INFLUENZA Influenza, commonly known as "the flu", is an infectious disease of birds and mammalscaused by RNA viruses of the family

Orthomyxoviridae, the influenza viruses. The most common symptoms are chills, fever, runny nose, sore throat, muscle pains, headache(often severe), coughing, weakness/fatigue and general discomfort.[1] Although it is often confused with other influenza-like illnesses, especially the common cold, influenza is a more severe disease caused by a different type of virus.[2] Influenza may produce nauseaand vomiting, particularly in children,[1] but these symptoms are more common in the unrelated gastroenteritis, which is sometimes inaccurately referred to as "stomach flu" or "24-hour flu".[3] Flu can occasionally lead to pneumonia, either direct viral pneumonia or secondarybacterial pneumonia, even for persons who are usually very healthy.[4][5][6] In particular it is a warning sign if a child (or presumably an adult) seems to be getting better and then relapses with a high fever as this relapse may be bacterial pneumonia.[7] Another warning sign is if the person starts to have trouble breathing.[6] Typically, influenza is transmitted through the air by coughs or sneezes, creating aerosolscontaining the virus. Influenza can also be transmitted by direct contact with bird droppings or nasal secretions, or through contact with contaminated surfaces. Airborne aerosols have been thought to cause most infections, although which means of transmission is most important is not absolutely clear.[8] Influenza viruses can be inactivated by sunlight,disinfectants and detergents.[9][10] As the virus can be inactivated by soap, frequent hand washing reduces the risk of infection.[11] Influenza spreads around the world in seasonal epidemics, resulting in about three to five million yearly cases of severe illness and about 250,000 to 500,000 yearly deaths,[12]rising to millions in some pandemic years. In the 20th century three influenza pandemicsoccurred, each caused by the appearance of a new strain of the virus in humans, and killed tens of millions of people. Often, new influenza strains appear when an existing flu virus spreads to humans from another animal species, or when an existing human strain picks up new genes from a virus that usually infects birds or pigs. An avian strain named H5N1 raised the concern of a new influenza pandemic after it emerged in Asia in the 1990s, but it has not evolved to a form that spreads easily between people.[13] In April 2009 a novel flu strain evolved that combined genes from human, pig, and bird flu. Initially dubbed "swine flu" and also known as influenza A/H1N1, it emerged in Mexico, the United States, and several other nations. The World Health Organization officially declared the outbreak to be a pandemic on 11 June 2009 (see 2009 flu pandemic). The WHO's declaration of a pandemic level 6 was an indication of spread, not severity, the strain actually having a lower mortality rate than common flu outbreaks.[14] Vaccinations against influenza are usually made available to people in developed countries.[15] Farmed poultry is often vaccinated to avoid decimation of the flocks.[16] The most common human vaccine is the trivalent influenza vaccine (TIV) that contains purified and inactivated antigens from three viral strains. Typically, this vaccine includes material from two influenza A virus subtypes and oneinfluenza B virus strain.[17] The TIV carries no risk of

transmitting the disease. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus evolves rapidly, and new strains quickly replace the older ones. Antiviral drugs such as theneuraminidase inhibitor oseltamivir (Tamiflu) have been used to treat influenza;[18] however, their effectiveness is difficult to determine due to much of the data remaining unpublished.

Approximately 33% of people with influenza are asymptomatic.[22] Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from 38 to 39 C (approximately 100 to 103 F).[23] Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worse in their backs and legs.[1] Symptoms of influenza may include:

Fever and extreme coldness (chills shivering, shaking (rigor)) Cough Nasal congestion Runny nose Body aches, especially joints and throat Fatigue Headache Irritated, watering eyes Reddened eyes, skin (especially face), mouth, throat and nose Petechial rash[24] In children, gastrointestinal symptoms such as diarrhea and abdominal pain,[25][26] (may be severe in children with influenza B)[27]

It can be difficult to distinguish between the common cold and influenza in the early stages of these infections,[2] but a flu can be identified by a high fever with a sudden onset and extreme fatigue. Influenza is a mixture of symptoms of common cold and pneumonia, body ache, headache, and fatigue. Diarrhea is not normally a symptom of influenza in adults,[20] although it has been seen in some human cases of the H5N1 "bird flu"[28] and can be a symptom in children.[25] The symptoms most reliably seen in influenza are shown in the table to the right.[20] Since antiviral drugs are effective in treating influenza if given early (see treatment section, below), it can be important to identify cases early. Of the symptoms listed above, the combinations of fever with cough, sore throat and/or nasal congestion can improve diagnostic accuracy.[29] Two decision analysis studies[30][31] suggest that during local outbreaks of influenza, the prevalence will be over 70%,[31]and thus patients with any of these combinations of symptoms may be treated with neuraminidase inhibitors without testing. Even in the absence of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the prevalence is over 15%.[31]

The available laboratory tests for influenza continue to improve. The United States Centers for Disease Control and Prevention (CDC) maintains an up-to-date summary of available laboratory tests.[32] According to the CDC, rapid diagnostic tests have a sensitivity of 7075% and specificity of 9095% when compared with viral culture. These tests may be especially useful during the influenza season (prevalence=25%) but in the absence of a local outbreak, or periinfluenza season (prevalence=10%[31]). On the more serious side, influenza can occasionally cause either direct viral or secondary bacterial pneumonia.[5][6] The obvious symptom is trouble breathing. In addition, if a child (or presumably an adult) seems to be getting better and then relapses with a high fever, that is a danger sign since this relapse can be bacterial pneumonia.

Transmission Influenza virus shedding (the time during which a person might be infectious to another person) begins the day before symptoms appear and virus is then released for five to seven days. People who contract influenza are most infective between the second and third days after infection.[67] The amount of virus shed appears to correlate with fever, with higher amounts of virus shed when temperatures are highest.[68] Children are much more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection.[67][69] Influenza can be spread in three main ways:[70][71] by direct transmission (when an infected person sneezes mucus directly into the eyes, nose or mouth of another person); the airborne route (when someone inhales the aerosols produced by an infected person coughing, sneezing or spitting) and through hand-to-eye, hand-to-nose, or hand-to-mouth transmission, either from contaminated surfaces or from direct personal contact such as a hand-shake. The relative importance of these three modes of transmission is unclear, and they may all contribute to the spread of the virus.[8][72] In the airborne route, the droplets that are small enough for people to inhale are 0.5 to 5 m in diameter and inhaling just one droplet might be enough to cause an infection.[70] Although a single sneeze releases up to 40,000 droplets,[73] most of these droplets are quite large and will quickly settle out of the air.[70] How long influenza survives in airborne droplets seems to be influenced by the levels of humidity and UV radiation: with low humidity and a lack of sunlight in winter aiding its survival.[70] As the influenza virus can persist outside of the body, it can also be transmitted by contaminated surfaces such as banknotes,[74]doorknobs, light switches and other household items.[1] The length of time the virus will persist on a surface varies, with the virus surviving for one to two days on hard, non-porous surfaces such as plastic or metal, for about fifteen minutes from dry paper tissues, and only five minutes on skin.[75] However, if the virus is present in mucus, this can protect it for longer periods (up to 17 days on banknotes).[70][74] Avian influenza viruses can survive indefinitely when frozen.[76] They are inactivated by heating to 56 C (133 F) for a minimum of 60 minutes, as well as by acids (at pH <2).[76]

The mechanisms by which influenza infection causes symptoms in humans have been studied intensively. One of the mechanisms is believed to be the inhibition ofadrenocorticotropic hormone (ACTH) resulting in lowered cortisol levels.[77]Knowing which genes are carried by a particular strain can help predict how well it will infect humans and how severe this infection will be (that is, predict the strain'spathophysiology).[45][78] For instance, part of the process that allows influenza viruses to invade cells is the cleavage of the viral hemagglutinin protein by any one of several humanproteases.[59] In mild and avirulent viruses, the structure of the hemagglutinin means that it can only be cleaved by proteases found in the throat and lungs, so these viruses cannot infect other tissues. However, in highly virulent strains, such as H5N1, the hemagglutinin can be cleaved by a wide variety of proteases, allowing the virus to spread throughout the body.[78] The viral hemagglutinin protein is responsible for determining both which species a strain can infect and where in the human respiratory tract a strain of influenza will bind.[79] Strains that are easily transmitted between people have hemagglutinin proteins that bind to receptors in the upper part of the respiratory tract, such as in the nose, throat and mouth. In contrast, the highly lethal H5N1 strain binds to receptors that are mostly found deep in the lungs.[80] This difference in the site of infection may be part of the reason why the H5N1 strain causes severe viral pneumonia in the lungs, but is not easily transmitted by people coughing and sneezing.[81][82] Common symptoms of the flu such as fever, headaches, and fatigue are the result of the huge amounts of proinflammatory cytokinesand chemokines (such as interferon or tumor necrosis factor) produced from influenza-infected cells.[2][83] In contrast to the rhinovirusthat causes the common cold, influenza does cause tissue damage, so symptoms are not entirely due to the inflammatory response.[84] This massive immune response might produce a lifethreatening cytokine storm. This effect has been proposed to be the cause of the unusual lethality of both the H5N1 avian influenza,[85] and the 1918 pandemic strain.[86][87] However, another possibility is that these large amounts of cytokines are just a result of the massive levels of viral replication produced by these strains, and the immune response does not itself contribute to the disease

The influenza vaccine is recommended by the World Health Organization and United StatesCenters for Disease Control and Prevention for high-risk groups, such as children, the elderly, health care workers, and people who have chronic illnesses such as asthma,diabetes, heart disease, or are immuno-compromised among others.[89][90] In healthy adults it is modestly effective in decreasing the amount of influenza-like symptoms in a population.[91] Evidence is supportive of a decreased rate of influenza in children over the age of two.[92] In those with chronic obstructive pulmonary disease vaccination reduces exacerbations,[93] it is not clear if it reduces asthma exacerbations.[94] There is insufficient evidence to support a change in patient outcomes via immunizing health care workers.[95]This includes health care workers who care for the elderly.[96] Evidence supports a lower rate of

influenza-like illness in many groups who are immunocompromised such as those with:HIV/AIDS, cancer, and post organ transplant.[97] Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. Every year, the World Health Organization predicts which strains of the virus are most likely to be circulating in the next year (see Historical annual reformulations of the influenza vaccine), allowing pharmaceutical companies to develop vaccines that will provide the best immunity against these strains.[98] The vaccine is reformulated each season for a few specific flu strains but does not include all the strains active in the world during that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time.[99] It is also possible to get infected just before vaccination and get sick with the strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.[100] Vaccines can cause the immune system to react as if the body were actually being infected, and general infection symptoms (many cold and flu symptoms are just general infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza. The most dangerous adverse effect is a severe allergic reaction to either the virus material itself or residues from the hen eggs used to grow the influenza; however, these reactions are extremely rare.[101] The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings. It has generally been found to be a cost-effective intervention, especially in children[102] and the elderly,[103] however the results of economic evaluations of influenza vaccination have often been found to be dependent on key assumptions.[104] Infection control Further information: Influenza prevention Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene habits such as: not touching your eyes, nose or mouth;[105] frequent hand washing (with soap and water, or with alcohol-based hand rubs);[106] covering coughs and sneezes; avoiding close contact with sick people; and staying home yourself if you are sick. Avoiding spitting is also recommended.[107] Although face masks might help prevent transmission when caring for the sick,[108][109] there is mixed evidence on beneficial effects in the community.[107][110] Smoking raises the risk of contracting influenza, as well as producing more severe disease symptoms.[111][112] Since influenza spreads through both aerosols and contact with contaminated surfaces, surface sanitizing may help prevent some infections.[113] Alcohol is an effective sanitizer against influenza viruses, while quaternary ammonium compounds can be used with alcohol so that the sanitizing effect lasts for longer.[114] In hospitals, quaternary ammonium compounds and bleach are used to sanitize rooms or equipment that have been occupied by patients with influenza symptoms.[114] At home, this can be done effectively with a diluted chlorine bleach.[115]

During past pandemics, closing schools, churches and theaters slowed the spread of the virus but did not have a large effect on the overall death rate.[116][117] It is uncertain if reducing public gatherings, by for example closing schools and workplaces, will reduce transmission since people with influenza may just be moved from one area to another; such measures would also be difficult to enforce and might be unpopular.[107] When small numbers of people are infected, isolating the sick might reduce the risk of transmission.[107]

People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid using alcohol and tobacco and, if necessary, take medications such as acetaminophen (paracetamol) to relieve the fever and muscle aches associated with the flu.[118] Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin during an influenza infection (especially influenza type B), because doing so can lead to Reye's syndrome, a rare but potentially fatal disease of the liver.[119] Since influenza is caused by a virus,antibiotics have no effect on the infection; unless prescribed for secondary infections such as bacterial pneumonia. Antiviral medication may be effective, but some strains of influenza can show resistance to the standard antiviral drugs and there is concern about the quality of the research.[120] Antivirals The two classes of antiviral drugs used against influenza are neuraminidase inhibitors (oseltamivir and zanamivir) and M2 proteininhibitors (adamantane derivatives). Neuraminidase inhibitors are currently preferred for flu virus infections since they are less toxic and possibly more effective.[88] However, their effectiveness is disputed.[19] In 2009, the World Health Organization recommended that persons in high-risk groups, including pregnant women, children under two, and persons with respiratory problems, begin taking antivirals as soon as they start experiencing flu symptoms.[121][122] Neuraminidase inhibitors Neuraminidase inhibitors include the antiviral medications oseltamivir (Tamiflu) and zanamivir (Relenza). These medications may be effective against both influenza A and B, however the confidence of the research community in this conclusion is low as much of the trial data remains unpublished.[19][123] In those believed to have the flu they decreased the length of time symptoms are present by about a day and do not appear to affect the risk of complications such as needing hospitalization or pneumonia.[124] Different strains of influenza viruses have differing degrees of resistance against these antivirals, and it is impossible to predict what degree of resistance a future pandemic strain might have.[125] The FDA deems their effect to be modest.[19] M2 inhibitors The antiviral drugs amantadine and rimantadine block a viral ion channel (M2 protein) and prevent the virus from infecting cells.[62] These drugs are sometimes effective against influenza A if given early in the infection but are ineffective against influenza B viruses, which lack the M2 drug target.[126] Measured resistance to amantadine and rimantadine in American isolates

of H3N2 has increased to 91% in 2005.[127] This high level of resistance may be due to the easy availability of amantadines as part of over-the-counter cold remedies in countries such as China and Russia,[128] and their use to prevent outbreaks of influenza in farmed poultry.[129][130] The CDC recommended against using M2 inhibitors during the 200506 influenza season due to high levels of drug resistance.[131] Prognosis Influenza's effects are much more severe and last longer than those of the common cold. Most people will recover completely in about one to two weeks, but others will develop lifethreatening complications (such as pneumonia). Thus, influenza can be deadly, especially for the weak, young and old, or chronically ill.[55] People with a weak immune system, such as people with advanced HIV infection or transplant patients (whose immune systems are medically suppressed to prevent transplant organ rejection), suffer from particularly severe disease.[132] Pregnant women and young children are also at a high risk for complications.[133] The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experience shortness of breath while they have the flu, and influenza may cause worsening of coronary heart disease or congestive heart failure.[134] Smoking is another risk factor associated with more serious disease and increased mortality from influenza.[135] According to the World Health Organization: "Every winter, tens of millions of people get the flu. Most are only ill and out of work for a week, yet the elderly are at a higher risk of death from the illness. We know the worldwide death toll exceeds a few hundred thousand people a year, but even in developed countries the numbers are uncertain, because medical authorities don't usually verify who actually died of influenza and who died of a flu-like illness."[136] Even healthy people can be affected, and serious problems from influenza can happen at any age. People over 50 years old, very young children and people of any age with chronic medical conditions are more likely to get complications from influenza, such as pneumonia, bronchitis, sinus, and ear infections.[100] In some cases, an autoimmune response to an influenza infection may contribute to the development of Guillain-Barr syndrome.[137]However, as many other infections can increase the risk of this disease, influenza may only be an important cause during epidemics.[137][138] This syndrome has been believed to also be a rare side effect of influenza vaccines. One review gives an incidence of about one case per million vaccinations.[139] Getting infected by influenza itself increases both the risk of death (up to 1 in 10,000) and increases the risk of developing GBS to a much higher level than the highest level of suspected vaccine involvement (approx. 10 times higher by recent estimates)