Influenza Viruses

James D. Cherry

Influenza viruses cause acute respiratory infections that usually occur in outbreaks or epidemics. In contrast to all other respiratory viral infections [except severe acute respiratory syndrome (SARS)] that occur in outbreaks, acute febrile illnesses occur in both adults and children. Influenza viral infections in children are associated with considerable morbidity and mortality, and the spectrum of clinical illness is broad. Influenza outbreaks and epidemics occur in birds, horses, pigs, and aquatic mammals, in addition to humans.

Influenza viruses are orthomyxoviruses. Three major antigenic types (A, B, and C) and multiple antigenic subtypes have been identified.

Influenza viruses are irregular, spherical particles 80 to 120 nm in diameter. The surface is composed of numerous hemagglutinin and neuraminidase “spikes.” Inside the virus is a lipid bilayer, a matrix protein, and an RNA nucleocapsid.

Four important antigenic components have been described. The nuclear protein and matrix protein are antigenically type-specific and stable. The nuclear protein is the antigenic basis for typing strains as A, B, or C. Hemagglutinin and neuraminidase antigens are subtype-specific and variable. Fifteen different hemagglutinin subtypes (H1 to H15) and nine neuroaminidase subtypes (N1 to N9) occur in nature. Each of these subtypes has the potential to combine through genetic reassortment to yield a different viral strain. However, since 1874, only three separate hemagglutinins, H1, H2, and H3, and two separate neuraminidases, N1 and N2, have been recognized in influenza A viruses causing epidemics in humans. Variation in these two antigens (hemagglutinin and neuraminidase) is the basis for antigenic drift and shift in the prevalent viruses. Drift implies a minor change in the hemagglutinin or the neuraminidase without a change in subtype; shift implies a major
change in either hemagglutinin or neuraminidase or both antigens, resulting in a change in subtype. Antigenic drift occurs in influenza A and B viruses, but shift occurs only in influenza A.

In the laboratory, influenza viruses can be cultivated in embryonated chicken eggs, in the MDCK cell line, and in primary monkey kidney tissue cultures.

Nomenclature for the classification of influenza virus strains specifies type, host (for strains of animal origin), geographic source, strain number, and year of isolation. To this, the code designations of hemagglutinin and neuraminidase subtypes are appended.

For example, recent strains that are included in the 2005–2006 vaccines are A/California/7/2004 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Shanghai/361/2002-like.

EPIDEMIOLOGY

Pandemics of influenza caused by different influenza A subtypes occurred in 1874, 1889, 1900, 1918, 1933, 1946, 1957, 1968, and 1977. The 1918 pandemic resulted in 20 million deaths worldwide. Pandemics of influenza A result from antigenic shift. Wild aquatic birds are thought to be the influenza A virus reservoir in nature from which transmission to poultry, pigs, and other mammals occurs. Subsequently, influenza A viruses can be transmitted from pigs and poultry to humans. The pandemics of 1957 and 1968, associated with genetic shifts, were caused by reassortant influenza viruses that likely were generated in pigs. In more recent years, extensive outbreaks of influenza A infections have occurred in domestic poultry in many countries. The types of virus involved have been H7N7, H5N1, H9N2, H7N3, and H7N2. Transmission in these outbreaks has, on occasion, occurred directly from birds to humans. Fortunately, as yet, these viruses have not spread in the human populations. However, it is soon expected that human infection will result in genetic reassortment between a circulating avian strain and a circulating human strain, which will lead to a worldwide pandemic in humans with a virus having the hemagglutinin and neuroaminidase of an avian strain.

After pandemic influenza of a new subtype, epidemics of generally lesser intensity occur approximately every 2 to 3 years in association with antigenic drift. Outbreaks of influenza B are more variable and occur at roughly 4- to 7-year intervals, and these epidemics are the result of antigenic drift. Infection with influenza C virus is common in children, but the epidemiologic pattern of this virus is not determined.

Populated areas generally experience some influenza viral activity each year. Epidemics and outbreaks usually occur at times of cooler weather; in the tropics, epidemic disease usually occurs during the rainy season. The highest attack rate of influenza usually occurs in children, followed by secondary peaks of illness in adult populations. Case-fatality rates are greatest in infants and the elderly. Influenza is more likely to be fatal in persons with preexisting heart disease, chronic pulmonary disorders, diabetes mellitus, chronic renal disease, neuromuscular disorders, and neoplasms.

Influenza is spread from person to person via the respiratory route. The most common mechanism is inhalation of large airborne particles produced by coughing and sneezing. Spread also may occur by direct or indirect contact with fine-particle aerosols.

PATHOGENESIS

The major site of infection is the ciliated epithelium of the respiratory tract. Extensive necrosis of nasal and tracheal ciliated cells occurs as early as the first day after the onset of symptoms. It is followed by edema and infiltration with lymphocytes, histiocytes, plasma cells, and polymorphonuclear cells. Repair of affected mucous membranes, indicated by mitoses in the surviving basal cells, begins by the third to fifth day of illness. A pseudometaplastic response of undifferentiated epithelium that reaches a maximum at 9 to 15 days after onset of infection occurs; thereafter, ciliary function and mucus production reappear.

Secondary bacterial infection is a common occurrence. More extensive inflammatory cell infiltration and destruction of the basal cell layer and basement membrane are seen, and delayed regeneration of the ciliated epithelium results.

Pneumonia may occur as a result of primary influenza viral infection, bacterial superinfection, or combined bacterial-viral infection. Although influenza is predominantly an infection of the respiratory tract, the heart, brain, and lymphoid tissues sometimes are involved in fatal cases. Specifically, focal and diffuse myocarditis, mediastinal lymph node disorganization and necrosis, and diffuse cerebral edema have been observed. In addition, Reye syndrome (diffuse encephalopathy and fatty degeneration of the liver) is a complication of influenza, particularly that caused by type B virus in children.

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