Influenza

I. Introduction.- 1. History of Influenza.- The Credibility of Historical Evidence.- Prehistory: The Origin of Influenza.- Influenza Prior to 1889.- Influenza 1889-1933: Seroarcheology and the Recycling of Antigens.- Influenza Post-1933.- Early History Revisited.- The Pandemics.- Pandemics Defined.- The Modern Pandemics.- Influenza 1918.- Influenza 1946-47.- Influenza 1957.- Influenza 1968.- Influenza Post-1968: Major Antigenic Changes in the Virus Are Not Necessarily Followed by Pandemics.- Influenza 1976: The First Epidemic of Swine Influenza Virus.- Infection in Man.- Influenza 1977.- References.- II. The Influenza Viruses.- 2. Taxonomy and Comparative Virology of the Influenza Viruses.- Taxonomy of Influenza Viruses.- Relation of Influenza Viruses to Other Enveloped Viruses with RNA Genomes.- Influenza Viruses as Segmented Genome Viruses.- References.- 3. Viral Structure and Composition.- Size and Morphology of Influenza Virus Particles.- The Viral Envelope.- Internal Structure.- Structure of the Envelope Glycoproteins.- Hemagglutinin Structure.- Neuraminidase Structure.- Carbohydrate.- Lipid.- RNA.- Structural Differences among Influenza A, B, and C Viruses.- Tick-Borne Viruses Structurally Similar to Orthomyxoviruses.- References.- 4. Replication of Influenza Viruses.- Replication Systems and Viral Quantitation.- Viral Genes and Gene Products Involved in Virus Replication: Coding Assignments of Influenza Virus Genes.- Stages of Infection and Replication.- Viral Attachment to Host Cells: Adsorption.- Viral Entry.- Proteolytic Activation of the HA and Virus-Cell Fusion.- Virus-Cell Fusion.- Cell Entry and Uncoating through Endocytosis.- Transcription and Replication of Influenza Virus RNA.- Primary Transcription.- Secondary Transcription and RNA Replication.- Synthesis of Viral Proteins.- The P Proteins.- NP.- The Nonstructural Proteins.- Hemagglutinin.- Neuraminidase.- Viral Maturation and Assembly.- Virus Budding and Release.- Abortive and Inefficient Virus Replication.- Anomalous Viral Replication and the Formation of Defective Virus.- Interference.- References.- 5. Cytopathogenesis and Cytopathology of Influenza Virus Infection of Cells in Culture.- Primary Intrinsic Cytotoxicity of Influenza Viruses.- Effects in Intact Animals.- In Vitro Effects of Influenza Viruses on Polymorphonuclear Leukocytes.- Viral Effects on Other Blood Leukocytes.- Viral Effects on Other Cells.- Cell Systems Supportive of Productive Replication and Plaque Formation by Influenza Viruses.- Cytopathic Effects of Influenza Viruses in Specialized Cells.- The Nature of Influenza Virus Cytopathic Effects.- Cytopathology.- Nuclear and Cytoplasmic Inclusions.- The Kinetics of CPE: Influenza Virus Plaque Formation in Cell Cultures as a Model of Microinfection.- The Possible Role of Lysosomal Enzymes in Influenza Virus CPE.- The Molecular Basis of CPE.- References.- 6. Influenza Virus Genetics, Viral Adaptation, and Evolution.- The Nature of the Viral Genome.- Genetic Systems.- Viral Heterogeneity.- Host Cell Heterogeneity.- Viral Mutation and Mutants.- Mutation Frequency.- Frequency of Influenza Virus Antigenic Variation.- Molecular Basis of Influenza Virus Mutations.- Laboratory-Derived Mutants and Their Contribution to Genetic Analysis of Influenza Viruses.- Phenotypic Markers.- Operational Mutants: Conditional Lethal Mutants Used in Definitive Genetic Studies of Influenza Viruses.- Temperature-Sensitive (ts) Mutants.- Host Range (hr) Mutants.- Temperature-Dependent Host Range (td-hr) Mutants.- Drug-Resistant Mutants.- Viral Variation.- Antigenic Variants.- Sites of Antigenic Variation: The HA Polypeptide.- The Molecular Basis of HA Antigenic Variation.- Antigenic Variation in the NA.- Antigenic Variation in Other Viral Proteins.- Biologically Selected (Nonimmunoselected) Variants.- Nonimmunoselected HA Variants.- Variants Selected by Replication Characteristics.- Host-Determined Antigenic Variation.- HA Glycosylation Mutants.- Pleiotropism and Covariation.- The Genetics of Major Antigenic Change in Influenza A Viruses.- Genetic and Nongenetic Viral Interactions.- Phenotypic Mixing.- Influenza Virus-Influenza Virus Pseudotypes.- Heterologous Pseudotypes.- Genetic Reassortment.- Complementation-Reassortment.- Multiplicity Reactivation and Gene Rescue.- Virulence and Attenuation as Genetic Phenomena.- Identification of Single Genes Influencing Virulence and Attenuation.- Analysis of Virulence through Genetic Reassortment.- Cloning and Expression of Influenza Virus Genes: The New Influenza Virus Genetics.- Contributions of Gene Cloning.- Gene Expression.- Contribution of the Expression of Isolated Viral Genes to the Understanding of Influenza Virus Infection.- Prospects and Potential of Site-Specific Mutagenesis.- Viral Variation and Attenuation in Nature.- Influenza Viral Adaptation, Genetic Polymorphism, and Evolution.- Viral Adaptation.- Genetic Dimorphism.- Viral Evolution.- Influenza Virus Evolution is the Study of the Evolution of Genes, Not Viruses.- Evolutionary Potential of Influenza Viruses as Segmented Genome Viruses.- Evolution of the Genes of Influenza Viruses by Sequential Mutations.- Evolution of the HA Gene.- Antigenic Drift.- Evolutionary Changes in the HA Affecting Other Than Antigenic Sites.- Evolution of Genes for Nonsurface Viral Proteins.- NS.- Other Genes.- References.- III. Influenza: Infection And Disease.- 7. Influenza in Man.- Clinical Response to Infection.- Findings on Physical Examination.- Host-Determined Variation in Disease Expression and Severity.- Variation in Symptoms Related to Age.- Influenza in Children.- Influenza in Infants.- Influenza in the Elderly.- Influence of Genetic Factors on the Expression of Disease.- The Influence of Prior Immunizing Experience on the Severity of Influenza.- Pregnancy.- Underlying Cardiovascular Disease.- Bronchopulmonary Disease.- Other Underlying Diseases.- Virus-Determined Variation in Disease Expression and Severity.- Clinical Responses to Infection with Influenza A, B, and C Viruses Compared.- Influenza B.- Influenza C.- Variation in Disease Severity Related to Viral Strain or Subtype.- Unusual Manifestations of Influenza Virus Infection.- Primary Viral Pneumonia.- Myopathy and Nephropathy.- Acute Transient Crural Myopathy in Children.- Acute Myopathy with Rhabdomyolysis and Myoglobinuria with Associated Renal Dysfunction.- Myopathy of the Elderly in the Absence of Classical Symptoms of Influenza.- Comment.- Carditis.- Encephalopathy.- Other Neurological Manifestations.- Miscellaneous.- Complications of Influenza.- Bacterial Infections.- Noninfectious Pulmonary Complications.- Complications of Viral Infection of the Respiratory Tract Not Specific for Influenza.- Asthenia and Depression.- Effects of Influenza on the Fetus.- Abortions and Stillbirths.- Teratogenic Effects.- Fetally Induced Neoplastic Disease.- Reye's Syndrome.- Pathogenesis and Pathophysiology of Influenza.- Sequence of Events.- Implantation of Virus in the Respiratory Tract.- Progression of Infection.- Viral Replication, Shedding, and Persistence.- Contribution of Host Response to Disease.- Viremia and Infection of Nonrespiratory Organs.- Pathophysiological Effects of Influenza.- Effects on Respiratory Function.- Effects on Ciliary Function.- In Vivo Effects on Leukocytes.- Polymorphonuclear Leukocytes.- Lymphocytes.- Monocytes and Alveolar Macrophages.- Effects on Host Resistance to Bacterial Infections.- Fever.- The Immunologic Response in Influenza.- Humoral Antibody Response.- Nature and Kinetics of the Response.- The Antigenic Spectrum of Primary Antibody Response in Influenza.- Antibody Response to NA.- Antibody Response to Internal Antigens of the Virus.- Anamnestic Response in Influenza: "Original Antigenic Sin".- Nonspecific Effects of Influenza Virus on Immune Response.- Cell-Mediated Immune Response in Influenza.- Macrophage Response.- Lymphocyte-Mediated Responses.- Helper T Cells.- Cytotoxic T Lymphocytes.- Antibody-Dependent Cell-Mediated Cytotoxicity against Influenza Virus-Infected Cells.- Immunologic Basis of Recovery from Influenza.- The Role of Interferon.- The Role of Antibody in Recovery from Influenza.- Early Cellular Immune Responses and Recovery.- Other Factors That May Influence Recovery.- Modulation of the Cellular Immune Response.- The Importance of an Intact Complement Pathway.- Immunity to Influenza.- Homologous Immunity.- Heterovariant (Intrasubtypic) Immunity.- Heterosubtypic Immunity.- Serum Antibody as a Marker for Immunity in Influenza.- The Pathology of Influenza.- Influenza Virus Pneumonia.- Clinical Pathology of Influenza.- Therapy of Influenza.- Specific Chemotherapy: Amantadine.- Mechanism of Action.- Pharmacology.- Toxicity.- Drug Resistance.- Ribavirin.- Supportive and Physiological Therapy.- Management of Influenza Virus Pneumonia.- References.- 8. The Laboratory Diagnosis of Influenza.- Virus Isolation and Identification.- Animal Inoculation.- Chick Embryos.- Cell Culture.- Primary Cell Culture.- Continuous Cell Lines.- Virus Identification.- Direct Demonstration of Influenza Viruses or Viral Proteins in Patients' Specimens.- Electron Microscopy.- Immunofluorescence.- Enzyme Immunoassay.- Measurement of Specific Antibody Response.- Hemagglutination Inhibition.- Neutralization.- Complement Fixation.- Single Radial Hemolysis.- Enzyme Immunoassay.- Neuraminidase Inhibition.- References.- 9. Animal Influenza: Ecology and Disease.- Ecology of Influenza Viruses.- Distribution of Influenza A Viruses in Nature.- Host Range of Influenza Viruses.- Animals in Which Serially Propagated Infections Occur.- Animals Subject to Sporadic Infection.- Animals Susceptible to Laboratory Infection.- Host Specificity of Influenza Viruses.- Interspecific Transmission.- Man to Animals.- Animals to Man.- Infection of Animals with Influenza B and C Viruses.- Disease in Commonly Infected Species.- Influenza in Swine.- The Viruses.- The Disease.- Epizootiology.- Swine Influenza Virus Infection Outside the United States.- Influenza in Horses.- The Viruses.- Antigenic Variation.- The Disease.- Epizootiology.- Influenza in Domestic Fowl.- Chicken.- The Viruses.- The Disease.- Epizootiology.- Turkey.- The Viruses.- The Disease.- Epizootiology.- Ducks.- The Viruses.- The Disease.- Epizootiology.- Animals Subject to Sporadic Infection.- Epizootic and Enzootic Influenza in Wild Mammals and Birds.- Influenza in Migratory and Other Birds.- Epizootic Influenza in Seals.- Influenza in Laboratory Animals.- References.- IV. Epidemiology, Surveillance, And Control.- 10. The Epidemiology of Influenza.- Influenza Surveillance and the Ascertainment of Infection.- Laboratory Surveillance.- Virus Isolation and Identification.- Serological Surveillance.- Measurements of Morbidity.- Direct Methods.- Indirect Methods.- Impact on Mortality Rates.- Influenza as a Burden on the Public Health.- Pandemic, Epidemic, and Endemic Disease.- Epidemiologic Determinants of Influenza.- Viral.- Antigenic Variation.- Variation in Other Viral Properties.- Host Factors.- Age.- Immune Phenotype.- Host Genotype.- Other Host Factors.- Environmental Factors.- Season and Climate.- Crowding and Infection Density.- Pandemic Influenza.- Pandemics Defined.- Pandemic Determinants.- Pandemicity and the Phenomenon of Viral Disappearance.- Conditions for the Entry of Pandemic Viruses.- Interpandemic Influenza.- Endemic Influenza.- Epidemiology of Influenza B and C.- Influenza B.- Influenza C.- Experimental and Theoretical Epidemiology of Influenza.- Theoretical Epidemiology.- Experimental Epidemiology.- Molecular Epidemiology and Epizootiology of Influenza.- Intraepidemic Viral Heterogeneity.- Reassortment of Influenza A H1N1 and H3N2 Viruses in Humans.- Tracing of an Epidemic (Epizootic) Virus.- Molecular Surveillance.- Evidence of Viral Fixation and Reappearance.- Implications of Molecular Evolution for Influenza Epidemiology:The Case of Influenza C Virus.- The Limitations and Promise of Molecular Epidemiology.- References.- 11. The Control of Influenza.- Vaccines: Licensed and Experimental.- The Immunology of Influenza Vaccination.- Categorical Problems in the Artificial Presentation of Antigen.- Kinetics and Duration of Response to Influenza Vaccines.- Homologous (Variant-Specific) Immunity.- Homosubtypic (Heterovariant) Immunity.- Homotypic (Heterosubtypic) Immunity.- Local versus Systemic Immunity.- Induction of Cellular Immunity by Vaccines.- Vaccine-Induced Response to Internal Viral Proteins.- Host Differences in Immunologic Responses to Vaccine.- The Influence of Vaccine Dosage on Response to Inactivated Influenza Vaccines.- Effects of the Route of Vaccine Administration: Nonreplicating Antigen Vaccines.- The Use of Adjuvants.- Nonreplicating Antigens.- Inactivated Virus.- Subvirion Components: Split and Subunit Vaccines.- New Approaches to the Formulation of Purified Antigen Vaccines.- Submolecular Antigens: Oligopeptides.- Antigenicity of the HA2 Chain of the HA.- Synthetic HA Oligopeptides and Cellular Immunity.- Potential Advantages and Problems of Submolecular and Synthetic Immunogens.- Replicating Antigens.- Mutants.- Empirically Selected Attenuated Viral Vaccines.- Marker-Selected Mutants.- Host range (hr) mutants.- Temperature-sensitive (ts) mutant vaccines.- Cold-adapted (ca) mutants.- Hemagglutinin (HA) inhibitor-resistant mutants.- Wild-Type (Avian/Human) Influenza Virus Reassortants.- Mutant Reassortants.- Wild-Type Laboratory-Adapted hr Mutants.- Wild-Type-ts Mutant Reassortants.- Wild-Type-ca Mutant Reassortants.- Reassortant Mutants.- Live Influenza Virus Vaccines: Summary.- Cloned Influenza Virus HA Gene Replicated and Expressed in Vaccinia.- Comparison of Replicating versus Nonreplicating Influenza Virus Antigens in Vaccination.- Infection-Permissive Immunization with NA-Specific Vaccine: A Diphasic Approach to Influenza Immunization.- Vaccine Standardization.- Complications of Influenza Vaccination.- Intrinsic Viral Cytotoxicity.- Nature of Vaccine Reactions.- Local Reactions.- Systemic Reactions.- Hypersensitivity Reactions.- Neurological Complications of Influenza Vaccination.- Vasculitis.- Effects of Influenza Vaccine on Drug Metabolism.- Untoward Effects of Live-Virus Vaccines.- Chemoprophylaxis.- Specific Recommendations for the Control of Influenza by Vaccine and Chemoprophylaxis.- Target Groups for Vaccination.- Vaccine Recommendations.- Antiviral Agent: Amantadine.- Control of Animal Reservoirs of Infection.- Sociological and Economic Problems in the Control of Influenza.- Implementation of Present Vaccination Policy.- Vaccine Efficacy in Different Populations.- Strategies for Vaccine Administration.- The Perennial Problem in Vaccine Supply.- Mass Vaccination against Pandemic Disease: The Swine Influenza Vaccination Program as Paradigm.- The Influenza Epidemic at Fort Dix, New Jersey in 1976.- Swine Influenza Virus Infection at Fort Dix as a Pandemic Threat.- New Information.- Unknown at That Time.- Known at That Time.- Epidemiologic Precedent.- The National Immunization Program.- The Decision to Undertake Mass Immunization.- Implementation of the Program.- The Lessons of 1976.- About Influenza.- About Mass Immunization: A Retrospective Assessment of the National Immunization Program.- Planning for Future Mass Immunization Programs in Response to Threats of Pandemic Disease.- References.