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History
Etymology
The word Influenza comes from the Italian language and refers to the cause of the disease; initially, this ascribed illness to unfavorable astrological influences.[125] Changes in medical thought led to its modification to influenza del freddo, meaning "influence of the cold". The word influenza was first used in English in 1743 when it was adopted, with an anglicized pronunciation, during an outbreak of the disease in Europe.[126] Archaic terms for influenza include epidemic catarrh, grippe (from the French), sweating sickness, and Spanish fever (particularly for the 1918 pandemic strain).[127]
Pandemics
Further information: Influenza pandemic, Spanish flu, Hong Kong flu
The difference between the influenza mortality age distributions of the 1918 epidemic and normal epidemics. Deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line).[128]
The symptoms of human influenza were clearly described by Hippocrates roughly 2,400 years ago.[129][130] Since then, the virus has caused numerous pandemics. Historical data on influenza are difficult to interpret, because the symptoms can be similar to those of other diseases, such as diphtheria, pneumonic plague, typhoid fever, dengue, or typhus. The first convincing record of an influenza pandemic was of an outbreak in 1580, which began in Russia and spread to Europe via Africa. In Rome, over 8,000 people were killed, and several Spanish cities were almost wiped out. Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of 1830–1833 being particularly widespread; it infected approximately a quarter of the people exposed.[131]
The most famous and lethal outbreak was the 1918 flu pandemic (Spanish flu pandemic) (type A influenza, H1N1 subtype), which lasted from 1918 to 1919. It is not known exactly how many it killed, but estimates range from 20 to 100 million people.[132][133] This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the Black Death.[131] This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms.[133] Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred."[132] The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.[128]
The 1918 flu pandemic (Spanish flu pandemic) was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%.[128][132] Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old.[134] This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that 2.5% to 5% of the world's population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.[132]
The influenza viruses that caused Hong Kong flu. (magnified approximately 100,000 times)
Later flu pandemics were not so devastating. They included the 1957 Asian Flu (type A, H2N2 strain) and the 1968 Hong Kong Flu (type A, H3N2 strain), but even these smaller outbreaks killed millions of people. In later pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality compared to the Spanish Flu of 1918.[128]
Known flu pandemics[131][32]
Name of pandemic
Date
Deaths
Subtype involved
Pandemic Severity Index
Asiatic (Russian) Flu
1889–1890
1 million
possibly H2N2
NA
1918 flu pandemic (Spanish flu)
1918–1920
20 to 100 million
H1N1
5
Asian Flu
1957–1958
1 to 1.5 million
H2N2
2
Hong Kong Flu
1968–1969
0.75 to 1 million
H3N2
2
2009 flu pandemic
2009–Present
NA
H1N1
NA
The first influenza virus to be isolated was from poultry, when in 1901 the agent causing a disease called "fowl plague" was passed through Chamberland filters, which have pores that are too small for bacteria to pass through.[135] The etiological cause of influenza, the Orthomyxoviridae family of viruses, was first discovered in pigs by Richard Shope in 1931.[136] This discovery was shortly followed by the isolation of the virus from humans by a group headed by Patrick Laidlaw at the Medical Research Council of the United Kingdom in 1933.[137] However, it was not until Wendell Stanley first crystallized tobacco mosaic virus in 1935 that the non-cellular nature of viruses was appreciated.
The main types of influenza viruses in humans. Solid squares show the appearance of a new strain, causing recurring influenza pandemics. Broken lines indicate uncertain strain identifications.[138]
The first significant step towards preventing influenza was the development in 1944 of a killed-virus vaccine for influenza by Thomas Francis, Jr.. This built on work by Australian Frank Macfarlane Burnet, who showed that the virus lost virulence when it was cultured in fertilized hen's eggs.[139] Application of this observation by Francis allowed his group of researchers at the University of Michigan to develop the first influenza vaccine, with support from the U.S. Army.[140] The Army was deeply involved in this research due to its experience of influenza in World War I, when thousands of troops were killed by the virus in a matter of months.[132] In comparison to vaccines, the development of anti-influenza drugs has been slower, with amantadine being licensed in 1966 and, almost thirty years later, the next class of drugs (the neuraminidase inhibitors) being developed.[33]
Society and culture
Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs.[141] However, the economic impacts of past pandemics have not been intensively studied, and some authors have suggested that the Spanish influenza actually had a positive long-term effect on per-capita income growth, despite a large reduction in the working population and severe short-term depressive effects.[142] Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30% sickness rate and a three-week length of illness would decrease the gross domestic product by 5%. Additional costs would come from medical treatment of 18 million to 45 million people, and total economic costs would be approximately $700 billion.[143]
Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.[144] On 1 November 2005, United States President George W. Bush unveiled the National Strategy to Safeguard Against the Danger of Pandemic Influenza[145] backed by a request to Congress for $7.1 billion to begin implementing the plan.[146] Internationally, on 18 January 2006, donor nations pledged US$2 billion to combat bird flu at the two-day International Pledging Conference on Avian and Human Influenza held in China.[147]

Dr. Terrence Tumpey examining a reconstructed 1918 Spanish Flu Virus at a CDC in a Biosafety level 3 environment.
Research on influenza includes studies on molecular virology, how the virus produces disease (pathogenesis), host immune responses, viral genomics, and how the virus spreads (epidemiology). These studies help in developing influenza countermeasures; for example, a better understanding of the body's immune system response helps vaccine development, and a detailed picture of how influenza invades cells aids the development of antiviral drugs. One important basic research program is the Influenza Genome Sequencing Project, which is creating a library of influenza sequences; this library should help clarify which factors make one strain more lethal than another, which genes most affect immunogenicity, and how the virus evolves over time.[148]
Research into new vaccines is particularly important, as current vaccines are very slow and expensive to produce and must be reformulated every year. The sequencing of the influenza genome and recombinant DNA technology may accelerate the generation of new vaccine strains by allowing scientists to substitute new antigens into a previously developed vaccine strain.[149] New technologies are also being developed to grow viruses in cell culture, which promises higher yields, less cost, better quality and surge capacity.[150] Research on a universal influenza A vaccine, targeted against the external domain of the transmembrane viral M2 protein (M2e), is being done at the University of Ghent by Walter Fiers, Xavier Saelens and their team[151][152][153] and has now successfully concluded Phase I clinical trials.
A number of biologics, therapeutic vaccines and immunobiologics are also being investigated for treatment of infection caused by viruses. Therapeutic biologics are designed to activate the immune response to virus or antigens. Typically, biologics do not target metabolic pathways like anti-viral drugs, but stimulate immune cells such as lymphocytes, macrophages, and/or antigen presenting cells, in an effort to drive an immune response towards a cytotoxic effect against the virus. Infuenza models, such as murine influenza, are convenient models to test the effects of prophylactic and therapeutic biologics. For example, Lymphocyte T-Cell Immune Modulator inhibits viral growth in the murine model of influenza.