Epidemiología de la tuberculosis en la población infantil de Manhiça, Mozambique Paediatric TB epidemiology in Manhiça, southern Mozambique Elisa López Varela ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. 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TESIS DOCTORAL Epidemiología de la tuberculosis en la población infantil de Manhi�a, Mozambique Paediatric TB epidemiology in Manhic;a, southern Mozambique Elisa López-Varela A los niños de ITACA Paediatric TB epidemiology in Manhiça Epidemiología de la tuberculosis en la población infantil de Manhiça, Mozambique Tesis presentada por Elisa López Varela para optar al grado de Doctora en Medicina Dirigida por: Pedro L. Alonso Fernández y Denise Naniche Línea de investigación: Salud internacional Grupo de investigación en epidemiología, salud pública y salud internacional Julio 2016 Barcelona Institute for Global Health (ISGlobal) & Centro de Investigação em Saúde de Manhiça (CISM) Thesis submitted by Elisa López Varela to aspire to the degree of Doctor in Medicine by the University de Barcelona under the direction of Dr Pedro Alonso and Dr Denise Naniche. The present Doctoral Thesis is presented following the University´s recommendations on presentation of Doctoral Thesis by compendium of publications, as certified by the directors of this thesis. Dr Denise Naniche Dr Pedro Alonso Barcelona, 14th July 2016 TABLE OF CONTENTS: ABBREVIATIONS AND ACRONYMS .................................................................................................. 1 RESUMEN (Español) ....................................................................................................................... 3 SUMMARY .................................................................................................................................... 11 A. INTRODUCTION ........................................................................................................................ 21 1.1. GENERAL INTRODUCTION ...................................................................................................... 21 i. Historical overview of TB control strategies ........................................................................ 21 ii. Current global situation of the TB epidemic ......................................................................... 28 iii. TB epidemiology in Mozambique ......................................................................................... 32 1.2. SPECIFIC INTRODUCCIÓN: PAEDIATRIC TB ............................................................................. 37 i. The problem ........................................................................................................................ 37 ii. The opportunity ................................................................................................................... 50 B. OBJECTIVES .............................................................................................................................. 55 i. General objective ................................................................................................................. 55 ii. Specific objectives ................................................................................................................ 55 C. MATERIALS AND METHODS ...................................................................................................... 59 i. Study area and population ................................................................................................... 59 ii. Methodology of studies ....................................................................................................... 64 D. ARTICLES ................................................................................................................................. 69 1. Incidence of Tuberculosis among young children in rural Mozambique ................................... 69 2. Low paediatric tuberculosis case detection rate in Southern Mozambique. ............................ 81 3. Adherence to Childhood Tuberculosis Treatment in Mozambique ........................................... 87 4. Radiological findings in young children investigated for tuberculosis in Mozambique. .......... 101 5- High rates of Non-Tuberculous Mycobacteria isolation in Mozambican Children with Presumptive Tuberculosis. ........................................................................................................ 115 6. Non-tuberculous mycobacteria in children: muddying the waters of TB diagnosis. .............. 131 7. Mothers and caretakers understanding and care-seeking practices for paediatric tuberculosis in a rural district of Southern Mozambique ................................................................................ 147 E. SUMMARY OF RESULTS AND DISCUSSION .............................................................................. 178 i. Burden of TB in children ..................................................................................................... 178 ii. Characterization of the disease and barriers to case detection ......................................... 182 F. GENERAL CONCLUSIONS ........................................................................................................ 188 G. BIBLIOGRAPHY ....................................................................................................................... 194 H. AGRADECIMIENTOS ................................................................................................................ 208 FIGURES and TABLES BOX 1. Basic facts on TB FIGURE1. Mycobacterium tuberculosis visualization using the Ziehl–Neelsen stain BOX 2. Overview of WHO TB control strategies FIGURE 2. WHO estimates of TB incidence rates (2014) FIGURE 3. Projected acceleration of the decline in the global TB incidence rates FIGURE 4. The National TB Program at Manhiça District Hospital BOX 3. WHO TB estimates for Mozambique (2014) FIGURE 5. Age and gender related differences of tuberculosis incidences in hypothetical high and low incidence populations BOX 4. Key facts about TB in children TABLE 1. Summary of the types of respiratory specimens used for pulmonary TB diagnosis, their characteristics and limitations FIGURE 6. Algorithm for diagnosing TB in children under 14 years in Mozambique FIGURE 7. The cascade from symptoms to reporting in children with tuberculosis BOX 5. Methodologies used to estimate the burden of paediatric children BOX 6. Overview of the WHO roadmap for childhood TB FIGURE 8. Location of Mozambique and Manhiça FIGURE 9. The Manhiça Health Research Center FIGURE 10. The paediatric TB procedure room at the Manhiça District Hospital FIGURE 11. Biosafety TB laboratory at CISM Paediatric TB epidemiology in Manhiça ABBREVIATIONS AND ACRONYMS ART Anti-retroviral therapy BCG Bacille Calmette-Guerin CDR Case detection rate CISM Centro de Investigação em Saúde de Manhiça CXR Chest radiograph DOTS Directly observed therapy GA Gastric aspirate HBC High burden countries HDSS Health and demographic surveillance system HIV Human immunodeficiency virus