Magister Public Health - MPH (Public Health) / Over the past two decades, despite a growing tuberculosis (TB) epidemic, the South African health system and National TB Programme (NTP) have taken significant steps to ensure improved clinical awareness, early diagnosis, prompt treatment initiation and follow-up of treatment outcomes in cases of TB. The effects of these programmatic measures over time on changes in the severity of disease and presenting clinical profile of patients with pulmonary TB have not been studied. Doing so may provide another window on the impact of TB control initiatives in South Africa.

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.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / NÃveis subterapÃuticos de drogas antimicobacterianas tÃm sido observados no curso do tratamento de pacientes com tuberculose e nos co-infectados TB/HIV e podem facilitar o surgimento de cepas de M. tuberculosis resistentes Ãs drogas. A mal-absorÃÃo intestinal inclue-se entre as provÃveis causas e tem sido descrita em tuberculosos desnutridos, alcoÃlatras, diabÃticos, aidÃticos ou com patologias gastrointestinais associadas. Estudos da permeabilidade intestinal permitem a avaliaÃÃo da funÃÃo intestinal em vÃrias doenÃas, mas tÃm sido escassos na tuberculose. O teste da lactulose / manitol tem sido utilizado como critÃrio de lesÃo com dÃficit absortivo da mucosa intestinal e pode ser de utilidade no prognÃstico da absorÃÃo intestinal de drogas em pacientes com tuberculose. Foram estudados 41 pacientes (30H e 11M). A coleta dos dados foi realizada no Hospital de MaracanaÃ, Fortaleza-CE, em 2001. Procedeu-se descriÃÃo clÃnica, social e laboratorial do grupo de pacientes e estudo piloto de observaÃÃo utilizando o teste da lactulose / manitol em 40 pacientes com tuberculose pulmonar ativa, comparando com grupo controle de 28 voluntÃrios sadios objetivando estudar a permeabilidade intestinal. Testes de sensibilidade Ãs drogas antituberculose, pelo mÃtodo das proporÃÃes indireto, foram realizados em 20 pacientes com cultura de escarro positivas. O grau de nutriÃÃo avaliado atravÃs do Ãndice de Massa CorpÃrea (IMC) e o nÃvel sÃrico das drogas foram correlacionados com os valores da permeabilidade intestinal. CinqÃenta e nove por cento (24 pacientes) foram considerados desnutridos pelo IMC<18,5 kg/m2, sendo vinte e dois por cento (9 pacientes) considerados severamente desnutridos (IMC<16 kg/m2). Em 18 pacientes, apÃs 2 h da tomada de 600mg de rifampicina (R) e 400 mg de isoniazida (H) os nÃveis sÃricos de R (CRM 2h) e H (CINH 2h) foram analisados por HPLC. A taxa de excreÃÃo urinÃria de manitol (mÃdia  desvio padrÃo) foi significativamente menor p<0,001 (9,52  5,70) nos pacientes que dos controles (20,14  10,84). A taxa de excreÃÃo de lactulose foi significativamente maior p<0,05 nos pacientes (0,59  1,79) que nos controles (0,52  0,47) e a razÃo L/M foi aumentada de forma consistente, embora nÃo significativa p>0,05 (0,05  0,10 pacientes contra 0,02  0,02 controles). Considerando a faixa terapÃutica da R (8-24 mcg/mL ) e da H (3-6 mcg/mL) observamos que as CRM2h e CINH2h em 16/18 (88,8%) pacientes nÃo atingiram nÃveis sÃricos adequados para as duas drogas. 8/18 (44,4%) pacientes nÃo alcanÃaram nÃveis sÃricos para ambas as drogas simultaneamente. Na anÃlise das drogas isoladas verificamos que em 12/18 (66,7%) pacientes a CRM2h o nÃvel sÃrico mÃnimo nÃo foi alcanÃado (mÃdia R =6,47 mcg/mL) e 13/18 (72,2%) a CINH2h tambÃm foi reduzida (mÃdia H =2,17 mcg/mL). Quanto ao perfil de resistÃncia do M. tuberculosis em cultura de escarro, observamos 4/20 (20%) multirresistentes (3 à R+H e 1 à todas as drogas) e 2/20 (10%) monorresistentes à H sendo 14/20 (70%) amostras consideradas sensÃveis Ãs drogas testadas. Os resultados observados sugerem uma intensa reduÃÃo na Ãrea de absorÃÃo e lesÃo da mucosa intestinal nos indivÃduos estudados. Os dados sÃo consistentes com a reduÃÃo na biodisponibilidade de rifampicina e isoniazida e com o estado nutricional destes pacientes. Os dados preliminares recomendam estudos adicionais na avaliaÃÃo completa da biodisponibilidade das drogas antimicobacterianas em pacientes com tuberculose / Subtherapeutic antimycobacterial drugs levels have been observed during treatment of patients with tuberculosis and in HIV coinfected. It may facilitate the development of M. tuberculosis resistant strains. Malabsorption may be one of the underlyne cause. It has been documented in tuberculosis patients associated to malnutrition, alchoolics, diabetes, AIDS and gastrointestinal symptoms. Intestinal permeability studies have been conducted in order to evaluate the intestinal function in some diseases but are scant in tuberculosis. Lactulose / manitol ratio in urine a widely used measure of malabsorption and intestinal permeability may be useful to assesss the drug absorption area in tuberculosis. In order to study the intestinal permeability in tuberculosis, we conducted in a pilot study 40 patients and 28 healthy volunteers, using the urinary excretion of ingested lactulose and manitol as respective markers of barrier disruption and overall villous surface area. The Maracanaà Hospital in Fortaleza-CE, was choosen and the data were collected in 2001. Eigthteen patients receiving 600 mg rifampicin (R) and 400 mg isoniazid (H) were evaluated through venous blood analysis obtained at 2 hours after directly observed ingestion. The serum samples were analysed by HPLC at the Infectious Disease Pharmacokinetics Laboratory / National Jewish Center / Denver, USA. Nutritional status by body mass index (BMI) and serum drug levels were correlated with intestinal permeability data. M. tuberculosis isolates from 20 clinical specimens were tested to drug susceptibility by standard proportion method (APM ) using Lowestein-Jensen medium. Forty-one patients (30 M, 11 F) were studied. Fifty nine per cent (24) patients were malnourish (BMI<18,5 kg/m2); 22% (9) were severely malnourish (BMI<16 kg/m2). The urinary excretion of mannitol (mean  standard deviation) showed a significant decrease p < 0,001 in patients (9,52  5,70) compared to controls (20,14  10,84). The excretion of lactulose was significant increased p < 0,05 in patients (0,59  1,79), than controls (0,52  0,47) and the L/M ratio shown consistent increased (0,05  0,10) in patients compared to controls (0,029  0,0,02) p > 0,05. Considering the reported target range for R (8-24 mcg/mL ) and H (3-6 mcg/mL) we observed that 2-h serum levels were below the lower limit for R and H in 88,8% (16/18) patients. Forty four per cent ( 8/18) of patients had reduced levels for the two drugs. Analysing single drugs we documented that 66,7% (12/18) patients had levels below the target limit for R (mean R =6,47 mcg/mL) and 72,2% (13/18) for H (mean H =2,17mcg/mL). Concerning to M. tuberculosis susceptibility profile in sputum culture, we observed 20% (4/20) multidrug resistants strains (3 for R + H and 1 for all drugs). Ten per cent (2/20) were resistant only for H and 70% (14/20) strains were sensitive. These results suggests an important decrease in the funcional absorptive surface of the intestine and damage of the intestine in patients studied. The data are consistent with reduced antituberculosis drugs bioavailability and compromissed nutritional status of these patients. The preliminary results indicate the necessity of new approaches to accurate portrait of drugs bioavailability in tuberculosis patients

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&lt; 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&lt;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&lt;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&lt;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&lt;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&lt;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&lt;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&lt;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.

Introduction: Les efforts globaux pour contrôler la tuberculose sont présentement restreints par la prévalence croissante du VIH/SIDA. Quoique les éclosions de la tuberculose multi résistante (TB-MDR) soient fréquemment rapportées parmi les populations atteintes du SIDA, le lien entre VIH/SIDA et le développement de résistance n’est pas clair. Objectifs: Cette recherche visait à : (1) développer une base de connaissances concernant les facteurs associés à des éclosions de la TB-MDR parmi les patients atteints du VIH/SIDA; (2) utiliser ce cadre de connaissances pour accroître des mesures préliminaires pour mieux contrôler la tuberculose pulmonaire chez les patients atteints du VIH/SIDA; et (3) afin d’améliorer l’application des ces mesures, affiner les techniques bactériologiques existantes pour Mycobacterium tuberculosis. Méthodologie: Quatre études ont été réalisées : (1) Une étude longitudinale pour identifier les facteurs associés avec une éclosion de la TB-MDR parmi les patients atteints du SIDA qui ont reçu le traitement directement supervisé de courte durée (DOTS) pour la tuberculose pulmonaire au Lima et au Pérou entre 1999 et 2005; (2) Une étude transversale pour décrire différentes étapes de l’histoire naturelle de la tuberculose, la prévalence et les facteurs associés avec la mycobactérie qu’on retrouve dans les selles des patients atteints du SIDA; (3) Un projet pilote pour développer des stratégies de dépistage pour la tuberculose pulmonaire parmi les patients hospitalisés atteints du SIDA, en utilisant l’essaie Microscopic Observation Drug Susceptibility (MODS); et (4) Une étude laboratoire pour identifier les meilleures concentrations critiques pour détecter les souches MDR de M. tuberculosis en utilisant l’essaie MODS. Résultats : Étude 1 démontre qu’une épidémie de TB-MDR parmi les patients atteints du SIDA qui ont reçu DOTS pour la tuberculose pulmonaire ait été causée par la superinfection du clone de M. tuberculosis plutôt que le développement de la résistance secondaire. Bien que ce clone ait été plus commun parmi la cohorte de patients atteints du SIDA, il n’avait aucune différence de risque pour superinfection entre les patients avec ou sans SIDA. Ces résultats suggèrent qu’un autre facteur, possiblement associé à la diarrhée, peu contribuer à la prévalence élevée de ce clone chez les patients atteints du SIDA. Étude 2 suggère que chez la plupart des patients atteints du SIDA il a été retrouvé une mycobactérie dans leurs selles alors qu’ils étaient en phase terminale au niveau de la tuberculose pulmonaire. Or, les patients atteints du SIDA ayant été hospitalisés pendant les deux dernières années pour une autre condition médicale sont moins à risque de se retrouver avec une mycobactérie dans leurs selles. Étude 3 confirme que la tuberculose pulmonaire a été commune à tous les patients hospitalisés atteints du SIDA, mais diagnostiquée incorrectement en utilisant les critères cliniques présentement recommandés pour la tuberculose. Or, l’essaie MODS a détecté pour la plupart de ces cas. De plus, MODS a été également efficace quand la méthode a été dirigée aux patients soupçonnés d’avoir la tuberculose, à cause de leurs symptômes. Étude 4 démontre les difficultés de détecter les souches de M. tuberculosis avec une faible résistance contre ethambutol et streptomycine en utilisant l’essai MODS avec les concentrations de drogue présentement recommandées pour un milieu de culture. Cependant, l’utilité diagnostique de MODS peut être améliorée ; modifier les concentrations critiques et utiliser deux plaques et non une, pour des tests réguliers. Conclusion: Nos études soulèvent la nécessité d’améliorer le diagnostic et le traitement de la tuberculose parmi les patients atteints du SIDA, en particulier ceux qui vivent dans des régions avec moins de ressources. Par ailleurs, nos résultats font ressortir les effets indirects que les soins de santé ont sur les patients infectés par le VIH et qu’ils peuvent avoir sur le développement de la tuberculose. / Background: Global efforts to control tuberculosis are currently being hampered by a continuing rise in the prevalence of HIV/AIDS. Although outbreaks of multidrug resistant tuberculosis (MDR-TB) are commonly reported among AIDS populations, the link between HIV/AIDS and the development of drug-resistance remains unclear. Objectives: This thesis aimed to: (1) build a knowledge foundation regarding underlying factors associated with outbreaks of MDR-TB among HIV/AIDS patients; (2) use this knowledge framework to develop preliminary health measures for controlling pulmonary tuberculosis among HIV/AIDS patients; and (3) in an effort to better implement these health measures, refine existing culture-based diagnostics for Mycobacterium tuberculosis. Methods: Four studies were conducted: (1) a longitudinal study to identify the underlying factors associated with an epidemic of MDR-TB among AIDS patients receiving Directly- Observed Therapy Short-course (DOTS) for pulmonary tuberculosis in Lima, Peru between 1999 and 2005; (2) a cross-sectional study to characterize the prevalence and factors associated with gastrointestinal shedding with mycobacteria among AIDS patients at different stages in the natural history of tuberculosis; (3) a pilot study to develop screening strategies for pulmonary tuberculosis among hospitalized HIV/AIDS patients using the Microscopic Observation Drug Susceptibility (MODS) assay; and (4) a laboratory-based study to define the optimal critical concentrations needed for detecting drug resistance in M. tuberculosis using MODS. Results: Study 1 revealed that an epidemic of MDR-TB among AIDS patients receiving DOTS for pulmonary tuberculosis was due to super-infection with a specific clone of M. tuberculosis rather than the development of secondary drug-resistance. Although this epidemic clone was more common among patients in the AIDS cohort, risk of superinfection did not differ between AIDS and non-AIDS patients after adjusting for baseline risk of exposure, suggesting that another factor possibly associated with diarrhea may be contributing to the strain’s high prevalence among AIDS patients. Study 2 showed that the majority of AIDS patients in the later stages of pulmonary tuberculosis exhibited gastrointestinal shedding with mycobacteria. Stool shedding was rare in the absence of pulmonary tuberculosis. AIDS patients were also less likely to shed mycobacteria if they had been hospitalized during the previous two years for another medical condition. Study 3 confirmed that pulmonary tuberculosis was common among hospitalized AIDS patients but frequently misdiagnosed using currently recommended diagnostic algorithms. The MODS assay detected most cases and was equally effective when targeted to patients clinically suspicious for tuberculosis. Study 4 demonstrated that low grade drug resistance in M. tuberculosis to ethambutol and streptomycin was difficult to detect with MODS using currently recommended drug-concentration standards in broth. Its diagnostic utility could be improved by modifying drug-concentration standards, and including two versus one critical concentration well for standardized testing. Conclusion: Our studies underscore the need to improve the diagnosis and treatment of tuberculosis among AIDS patients living in resource-constrained settings, all in an effort to prevent morbidity, mortality and the transmission of drug-resistant strains. They also highlight the indirect effect that general health care among HIV-infected patients can have on the development of tuberculosis.

Introduction: Les efforts globaux pour contrôler la tuberculose sont présentement restreints par la prévalence croissante du VIH/SIDA. Quoique les éclosions de la tuberculose multi résistante (TB-MDR) soient fréquemment rapportées parmi les populations atteintes du SIDA, le lien entre VIH/SIDA et le développement de résistance n’est pas clair. Objectifs: Cette recherche visait à : (1) développer une base de connaissances concernant les facteurs associés à des éclosions de la TB-MDR parmi les patients atteints du VIH/SIDA; (2) utiliser ce cadre de connaissances pour accroître des mesures préliminaires pour mieux contrôler la tuberculose pulmonaire chez les patients atteints du VIH/SIDA; et (3) afin d’améliorer l’application des ces mesures, affiner les techniques bactériologiques existantes pour Mycobacterium tuberculosis. Méthodologie: Quatre études ont été réalisées : (1) Une étude longitudinale pour identifier les facteurs associés avec une éclosion de la TB-MDR parmi les patients atteints du SIDA qui ont reçu le traitement directement supervisé de courte durée (DOTS) pour la tuberculose pulmonaire au Lima et au Pérou entre 1999 et 2005; (2) Une étude transversale pour décrire différentes étapes de l’histoire naturelle de la tuberculose, la prévalence et les facteurs associés avec la mycobactérie qu’on retrouve dans les selles des patients atteints du SIDA; (3) Un projet pilote pour développer des stratégies de dépistage pour la tuberculose pulmonaire parmi les patients hospitalisés atteints du SIDA, en utilisant l’essaie Microscopic Observation Drug Susceptibility (MODS); et (4) Une étude laboratoire pour identifier les meilleures concentrations critiques pour détecter les souches MDR de M. tuberculosis en utilisant l’essaie MODS. Résultats : Étude 1 démontre qu’une épidémie de TB-MDR parmi les patients atteints du SIDA qui ont reçu DOTS pour la tuberculose pulmonaire ait été causée par la superinfection du clone de M. tuberculosis plutôt que le développement de la résistance secondaire. Bien que ce clone ait été plus commun parmi la cohorte de patients atteints du SIDA, il n’avait aucune différence de risque pour superinfection entre les patients avec ou sans SIDA. Ces résultats suggèrent qu’un autre facteur, possiblement associé à la diarrhée, peu contribuer à la prévalence élevée de ce clone chez les patients atteints du SIDA. Étude 2 suggère que chez la plupart des patients atteints du SIDA il a été retrouvé une mycobactérie dans leurs selles alors qu’ils étaient en phase terminale au niveau de la tuberculose pulmonaire. Or, les patients atteints du SIDA ayant été hospitalisés pendant les deux dernières années pour une autre condition médicale sont moins à risque de se retrouver avec une mycobactérie dans leurs selles. Étude 3 confirme que la tuberculose pulmonaire a été commune à tous les patients hospitalisés atteints du SIDA, mais diagnostiquée incorrectement en utilisant les critères cliniques présentement recommandés pour la tuberculose. Or, l’essaie MODS a détecté pour la plupart de ces cas. De plus, MODS a été également efficace quand la méthode a été dirigée aux patients soupçonnés d’avoir la tuberculose, à cause de leurs symptômes. Étude 4 démontre les difficultés de détecter les souches de M. tuberculosis avec une faible résistance contre ethambutol et streptomycine en utilisant l’essai MODS avec les concentrations de drogue présentement recommandées pour un milieu de culture. Cependant, l’utilité diagnostique de MODS peut être améliorée ; modifier les concentrations critiques et utiliser deux plaques et non une, pour des tests réguliers. Conclusion: Nos études soulèvent la nécessité d’améliorer le diagnostic et le traitement de la tuberculose parmi les patients atteints du SIDA, en particulier ceux qui vivent dans des régions avec moins de ressources. Par ailleurs, nos résultats font ressortir les effets indirects que les soins de santé ont sur les patients infectés par le VIH et qu’ils peuvent avoir sur le développement de la tuberculose. / Background: Global efforts to control tuberculosis are currently being hampered by a continuing rise in the prevalence of HIV/AIDS. Although outbreaks of multidrug resistant tuberculosis (MDR-TB) are commonly reported among AIDS populations, the link between HIV/AIDS and the development of drug-resistance remains unclear. Objectives: This thesis aimed to: (1) build a knowledge foundation regarding underlying factors associated with outbreaks of MDR-TB among HIV/AIDS patients; (2) use this knowledge framework to develop preliminary health measures for controlling pulmonary tuberculosis among HIV/AIDS patients; and (3) in an effort to better implement these health measures, refine existing culture-based diagnostics for Mycobacterium tuberculosis. Methods: Four studies were conducted: (1) a longitudinal study to identify the underlying factors associated with an epidemic of MDR-TB among AIDS patients receiving Directly- Observed Therapy Short-course (DOTS) for pulmonary tuberculosis in Lima, Peru between 1999 and 2005; (2) a cross-sectional study to characterize the prevalence and factors associated with gastrointestinal shedding with mycobacteria among AIDS patients at different stages in the natural history of tuberculosis; (3) a pilot study to develop screening strategies for pulmonary tuberculosis among hospitalized HIV/AIDS patients using the Microscopic Observation Drug Susceptibility (MODS) assay; and (4) a laboratory-based study to define the optimal critical concentrations needed for detecting drug resistance in M. tuberculosis using MODS. Results: Study 1 revealed that an epidemic of MDR-TB among AIDS patients receiving DOTS for pulmonary tuberculosis was due to super-infection with a specific clone of M. tuberculosis rather than the development of secondary drug-resistance. Although this epidemic clone was more common among patients in the AIDS cohort, risk of superinfection did not differ between AIDS and non-AIDS patients after adjusting for baseline risk of exposure, suggesting that another factor possibly associated with diarrhea may be contributing to the strain’s high prevalence among AIDS patients. Study 2 showed that the majority of AIDS patients in the later stages of pulmonary tuberculosis exhibited gastrointestinal shedding with mycobacteria. Stool shedding was rare in the absence of pulmonary tuberculosis. AIDS patients were also less likely to shed mycobacteria if they had been hospitalized during the previous two years for another medical condition. Study 3 confirmed that pulmonary tuberculosis was common among hospitalized AIDS patients but frequently misdiagnosed using currently recommended diagnostic algorithms. The MODS assay detected most cases and was equally effective when targeted to patients clinically suspicious for tuberculosis. Study 4 demonstrated that low grade drug resistance in M. tuberculosis to ethambutol and streptomycin was difficult to detect with MODS using currently recommended drug-concentration standards in broth. Its diagnostic utility could be improved by modifying drug-concentration standards, and including two versus one critical concentration well for standardized testing. Conclusion: Our studies underscore the need to improve the diagnosis and treatment of tuberculosis among AIDS patients living in resource-constrained settings, all in an effort to prevent morbidity, mortality and the transmission of drug-resistant strains. They also highlight the indirect effect that general health care among HIV-infected patients can have on the development of tuberculosis.

This thesis focuses on the attitudes and policies which shaped the history of pulmonary tuberculosis in the Cape from 1870 to 1920 and culminated in the passing of the Public Health Act, Act 36 of 1919. It was this act which formed the basis of public health legislation in South Africa until the 1970s. The thesis is a contribution to the history of medicine and to the history of legislation. Topics explored include pulmonary tuberculosis and its early global history. When the practice of sufferers visiting places with particular climates became fashionable, towns in the Karoo became a popular destination. Their journey to the colony, together with their experience in Cradock is the subject of a chapter. Once the disease spread to the local population, the focus shifted to the attitudes and policies of the local authorities and their failure to address its spread. In contrast, in Cape Town the city council and its medical officer of health took up the challenge, but with limited success. The fight against tuberculosis was assisted by a number of dedicated individuals such as Dr Neil Macvicar who was the founder of the Native Health Society. The Society for the Prevention of Consumption, which was officially launched in Cape Town in June 1904, also contributed to educating the public about the disease. Once the Cape Colony entered into political Union in 1910 there was the added dimension of tuberculosis on the mines and the reluctance of mine officials to take care of workers suffering from the disease. This became an issue during the proceedings of the Tuberculosis Commission. The attitudes and prejudices towards the local population became formalised in the Public Health Act, Act 36 of 1919 because the act was drafted with the health of the white population in mind. By providing a skeleton budget for local authorities to deal with tuberculosis, the legislature ensured that the healthcare of the majority of the population, especially those who were most vulnerable to the disease, was not addressed. The legacy of that decision continues to haunt South Africa to the present day. / History / D.Litt.et Phil. (History)

Solicitud de embargo por publicación en revista indexada. / OBJECTIVE. To synthesize the evidence regarding prognostic models to predict mortality in patients diagnosed with pulmonary tuberculosis. METHODOLOGY. The current study followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (The PRISMA Group, 2020) Statement. A literature search on prognostic models aimed to predict mortality in patients diagnosed with pulmonary tuberculosis was conducted by three revisers. We included prospective and retrospective studies where prognostic models predicting mortality were either developed or validated in patients diagnosed with pulmonary tuberculosis. Three reviewers independently assessed the quality of the included studies using the PROBAST tool. (¨Prediction model study Risk Of Bias Assessment Tool¨), which assesses both the risk of bias (RoB) and the applicability of each model. A descriptive analysis of each of the prediction models developed, their performance and the population characteristics of each article was conducted. RESULTS. Only 6 articles met the selection criteria. There was a total of 6 prognostic rules, one in each article. Most studies (5 out of 6) were retrospective cohorts, only 1 study was a prospective case-control study. When adding the population of all the studies, there were a total of 3,553 participants, with samples ranging from 103 participants to 1070 participants. All the studies had a high risk of bias according to the PROBAST tool in the overall assessment. The overall assessment showed that 3 studies had a low concern of applicability, 2 high concern and 1 unclear concern. Only 5 studies developed new prediction rules. In general, the presented models had a good discriminatory ability, with areas under the curve fluctuating between 0.65 up to 0.91. The predictive model with the highest discriminatory power was the one reported by Horita, et - al. with an AUC of 0.910 in the development cohort and 0.893 in the validation cohort. CONCLUSION. Considering that pulmonary tuberculosis is a highly prevalent disease in low-income countries, it would be very useful to have quality tools that allow healthcare personnel to be able to catalog patients with a higher risk of death so that they can receive priority medical attention. / OBJETIVO Sintetizar la evidencia acerca de modelos pronósticos que predicen mortalidad en pacientes con tuberculosis pulmonar. METODOLOGÍA. El siguiente estudio sigue las guías PRISMA del año 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Se realizó una búsqueda literaria, por tres revisores, de modelos pronósticos que se enfocaban en predecir mortalidad en pacientes diagnosticados con tuberculosis pulmonar. Se incluyeron estudios prospectivos y retrospectivos, donde los modelos pronósticos que predecían mortalidad habían sido desarrollados o validados en pacientes con tuberculosis pulmonar. De manera independiente, tres revisores evaluaron la calidad de los estudios incluidos usando la herramienta PROBAST (¨Prediction model study Risk Of Bias Assessment Tool¨), la cual evalúa el riesgo de sesgo y la aplicabilidad de cada modelo. Se realizó un análisis descriptivo de cada modelo de predicción, su performance, y las características de la población. RESULTADOS. Solo 6 artículos cumplieron los criterios de selección. Hubo un total de 6 modelos pronósticos, uno en cada artículo. La mayoría de los estudios (5 de 6) fueron cohortes retrospectivas, y solo uno fue un estudio de casos y controles prospectivo. Al sumar la población total de los estudios, hubo un total de 3,553 participantes, con muestras desde 103 hasta 1070 participantes. Todos los estudios obtuvieron un alto riesgo de sesgo, de acuerdo a la herramienta PROBAST, en la evaluación global. Además, la evaluación global mostró que 3 estudios obtuvieron una baja preocupación de aplicabilidad, 2 alta preocupación y un estudio preocupación indeterminada. Solo 5 estudios desarrollaron nuevas reglas de predicción, mientras que uno válido una ya existente. En general los modelos de predicción mostraron una buena habilidad discriminatoria, con valores de área bajo la curva que fluctuaban entre 0.65 hasta 0.91. El modelo de predicción con mayor poder discriminatorio fue el reportado por Horita, et – al con un valor de área bajo la curva de 0.910 en la cohorte de desarrollo y 0.893 en la cohorte de validación. CONCLUSIÓN. Tomando en cuenta que la tuberculosis pulmonar es una enfermedad prevalente en países de desarrollo, sería útil contar con herramientas que ayuden a los profesionales de la salud a catalogar a los pacientes con mayor riesgo de mortalidad, para que así ellos puedan recibir atención médica prioritaria. / Tesis

L'isolement de Mycobacterium tuberculosis par culture est la méthode de référence pour le diagnostic de la tuberculose. Le but de notre travail était d'améliorer et de faciliter le diagnostic par culture de la tuberculose. Dans un premier temps, nous avons produit une revue bibliographique en comparant les différentes techniques ou protocoles utilisés pour le diagnostic de la tuberculose. Ce travail nous a permis d'actualiser notre protocole de diagnostic, avec la mise en place d’un "kit-tuberculose" contenant des containers imprégnés de chlorhexidine pour la récupération et la décontamination directe d’échantillons cliniques non- invasifs, suivi par la culture sur un milieu solide à base d'oeuf, et détection des colonies par microscope inversé ou par un système d'imagerie en temps réel. Nous avons mis en place une méthode de décontamination par 0,7%-chlorhexidine et avons montré que cette méthode était plus efficace que la méthode de référence NALC-NaOH. Ensuite, nous avons développé un milieu de culture à base de sérum animal, le MOD9 dont nous avons montré par une étude comparative qu'il était supérieur au milieu solide LJ de référence. Une deuxième étude comparant un protocole de décontamination par la chlorhexidine et culture sur milieu MOD9 au protocole standard, NALC-NaOH/Bactec960 a montré une supériorité par rapport au protocole standard. Enfin, la mise en place d'un système de détection des micro-colonies de M. tuberculosis sur MOD9 par imagerie en temps réel Advencis-Biosystem a permis de réduire le temps de détection de M. tuberculosis à 3,2 jours avec le protocole chlorhexidine/MOD9/Advencis, avec un record mondial de détection en 25h. / Isolation of Mycobacterium tuberculosis by culture is the gold standard for the diagnosis of tuberculosis. The aim of my thesis work was to simplify and improve the culture diagnosis of tuberculosis. At first we started with a bibliographic study, comparing step by step the different techniques and protocols that have been used for the diagnosis of tuberculosis. This work has allowed us to update our tuberculosis diagnosis protocol, starting with the implementation of a "Tuberculosis-kit" consisting of chlorhexidine containing containers for the recovery and decontamination of non-invasive specimens, followed by culture on an egg-based medium, a micro- colonies detection using an inverted microscope or an automated real-time imaging incubator system and finally an identification using mass spectrometry. We established a new chlorhexidine- based decontamination method that we showed to be more efficient for the recovery and isolation of M. tuberculosis than the standard NALC-NaOH method. Than we developed a new serum-based culture medium, the MOD9 that we showed in a comparative study to be superior to the reference LJ medium for the recovery of M. tuberculosis. In a second study we proved that our chlorhexidine/MOD9 protocol was superior to the standard NALC-NaOH/Bactec 960 MGIT protocol for the isolation of M. tuberculosis. And finally the implementation of a real time imaging system for the detection of M. tuberculosis micro-colonies on MOD9 permits us to dramatically reduce the detection time from 15 days with the standard NALC-NaOH/Bactec 960 MGIT protocol to 3.2 days with our 0.7%-chlorhexidine/MOD9/Advencis-Biosystem protocol with a world record detection time of 25h.

La tuberculose, causée par Mycobacterium tuberculosis, connaît actuellement une résurgence inquiétante, et l’OMS estime à plus de 10 millions le nombre de nouveaux cas cliniques en 2015 avec environ 1,8 millions de décès dus à la maladie. Environ un tiers de la population mondiale est exposée à M.tuberculosis, et après exposition, la plupart des individus sont infectés par la mycobactérie. La grande majorité (~90%) des individus infectés ne présentera jamais de symptomatologie clinique. Parmi les 10% qui développent la maladie, environ la moitié le fera dans les deux années suivant l’infection, ce qui est en général considéré comme une forme primaire de tuberculose. Les autres patients présenteront leur maladie à distance de l’infection primaire (parfois plusieurs dizaines d’années plus tard) ; il s’agit des formes pulmonaires classiques de l’adulte. Chez l’homme, le rôle de certains facteurs génétiques a été maintenant démontré dans le développement d’une tuberculose active, à la fois la tuberculose pulmonaire de l’adulte et les formes plus disséminées de l’enfant, et aussi dans le contrôle de l’infection tuberculeuse. Cependant, la plus grande part de ces facteurs génétiques reste à identifier. Le premier objectif de ma thèse était d'identifier les facteurs génétiques de l'hôte modulant les phénotypes immunologiques de production d'Interféron gamma in vitro (IGRA) après exposition à M. tuberculosis dans un échantillon de 590 individus ayant été en contact avec un cas avéré de tuberculose dans le Val de Marne, en région parisienne. Puis, dans un second temps, de voir si les facteurs trouvés pouvaient être répliquées dans un échantillon familial d'Afrique du Sud, zone de très forte endémie tuberculeuse. Pour cela, j'ai tout d'abord réalisé des analyses de liaison génétique à l'échelle du génome entier sur plusieurs phénotypes quantitatifs d'IGRA. Celles-ci ont permis de mettre en évidence 2 loci majeurs (p < 10-4) répliqués en Afrique du Sud et liés à la production d'interféron gamma induite pour l’un par le bacille du BCG, et pour l’autre, par la part spécifique de l'antigène ESAT6 de M. tuberculosis (absent de la plupart des mycobactéries environnementales et du BCG), indépendamment de la capacité intrinsèque de réponse aux mycobactéries. La seconde étape a consisté en la réalisation d'une étude d'association sur les régions de liaison ainsi identifiées. Un variant associé au phénotype spécifique de l’ESAT6 (p < 10-5) a ainsi été trouvé, variant contribuant de manière significative au pic de liaison précédemment découvert (p<0.001) et ayant été rapporté comme modulant l’expression du gène ZXDC. Le second objectif de la thèse concernait l’identification de variants génétiques rares sous-jacents à la déclaration d’une tuberculose pulmonaire chez les individus infectés par le bacille. A cette fin, j’ai comparé les exomes de 120 patients tuberculeux à ceux de 136 individus infectés par le bacille mais non malades, tous originaires du Maroc. Cette étude m’a permis d’identifier le gène BTNL2, en bordure de la région HLA, dans lequel près de 10% des patients comportaient un variant rare perte de fonction contrairement aux contrôles qui n’en présentaient aucun. / Tuberculosis remains a major public health concern, with approximately 10.4 million new cases and 1.8 million deaths due to the disease in 2015 according to WHO. While an estimated one third of the world population is estimated to be infected with Mycobacterium tuberculosis, only about 10% of infected individuals go on to develop a clinical disease. Among them, half will declare the disease in the 2 years following infection, which is generally considered as primary tuberculosis. The other patients will develop the disease more distant in time of primary infection, sometimes several tens of years latter; these are classical pulmonary forms in adults. In humans, the role of genetic factors have been demonstrated in the development of active tuberculosis, in pulmonary forms as in disseminated forms in childhood, et also in the control of M.tuberculosis infection. Nevertheless, most of these genetic factors remain to identify. The first aim of my PhD was to identify genetic factors controlling in vitro interferon-gamma production phenotypes (IGRA) after exposure to M.tuberculosis in a sample of 590 subjects who were in contact with a proven tuberculous patient in Val-de-Marne, Paris suburbs, and in a second time, to try to replicate the findings in a south African familial sample where the tuberculosis is highly endemic. For this purpose, I first performed genome-wide genetic linkage analysis for several quantitative IGRA phenotypes. They led to identify 2 major loci (p<10-4) replicated in South-Africa and linked to the interferon-gamma production induced by live BCG for the first one, and for the second one, by the specific part of the ESAT6 antigen of M.tuberculosis (absent from most of environmental mycobacteria and from BCG), independently of intrinsic ability to respond to mycobacteria. The second step was an association study in the identified linkage regions. A variant associated to the specific ESAT6 phenotype was found (p<10-5), which was significantly contributing to the linkage peak (p<0.001) and previously reported as eQTL of ZXDC gene. The second objective of my PhD was the identification of rare genetic variants underlying the development of pulmonary tuberculosis in infected individuals. To this end, I compared exome data from 120 tuberculous patients and 136 infected individuals without any clinical symptoms. All of them were from Morocco. This study resulted in the lighting of BTNL2 gene, very closed to the HLA region, in which around 10% of patients had a rare loss of function variant whereas the controls didn’t have any.