Abstract The aim of the thesis: To determine most common causes of pertussis in childhood is the aim of this submitted research thesis. It also describes the possibilities of child prevention from the point of view of nurses. The other aims are description the specifics of nursing care for children with pertussis. Five research questions have been defined in relations to these objectives. The way of achieving the aim: The qualitative research method was chosen to achieve the objectives of the thesis. This method was implemented through in-depth interviews. On the basis of identified research questions, individual categories have been formulated in order to get answers to individual questions. For selection of communication partners the method of intentional selection was chosen. Research was realized at Jihlava Hospital in Children's Department. Anonymous interviewing was attended by a total of 20 communication partners. All of them have a nursing education and have performed nursing care for a child with a pertussis disease. In-depth interviews with parents were carried out in General Practitioner for children and adoration. Anonymous survey were agreed by 7 parents whose children suffered from pertussis. Scientific benefits of the thesis: This research study deals with the current issue of pertussis as an omitted infection. The scientific results of the research are intended for both the lay and professional public. The research study presents a complex and comprehensive overview of nursing care for children with pertussis. It will find use in both preventive care and also in taking care of the patient directly on the bed. Part of the scientific thesis is application into practice. The lessons learned and conclusions: Diseases of pertussis are most at risk for newborns and infants, for whom their parents pose a significant threat of infection without the parents becoming aware of it. One of the main measures is to vaccinate not only children but also parents and close relatives who come to close contact with the newborn. Parents are often unaware of adult vaccination in the prevention of childhood illness. Nursing care for a child with pertussis disease has its specificities in that it is highly contagious illness and can endanger the life of the child.

La voie de sécrétion bactérienne de type V permet l’exportation à la surface cellulaire de protéines dont certaines ont été identifiées comme d’importants facteurs de la pathogénicité bactérienne. Le type V regroupe la sécrétion des autotransporteurs et la sécrétion à deux partenaires (TPS). Les autotransporteurs sont constitués d’un domaine en tonneau β; et d’un domaine passager. L’interaction de l’autotransporteur avec le complexe protéique Bam, dont la pièce centrale est le transporteur BamA, permet l’insertion dans la membrane externe du tonneau β; et la sécrétion du passager. En revanche, la sécrétion à deux partenaires fait intervenir deux protéines, l’une appelée TpsA correspondant à la protéine exportée et l’autre, TpsB, formant un tonneau β qui contrôle le transport à travers la membrane externe. Les protéines TpsB sont spécifiques à leur(s) TpsA associée(s), et font partie de la superfamille des transporteurs Omp85 qui effectuent l’insertion de protéines dans la membrane externe bactérienne comme BamA, et dans celles des organites eucaryotes dont les chloroplastes et les mitochondries. Au cours de mon doctorat, je me suis intéressé à la sécrétion de l’hémagglutinine filamenteuse (FHA), qui est l’adhésine majoritaire de Bordetella pertussis, l’agent étiologique de la coqueluche. Cette adhésine qui permet à la bactérie de coloniser le tractus respiratoire de l’hôte est une protéine TpsA de 220 kD. Elle est très efficacement sécrétée par la voie de sécrétion à deux partenaires grâce à son transporteur spécifique TpsB nommé FhaC. L’étude cristallographique de FhaC a révélé un tonneau β; à 16 brins qui forme un canal dans la membrane externe obstrué par l’hélice-α; amino-terminale, H1, partagée par la majorité des TpsB, et par une boucle de surface, L6, conservée dans la superfamille Omp85. Cette conformation suggère un état au repos dans lequel le canal bouché ne pourrait pas transporter son partenaire. Afin de comprendre comment la FHA transite à l’intérieur du pore, il est donc nécessaire de connaître les changements de conformations que subit FhaC. Durant mon travail de thèse, nous avons apporté une vision plus dynamique de la sécrétion à deux partenaires en utilisant le couple FHA/FhaC comme modèle d’étude. Pour cela nous avons utilisé principalement la Résonance Paramagnétique Electronique (RPE). Cette technique de biophysique permet d’étudier FhaC en solution ou réincorporée dans une bicouche lipidique et de rendre compte de la mobilité à un site donné par l’utilisation de sondes paramagnétiques. Ainsi nous avons pu montrer que FhaC est en équilibre entre plusieurs conformations, avec H1 dans le pore ou du côté périplasmique de FhaC. La présence de la FHA déplace cet équilibre, favorisant ainsi la sortie de l’hélice hors du pore. Nous avons, par ailleurs, pu démontrer expérimentalement que la FHA transitait bien à l’intérieur du pore formé par FhaC et que l’hélice H1 se trouvait alors dans le périplasme. L’étude de la boucle L6 nous a permis de montrer que la mobilité de cette boucle était fortement contrainte à l’intérieur du pore même lors de la reconnaissance avec la FHA. Ce ralentissement de mobilité est lié, en autre, à une interaction avec un résidu d’un motif conservé présent sur le brin β13 qui influence la taille du pore. De manière plus générale, cette étude de la dynamique de FhaC contribue à la compréhension des mécanismes moléculaires de la voie TPS et des transporteurs de la superfamille Omp85. / Type V secretion in bacteria mediates the export to the cell surface of proteins, some of which have been identified as important factors of pathogenicity. Type V includes the secretion of autotransporters and the ‘Two-partner Secretion’ (TPS) pathway. Autotransporters consist of a β barrel domain and a passenger domain. The interaction of autotransporters with the Bam complex, of which the BamA transporter is the central component, allows the insertion of the β; barrel in the outer membrane and the secretion of passenger domain. In contrast, the two-partner secretion involves two proteins, the exported ‘TpsA’ protein and its TpsB partner that controls its transport across the outer membrane. TpsB proteins are specific to their associated TpsA(s) and belong to the superfamily of the Omp85 transporters, which carry out the insertion of proteins into the bacterial outer membrane, like BamA, or in the outer membranes of eukaryotic organelles including chloroplasts and mitochondria. For my PhD work, I have been interested in the secretion of filamentous hemagglutinin (FHA), which is the major adhesin of Bordetella pertussis, the causative agent of whooping cough. This adhesin allows the colonization by this bacterium of its host’s respiratory tract. This protein corresponds to a 220kD TpsA protein efficiently secreted by its specific transporter TpsB named FhaC. Crystallographic studies have revealed that FhaC harbours a 16-stranded β;-barrel occluded by both the N-terminal α;-helix, H1, shared by the majority of TpsB proteins, and by a surface loop, L6, that carries a conserved, hallmark motif of the Omp85 superfamilly. This conformation suggests that FhaC is in a resting state in which the channel does not transport its partner. To understand how the FHA passes through the FhaC pore, it is necessary to address the conformational changes undergone by FhaC. During my thesis work, we provided a more dynamic view of the TPS pathway using the FHA/FhaC couple as study model. For this we used Electron Paramagnetic Resonance (EPR). This biophysical technique allows to study of FhaC in solution or reincorporated into a lipid bilayer and it reports the mobility at specific sites of the protein by using paramagnetic probes. Thus we have shown that FhaC is in equilibrium between multiple conformations, with H1 in the pore or at the periplasmic side of FhaC. The presence of FHA displaces the conformational equilibrium, promoting the exit of the helix going from the pore. We have also experimentally demonstrated that FHA does transit through the pore formed by FhaC while helix H1 is then in the periplasm. The study of the L6 loop enabled us to show that the mobility of this loop is highly constrained in the pore and remains so upon the recognition of FHA. Its slow mobility is linked to an interaction between an invariant L6 residue and a conserved motif present on the β; strand 13 of the barrel. This interaction affects the size of the FhaC pore.More generally, the study of the dynamics of FhaC contributes to the understanding the molecular mechanisms of the TPS pathway and of transporters of the Omp85 superfamily.

No description available.

A imunização materna com a vacina acelular para pertussis (dTpa) é uma intervenção adicional que visa fornecer proteção aos recém-nascidos (RN). No entanto, tem sido relatado que altos níveis de anticorpos adquiridos por transferência placentária podem afetar adversamente a resposta imune desses RN após a imunização ativa, devido ao mascaramento antigênico. Neste estudo, avaliamos a aquisição passiva neonatal de anticorpos específicos para pertussis e sua influência na resposta imune celular dos neonatos. A casuística foi composta por gestantes vacinadas com a vacina dTpa (grupo caso, n=66) ou por gestantes que não receberam a vacina (grupo controle, n=101). As concentrações de anticorpos IgG séricos específicos para Bordetella pertussis total (Bp), toxina pertussis (PT), hemaglutinina filamentosa (FHA) e pertactina (PRN) foram quantificadas em soro materno e de cordão umbilical de seu respectivo RN, e as concentrações de anticorpos IgA específicos para Bp e PT foram dosadas nas amostras de colostro por meio de ensaio imunoenzimático. A responsividade dos linfócitos do sangue neonatal foi avaliada após estimulação ex vivo com Bp inativada por citometria de fluxo com o intuito de detectar a proliferação, produção de citocinas e fenótipo de ativação dos linfócitos T em um contexto de altas concentrações de IgG específicas adquiridas após a vacinação materna. As concentrações de anticorpos IgG anti-Bp, PT, FHA e PRN foram maiores nas amostras de soro materno e de cordão umbilical do grupo caso quando comparadas ao grupo controle (p < 0,0001), com índices de correlação positivos em ambos os grupos para todos os antígenos estudados (p < 0,0001). As vacinações realizadas entre 26 e 31 semanas de gestação foram associadas com as melhores taxas de transferência placentária, embora índices significativamente menores foram detectados no grupo caso (p < 0,01). As concentrações de anticorpos IgA anti-Bp e anti-PT no colostro não foram afetadas pelo estado vacinal da parturiente. Os ensaios de cultura celular revelaram que os RN responderam ao estímulo com Bp, com maior expressão de CD40L, CD69 e proliferação de células T CD4, em comparação com células não estimuladas. Também foi observada uma menor resposta Th1, enquanto a resposta Th2 foi preservada, em comparação com os adultos, mas sem diferenças entre os grupos de neonatos em nenhum dos parâmetros estudados. Nossos resultados indicam que níveis mais altos de anticorpos IgG específicos para B. pertussis no soro dos RN após a vacinação materna não afetam a resposta imune neonatal mediada por células / Maternal immunization with pertussis acellular vaccine (Tdap) is an additional intervention that provides protection to newborns. However, it has been reported that high antibody levels acquired via placental transfer may adversely affect the immune response of newborns after active immunization due to epitope masking. In this study, we evaluated neonatal passive acquisition of pertussis-specific antibodies and their influence on the neonatal cell-mediated immune response. The sample consisted of pregnant women vaccinated with the Tdap vaccine (case group, n=66) or pregnant women who received no vaccine (control group n=101). Whole-cell Bordetella pertussis (Bp), pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN)-specific serum IgG concentrations were quantified in paired maternal-cord sera, and Bp- and PT-specific IgA concentrations were evaluated in colostrum samples by immunoenzymatic assay. Ex vivo neonatal blood lymphocyte responsiveness after inactivated Bp stimulation was assessed using flow cytometry to detect the proliferation, cytokine production and activation phenotype of T lymphocytes in the context of high specific IgG concentrations acquired after maternal vaccination. Anti-Bp, PT, FHA and PRN IgG antibody concentrations in maternal and cord serum samples from case group were higher than those in control group (p < 0.0001), with positive correlation indexes in both groups for all pertussis antigens (p < 0.0001). Vaccinations performed between 26 and 31 gestation weeks were associated with the best placental transfer ratios, although significantly lower ratios were detected in case group (p < 0.01). Anti-Bp and anti-PT IgA concentrations in colostrum were not affected by vaccine status. Cell culture assays revealed that newborns responded to Bp stimulation with higher expression of CD40L CD69 and CD4+ T cell proliferation compared to unstimulated cells. It was also observed a lower Th1 response, while a preserved Th2 response compared to adults, but there were no differences between neonatal groups for any of the studied parameters. Our results indicate that higher pertussis-specific IgG levels in newborn sera after maternal vaccination do not affect the neonatal cell-mediated immune response

A imunização materna com a vacina acelular para pertussis (dTpa) é uma intervenção adicional que visa fornecer proteção aos recém-nascidos (RN). No entanto, tem sido relatado que altos níveis de anticorpos adquiridos por transferência placentária podem afetar adversamente a resposta imune desses RN após a imunização ativa, devido ao mascaramento antigênico. Neste estudo, avaliamos a aquisição passiva neonatal de anticorpos específicos para pertussis e sua influência na resposta imune celular dos neonatos. A casuística foi composta por gestantes vacinadas com a vacina dTpa (grupo caso, n=66) ou por gestantes que não receberam a vacina (grupo controle, n=101). As concentrações de anticorpos IgG séricos específicos para Bordetella pertussis total (Bp), toxina pertussis (PT), hemaglutinina filamentosa (FHA) e pertactina (PRN) foram quantificadas em soro materno e de cordão umbilical de seu respectivo RN, e as concentrações de anticorpos IgA específicos para Bp e PT foram dosadas nas amostras de colostro por meio de ensaio imunoenzimático. A responsividade dos linfócitos do sangue neonatal foi avaliada após estimulação ex vivo com Bp inativada por citometria de fluxo com o intuito de detectar a proliferação, produção de citocinas e fenótipo de ativação dos linfócitos T em um contexto de altas concentrações de IgG específicas adquiridas após a vacinação materna. As concentrações de anticorpos IgG anti-Bp, PT, FHA e PRN foram maiores nas amostras de soro materno e de cordão umbilical do grupo caso quando comparadas ao grupo controle (p < 0,0001), com índices de correlação positivos em ambos os grupos para todos os antígenos estudados (p < 0,0001). As vacinações realizadas entre 26 e 31 semanas de gestação foram associadas com as melhores taxas de transferência placentária, embora índices significativamente menores foram detectados no grupo caso (p < 0,01). As concentrações de anticorpos IgA anti-Bp e anti-PT no colostro não foram afetadas pelo estado vacinal da parturiente. Os ensaios de cultura celular revelaram que os RN responderam ao estímulo com Bp, com maior expressão de CD40L, CD69 e proliferação de células T CD4, em comparação com células não estimuladas. Também foi observada uma menor resposta Th1, enquanto a resposta Th2 foi preservada, em comparação com os adultos, mas sem diferenças entre os grupos de neonatos em nenhum dos parâmetros estudados. Nossos resultados indicam que níveis mais altos de anticorpos IgG específicos para B. pertussis no soro dos RN após a vacinação materna não afetam a resposta imune neonatal mediada por células / Maternal immunization with pertussis acellular vaccine (Tdap) is an additional intervention that provides protection to newborns. However, it has been reported that high antibody levels acquired via placental transfer may adversely affect the immune response of newborns after active immunization due to epitope masking. In this study, we evaluated neonatal passive acquisition of pertussis-specific antibodies and their influence on the neonatal cell-mediated immune response. The sample consisted of pregnant women vaccinated with the Tdap vaccine (case group, n=66) or pregnant women who received no vaccine (control group n=101). Whole-cell Bordetella pertussis (Bp), pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN)-specific serum IgG concentrations were quantified in paired maternal-cord sera, and Bp- and PT-specific IgA concentrations were evaluated in colostrum samples by immunoenzymatic assay. Ex vivo neonatal blood lymphocyte responsiveness after inactivated Bp stimulation was assessed using flow cytometry to detect the proliferation, cytokine production and activation phenotype of T lymphocytes in the context of high specific IgG concentrations acquired after maternal vaccination. Anti-Bp, PT, FHA and PRN IgG antibody concentrations in maternal and cord serum samples from case group were higher than those in control group (p < 0.0001), with positive correlation indexes in both groups for all pertussis antigens (p < 0.0001). Vaccinations performed between 26 and 31 gestation weeks were associated with the best placental transfer ratios, although significantly lower ratios were detected in case group (p < 0.01). Anti-Bp and anti-PT IgA concentrations in colostrum were not affected by vaccine status. Cell culture assays revealed that newborns responded to Bp stimulation with higher expression of CD40L CD69 and CD4+ T cell proliferation compared to unstimulated cells. It was also observed a lower Th1 response, while a preserved Th2 response compared to adults, but there were no differences between neonatal groups for any of the studied parameters. Our results indicate that higher pertussis-specific IgG levels in newborn sera after maternal vaccination do not affect the neonatal cell-mediated immune response

Le manuscrit constituant l'annexe 1 a été publié en décembre 2013 sous la référence : Vaccine. 2013 Dec 9;31(51):6087-91. / Contexte. La coqueluche est une infection endémique dont l’incidence, la morbidité et la mortalité restent élevées chez les nourrissons. Dans ce groupe d’âge, l’exposition à des adultes infectés est un facteur de risque d’infection reconnu. La méthode de cocooning est une stratégie efficace pour protéger indirectement les jeunes nourrissons, cependant, la couverture vaccinale des adultes reste faible. Le fait d’offrir la vaccination de rappel à la maternité augmente la couverture vaccinale des deux parents, comparativement aux structures communautaires. Compte tenu de la limitation des ressources dans le domaine de la santé, le caractère coût-efficace de cette stratégie doit être évalué. Le but est de réaliser une évaluation économique de cette méthode dans la réalité du Québec, car les analyses économiques sont difficilement transposables. Objectif. L’objectif principal de l’évaluation est de mener une analyse coût-efficacité de l’implantation de la stratégie du cocooning dans les maternités du Québec. Méthode. Un modèle statique et compartimental est développé pour représenter la dynamique de transmission et le fardeau de la coqueluche au sein d’une cohorte de 1000 familles avec un nouveau-né, avec ou sans l’immunisation des deux parents contre la coqueluche, à la maternité. La stratégie du cocooning est comparée à la situation actuelle qui tient lieu de référence. Le point de départ est la naissance de l’enfant et l’horizon temporel est dix ans. Les effets observés sont le nombre de cas de coqueluche, le nombre d’années de vie perdues et le nombre d’années de vie pondérées pour la qualité (QALY) perdues. Les ratios coût-efficacité incrémentaux sont présentés selon la perspective du système de soins de santé et selon celle de la société : les coûts du système de soins, les coûts pour les familles et la perte de productivité sont considérés. Tous les coûts sont ajustés pour la valeur du dollar canadien de 2012. Les effets et les coûts sont actualisés selon un taux annuel de 3%. Le modèle est élaboré avec le programme informatique Excel 2010. La valeur des paramètres introduits dans le modèle est extraite de données publiées, d’opinions d’experts et de l’étude pilote menée dans notre institution. Des analyses de sensibilité uni-variées et multi-variées sont réalisées pour tenir compte de l’incertitude. Résultats. L’analyse de base aboutit à une diminution de 10,5% du nombre de cas de coqueluche lors de l’application de la stratégie du cocooning, et de 19,1% des hospitalisations, 13,3% des séquelles neurologiques et 26,5% des décès liés à la coqueluche. Selon la perspective du système de soins de santé, le rapport coût-efficacité incrémental est de 34 941 CAD$/QALY gagné, et, de 16 945 CAD$/QALY gagné selon la perspective de la société. Les taux d’incidence des cas de coqueluche ont un impact substantiel sur le modèle comme le montrent les analyses de sensibilité uni-variée et multi-variées. Conclusion. L’implantation de la stratégie du cocooning dans les maternités du Québec augmentera probablement la couverture vaccinale des jeunes parents, et, est un programme potentiellement coût-efficace selon notre analyse de base. Les analyses de sensibilité multi-variées montrent que l’ICER obtenus est cependant très sensible aux taux d’incidence de la coqueluche. / Background. Pertussis disease remains endemic with persistence of peak incidence and highest morbidity and mortality among infants. Exposure to infected adults is a commonly reported risk factor for disease in children. The cocoon strategy is an effective indirect strategy to protect very young infants. However, reaching adults for vaccination is challenging. Unlike community settings, a cocoon strategy implemented in a maternity ward improved vaccine uptake among new parents. In the context of limited public resources, health and economic impact of this particular option has to be evaluated. As studies are hardly transposable, our intention was to evaluate this strategy in the context of the province of Quebec. Objective. Our main goal is to carry out a cost-effectiveness analysis of the implementation of a cocoon strategy in the maternity wards of the province of Quebec. Methods. A compartmental and static model is developed to represent the dynamic of transmission and burden of pertussis in a 1000-family cohort with a newborn baby, without or with vaccination of both parents at the time of delivery. The cocoon strategy is compared with the current situation, taken as the reference. The starting point is the birth of a child and the time horizon is 10 years. Outcomes of interest are pertussis disease cases, life-year losses and quality-adjusted life year (QALY) losses. Incremental cost-effectiveness ratios are presented in both a health care and societal perspectives: inclusion of health services costs, patients and caretaker costs and costs due to productivity losses. All costs are updated to 2012 CAD$. Human and financial costs are discounted to their present (birth) value using annual rates of 3%. The pseudo-Markov model is developed using Excel 2010 software. Parameters values are derived from published data, expert panel opinion and a pilot study conducted in our institution. One-way and multivariate sensitivity analyses are performed to take into account uncertainties in parameters values. Results. The base case analysis resulted in a 10,5% reduction in pertussis cases and in a 19,1%, 13,3% and 26,5% reduction in pertussis-related hospitalizations, neurologic sequalae and death, respectively. From a health care system perspective, the incremental cost-effectiveness ratio is 34 941 CAD$/ QALY gained and is 16 945 CAD$/QALY gained from a societal perspective. Incidence rates of pertussis cases have a substantial impact on the model as shown in one-way and multi-way sensitivity analysis. Conclusion. Hospital-based postpartum dTap immunization of both parents is likely to improve vaccine uptake among new parents and is a potential cost-effective strategy from both societal and health care system perspectives, according to our analysis. Multi-way sensitivity analysis show that ICER is highly sensitive to the pertussis incidence rate.

1 Abstract Adenylate cyclase toxin (CyaA) is one of the major virulence factors of bacterium Bordetella pertussis, which is a causative agent of whooping cough. CyaA belongs to the family of RTX toxin-hemolysins. The toxin targets primarily cells expressing integrin receptor CD11b/CD18 but it can also penetrate cells lacking this receptor. CyaA acts on host cells by two independent activities. One is formation of small cation-selective channels, which can lead to colloid osmotic lysis of target cells. The second is disruption of cell signaling through the translocation of the adenylate cyclase (AC) domain to host cell cytosol, which leads to the conversion of ATP into cyclic AMP. It was recently shown that cholesterol affects endocytosis of CyaA. CyaA translocates it's AC domain after relocation of CyaA molecule to the cholesterol-rich lipid raft (Bumba et al. 2010). In this work I examined the effect of cholesterol on channel- forming activity and selectivity of ion channels created by CyaA. For measurements I used artificial membranes enriched with cholesterol. CyaA channels are voltage-dependent. The positive membrane potential on the side of toxin is rquired for incorporation of CyaA molecule into cell membrane. I tried to find out whether the value of voltage has effect on channels opening time....

INTRODUÇÃO: Uma epidemia de coqueluche ocorreu no Brasil, de 2011 a 2014. Isto levou à introdução da vacina tríplice acelular de adultos (dTpa) no calendário público de vacinação da gestante. Existem outras estratégias de vacinação envolvendo a dTpa, que poderiam complementar o controle da doença. Os objetivos deste estudo são descrever a epidemiologia da doença e avaliar custo-efetividade da vacinação de adultos com dTpa. MÉTODOS: 1) Uma revisão de literatura foi realizada nas bases MEDLINE, Excerpta Medica, CRD e Lilacs a partir de 2000. 2) Foi desenvolvido estudo observacional incluindo dados de vacinação e os casos notificados para o sistema de vigilância no Estado de São Paulo (ESP), de 2001 a 2015. 3) Foi realizado estudo descritivo dos pacientes com idade de 20 a <40 anos atendidos em um hospital do ESP entre 2010 e 2014, destacando-se a utilização de serviços de saúde. 4) Foi desenvolvido modelo dinâmico, para comparar a estratégia de vacinação com dTpa aos 20 anos de idade com o programa atual (vacinação com dT). Dados epidemiológicos e de custos foram retirados de sistemas de informação de saúde e da literatura nacional e internacional. Foram considerados como desfecho número de casos e mortes por coqueluche e anos de vida ganho (AVG). Considerouse a perspectiva do sistema de saúde, horizonte temporal de vinte anos e custos em Reais (R$) de 2015. Os resultados foram sumarizados em razão de custo-efetividade incremental (RCEI). Análises de sensibilidade uni e multivariadas foram realizadas. RESULTADOS: 1) Foram revisadas 28 avaliações econômicas de estratégias com dTpa. A vacinação de adolescentes e de adultos foram as mais avaliadas. A correção da subnotificação, uso de modelos dinâmicos, proteção de rebanho e altas coberturas vacinas influenciaram para o bom desempenho das estratégias. 2) Houve aumento de incidência da coqueluche entre 2011 e 2014 e queda da mesma em 2015, em todas as faixas etárias no ESP. Os lactentes foram os principais acometidos, mas a proporção de casos nessa faixa etária apresentou tendência de queda ao longo dos anos. A proporção de casos com idade de 1 a < 4, 5 a = 20 anos aumentou significativamente. Houve queda não significativa na proporção dos casos com idade < 2 meses de idade. 3) Entre 36 casos estudados no hospital, 33,3% passou por consulta prévia, 25,3% por consulta de retorno e 8,33% foram hospitalizados. Hemograma e radiografia de tórax foram os exames mais realizados. Não houve complicações ou óbito. 4) A vacinação de adultos com dTpa, com cobertura vacinal de 40% e efetividade de 75%, incluindo proteção de rebanho para os menores de um ano, evitaria 19.300 casos sintomáticos e 221 óbitos em 10 anos. A RCEI seria R$28.054,38/AVG. Na análise de sensibilidade, os resultados foram mais sensíveis a variações da incidência e à retirada da proteção de rebanho. CONCLUSÃO: O comportamento cíclico da doença é a principal causa da epidemia de coqueluche entre 2011 e 2014 e queda da incidência em 2015. A vacinação de adultos com dTpa não se mostrou custo-efetiva na realidade brasileira de 2015 / INTRODUCTION: A pertussis outbreak occurred in Brazil from 2011 to 2014. This led to the introduction of the maternal vaccination with tetanus-diphtheria-acellular pertussis vaccine (Tdap) in the public immunization schedule. There are other vaccination strategies involving Tdap, which could complement the strategies of disease control. The objectives of this study are to describe the epidemiology of the disease and to evaluate cost-effectiveness of vaccination of adults with Tdap. METHODS: 1) A review was performed in the MEDLINE, Excerpta Medica, CRD and Lilacs databases from 2000. 2) Observational study was performed including vaccination data and the cases reported data from health surveillance datasets in the State of São Paulo from 2001 to 2015. 3) A descriptive study of patients aged 20 to < 40 years attended at a State of São Paulo hospital between 2010 and 2014 was performed, highlighting the use of health services.4) A dynamic model was developed to compare the vaccination strategy with Tdap at the age of 20 years with the current program (dT vaccination). Epidemiological and cost data were collected from health information systems and national and international studies. Number of cases and deaths by pertussis and life years saved (LYS) were considered as outcome. It was considered the health system perspective, a time horizon of 20 years and costs in 2015 Real (R$). The results were summarized by incremental costeffectiveness ration (ICER). Univariate and multivariate sensitivity analyzes were performed. RESULTS: 1) 28 economic evaluations of strategies with Tdap were reviewed. Vaccination of adolescents and adults were the most evaluated strategies. Underreporting correction, use of dynamic models, herd protection and high vaccination coverage influenced positively the performance of strategies. 2) The incidence of pertussis increased between 2011 and 2014, and its fall in 2015, among all age groups. Infants were the main affected, but the proportion of cases in this age group showed a downward trend over the years. The proportion of cases aged 1 to < 4, 5 to = 20 years increased significantly. There was a non-significant decrease in the proportion of cases aged < 2 months of age. 3) Among 36 cases studied in the hospital, 33.3% had a prior medical visit, 25.3% a return visit, and 8.33% were hospitalized. Blood count and chest X-ray were the most performed exams. There were no complications or death. 4) Vaccination of adults with Tdap, with 40% vaccine coverage and 75% effectiveness, including herd protection for children less than one year, would prevent 19,300 symptomatic cases and 221 deaths in 10 years. The ICER would be R$ 28,054.38/AVG. In the sensitivity analysis, the results were more sensitive to variations in incidence and withdrawal of herd protection. CONCLUSION: The cyclical pattern of the disease is the main cause of the pertussis epidemic between 2011 and 2014, and decreasing incidence in 2015. Adult vaccination with Tdap was not cost-effective in the 2015 Brazilian scenario

This thesis deals with the problems of pertussis epidemiological problems in the Czech Republic, especially the possibilities of improvement of the epidemiological situation of pertussis. Pertussis is a serious infectious disease of the respiratory system and is monitored long-term in Czech Republic. The incidence of pertussis in its epidemic cycles continues to increase since the 90s. Last year's reported sickness rate was 11.7 of 100 000 people (1233 cases total).The thesis is divided into theoretical and practical part. The theoretical part shows the characteristics of pertussis and describes the preventive and repressive measures. Last part of the theoretical section describes epidemiological situation of pertussis from history to the present day while last four years are described in more detail. The practical part of the thesis consists of research.The research was conducted using qualitative method. As data collection method was chosen interviews with first contact physicians, which are pediatricians and physicians for adults. Two objectives were set in research area. The first objective was to map the compliance with the conditions laid down under the "case" definition of pertussis and its methods of diagnosis for pediatricians and physicians for adults (first contact physicians). The second objective was to create intervention for affecting the adverse epidemiological situation of pertussis. Intervention is based on the results of research aimed at compliance with procedures of "case" definition of pertussis and on knowledge of pediatricians and physicians for adults about the epidemiology of pertussis issue and their views on vaccination.

INTRODUÇÃO: Uma epidemia de coqueluche ocorreu no Brasil, de 2011 a 2014. Isto levou à introdução da vacina tríplice acelular de adultos (dTpa) no calendário público de vacinação da gestante. Existem outras estratégias de vacinação envolvendo a dTpa, que poderiam complementar o controle da doença. Os objetivos deste estudo são descrever a epidemiologia da doença e avaliar custo-efetividade da vacinação de adultos com dTpa. MÉTODOS: 1) Uma revisão de literatura foi realizada nas bases MEDLINE, Excerpta Medica, CRD e Lilacs a partir de 2000. 2) Foi desenvolvido estudo observacional incluindo dados de vacinação e os casos notificados para o sistema de vigilância no Estado de São Paulo (ESP), de 2001 a 2015. 3) Foi realizado estudo descritivo dos pacientes com idade de 20 a <40 anos atendidos em um hospital do ESP entre 2010 e 2014, destacando-se a utilização de serviços de saúde. 4) Foi desenvolvido modelo dinâmico, para comparar a estratégia de vacinação com dTpa aos 20 anos de idade com o programa atual (vacinação com dT). Dados epidemiológicos e de custos foram retirados de sistemas de informação de saúde e da literatura nacional e internacional. Foram considerados como desfecho número de casos e mortes por coqueluche e anos de vida ganho (AVG). Considerouse a perspectiva do sistema de saúde, horizonte temporal de vinte anos e custos em Reais (R$) de 2015. Os resultados foram sumarizados em razão de custo-efetividade incremental (RCEI). Análises de sensibilidade uni e multivariadas foram realizadas. RESULTADOS: 1) Foram revisadas 28 avaliações econômicas de estratégias com dTpa. A vacinação de adolescentes e de adultos foram as mais avaliadas. A correção da subnotificação, uso de modelos dinâmicos, proteção de rebanho e altas coberturas vacinas influenciaram para o bom desempenho das estratégias. 2) Houve aumento de incidência da coqueluche entre 2011 e 2014 e queda da mesma em 2015, em todas as faixas etárias no ESP. Os lactentes foram os principais acometidos, mas a proporção de casos nessa faixa etária apresentou tendência de queda ao longo dos anos. A proporção de casos com idade de 1 a < 4, 5 a = 20 anos aumentou significativamente. Houve queda não significativa na proporção dos casos com idade < 2 meses de idade. 3) Entre 36 casos estudados no hospital, 33,3% passou por consulta prévia, 25,3% por consulta de retorno e 8,33% foram hospitalizados. Hemograma e radiografia de tórax foram os exames mais realizados. Não houve complicações ou óbito. 4) A vacinação de adultos com dTpa, com cobertura vacinal de 40% e efetividade de 75%, incluindo proteção de rebanho para os menores de um ano, evitaria 19.300 casos sintomáticos e 221 óbitos em 10 anos. A RCEI seria R$28.054,38/AVG. Na análise de sensibilidade, os resultados foram mais sensíveis a variações da incidência e à retirada da proteção de rebanho. CONCLUSÃO: O comportamento cíclico da doença é a principal causa da epidemia de coqueluche entre 2011 e 2014 e queda da incidência em 2015. A vacinação de adultos com dTpa não se mostrou custo-efetiva na realidade brasileira de 2015 / INTRODUCTION: A pertussis outbreak occurred in Brazil from 2011 to 2014. This led to the introduction of the maternal vaccination with tetanus-diphtheria-acellular pertussis vaccine (Tdap) in the public immunization schedule. There are other vaccination strategies involving Tdap, which could complement the strategies of disease control. The objectives of this study are to describe the epidemiology of the disease and to evaluate cost-effectiveness of vaccination of adults with Tdap. METHODS: 1) A review was performed in the MEDLINE, Excerpta Medica, CRD and Lilacs databases from 2000. 2) Observational study was performed including vaccination data and the cases reported data from health surveillance datasets in the State of São Paulo from 2001 to 2015. 3) A descriptive study of patients aged 20 to < 40 years attended at a State of São Paulo hospital between 2010 and 2014 was performed, highlighting the use of health services.4) A dynamic model was developed to compare the vaccination strategy with Tdap at the age of 20 years with the current program (dT vaccination). Epidemiological and cost data were collected from health information systems and national and international studies. Number of cases and deaths by pertussis and life years saved (LYS) were considered as outcome. It was considered the health system perspective, a time horizon of 20 years and costs in 2015 Real (R$). The results were summarized by incremental costeffectiveness ration (ICER). Univariate and multivariate sensitivity analyzes were performed. RESULTS: 1) 28 economic evaluations of strategies with Tdap were reviewed. Vaccination of adolescents and adults were the most evaluated strategies. Underreporting correction, use of dynamic models, herd protection and high vaccination coverage influenced positively the performance of strategies. 2) The incidence of pertussis increased between 2011 and 2014, and its fall in 2015, among all age groups. Infants were the main affected, but the proportion of cases in this age group showed a downward trend over the years. The proportion of cases aged 1 to < 4, 5 to = 20 years increased significantly. There was a non-significant decrease in the proportion of cases aged < 2 months of age. 3) Among 36 cases studied in the hospital, 33.3% had a prior medical visit, 25.3% a return visit, and 8.33% were hospitalized. Blood count and chest X-ray were the most performed exams. There were no complications or death. 4) Vaccination of adults with Tdap, with 40% vaccine coverage and 75% effectiveness, including herd protection for children less than one year, would prevent 19,300 symptomatic cases and 221 deaths in 10 years. The ICER would be R$ 28,054.38/AVG. In the sensitivity analysis, the results were more sensitive to variations in incidence and withdrawal of herd protection. CONCLUSION: The cyclical pattern of the disease is the main cause of the pertussis epidemic between 2011 and 2014, and decreasing incidence in 2015. Adult vaccination with Tdap was not cost-effective in the 2015 Brazilian scenario