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This thesis presents an historical account of the introduction and use of two medical technologies, mass miniature radiography (MMR) and chemotherapeutic regimes, respectively, for the detection and treatment of Tuberculosis (TB) after the Second World War. The thesis focuses on two specific locations, the cities of Glasgow, in Scotland, and Cape Town, in South Africa, to present parallel case studies of the innovation, adoption and adaption of new medical technologies.

Tuberculosis (TB) continues to be a public health concern in high-income countries, such as the UK, with disease notifications primarily, and disproportionately, occurring in foreign-born immigrants who have a higher TB incidence than the local-born population. Underlying this epidemiology is the synergy of migration from high TB burden regions and the reactivation of imported latent TB infection (LTBI) in the initial years after migration which has refocused attention on immigrant screening for TB. In addition, amongst foreign-born individuals, TB disease primarily manifests as an extrapulmonary phenotype although the relative importance of demographic, host, mycobacterial lineage and environmental factors remains unclear. International, and national (UK-specific), surveys of the current systems in place for immigrant screening were undertaken. Using empirical UK immigrant screening data obtained from a multi-centre assessment of single-step IGRA testing and a prospective, community-based evaluation of different screening modalities, estimates for LTBI prevalence, yields for screening and the relative performance of different screening methods were computed. Decision-analysis models were constructed, with the data obtained from these empirical studies, to assess the cost-effectiveness of screening for LTBI at different incidence thresholds with different screening tools with and without port-of-arrival chest radiography to enable specific policy recommendations to be made. To assess demographic, mycobacterial lineage and environmental factors associated with specific clinical phenotypes, data from three independent Northern hemisphere TB databases (Birmingham, UK; US CDC and London, UK) were analysed. High-income countries prioritised screening for active TB but LTBI screening, paradoxically, was limited and those countries that did screen for LTBI varied significantly in whom they targeted and how they screened. Similar patterns were seen in the UK with heterogeneity particularly evident in the incidence threshold at which screening was instigated and the screening tools used. Moreover, screening for LTBI was inversely related to TB burden in the responding area. Data from the empirical studies of immigrant screening revealed that LTBI prevalence varied from 17-30% (depending on screening tool) and that prevalence was independently associated with increasing TB incidence in country of origin. The proportion of latently infected individuals identified (with LTBI) decreased as the TB incidence screening threshold increased. Health economic analyses revealed that the most cost-effective screening model would be to dispense with port-of-arrival chest radiographic screening and screen for LTBI at an intermediate screening threshold (250 or 150/100000) using single-step IGRA testing (with the QuantiFERON Gold in-tube). Data on the association of demographic and mycobacterial lineage factors revealed that, on multivariate analysis, extrapulmonary disease was most strongly associated (and more strongly than lineage) with non-White ethnicity. Mycobacterial lineages were geo-ethnically restricted and certain lineages (Euro-American and East African Indian) were preferentially associated with pulmonary disease whilst others, such as the East Asian lineage, were associated with extrapulmonary disease. In a separate assessment of demographic and environmental factors, local-born Whites had a significantly lower proportion of extrapulmonary disease compared to local-born Non-Whites; both groups had a significantly lower proportion of extrapulmonary disease as compared to foreign-born Non-Whites. In foreign-born Non-Whites, the proportion of cases that were extrapulmonary significantly increased as time elapsed between migration and the development of active TB before stabilising. In the US dataset, states with higher levels of sunshine had significantly lower levels of extrapulmonary TB. In the London cohort, individuals with purely extrapulmonary tuberculosis (14.1 nmol/L) had significantly lower mean vitamin D levels compared to individuals with pulmonary tuberculosis only (25.8 nmol/L)(p=0.0003). Severe vitamin D deficiency (<20 nmol/L) was significantly more common amongst individuals with purely extrapulmonary tuberculosis than subjects with purely pulmonary tuberculosis (p=0.002). For the first time, it was found that Vitamin D deficiency (<20 nmol/L) was independently associated with extrapulmonary disease (OR 4.70; 95% CI 1.22-18.09 for purely extrapulmonary TB, OR 4.32;95% CI 1.26-14.76 for any extrapulmonary TB). The work contained in this thesis highlights LTBI screening for immigrants is currently very limited but that with empirical data objective cost-effective policy recommendations can be, and have been, made about which groups to screen and with which diagnostic modalities. The distinct clinical phenotypic presentation of TB disease in immigrants appears to relate primarily to the interaction of demographic (ethnicity) and environmental (vitamin D) factors with mycobacterial lineage playing a role, albeit lesser, in comparison to other factors.

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La tuberculose est la neuvième cause de mortalité dans le monde. Les progrès pour contrôler cette maladies ont été ralentis par plusieurs facteurs, notamment la diffusion de souches de tuberculose à bacilles multirésistants aux antibiotiques (MDR). Le traitement de la tuberculose MDR est long, toxique, et souvent inefficace. Après plus de 40 ans de pénurie, deux nouveaux médicaments ont été approuvé pour le traitement de la tuberculose MDR : la bédaquiline et le delamanide. Globalement, il y eu des délais considérables dans l'introduction de ces nouveaux médicaments dans la pratique clinique, comme souligné par le faible nombre d'études présentes en littérature. Les études présentés dans ce travail ont décrit des cohortes de patients atteints de tuberculose MDR et traités par bédaquiline et/ou delamanide en France, en montrant d'abord une tolérance satisfaisante, même pour des durées prolongées de traitement et pour l'association des deux nouveaux médicaments. En outre, l'efficacité microbiologique de la bédaquiline apparait comparable à celle des fluoroquinolones, la classe d'antibiotiques la plus efficace pour la tuberculose MDR. Dans une autre étude, l'on a mis en évidence l'apparition rapide de la résistance à la bédaquiline en France, ce qui était inattendu, en particulier pour les cas de résistance primaire. Malgré les limitations méthodologiques associées aux études observationnelles et rétrospectives, ce travail a permis d'augmenter les connaissances sur la tolérance et l'efficacité du traitement avec les nouvelles molécules pour la tuberculose MDR. Une suite des recherches est envisagée avec la mise en place d'une cohorte national prospective des cas MDR. / Tuberculosis is the ninth leading cause of death worldwide. Progress in controlling this disease has been slowed down by multiple factors, including the emergence of multidrug-resistant (MDR) strains. MDR tuberculosis treatment is long, toxic, and often not effective. After more than 40 years of draught, two new drugs have been approved for the treatment of MDR tuberculosis: bedaquiline and delamanid. Globally, there have been considerable delays in the introduction of these new drugs in clinical practice, as shown by the little number of studies which are available in literature. The studies described in this manuscript have described cohorts of patients affected by MDR tuberculosis and treated with bedaquiline and/or delamanid in France: the main finding was a satisfying safety, even for prolonged treatment durations and for the association of the two new drugs. In addition, the microbiological efficacy of bedaquiline was shown to be comparable to the one of the fluoroquinolones, the most effective antibiotic class to treat MDR tuberculosis. In another study, we have shown the rapid appearance of bedaquiline resistance in France, an unexpected finding in particular for the cases of primary resistance. Notwithstanding the methodologic weaknesses associated with observational and retrospective studies, this work has increased the evidence on safety and efficacy of MDR tuberculosis treatment with the new drugs. The next step will be represented by the establishment of a prospective national research cohort of MDR tuberculosis cases.