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Clinical Features of Influenza Influenza, commonly called "the flu," is caused by viruses that infect the respiratory tract. Compared with most other viral respiratory infections, such as the common cold, influenza infection often causes a more severe illness. Typical clinical features of influenza include fever (usually 100oF to 103oF in adults and often even higher in children) and respiratory symptoms, such as cough, sore throat, runny or stuffy nose, as well as headache, muscle aches, and often extreme fatigue. Although nausea, vomiting, and diarrhea can sometimes accompany influenza infection, especially in children, gastrointestinal symptoms are rarely prominent. The term "stomach flu" is a misnomer that is sometimes used to describe gastrointestinal illnesses caused by other microorganisms. Most people who get the flu recover completely in 1 to 2 weeks, but some people develop serious and potentially lifethreatening medical complications, such as pneumonia. In an average year, influenza is associated with about 20,000 deaths nationwide and many more hospitalizations. Flu related complications can occur at any age; however,the elderly and people with chronic health problems are much more likely to develop serious complications after influenza infection than are younger, healthier people. The Influenza Viruses Influenza viruses are divided into three types, designated A, B, and C. Influenza types A and B are responsible for epidemics of respiratory illness that occur almost every winter and are often associated with increased rates for hospitalization and death. Influenza type C differs from types A and B in some important ways. Type C infection usually causes either a very mild respiratory illness or no symptoms at all; it does not cause epidemics and does not have the severe public health impact that influenza types A and B do. Efforts to control the impact of influenza are aimed at types A and B, and the remainder of this discussion will be devoted only to these two types. Influenza viruses continually change over time, usually by mutation. This constant changing enables the virus to evade the immune system of its host, so that people are susceptible to influenza virus infection throughout life. This process works as follows: a person infected with influenza virus develops antibody against that virus; as the virus changes, the "older" antibody no longer recognizes the "newer" virus, and reinfection can occur. The older antibody can, however, provide partial protection against reinfection. Currently, three different influenza strains circulate worldwide: two type A viruses and one type B. Type A viruses are divided into subtypes based on differences in two viral proteins called the hemagglutinin (H) and the neuraminidase (N). The current subtypes of influenza A are designated A(H1N1) and A(H3N2). Influenza type A viruses undergo two kinds of changes. One is a series of mutations that occur over time and cause a gradual evolution of the virus. This is called antigenic "drift." The other kind of change is an abrupt change in the hemagglutinin and/or the neuraminidase proteins. This is called antigenic "shift." In this case, a new subtype of the virus suddenly emerges. Type A viruses undergo both kinds of changes; influenza type B viruses change only by the more gradual process of antigenic drift. Natural History of Human Influenza Influenza A and B viruses continually undergo antigenic drift. This process accounts for most of the changes that occur in the viruses from one influenza season to another. Antigenic shift occurs only occasionally. When it does occur, large numbers of people, and sometimes the entire population, have no antibody protection against the virus. This results in a worldwide epidemic, called a pandemic. During this century, pandemics occurred in 1918, 1957, and 1968, each of which resulted in large numbers of deaths, as noted below. Mortality associated with pandemics: 1918-19 "Spanish flu" A(H1N1) -- Caused the highest known influenza-related mortality: approximately 500,000 deaths occurred in the United States, 20 million worldwide. 1957-58 "Asian flu" A(H2N2) -- 70,000 deaths in the United States. 1968-69 "Hong-Kong flu" A(H3N2) -- 34,000 deaths in the United States. The emergence of the "Hong Kong flu" in 1968-69 marked the beginning of the type A(H3N2) era. When this virus first emerged, it was associated with lower mortality than that caused by the two previous pandemic viruses. Several possible reasons for this lower mortality have been hypothesized. First, only the hemagglutinin changed from the "Asian" strain [type A(H2N2)]; the neuraminidase (N2) stayed the same, and therefore existing antibody could be expected to offer some protection. A second possibility is suggested by evidence that a virus with a similar hemagglutinin may have circulated from the late 1890s to the early 1900s. If this were the case, people who were in their sixties and older in 1968 may have had some protection from antibody acquired in their youth. There are still many things about influenza viruses that are not understood. Although the newly emerged type A(H3N2) virus caused only moderate mortality in 1968 compared with other pandemic viruses, this virus has continued to cause substantial mortality as it has continued to circulate and evolve. In the years since its emergence, type A(H3N2) epidemics have caused approximately 400,000 deaths in the United States alone, and more than 90% of these deaths have occurred among elderly people. Of the influenza viruses currently in worldwide circulation, A(H3N2) still has the most severe overall impact. The other influenza A subtype currently in circulation, type A(H1N1), also has an interesting history. After the devastating pandemic of 1918-19, this subtype continued to circulate and undergo antigenic drift. It periodically caused large epidemics, but never on the scale of the 1918-19 pandemic. When the "Asian" strain [(A(H2N2)] emerged in 1957, the A(H1N1) viruses disappeared (as did the A(H2N2) viruses when the "Hong Kong" virus emerged in 1968). In 1977, the A(H1N1) viruses reappeared and have cocirculated with A(H3N2) viruses ever since. However, the impact of A(H1N1) has been different during its most recent appearance. The virus that reappeared in 1977 was virtually identical to an A(H1N1) virus that circulated in 1950. Therefore, most people born before 1950 were immune, and epidemics caused by A(H1N1) viruses since 1977 have primarily affected younger people. The fact that the elderly appear to have natural protection against current A(H1N1) viruses probably explains the low mortality associated with recent epidemics in which this subtype was the predominant strain. However, as A(H1N1) viruses continue to evolve, they could begin to have a more severe impact on the elderly. Influenza Vaccine Much of the illness and death caused by influenza can be prevented by annual influenza vaccination. Influenza vaccine is specifically recommended for people who are at high risk for developing serious complications as a result of influenza infection. These highrisk groups include all people aged 65 years or older and people of any age with chronic diseases of the heart, lung or kidneys, diabetes, immunosuppression, or severe forms of anemia. Other groups for whom vaccine is specifically recommended are residents of nursing homes and other chroniccare facilities housing patients of any age with chronic medical conditions, and children and teenagers who are receiving longterm aspirin therapy and who may therefore be at risk for developing Reye syndrome after an influenza virus infection. Influenza vaccine is also recommended for people who are in close or frequent contact with anyone in the highrisk groups defined above. These people include health care personnel and volunteers who work with highrisk patients and people who live in a household with a highrisk person. Although annual influenza vaccination has long been recommended for people in the highrisk groups, many still do not receive the vaccine. Some people are not vaccinated because of misperceptions about influenza and the vaccine. They mistakenly perceive influenza as merely a nuisance and believe that the vaccine causes unpleasant side effects or that it may even cause the flu. The truth is that influenza vaccine causes no side effects in most people. The most serious side effect that can occur after influenza vaccination is an allergic reaction in people who have severe allergy to eggs, since the viruses used in the vaccine are grown in hens' eggs. For this reason, people who have an allergy to eggs should not receive influenza vaccine. Less than onethird of those who receive vaccine have some soreness at the vaccination site, and about 5% to 10% experience mild side effects, such as headache or low-grade fever for about a day after vaccination. These side effects are most likely to occur in children who have not been exposed to influenza virus in the past. Nevertheless, some older people remember earlier influenza vaccines that did, in fact, produce more unpleasant side effects. Vaccines produced from the 1940s to the mid1960s were not as highly purified as modern influenza vaccines, and it was these impurities that caused most of the side effects. Since the side effects associated with these early vaccines, such as fever, headache, muscle aches, and fatigue, were similar to some of the symptoms of influenza, people believed that the vaccine had caused them to get the flu. However, influenza vaccine produced in the United States has never been capable of causing influenza. The only type of influenza vaccine that has been licensed in the United States to the present time is made from killed influenza viruses, which cannot cause infection. An influenza vaccine that is made with live influenza viruses has been developed and may be marketed in the future. This vaccine is made with viruses that can confer immunity but do not cause classic influenza symptoms. Some people do not receive influenza vaccine because they believe it is not very effective. There are several different reasons for this belief. People who have received influenza vaccine may subsequently have an illness that is mistaken for influenza, and they believe that the vaccine failed to protect them. In other cases, people who have received vaccine may indeed have an influenza infection. Overall vaccine effectiveness varies from year to year, depending upon thedegree of similarity between the influenza virus strains included in the vaccine and the strain or strains that circulate during the influenza season. Because the vaccine strains must be chosen 9 to 10 months before the influenza se

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