Tuberculosis: Integrated Studies for a Complex Disease

Description

Tuberculosis have been documented since antiquity and the search of the microbes that cause this disease started more than three hundred years ago. Nevertheless, tuberculosis remains an important global health issue, with millions of people affected per year in addition to millions that remain undiagnosed and untreated. Patients with tuberculosis face the full range of recurrence, reinfection, and resistance due to diagnostic, prophylactic, and therapeutic procedures that are not as effective as they should be. In addition, variability in susceptibility to tuberculosis pose a complex problem with numerous interrelated variables. This volume is devoted to the understanding of Tuberculosis focusing on its heterogeneity, its transmission, manifestations, related conditions, diagnosis, treatments, drug resistance and prevention. Preface Contents Abbreviations 1 Introduction to Tuberculosis: Integrated Studies for a Complex Disease 1 Introduction 1.1 Heterogeneity in TB Transmission and Manifestations 1.2 TB and Related Conditions 1.2.1 Tobacco Use 1.2.2 Cancer 2 Diagnosis 3 Treatment 3.1 Anti-TB Drugs 3.2 Immunotherapy 3.3 Inhaled Anti-TB Therapy 3.4 Malnutrition Treatment 4 Drug Resistance 5 Prevention 6 Experience Before US 6.1 Integrated Prevention Services 6.2 Integrated Therapy 6.3 Integrated Research 6.4 Integrated Understanding of Pathogenesis 6.4.1 Integrated Immune and Endocrine View 6.4.2 Integrated Whole-Genome Analysis 6.5 Integrated Diagnostic Approach 6.6 Integrated Anti-resistance Platform 6.7 Integrated Social Epidemiology 6.8 Integrated Contact Tracing 6.9 Integrated Forecasting Model 7 Conclusion References 2 Global Tuberculosis Epidemiology 1 Introduction 2 History of Strategies and Commitments to Control the Tuberculosis Epidemic 3 Global Monitoring of TB 3.1 Classification (Anatomical Site) 3.1.1 Pulmonary Tuberculosis 3.1.2 Extrapulmonary Tuberculosis 3.2 Classification Based on the History of Previous Tuberculosis Treatment 3.2.1 New Patients 3.2.2 Previously Treated Patients 3.3 Classification Based on Drug Sensitivity 3.4 Classification Based on HIV Status 3.5 TB Treatment Outcome Definition 3.5.1 Successful Treatment Outcomes 3.5.2 Unsuccessful Treatment Outcomes 3.5.3 TB Death 3.6 Latent TB Infection (Exposure and Infection with M. tb) 4 The Magnitude of Global TB Disease 4.1 Drug-Sensitive Tuberculosis Incidence 4.1.1 Age and Sex Distribution 4.1.2 Trends in Line with Global Commitments 4.2 Drug-Sensitive Tuberculosis Case Notification and Treatment Success 4.2.1 Notification 4.2.2 Age and Sex Distribution 4.2.3 Pulmonary Tuberculosis Versus Extrapulmonary Tuberculosis 4.2.4 The Trend Is in Line with Global Commitments 4.3 Childhood Tuberculosis 4.3.1 Incidence Estimation 4.3.2 Notification and Treatment 4.4 Drug-Resistant Tuberculosis 4.5 Access to Drug SensitivityTesting 4.6 Gaps in the Drug-Resistant Tuberculosis Care Cascade 4.7 Tuberculosis-Human Immunodeficiency Virus Comorbidity 4.8 Treatment Success Rate 4.9 Estimated Mortality 5 Conclusion References 3 Heterogeneity in Tuberculosis 1 Introduction 2 Genotypic and Phenotypic Heterogeneity in Mycobacterium Tuberculosis Isolates 2.1 Stochastic Processes 2.2 Growth Phase and Growth Rate 2.3 Asymmetric Cell Division and Cell Aging 2.4 Host Microenvironment 3 Heterogeneity in Host Genetic Susceptibility to Tuberculosis 4 Anthropometric Heterogeneity in Tuberculosis 5 Age- and Sex-Specific Heterogeneity in Tuberculosis 6 Socioeconomic Heterogeneity in Tuberculosis 7 Heterogeneity in Tuberculosis Transmission 8 Heterogeneity in Treatment Responses 9 Heterogeneity in Immunity and Antibody Responses to Tuberculosis 10 Geographical Heterogeneity in Tuberculosis 11 Conclusion References 4 The Unequivocal Relationship Between Tuberculosis and Tobacco: Integration of Two Maladies 1 Introduction 1.1 Epidemiology of Tuberculosis 1.2 Epidemiology of Tobacco Use 2 Interaction Between Tuberculosis and Tobacco 3 Joint Global Policies for Tackling Tuberculosis and Tobacco 4 Challenges to Implementation of Global Policies 4.1 Patient-Level 4.2 Healthcare Provider Level 4.3 Health System Level 5 Strategies to Overcome Challenges 5.1 Patient-Level Strategies 5.2 Healthcare Provider Level Strategies 5.3 Health System-Level Strategies 6 Recommendations 6.1 Establishment of the Joint Working Group at All Levels 6.2 Modification of Reporting Mechanism 6.3 Integration into Health and Development Agendas 6.4 Advocacy for Smoke-Free Policies 7 Conclusion References 5 Relationship Between Pre-existing Cancer and Tuberculosis 1 Introduction 2 Incidence and Risk of Tuberculosis and Cancer 3 Mortality of Tuberculosis Associated with Cancer 4 LTBI Screening in Patients with Cancer 5 Conclusion References 6 Laboratory Diagnosis of Tuberculosis 1 Introduction 2 Laboratory Diagnosis 2.1 Laboratory Safety 2.2 Specimen Collection 2.2.1 Sputum 2.2.2 Blood 2.2.3 Other Specimens 2.3 Digestion and Decontamination 2.4 Microscopy 2.5 Culture 2.5.1 Solid Culture Media Non-selective Media Selective Media 2.5.2 Liquid Culture System Mycobacterial Growth Indicator Tube (MGIT) System (BD Diagnostic) MB/BacT ALERT System Versa TREK (Thermo Scientific) BACTEC MYCO/F LYTIC (Becton Dickinson, Sparks, MD) 2.6 Immunodiagnosis 2.6.1 Tuberculin Skin Test (TST) 2.6.2 Interferon-Gamma Release Assays (IGRAs) 2.7 Molecular Methods 2.7.1 Signal Amplification Method Nucleic Acid Probe Nucleic Acid Amplification Methods 2.7.2 Post-Amplification Analysis Line Probe Assays (Reverse Hybridization) DNA Sequencing TB-Lamp Microarray Analysis 2.8 Nanodiagnosis 2.8.1 Gold Nanoparticles (AuNPs) 2.8.2 Array Format-Based Surface Plasmon Resonance (SPR) 2.8.3 Fluorescent Silica Nanoparticle-Based Indirect Immunofluorescence Microscopy 2.8.4 Magnetic Nanoparticles 2.8.5 Quantum Dots Assay 2.9 Biosensing Techniques 3 Conclusion References 7 The Role of Diagnostic Microdevices in the Fight Against Tuberculosis 1 Introduction 2 Diagnostic Microdevices for Tuberculosis 2.1 Tuberculosis Diagnosis from Bacterial Elements 2.1.1 Fluorescent Detection of BlaC 2.1.2 Immunoassays 2.2 TB Diagnosis Through Genotyping 2.2.1 Nucleic Acids Amplification Tests for Diagnosis 2.2.2 Nanoparticles Applied to Genotyping 2.2.3 NAATs for Drug Resistance Screening 3 Conclusion Acknowledgements References 8 Immunodiagnostics of Tuberculosis: Recent Discoveries 1 Introduction 2 Biomarker Discoveries for Tuberculosis 2.1 M. tb Components Antigen Detection 2.2 Host Responses to M. tb Antigens 2.3 Host Cytokine Responses to M. tb Antigens–interferon-Gamma 2.4 Other Host Cytokine Responses to M. tb Antigens 3 Host Gene Expression 4 Biomarkers Using “Omics” Approach 5 Cell-Derived Microparticles 6 microRNA 7 Conclusion References 9 Role of Bronchoscopy in Diagnostics and Treatment of Tuberculosis 1 Introduction 2 Indications for Bronchoscopy in Pulmonary Tuberculosis 3 Efficacy of Diagnostic Bronchoscopy in Pulmonary Tuberculosis: From Diagnosis to Treatment 3.1 Washings and Bronchoalveolar Lavage 3.2 Brush-Biopsy 3.3 Transbronchial Lung Biopsy with Forceps 3.4 Transbronchial Cryobiopsy 3.5 Conventional Transbronchial Needle Aspiration of the Mediastinum and Pulmonary Tissue 3.6 Endoscopic Ultrasound-Guided Biopsies of the Mediastinum and Pulmonary Tissue 3.7 Endoscopic Lung Volume Reduction in Cavitary Pulmonary Tuberculosis 4 Bronchoscopy in Endobronchial Tuberculosis: From Diagnosis to Treatment 4.1 Bronchoscopic Findings in Endobronchial Tuberculosis and Possible Biopsies 4.2 Endobronchial Treatment of Active Endobronchial Tuberculosis and Its Consequences 5 Conclusion References 10 Diagnosis of Childhood Tuberculosis in Low- and Middle-Income Countries 1 Introduction 2 Diagnosis of Childhood Tuberculosis in Resource-Limited Settings 3 Poor Screening of Presumptive Child Tuberculosis Cases at Triage 4 Difficulties for Sustainability of Active Case Finding Strategies 4.1 Lack of Diagnostic Tools 4.1.1 Mantoux Test 4.1.2 Chest X-ray 4.1.3 Smear Microscopy 4.1.4 Xpert MTB/RIF Assay 4.1.5 Culture 4.2 Poor Knowledge About Childhood Tuberculosis Among Parents and HCWs 5 Conclusion References 11 Pediatric Tuberculosis: Current Evidence for Laboratory Diagnosis 1 Introduction 2 Non-specific Tests 3 Immunological Tests 3.1 Tuberculin Skin Test 3.2 Interferon-Gamma Release Assay 3.3 Tuberculin Skin Test Versus Interferon-Gamma Release Assay 4 Bacteriological Tests 4.1 Bacilloscopy (Direct Examination) 4.2 Culture 5 Nucleic Acid Amplification Tests 6 Serial Samples, Different Specimens, and Faster Methods 7 Biomarkers 7.1 Serology 7.2 Lipoarabinomannan 7.3 Cytokines 8 Omics Technologies 9 Conclusion References 12 A Multidisciplinary Approach Towards Finding and Treating All Tuberculosis Patients 1 Introduction 2 Animal Behaviour and Training 2.1 Reinforcer Selection 2.2 Clicker Training 2.3 Indication Training 2.4 Discrimination Training 2.5 Final Training 3 Rat Evaluation Setups 3.1 Rectilinear Manual Cage 3.2 Semi-Automated Line Cage (ALC) 3.3 Fully-Automated Line Cage Odor Nose Poke Holes Apparatus 3.4 Tuberculosis-Specific Odor 3.5 Urban Model for a Sample Referral Network 3.6 How the Tuberculosis Detection Rats Technology Is Deployed in the Field 4 Social Impact of Tuberculosis Detection Rat Technology 4.1 Tanzanian Enhanced Case Finding Programs 4.2 Mozambican Enhanced Case Finding Programs 4.3 Ethiopian Enhanced Case Finding Programs 5 Conclusion Acknowledgements References 13 Chemotherapy for Drug-Susceptible Tuberculosis 1 Introduction 2 Anti-Tuberculosis Drugs 2.1 The First-Line Anti-Tuberculosis Drugs 2.1.1 Isoniazid 2.1.2 Rifampicin 2.1.3 Pyrazinamide 2.1.4 Ethambutol 2.2 The Second-Line Injectable Anti-Tuberculosis Drugs 2.2.1 Streptomycin 2.2.2 Amikacin, Kanamycin, and Capreomycin 2.2.3 Fluoroquinolones 2.2.4 Ethionamide/Prothionamide 2.2.5 Cycloserine/Terizidone 2.2.6 Para-Aminosalicylic Acid/Para-Aminosalicylic Acid Sodium 2.2.7 Bedaquiline 2.2.8 Delamanid 2.2.9 Linezolid 2.2.10 Clofazimine 2.2.11 Augmentin 2.2.12 Thioacetazone 3 Treatment in Adults 4 Treatment in Children 5 Treatment in HIV-Positive Patients 6 Treatment of Latent Infections 7 Factors Associated with Treatment Outcome 8 Conclusion Acknowledgements References 14 The Pharmacokinetic and Pharmacodynamic Properties of Antitubercular Medications 1 Introduction 2 First-Line Medications 2.1 Rifampin 2.2 Rifapentine 2.3 Rifabutin 2.4 Isoniazid 2.5 Pyrazinamide 2.6 Ethambutol 3 Second-Line Medications 3.1 Fluoroquinolones 3.2 Aminoglycosides 3.3 Cycloserine 3.4 Bedaquiline 3.5 Delamanid 4 Conclusion References 15 Immune Approaches in Tuberculosis Treatment 1 Introduction 2 Cytokines and Their Inhibitors as Adjunctive Immunotherapeutic in TB 3 Immunotherapeutic Vaccines Against Tuberculosis 4 Corticosteroids as Adjunctive Immunotherapeutic Agents for Tuberculosis Treatment 5 Vitamin D Adjunctive Treatment in Tuberculosis 6 Other Immunotherapeutic Agents 7 Conclusion References 16 Inhalation Therapy in Pulmonary Tuberculosis 1 Introduction 2 History 3 Modern Work 4 The Future 5 Conclusion Acknowledgements References 17 Role of Micronutrients in Tuberculosis Management 1 Introduction 2 Zinc 3 Vitamin A 4 Vitamin B6 5 Vitamin C 6 Vitamin D 6.1 Vitamin D3 and Phenylbutyrate 7 Vitamin E 8 Other Micronutrients 9 World Health Organization Approach 10 Conclusion References 18 Drug Resistance in Tuberculosis: Mechanisms, Diagnosis, New Responses, and the Need for an Integrated Approach 1 Introduction 2 Epidemiological Situation of Tuberculosis and the Increasing Problem of Drug-Resistance 3 Molecular Mechanisms Associated with Tuberculosis Drug Resistance 4 Novel Mechanisms Related to Drug-Resistant Tuberculosis: Efflux Bumps and DNA Repair Systems 5 The Drug-Resistant Tuberculosis Diagnosis 6 The Response: Development of New Drugs and Diagnostic Assays for Drug-Resistant Tuberculosis 6.1 New Drugs Against Tuberculosis 7 New Approaches for the Molecular Diagnostic of Drug-Resistant Tuberculosis 8 Whole-Genome Sequencing of Mycobacterium tuberculosis: Towards a Fast and Affordable Diagnostic of Drug-Resistant Tuberculosis 9 Conclusion Acknowledgements References 19 Resistance in Tuberculosis: Molecular Mechanisms and Modulation 1 Introduction 2 Molecular Mechanisms of Resistance in Tuberculosis 2.1 Permeability Associated Resistance 2.2 Acquired Resistance by a Genetic Mutation 2.3 Drug Efflux 2.4 Target Mimicry 2.5 Drug Degradation and Modification 3 Strategies to Modulate Resistance in Tuberculosis 3.1 Structural Modification in Existing Drugs to Address Mutation-Associated Resistance 3.2 Targeting Efflux Pumps Responsible for Drug Efflux 3.3 Bypassing Drug Inactivating Enzymes 3.3.1 N-acetyltransferase 3.3.2 Acetyltransferase Eis 3.3.3 β-Lactamases 4 New Drugs Under Development or in Clinical Trials for the Treatment of Tuberculosis 5 Current Therapy Available for Drug-Resistant Tuberculosis 6 Conclusion References 20 Personalized Tuberculosis Care for Drug-Resistant Tuberculosis 1 Introduction 2 Treating Multidrug-Resistant Tuberculosis: Basic Rules of Engagement and Designing a Regimen 2.1 Individual Drugs 2.1.1 Core Drugs 2.1.2 Companion Drugs 2.2 Susceptibility Testing 2.3 Adequate Dosing 2.4 Treatment Duration 3 Pharmacokinetic/Pharmacodynamic Modeling: Therapeutic Drug Monitoring 4 Host Factors: Coinfections and Comorbidities 5 Host-Directed Therapies 6 Therapeutic Vaccination 7 Surgery 8 Conclusion References 21 Important Targets and Inhibitors of Mycobacterium tuberculosis 1 Introduction 2 New M. tb Targets and Their Potential Inhibitors 2.1 ATP Synthase and Its Potential Inhibitors 2.2 Type II NADH Dehydrogenase and Its Potential Inhibitors 2.3 DNA Gyrase and Its Potential Inhibitors 2.4 Diaminopimelate (DAP) Epimerase and Its Potential Inhibitors 2.5 LipY and Its Potential Inhibitors 2.6 Cytidine Triphosphate Synthetase and Its Potential Inhibitors 2.7 Transcription Factor IdeR and Its Potential Inhibitors 2.8 Lysine ε-aminotransferase (LAT) and Its Potential Inhibitors 2.9 ClpC1 and Its Potential Inhibitors 2.9.1 MraY and Its Potential Inhibitors 3 Conclusion References 22 P-Type ATPases: A Relevant Component in Mycobacterium tuberculosis Viability 1 Introduction 2 Structure, Classification, and Function of P-Type ATPases 3 M. tb P-Type ATPases 3.1 Heavy Metal P-Type ATPases of M. tb 3.1.1 Cu+ transporters 3.1.2 Zn2+ Transporters 3.1.3 Mn2+ Transporters 3.1.4 Fe2+, Co2+, and Ni2+ Transporters 3.1.5 Cd2+ Transporters 3.2 Alkali/Alkaline Earth Cation P-Type ATPases of M. tb 3.2.1 K+ and Na+/K+ Transporters 3.2.2 Ca2+ Transporters 4 CtpF as a Pivotal Target for M. tb Viability 4.1 CtpF as a Therapeutic Target 4.2 CtpF as a Target for M. tb Attenuation 5 Conclusion Acknowledgements References 23 The Challenges of Antitubercular Drug Discovery 1 Introduction 2 Approved Drugs 2.1 Bedaquiline 2.2 Pretomanid and Delamanid 2.3 Linezolid 3 Drug Candidates in Clinical Trials 3.1 Oxazolidinone Derivatives 3.2 1,2-Ethylene Diamine 3.3 Imidazopyridine 3.4 Oxaborole 3.5 Decaprenylphosphoryl-β-d-Ribose-20-Epimerase (DprE1) Inhibitors 3.6 Riminophenazine 4 Future Challenges 5 Conclusion References 24 Exploring Decaprenylphosphoryl-β-d-Ribose 2′-Epimerase 1 (DprE1): A Target for Anti-tubercular Drugs 1 Introduction 2 Special Features of the Enzyme Decaprenylphosphoryl-β-d-Ribose 2′-Epimerase 1 Which Make It a Target 2.1 Location and Role 2.2 Mechanism of Action 2.3 Crystal Structure 3 Insight into DprE1 Inhibitors 3.1 Covalent Binding Inhibitors 3.1.1 Benzothiazinones as the Leading Inhibitors of DprE1 3.1.2 Benzothiazole Containing DprE1 Inhibitors 3.1.3 Triazole Scaffold Containing DprE1 Inhibitors 3.1.4 Quinoxalines as DprE1 Inhibitors 3.1.5 Nitrobenzamide-Based DprE1 Inhibitors 3.2 Non-covalent Inhibitors 3.2.1 Benzothiazinone Containing DprE1 Inhibitors 3.2.2 Benzothiazole Based DprE1 Inhibitors 3.2.3 Imidazopyridine Based DprE1 Inhibitors 3.2.4 Quinoxalines as DprE1 Inhibitors 3.2.5 Thiadiazole Containing Inhibitors 3.2.6 Azaindoles as DprE1 Inhibitors 3.2.7 Benzimidazole as DprE1 Inhibitors 3.2.8 Pyrazolopyridine Based DprE1 Inhibitors 3.2.9 Aminoquinolone Scaffold Containing DprE1 Inhibitors 3.2.10 Hydantoins as DprE1 Inhibitors 3.3 Miscellaneous Inhibitors 3.4 Covalent vs. Non-covalent Binding Inhibitors 4 Patented DprE1 Inhibitors 5 DprE1 Inhibitors in Clinical Trials 6 Microbial Resistance and DprE1 Inhibitors 7 Conclusion References 25 Energy Pathways in Mycobacterium Tuberculosis 1 Introduction 2 Energy Pathways in Mycobacterium Tuberculosis 3 Enzymes Involved in Oxidative Phosphorylation 3.1 Type-I NADH Dehydrogenase 3.2 Type-II NADH Dehydrogenase 3.3 Succinate Dehydrogenase 3.4 Cytochrome bc1-aa3 Super Complex 3.5 Cytochrome bd 3.6 ATP Synthase 4 Enzymes Involved in Substrate-Level Phosphorylation 4.1 Fructose-1, 6-bisphosphate Aldolase 4.2 Pyruvate Kinase 4.3 Nitrate Reductase 4.4 Nitrite Reductase 5 Major Classes of Inhibitors Targeting Mycobacterium Tuberculosis Energetics 6 Conclusion References 26 Drug Discovery for Non-tuberculous Mycobacteria: Recent Updates 1 Introduction 2 Classification of Mycobacteria 3 Disease Burden 4 Present Guidelines Regarding NTM Diseases 4.1 Diagnosis of NTM Infections 4.2 Therapeutics for NTM Infections 4.2.1 Pulmonary NTM Diseases 4.2.2 MAC 4.2.3 M. kansasii 4.2.4 M. abscessus 4.2.5 M. malmoense 4.2.6 M. xenopi 4.3 Treatment for Extrapulmonary NTM Disease 4.3.1 Skin and Soft Tissues Disease 4.3.2 Lymphadenitis 4.3.3 Disseminated Infection 5 Therapeutic Options for NTM Diseases 5.1 Macrolides 5.2 Aminoglycosides 5.3 Fluoroquinolones 5.4 Anti-TB Drugs 5.5 Surgical Intervention 5.6 New Drugs Against NTM 5.6.1 Delamanid 5.6.2 Pretomanid 5.6.3 Bedaquiline 5.7 Other Anti-mycobacterial at the Preclinical Stage 5.7.1 Repurposed Drugs 5.7.2 Clofazimine 5.7.3 Linezolid 5.7.4 Tedizolid 5.7.5 SPR719/720 5.7.6 Omadacycline 5.7.7 Tigecycline 5.7.8 β-lactams 5.7.9 Mefloquine 5.7.10 Thioridazine 5.7.11 Disulfiram 5.7.12 Sildenafil 5.8 Alternative Approaches for the Treatment of NTM Infections 5.8.1 Antimicrobial Peptides (AMPs) 5.8.2 Bacteriophages 5.8.3 Host Directed Therapeutics 5.8.4 Ion Chelators 5.8.5 Natural Oils 5.8.6 Nitric Oxide 6 Clinical Trials 7 Conclusion Acknowledgements References 27 Challenges for Contact Tracing and Tuberculosis Preventive Therapy Scale-up 1 Introduction 2 Identification of the Targeted Population for Tuberculosis Preventive Therapy 3 Diagnosis of Tuberculosis Infection 4 Exclusion of Active Tuberculosis 5 Tuberculosis Preventive Therapy Regimen Options 6 Public Health Approach 7 Conclusion References 28 Exploring Problematizations Underlying Tuberculosis Control Strategies: A Cross-Country Analysis of India and Kenya 1 Introduction 2 Challenges of Tuberculosis Control 2.1 The Problem of ‘Missing’ Cases 2.2 Drug-Resistant Tuberculosis 2.3 Gender Disparities 3 Inequalities in Tuberculosis Distribution 4 Conceptualization of the ‘Tuberculosis Problem’ 5 Tuberculosis Control in India 5.1 Tuberculosis in India: An Overview 5.2 The Problematization of Tuberculosis Control: India (1997–2020) 5.2.1 Phase I: 1997–2005 Problem Representation What Could Be the Possible Underlying Assumptions? What Could Be the Possible Silences? 5.2.2 Phase II: 2006–2011 Problem Representation What Could Be the Possible Underlying Assumptions? What Could Be the Possible Silences? 5.2.3 Phase III: 2012–2017 Problem Representation What Could Be the Possible Underlying Assumptions? What Could Be the Possible Silences? 5.2.4 Phase IV (2017 Onwards) Problem Representation What Could Be the Possible Underlying Assumptions? What Could Be the Possible Silences? 6 Tuberculosis Control in Kenya 6.1 Tuberculosis in Kenya: An Overview 6.2 The Problematization of Tuberculosis Control: Kenya (1999–2018) 6.2.1 Phase I: 1999–2004 Problem Representation What Could Be the Possible Underlying Assumptions? What Could Be the Possible Silences? 6.2.2 Phase II: 2007–2010 Problem Representation What Could Be the Possible Underlying Assumptions? What Could Be the Possible Silences? 6.2.3 Phase III: 2011–2014 Problem Representation What Could Be the Possible Assumptions? What Could Be the Possible Silences? 6.2.4 Phase IV: 2015–2018 Problem Representation What Could Be the Possible Assumptions? What Could Be the Possible Silences? 7 Conclusion References 29 Challenges in Prevention and Management of Tuberculosis 1 Introduction 2 Challenges with Tuberculosis Control 3 Conclusion Acknowledgements References 30 Tuberculosis in Contacts and Healthcare Workers 1 Introduction 2 Screening for Infection and Tuberculosis Among Contacts 3 Infection and Tuberculosis in Healthcare Workers 4 Problems and Controversies 4.1 Contact Investigation and Preventive Treatment 4.2 Healthcare Workers 5 Conclusion References 31 Tuberculosis Among People Who Use Drugs: Multilevel Considerations for Prevention, Diagnosis, and Treatment 1 Introduction 2 Global Epidemiology of Tuberculosis, and Drug Use, and Their Intersection 2.1 Global Tuberculosis Epidemiology 2.2 Global Substance Use Epidemiology 2.3 Global Overlap of Tuberculosis and Substance Use Epidemiology 3 Historical Context of Tuberculosis and Drug Use 3.1 Human History and TB 3.2 The Human History of Substance Use 4 People Who Use Drugs as A Population Construct and Historical Context of Tuberculosis and Drug Use Overlap 5 Multilevel Conditions that Create Risk for Tuberculosis, Particularly Among People Who Use Drugs 5.1 Structural-Level Vulnerability 5.2 Social and Environmental Factors 5.3 Individual-Level Factors 6 Diagnosis of Tuberculosis Infection 7 Treatment of Tuberculosis Infection 8 Potential Structural and Policy Responses to Address Tuberculosis Among People Who Use Drugs 9 Conclusion Acknowledgements References 32 Anti-tumor Necrosis Factor-α Antagonists and Tuberculosis 1 Introduction 1.1 TNF-α Biology 1.2 TNF-α-Medicated Immune Response to Tuberculosis 1.3 TNF-α Inhibitors: Structural and Pharmacologic Differences 2 Risk of Tuberculosis Associated with TNF-α Inhibitors 3 Screening for Latent Tuberculosis Infection 3.1 Chemoprophylaxis 4 Active Tuberculosis Among TNFi Users 4.1 Site of Tuberculosis 4.2 Timing of Tuberculosis Diagnosis 4.3 Treatment of TNFi-Associated Tuberculosis 5 Conclusion References 33 Breast Tuberculosis 1 Introduction 2 Descriptions of 12 Cases of Breast Tuberculosis at Wolisso Hospital 3 Epidemiology 4 Risk Factors 5 Clinical Presentation 6 Diagnosis 7 Treatment 8 Tuberculous Mastitis in Men 9 Conclusion References 34 Central Nervous System Tuberculosis: Pathogenesis, Diagnosis, and Management 1 Introduction 2 Pathophysiology 3 Tuberculoma 3.1 Diagnosis 3.2 Management 3.3 Surgical Technique 4 Tuberculous Meningitis 4.1 Pathogenesis 4.2 Diagnosis 4.3 Management 5 Tuberculous Hydrocephalus 5.1 Diagnosis 5.2 Management 6 Other CNS Tuberculosis Manifestations 7 Conclusion References 35 Pleural Tuberculosis 1 Introduction 2 Pathogenesis 3 Clinical Manifestations 4 Diagnosis 4.1 Smear Microscopy and Cultures 4.2 Nucleic Acid Amplification Assays 4.3 Pleural Fluid Biomarkers 4.3.1 Adenosine Deaminase 4.3.2 Interferon-Gamma 4.3.3 Interleukin-27 4.4 Pleural Biopsy 5 Treatment 6 Conclusion References 36 Ocular Tuberculosis 1 Introduction 2 Tubercular External Eye Disease 2.1 Eyelid 2.2 Conjunctiva 2.3 Orbit 2.4 Cornea 2.5 Sclera and Episclera 3 Tubercular Uveitis 3.1 Tubercular Anterior Uveitis 3.2 Tubercular Intermediate Uveitis 3.3 Tubercular Posterior Uveitis 3.4 Tubercular Panuveitis 3.5 Tubercular Retinal Vasculitis (TRV) 4 Optic Nerve Involvement 5 Endophthalmitis and Panophthalmitis 6 Diagnosis and Management 7 Conclusion References 37 Ocular Tuberculosis: Biomarkers for Risk Stratification 1 Introduction 2 Challenge in Tuberculosis-Associated Uveitis Diagnosis 3 Potential Biomarkers to Improve Diagnosis Accuracy 3.1 M. tb-Derived Biomarker 3.2 Host-Derived Biomarker of M. tb Infection 3.2.1 Host-Derived Biomarker to Distinguish Active and Latent Pulmonary Tuberculosis Gene Expression MicroRNAs Protein Cellular Immunophenotype 3.2.2 Current Situation of the Host-Derived Biomarker to Assist Ocular Tuberculosis Diagnosis Gene Expression Protein Cellular Immunophenotype 4 Ocular Tuberculosis in HIV Patients: A Condition that Can Affect Potential Biomarkers 5 Conclusion References 38 Bone and Joint Tuberculosis 1 Introduction 2 Bacteriology of Bone and Joint Tuberculosis 3 Pathophysiology 4 Clinical Features 5 Diagnosis 6 Treatment 7 Prevention 8 Patient’s Adherence 9 Conclusion References 39 Abdominal Tuberculosis: Pathogenesis, Clinical Features, and Diagnosis 1 Introduction 2 Pathogenesis 3 Clinical Features 3.1 Generalized Symptoms 3.2 Site-Specific Symptoms 3.2.1 Visceral Tuberculosis 3.2.2 Gastroduodenal Tuberculosis 3.2.3 Ileo-Jejunal Tuberculosis 3.2.4 Colonic Tuberculosis 3.3 Tubercular Complications 4 Diagnosis 5 Hematological Tests 6 Radiological Investigations 6.1 Plain Chest X-Ray 6.2 Plain Abdomen X-Ray 6.3 Barium Meal 6.4 Ultrasonogram 6.5 Abdomen Contrast-Enhanced Computed Tomography 6.6 Diagnostic Laparoscopy 6.7 Ascitic Fluid Tap 6.8 Nuclear Scans 6.9 Histopathology 7 Treatment 8 Conclusion References 40 Bovine Tuberculosis at the Interface of Cattle, Wildlife, and Humans 1 Introduction 2 Cattle-Wildlife Interface 3 Human-Animal Interface 4 Conclusion References 41 Evolution and Molecular Characteristics of Mycobacterium tuberculosis and Mycobacterium bovis 1 Introduction 2 The M. tuberculosis Complex 3 Functional Genomics 4 Genotyping and Genetic Epidemiology of Mycobacterium tuberculosis and Mycobacterium bovis 5 Genetic History of Mycobacterium tuberculosis and Mycobacterium bovis 6 Conclusion References 42 Animal Tuberculosis: Gross Lesions and Anatomopathological Diagnosis 1 Introduction 2 The Anatomopathological Diagnosis of Animal Tuberculosis 2.1 Tuberculosis in Ruminants 2.2 Tuberculosis in Dogs and Cats 2.3 Tuberculosis in Pigs 2.4 Tuberculosis in Horses 3 The Importance of Tuberculosis Anatomopathological Diagnosis in Meat Inspection 4 Conclusion References 43 Estimation of Microbial Mutation Rates in Tuberculosis Research 1 Introduction 2 Basics of the Fluctuation Experiment 3 Mutation Rate or Mutant Frequency? 4 Relevant Developments and Associated Formulas 5 An Example 6 Likelihood Function or Generating Function? 7 Conclusion 44 The Role of Epigenetics in the Development of Anti-Tuberculosis Drug Resistance 1 Introduction 1.1 Epidemiology of Tuberculosis 1.2 Diagnosis of Tuberculosis 1.3 Prevention of Tuberculosis 1.4 Treatment of Tuberculosis 2 Epigenetics 2.1 The DNA Methylation Epigenetic Mark 2.2 Acetylation 2.3 Phosphorylation 3 Discussion 4 Conclusion Acknowledgements References 45 Multiomics Integration of Tuberculosis Pathogenesis 1 Introduction 2 Multiomics Integration to Study M. Tuberculosis Pathogenesis 2.1 Multiomics Technology as a Window to Visualize M. Tuberculosis Physiology 2.2 Metabolic Networks of M. Tuberculosis in Diverse Phenotypic States 2.2.1 Actively Replicating State Permissive Carbon Sources Cholesterols Antibiotic Targets of Actively Replicating M. Tuberculosis Mycolic Acid Synthesis Membrane Energetics 2.2.2 Non-Replicating Persistent State Alternate Carbon Sources Trehalose Antibiotic Targets of Non-Replicating M. Tuberculosis Altered Membrane Bioenergetics 2.2.3 Exiting from the Non-Replicating Quiescent State Carbon Sources Potential Antibiotic Targets Preventing Reactivation of Non-Replicating M. Tuberculosis Succinate Dehydrogenase UDP-N-Acetylglucosamine 1-carboxylvinyltransferase (MurA) 3 Conclusion Acknowledgements References 46 Lung Microbiome in Tuberculosis 1 Introduction 2 The Lung Microbiota in Tuberculosis 3 The Lung Microbiota in Antituberculous Treatment 4 Future Prospects 5 Conclusion References 47 The Correlation of Microbiota and Host Epigenome in Tuberculosis 1 Introduction 1.1 Human Microbiota and Tuberculosis 2 Human Microbiota and Epigenetics 3 Microbiota, Epigenetics, and Tuberculosis 3.1 Histone Epigenetic Alterations in Tuberculosis 3.2 DNA Methylation in Tuberculosis 3.2.1 Mycobacterial Methyltransferases 3.2.2 Mycobacterial DNA Methyltransferases 3.2.3 Mycobacterial RNA Methyltransferases 3.2.4 Mycobacterial Protein Methyltransferases 3.2.5 Mycobacterial Mycolic Acid Methyltransferases 3.2.6 Other Mycobacterial Methyltransferases 3.3 MiRNA-Based Regulation During Tuberculosis Infection 4 Conclusion References 48 The Pathogenesis and Progression of Sarcoidosis from the Standpoint of Tuberculosis 1 Introduction 2 Pathogenesis of Tuberculosis 2.1 Human Pathology 2.2 Animal Experiments in Tuberculosis 3 Causes, Pathogenesis, and Progression of Sarcoidosis 3.1 Causative Agents 3.2 P. Acnes and Culture with Inflammatory Cells 3.3 Comparison of P. Acnes in Sarcoidosis Patients and Non-sarcoidosis Cases 3.4 Animal Experimental Data 3.5 Genetic Predisposition 3.6 Histological Findings of Sarcoidosis and Correlation with P. Acnes 3.7 Early-Onset Sarcoidosis Following Primary Infection and Disease Patterns 3.8 Chronic Sarcoidosis, Mainly Pulmonary Sarcoidosis 3.9 Drug-Related Sarcoidosis and Sarcoidosis in Treated Cases of AIDS 3.10 Sarcoidosis Therapy 3.11 Remaining Subjects 4 Conclusion Acknowledgements References 49 Tuberculosis: A Historical and Global Bioethical Perspective 1 Introduction 2 A Historical Perspective 3 TB Through the Lens of Global Bioethics 4 Conclusion References 50 The Problem of Tuberculosis: Myths, Stigma, and Mimics 1 Introduction 2 Tuberculosis-Related Myths 2.1 Tuberculosis Is a Curse 2.2 Tuberculosis Is Hereditary 2.3 Tuberculosis Is Incurable 2.4 Tuberculosis Is a Disease of the Lungs 2.5 Tuberculosis Can Be Acquired Through Kissing or Sexual Contact 2.6 Tuberculosis Is Spread Through Sharing Utensils or Food 2.7 Tuberculosis Is Spread by Mosquitoes 2.8 All Patients with Tuberculosis Are Infectious 2.9 One Can Get Tuberculosis Only Once 2.10 Tuberculosis Infection Always Leads to Disease 2.11 Tuberculosis Is a Problem in Developing Countries 3 Tuberculosis-Related Stigma 4 Conditions that Mimic Tuberculosis 4.1 Non-tuberculous Mycobacteria 4.2 Bacterial Infections 4.3 Fungal Infections 4.4 Parasitic Infections 4.5 Viral Infections 4.6 Malignancies 4.7 Autoimmune Disorders 5 Conclusion References 51 Tuberculosis: Integrated Studies for a Complex Disease 2050 1 Introduction 2 TB and Related Conditions 2.1 TB and Tobacco Use 2.2 TB and Drug Use 2.3 TB and Cancer 3 Resistance and Drug Discovery 3.1 A New Vaccine 3.2 De Novo Drug Deisgn 3.3 OMICs 3.4 A New Targeted Therapy 4 Pathogenesis 4.1 Lung Microbiota 4.2 Mutagenesis 4.3 Epigenetics 5 Diagnosis 6 Extrapulmonary TB 6.1 Tubercular Uveitis 7 Elimination 8 Challenges 8.1 Pediatric TB 8.2 TB—An Opportunistic Infection 8.3 Failure to Meet Commitments by 2035 8.4 Non-tuberculous Mycobacteria 8.5 Medical Ethics 8.6 Unhealthy Lifestyle 8.7 Myths and Stigma 9 Treatment 9.1 Inhalation Techniques 9.2 Nutrition 9.3 Bronchoscopy 9.4 Precision Medicine 9.5 Surgery 9.6 Adjunctive Immunotherapy 10 Animal TB 11 Integrated Science 11.1 Future Epidemics 11.2 Implementation Research 11.3 Ophthalmology 11.4 Neurosurgery 11.5 Genomics and Molecular Epidemiology 11.6 Integrated Computational Approaches 11.7 AI 12 Conclusion References Index