Etiology

Influenza viruses are members of the family Orthomyxoviridae. They are large, single-stranded RNA viruses with a segmented genome encased in a lipid-containing envelope. The 2 major surface proteins that determine the serotype of influenza, hemagglutinin (HA) and neuraminidase (NA), project as spikes through the envelope. Influenza viruses are divided into three types: A, B, and C. Influenza virus types A and B are the primary human pathogens and cause epidemic disease. Influenza virus type C is a sporadic cause of predominantly upper respiratory tract disease. Influenza virus types A and B are further divided into serotypically distinct strains that circulate on a yearly basis through the population.

Epidemiology

Influenza A viruses have a complex epidemiology involving avian and mammalian hosts that serve as reservoirs for diverse strains with the potential for infecting the human population. The segmented nature of the influenza genome allows reassortment to occur between an animal virus and a human virus when co-infection occurs. Thus, potentially any of 15 HAs and 9 NAs residing in animal reservoirs may be introduced into humans; these influenza A viruses behave epidemiologically as though they were immunologically distinct serotypes without apparent cross-protection. Minor changes within a serotype are termed antigenic drift; major changes in serotype are termed antigenic shift. Migratory birds can spread disease, as illustrated by H5N1 avian influenza. The introduction of novel HA strains has occurred in the Far East with H5N1 and H9N2 viruses, in the Netherlands with H7N7 virus, and in Mexico with the 2009 novel swine-origin H1N1 virus.

The highly virulent avian H5N1 influenza virus remains a potential threat to spread more broadly in the human population. By mid 2009, >400 cases had been documented. It has demonstrated major virulence, with mortality consistently >50% in humans in direct contact with infected poultry, although it has not yet acquired the ability to spread readily from person to person.

The novel H1N1 virus emerged in Mexico in the spring of 2009 and circulated widely enough that by June of 2009 it was declared a global pandemic. In the fall of 2009 it circulated throughout the USA, generally producing mild disease but occasionally resulting in death, especially in pregnant women and in patients with underlying disease. Influenza B virus has much less capacity for major antigenic change and no identified animal reservoir.

The worldwide epidemiology of influenza viruses demonstrates annual spread between the Northern and Southern hemispheres, with the origins of new strains often traced to Asia. When a virus identified by a novel and serologically distinct HA or NA enters the population, there is potential for a pandemic of influenza with excess morbidity and mortality on a global scale in a largely nonimmune population. The most dramatic pandemic in recorded history occurred in 1918, when influenza was estimated to have killed >20 million people. More common is the almost yearly variation in the antigenic composition of the surface proteins, conferring a selective advantage to a new strain and resulting in localized epidemics of disease with hospitalization and mortality greatest in infants, the elderly, and patients with underlying cardiopulmonary disease. Each year’s strain is novel for infants, because they have no pre-existing antibody except for maternally transferred antibody in the first few months of life.

The attack rate and frequency of isolation of influenza are highest in young children. In a typical year as many as 30-50% of children have serologic evidence of infection. Influenza is marked by increased school absenteeism and a yearly peak in sick visits to the pediatrician. Children undergoing primary exposure to an influenza strain have higher levels and more prolonged shedding of the virus than adults, making the former extremely effective transmitters of infection. Influenza is a disease of the colder months of the year in temperate climates. Spread of influenza appears to occur by small-particle aerosol, and transmission through a community is rapid, with the highest incidence of illness occurring within 2-3 wk of introduction. Influenza has been implicated in hospital spread of infection and may complicate the original illness that required hospitalization.

On a country or global basis, 1 or 2 predominant strains spread to create the annual epidemic. Until 2009, influenza type A strains with the H1N1 and H3N2 serotypes and type B strains were co-circulating, and either type could predominate in a given year, making predictions about the serotype and severity of the upcoming influenza season difficult. It is not clear whether the novel H1N1 strain will alter this pattern.

Strain variants are identified by their HA and NA serotypes, by the geographic area from which they were originally isolated, by their isolate number, and by year of isolation. Thus, the seasonal influenza vaccine for 2009-2010 was trivalent, containing A/Brisbane/59/2007 (H1N1)–like, A/Brisbane/10/2007 (H3N2)–like, and B/Brisbane 60/2008–like antigens.

Pathogenesis

Influenza virus attaches to sialic acid residues on cells via the HA and, by endocytosis, makes its way into vacuoles, where with progressive acidification there is fusion to the endosomal membrane and release of the viral RNA into the cytoplasm. The RNA is transported to the nucleus and transcribed. Newly synthesized RNA is returned to the cytoplasm and translated into proteins, which are transported to the cell membrane. Subsequently, viral assembly and budding through the cell membrane take place. In a manner that is not well understood, the packaging usually incorporates the appropriate 10 segments of the genome. A host cell–mediated proteolytic cleavage of the HA occurs at some point in the assembly or release of the virus, which is essential for successful fusion and release from the endosome and amplification of virus titer. In humans, the influenza virus replicative cycle is confined to the respiratory epithelium. With primary infection, virus replication continues for 10-14 days.

Influenza virus causes a lytic infection of the respiratory epithelium with loss of ciliary function, decreased mucus production, and desquamation of the epithelial layer. These changes permit secondary bacterial invasion, either directly through the epithelium or, in the case of the middle ear space, through obstruction of the normal drainage through the eustachian tube. Influenza types A and B have been reported to cause myocarditis, and influenza type B can cause myositis. Reye syndrome can result with the use of salicylates during influenza type B infection (Chapter 353).

The exact immune mechanisms involved in termination of primary infection and protection against re-infection are not well understood but may correspond to the induction of cytokines that inhibit viral replication, such as interferon and tumor necrosis factor. The incubation period of influenza can be as short as 48-72 hr. The extremely short incubation period of influenza and the growth of influenza virus on the mucosal surface pose particular problems for invoking an adaptive immune response. Antigen presentation occurs primarily at mucosal sites acting through the bronchial tract–associated lymphoid tract. The most easily detected humoral response is directed against the HA. High serum antibody levels inhibiting HA activity are generated by inactivated vaccine and correlate with protection. Mucosally produced immunoglobulin A (IgA) antibodies are thought to be the most effective and immediate protective response generated during influenza infection. Unfortunately, detectable IgA antibodies against influenza virus persist for a relatively short period. Because of the short duration of appreciable IgA as well as strain variation, symptomatic re-infection with influenza virus can be seen at intervals of 3-4 yr. Although heterotypic immunity can be demonstrated in the mouse through cell-mediated immune mechanisms directed toward common internal proteins, heterotypic immunity has been more difficult to show in humans.

Clinical Manifestations

Influenza types A and B cause predominantly respiratory illness. The onset of illness is abrupt and is dominated by fever, myalgias, chills, headache, malaise, and anorexia; coryza, pharyngitis, and dry cough are associated features overshadowed by the other systemic signs (Table 250-1). The predominant symptoms may localize anywhere in the respiratory tract, producing an isolated upper respiratory tract illness, croup, bronchiolitis, or pneumonia. More than any other respiratory virus, influenza virus causes systemic signs such as high temperature, myalgia, malaise, and headache. Many of these signs and symptoms may be mediated through cytokine production by the respiratory tract epithelium, because there is no systemic spread of the virus. The typical duration of the febrile illness is 2-4 days. Cough may persist for longer periods, and evidence of small airway dysfunction is often found weeks later.

Table 250-1 RELATIVE FREQUENCY OF SYMPTOMS AND SIGNS DURING CLASSIC INFLUENZA IN OLDER CHILDREN AND ADOLESCENTS