Influenza

My lifetime encompasses the postwar subsidence in the early 1920s of the greatest influenza pandemic in history, direct encounters with FM1 virus at Fort Mon­ mouth in 1947, the care of influenza patients in the 1950s, the pursuit of the in­ fluenza virus through the modern pandemics of 1957 and 1968, and a present in which the genes of the virus have dissembled in the DNA of vaccinia virus and Escherichia coli through the wand of "high tech. " If my corpus could be fossilized for archival and archaeological purposes, it would be found to contain immune cells branded with the imprint of the "swine" influenza virus of post-1918 and brain cells no less imprinted with memories of the abortive return of its descendant during America's bicentennial. But before that unlikely event, I wanted to try to make some sense out of this baffling dis­ ease and its viruses-expecting no definitive revelations but hoping for a sharper definition of problems. Hence this book. It is an audacious act in these days of specialization to essay a book such as this singlehandedly, but I have done so for selfish reasons. I wanted to reexam­ ine old questions about the nature of influenza and its epidemics in the light of the dazzling advances in molecular biology of the past few years. No virus has been better studied, but few diseases are less well understood.

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.