General Concepts

Control

An inactivated virus vaccine is developed each year against the strains most likely to cause disease the next winter. The drugs amantadine and rimantadine can be used for prophylaxis and treatment of influenza A infections.

Introduction

The orthomyxoviruses (influenza viruses) constitute the genus Orthomyxovirus, which consists of three types (species): A, B, and C. These viruses cause influenza, an acute respiratory disease with prominent systemic symptoms. Pneumonia may develop as a complication and may be fatal, particularly in elderly persons with underlying chronic disease. Type A viruses cause periodic worldwide epidemics (pandemics); both types A and B cause recurring regional and local epidemics. Influenza epidemics have been recorded throughout history. In temperate climates, the epidemics typically occur in the winter and cause considerable morbidity in all age groups. An epidemic with associated mortality has occurred in most of the past 100 years. The worst of these was the 1918 pandemic, which caused about 20 million deaths worldwide and about 500,000 deaths in the United States.

Clinical Manifestation

The classic influenza syndrome is a febrile illness of sudden onset, characterized by tracheitis and marked myalgias (Fig. 58-1). Headache, chills, fever, malaise, myalgias, anorexia, and sore throat appear suddenly. The fever rapidly climbs to 101 to 104°F (38.3 to 40.0°C), and respiratory symptoms ensue. A nonproductive cough is characteristic. Sneezing, rhinorrhea, and nasal obstruction are common. Patients may also report photophobia, hoarseness, nausea, vomiting, diarrhea, and abdominal pain. They appear acutely ill and are usually coughing. Minimal to moderate nasal obstruction, nasal discharge, and pharyngeal inflammation may be present. Lung examination is usually negative.

Figure 58-1

A case of acute uncomplicated influenza in a healthy 18-year-old college student.

Most adults ill with an influenza virus infection do not display the classic syndrome described above. Moreover, the influenza syndrome is uncommon in children and is not seen in infants. A given patient may exhibit symptoms including predominantly sneezing, nasal obstruction, and nasal discharge (common cold), nasal obstruction, discharge, and sore throat (upper respiratory illness); sore throat with erythema (pharyngitis); hoarseness (laryngitis); or cough (tracheobronchitis). Fever may be absent.

The respiratory and systemic symptoms of influenza generally last 1 to 5 days. Complications of influenza are many, but an influenza pneumonia, which can be extensive, and secondary bacterial pneumonia are the most common.

Structure

Influenza viruses are spherical and 80 to 120 nm in diameter, although filamentous forms may also occur. Figure 58-2 shows the structure of a type A or B influenza virus. The antisense RNA genome occurs in eight separate segments containing 10 genes. The segments are complexed with nucleoprotein to form a nucleocapsid with helical symmetry. The nucleocapsid is enclosed in an envelope consisting of a lipid bilayer and two surface glycoproteins, a hemagglutinin and a neuraminidase. Because influenza viruses are enveloped, they are readily inactivated by nonpolar solvents and by surface-active agents. The influenza C virus is less well studied, but is known to contain only seven RNA segments and a single surface glycoprotein.

Figure 58-2

Diagrammatic representation of a segment of the influenza virus particle. Hemagglutinin and neuraminidase proteins protrude from the surface of the virus. The orientation of the nucleoprotein—RNA complex in the virion has not been fully elucidated. (more...)

Classification and Antigenic Types

Three influenza virus antigens—the nucleoprotein, the hemagglutinin, and the neuraminidase—are used in classification. The nucleoprotein antigen is stable and is used to differentiate the three influenza virus types. The nucleoprotein antigens of influenza viruses A, B, and C exhibit no serologic cross reactivity. The hemagglutinin and neuraminidase antigens, on the other hand, are variable. Antibody directed against these two surface antigens is responsible for immunity to infection.

Multiplication

Orthomyxovirus replication takes about 6 hours and kills the host cell. The viruses attach to permissive cells via the hemagglutinin subunit, which binds to cell membrane glycolipids or glycoproteins containing N-acetylneuraminic acid, the receptor for virus adsorption. The virus is then engulfed by pinocytosis into endosomes. The acid environment of the endosome causes the virus envelope to fuse with the plasma membrane of the endosome, uncoating the nucleocapsid and releasing it into the cytoplasm. A transmembrane protein derived from the matrix gene (M2) forms an ion channel for protons to enter the virion and destabilize protein binding allowing the nucleocapsid to be transported to the nucleus, where the genome is transcribed by viral enzymes to yield viral mRNA. Unlike replication of other RNA viruses, orthomyxovirus replication depends on the presence of active host cell DNA. The virus scavenges cap sequences from the nascent mRNA generated in the nucleus by transcription of the host DNA and attaches them to its own mRNA. These cap sequences allow the viral mRNA to be transported to the cytoplasm, where it is translated by host ribosomes. The nucleocapsid is assembled in the nucleus.

Virions acquire an envelope and undergo maturation as they bud through the host cell membrane. During budding, the viral envelope hemagglutinin is subjected to proteolytic cleavage by host enzymes. This process is necessary for the released particles to be infectious. Newly synthesized virions have surface glycoproteins that contain N acetylneuraminic acid as a part of their carbohydrate structure, and thus are vulnerable to self-agglutination by the hemagglutinin. A major function of the viral neuraminidase is to remove these residues.

Pathogenesis

Influenza virus is transmitted from person to person primarily in droplets released by sneezing and coughing. Some of the inhaled virus lands in the lower respiratory tract, and the primary site of disease is the tracheobronchial tree, although the nasopharynx is also involved (Fig. 58-3). The neuraminidase of the viral envelope may act on the N-acetylneuraminic acid residues in mucus to produce liquefaction. In concert with mucociliary transport, this liquified mucus may help spread the virus through the respiratory tract. Infection of mucosal cells results in cellular destruction and desquamation of the superficial mucosa. The resulting edema and mononuclear cell infiltration of the involved areas are accompanied by such symptoms as nonproductive cough, sore throat, and nasal discharge. Although the cough may be striking, the most prominent symptoms of influenza are systemic: fever, muscle aches, and general prostration. Viremia is rare, so these systemic symptoms are not caused directly by the virus. Circulating interferon is a possible cause: administration of therapeutic interferon causes systemic symptoms resembling those of influenza.

Figure 58-3

Pathogenesis of influenza.

Current evidence indicates that the extent of virus-induced cellular destruction is the prime factor determining the occurrence, severity, and duration of clinical illness. In an uncomplicated case, virus can be recovered from respiratory secretions for 3 to 8 days. Peak quantities of 10⁴ to 10⁷ infectious units/ml are detected at the time of maximal illness. After 1 to 4 days of peak shedding, the titer begins to drop, in concert with the progressive abatement of disease.

Occasionally—particularly in patients with underlying heart or lung disease—the infection may extensively involve the alveoli, resulting in interstitial pneumonia, sometimes with marked accumulation of lung hemorrhage and edema. Pure viral pneumonia of this type is a severe illness with a high mortality. Virus titers in secretions are high, and viral shedding is prolonged. In most cases, however, pneumonia associated with influenza is caused by bacteria, principally pneumococci, staphylococci, and Gram-negative bacteria. These bacteria can invade and cause disease because the preceding viral infection damages the normal defenses of the lung.

Host Defenses

The immune mechanisms responsible for recovery from influenza have not been clearly delineated. Several mechanisms probably act in concert. Interferon appears in respiratory secretions shortly after viral titers reach their peak level, and may play a role in the subsequent reduction in viral shedding. Antibody usually is not detected in serum or secretions until later in recovery or during convalescence; nevertheless, local antibody appears responsible for the final clearing of virus from secretions. T cells and antibody-dependent cell-mediated cytotoxicity also participate in clearing the infection.

Antibody is the primary defense in immunity to reinfection. IgG antibody, which predominates in lower respiratory secretions, appears to be the most important. The IgG in these secretions is derived from the serum, which accounts for the close correlation between serum antibody titer and resistance to influenza. IgA antibody, which predominates in upper respiratory secretions, is less persistent than IgG but also contributes to immunity.

Only antibody directed against the hemagglutinin is able to prevent infection. A sufficient titer of anti-hemagglutinin antibody will prevent infection. Lower titers of anti-hemagglutinin antibody lessen the severity of infection. Anti-hemagglutinin antibody administered after an infection is under way reduces the number of infectious units released from infected cells, presumably because the divalent antibody aggregates many virions into a single infectious unit. Antibody directed against the neuraminidase also reduces the number of infectious units (and thus the intensity of disease), presumably by impairing the action of neuraminidase against N-acetylneuraminic acid residues in the virion envelope and thus promoting virus aggregation. Antibody directed against nucleoprotein has no effect on virus infectivity or on the course of disease.

Immunity to an influenza virus strain lasts for many years. Recurrent cases of influenza are caused primarily by antigenically different strains.

Epidemiology

A community experiences an influenza epidemic every year. Figure 58-4 shows the course of a typical epidemic of type A influenza in an urban community. In the initial phases of an epidemic, infection and illness appear predominantly in school-aged children, as indicated by a sharp rise in school absences, physician visits, and pediatric hospital admissions. These children bring the virus into the home, where preschool children and adults acquire infection. Infection and illness in adults are reflected in industrial absenteeism, adult hospital admissions, and an increase in mortality from influenza-related pneumonia. The epidemic generally lasts 3 to 6 weeks, although the virus is present in the community for a variable number of weeks before and after the epidemic. The highest attack rates during type A epidemics are in children 5 to 9 years old, although the rate is also high in preschool children and adults. Influenza B epidemics exhibit a similar pattern, except that the attack rates in preschool children and adults usually are lower and the epidemic may not cause an increase in mortality over the expected number of deaths (“excess mortality”).

Figure 58-4

Correlation of nonvirologic indices of epidemic influenza with the number of isolates of influenza A/Victoria virus according to week in Houston during 1976. (Industrial absenteeism is indicated by the percentage with respiratory complaints.) (From Glezen (more...)

Although influenza virus types A and B (and probably C) cause illness every winter, an epidemic is usually caused by only one variant. The constellation of factors that precipitate an epidemic are not fully understood, but the most important is a population susceptible to the circulating strains. Influenza can recur despite the development of immunity because type A and B viruses are proficient at altering their surface antigens and thus at generating strains that evade the existing immunity. Influenza strains are constantly appearing to which part or all of the human population is susceptible.

Influenza epidemics are of two types. Yearly epidemics are caused by both type A and type B viruses. The rare, severe influenza pandemics are always caused by type A virus. Two different mechanisms of antigenic change are responsible for producing the strains that cause these two types of epidemic. A major change in one or both of the surface antigens—a change that yields an antigen showing no serologic relationship with the antigen of the strains prevailing at the time—is called antigenic shift. Changes of this magnitude have been demonstrated in type A virus only and produce the strains responsible for influenza pandemics. Repeated minor antigenic changes, on the other hand, which generate strains that retain a degree of serologic relationship with the currently prevailing strain, are called antigenic drift. Antigenic drift occurs in both type A and type B influenza viruses and is responsible for the strains that cause yearly influenza epidemics. When persons are reinfected with drift viruses, the serum antibody responses to the surface antigens that are shared with earlier strains to which the person has been exposed are frequently stronger and of greater avidity than are the responses to the new antigens. This phenomenon, which has been called “original antigenic sin,” is sometimes useful in serologic diagnosis.

Antigenic drift represents selection for naturally occurring variants under the pressure of population immunity. The completely novel antigens that appear during antigenic shift, in contrast, are acquired by gene reassortment. The donor of the new antigens is probably an animal influenza virus. Type A viruses have been identified in pigs, horses, and birds, and animal influenza viruses possessing antigens closely related to those of human viruses have been described. Fourteen distinct hemagglutinin and nine neuraminidase antigens are known. Since continued surveillance of animal influenza viruses in recent years has failed to discover new antigens, these may represent the full variety of major influenza virus surface antigens (subtypes).

Since the initial isolation of influenza viruses from swine in 1931 and from humans in 1933, the emergence and prevalence of human antigenic strains have been monitored. Table 58-1 shows the current classification and years of prevalence of the human viruses. New subtypes that arise spread around the world along transportation routes. A new virus can seed a population during the “off season” and may cause localized outbreaks, but epidemics generally do not begin until after school opens in the fall or during the succeeding winter.

Table 58-1

Classification of Human Influenza Viruses ^a.

Diagnosis

A diagnosis of influenza is suggested by the clinical picture of sudden onset of fever, malaise, headache, marked muscle aches, sore throat, nonproductive cough, and coryza. When a syndrome resembling influenza occurs in the winter in an adult (the etiologies of illnesses of this type are more complex in children), an influenza virus is a likely cause. If an epidemic of febrile respiratory disease is known to be under way in the community, the diagnosis is yet more likely. Definitive diagnosis, however, relies on detecting either the virus or a significant rise in antibody titer between acute phase and convalescent-phase sera.

A rapid specific diagnosis of influenza may be obtained by demonstrating viral antigens in cells obtained from the nasopharynx in immunostaining tests such as immunofluorescence or in enzyme immunoassays (ELISA) employing respiratory secretions. Influenza virus is usually isolated from respiratory secretions by being grown in tissue cultures or chick embryos. Virus growth in tissue cultures is detected by testing for hemadsorption: red cells are added to the culture and adhere to virus budding from infected cells. If the culture tests positive, serologic tests with specific antisera may be used to identify the virus. In the chick embryo culture method, fluid from the amniotic or allantoic cavity of chick embryos is tested for the presence of newly formed viral hemagglutinin; the virus in positive fluids is then identified by hemagglutination inhibition tests with specific antisera. Finally, a rise in serum antibody titer between acute-phase and convalescent-phase sera can be identified by various tests, of which complement fixation, hemagglutination inhibition, and immunodiffusion (using specific viral antigens) are the most common. None of these techniques will identify all infections.

Control

References

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