Influenza virus types A and B typically cause more severe symptoms than influenza virus type C. The typical illness is characterized by an abrupt onset (over several hours) of fever, diffuse muscle aches and chills. This is followed within 12 to 36 hours by respiratory signs, such as rhinitis, cough, and respiratory distress. The acute phase usually lasts 3 to 5 days, but a complete return to normal activities may take 2 to 6 weeks. Serious complications, especially pneumonia, are common.
Humans are the major hosts of the influenza viruses, and severe respiratory disease is the pri-mary manifestation of infection. However, influenza A viruses closely related to those preva-lent in humans circulate among many mammalian and avian species. As noted previously, some of these may undergo antigenic mutation or genetic recombination and emerge as new human epidemic strains.
Characteristic influenza outbreaks have been described since the early 16th century, and outbreaks of varying severity have occurred nearly every year. Severe pandemics oc-curred in 1743, 1889–1890, 1918–1919 (the Spanish flu), and 1957 (the Asian flu). These episodes were associated with particularly high mortality; the Spanish flu was thought to have caused at least 20 million deaths. Usually, the elderly and persons of any age group with cardiac or pulmonary disease have the highest death rate.
Direct droplet spread is the most common mode of transmission. Influenza infec-tions in temperate climates tend to occur most frequently during midwinter months. Major epidemics of influenza A usually occur at 2- to 3-year intervals, and influenza B epidemics occur irregularly, usually every 4 to 5 years. The typical epidemic develops over a period of 3 to 6 weeks and can involve 10% of the population. Illness rates may exceed 30% among school-aged children, residents of closed institutions, and industrial groups. One major indicator of influenza virus activity is an abrupt rise in school or in-dustrial absenteeism. In severe influenza A epidemics, the number of deaths reported in a given area of the country often exceeds the number expected for that period. This signifi-cant increase, referred to as excess mortality, is another indicator of severe, widespread illness. Influenza B rarely causes such severe epidemics.
Influenza viruses have a predilection for the respiratory tract, and viremia is rarely detected. They multiply in ciliated respiratory epithelial cells, leading to functional and structural ciliary abnormalities. This is accompanied by a switch-off of protein and nu-cleic acid synthesis in the affected cells, the release of lysosomal hydrolytic enzymes, and desquamation of both ciliated and mucus-producing epithelial cells. Thus, there is sub-stantial interference with the mechanical clearance mechanism of the respiratory tract. The process of programmed cell death (apoptosis) results in the cleavage of complement components, leading to localized inflammation. Early in infection, the primary chemotac-tic stimulus is directed toward mononuclear leukocytes, which constitute the major cellular inflammatory component. The respiratory epithelium may not be restored to nor-mal for 2 to 10 weeks after the initial insult.
The virus particles are also toxic to tissues. This toxicity can be demonstrated by in-oculating high concentrations of inactivated virions into mice, which produces acute inflammatory changes in the absence of viral penetration or replication within cells. Other host cell functions are also severely impaired, particularly during the acute phase of infec-tion. These functions include chemotactic, phagocytic, and intracellular killing functions of polymorphonuclear leukocytes and perhaps of alveolar macrophage activity.
The net result of these effects is that, on entry into the respiratory tract, the viruses cause cell damage, especially in the respiratory epithelium, which elicits an acute inflam-matory response and impairs mechanical and cellular host responses. This damage ren-ders the host highly susceptible to invasive bacterial superinfection. In vitro studies also suggest that bacterial pathogens such as staphylococci can more readily adhere to the sur-faces of influenza virus-infected cells. Recovery from infection begins with interferon production, which limits further virus replication, and with rapid generation of natural killer cells. Shortly thereafter, class I major histocompatibility complex (MHC)–restricted cytotoxic T cells appear in large numbers to participate in the lysis of virus-infected cells and, thus, in initial control of the infection. This is followed by the appearance of local and humoral antibody along with an evolving, more durable cellular immunity. Finally, there is repair of tissue damage.
Although cell-mediated immune responses are undoubtedly important in influenza virus infections, humoral immunity has been investigated more extensively. Typically, patients respond to infection within a few days by producing antibodies directed toward the group ribonucleoprotein antigen, the hemagglutinin, and the neuraminidase. Peak anti-body titer levels are usually reached within 2 weeks of onset and then gradually wane over the following months to varying low levels. Antibody to the ribonucleoprotein appears to confer little or no protection against reinfection. Antihemagglutinin antibody is considered the most protective; it has the ability to neutralize virus on reexposure. However, such immunity is relative, and quantitative differences in responsiveness exist between individuals. Furthermore, antigenic shifts and drifts often allow the virus to subvert the antibody response on subsequent exposures. Antibody to neuraminidase anti-gen is not as protective as antihemagglutinin antibody but plays a role in limiting virus spread within the host.
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