Three immunologic types of influenza viruses are known, designated A, B, and C. Antigenic changes continually occur within the type A group of influenza viruses and to a lesser degree in the type B group, whereas type C appears to be antigenically stable. Influenza A strains are also known for aquatic birds, chickens, ducks, pigs, horses, and seals. Some of the strains isolated from animals are antigenically similar to strains circulating in the human population. Important Properties of Orthomyxoviruses Virion: Spherical, pleomorphic, 80–120 nm in diameter (helical nucleocapsid) Composition: RNA (1%), protein (73%), lipid (20%), carbohydrate (6%) Genome: Single-stranded RNA, segmented (eight molecules). Proteins: Nine structural proteins, one nonstructural. Envelope: Contains viral hemagglutinin (HA) and neuraminidase (NA) proteins.

Structure & Composition Virus particles have segmented genomes consisting of 7–8 different RNA molecules, each coated by capsid proteins and forming helical nucleocapsids. Viral glycoproteins (hemagglutinin and neuraminidase) protrude as spikes through the lipid envelope.

Classification & Nomenclature : Antigenic differences exhibited by two of the internal structural proteins, the nucleocapsid (NP) and matrix (M) proteins, are used to divide influenza viruses into types A, B, and C. These proteins possess no cross-reactivity among the three types. Antigenic variations in the surface glycoproteins, HA and NA, are used to subtype the viruses. Only type A has designated subtypes. The standard nomenclature system for influenza virus isolates includes the following information: type, host of origin, geographic origin, strain number, and year of isolation. Antigenic descriptions of the HA and the NA are given in parentheses for type A. The host of origin is not indicated for human isolates, eg, A/Hong Kong/03/68(H3N2), but it is indicated for others, eg, A/swine/Iowa/15/30(H1N1).

Structure & Function of Hemagglutinin : The HA protein of influenza virus binds virus particles to susceptible cells and is the major antigen against which neutralizing (protective) antibodies are directed. Variability in HA is primarily responsible for the continual evolution of new strains and subsequent influenza epidemics. Hemagglutinin derives its name from its ability to agglutinate erythrocytes under certain conditions. Antigenic Drift & Antigenic Shift : Influenza viruses are remarkable because of the frequent antigenic changes that occur in HA and NA. Antigenic variants of influenza virus have a selective advantage over the parental virus in the presence of antibody directed against the original strain. This phenomenon is responsible for the unique epidemiologic features of influenza. Other respiratory tract agents do not display significant antigenic variation. The two surface antigens of influenza undergo antigenic variation independent of each other. Minor antigenic changes are termed antigenic drift; major antigenic changes in HA or NA, called antigenic shift, result in the appearance of a new subtype (Figure ). Antigenic shift is most likely to result in an epidemic.

Antigenic drift is due to the accumulation of point mutations in the gene, resulting in amino acid changes in the protein. Sequence changes can alter antigenic sites on the molecule such that a virion can escape recognition by the host's immune system. The immune system does not cause the antigenic variation, but rather functions as a selection force that allows new antigenic variants to expand. A variant must sustain two or more mutations before a new, epidemiologically significant strain emerges.

Antigenic shift reflects drastic changes in the sequence of a viral surface protein, changes too extreme to be explained by mutation. The segmented genomes of influenza viruses reassort readily in doubly infected cells. The mechanism for shift is genetic reassortment between human and avian influenza viruses. Influenza B and C viruses do not exhibit antigenic shift because few related viruses exist in animals. Pathogenesis & Pathology Influenza virus spreads from person to person by airborne droplets or by contact with contaminated hands or surfaces. A few cells of respiratory epithelium are infected if deposited virus particles avoid removal by the cough reflex and escape neutralization by preexisting specific IgA antibodies or inactivation by nonspecific inhibitors in the mucous secretions. Progeny virions are soon produced and spread to adjacent cells, where the replicative cycle is repeated. Viral NA lowers the viscosity of the mucous film in the respiratory tract, laying bare the cellular surface receptors and promoting the spread of virus-containing fluid to lower portions of the tract. Within a short time, many cells in the respiratory tract are infected and eventually killed.

The incubation period from exposure to virus and the onset of illness varies from 1 day to 4 days, depending upon the size of the viral dose and the immune status of the host. Viral shedding starts the day preceding onset of symptoms, peaks within 24 hours, remains elevated for 1–2 days, and then declines over the next 5 days. Infectious virus is very rarely recovered from blood. Influenza infections cause cellular destruction and desquamation of superficial mucosa of the respiratory tract but do not affect the basal layer of epithelium. Complete reparation of cellular damage probably takes up to 1 month. Viral damage to the respiratory tract epithelium lowers its resistance to secondary bacterial invaders, especially staphylococci, streptococci, and Haemophilus influenzae.

Clinical Findings : Influenza attacks mainly the upper respiratory tract. It poses a serious risk for the elderly, the very young, and people with underlying medical conditions such as lung, kidney, or heart problems, diabetes, or cancer. Uncomplicated Influenza : Symptoms of classic influenza usually appear abruptly and include chills, headache, and dry cough, followed closely by high fever, generalized muscular aches, malaise, and anorexia. The fever usually lasts 3–5 days, as do the systemic symptoms. Respiratory symptoms typically last another 3–4 days. The cough and weakness may persist for 2–4 weeks after major symptoms subside. Mild or asymptomatic infections may occur. These symptoms may be induced by any strain of influenza A or B. In contrast, influenza C rarely causes the influenza syndrome, causing instead a common cold illness. Coryza and cough may last for several weeks. Clinical symptoms of influenza in children are similar to those in adults, although children may have higher fever and a higher incidence of gastrointestinal manifestations such as vomiting. Febrile convulsions can occur. Influenza A viruses are an important cause of croup in children under 1 year of age, which may be severe. Finally, otitis media may develop. However, those other agents rarely cause severe viral pneumonia, which is a complication of influenza A virus infection.

Pneumonia : Serious complications usually occur only in the elderly and debilitated, especially those with underlying chronic disease. Pregnancy appears to be a risk factor for lethal pulmonary complications in some epidemics. The lethal impact of an influenza epidemic is reflected in the excess deaths due to pneumonia and cardiopulmonary diseases. Pneumonia complicating influenza infections can be viral, secondary bacterial, or a combination of the two. Increased mucous secretion helps carry agents into the lower respiratory tract. Influenza infection enhances susceptibility of patients to bacterial super infection. This is attributed to loss of ciliary clearance, dysfunction of phagocytic cells, and provision of a rich bacterial growth medium by the alveolar exudate. Bacterial pathogens are most often Staphylococcus aureus, Streptococcus pneumoniae, and H influenzae. Combined viral-bacterial pneumonia is approximately three times more common than primary influenza pneumonia. S aureus coinfection has been reported to have a fatality rate of up to 42%. A molecular basis for a synergistic effect between virus and bacteria may be that some S aureus strains secrete a protease able to cleave the influenza HA, thereby allowing production of much higher titers of infectious virus in the lungs.

Reye's Syndrome : Reye's syndrome is an acute encephalopathy of children and adolescents, usually between 2 and 16 years of age. The mortality rate is high (10–40%). The cause of Reye's syndrome is unknown, but it is a recognized rare complication of influenza B, influenza A, and herpesvirus varicella-zoster infections. There is a possible relationship between salicylate use and subsequent development of Reye's syndrome. The incidence of the syndrome has decreased with the reduced use of salicylates in children with flu-like symptoms. Immunity : Immunity to influenza is long-lived and subtype-specific. Antibodies against HA and NA are important in immunity to influenza, whereas antibodies against the other virus-encoded proteins are not protective. Resistance to initiation of infection is related to antibody against the HA, whereas decreased severity of disease and decreased ability to transmit virus to contacts are related to antibody directed against the NA.

Protection correlates with both serum antibodies and secretory IgA antibodies in nasal secretions. The local secretory antibody is probably important in preventing infection. Serum antibodies persist for many months to years, whereas secretory antibodies are of shorter duration (usually only several months). Antibody also modifies the course of illness. Laboratory Diagnosis : Clinical characteristics of viral respiratory infections can be produced by many different viruses. Consequently, diagnosis of influenza relies on isolation of the virus, identification of viral antigens or viral nucleic acid in the patient's cells, or demonstration of a specific immunologic response by the patient. Isolation and Identification of Virus : Nasal washings, gargles, and throat swabs are the best specimens for viral isolation and should be obtained within 3 days after the onset of symptoms. The sample should be held at 4 °C until inoculation into cell culture, as freezing and thawing reduce the ability to recover virus. However, if storage time will exceed 5 days, the sample should be frozen at –70 °C.

Serology : Antibodies to several viral proteins (hemagglutinin, neuraminidase, nucleoprotein, and matrix) are produced during infection with influenza virus. The immune response against the HA glycoprotein is associated with resistance to infection. Routine serodiagnostic tests in use are based on hemagglutination inhibition (HI) and ELISA. Antigenic Change : All three types of influenza virus exhibit antigenic drift. However, only influenza A undergoes antigenic shift, presumably because types B and C are restricted to humans, whereas related influenza A viruses circulate in animal and bird populations. These animal strains account for antigenic shift by genetic reassortment of the glycoprotein genes. Influenza A viruses have been recovered from many aquatic birds, especially ducks; from domestic poultry, such as turkeys, chickens, geese, and ducks; from pigs and horses; and even from seals and whales.

Influenza outbreaks occur in waves, although there is no regular periodicity in the occurrence of epidemics. The experience in any given year will reflect the interplay between extent of antigenic drift of the predominant virus and waning immunity in the population. The period between epidemic waves of influenza A tends to be 2–3 years; the interepidemic period for type B is longer (3–6 years). Every 10–40 years, when a new subtype of influenza A appears, a pandemic results. Avian Influenza :- Avian influenza ranges from in apparent infections to highly lethal infections in chickens and turkeys. Most influenza infections in ducks are avirulent. Influenza viruses of ducks multiply in cells lining the intestinal tract and are shed in high concentrations in fecal material into water, where they remain viable for days or weeks, especially at low temperatures. It is likely that avian influenza is a waterborne infection, moving from wild to domestic birds and pigs. To date, all human pandemic strains have been reassortants between avian and human influenza viruses. Evidence supports the model that pigs serve as mixing vessels for reassortants as their cells contain receptors recognized by both human and avian viruses (Figure ). School-age children are the predominant vectors of influenza transmission. Crowding in schools favors the aerosol transmission of virus, and children take the virus home to the family.