Hot Topics in Infection and Immunity in Children V (eBook)

Preface 6
Acknowledgments 7
Contents 8
Contributors 10
Shiga-Toxin Producing Escherichia coli and the Hemolytic Uremic Syndrome: What Have We Learned in the Past 25 Years? 14
1 Introduction 14
2 History 15
3 Epidemiology of E. coli O157:H7 Infections and HUS 15
4 Clinical Course of E. coli Infection 16
5 Pathophysiology of E. coli O157:H7 Infections 17
6 Diagnostic Considerations for Pathogenic STEC 17
7 Management of Patients with Confirmed or Suspected E. coli O157:H7 Infection 19
8 HUS and the Course of E. coli O157:H7 Infections 21
9 Pathophysiology of HUS 23
10 Conclusions 25
References 26
Global Epidemiology of Pneumococcal Disease-New Prospects for Vaccine Control 31
1 Overview of the Pneumococcus and Pneumococcal Disease 31
2 Pneumonia 32
3 Invasive Pneumococcal Disease 32
4 Acute Otitis Media 34
5 Pneumococcal Vaccines 35
6 The Power of Pneumococcal Conjugate Vaccines I: Effect of PCV-7 on Rates of IPD in the US after Introduction in 2000 36
7 The Power of Pneumococcal Conjugate Vaccines II: Effect of the 11-Valent PHiD-Conjugate Vaccine on AOM in a Phase III Efficacy Trial 37
8 Pneumococcal Vaccines for Adults 38
9 Conclusions 38
References 39
Current Concepts of the Pathogenesis of RSV Bronchiolitis 42
1 Introduction 42
2 Genetic Determinants of RSV Bronchiolitis and Post-bronchiolitis Wheeze 43
3 Pre-existent Airway Morbidity 45
4 Immature Immune Responses 45
5 Immunopathogenesis 46
6 Parallel Versus Serial Hypothesis 47
7 Conclusions 48
References 48
How Can We Eradicate Pertussis 52
1 Introduction 52
2 Bordetella pertussis: The Organism and Its Pathogenesis 52
3 Clinical Disease 53
3.1 Pertussis in Young Infants 54
3.2 Adults 54
4 Laboratory Diagnosis of B. pertussis Infection 55
4.1 Culture 55
4.2 Direct Detection of B. pertussis 55
4.3 Serologic Diagnosis of B. pertussis Infection 55
5 Epidemiology 56
5.1 Reported Pertussis 56
5.2 Epidemiology of B. pertussis Infections 57
6 Vaccines 59
7 Conclusions 61
References 61
Recognition and Management of Encephalitis in Children 63
1 Introduction 63
2 History 63
3 Etiology 64
4 Postimmunization Neurological Disease 66
5 Postinfectious Encephalitis 66
6 Chronic Encephalitic or Encephalopathic Illnesses (Slow Infections) 67
7 Encephalitis Epidemiology 67
8 Clinical Manifestations 67
9 Differential Diagnosis 68
10 Specific Diagnosis 68
11 Treatment 69
12 Prognosis 70
13 Prevention 70
References 70
Microbiology and Management of Pleural Empyema 71
1 Introduction 71
2 Epidemiology and Aetiology 72
2.1 Epidemiology 72
2.2 Aetiology 72
2.3 Risk Factors for Progression to Empyema 73
3 Potential Reasons for Increasing Incidence of Empyema 74
3.1 Serotype 1 74
3.2 Sequence Types 74
4 Management 75
4.1 Prevention 75
4.2 Drainage of Fluid 75
5 Summary 76
References 77
Pneumococcal Conjugate Vaccines Probe Studies: The Solution Points to the Problem 79
1 Observed Versus Expected Effect of a Vaccine - The Vaccine Probe Concept 79
2 Vaccine Probe-Derived Insights into PCVs - Selected Examples 80
2.1 Probe Studies in Pneumonia - the ‘pneumonia detective’ 80
3 Potential Role of PCVs in the Prevention of Mortality in Developing Populations 82
4 Indirect Effect of PCV - the Herd Immunity Effect 82
5 How Many Doses of PCV Are Appropriate for Infant Immunization Programs? 83
6 Hypothesis Generating Results: A Study on Social Mixing During Infancy and Antibody Response to PCV7 at 1 Year of Age 85
7 Conclusions 85
References 86
New Findings in Primary Immunodeficiency 88
1 Introduction 88
2 Severe Combined Immunodeficiency 88
2.1 New T Lymphocyte Receptor Signalling Defects 90
2.1.1 CD3 zeta Subunit Deficiency 90
2.1.2 ORAI Deficiency 90
2.2 New Defects of T and B Lymphocyte Receptor Recombination 90
2.2.1 DNA Ligase IV Deficiency 90
2.2.2 Cernunnos-XLF Deficiency 91
3 X-Linked Lymphoproliferative Syndromes 91
4 Common Variable Immunodeficiency 92
4.1 Inducible Costimulator Deficiency 92
4.2 CD19 Deficiency 92
4.3 Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor Deficiency 92
4.4 MutS Homologue 5 Defects 93
5 Defects in Innate Immunity 93
5.1 Severe Congenital Neutropenia 93
5.2 Hyperimmunoglobulin E Syndrome 94
5.2.1 Autosomal Dominant HIES 94
5.2.2 Autosomal Recessive HIES 95
6 Toll-Like Receptor Pathway Deficiencies 95
6.1 Defects in the NFkappaB Essential Modulator Signalling Pathway 95
6.2 Toll-Like Receptor Deficiency 96
7 Regulatory T Lymphocyte-Mediated Autoimmunity 96
7.1 CD25 Deficiency 97
7.2 Other Immunodeficiencies Associated with Reduced Regulatory T Lymphocytes 97
8 Conclusion 98
References 98
Routine Use of Influenza Vaccine 103
1 Background 103
2 Virology 103
3 Epidemiology 104
4 Transmission 104
5 Severity of Influenza in Children 105
6 Children as a Source of Infection 107
7 Influenza and Otitis Media 108
8 Influenza Immunization 109
9 Immunogenicity of Influenza Vaccines in Children 110
10 Safety of Influenza Vaccines 111
11 Vaccine Efficacy for High-Risk Children 111
12 Vaccine Efficacy for Universal Childhood Vaccination 112
13 Cost-Effectiveness of Universal Childhood Influenza Immunization 114
14 Delivery of Vaccine 114
15 Conclusions 115
References 115
Challenges in the Evaluation and Management of Bone and Joint Infections and the Role of New Antibiotics for Gram Positive Infections 119
1 Introduction 119
2 Site of Acute Hematogenous Osteomyelitis in Children 119
3 Etiology 119
4 Clinical Manifestations 120
5 Diagnosis 121
6 Treatment 123
7 Surgical Therapy 125
8 Summary 125
References 125
The Significance of Serotype Replacement for Pneumococcal Disease and Antibiotic Resistance 129
1 Introduction 129
2 Replacement in Carriage 130
3 Replacement in Otitis Media 130
3.1 Replacement in Carriage and Otitis Media by Other Bacterial Species 131
4 Replacement in Invasive Pneumococcal Disease 131
5 Genetics of Replacement Strains 132
6 Replacement in Antibiotic-Resistant Strains 133
7 Conclusions 133
References 134
Childhood Intra-thoracic Tuberculosis 137
1 Background 137
2 Epidemiology 138
3 Natural History of Disease 139
4 Intra-thoracic TB 140
4.1 Lymph Node Disease 141
4.2 Pleural Effusion 143
4.3 Pericardial Effusion 144
4.4 Disseminated (Miliary) Disease 144
4.5 Adult-Type Disease 145
4.6 Immune Reconstitution Phenomena 146
5 Diagnosis 146
5.1 Symptom-Based Approaches 146
5.1.1 Screening for Active TB 146
5.1.2 Diagnosing Active TB 147
5.2 Immune-Based Approaches 148
5.2.1 T Cell Assays 148
6 Treatment 149
6.1 Preventive Chemotherapy 149
6.2 Standard Treatment 150
6.3 Drug Resistance 151
References 152
The Antibiotic Pipeline in Pediatrics 155
1 The Approval Process 155
2 Pediatric Labeling Efforts in the United States 155
3 Antibiotic-Approval Mechanism in the United States 156
4 Drug Development in the United States Food and Drug Administration 157
5 New Antibacterial Agents in Development 158
6 The Future for Antibiotics in Pediatrics 158
References 159
Paediatric Drug Development and Clinical Trials 160
1 Introduction 160
2 The ‘New’ European Paediatric Legislation 160
3 Extrapolation 162
4 When Should ‘Small’ Studies Maximizing the Use of PK Be Performed? 163
5 When Should a Full Drug-Development Programme Be Performed? 163
6 Developing Off-Patent Medicines for Paediatric Use 163
7 US Legislation 164
8 Economic Return of Clinical Trials Performed Under the US Paediatric Exclusivity Programme 165
9 Safety 165
10 Conclusions 166
References 166
Influenza in Pregnancy: The Case for Prevention 167
1 Introduction 167
2 Epidemiology of Influenza 167
3 Epidemiology of Influenza in Pregnant Women 170
3.1 Pandemic Influenza 170
3.2 Interpandemic Influenza 171
3.2.1 Mortality 171
3.2.2 Morbidity 172
3.3 Impact of Influenza in Pregnancy on the Fetus 175
4 Prevention of Influenza 177
4.1 Influenza Immunization 177
4.2 Influenza Immunization During Pregnancy 178
4.3 Influenza Immunization in Pregnancy Recommendations by Country 180
5 Barriers to Influenza Immunization of Pregnant Women 181
6 Next Steps to Improve Influenza Vaccine Uptake in Pregnant Women 182
7 Areas for Future Research 183
8 Conclusions 184
References 185
Febrile Neutropenia in Children with Cancer 190
1 Introduction 190
2 Definitions 190
3 Microbiology and Antimicrobials in Febrile Neutropenia 190
3.1 Common Pathogens 191
3.2 Empiric Therapy Choices 191
4 Practice Surveys 193
5 Defining Low-Risk and High-Risk Patients 194
6 Outpatient Management for FN 195
7 Imaging 197
8 The Role of Respiratory Viruses 200
9 Emerging Pathogens 201
9.1 Viridans Group Streptococcus 201
9.2 beta-Lactamase-Producing Organisms 202
9.3 Vancomycin-Resistant Enterococcus 202
10 Best Practice 203
11 Summary 205
References 205
The PANDAS Syndrome 210
1 Introduction 210
2 Historical Overview 210
3 Pathogenesis 212
4 Heritability 213
5 Neuroimaging 213
6 Clinical Diagnosis 214
7 Laboratory Testing 215
8 Treatment 215
9 Perspective on the PANDAS Construct 216
References 218
Fever in the Returned Paediatric Traveller 222
1 Introduction 222
2 Children Are at Increased Risk of Imported Infections 222
2.1 Age 223
2.2 Reason for Travel-Visiting Friends and Relatives 223
2.3 Destination 223
2.4 Preventive Measures 224
3 Causes of Fever in Children Who Have Travelled to the Tropics or Subtropics 224
3.1 Investigations 225
4 Common Imported Infections in Children Presenting with Fever 226
4.1 Malaria 226
4.1.1 Presenting Symptoms 226
4.1.2 Diagnosis 227
4.1.3 Management 227
4.2 Non-Falciparum Malaria 227
4.3 Falciparum Malaria 227
4.3.1 Uncomplicated Falciparum Malaria 227
4.3.2 Severe/Complicated Falciparum Malaria in Children 228
4.4 Diarrhoea 228
4.4.1 Treatment 229
4.5 Hepatitis 229
4.5.1 Clinical Features 229
4.5.2 Treatment 229
4.5.3 Prevention 229
4.6 Enteric Fever in Travellers 229
4.6.1 Presentation 230
4.6.2 Investigation 230
4.6.3 Treatment 230
4.6.4 Prevention 230
4.7 Dengue Fever 230
4.7.1 Clinical Features 231
4.7.2 Treatment 231
4.7.3 Prevention 231
4.8 Ricketsial Infection 231
4.8.1 Spotted Fevers 231
4.8.2 Diagnosis 232
4.8.3 Treatment 232
4.8.4 Prevention 232
4.9 Tuberculosis 232
4.9.1 Treatment 232
4.10 Cosmopolitan Infection 232
References 233
Molecular Diagnostics of Primary Immunodeficiencies: Benefits and Future Challenges 236
1 Introduction 236
2 Relevance of Molecular Diagnostics 237
3 Mutation Spectrum in Human Disease 237
3.1 Single-Base-Pair Substitutions 238
3.2 Small Deletions and Insertions 239
3.3 Gross Lesions 239
4 Molecular Analysis of a Candidate Gene 240
5 Interpretation of Sequence Variants 240
6 Pitfalls and Limitations 242
6.1 Disease-Causing Mutation or Polymorphism? 242
6.2 Reduction of False Negative Results 242
7 Future Perspectives 243
References 244
Human Genetic Resistance to Malaria 247
1 Introduction 247
2 Malaria 247
2.1 Health Impact of Malaria on Global Health and Development 247
3 Malaria Biology 248
4 Clinical Features 250
5 Severe Malaria 250
6 Defining Malaria for the Purpose of Genetic Association Studies 250
7 The Haemoglobinopathies: Sickle Cell Trait and alpha-Thalassaemia 251
8 The Thalassaemias 252
9 Genetic Epistasis 254
10 Summary and Conclusions 254
References 255
Index 258