Orthomyxoviridae

Influenza epidemics have been recorded throughout history. In temperate climates, the epidemics typically occur in winter and cause significant morbidity in all age groups. They have occurred almost annually during the last 100 years. The worst epidemic was the 1918 pandemic, which caused about 20 million deaths worldwide and about 500,000 deaths in the United States.

The family Orthomyxviridae forms the genus Influenza virus, which consists of three species (Influenza virusA/B/C):

Influenzavirus A (highest pathogenicity to humans).

• Influenza virus A variant (H1N1) - causative agent of the Spanish flu (1918)
• Influenza virus A variant (H1N1) - causative agent of swine flu (2009)
• Influenza virus A variant (H2N2) - agent of Asian influenza (1957)
• Influenza virus A variant (H3N2) - agent of Hong Kong flu (2009)
• (avian) influenza virus A variant (H5N1), highly pathogenic avian influenza virus (HPAIV), increasingly pathogenic to humans.
• (avian) influenza virus A variant (H7N2), low pathogenic avian influenza virus (LPAIV)
• (avian) influenza virus A variant (H7N3), low pathogenic avian influenza virus (LPAIV)
• (avian) influenza virus A variant (H7N7), highly pathogenic avian influenza virus (HPAIV)
• (avian) influenza virus A variant (H9N2), low pathogenic avian influenza virus (LPAIV)

Influenzavirus B (clinically indistinguishable from influenza virus A)

Influenza virusC (rare occurrence)

These viruses cause influenza, an acute respiratory illness with pronounced systemic symptoms. Pneumonia may develop as a complication and may be fatal, especially in the elderly with underlying chronic disease. Type A viruses cause periodic worldwide epidemics (pandemics), species A and B cause recurrent local epidemics.

Structure: Orthomyxviridae are viruses with negative-stranded RNA genomes. They are spherical in shape and range from 80 to 120 nm in diameter, although filamentous forms may occur. The antisense RNA genome occurs in 8 single-stranded segments (gRNA) containing 10 genes. The segments are complexed with the nucleoprotein (NP) to form a nucleocapsid with helical symmetry. Associated with each segment is the polymerase complex (PA, PB1, PB2), which is responsible for transcription and replication of the gene segments. The nucleocapsid is surrounded by an envelope (enveloped virus) consisting of a lipid bilayer. The inner lipid layer is lined with the matrix protein M1. Inside the envelope there is another matrix protein M2, which has a channel function for ions (especially H+ ions). Furthermore, the envelope contains trimers of hemagglutinin (HA), which are necessary for the adsorption of the virus to its cellular receptor, and tetramers of the enzyme neuroaminidase (NA). NA can destroy cellular receptors for the virus to allow virus particles budding from the cell to detach from their cellular receptor. Because influenza viruses are enveloped, they are easily inactivated by nonpolar solvents and by surface-active agents. Influenza C virus is less well studied, but is known to contain only seven RNA segments and a single surface glycoprotein.

Classification and antigen types: Three antigens of influenza virus - the nucleoprotein, hemagglutinin and neuraminidase - are used for classification. The nucleoprotein antigen is stable and is used to distinguish the three influenza virus types. The nucleoprotein antigens of influenza viruses A, B, and C do not exhibit serologic cross-reactivity. In contrast, the hemagglutinin and neuraminidase antigens are variable. Antibodies directed against these two surface antigens are responsible for immunity to infection.

Replication: Repl ication of orthomyxovirus takes about 6 hours and kills the host cell. The virus adsorbs to N-acteyl neuraminidase-bearing receptors of permissive cells with hemagglutinin and is taken up into endosomes by pinocytosis. The acidic environment of the endosome causes the viral envelope to fuse with the plasma membrane of the endosome, stripping the nucleocapsid and releasing it into the cytoplasm. The nucleocapsid can now be transported into the nucleus, where the genome is transcribed to viral mRNA by viral enzymes. In contrast to the replication of other RNA viruses, replication of orthomyxovirus occurs in the nucleus. It is dependent on the presence of active host cell DNA. The virus intercepts cap sequences from nascent mRNA produced in the nucleus by transcription of host DNA and attaches them to its own mRNA. These cap sequences allow transport of the viral mRNA into 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 hemagglutinin of the viral envelope is proteolytically cleaved 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 part of their carbohydrate structure and are therefore susceptible to self-agglutination by hemagglutinin. A major function of viral neuraminidase is to remove these residues.

Genetic reassortment: Because the genome of influenza virus is segmented, genetic reassortment can occur when a host cell is simultaneously infected with viruses from two different parental strains. For example, when a cell is infected with two strains of type A virus, some of the progeny virions contain a mixture of genome segments from the two strains. This process of genetic reassortment is probably responsible for the periodic appearance of the new type A strains that cause influenza pandemics.

Transmission: Influenza virus is transmitted from person to person mainly in droplets released by sneezing and coughing. Some of the inhaled virus ends up in the lower respiratory tract, and the primary site of disease is the tracheobronchial tree, although the nasopharynx is also involved. The neuraminidase of the viral envelope can act on the N-acetylneuraminic acid residues in the mucus and cause liquefaction. In concert with mucociliary transport, this liquefied mucus can help spread the virus through the respiratory tract. Infection of the mucosal cells leads to cell destruction and desquamation of the superficial mucosa. The resulting edema and mononuclear cell infiltration of the affected areas are accompanied by symptoms such as nonproductive cough, sore throat, and rhinorrhea. Although the cough may be prominent, the most prominent symptoms of influenza are systemic: fever, muscle aches, and general fatigue. Viremia is rare, so these systemic symptoms are not directly caused by the virus. Circulating interferon is a possible cause: Administration of therapeutic interferon causes systemic symptoms similar to those of influenza.

Pathogenesis of influenza: Current evidence suggests that the extent of virus-induced cell destruction is the most important factor determining the onset, severity, and duration of clinical disease. In an uncomplicated case, virus can be recovered from respiratory secretions for 3 to 8 days. Peak levels of 104 to 107 infectious units/ml are detected at the time of maximum illness. After 1 to 4 days of peak shedding, the titer begins to decline in line with the progressive resolution of the disease. Occasionally-especially in patients with underlying cardiac or pulmonary disease-the infection may extensively invade the alveoli, resulting in interstitial pneumonia, sometimes with marked accumulation of pulmonary hemorrhage and edema. Purely viral pneumonia of this type is a severe disease with high mortality. The viral titres in the secretions are high and viral elimination is protracted. In most cases, however, pneumonia associated with influenza is caused by bacteria, especially pneumococci, staphylococci, and gram-negative bacteria. These bacteria can enter as "free riders" of the viral infection and cause the disease.

Host defense: The immune mechanisms responsible for recovery from influenza are not clearly understood. It is likely that several mechanisms act together. Interferon appears in respiratory secretions shortly after viral titers peak and may play a role in the subsequent reduction of viral shedding. Antibodies are usually detected in serum or secretions later in recovery or during convalescence; nevertheless, local antibodies appear to be responsible for the final clearance of virus from secretions. T cells and antibody-dependent cell-mediated cytotoxicity are also involved in the clearance of infection. Antibodies are the primary defense in immunity to reinfection. IgG antibodies predominant in lower respiratory tract secretions appear to be the most important. The IgG in these secretions is derived from serum, which explains the close correlation between serum antibody titers and resistance to influenza. IgA antibodies, which predominate in upper respiratory tract secretions, are less persistent than IgG but also contribute to immunity.

Only antibodies directed against hemagglutinin are able to prevent infection. A sufficient titer of anti-hemagglutinin antibodies prevents infection. Lower titers of anti-hemagglutinin antibodies decrease the severity of infection. Anti-hemagglutinin antibodies administered after an ongoing infection reduce the number of infectious units released from infected cells, presumably because the divalent antibody aggregates many virions into a single infectious unit. An antibody directed against 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 thereby promoting viral aggregation. Antibody directed against nucleoprotein has no effect on viral infectivity or disease progression. Immunity to an influenza virus strain lasts for many years. Recurrent influenza cases are mainly caused by antigenically distinct strains.

X-any community experiences an influenza epidemic each year. In the early stages of an epidemic, infection and illness occur primarily in school-age children, as evidenced by a sharp increase in school absenteeism, doctor visits, and admissions to children's hospitals. Children bring the virus home with them, where preschool-aged children and adults become infected. Adult infection and illness is reflected in industry absenteeism, adult hospitalizations, and an increase in mortality from influenza-related pneumonia. The epidemic usually 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 rates of illness during type A epidemics occur in children 5 to 9 years of age, although rates are also high in preschool-aged children and adults. Influenza B epidemics show a similar pattern, except that attack rates are usually lower in preschool children and adults and the epidemic may not cause an increase in mortality above the expected number of deaths ("excess mortality").

Although influenza virus types A and B (and probably C) cause illness each winter, an epidemic is usually caused by only one variant. The constellation of factors that trigger an epidemic is not fully known, but the most important is a population susceptible to the circulating strains. Influenza can recur despite the development of immunity because the type A and B viruses alter their surface antigens to produce strains that escape existing immunity. Influenza strains to which some or all of the human population is susceptible continually emerge.

Two different mechanisms of antigenic change are responsible for the emergence of the strains that cause these epidemics.

A major change in one or both of the surface antigens - a change that produces an antigen that bears no serological relationship to the antigen of the predominant strains at that time - is termed antigenic shift . Changes of this magnitude have only been detected in type A virus and result in the strains responsible for influenza pandemics. Repeated minor antigenic changes, on the other hand, which produce strains that maintain some serological relationship with the current predominant strain, are referred to as antigenic drift. Antigenic drift occurs in both type A and type B influenza viruses and is responsible for the strains that cause annual influenza epidemics. When individuals are reinfected with drift viruses, serum antibody responses to surface antigens common to previous strains to which the individual was exposed are often stronger and of greater avidity than responses to the new antigens. This phenomenon, which has been termed "original antigenic sin," is sometimes useful in serologic diagnosis.

Antigenic drift represents selection for naturally occurring variants under the pressure of population immunity. In contrast, the completely novel antigens that occur in antigenic shift are acquired by gene reassortment. The donor of the novel antigens is probably an animal influenza virus. Type A viruses have been identified in pigs, horses, and birds, and animal influenza viruses have been described that possess antigens closely related to those of human viruses. Fourteen different hemagglutinin and nine neuraminidase antigens are known. As no new antigens have been discovered during the continuous surveillance of animal influenza viruses in recent years, these may represent the full diversity of the major influenza virus surface antigens (subtypes).

Classic influenza syndrome is a variable, febrile illness with sudden onset, characterized by tracheitis, headache, chills, fever, malaise, myalgias, anorexia. The fever rises rapidly to 38.3 to 40.0 °C, and respiratory symptoms appear. An unproductive cough is characteristic. Rhinorrhea and nasal obstruction are common. Influenza syndrome is uncommon in children and is not seen in infants. Respiratory and systemic symptoms of influenza generally last 1 to 5 days.

The diagnosis of influenza is made by the clinical picture of sudden onset of fever, malaise, headache, pronounced muscle pain, sore throat, non-productive cough and rhinitis. When a flu-like syndrome occurs in an adult in winter (the etiology of illnesses of this type is more complex in children), an influenza virus is the likely cause. If there is a known epidemic of febrile respiratory illness in the community, the diagnosis is even more likely. However, the definitive diagnosis is based on the detection of either the virus or a significant increase in antibody titer between the acute phase and convalescent phase sera.

Inactivated influenza virus vaccines have been used to prevent influenza for about 40 years. The viruses for the vaccine are grown in chicken embryos, inactivated with formalin, purified to some degree, and adjusted to a dosage known to elicit an antibody response in most people. A particular vaccine contains the strains of virus types A and B that are thought to be most likely to cause epidemics the following winter. The vaccine is administered parenterally in the fall; one or two doses are required, depending on the population's experience with immunity to related antigens. Protection against disease varies from 50 to 90 percent in the civilian population and from 70 to 90 percent in the military population. Local and systemic reactions to the vaccine are mild and occur in the first one to two days after vaccination. During the 1976 nationwide swine flu vaccination in the United States, an increased risk of developing Guillain-Barre syndrome was associated with vaccination; however, this association has not been noted since. Annual use of inactivated influenza virus vaccine is currently recommended in the United States for persons at increased risk of developing pneumonia and their close relatives. Attenuated live vaccines are being developed as alternatives to the inactivated vaccine.

The synthetic drugs amantadine and rimantadine hydrochloride are effective in preventing infection and disease from type A viruses, but not from type B viruses. The drugs interfere with viral envelopment and transport by blocking the M2 transmembrane ion channel. The drugs prevent about 50 percent of infections and about 67 percent of illnesses under natural conditions. When given over 10 days to household contacts of a person with influenza, the drugs protect up to 80 percent of people from getting sick. Side effects are more severe with amantadine and are limited primarily to the central nervous system.

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