquer les mêmes raisonnements dans tous les pays du monde pour lutter contre ces infections ? Cette thèse apporte de nouvelles connaissances sur ce sujet en se focalisant sur les virus influenza et le virus respiratoire syncytial :1) Pendant la pandémie H1N1 au Canada, la mise en évidence de l’augmentation des hospitalisations des enfants asthmatiques, paradoxalement moins souvent ventilés durant leurs séjours en réanimation pédiatrique.2) L’intérêt de la vaccination contre le virus pandémique H1N1 pour diminuer le recours à la ventilation assistée chez les enfants hospitalisés en réanimation pédiatrique.3) Le Canada n’a pas connu de 3ème vague pandémique en raison d’une campagne vaccinale massive qui bien que tardive, a été efficace même 1 an plus tard.(4) La saisonnalité de la bronchiolite dans les régions tropicales est très différente de celle retrouvée dans les pays tempérés et nécessite de réajuster les recommandations de prise en charge à l’aune des données localesEn décrivant la cinétique et l’impact de la pandémie grippale de 2009 sur les enfants hospitalisés en soins intensifs pédiatriques au Canada d’Octobre 2009 à Mars 2011, en comparant cette cohorte à une cohorte similaire en France Hexagonale, et en décrivant 2 épidémies de VRS en Martinique en 2007 et 2008 pour confronter ces données avec celles décrites dans les pays tempérés, ce travail illustre combien nos connaissances doivent toujours être remises en question du fait de l’évolution du climat, de l’évolution de la société et de l’évolution des connaissances médicales / Respiratory viruses are responsible for much pediatric pathology with significant morbidity. These viruses are well known for a long time but are subject to constant changes. The development of antibiotics, antivirals, intensive care, vaccination, knowledge on hygiene has modified the impact of these viruses on human populations. Our predominantly urban lifestyles support local viral spread by bringing almost all children together in nurseries or schools. In the same way, the large use of modern transport facilities especially air transport (which connect all continents between them) facilitate the world viral spread. In this new environment, should we apply the same medical reasoning all over the world to fight against these infections? This thesis brings new knowledge on this topic, focusing on influenza virus and syncytial respiratory virus:1) During Influenza A(H1N1)pdm09, hospitalizations of children with asthma increase, but they were least often to be ventilated during their pediatric intensive care stay.2) The value of vaccination against the pandemic virus to reduce the use of assisted ventilation in children hospitalized in Pediatric Intensive Care Unit.3) Canada did not experience a third pandemic wave in 2010 because of a massive vaccination campaign that, even late, was effective one year later.4) The bronchiolitis season in the tropics is different from what we know in temperate countries. It is mandatory to adjust management recommendations in the light of regional data.By describing the kinetics and impact of the 2009 influenza pandemic on children in pediatric intensive care in Canada from October 2009 to March 2011, comparing this cohort to a similar cohort in France, and comparing 2 epidemics of VRS in Martinique (French West Indies) in 2007 and 2008 with those that have been carried out in temperate countries, this thesis is an example why we have to constantly question our knowledge because of climate change, change in society and medical knowledge evolution.