Hot Topics in Infection and Immunity in Children II (Advances in Experimental Medicine and Biology Vol 568)

Acknowledgments

We are indebted to all of the contributors to this text who have generously provided their carefully written manuscripts in good time for editing and publication. We are also grateful to the staff of Keble College, Oxford, UK who hosted Infection and Immunity in Children 2004 on which the text is based. We are particularly grateful to Julia Bremble for administration of the Course, to Sue Sheaf who assisted with the preparation of the edited manuscripts and to our colleagues and families who supported our own activities in this venture. Our gratitude also for the support provided by the European Society for Paediatric Infectious Disease (ESPID), the British Paediatric Allergy Infection and Immunity Group (BPAIIG), and the Royal College of Paediatrics and Child Health (RCPCH). Lastly, we are pleased to acknowledge the generous and unrestricted financial support of Acambis, Aventis Pasteur, Baxter, Chiron Vaccines, GlaxoSmithKline vaccines, and Wyeth Vaccines who made the meeting possible. The Editors are especially grateful to Nigel Curtis for providing the photographs of the contributors to this volume taken at the course “Infection and Immunity in Children 2004, Keble College, Oxford, UK”.

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Contributing Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Emerging Infections and Children: Influenza and Acute Necrotizing Encephalopathy Sarah S. Long 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology of Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mortality from Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Influenza-Associated Acute Necrotizing Encephalopathy . . . . . . . . . . . . . . 4.1. An Illustrative Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. History of Emergence of Acute Necrotizing Encephalopathy . . . . . . . . 4.3. Clinical Manifestations of ANE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Pathogenesis of ANE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Suggestions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 2 3 4 4 5 6 7 8 8

2. Chickenpox Party or Varicella Vaccine? Sophie Hambleton and Ann M. Arvin 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. VZV Disease in Unvaccinated Populations . . . . . . . . . . . . . . . . . . . . . . . . . 3. Varicella Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Safety, Immunogenicity, and Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. The US Varicella Vaccination Program: Design and Coverage . . . . . . . 3.3. Impact of the US Varicella Vaccination Program . . . . . . . . . . . . . . . . . 3.3.1. Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Hospitalizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Issues of Concern in the Varicella Vaccine Era . . . . . . . . . . . . . . . . . . . . . . 4.1. Identification and Vaccination of Varicella-Susceptibles . . . . . . . . . . . . 4.2. Breakthrough Varicella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Herpes Zoster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11 11 13 13 14 15 15 17 17 17 18 18 19 20 21

3. The ABC of Epstein-Barr Virus Infections Upton D. Allen 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Epidemiology and Model of Human Infection . . . . . . . . . . . . . . . . . . . . . . . ix

25 26

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2.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Model of Human Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. EBV-Related Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Infectious Mononucleosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. X-Linked Lymphoproliferative Syndrome . . . . . . . . . . . . . . . . . . . . . . 3.3. B-Cell Lymphoproliferative Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Chronic Active EBV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Serologic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Nucleic Acid Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. EBV and the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. EBV-Encoded Genes in Different States of EBV Infection . . . . . . . . . . 5.1.1. Lytic Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Latent Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.3. Healthy Persons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.4. Immunodeficient Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Evasion of Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Acquired Disturbances in Immune Surveillance for EBV . . . . . . . . . . . 5.3.1. Immune Dysregulation due to Space Flight . . . . . . . . . . . . . . . . 5.3.2. Immune Dysregulation due to Organ Transplantation . . . . . . . . 6. Post-Transplant Lymphoproliferative Disorders . . . . . . . . . . . . . . . . . . . . . . 6.1. Clinical Manifestations and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. PTLD Burden and Associated Risk Factors . . . . . . . . . . . . . . . . . . . . . 6.3. Detecting EBV Lymphoproliferation . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. EBV Viral Load as a Marker of EBV Lymphoproliferation . . . . . . . . . 6.5. Treatment of PTLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26 27 27 28 30 30 30 30 30 31 31 31 32 32 32 32 33 33 33 34 34 34 35 35 35 36 37 37

4. The Immune Response to Viral Lower Respiratory Tract Infection Caroline A. Lindemans and Jan L. L. Kimpen 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Epidemiology and Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Respiratory Syncytial Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. The Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. RSV Respiratory Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. The Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Influenza Respiratory Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Adenovirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. The Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Adenovirus-Induced Respiratory Disease . . . . . . . . . . . . . . . . . 2.4. Parainfluenza Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Rhinovirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Human Metapneumovirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. SARS Coronavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Immunology of Viral Lower Respiratory Tract Infections . . . . . . . . . . . . . . 3.1. Innate Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41 41 42 42 42 43 43 44 44 44 44 44 45 45 46 47 47

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3.2. Adaptive Immune Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Immature Immune Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Genetic Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Virus Infection in the Immunocompromised Host . . . . . . . . . . . . . . . . . . . . 4.1. Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Impaired Innate Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Respiratory Viruses and Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Virus Infections and Asthma Exacerbations . . . . . . . . . . . . . . . . . . . . 5.2. Viral Respiratory Tract Infections and the Inception of Asthma . . . . . . 6. Viral Evasion of the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Viral Entry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. The Interferon Antiviral Response . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Evasion of Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Immune Evasion Techniques by Adenoviruses . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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50 51 51 52 52 53 53 53 54 56 56 57 58 58 60

5. Chronic Granulomatous Disease: From Genetic Defect to Clinical Presentation Johan Bylund, David Goldblatt, and David P. Speert 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biochemistry and Genetics of the NADPH-oxidase and its Deficiency . . . . Animal Models of CGD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roles of ROS in Health and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Microbial Killing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Cell Death Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Regulation of Inflammatory Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Other Effects of ROS with Possible Implications for the Development and Resolution of Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Clinical Characterization of CGD and Current Therapies . . . . . . . . . . . . . . 5.1. Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Inflammatory Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Current Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Newer Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67 68 70 71 71 74 75 76 77 77 79 80 81 82

6. Novel Primary Immunodeficiencies Capucine Picard and Jean-Laurent Casanova 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Mendelian Susceptibility to Mycobacterial Disease . . . . . . . . . . . . . . . . . . . 2.1. Complete Interferon-
Receptor 1 Deficiency . . . . . . . . . . . . . . . . . . . 2.2. Complete Interferon-
Receptor 2 Deficiency . . . . . . . . . . . . . . . . . . . 2.3. Partial Recessive IFN
R1 and IFNgR2 Deficiencies . . . . . . . . . . . . . . 2.4. Partial Dominant IFN
R1 Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. IL-12R1 Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. IL-12 p40 Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Partial STAT1 Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. Complete STAT1 Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89 89 90 90 91 91 92 92 93 93

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3. Inherited Disorders of the NF-B Signaling Pathway . . . . . . . . . . . . . . . . . 3.1. NEMO Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. IB Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Interleukin-1 Receptor-Associated Kinase-4 Deficiency . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

93 94 94 95 95 96 96

7. Periodic Fever Sarah S. Long 1. A Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Approach to the Child with Recurring Fevers . . . . . . . . . . . . . . . . . . . . . . . 2.1. History of Episodes and Intervening Periods . . . . . . . . . . . . . . . . . . . . 2.2. Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Laboratory Evaluations and Imaging Studies . . . . . . . . . . . . . . . . . . . . 3. Differential Diagnosis of Periodic Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Epidemiology and History . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Treatment and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Cyclic Neutropenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Epidemiology and History . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Etiology and Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. Treatment and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Familial Mediterranean Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Epidemiology and History . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Etiology and Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.4. Treatment and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Hyper-Immunoglobulinemia D and Periodic Fever Syndrome . . . . . . . 3.4.1. Epidemiology and History . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. Etiology and Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.4. Treatment and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Tumor Necrosis Factor Receptor Associated Periodic Syndrome . . . . . 3.5.1. Epidemiology and History . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.2. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.3. Etiology and Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.4. Treatment and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Case Denouement and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

101 102 102 102 103 103 104 104 104 106 106 106 106 107 107 108 108 108 109 109 110 110 110 111 111 111 111 112 112 113 113 113

8. BCG Vaccine Stephen Sze Shing Teo and Delane Shingadia 1. History of BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Phylogeny of BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2.1. How BCG Differs from M. bovis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. The Immunological Response to BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Host Response to M. tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Host Response to BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Efficacy of BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Early Studies of BCG Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Student Nurses in Norway . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Trial in American Indians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. BCG Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. Medical Research Council Trial . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Tuberculosis Prevention Trial, Madras . . . . . . . . . . . . . . . . . . . 4.3. Meta-analyses of BCG Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Duration of Efficacy of BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Explanations for Variability in Observed BCG Efficacy in Trials . . . . . 4.5.1. Latitude and Environmental Mycobacteria . . . . . . . . . . . . . . . . 4.5.2. BCG Strain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.3. Different Routes of Administration of BCG Vaccine . . . . . . . . . 4.5.4. Genetic Differences Between Populations . . . . . . . . . . . . . . . . . 4.5.5. Methodological and Statistical Rigor . . . . . . . . . . . . . . . . . . . . . 5. Complications of BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Classification of Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Frequency of Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Specific Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1. Local Lymphadenitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2. Disseminated BCG Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. BCG Vaccination Policies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. World Health Organization Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1. WHO Indications for BCG Vaccination . . . . . . . . . . . . . . . . . . 6.1.2. WHO Contraindications to BCG Vaccination . . . . . . . . . . . . . . 6.1.3. WHO Recommendations Regarding BCG Vaccination and HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Policy in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Variations Within Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Policy in the United Kingdom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4.1. Indications for BCG Vaccination . . . . . . . . . . . . . . . . . . . . . . . . 6.4.2. Contraindications to BCG Vaccination . . . . . . . . . . . . . . . . . . . 6.4.3. Selective Versus Universal BCG Vaccination . . . . . . . . . . . . . . 7. The Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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117 118 118 118 120 120 120 120 120 120 121 122 125 125 125 127 127 128 128 128 128 128 129 129 129 129 129 129 130 130 130 130 130 130 131 131 132 132 132

9. Helminth Infections of Children: Prospects for Control Peter J. Hotez, Sonia Arora, Jeffrey Bethony, Maria Elena Bottazzi, Alex Loukas, Rodrigo Correa-Oliveira, and Simon Brooker 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Global Disease Burden of Helminth Infections . . . . . . . . . . . . . . . . . . . . . . Anthelminthic Drugs in the Control of Childhood Helminth Infections . . . . Downstream Alternatives to School-Based De-worming: Rationale and Promise for Developing Anthelminthic Vaccines . . . . . . . . . . . . . . . . . . . . .

135 136 139 140

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4.1. Anti-hookworm Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Anti-schistosomiasis Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

140 141 141 142 142

10. Rabies on the Doorstep David A. Warrell 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Implications of Having Enzootic EBLV in Britain . . . . . . . . . . . . . . . . . . . 2.1. How prevalent is EBLV among British bats? . . . . . . . . . . . . . . . . . . . 2.2. Can EBLV be transmitted to other mammals? . . . . . . . . . . . . . . . . . . . 2.3. How effective are standard rabies vaccines and rabies immune globulin against EBLV? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. To whom should pre- and post-exposure prophylaxis be given in the United Kingdom? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Other Rabies-Related Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. The Global Problem of Rabies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Rabies in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Diagnosis of Rabies in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Survival from Rabies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Pre- and Post-exposure Prevention of Rabies by Vaccination . . . . . . . . . . . 8.1. Post-exposure Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Passive Immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Pre-exposure Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Control of Rabies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

145 146 146 146 146 147 147 147 152 153 153 154 154 155 156 156 158 158

11. Prevention of Typhoid Fever Myron M. Levine and Philippe Lepage 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Secondary Prevention of Typhoid Morbidity and Mortality . . . . . . . . . . . . . 3. Primary Prevention of Typhoid Morbidity and Mortality . . . . . . . . . . . . . . 3.1. Environmental Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Identification, “Epidemiologic Neutralization,” and Treatment of Chronic Typhoid Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Typhoid Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Disease Burden and Target Populations for Immunization . . . . . 3.3.2. Ty21a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Vi Polysaccharide Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. New Live Oral Typhoid Vaccine in Development . . . . . . . . . . . . . . . . . 3.5. Vi Conjugate Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Commentary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

161 162 162 163 163 164 164 166 167 169 169 170 170

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12. Dexamethasone in the Treatment of Pediatric Bacterial Meningitis in Developing Countries: Is it Beneficial? Elizabeth Molyneux 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Context of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Why Steroids? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Causes of Bacterial Meningitis in Children in Developing Countries . . . . . 4.1. Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Studies of Adjuvant Steroid Therapy in Children with Bacterial Meningitis in Developing Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. The Blantyre Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. What Affected Mortality? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. What Affected Hearing Loss? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. What was the Role of HIV in Outcome in the Steroid Treated and Placebo Group? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Overall Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

175 175 176 176 178 178 183 184 185 185 185 186 186

13. Should Dexamethasone be Part of Routine Therapy of Bacterial Meningitis in Industrialised Countries? Peter McIntyre 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Steroids and Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Steroids and Bacterial Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The 1997 Meta-Analysis (5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Included Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. The 2003 Cochrane Review (6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Included Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. The Netherlands Adult Trial (8) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Dexamethasone in Practice—Pneumococcal Meningitis, Sydney 1994–99 (11) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

189 190 190 190 190 191 191 192 192 192 192 193 193 193 194 194 194 195 196 196

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14. How to Interpret a CSF—The Art and the Science Tom Connell and Nigel Curtis 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Variation in CSF Normal Values with Age . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. White Cell Count . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Neutrophil Count . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Can CSF Abnormalities be Caused by Convulsions? . . . . . . . . . . . . . . . . . . 4. CSF Eosinophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Eosinophilic Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Shunt Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Interpretation of Blood-Contaminated CSF (“Traumatic Taps”) . . . . . . . . . 6. Distinguishing Viral and Bacterial Meningitis on the Basis of CSF Findings 6.1. “Scary Facts” About CSF Findings in Meningitis . . . . . . . . . . . . . . . . 6.2. CSF Scores and Algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Approach for Patients with Mild CSF Pleocytosis Only . . . . . . . . . . . . 7. Alternative Methods for Distinguishing Bacterial and Viral Meningitis . . . 7.1. Rapid Antigen Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Inflammatory Cytokines and Other Marker . . . . . . . . . . . . . . . . . . . . . 7.3. The Future: Molecular Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

199 200 200 200 201 201 203 203 204 204 204 205 206 206 208 209 209 209 210 210 210 211

15. Reverse Vaccinology and Vaccines for Serogroup B Neisseria meningitidis Dominic F. Kelly and Rino Rappuoli Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Reverse Vaccinology—An Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Serogroup B N. meningitidis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Advantages and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Index

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217 217 218 220 222 222 225

Contributing Authors

Johan Bylund Department of Pediatrics B.C Research Institute for Children’s and Women’s Health University of British Columbia, Vancouver, Canada

Upton D. Allen Division of Infectious Diseases Hospital for Sick Children University of Toronto Sonia Arora Department of Microbiology and Tropical Medicine The George Washington University Medical Center Washington, DC USA

Jean-Laurent Casanova Unité d’Immunologie et d’Hématologie Pédiatriques Hôpital Necker-Enfants Malades 149, rue de Sèvres 75015 Paris, France, EU and Laboratoire de Génétique Humaine des Maladies Infectieuses Unité Mixte de Recherche Université René Descartes-INSERM U550 Faculté de Médecine Necker-Enfants Malades 156 rue de Vaugirard 75015 Paris, France, EU

Ann M. Arvin Lucile Salter Packard Professor of Pediatrics and Microbiology and Immunology Stanford University School of Medicine 300 Pasteur Drive, Room G311 Stanford, CA 94305-5208 USA Jeffrey Bethony FIOCRUZ-Rene Rachou Research Center Belo Horizonte, Brazil

Tom Connell Department of Paediatrics, University of Melbourne; and Paediatric Infectious Diseases Unit, Department of General Medicine Royal Children's Hospital Melbourne Parkville, VIC 3052, Australia

Maria Elena Bottazzi Department of Microbiology and Tropical Medicine The George Washington University Medical Center, Washington, DC, USA Simon Brooker Department of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine, London, United Kingdom Rodrigo Correa-Oliveira FIOCRUZ-Rene Rachou Research Center Belo Horizonte Brazil

Nigel Curtis Associate Professor Department of Paediatrics, University of Melbourne; and Head of Paediatric Infectious Diseases Unit, Department of General Medicine Royal Children’s Hospital Melbourne Parkville, VIC 3052 Australia

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Contributing Authors

David Goldblatt Immunobiology Unit, Institute of Child Health University College London and Great Ormond Street Children’s Hospital NHS Trust London, United Kingdom

Sarah S. Long Professor Drexel University College of Medicine Chief, Section of Infectious Diseases St. Christopher’s Hospital for Children Philadelphia, PA

Dr Sophie Hambleton Columbia University Department of Pediatrics 650 W 168 St, #BB427 New York NY 10032

Alex Loukas Department of Microbiology and Tropical Medicine The George Washington University Medical Center Washington, DC, USA

Peter J. Hotez Department of Microbiology and Tropical Medicine The George Washington University Medical Center 2300 Eye Street, NW Washington, DC 20037

Peter McIntyre National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, The Children's Hospital at Westmead, Westmead NSW, Australia

Dominic Kelly Department of Paediatrics University of Oxford John Radcliffe Hospital Oxford OX3 9DU United Kingdom

Elizabeth Molyneux Paediatric Department College of Medicine P.O. Box 360 Blantyre Malawi Africa

Jan L.L. Kimpen Wilhelmina Children’s Hospital KB 03.023.2 P.O. Box 3508 3508 AB Philippe Lepage Département de Pédiatrie, Université de Liège 4000 Liège, Belgium Myron M. Levine University of Maryland School of Medicine 685 W. Baltimore St. Baltimore, MD 21201, USA Caroline A. Lindemans Wilhelmina Children’s Hospital KE04.133.1 P.O. Box 85090 3508 AB

Capucine Picard Unité d’Immunologie et d’Hématologie Pédiatriques Hôpital Necker-Enfants Malades 149, rue de Sèvres 75015 Paris, France, EU and Laboratoire de Génétique Humaine des Maladies Infectieuses Unité Mixte de Recherche Université René Descartes-INSERM U550 Faculté de Médecine Necker-Enfants Malades 156 rue de Vaugirard 75015 Paris, France, EU Rino Rappuoli Chiron Vaccines Sienna Italy

Contributing Authors

xix

Delane Shingadia Centre for Child Health Royal London Hospital 38 New Road London E1 2AX United Kingdom

Stephen Teo Centre for Child Health Royal London Hospital 38 New Road London E1 2AX United Kingdom

David P. Speert Department of Pediatrics B.C Research Institute for Children’s and Women’s Health University of British Columbia, Vancouver, Canada

David A Warrell University of Oxford Nuffield Department of Clinical Medicine John Radcliffe Hospital, Oxford OX3 9DU

Keble College

Sarah Long

The Audience

Ann Arvin

Upton Allen

Jan Kimpen

David Goldblatt

David Speert

Delane Shingadia

Peter Hotez

Myron Levine

Elizabeth Molyneux

Peter McIntyre

Nigel Curtis

Rino Rappuoli

The Paediatric Infectious Diseases Panel (From Left to Right: David Speert, Sarah Long, Ulrich Heininger, Karina Butler, Ronald De Groot.

Andrew J Pollard

Adam Finn

The Immunodeficiency Panel (From left to right: David Goldblatt, Andrew Cant, Graham Davies, David Speert)

1 Emerging Infections and Children: Influenza and Acute Necrotizing Encephalopathy Sarah S. Long

1. Introduction Children can play a variety of roles in emerging infectious diseases. They can be victims, as in the vertical transmission of human immunodeficiency virus infection. They can be affected in a minor way compared with adults, as in West Nile virus infection, legionellosis, and coronavirus infection leading to severe acute respiratory syndrome (SARS). Sometimes, however, they play predominant roles—sources for other age groups—as do toddlers in out-of-the-home child care for transmission of penicillinresistant pneumococci and cytomegalovirus to family members. Children have a uniquely central role in transmitting the influenza viruses that cause annual seasonal outbreaks and epidemic disease and could cause global epidemic (or pandemic) disease. Children themselves suffer excessive morbidity and mortality from influenza. Continuous minor changes in virus neuraminidase and haemagglutinin components (antigenic drift) or a major change in either (antigenic shift) render naïve children especially vulnerable. Anticipating that pandemic influenza could occur at any time because of a major change in a human strain of influenza virus or through acquisition of human transmissibility of reassortant avian influenza strain(s) (Nicholson et al., 2003), the international community of healthcare experts are collaborating increasingly, and countries are drafting influenza pandemic preparedness plans. A draft by the U.S. Department of Health and Human Services of “Pandemic Influenza Preparedness and Response Plan” was released for comment in August 2004 (http://www.hhs.gov/ nvpo/pandemicplan). All plans highlight the critical importance of international surveillance, openness, and rapid response to investigate and contain emergent avian or human strains. In the midst of concern for novel influenza viruses, an apparently novel clinical manifestation of extant influenza virus has emerged recently. Acute necrotizing encephalopathy (ANE) is a new and severe manifestation of influenza in children. Hot Topics in Infection and Immunity in Children, edited by Andrew J. Pollard, and Adam Finn. Springer, New York, 2005. 1

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Sarah S. Long

2. Epidemiology of Influenza In prospective studies in the United States (Glezen and Couch, 1978; Neuzil et al., 2002) annual attack rates of influenza illness are between 15% and 42% in preschool- and school-aged children. Globally, it is estimated that 20% of children and 5% of adults have symptomatic influenza illness annually. Influenza is responsible for approximately one-third of excess outpatient visits to healthcare providers for children less than 3 years of age and for approximately one-third of excess prescriptions for antibiotics in the winter season for individuals less than 15 years of age (Neuzil et al., 2000; O’Brien et al., 2004). Antecedent influenza infection is associated with the development of invasive pneumococcal infection and staphylococcal pneumonia in children (O’Brien et al., 2000) as well as in adults. Children have undue risk for complications of influenza and for hospitalization (Izurieta et al., 2000). Influenza-associated illnesses in children are not restricted to acute respiratory syndromes with systemic complaints or complications, and can involve a variety of organ systems (Table 1.1). Children under the age of 2 years have substantially higher risk of hospitalization than do older children. There are more than 10,000 children younger than 2 years of age hospitalized for influenza annually in the United States; rates of hospitalization range from approximately 200 to 500 per 100,000 population. The risk of hospitalization among children less than 4 years of age in one study was approximately 100 per 100,000 in healthy children and 500 per 100,000 in children with underlying conditions (Neuzil et al., 2000). The overall health impact of influenza in children, and the risk of hospitalization among children younger than 2 years of age, is similar to or greater than that among high-risk children and healthy 50- to 64-year-old adults (both groups for whom annual influenza immunization has been recommended in the United States for years). Recognizing this, universal influenza vaccine was recommended by the American Academy of Pediatrics (AAP) and the Centers for Disease Control and Prevention (CDC) in 2004 for healthy children 6 months to 24 months of age and for household contacts and out-of-home caregivers of all children younger than 24 months of age (Committee on Infectious Diseases, AAP, 2004; Table 1.2). Because of an unexpected shortage of vaccine doses in October 2004, recommendations

Table 1.1 Clinical Manifestations of Influenza Beyond Acute Respiratory Tract Illness ● ●

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Febrile illness with vomiting and diarrhea in the absence of respiratory tract symptoms Sepsis-like illness (especially in young infants) in the absence of respiratory tract or gastrointestinal symptoms Myocarditis Bilateral gastrocnemius myositis Rhabdomyolysis Invasive group A streptococcal, pneumococcal and meningococcal infection Toxic shock Post-influenza asthenia

Emerging Infections and Children

Table 1.2.

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Recommendations by the American Academy of Pediatrics, 2004, for Influenza Immunization

I. High-risk children and adolescents with the following conditions ● Asthma or other chronic pulmonary disease ● Hemodynamically significant cardiac disease ● Immunosuppressive disorders or therapy ● Human immunodeficiency virus infection ● Sickle cell anemia and other hemoglobulopathies ● Disorders requiring long-term aspirin therapy (e.g., rheumatoid arthritis and Kawasaki disease) ● Chronic renal dysfunction ● Chronic metabolic disease (e.g., diabetes mellitus) II. Women who will be in second or third trimester of pregnancy during influenza season III. Persons who are in close contact with high-risk children. These include: ● All healthcare professionals in contact with children in hospitals and outpatient settings ● Household contacts and out-of-home caregivers of high-risk individuals of any age IV. Young, healthy children 6 through 23 months of age (because of excessive risk of hospitalization, morbidity, and mortality) V. Household contacts and out-of-home caregivers of children younger than 24 months of agea VI. Any person older than 6 months of age who (or whose parent) wishes to be protected against influenzaa a

Because of shortages of influenza vaccines that occurred in October 2004, the CDC and AAP have altered these recommendations temporarily. Regarding healthy contacts of healthy children (Recommendation V), only those children under 6 months of age (too young to be immunized) are recommended to receive vaccine. Other healthy individuals to whom these recommendations apply (Recommendation VI) were asked to defer immunization in order to channel available vaccine to high-risk individuals and their contacts (CDC, 2004a, b).

were modified temporarily to include healthy contacts only for infants under 6 months of age (who are themselves too young to be vaccinated) (CDC, 2004a, b).

3. Mortality from Influenza Death from influenza has not been a reportable disease in the United States. However, more than 150 influenza-associated deaths among children under 18 years of age were reported to the CDC in the 2003–2004 influenza season. This voluntary reporting probably reflects a gross underestimate. Death due to influenza has been made a reportable disease for 2004–2005. Preliminary data from the 2003–2004 fatal cases show a median age of approximately 3 years; two-thirds were less than 5 years of age. Approximately one-half of the children were previously healthy, the others having a wide variety of underlying conditions, especially involving the central nervous system. Deaths did not occur in fully immunized children. In more than one-quarter of fatalities, death was rapid, occurring either at home or in a hospital emergency department. Causes included viral and bacterial pneumonia, invasive bacterial infection, cardiorespiratory deaths, and central nervous system syndromes. An emerging disease, influenza-associated ANE was one cause of mortality and significant morbidity.

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4. Influenza-Associated Acute Necrotizing Encephalopathy 4.1. An Illustrative Case A 3-year old US-born, previously healthy male of Indian descent was brought to medical attention in February 2004 because of lethargy and abnormal tongue movements. From 3 weeks until 1 week prior to admission, he was traveling in India with his family where he lived rurally with extended family members. He was exposed to multiple dogs, cows, and birds. He drank unpasteurized milk and had many insect bites. He took no malaria prophylaxis. Three days prior to admission he had sudden onset of fever to 39.0C, vomiting, diarrhea, and abdominal pain. On the day of admission he was sleepy, unwilling to rise from his bed, and had unusual tongue movements. Physical examination revealed a well-grown boy who was difficult to arouse. He appeared to understand some commands but was mute. Vital signs were normal as was the general physical examination. Function of cranial nerves were normal as far as could be assessed as was fundoscopic examination. He had generalized tremulousness (also affecting his tongue) and increased tone on the left side. Full blood count, electrolyte and metabolic screening tests, and chest radiograph were normal. Electroencephalogram showed continuous epileptiform discharges. Cerebrospinal fluid was acellular with protein concentration of 0.6 g/l and normal glucose concentration. Magnetic resonance imaging of the brain (see Figure 1.1) was abnormal.

Figure 1.1. Appearance of T2-weighted images of the brain show increased signal intensity bilaterally and symmetrically in the periventricular and deep white matter (on the left) and the corona radiata (on the right). T1-weighted images were not remarkable. There was no enhancement after administration of gadolinium. Images are courtesy of Eric Faerber, M.D., Department of Radiology, St. Christopher’s Hospital for Children, Philadelphia, USA

Emerging Infections and Children

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The differential diagnosis was lengthy, especially considering exposures. Multiple tests for possible aetiological infectious agents including bacterial cultures, antigen-detection tests, antibody tests, blood smears, and polymerase chain reaction assays were negative. Influenza B was isolated from the respiratory tract. The virus was subsequently identified by the CDC to be Sichuan group/Shanghailike. Polymerase chain reaction testing for influenza was performed on the patient’s cerebrospinal fluid at the CDC and was negative. Despite all of this patient’s exposures in India to what would be rather exotic infectious agents in the United States, he turned out to have an unusual manifestation of the most common infection (influenza) in the United States and Europe at that time. Incubation period would be compatible with acquisition during transcontinental travel or immediately upon return to the United States. More than 90% of influenza viruses isolated in the United States in the 2003–2004 season were type A. Type B accounted for the remainder; Sichuan group/Shanghai-like was the most common type B virus isolated. Diagnosis was highly compatible with acute necrotizing encephalitis. Hospital course was protracted and complicated, with major problems of seizures, stupor, mutism, and left hemiparesis. Therapeutic manoeuvers included administration of oseltamivir, intravenous immunoglobulin, and solumedrol. None had immediate temporal benefit, but at the time of transfer to a rehabilitation hospital after 21 days of hospitalization under intensive care, he had increasing periods of alertness, appeared to recognize parents, demonstrated visual tracking, and made guttural sounds. Eight months after the illness, he has recovered remarkably, with mild residual hemiparesis and difficulty in speech and language.

4.2. History of Emergence of Acute Necrotizing Encephalopathy In pandemics of influenza, as in 1918 and 1930, Encephalitis lethargica was a frequent cause of death. As gleaned from descriptions, the disease probably was in some cases influenza virus encephalitis and in others post-infectious encephalitis. We recognize both syndromes as occurring currently, sporadically during annual influenza seasons. In addition, rarely, hemorrhagic shock and encephalopathy, as well as Reye’s syndrome can be associated with influenza, the latter especially but not always in conjunction with use of aspirin. The CNS disease represented by our case, ANE, was first described in Japanese children in 1995. By 1998, 148 cases of ANE were reported in Japan (Morishima et al., 2002) and it was estimated subsequently that more than 100 deaths were occurring annually in Japanese children from influenza-associated ANE (Kasai et al., 2000). Emergence of ANE in Japan occurred the year after cessation in 1994 of routine annual influenza immunization in children, a policy that had been in place since 1960s. Influenza A and B viruses were associated with direct proportion to causation of uncomplicated respiratory tract infection. In the United States, physicians were alerted to ANE in late 2003 and were encouraged to report cases to the CDC. More than 103 possible cases were reported. At this time, the reports of only a minority of cases meeting the screening case definition of having proven influenza plus more than 24 hr of altered mental status have been

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Table 1.3. Clinical Characteristics of Influenza-Associated Necrotizing Encephalopathy ●

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Clinical – Age 5 years, rarely 10 years – Onset during the peak of the febrile illness (fever ± cough, vomiting) – Presentation with seizures – Presentation with altered mental status – Propensity for finding of akinetic mutism – Multiorgan failure that follows CNS symptoms – Disseminated intravascular coagulopathy that follows CNS symptoms – Unremarkable severity of influenza symptoms – Unremarkable complete blood count, serum chemical and hepatic enzyme tests – Normal cerebrospinal fluid (may have increased pressure, or protein elevation