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Table of contents

Summary ... 4 Abbreviations ... 7 GENERAL INTRODUCTION ... 9 CHAPTER 1: EPIDEMIOLOGY ... 11 1. INTRODUCTION ... 11

2. GLOBAL TUBERCULOSIS EPIDEMIOLOGY ... 11

2.1. Global incidence ... 11

2.2. Global mortality ... 13

2.3. WHO targets and trends ... 15

2.4. Epidemiology of TB in children ... 16

3. EPIDEMIOLOGY OF TUBERCULOSIS IN BELGIUM ... 19

3.1. General epidemiology ... 19

3.2. Epidemiology in children ... 21

CHAPTER 2: PATHOGENESIS ... 23

1. NATURAL HISTORY OF TUBERCULOSIS ... 23

2. NATURAL HISTORY OF TUBERCULOSIS IN CHILDREN ... 27

2.1. Introduction to pediatric TB ... 27

2.2. Time-table of primary tuberculosis in children ... 28

2.3. Age-related risk of developing disease after primary infection ... 30

CHAPTER 3: IMMUNOPATHOGENESIS ... 34

1. INTRODUCTION ... 34

2. INNATE DEFENSE MECHANISMS ... 35

3. ADAPTIVE IMMUNITY ... 45

4. DEFENSE MECHANISMS OF M. TUBERCULOSIS ... 53

5. IMMATURITY OF THE IMMUNE RESPONSE TO M. TUBERCULOSIS IN NEONATES AND INFANTS ... 59

CHAPTER 4: CLINICAL MANIFESTATIONS AND DIAGNOSIS ... 62

1. CLINICAL MANIFESTATIONS ... 62

1.1. Introduction ... 62

1.2. Symptoms and signs suggestive of TB... 64

1.3. Physical examination in case of suspected TB ... 66

1.4. Radiological features of intrathoracic TB ... 68

1.5. TB meningitis ... 71

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2. DIAGNOSTIC TESTS ... 73

2.1. Laboratory tests ... 74

2.2. Microbiological studies ... 74

2.3. Histopathology ... 78

2.4. Immune based tests ... 78

2.5. Systematic approach to diagnosis of intrathoracic TB ... 91

2.6. Specificities of the diagnostic process in case of suspected perinatal TB ... 91

2.7. Non-tuberculous mycobacteria ... 93

2.8. Unusually severe manifestations of tuberculosis ... 94

2.9. Treatment ... 95

AIMS ... 99

RESULTS ... 103

1. “Recurrent Tuberculosis in a Young Child” ... 105

2. “Identification of Mycobacterium tuberculosis Infection in Infants and Children With Partial Discrimination Between Active Disease and Asymptomatic Infection” ... 108

3. Comparison FASCIA/in-house IGRA (Supplementary material) ... 125

4. “Age-stratified T cell responses in children infected with Mycobacterium tuberculosis” ... ... 130

5. Supplementary data: Age-related production of IL-17 by CD4+ T lymphocytes in response to HBHA ... 142

6. SUPPLEMENTARY DATA: Cytokine and chemokine concentrations secreted by PBMC stimulated with mycobacterial antigens ... 144

GENERAL DISCUSSION ... 167

CONCLUSIONS AND PERSPECTIVES ... 187

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