Doctoral Degrees (Paediatrics and Child Health)

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Browsing Doctoral Degrees (Paediatrics and Child Health) by Subject "BCG vaccines"

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    Development of a conceptual framework of childhood tuberculosis within which to study the impact of a preventive therapy program for childhood tuberculosis prevention in high burden communities
    (Stellenbosch : Stellenbosch University, 2015-12) Mandalakas, Anna Maria; Gie, Robert Peter; Hesseling, Anneke; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
    ENGLISH ABSTRACT: Tuberculosis (TB) control remains a global challenge, with childhood TB representing 15-40% of the disease burden in resource-limited high-burden countries. Following infection with Mycobacterium tuberculosis (M.tb), the 5-year risk of TB is 33% in children under five years of age and 20% for children five to 14 years of age. TB risk is greatest in the year following infection and highest among young, malnourished and immune-compromised children. Preventive therapy (PT) decreases TB morbidity and mortality amongst child contacts. Nevertheless, in 2010, of 7.6 million children infected with M.tuberculosis, over 650,000 developed TB, and 74,000 HIV-uninfected children died of TB. The World Health Organization (WHO) routinely recommends PT in children younger than five years of age and HIV-infected children (regardless of age) who are in close contact with an infectious TB case. Nevertheless, childhood TB has become a public health priority only in the last decade and limited resources have been allocated towards prevention. Major gaps therefore remain between guidelines and implementation of PT in most TB high-burden settings. Childhood TB remains a field with many unanswered questions. How can we accurately identify children with M.tuberculosis infection to support more effective allocation of limited resources through targeted delivery of PT? How may policy be changed to improve PT uptake and adherence? What factors accurately predict which children are at highest risk of acquiring M.tuberculosis infection and progressing to disease? This thesis aimed to address these questions and develop a conceptual framework within which to study the impact of PT as a TB control strategy to reduce the burden of childhood TB in communities with high burden of TB. A stepwise approach supported completion of this thesis. A comprehensive review of the literature and pilot studies were completed to inform subsequent PhD work. A standardized measure of TB contact was developed to serve as a surrogate measure of M.tuberculosis infection in the absence of an accepted gold standard. This standardized measure of TB contact was validated in a well controlled, hospital-based, case-control study that supported comparison of the diagnostic accuracy of tests of M.tuberculosis infection among HIV-infected and HIV-uninfected children in the community. Original data was then generated and compared to the validated measure of TB contact to demonstrate that in a model controlling for multiple confounders new tests of infection correlate better with TB exposure than the traditional Tuberculin skin test. This study further demonstrated that active contact investigation can detect TB in up to 8% of child contacts within three months of exposure. Development of the conceptual framework was complemented by systematic review and metaanalysis of the diagnostic accuracy of tests of M.tuberculosis infection, and decision analysis modeling of the cost-effectiveness of M.tuberculosis testing strategies in child contacts. The conceptual framework was further enriched by a collection of complementary research projects including i) PT operational and qualitative research, ii) epidemiologic studies in South Africa, iii) diagnostic studies in the United States, and iv) invited reviews, commentaries and letters to the editor. The thesis concludes by highlighting remaining gaps in the evidence and future research that could potentially fill these gaps.