Mycobacterium tuberculosis, the causative agent of tuberculosis, can manipulate host cell death pathways as virulent strains inhibit apoptosis to protect its replication niche and induce necrosis as a mechanism of escape. In vitro studies revealed that similar to lytic viruses, M. tuberculosis has the ability to induce cytolysis in macrophages when it reaches an intracellular burden of ~25 bacilli. Base on this finding, we proposed the burst size hypothesis that states when M. tuberculosis invades a macrophage at a low multiplicity of infection it replicates to a burst size triggering necrosis to escape the cell and infect naïve nearby phagocytes, propagating the spread of infection. The first part of this study investigated if the in vitro observations of M. tuberculosis cytolysis were relevant to cell death of infected phagocytes during pulmonary tuberculosis in vivo. Mice infected with a low dose of M. tuberculosis revealed during TB disease, the major host cell shifted from one type of phagocyte to another. Enumeration of intracellular bacilli from infected lung cells revealed the predictions of the hypothesis were confirmed by the distribution of bacillary loads across the population of infected phagocytes. Heavily burdened cells appeared nonviable sharing distinctive features similar to infected macrophages from in vitro studies. Collectively, the data indicates that M. tuberculosis triggers necrosis in mononuclear cells when its number reaches the threshold burst size. The previous study showed during the period of logarithmic bacterial expansion, neutrophils were the primary host cell for M. tuberculosis coinciding with the timeframe of the highest rate of burst size necrosis. The second part of this study examined this link by infecting mice with one of four different M. tuberculosis strains ranging in virulence. Mice infected with the most virulent strain had the highest bacterial burden and elicited the greatest number of infected neutrophils with the most extensive lung inflammation and greater accounts of cell death. Treating these mice with a bacteriostatic agent decreased the bacterial load and infected neutrophils in a dose-dependent manner indicating necrosis induced by virulent M. tuberculosis recruited neutrophils to the lungs. Infected neutrophils can serve as a biomarker in tuberculosis as evidenced by poorly controlled infection and increased severity of lung immune pathology.

This study sought to describe the challenges of diagnosing pulmonary tuberculosis (PTB) in children under the age of 5 years at clinics under the Prince Mshiyeni Hospital at Ethekwini Health District in KwaZulu-Natal. The study showed that primary health care (PHC) nurses do not have adequate knowledge to effectively diagnose PTB in children and, in addition, that PHC clinics are not adequately equipped to effectively diagnose PTB in children. / Health Studies / M.A. (Public Health)

Pulmonary Tuberculosis (TB) is a significant cause of morbidity in Uganda. TB control in the Ugandan district of Butaleja remains poor, characterised by TB case detection and cure rates below national targets. A qualitative exploratory and descriptive study was conducted to identify factors associated with health-seeking behaviour of TB patients in Butaleja district; with an aim to present recommendations for promoting positive health-seeking behaviour amongst the patients. Data was collected through individual in-depth interviews with seven diagnosed TB patients and analysed using Creswell’s (2009:186) analytic spiral steps. The findings revealed three major themes, namely; the nature of health-seeking behaviour, factors associated with the health-seeking behaviour and advice to others experiencing similar symptoms. The health-seeking behaviour of participants was generally poor, characterised by delay in seeking proper medical treatment for TB. Health system, individual and social factors contributed to poor health-seeking behaviour among the participants. The study recommends health system and community interventions targeted at individuals to improve health-seeking behaviour for Pulmonary TB / Health Studies / M.A. (Public Health)

The efficacy of Bacille-Calmette Guerin (BCG) vaccination in protection against pulmonary tuberculosis (TB) is highly variable between populations. One possible explanation is increased exposure of certain populations to non-tuberculous mycobacteria (NTM). Given the variable efficacy of BCG an improved vaccine against TB is required. The novel TB vaccine MVA85A has shown promising results, however, the immunogenicity of the vaccine is reduced when it is administered in the Expanded Programme on Immunisation (EPI) schedule. This thesis aims to explore: (A) the effect of exposure to NTM on the level of protection afforded by BCG vaccination against Mycobacterium tuberculosis (M. tb) and (B) the immunological mechanisms behind EPI interference with MVA85A. The effect of M. avium (MA) exposure via systemic and oral routes on the efficacy of BCG was tested using M. tb aerosol infection in a mouse model. The adaptive immune response was profiled in BCG vaccinated mice with and without exposure to MA pre- and post- M. tb infection. The results showed BCG efficacy could be enhanced by exposure to dead MA by a systemic route; T helper 1 and T helper 17 responses were associated with increased protection. In contrast, BCG efficacy may have been reduced by exposure to live MA by the oral route; T helper 2 and regulatory T cells were associated with reduced protection. To answer the second aim MVA85A was co-administered to mice with aluminium adjuvants or aluminium-containing vaccines to replicate the effect of co-administration in the EPI schedule; the adaptive immune response was profiled. T helper 2 and regulatory T cell responses induced by aluminium-containing vaccines were associated with a reduction in the immunogenicity of MVA85A.

O objetivo deste estudo foi analisar a distribuição espacial dos óbitos por tuberculose pulmonar e sua relação com indicadores sociais em São Luís-MA. Trata-se de um estudo ecológico em que foram considerados os óbitos ocorridos na zona urbana do município entre 2008 e 2012, segundo as causas A15.0 a A15.3 e A16.0 a A16.2 (CID-10), disponíveis no Sistema de Informação sobre Mortalidade. Procedeu-se inicialmente as análises univariada e bivariada das variáveis sociodemográficas e operacionais dos óbitos investigados. Para construção dos indicadores sociais utilizou-se a análise de componentes principais, sendo selecionadas variáveis das áreas de ponderação do Censo Demográfico de 2010. Recorreu-se à regressão linear múltipla, pelo método dos mínimos quadrados e à regressão espacial para análise da relação de dependência espacial entre os indicadores sociais e as taxas de mortalidade padronizadas pela idade por meio do Teste Global I de Moran. Utilizou-se ainda técnicas de estatística de varredura para a detecção de aglomerados espaciais e espaço- temporais dos óbitos nos setores censitários do município, sendo empregado o modelo discreto de Poisson. A geocodificação dos óbitos foi processada no TerraView versão 4.2.2, sendo considerados também nas análises os softwares Arcgis-versão 10.1, Statistica versão 12.0, OpenGeoDa versão 1.0, R versão 3.0.2 e SaTScanTM versão 9.2. Em todos os testes, foi fixado o nível de significância em alfa de 5% (p< 0,05). Identificou-se 193 indivíduos que evoluíram para óbito por tuberculose pulmonar, com idade mediana de 52 anos, sendo maior percentual referente ao sexo masculino (n=142; 73,60%), raça/cor parda (n=133; 68,91%), estado civil solteiro (n=102; 53,13%), ensino fundamental completo (n=64; 33,16%) e com ocorrência do óbito no hospital (n=143; 74,08%). Observou-se que não ter assistência médica previamente ao óbito teve associação estatisticamente significativa com a realização de necropsia (p=0,001). Foram geocodificados 95% dos óbitos e as taxas de mortalidade por tuberculose pulmonar padronizadas pela idade variaram de 0,00 a 8,10 óbitos/100.000 habitantes-ano. Na construção dos indicadores sociais, duas novas variáveis surgiram, apresentando variância total de 73,07%. A primeira componente (56,75%) foi denominada indicador de bem-estar social e a segunda (16,32%), indicador de iniquidade social, que, na regressão linear múltipla, apresentou-se estatisticamente significante (R2 =23,86%; p=0,004), verificando-se posteriormente a existência de dependência espacial (Moran I=0,285; p<0,001), sendo o Erro Espacial o melhor modelo explicativo. Foi possível evidenciar ainda que áreas de ponderação com alta e intermediária iniquidade social apresentaram as maiores taxas de mortalidade. Na análise de varredura espacial, identificou-se dois aglomerados espaciais, sendo um de alto risco relativo (RR=3,87; p<0,001) e outro de baixo (RR=0,10; p=0,002), enquanto que a análise espaço-temporal evidenciou apenas um aglomerado de alto risco relativo (RR=3,0; p<0,001) que ocorreu entre novembro de 2008 e abril de 2011. A investigação revelou áreas prioritárias para investimentos em tecnologias de saúde e um perfil de população fatalmente atingida pela doença, evidenciando aspectos importantes a serem considerados em termos de gestão e organização dos serviços de saúde para a equidade no acesso. / This study aimed to analyze the spatial distribution of deaths by pulmonary tuberculosis and the relation with social indicators, in São Luís-MA. It is an ecological study that considered deaths occurring in the urban area of the municipality, between 2008 and 2012, according to causes A15.0 to A15.3 and A16.0 to A16.2 (ICD-10), which are available in the Mortality Information System. It was initially used univariate and bivariate analyzes of demographic and operational variables from the investigated deaths. For the construction of social indicators, it was possible to use the principal components analysis, with variables selected from weighting areas of the Population Census, in 2010. It was utilized the multiple linear regression through the method of least squares and spatial regression to analyze the spatial dependence relationship between social indicators and standardized mortality rates by age, and with the Global I Test of Moran. Also, it was possible to use statistical techniques of scanning for detecting spatial-temporal and spatial clusters of deaths, in the municipality census tracts, and with the use of Poisson\'s discrete model. The geocoding of deaths was processed in TerraView version 4.2.2, and it was also considered, in the analysis, the softwares Arcgis version 10.1, Statistica version 12.0, OpenGeoDa version 1.0, R version 3.0.2 and SaTScanTM version9.2. It was fixed, in all tests, the level of significancein alpha of 5% (p<0.05). It was identified 193 individuals who died due to pulmonary tuberculosis, with a median age of 52 years, with higher percentage for males (n=142, 73.60%), mulatto race (n=133, 68.91%), single marital status (n=102, 53.13%), complete primary school (n=64, 33.16%), and with deaths at the hospital (n=143, 74.08%). It was seen that having no medical care prior to death was statistically associated with the performance of necropsy (p=0.001). It was possible to geocode 95% of deaths, and death rates due to pulmonary tuberculosis standardized by age ranged from 0.00 to 8.10 deaths per 100.000 inhabitants a year. In the construction of social indicators, two new variables emerged and showed a total variance of 73.07%. The first (56.75%) was denominated indicator of social welfare, and the second (16.32%) as an indicator of social inequity, which was statistically significant in the multiple linear regression (R2 =23.86 %, p=0.004). It was verified the existence of spatial dependence (Moran I=0.285, p<0.001), and the Spatial Error was the best explanatory model. It was also possible to show that weighting areas with high and intermediate social inequity presented the highest mortality rates. In the analysis of spatial scan, it was identified two spatial clusters, one of relatively high risk (RR=3.87, p<0.001) and the other one of low risk (RR=0.10, p=0.002). On the other hand, the spatial-temporal analysis evidenced only a cluster of relatively high risk (RR=3.0, p<0.001), which happened between November, 2008 and April, 2011. The research revealed priority areas for investments on health technology, and population profile fatally afflicted by the disease. It also pointed important aspects to be considered in terms of management and organization of health services for an equity access.

RESUMO Objetivo: Investigar fatores associados à recidiva, retratamento por abandono e óbito entre retratados por abandono para pacientes com TB pulmonar, de ambos os sexos, maiores que treze anos, residentes em área periférica do município de São Paulo. Material e Métodos: Estudos de caso-controle não pareado aninhado a uma coorte prospectiva de pacientes com TB pulmonar confirmada por cultura, selecionados entre 2001 e 2002 e acompanhados até 2006. Os casos foram pacientes que apresentaram recidivas, retratamento por abandono e óbito entre retratados por abandono; os controles foram pacientes com cura sem retratamento. Os dados foram obtidos mediante aplicação de questionários estruturados aplicados à época do ingresso no estudo e por entrevista domiciliar em 2004 e 2006, complementados por informação da Vigilância de TB. Na investigação dos fatores associados à recidiva, ao retratamento por abandono e óbito entre retratados por abandono, esses três desfechos foram tomados como variáveis dependentes e como variáveis independentes, as exposições de interesse. As odds ratio (OR) brutas e ajustadas foram estimadas com os respectivos intervalos de 95% de confiança pela regressão logística multivariada não condicional. A importância das variáveis para o modelo final foi avaliada através do teste da razão de verossimilhança, utilizando-se p<0,05. Resultados: As variáveis associadas à recidiva e ajustadas para sexo e idade independentemente das demais foram: co-infecção com HIV (OR=9,3; IC95%= 1,6 - 54,1), contato domiciliar prévio (OR= 2,2; IC95% = 0,8 - 6,2), caso de TB no domicílio após o paciente (OR= 3,8; IC95%= 1,2 - 12,8); diabetes (OR=1,6; IC95%= 0,3 - 7,7), MDR (OR=15,5; IC95%= 1,2 - 200,5). As variáveis associadas ao retratamento por abandono ajustadas para sexo e idade independentes das demais variáveis foram: TBMDR (OR=38,7; IC95%= 2,9 - 515,3), co-infecção com HIV (OR=24,8; IC95%= 3,8 - 163,0), história de alcoolismo (OR= 4,2; IC95%=1,1 - 17,5) e internação por complicações de TB (OR= 7,2; IC95% =2,5 - 21,0). As variáveis associadas ao óbito entre retratados por abandono ajustadas para sexo e idade independente das demais e foram: TBMDR (OR=152,4; IC95%= 9,8 - 237,4), co-infecção com HIV (OR=29,0; IC95%=7,1 -1 19,1), alcoolismo (OR=11,8; IC95%=1,3-102,8) e regime prisional (OR=5,0; IC95%= 1,0-25,8). Conclusões: Os resultados apresentados apontam grupos de maior risco para retratamento por TB por recidiva, abandono de tratamento e óbito que devem ser considerados no aperfeiçoamento do DOTS em nosso país. / ABSTRACT Objective: Investigate factors associated to relapse, re-treatment by default and death among patients retreated by default for patients with pulmonary tuberculosis, of both sexes, more than thirteen years old, living in the periphery of the city of São Paulo. Material and Methods: A nested case-control study not paired to a prospective cohort of pulmonary tuberculosis patients confirmed by culture, selected between 2001 e 2002 and followed up until 2006. Cases were patients who had relapses, re-treatment by default and death among patients retreated by default; controls were patients with cure without re-treatment. The data were obtained through application of structured questionnaires applied at the time of entry in the study and interview at home in 2004 and 2006, supplemented by information from the surveillance of TB and Information System Mortality of the Foundation SEADE. Relapse, re-treatment by default and death among patients retreated by default were taken as dependent variables and the variables of interest as independent. Crude and adjusted odds ratio (OR) and its 95% confidence interval were calculated by multiple logistic regression not conditional. Statistical significance was assessed by the likelihood ratio test with p < 0.05. Results: The variables associated independently with relapse and adjusted for sex and age were: case of MDR-TB (OR=15.5; 95% CI: 1.2-200.5), co-infection with HIV (OR=9.3 ,95%CI: 1.6-54.1), diabetes (OR=1.6, 95% CI: 0.3-7.7), previous household contact with TB (OR=2.2, 95% CI: 0.8-6.2) and TB at home after patient studied (OR=3,8, 95% CI: 1,2-12,8). The variables associated independently with the retreatment of default and adjusted for sex and age were: case of MDR-TB (OR = 38.7, 95 % CI: 2.9-515.3), co-infection with HIV (OR=24.8, 95% CI: 3.8-163.0), alcohol abuse (OR=4.2, 95% CI: 1.1-17.5) and hospitalization to TB complications (OR=7.2, 95% CI: 2.5-21.0). The variables associated independently with death among patients retreated by default and adjusted for sex and age were: case of MDR-TB (OR=152.4, 95% CI: 9.8-237.4), co-infection with HIV (OR=29.0, 95%CI: 7.1-119.1), alcohol (OR=11.8, 95% CI: 1.3-102.8) and prison system (OR=5.0, 95%CI: 1.0-25.8). Conclusions: The results presented here show groups of higher risk among TB patients for re-treatment by relapse, treatment default and death among re-treated by default to be considered in the improvement of DOTS in our country.

Submitted by Ana Lúcia Torres (bfmhuap@gmail.com) on 2017-10-04T12:28:58Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) DISSERTAÇAO TERESA SARMET SANTOS.pdf: 11566242 bytes, checksum: a43d71b5b5835fad2a1d8c29cc647012 (MD5) / Approved for entry into archive by Ana Lúcia Torres (bfmhuap@gmail.com) on 2017-10-04T12:29:53Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) DISSERTAÇAO TERESA SARMET SANTOS.pdf: 11566242 bytes, checksum: a43d71b5b5835fad2a1d8c29cc647012 (MD5) / Made available in DSpace on 2017-10-04T12:29:53Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) DISSERTAÇAO TERESA SARMET SANTOS.pdf: 11566242 bytes, checksum: a43d71b5b5835fad2a1d8c29cc647012 (MD5) Previous issue date: 2014 / Universidade Federal Fluminense. Hospital Universitário Antonio Pedro / Estudo descritivo de casos de tuberculose em lactentes imunocompetentes, com idades entre um e 36 meses, cujas imagens e prontuários estavam arquivados nos Serviços de Radiologia do Instituto Fernandes Figueira/FIOCRUZ-RJ e do Hospital Universitário Antônio Pedro/UFF. Foram estudados todos os exames realizados no período de janeiro de 2004 a junho de 2013, com a finalidade de avaliar os principais achados radiológicos em tomografia computadorizada. As manifestações radiológicas da tuberculose devem ser documentadas precocemente, de forma a viabilizar imediatamente o tratamento específico, sendo que estas manifestações na faixa etária estudada não são as mesmas descritas em pacientes pré-escolares, escolares e adultos, e os lactentes são mais sintomáticos e tem maior propensão a complicações sistêmicas como meningite e tuberculose miliar. A tomografia computadorizada foi de grande valia para estabelecer o diagnóstico precoce e para a instituição rápida do tratamento, com achados de consolidação e linfonodomegalias em 100% dos casos / A descriptive study of cases of tuberculosis in immunocompetent infants, aged one to 36 months, whose medical records and images are archived at the Radiology Services of Instituto Fernandes Figueira/FIOCRUZ-RJ and Hospital Universitário Antonio Pedro/UFF. All xaminations performed between January 2004 and June 2013 were studied with the aim of assessing the main radiological findings on computed tomography (excavation, nodules, airspace disease). The radiological manifestations of tuberculosis must be documented early in order to enable specific treatment immediately. It was found that the radiological manifestations of tuberculosis in the studied age group are not the same as those described in pre-school, school and adult patients. Infants are more symptomatic and are more prone to systemic complications such as meningitis and miliary tuberculosis. Computed tomography is very useful for an early diagnosis and rapid initiation of treatment in these patients, with consolidation and enlarged lymph nodes in 100% of cases

Text in English / Botswana has witnessed highest TB rates in the southern African countries, ranking the fourth after South Africa, Swaziland and Zimbabwe. In 2012, the TB rate was on average 531/100 000 population. About 2 380 contacts out of a possible 8 110 (amounting to 29.30%) were traced nationally (Botswana 2011:8), indicating a possible gap of 5 730 which was yet to be traced in 2011. The TBCT strategies might be inadequate leading to absence of screening and treating TB contacts and reducing PTB related deaths. The purpose of this study was to describe utilisation of current TBCT and develop a strategy for a more effective TBCT in Botswana. Data was collected through a quantitative cross-sectional research design. The study further described the association between TBCT strategies and practices and determined the gaps, challenges and needs in the TBCT. Results revealed under-tracing of contacts in the number of registered and enumerated TB contacts. The results further established the risk of mixing TB contacts and the general patients. The differences in the perceptions and knowledge of the cause of TB as well as poor utilisation of the current programmes by the PTB patients denotes the need for aggressive awareness raising and health promotion strategies. The results were used to develop an alternative strategy, the IC-TBCT, which has a potential to trace all TB contacts. The strategy encourages participation, effective accountability and involvement of the beneficiaries in all efforts aiming at early contact identification and reducing the incidence of PTB. / Health Studies / D. Litt. et Phil. (Health Studies)

This study sought to describe the challenges of diagnosing pulmonary tuberculosis (PTB) in children under the age of 5 years at clinics under the Prince Mshiyeni Hospital at Ethekwini Health District in KwaZulu-Natal. The study showed that primary health care (PHC) nurses do not have adequate knowledge to effectively diagnose PTB in children and, in addition, that PHC clinics are not adequately equipped to effectively diagnose PTB in children. / Health Studies / M.A. (Public Health)

Pulmonary Tuberculosis (TB) is a significant cause of morbidity in Uganda. TB control in the Ugandan district of Butaleja remains poor, characterised by TB case detection and cure rates below national targets. A qualitative exploratory and descriptive study was conducted to identify factors associated with health-seeking behaviour of TB patients in Butaleja district; with an aim to present recommendations for promoting positive health-seeking behaviour amongst the patients. Data was collected through individual in-depth interviews with seven diagnosed TB patients and analysed using Creswell’s (2009:186) analytic spiral steps. The findings revealed three major themes, namely; the nature of health-seeking behaviour, factors associated with the health-seeking behaviour and advice to others experiencing similar symptoms. The health-seeking behaviour of participants was generally poor, characterised by delay in seeking proper medical treatment for TB. Health system, individual and social factors contributed to poor health-seeking behaviour among the participants. The study recommends health system and community interventions targeted at individuals to improve health-seeking behaviour for Pulmonary TB / Health Studies / M.A. (Public Health)