View source for Influenza

{{redirect|Flu}}
{{otheruses4|the disease influenza|the family of [[virus]]es that cause the disease|Orthomyxoviridae}}
{{Infobox_Disease
 |Name          =Influenza
 |Image         =EM of influenza virus.jpg
 |Caption       =[[transmission electron microscopy|TEM]] of negatively stained influenza virons, magnified approximately 100,000 times
 |Width         =226
 |DiseasesDB    =6791
 |ICD10         ={{ICD10|J|10||j|09}}, {{ICD10|J|11||j|09}}
 |ICD9          ={{ICD9|487}}
 |MedlinePlus   =000080
 |eMedicineSubj =med
 |eMedicineTopic=1170
 |eMedicine_mult={{eMedicine2|ped|3006}}
 |MeshID        =D007251
 |
}}
'''Influenza''', commonly referred to as the '''flu''', is an [[infectious disease]] caused by [[RNA virus]]es of the [[biological family|family]] [[Orthomyxoviridae]] (the influenza viruses), that affects [[bird]]s and [[mammal]]s.  The name ''influenza'' comes from the [[Italian language|Italian]] ''influenza'', meaning "influence" ({{Lang-la|influentia}}). The most common symptoms of the disease are [[chills]], [[fever]], [[pharyngitis]], [[myalgia|muscle pains]], severe [[headache]], [[cough]]ing, [[fatigue (medical)|weakness]] and [[malaise|general discomfort]].<ref name=Merck>{{cite web
|url=http://www.merck.com/mmhe/sec17/ch198/ch198d.html
|title=Influenza: Viral Infections: Merck Manual Home Edition
|publisher=www.merck.com
|accessdate=2008-03-15
|last=
|first=
}}
</ref> Fever and coughs are the most frequent symptoms. In more serious cases, influenza [[sequela|causes]] [[pneumonia]], which can be fatal, particularly for the young and the elderly. Although it is often confused with the [[common cold]], influenza is a much more severe disease and is caused by a different type of virus.<ref name=Eccles>{{cite journal |last=Eccles |first=R |title=Understanding the symptoms of the common cold and influenza |journal=Lancet Infect Dis |volume=5 |issue=11 |pages=718–25 |year=2005 |pmid=16253889 |doi=10.1016/S1473-3099(05)70270-X }}</ref> Influenza may produce [[nausea]] and [[vomiting]], particularly in children,<ref name=Merck/> but these symptoms are more common in the unrelated disease [[gastroenteritis]], which is sometimes called "stomach flu" or "24-hour flu".<ref>[http://coldflu.about.com/od/flumisconceptions/f/stomachflu.htm Seasonal Flu vs. Stomach Flu] by Kristina Duda, R.N.; accessed 12 March 2007 (Website: "About, Inc., A part of The New York Times Company")</ref>

Typically, influenza is transmitted from infected mammals through the air by coughs or sneezes, creating [[aerosols]] containing the virus, and from infected birds through their [[feces|droppings]].  Influenza can also be transmitted by [[saliva]], [[mucus|nasal secretions]], [[feces]] and [[blood]].  Infections also occur through contact with these [[Bodily fluid|body fluids]] or with contaminated surfaces. Flu viruses can remain infectious for about one week at [[Human anatomy|human body]] temperature, over 30 days at 0 [[Celsius|°C]] (32 [[Fahrenheit|°F]]), and for much longer periods at very low temperatures.<ref>{{cite journal |author=Reid AH, Fanning TG, Hultin JV, Taubenberger JK |title=Origin and evolution of the 1918 "Spanish" influenza virus hemagglutinin gene |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=4 |pages=1651–6 |year=1999 |pmid=9990079 | doi = 10.1073/pnas.96.4.1651}}</ref><ref>{{cite journal |author=Mase M, Tanimura N, Imada T, Okamatsu M, Tsukamoto K, Yamaguchi S |title=Recent H5N1 avian influenza A virus increases rapidly in virulence to mice after a single passage in mice |journal=J Gen Virol. |volume=87 |issue=Pt 12 |pages=3655–9 |year=2006 |month=December |pmid=17098982 |doi=10.1099/vir.0.81843-0 |url=http://vir.sgmjournals.org/cgi/content/full/87/12/3655 |quote=To prepare the original virus stock for this study, virus was propagated once in the allantoic cavity of embryonated eggs at 37 °C for 1–2 days and then stored at –80 °C until use.}}</ref> Influenza viruses can be inactivated by [[disinfectant]]s and [[detergent]]s.<ref>{{cite journal |last=Suarez |first=D |coauthors=Spackman E, Senne D, Bulaga L, Welsch A, Froberg K |title=The effect of various disinfectants on detection of avian influenza virus by real time RT-PCR |journal=Avian Dis |volume=47 |issue=3 Suppl |pages=1091–5 |year=2003 |pmid=14575118 |doi=10.1637/0005-2086-47.s3.1091}}</ref><ref>[http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/biofacts/avflu_human.html  Avian Influenza (Bird Flu)]: Implications for [[Disease|Human Disease]].  Physical characteristics of influenza A viruses.  UMN CIDRAP.</ref><ref name="NHZ2006-11-30">[http://www.nzherald.co.nz/category/story.cfm?c_id=204&objectid=10413124  Flu viruses 'can live for decades' on ice], NZ Herald, 30 November 2006.</ref> As the virus can be inactivated by soap, frequent hand washing reduces the risk of infection.

Flu spreads around the world in [[flu season|seasonal]] [[epidemic]]s, resulting in the deaths of hundreds of thousands annually — millions in [[pandemic]] years. Three influenza pandemics occurred in the 20th century and killed tens of millions of people, with each of these pandemics being caused by the appearance of a new [[strain (biology)|strain]] of the virus in humans. Often, these new strains result from the spread of an existing flu virus to humans from other animal [[species]]. An avian strain named [[H5N1]] had until recently posed the greatest risk for a new [[influenza pandemic]] since it first killed humans in Asia in the 1990s. Although H5N1 virus has not [[mutation|mutated]] to a form that spreads easily between people <ref>{{cite web |title=Avian influenza ("bird flu") fact sheet |url= http://www.who.int/mediacentre/factsheets/avian_influenza/en/ |month=February | year=2006 |publisher=WHO |accessdate=2006-10-20}}</ref>, in April 2009 a novel H1N1 flu strain that combined genes from human, pig, and bird flu, initially dubbed the "[[swine flu]]," emerged in Mexico, the United States, and several other nations.  By late April, the H1N1 swine flu was suspected of having killed over 150 in Mexico,<ref>[http://news.bbc.co.uk/1/hi/world/americas/8022437.stm]</ref> and prompted concern that a new pandemic is imminent. 

[[Vaccination]]s against influenza are usually given to people in [[developed country|developed countries]] <ref name=WHOvaccines>[http://www.who.int/wer/2005/wer8033.pdf WHO position paper: influenza vaccines] ''WHO weekly Epidemiological Record'' 19 August 2005, vol. 80, 33, pp. 277–288.</ref> and to farmed poultry.<ref>{{cite journal |last=Villegas |first=P |title=Viral diseases of the respiratory system |journal=Poult Sci |volume=77 |issue=8 |pages=1143–5 |year=1998 |pmid=9706079}}</ref> The most common human vaccine is the trivalent [[influenza vaccine]] (TIV) that contains purified and inactivated material from three viral strains. Typically, this vaccine includes material from two [[influenzavirus A|influenza A virus]] subtypes and one [[Influenzavirus B|influenza B virus]] strain.<ref>{{cite journal |author=Horwood F, Macfarlane J |title=Pneumococcal and influenza vaccination: current situation and future prospects |journal=Thorax |volume=57 |issue=Suppl 2 |pages=II24–II30 |year=2002 |month=October |pmid=12364707 |pmc=1766003 |url=http://thorax.bmj.com/cgi/pmidlookup?view=long&pmid=12364707}}</ref>  The TIV carries no risk of transmitting the disease, and it has very low reactivity.  A vaccine formulated for one year may be ineffective in the following year, since the influenza virus evolves rapidly, and different strains become dominant.  [[Antiviral drug]]s can be used to treat influenza, with [[neuraminidase inhibitor]]s being particularly effective.
{{Flu}}

== Etymology ==
The word ''Influenza'' comes from the [[Italian language]] and refers to the cause of the disease; initially, this ascribed illness to unfavorable [[astrology|astrological]] influences.<ref>''Influenza'', [[Oxford English Dictionary|The Oxford English Dictionary]], second edition.</ref> 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.<ref name=Harper>{{cite web |last=Harper |first=D |title=Influenza |url=http://www.etymonline.com/index.php?search=influenza&searchmode=none  |publisher= Etymonlin}}</ref> Archaic terms for influenza include ''epidemic catarrh'', ''grippe'' (from the French), ''sweating sickness'', and ''Spanish fever'' (particularly for the [[Spanish flu|1918 pandemic]] strain).<ref>{{cite web |last=Smith |first=P |title=Archaic Medical Terms |url= http://www.paul_smith.doctors.org.uk/ArchaicMedicalTerms.htm |accessdate=2006-10-23}}</ref>

== History ==
{{further|[[Influenza pandemic]], [[Spanish flu]]}}

[[File:Influenza virus.png|thumb|300px|right|The influenza viruses that caused [[Spanish Flu]]. (magnified approximately 100,000 times)]]
[[File:W curve.png|thumb|300px|right|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).<ref name="Taubenberger">{{cite journal |last=Taubenberger |first=J |coauthors=Morens D |title=1918 Influenza: the mother of all pandemics |url=http://www.cdc.gov/ncidod/EID/vol12no01/05-0979.htm |journal=Emerg Infect Dis |volume=12 |issue=1 |pages=15–22 |year=2006 |pmid=16494711}}</ref>]]

The symptoms of human influenza were clearly described by [[Hippocrates]] roughly 2,400 years ago.<ref>{{cite journal |last =Martin |first=P |coauthors=Martin-Granel E |title=2,500-year evolution of the term epidemic |url= http://www.cdc.gov/ncidod/EID/vol12no06/05-1263.htm#cit |journal=Emerg Infect Dis |year=2006 |month=June |volume=12 |issue=6 |pmid=16707055}}</ref><ref>{{cite web |author=Hippocrates |coauthors=[[Francis Adams (translator)|Adams, Francis]] (transl.) |title=Of the Epidemics |url= http://classics.mit.edu/Hippocrates/epidemics.html |date= 400 BCE |accessdate=2006-10-18}}</ref> 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 [[History of Rome#Renaissance Rome|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.<ref name=Potter>{{cite journal |author =Potter CW
|title= A History of Influenza |journal= Journal of Applied Microbiology |year=2001
|month=October |volume=91 |issue= 4 |pages=572–579 |pmid=11576290 |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/120718156/HTMLSTART
| doi = 10.1046/j.1365-2672.2001.01492.x}}</ref>

The most famous and lethal outbreak was the so-called [[Spanish flu]] pandemic ([[Influenzavirus A|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.<ref name=Knobler>{{cite book |editor=Knobler S, Mack A, Mahmoud A, Lemon S |title=The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) |chapter=1: The Story of Influenza  |pages=60–61 |chapterurl=http://books.nap.edu/openbook.php?record_id=11150&page=58 |publisher=The National Academies Press |location=Washington, D.C.}}</ref><ref name=Patterson1>{{cite journal |last =Patterson |first=KD |coauthors=Pyle GF |title=The geography and mortality of the 1918 influenza pandemic |journal= Bull Hist Med. |year=1991 |month=Spring |volume=65 |issue=1 |pages=4–21 |pmid=2021692}}</ref> This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the [[Black Death]].<ref name=Potter/> 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 storm]]s.<ref name=Patterson1/> 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 membrane]]s, especially from the nose, stomach, and intestine. Bleeding from the ears and [[petechia|petechial hemorrhages]] in the skin also occurred."<ref name=Knobler/> The majority of deaths were from [[bacterial pneumonia]], a [[secondary infection]] caused by influenza, but the virus also killed people directly, causing massive [[bleeding|hemorrhages]] and [[edema]] in the lung.<ref name=Taubenberger>{{cite journal |last=Taubenberger |first=J |coauthors=Reid A, Janczewski T, Fanning T |title=Integrating historical, clinical and molecular genetic data in order to explain the origin and virulence of the 1918 Spanish influenza virus |journal=Philos Trans R Soc Lond B Biol Sci |volume=356 |issue=1416 |pages=1829–39 |year=2001 |month=December 29 |pmid=11779381 |url= http://www.journals.royalsoc.ac.uk/(3sud2455cjw1ut55yowx1d45)/app/home/contribution.asp?referrer=parent&backto=issue,3,22;journal,61,225;linkingpublicationresults,1:102022,1 |doi=10.1098/rstb.2001.1020}}</ref>

The Spanish flu pandemic was truly global, spreading even to the [[Arctic]] and remote [[Pacific Islands|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%.<ref name=Taubenberger/><ref name=Knobler/> 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.<ref>{{cite journal |last=Simonsen |first=L |coauthors=Clarke M, Schonberger L, Arden N, Cox N, Fukuda K |title=Pandemic versus epidemic influenza mortality: a pattern of changing age distribution |journal=J Infect Dis |volume=178 |issue=1 |pages=53–60 |year=1998 |month=July |pmid=9652423}}</ref>  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, [[AIDS|HIV/AIDS]] has killed 25 million in its first 25 years.<ref name=Knobler/>

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 [[antibiotic]]s were available to control secondary infections and this may have helped reduce mortality compared to the Spanish Flu of 1918.<ref name= Taubenberger/>

{|class="wikitable" style="text-align:center"
|+ Known [[flu pandemic]]s<ref name=Hilleman>{{cite journal |last=Hilleman |first=M |title=Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control |journal=Vaccine |volume=20 |issue=25–26 |pages=3068–87 |year=2002 |month=August 19 |pmid=12163258 |doi=10.1016/S0264-410X(02)00254-2}}</ref><ref name=Potter/>
! Name of pandemic !! Date !! Deaths !! Subtype involved !! [[Pandemic Severity Index]]
|-
! [[Influenza A virus subtype H2N2#Russian flu|Asiatic (Russian) Flu]]
|1889–1890 ||1 million ||possibly [[H2N2]] ||?
|-
! [[Spanish flu|Spanish Flu]]
|1918–1920 ||40 to 100 million ||[[H1N1]] ||5
|-
! [[H2N2#Asian Flu|Asian Flu]]
|1957–1958 ||1 to 1.5 million ||[[H2N2]] ||2
|-
! [[H3N2#Hong Kong Flu|Hong Kong Flu]]
|1968–1969 ||0.75 to 1 million ||[[H3N2]] ||2
|-
|}

The [[etiology|etiological]] cause of influenza, the Orthomyxoviridae family of viruses, was first discovered in [[pig]]s by [[Richard Shope]] in 1931.<ref>{{cite journal |last =Shimizu |first=K |title= History of influenza epidemics and discovery of influenza virus |journal=Nippon Rinsho |year= 1997 |month=October |volume=55 |issue=10|pages=2505–201 |pmid=9360364}}</ref> 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 (UK)|Medical Research Council]] of [[United Kingdom|the United Kingdom]] in 1933.<ref>{{cite journal |last =Smith |first=W |coauthors=Andrewes CH, Laidlaw PP |title=A virus obtained from influenza patients |journal=Lancet |year=1933 |volume=2 |pages=66–68 |doi=10.1016/S0140-6736(00)78541-2}}</ref> However, it was not until [[Wendell Stanley]] first crystallized [[tobacco mosaic virus]] in 1935 that the [[cell (biology)|non-cellular]] nature of viruses was appreciated.

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.<ref name="Nobel">[http://nobelprize.org/nobel_prizes/medicine/laureates/1960/burnet-bio.html Sir Frank Macfarlane Burnet: Biography] The [[Nobel Foundation]]. Accessed 22 Oct 06</ref> 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 [[United States Army|U.S. Army]].<ref>{{cite journal |last=Kendall |first=H |title=Vaccine Innovation: Lessons from World War II |url= http://docstore.ingenta.com/cgi-bin/ds_deliver/1/u/d/ISIS/32620254.1/pal/jphp/2006/00000027/00000001/art00005/FB2494BF0313967611615398189A7A906334373166.pdf?link=http://www.ingentaconnect.com/error/delivery&format=pdf |journal=Journal of Public Health Policy |volume=27 |issue=1 |pages=38–57 |year=2006 |doi=10.1057/palgrave.jphp.3200064 |format={{dead link|date=April 2009}} &ndash; <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=author%3AKendall+intitle%3AVaccine+Innovation%3A+Lessons+from+World+War+II&as_publication=Journal+of+Public+Health+Policy&as_ylo=2006&as_yhi=2006&btnG=Search Scholar search]</sup>}}</ref> 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.<ref name= Knobler/>

Although there were scares in the State of [[New Jersey]] in 1976 (with the [[Swine Flu]]), worldwide in 1977 (with the Russian Flu), and in [[Hong Kong]] and other [[List of Asian countries|Asian countries]] in 1997 (with [[H5N1]] avian influenza), there have been no major pandemics since the 1968 Hong Kong Flu. Immunity to previous pandemic influenza strains and vaccination may have limited the spread of the virus and may have helped prevent further pandemics.<ref name=Hilleman/>

== Microbiology ==
=== Types of influenza virus ===
[[File:3D Influenza virus.png|thumb|400px|right|Structure of the influenza [[wikt:virion|virion]].  The [[hemagglutinin]] (HA) and [[neuraminidase]] (NA) proteins are shown on the surface of the particle. The viral RNAs that make up the [[genome]] are shown as red coils inside the particle and bound to Ribonuclear Proteins (RNPs).]]
[[File:Influenza nomenclature.svg|thumb|350px|right|Diagram of influenza virus [[International Committee on Taxonomy of Viruses|nomenclature]] (for a [[Fujian flu]] virus)]]
The influenza virus is an [[RNA virus]] of the family [[Orthomyxoviridae]], which comprises five [[genera]]<ref name=Kawaoka>{{cite book |author=Kawaoka Y (editor). |title=Influenza Virology: Current Topics |publisher=Caister Academic Press |year=2006 |url=http://www.horizonpress.com/flu |isbn=978-1-904455-06-6}}</ref>:
* [[Influenzavirus A]]
* [[Influenzavirus B]]
* [[Influenzavirus C]]
* [[Isavirus]]
* [[Thogotovirus]]

==== Influenzavirus A ====
This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza [[pandemic]]s.<ref name=sobrino6>{{cite book |chapterurl=http://www.horizonpress.com/avir|author=Klenk et al|year=2008|chapter=Avian Influenza: Molecular Mechanisms of Pathogenesis and Host Range|title=Animal Viruses: Molecular Biology|publisher=Caister Academic Press|isbn=978-1-904455-22-6}}</ref>
The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease.  The influenza A virus can be subdivided into different [[serovar|serotypes]] based on the [[antibody]] response to these viruses.<ref name=hay/> The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:
* [[H1N1]], which caused [[Spanish flu]] in 1918 and has been identified as the serotype of the 2009 outbreak of [[swine flu]] originating from Mexico (see [[2009 swine flu outbreak]])
* [[H2N2]], which caused Asian Flu in 1957
* [[H3N2]], which caused Hong Kong Flu in 1968
* [[H5N1]], a [[pandemic]] threat in the 2007–08 flu season
* [[H7N7]], which has unusual [[zoonotic]] potential<ref>{{cite journal |last=Fouchier |first=R |coauthors=Schneeberger P, Rozendaal F, Broekman J, Kemink S, Munster V, Kuiken T, Rimmelzwaan G, Schutten M, Van Doornum G, Koch G, Bosman A, Koopmans M, Osterhaus A |title=Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome |url= http://www.pnas.org/cgi/content/full/101/5/1356 |journal=Proc Natl Acad Sci U S a |volume=101 |issue=5 |pages=1356–61 |year=2004 |pmid=14745020 |doi=10.1073/pnas.0308352100}}</ref>
* [[H1N2]], endemic in humans and pigs
* [[H9N2]]
* [[H7N2]]
* [[H7N3]]
* [[H10N7]]

In 2009, a recombinant influenza virus derived in part from [[H1N1]] was first detected in Mexico and the United States (see [[2009 H1N1 flu outbreak]]).

==== Influenzavirus B ====
This genus has one species, influenza B virus. Influenza B almost exclusively infects humans<ref name=hay>{{cite journal |last=Hay |first=A |coauthors=Gregory V, Douglas A, Lin Y |title=The evolution of human influenza viruses |journal=Philos Trans R Soc Lond B Biol Sci |volume=356 |issue=1416 |pages=1861–70 |year=2001 |month=December 29 |pmid=11779385 |doi=10.1098/rstb.2001.0999}}</ref> and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the [[pinniped|seal]]<ref>{{cite journal |last=Osterhaus |first=A |coauthors=Rimmelzwaan G, Martina B, Bestebroer T, Fouchier R |title=Influenza B virus in seals |journal=Science |volume=288 |issue=5468 |pages=1051–3 |year=2000 |pmid=10807575 |doi=10.1126/science.288.5468.1051}}</ref>. This type of influenza mutates at a rate 2–3 times lower than type A<ref>{{cite journal |last=Nobusawa |first=E |coauthors=Sato K |title=Comparison of the mutation rates of human influenza A and B viruses |journal=J Virol |volume=80 |issue=7 |pages=3675–8 |year=2006 |month=April |pmid=16537638 |doi=10.1128/JVI.80.7.3675-3678.2006}}</ref> and consequently is less genetically diverse, with only one influenza B serotype.<ref name=hay/> As a result of this lack of [[antigen]]ic diversity, a degree of [[immunity (medical)|immunity]] to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.<ref name=webster>{{cite journal |first=Webster |last=R |coauthors=Bean W, Gorman O, Chambers T, Kawaoka Y |title=Evolution and ecology of influenza A viruses |pmc=372859  |journal=Microbiol Rev |volume=56 |issue=1 |pages=152–79 |year=1992 |pmid=1579108}}</ref> This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species [[antigenic shift]]), ensures that pandemics of influenza B do not occur.<ref name=Zambon>{{cite journal |last=Zambon |first=M |title=Epidemiology and pathogenesis of influenza |journal=J Antimicrob Chemother |volume=44 Suppl B |issue=|pages=3–9 |year=1999 |month=November |pmid=10877456 |url=http://jac.oxfordjournals.org/cgi/reprint/44/suppl_2/3 |doi=10.1093/jac/44.suppl_2.3}}</ref>

==== Influenzavirus C ====
This genus has one species, influenza C virus, which infects humans and pigs and can cause severe illness and local epidemics.<ref name="Matsuzaki">{{cite journal |last=Matsuzaki |first=Y |coauthors=Sugawara K, Mizuta K, Tsuchiya E, Muraki Y, Hongo S, Suzuki H, Nakamura K |title=Antigenic and genetic characterization of influenza C viruses which caused two outbreaks in Yamagata City, Japan, in 1996 and 1998 |pmc=153379 |journal=J Clin Microbiol |volume=40 |issue=2 |pages=422–9 |year=2002 |pmid=11825952 |doi=10.1128/JCM.40.2.422-429.2002}}</ref>  However, influenza C is less common than the other types and usually seems to cause mild disease in children.<ref>{{cite journal |last=Matsuzaki |first=Y |coauthors=Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, Kitaoka S, Mizuta K, Nishimura H |title=Clinical features of influenza C virus infection in children |journal=J Infect Dis |volume=193 |issue=9 |pages=1229–35 |year=2006 |month=1 May |pmid=16586359 |doi=10.1086/502973}}</ref><ref name="Katagiri">{{cite journal |last=Katagiri |first=S |coauthors=Ohizumi A, Homma M |title=An outbreak of type C influenza in a children's home |journal=J Infect Dis |volume=148 |issue=1 |pages=51–6 |year=1983 |month=July |pmid=6309999}}</ref>

=== Structure, properties, and subtype nomenclature ===
Influenzaviruses A, B and C are very similar in overall structure.<ref> International Committee on Taxonomy of Viruses descriptions of: [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/46000000.htm Orthomyxoviridae], [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/46040000.htm Influenzavirus B] and [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/00.046.0.02.htm Influenzavirus C]</ref> The virus particle is 80–120 [[nanometre]]s in diameter and usually roughly spherical, although filamentous forms can occur.<ref>{{cite web |author= International Committee on Taxonomy of Viruses |title=The Universal Virus Database, version 4: Influenza A |url=http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/00.046.0.01.htm}}</ref><ref name=Lamb>{{cite journal |author=Lamb RA, Choppin PW |title=The gene structure and replication of influenza virus |journal=Annu. Rev. Biochem. |volume=52 |issue= |pages=467–506 |year=1983 |pmid=6351727 |doi=10.1146/annurev.bi.52.070183.002343}}</ref> These filamentous forms are more common in influenza C, which can form cordlike structures up to 500&nbsp;[[micrometre]]s long on the surfaces of infected cells.<ref name=Bouvier/> However, despite these varied shapes, the viral particles of all influenza viruses are similar in composition.<ref name=Bouvier/> These are made of a [[viral envelope]] containing two main types of [[glycoprotein]]s, wrapped around a central core. The central core contains the viral [[RNA]] [[genome]] and other viral proteins that package and protect this RNA.<ref name=Lamb/> Unusually for a virus, its genome is not a single piece of [[nucleic acid]]; instead, it contains seven or eight pieces of segmented [[negative-sense]] RNA, each piece of RNA contains either one or two [[gene]]s.<ref name=Bouvier/> The influenza A genome contains 11 genes in total, encoding for 11 [[protein]]s: [[hemagglutinin]] (HA), [[neuraminidase]] (NA), nucleoprotein (NP), [[M1 protein|M1]], [[M2 protein|M2]], [[NS1 Influenza Protein|NS1]], NS2(NEP), PA, PB1, PB1-F2 and PB2.<ref name=Ghedin>{{cite journal |last=Ghedin |first=E |coauthors=Sengamalay N, Shumway M, Zaborsky J, Feldblyum T, Subbu V, Spiro D, Sitz J, Koo H, Bolotov P, Dernovoy D, Tatusova T, Bao Y, St George K, Taylor J, Lipman D, Fraser C, Taubenberger J, Salzberg S |title=Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution |journal=Nature |volume=437 |issue=7062 |pages=1162–6 |year=2005 |month=October 20 |pmid=16208317 |doi=10.1038/nature04239}}</ref>

Hemagglutinin (HA) and neuraminidase (NA) are the two large glycoproteins on the outside of the viral particles.  HA is a [[lectin]] that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles.<ref>{{cite journal |last=Suzuki |first=Y |title=Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses |url= http://www.jstage.jst.go.jp/article/bpb/28/3/399/_pdf |journal=Biol Pharm Bull |volume=28 |issue=3 |pages=399–408 |year=2005 |pmid=15744059 |doi=10.1248/bpb.28.399}}</ref> Thus, these proteins are targets for [[antiviral drugs]].<ref name=Itzstein>{{cite journal |last=Wilson |first=J |coauthors=von Itzstein M |title=Recent strategies in the search for new anti-influenza therapies |journal=Curr Drug Targets |volume=4 |issue=5 |pages=389–408 |year=2003 |month=July |pmid=12816348 |doi=10.2174/1389450033491019}}</ref> Furthermore, they are [[antigen]]s to which [[antibodies]] can be raised.  Influenza A viruses are classified into subtypes based on antibody responses to HA and NA. These different types of HA and NA form the basis of the ''H'' and ''N'' distinctions in, for example, ''H5N1''.<ref name=Hilleman/> There are 16 H and 9 N subtypes, of which only H 1-3 and N 1 and 2 are commonly found in humans.<ref name=Lynch>{{cite journal |author=Lynch JP, Walsh EE |title=Influenza: evolving strategies in treatment and prevention |journal=Semin Respir Crit Care Med |volume=28 |issue=2 |pages=144–58 |year=2007 |month=April |pmid=17458769 |doi=10.1055/s-2007-976487}}</ref>

=== Infection and replication ===

Viruses can only replicate in living cells.<ref>{{cite journal |author=Smith AE, Helenius A |title=How viruses enter animal cells |journal=Science |volume=304 |issue=5668 |pages=237–42 |year=2004 |month=April |pmid=15073366 |doi=10.1126/science.1094823}}</ref> Influenza infection and replication is a multi-step process: firstly the virus has to bind to and enter the cell, then deliver its genome to a site where it can produce new copies of viral proteins and RNA, assemble these components into new viral particles and finally exit the host cell.<ref name=Bouvier>{{cite journal |author=Bouvier NM, Palese P |title=The biology of influenza viruses |journal=Vaccine |volume=26 Suppl 4 |pages=D49–53 |year=2008 |month=September |pmid=19230160}}</ref>

[[File:Virus Replication large.svg|thumb|400px|left|Host cell invasion and replication by the influenza virus. The steps in this process are discussed in the text.]]

Influenza viruses bind through [[hemagglutinin]] onto [[sialic acid]] sugars on the surfaces of [[epithelium|epithelial cells]]; typically in the nose, throat and [[lung]]s of mammals and [[intestine]]s of birds (Stage 1 in infection figure).<ref name=Wagner>{{cite journal |last=Wagner |first=R |coauthors=Matrosovich M, Klenk H |title=Functional balance between haemagglutinin and neuraminidase in influenza virus infections |journal=Rev Med Virol |volume=12 |issue=3 |pages=159–66 |year=2002 |month=May–June|pmid=11987141 |doi=10.1002/rmv.352}}</ref> The cell imports the virus by [[endocytosis]]. The acidic conditions in the [[endosome]] cause two events to happen: first part of the hemagglutinin protein fuses the [[viral envelope]] with the vacuole's membrane, then the M2 [[ion channel]] allows [[proton]]s to move through the viral envelope and acidify the core of the virus, which causes the core to dissemble and release the viral RNA and core proteins.<ref name=Bouvier/> The viral RNA (vRNA) molecules, accessory proteins and [[RNA-dependent RNA polymerase]] are then released into the [[cytoplasm]] (Stage 2).<ref>{{cite journal |last=Lakadamyali |first=M |coauthors=Rust M, Babcock H, Zhuang X |title=Visualizing infection of individual influenza viruses |journal=Proc Natl Acad Sci U S a |volume=100 |issue=16 |pages=9280–5 |year=2003 |month=August 5 |pmid=12883000 |doi=10.1073/pnas.0832269100}}</ref> It is the action of the M2 ion channel that is blocked by [[amantadine]] drugs, preventing infection.<ref>{{cite journal |author=Pinto LH, Lamb RA |title=The M2 proton channels of influenza A and B viruses |journal=J. Biol. Chem. |volume=281 |issue=14 |pages=8997–9000 |year=2006 |month=April |pmid=16407184 |doi=10.1074/jbc.R500020200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=16407184}}</ref>

These core proteins and vRNA form a complex that is transported into the [[cell nucleus]], where the RNA-dependent RNA polymerase begins transcribing complementary positive-sense vRNA (Steps 3a and b).<ref>{{cite journal |last=Cros |first=J |coauthors=Palese P |title=Trafficking of viral genomic RNA into and out of the nucleus: influenza, Thogoto and Borna disease viruses |journal=Virus Res |volume=95 |issue=1–2 |pages=3–12 |year=2003 |month=September |pmid=12921991 |doi=10.1016/S0168-1702(03)00159-X}}</ref> The vRNA is either exported into the cytoplasm and translated (step 4), or remains in the nucleus.  Newly-synthesised viral proteins are either secreted through the [[Golgi apparatus]] onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellular [[mRNA]] and using the released [[nucleotide]]s for vRNA synthesis and also inhibiting [[translation (biology)|translation]] of host-cell mRNAs.<ref>{{cite journal |last=Kash |first=J |coauthors=Goodman A, Korth M, Katze M |title=Hijacking of the host-cell response and translational control during influenza virus infection |journal=Virus Res |volume=119 |issue=1 |pages=111–20 |year=2006 |month=July |pmid=16630668 |doi=10.1016/j.virusres.2005.10.013}}</ref>

Negative-sense vRNAs that form the [[genome]]s of future viruses, RNA-dependent RNA polymerase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the cell membrane. The vRNA and [[Capsid|viral core]] proteins leave the nucleus and enter this membrane protrusion (step 6). The mature virus buds off from the cell in a sphere of host [[Lipid bilayer|phospholipid membrane]], acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).<ref>{{cite journal |last=Nayak |first=D |coauthors=Hui E, Barman S |title=Assembly and budding of influenza virus |journal=Virus Res |volume=106 |issue=2 |pages=147–65 |year=2004 |month =December |pmid=15567494 |doi=10.1016/j.virusres.2004.08.012}}</ref> As before, the viruses adhere to the cell through hemagglutinin; the mature viruses detach once their [[neuraminidase]] has cleaved sialic acid residues from the host cell.<ref name=Wagner/> Drugs that inhibit neuraminidase, such as [[oseltamivir]], therefore prevent the release of new infectious viruses and halt viral replication.<ref name=Itzstein/> After the release of new influenza viruses, the host cell dies.

Because of the absence of RNA [[proofreading (biology)|proofreading]] enzymes, the RNA-dependent RNA polymerase makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, the majority of newly-manufactured influenza viruses are mutants, this causes "antigenic drift", which is a slow change in the antigens on the viral surface over time.<ref>{{cite journal |last=Drake |first=J |title=Rates of spontaneous mutation among RNA viruses |journal=Proc Natl Acad Sci USA |volume=90 |issue=9 |pages=4171–5 |year=1993 |month=1 May |pmid=8387212 |doi=10.1073/pnas.90.9.4171}}</ref> The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one type of influenza virus infects a single cell. The resulting rapid change in viral genetics produces [[antigenic shift]]s, which are sudden changes from one antigen to another. These sudden large changes allow the virus to infect new host species and quickly overcome protective immunity.<ref name=Hilleman/> This is important in the emergence of pandemics, as discussed below in the section on [[#Epidemiology|Epidemiology]].

== Symptoms and diagnosis ==

[[File:Symptoms of influenza.svg|thumb|250px|Symptoms of influenza,<ref>[http://www.cdc.gov/flu/symptoms.htm Centers for Disease Control and Prevention > Influenza Symptoms] Page last updated November 16, 2007. Retrieved April 28, 2009</ref>, with fever and cough the most common symptoms.<ref name="pmid15728170"/>]]

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 38-39 °C (approximately 100-103 °F).<ref>{{cite journal |author=Suzuki E, Ichihara K, Johnson AM |title=Natural course of fever during influenza virus infection in children |journal=Clin Pediatr (Phila) |volume=46 |issue=1 |pages=76–9 |year=2007 |month=January |pmid=17164515 |doi=10.1177/0009922806289588}}</ref> 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.<ref name=Merck /> Symptoms of influenza may include:

* Body aches, especially joints and throat
* Extreme coldness and [[fever]]
* [[Fatigue (medical)|Fatigue]]
* [[Headache]]
* Irritated watering eyes
* Reddened eyes, skin (especially face), mouth, throat and nose
* [[Abdominal pain]] (in children with influenza B)<ref>{{cite journal |author=Kerr AA, McQuillin J, Downham MA, Gardner PS |title=Gastric 'flu influenza B causing abdominal symptoms in children |journal=Lancet |volume=1 |issue=7902 |pages=291–5 |year=1975 |pmid=46444 |doi=10.1016/S0140-6736(75)91205-2}}</ref>

It can be difficult to distinguish between the [[common cold]] and influenza in the early stages of these infections,<ref name=Eccles/> but a flu can be identified by a high fever with a sudden onset and extreme fatigue. Diarrhea is not normally a symptom of influenza in adults,<ref name="pmid15728170"/> although it has been seen in some human cases of the [[H5N1]] "bird flu"<ref>{{cite journal |author=Hui DS |title=Review of clinical symptoms and spectrum in humans with influenza A/H5N1 infection |journal=Respirology |volume=13 Suppl 1 |issue= |pages=S10–3 |year=2008 |month=March |pmid=18366521 |doi=10.1111/j.1440-1843.2008.01247.x}}</ref> and can be a symptom in children.<ref>{{cite journal |author=Richards S |title=Flu blues |journal=Nurs Stand |volume=20 |issue=8 |pages=26–7 |year=2005 |pmid=16295596}}</ref> The symptoms most reliably-seen in influenza are shown in the table to the right.<ref name="pmid15728170">{{cite journal |author=Call S, Vollenweider M, Hornung C, Simel D, McKinney W |title=Does this patient have influenza? |journal=JAMA |volume=293 |issue=8 |pages=987–97 |year=2005 |doi=10.1001/jama.293.8.987 |pmid=15728170}}</ref>

{|class="wikitable" style="text-align:center" align="right" width="40%"
|+ Most [[sensitivity (tests)|sensitive]] symptoms for diagnosing influenza<ref name="pmid15728170"/>
! Finding: !! [[sensitivity (tests)|sensitivity]] !! [[specificity (tests)|specificity]]
|-
! Fever
|68-86% ||25-73%
|-
! Cough
|84-98% || 7-29%
|-
! Nasal congestion
|68–91% ||19–41%
|-
|colspan="3" align="left"|
<small>
Notes to table:
* The ranges given represent different studies that were reviewed.
* [[Sensitivity (tests)|Sensitivity]] is the proportion of people having influenza who exhibit the symptom.
* [[Specificity (tests)|Specificity]] is the proportion of people not having influenza who do not exhibit the symptom.
* All three findings, especially fever, were less sensitive in patients over 60 years of age.
</small>
|}

Since [[Antiviral|anti-viral]] 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 conjection can improve diagnostic accuracy.<ref name="pmid11088084">{{cite journal |author=Monto A, Gravenstein S, Elliott M, Colopy M, Schweinle J |title=Clinical signs and symptoms predicting influenza infection |journal=Arch Intern Med |volume=160 |issue=21 |pages=3243–7 |year=2000 |pmid=11088084 | doi = 10.1001/archinte.160.21.3243 |url=http://archinte.ama-assn.org/cgi/content/abstract/160/21/3243}}</ref> Two [[decision analysis]] studies<ref name="pmif12361816">{{cite journal |author=Smith K, Roberts M |title=Cost-effectiveness of newer treatment strategies for influenza |journal=Am J Med |volume=113 |issue=4 |pages=300–7 |year=2002 |doi=10.1016/S0002-9343(02)01222-6 |pmid=12361816}}</ref><ref name="pimd12965940">{{cite journal |author=Rothberg M, Bellantonio S, Rose D |title=Management of influenza in adults older than 65 years of age: cost-effectiveness of rapid testing and antiviral therapy |journal=Ann Intern Med |volume=139 |issue=5 Pt 1 |pages=321–9 |year=2003 |url=http://www.annals.org/cgi/content/abstract/139/5_Part_1/321 |pmid=12965940 |month=Sep |day=02}}</ref> suggest that ''during local outbreaks'' of influenza, the prevalence will be over 70%,<ref name="pimd12965940"/> and thus patients with any of these combinations of symptoms may be treated with neuramidase 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%.<ref name="pimd12965940"/>

=== Laboratory tests ===
The available laboratory tests for influenza continue to get better. The United States [[Centers for Disease Control and Prevention]] (CDC) maintains an up-to-date summary of available laboratory tests.<ref>Centers for Disease Control and Prevention. [http://www.cdc.gov/flu/professionals/labdiagnosis.htm Lab Diagnosis of Influenza.]  Accessed on 1 January 2007</ref> According to the CDC, rapid diagnostic tests have a sensitivity of 70–75% and specificity of 90–95% 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 peri-influenza season (prevalence=10%<ref name="pimd12965940"/>).

==Prognosis==
Influenza's effects are much more severe and last longer than those of the [[common cold]]. Most people will recover in about one to two weeks, but others will develop life-threatening complications (such as [[pneumonia]]).. Influenza, however, can be deadly, especially for the weak, old or chronically ill.<ref name=Hilleman/> The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experience [[Dyspnea|shortness of breath]] while they have the flu, and influenza may cause worsening of [[coronary heart disease]] or [[congestive heart failure]].<ref>{{cite journal |author=Angelo SJ, Marshall PS, Chrissoheris MP, Chaves AM |title=Clinical characteristics associated with poor outcome in patients acutely infected with Influenza A |journal=Conn Med |volume=68 |issue=4 |pages=199–205 |year=2004 |month=April |pmid=15095826 }}</ref> [[Tobacco smoking|Smoking]] is another [[risk factor]] associated with more serious disease and increased mortality from influenza.<ref>{{cite journal |author=Murin S, Bilello K |title=Respiratory tract infections: another reason not to smoke |journal=Cleve Clin J Med |volume=72 |issue=10 |pages=916–20 |year=2005 |pmid=16231688 |doi=10.3949/ccjm.72.10.916}}</ref> 

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."<ref>Peter M. Sandman and Jody Lanard [http://www.paho.org/English/DD/PIN/Number22_article1a.htm "Bird Flu: Communicating the Risk"] 2005 ''Perspectives in Health Magazine'' Vol. 10 issue 2.</ref> 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]], [[Paranasal sinus|sinus]], and [[ear infection]]s.<ref name=CDCkeyfacts> [http://www.cdc.gov/flu/protect/keyfacts.htm Key Facts about Influenza (Flu) Vaccine] CDC publication. Published 17 October 2006. Accessed 18 Oct 2006.</ref>

Common symptoms of the flu such as fever, headaches, and fatigue come from the huge amounts of proinflammatory [[cytokine]]s and [[chemokine]]s (such as [[interferon]] or [[Tumor necrosis factor-alpha|tumor necrosis factor]]) produced from influenza-infected cells.<ref name=Eccles/><ref>{{cite journal |author=Schmitz N, Kurrer M, Bachmann M, Kopf M |title=Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection |journal=J Virol |volume=79 |issue=10 |pages=6441–8 |year=2005 |pmid=15858027 | doi = 10.1128/JVI.79.10.6441-6448.2005}}</ref> In contrast to the [[rhinovirus]] that causes the [[common cold]], influenza does cause tissue damage, so symptoms are not entirely due to the [[Inflammation|inflammatory response]].<ref>{{cite journal |author=Winther B, Gwaltney J, Mygind N, Hendley J |title=Viral-induced rhinitis |journal=Am J Rhinol |volume=12 |issue=1 |pages=17–20 |year=1998|pmid=9513654 |doi=10.2500/105065898782102954}}</ref> This massive immune response can produce a life-threatening [[cytokine storm]]. This effect has been proposed to be the cause of the unusual lethality of both the H5N1 avian influenza,<ref>{{cite journal |author=Cheung CY, Poon LL, Lau AS, ''et al'' |title=Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? |journal=Lancet |volume=360 |issue=9348 |pages=1831–7 |year=2002 |month=December |pmid=12480361}}</ref> and the 1918 pandemic strain.<ref>{{cite journal |author=Kobasa D, Jones SM, Shinya K, ''et al'' |title=Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus |journal=Nature |volume=445 |issue=7125 |pages=319–23 |year=2007 |month=January |pmid=17230189 |doi=10.1038/nature05495}}</ref><ref>{{cite journal |author=Kash JC, Tumpey TM, Proll SC, ''et al'' |title=Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus |journal=Nature |volume=443 |issue=7111 |pages=578–81 |year=2006 |month=October |pmid=17006449 |pmc=2615558 |doi=10.1038/nature05181 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17006449}}</ref>

In some cases, an [[autoimmune]] response to an influenza infection may contribute to the development of [[Guillain-Barré syndrome]].<ref name=Sivadon-Tardy>{{cite journal |author=Sivadon-Tardy V, Orlikowski D, Porcher R, ''et al'' |title=Guillain-Barré syndrome and influenza virus infection |journal=Clin. Infect. Dis. |volume=48 |issue=1 |pages=48–56 |year=2009 |month=January |pmid=19025491 |doi=10.1086/594124}}</ref> However, as many other infections can increase the risk of this disease, influenza may only be an important cause during epidemics.<ref>{{cite journal |author=Jacobs BC, Rothbarth PH, van der Meché FG, ''et al'' |title=The spectrum of antecedent infections in Guillain-Barré syndrome: a case-control study |journal=Neurology |volume=51 |issue=4 |pages=1110–5 |year=1998 |month=October |pmid=9781538}}</ref><ref name=Sivadon-Tardy/> This syndrome can also be a rare side-effect of influenza vaccines, with an incidence of about one case per million vaccinations.<ref>{{cite journal |author=Vellozzi C, Burwen DR, Dobardzic A, Ball R, Walton K, Haber P |title=Safety of trivalent inactivated influenza vaccines in adults: Background for pandemic influenza vaccine safety monitoring |journal=Vaccine |volume=27 |issue=15 |pages=2114–2120 |year=2009 |month=March |pmid=19356614 |doi=10.1016/j.vaccine.2009.01.125}}</ref>

== Epidemiology ==
=== Seasonal variations ===
{{further|[[Flu season]]}}

Influenza reaches peak prevalence in winter, and because the [[Northern Hemisphere|Northern]] and [[Southern Hemisphere]]s have winter at different times of the year, there are actually two different flu seasons each year. This is why the [[World Health Organization]] (assisted by the [[National Influenza Centers]]) makes recommendations for two different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.<ref name= WHOrecommendation>[http://www.who.int/csr/disease/influenza/2007northreport.pdf  Recommended composition of influenza virus vaccines for use in the 2006–2007 influenza season] WHO report 2006-02-14. Accessed 19 October 2006.</ref>

It is not clear why outbreaks of the flu occur seasonally rather than uniformly throughout the year. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Another is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The virus may also survive longer on exposed surfaces (doorknobs, countertops, etc.) in colder temperatures. Increased travel due to the Northern Hemisphere winter holiday season may also play a role.<ref name="NPR2003-12-17">[http://www.npr.org/templates/story/story.php?storyId=1551913 Weather and the Flu Season] NPR Day to Day, 17 December 2003. Accessed, 19 October 2006</ref> A contributing factor is that aerosol transmission of the virus is highest in cold environments (less than 5&nbsp;°C) with low humidity.<ref>{{cite journal |author=Lowen AC, Mubareka S, Steel J, Palese P |title=Influenza virus transmission is dependent on relative humidity and temperature |journal=PLoS Pathog. |volume=3 |issue=10 |pages=1470–6 |year=2007 |pmid=17953482 |pmc=2034399 | doi = 10.1371/journal.ppat.0030151}}</ref> However, seasonal changes in infection rates also occur in tropical regions, and these peaks of infection are seen mainly during the rainy season.<ref>Shek LP, Lee BW. "Epidemiology and seasonality of [[respiratory tract]] virus infections in the tropics." ''Paediatr Respir Rev.'' 2003 Jun;4(2):105–11. PMID 12758047</ref> Seasonal changes in contact rates from school terms, which are a major factor in other [[List of childhood diseases|childhood diseases]] such as [[measles]] and [[pertussis]], may also play a role in the flu.  A combination of these small seasonal effects may be amplified by dynamical resonance with the endogenous disease cycles.<ref>Dushoff J, Plotkin JB, Levin SA, Earn DJ. "Dynamical resonance can account for seasonality of influenza epidemics." ''Proc Natl Acad Sci U S A.'' 30 November 2004;101(48):16915–6. PMID 15557003</ref> [[H5N1]] exhibits seasonality in both humans and birds.<ref name=WHOH5N1data>[http://www.who.int/csr/disease/avian_influenza/country/en/ WHO Confirmed Human Cases of H5N1] Data published by WHO Epidemic and Pandemic Alert and Response (EPR). Accessed 24 Oct. 2006</ref>

An alternative hypothesis to explain seasonality in influenza infections is an effect of [[vitamin D]] levels on immunity to the virus.<ref>{{cite journal |last=Cannell |first=J |coauthors=Vieth R, Umhau J, Holick M, Grant W, Madronich S, Garland C, Giovannucci E |title=Epidemic influenza and vitamin D |journal=Epidemiol Infect |volume=134 |issue=6 |pages=1129–40 |year=2006 |pmid=16959053 |doi=10.1017/S0950268806007175}}</ref> This idea was first proposed by [[Robert Edgar Hope-Simpson]] in 1965.<ref>{{cite journal |last=HOPE-SIMPSON |first=R |title=The nature of herpes zoster: a long-term study and a new hypothesis |journal=Proc R Soc Med |volume=58 |issue=|pages=9–20 |year=|pmid=14267505}}</ref> He proposed that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of vitamin D, which is produced in the skin under the influence of solar (or artificial) [[ultraviolet|UV radiation]]. This could explain why influenza occurs mostly in winter and during the tropical rainy season, when people stay indoors, away from the sun, and their vitamin D levels fall.

=== Epidemic and pandemic spread ===
{{further|[[Flu pandemic]]}}

[[File:Antigenic drift vs shift.png|thumb|right|300px|[[Antigenic drift]] creates influenza viruses with slightly modified antigens, while [[antigenic shift]] generates viruses with entirely novel antigens.]]
[[File:Influenza geneticshift.jpg|thumb|right|300px|How antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human influenza]]

As influenza is caused by a variety of species and strains of [[virus]]es, in any given year some strains can die out while others create [[epidemic]]s, while yet another strain can cause a [[pandemic]]. Typically, in a year's normal two [[flu season]]s (one per hemisphere), there are between three and five million cases of severe illness and up to 500,000 deaths worldwide, which by some definitions is a yearly influenza epidemic.<ref>[http://www.who.int/mediacentre/factsheets/fs211/en/ Influenza] WHO Fact sheet No. 211 revised March 2003. Accessed 22 October 2006</ref>  Although the incidence of influenza can vary widely between years, approximately 36,000 deaths and more than 200,000 hospitalizations are directly associated with influenza every year in America.<ref>{{cite journal |last=Thompson |first=W |coauthors=Shay D, Weintraub E, Brammer L, Cox N, Anderson L, Fukuda K |title=Mortality associated with influenza and respiratory syncytial virus in the United States |url=http://jama.ama-assn.org/cgi/content/full/289/2/179 |journal=JAMA |volume=289 |issue=2 |pages=179–86 |year=2003 |pmid=12517228 |doi=10.1001/jama.289.2.179}}</ref><ref>{{cite journal |last=Thompson |first=W |coauthors=Shay D, Weintraub E, Brammer L, Bridges C, Cox N, Fukuda K |title=Influenza-associated hospitalizations in the United States |url= http://jama.ama-assn.org/cgi/content/full/292/11/1333 |journal=JAMA |volume=292 |issue=11 |pages=1333–40 |year=2004 |pmid=15367555 |doi=10.1001/jama.292.11.1333}}</ref> Roughly three times per century, a pandemic occurs, which infects a large proportion of the world's population and can kill tens of millions of people (see history section). Indeed, if a strain with similar [[virulence]] to the 1918 influenza emerged today, it could kill between 50 and 80 million people.<ref>{{cite journal |author=Murray CJ, Lopez AD, Chin B, Feehan D, Hill KH |title=Estimation of potential global pandemic influenza mortality on the basis of vital registry data from the 1918-20 pandemic: a quantitative analysis |journal=Lancet |volume=368 |issue=9554 |pages=2211–8 |year=2006 |month=December |pmid=17189032 |doi=10.1016/S0140-6736(06)69895-4}}</ref>

New influenza viruses are constantly being produced by [[mutation]] or by [[reassortment]].<ref name= hay/> Mutations can cause small changes in the [[hemagglutinin]] and [[neuraminidase]] [[antigen]]s on the surface of the virus. This is called [[antigenic drift]], which creates an increasing variety of strains over time until one of the variants eventually achieves higher [[fitness (biology)|fitness]], becomes dominant, and rapidly sweeps through the human population—often causing an epidemic.<ref>{{cite journal |author=Wolf, Yuri I|title=Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza A virus |journal=Biol Direct |volume=1 |issue=1 |pages=34 |year=2006 |pmid=17067369|doi=10.1186/1745-6150-1-34}}</ref>  In contrast, when influenza viruses reassort, they may acquire new antigens—for example by reassortment between avian strains and human strains; this is called antigenic shift.  If a human influenza virus is produced with entirely novel antigens, everybody will be susceptible, and the novel influenza will spread uncontrollably, causing a pandemic.<ref>{{cite journal |last=Parrish |first=C |coauthors=Kawaoka Y |title=The origins of new pandemic viruses: the acquisition of new host ranges by canine parvovirus and influenza A viruses |journal=Annual Rev Microbiol |volume=59 |issue=|pages=553–86 |year=2005|pmid=16153179 |doi=10.1146/annurev.micro.59.030804.121059}}</ref> In contrast to this model of pandemics based on antigenic drift and shift, an alternative approach has been proposed where the periodic pandemics are produced by interactions of a fixed set of viral strains with a human population with a constantly changing set of immunities to different viral strains.<ref>{{cite journal |author=Recker M, Pybus OG, Nee S, Gupta S |title=The generation of influenza outbreaks by a network of host immune responses against a limited set of antigenic types |url=http://www.pnas.org/cgi/content/full/104/18/7711 |journal=Proc Natl Acad Sci U S A.  |volume=104 |issue=18 |pages=7711–7716 |year=2007 |pmid=17460037 | doi = 10.1073/pnas.0702154104}}</ref>

== Prevention ==
=== Vaccination ===
{{further|[[Influenza vaccine]]}}

Vaccination against influenza with an [[influenza vaccine]] is often recommended for high-risk groups, such as children and the elderly, or in people who have [[asthma]], [[diabetes]], or [[heart disease]]. Influenza vaccines can be produced in several ways; the most common method is to grow the virus in fertilized [[chicken|hen]] eggs.  After purification, the virus is inactivated (for example, by treatment with detergent) to produce an inactivated-virus vaccine. Alternatively, the virus can be grown in eggs until it loses [[virulence]] and the avirulent virus given as a live vaccine.<ref name=Hilleman/> The effectiveness of these influenza vaccines is variable. 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, allowing [[pharmaceutical company|pharmaceutical companies]] to develop vaccines that will provide the best immunity against these strains.<ref name= WHOrecommendation/> Vaccines have also been developed to protect [[poultry]] from [[avian influenza]]. These vaccines can be effective against multiple strains and are used either as part of a preventative strategy, or combined with [[culling]] in attempts to eradicate outbreaks.<ref>{{cite journal |last=Capua |first=I |coauthors=Alexander D |title=The challenge of avian influenza to the veterinary community |url= http://www.informaworld.com/smpp/section?content=a747651074&fulltext=713240928 |journal=Avian Pathol |volume=35 |issue=3 |pages=189–205 |year=2006 |pmid=16753610 |doi=10.1080/03079450600717174}}</ref>

It is possible to get vaccinated and still get influenza.  The vaccine is reformulated each season for a few specific flu strains but cannot possibly include all the strains actively infecting people in the world for 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 and infects people although they have been vaccinated (as by the [[Fujian flu|H3N2 Fujian flu]] in the 2003–2004 flu season).<ref>{{cite journal |last=Holmes |first=E |coauthors=Ghedin E, Miller N, Taylor J, Bao Y, St George K, Grenfell B, Salzberg S, Fraser C, Lipman D, Taubenberger J |title=Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses |journal=PLoS Biol |volume=3 |issue=9 |pages=e300 |year=2005 |pmid=16026181 |doi=10.1371/journal.pbio.0030300}}</ref> It is also possible to get infected just before vaccination and get sick with the very strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.<ref name=CDCkeyfacts/> 

The 2006–2007 season was the first in which the CDC had recommended that children younger than 59 months receive the annual influenza vaccine.<ref name=cdcreport> [http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5510a1.htm Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP)] CDC report (MMWR 2006 Jul 28;55(RR10):1–42) accessed 19 Oct 2006.</ref> 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|side-effect]] is a severe [[allergy|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.<ref>[http://www.cdc.gov/flu/about/qa/flushot.htm  Questions & Answers: Flu Shot] CDC publication updated Jul 24, 2006. Accessed 19 Oct 06.</ref>
[[File:Vaccination US Navy.jpg|thumb|240px|left|Administration of an influenza vaccination.]]

=== Infection control ===
[[Influenza pandemic#Personal health and hygiene|Good personal health and hygiene habits]], like [[Hand washing‎|hand washing]], avoiding spitting, and covering the nose and mouth whan sneezing or coughing, are reasonably effective in avoiding and minimizing influenza.<ref name=Aledort>{{cite journal |author=Aledort JE, Lurie N, Wasserman J, Bozzette SA |title=Non-pharmaceutical public health interventions for pandemic influenza: an evaluation of the evidence base |journal=BMC Public Health |volume=7 |issue= |pages=208 |year=2007 |pmid=17697389 |pmc=2040158 |doi=10.1186/1471-2458-7-208 |url=}}</ref> These simple personal hygiene precautions are recommended as the main way of reducing influenza transmission during pandemics.<ref name=Aledort/> Although face masks might help reduce transmission when caring for the sick,<ref>{{cite journal |author=MacIntyre CR, Cauchemez S, Dwyer DE, ''et al'' |title=Face mask use and control of respiratory virus transmission in households |journal=Emerging Infect. Dis. |volume=15 |issue=2 |pages=233–41 |year=2009 |month=February |pmid=19193267 |pmc=2662657 |url=http://www.cdc.gov/eid/content/15/2/233_cme_activity.htm |doi=10.3201/eid1502.081167}}</ref><ref>{{cite journal |author=Bridges CB, Kuehnert MJ, Hall CB |title=Transmission of influenza: implications for control in health care settings |journal=Clin. Infect. Dis. |volume=37 |issue=8 |pages=1094–101 |year=2003 |month=October |pmid=14523774 |doi=10.1086/378292}}</ref> the evidence on if they reduce transmission in the community is mixed.<ref name=Aledort/><ref>[http://www.cdc.gov/flu/professionals/infectioncontrol/maskguidance.htm Interim Guidance for the Use of Masks to Control Influenza Transmission] ''Coordinating Center for Infectious Diseases (CCID)'' August 8, 2005</ref>

People who contract influenza are most infective between the second and third days after infection and infectivity lasts for around ten days.<ref name=Carrat>{{cite journal |author=Carrat F, Luong J, Lao H, Sallé A, Lajaunie C, Wackernagel H |title=A 'small-world-like' model for comparing interventions aimed at preventing and controlling influenza pandemics  |pmc=1626479 |journal=BMC Med |volume=4 |issue= |pages=26 |year= 2006|pmid=17059593 |doi=10.1186/1741-7015-4-26}}</ref> Children are notably more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection.<ref name=Carrat/><ref>{{cite journal |author=Mitamura K, Sugaya N |title=[Diagnosis and Treatment of influenza—clinical investigation on [[viral shedding]] in children with influenza] |journal=Uirusu |volume=56 |issue=1 |pages=109–16 |year=2006 |pmid=17038819 |doi=10.2222/jsv.56.109}}</ref> When small numbers of people are infected, isolation might reduce the risk of transmission.<ref name=Aledort/>

Since influenza spreads through both [[particulate|aerosols]] and contact with contaminated surfaces, surface sanitizing is recommended in areas where influenza may be present on surfaces.<ref>{{cite journal |author=Hota B |title=Contamination, disinfection, and cross-colonization: are hospital surfaces reservoirs for nosocomial infection? |journal=Clin Infect Dis |volume=39 |issue=8 |pages=1182–9 |year=2004 |pmid=15486843 | doi = 10.1086/424667}}</ref> [[Alcohol]] is an effective sanitizer against influenza viruses, while [[quaternary ammonium]] compounds can be used with alcohol to increase the duration of the sanitizing action.<ref name=McDonnell>{{cite journal |author=McDonnell G, Russell A |title=Antiseptics and disinfectants: activity, action, and resistance |url=http://cmr.asm.org/cgi/content/full/12/1/147?view=long&pmid=9880479 |journal=Clin Microbiol Rev |volume=12 |issue=1 |pages=147–79 |year=1999 |pmid=9880479 |month=Jan |day=01}}</ref> In hospitals, [[Quaternary ammonium cation|quaternary ammonium compounds]] and halogen-releasing agents such as [[sodium hypochlorite]] (bleach) are commonly used to sanitize rooms or equipment that have been occupied by patients with influenza symptoms.<ref name=McDonnell/> 

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.<ref>{{cite journal |author=Hatchett RJ, Mecher CE, Lipsitch M |title=Public health interventions and epidemic intensity during the 1918 influenza pandemic |url=http://www.pnas.org/cgi/content/full/104/18/7582 |journal=Proc Natl Acad Sci U S A. |volume=104 |issue=18 |pages=7582–7587 |year=2007 |pmid=17416679 | doi = 10.1073/pnas.0610941104}}</ref><ref>{{cite journal |author=Bootsma MC, Ferguson NM |title=The effect of public health measures on the 1918 influenza pandemic in U.S. cities |url=http://www.pnas.org/cgi/content/full/104/18/7588 |journal=Proc Natl Acad Sci U S A. |volume=104 |issue=18 |pages=7588–7593 |year=2007 |pmid=17416677 | doi = 10.1073/pnas.0611071104}}</ref> 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.<ref name=Aledort/>

== Treatment ==
{{further|[[Influenza treatment]]}}

People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid using [[alcoholic beverage|alcohol]] and [[tobacco smoking|tobacco]] and, if necessary, take medications such as [[paracetamol]] (acetaminophen) to relieve the fever and muscle aches associated with the flu.  Children and teenagers with flu symptoms (particularly fever) should avoid taking [[aspirin]] during an influenza infection (especially [[Influenzavirus B|influenza type B]]), because doing so can lead to [[Reye's syndrome]], a rare but potentially fatal disease of the [[liver]].<ref>{{cite journal |last=Glasgow |first=J |coauthors=Middleton B |title=Reye syndrome — insights on causation and prognosis |url=http://adc.bmjjournals.com/cgi/content/full/85/5/351 |journal=Arch Dis Child |volume=85 |issue=5 |pages=351–3 |year=2001 |pmid=11668090 |doi=10.1136/adc.85.5.351}}</ref> Since influenza is caused by a virus, [[antibiotic]]s have no effect on the infection; unless prescribed for [[secondary infection]]s such as [[bacterial pneumonia]].  Antiviral medication can be effective, but some strains of influenza can show resistance to the standard antiviral drugs.<ref>{{cite journal |author=Hurt AC, Ho HT, Barr I |title=Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors |journal=Expert Rev Anti Infect Ther |volume=4 |issue=5 |pages=795–805 |year=2006 |month=October |pmid=17140356 |doi=10.1586/14787210.4.5.795}}</ref>

The two classes of antiviral drugs used against influenza are neuraminidase inhibitors and [[M2 protein]] inhibitors ([[adamantane]] derivatives). Neuraminidase inhibitors are currently preferred for flu virus infections since they are less toxic and more effective.<ref>{{cite journal |author=Beigel J, Bray M |title=Current and future antiviral therapy of severe seasonal and avian influenza |journal=Antiviral Res. |volume=78 |issue=1 |pages=91–102 |year=2008 |month=April |pmid=18328578 |pmc=2346583 |doi=10.1016/j.antiviral.2008.01.003}}</ref> The CDC recommended against using M2 inhibitors during the 2005–06 influenza season due to high levels of [[drug resistance]].<ref>Centers for Disease Control and Prevention. [http://www.cdc.gov/flu/han011406.htm CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005–06 Influenza Season.] 14 January 2006.  Retrieved on [[2007-01-01]]</ref>

=== Neuraminidase inhibitors ===
Antiviral drugs such as [[oseltamivir]] (trade name Tamiflu) and [[zanamivir]] (trade name Relenza) are [[neuraminidase inhibitor]]s that are designed to halt the spread of the virus in the body.<ref name= Neuraminidase_inhibitors>{{cite journal |last=Moscona |first=A |title=Neuraminidase inhibitors for influenza |url=http://content.nejm.org/cgi/content/full/353/13/1363 |journal=N Engl J Med |volume=353 |issue=13 |pages=1363–73 |year=2005 |pmid=16192481 |doi=10.1056/NEJMra050740}}</ref> These drugs are often effective against both influenza A and B.<ref name=Stephenson/> The [[Cochrane Collaboration]] reviewed these drugs and concluded that they reduce symptoms and complications.<ref name="pmid16855962">{{cite journal |last=Jefferson |first=T |coauthors=Demicheli V, Di Pietrantonj C, Jones M, Rivetti D |title=Neuraminidase inhibitors for preventing and treating influenza in healthy adults |journal=Cochrane Database Syst Rev |volume=3 |issue=|pages=CD001265 |year=2006|doi=10.1002/14651858.CD001265.pub2 |pmid=16855962}}</ref>  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.<ref> {{cite journal |last=Webster |first=Robert G. |title=H5N1 Influenza — Continuing Evolution and Spread |url=http://content.nejm.org/cgi/content/full/355/21/2174 |journal=N Engl J Med |volume=355 |issue=21 |pages=2174–77 |year=2006 |pmid=16192481 |doi=10.1056/NEJMp068205}}</ref>

=== M2 inhibitors (adamantanes) ===
The [[antiviral drug]]s [[amantadine]] and [[rimantadine]] are designed to block a viral [[ion channel]] ([[M2 protein]]) and prevent the virus from infecting cells. These drugs are sometimes effective against influenza A if given early in the infection but are always ineffective against influenza B.<ref name= Stephenson>{{cite journal |last=Stephenson |first=I |coauthors=Nicholson K |title=Chemotherapeutic control of influenza |url=http://jac.oxfordjournals.org/cgi/content/full/44/1/6 |journal=J Antimicrob Chemother |volume=44 |issue=1 |pages=6–10 |year=1999 |pmid=10459804 |doi=10.1093/jac/44.1.6}}</ref>  Measured resistance to amantadine and rimantadine in American isolates of [[H3N2]] has increased to 91% in 2005.<ref>{{cite journal |author=|title=High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents — United States, 2005–06 influenza season |url=http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5502a7.htm |journal=MMWR Morb Mortal Wkly Rep |volume=55 |issue=2 |pages=44–6 |year=2006 |pmid=16424859}}</ref>

== Research ==
{{further|[[Influenza research]]}}
[[File:Influenza virus research.jpg|thumb|210px|right|CDC scientist working on influenza under high bio-safety conditions]]

Research on influenza includes studies on [[molecular virology]], how the virus produces disease ([[pathogenesis]]), host [[immune response]]s, [[genomics|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 [[Research|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 [[evolution|evolves]] over time.<ref> [http://msc.tigr.org/infl_a_virus/index.shtml Influenza A Virus Genome Project] at The Institute of Genomic Research. Accessed 19 Oct 06</ref>

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.<ref>{{cite journal |author=Subbarao K, Katz J |title=Influenza vaccines generated by reverse genetics |journal=Curr Top Microbiol Immunol |volume=283 |issue=|pages=313–42 |year=|pmid=15298174}}</ref> New technologies are also being developed to grow viruses in [[cell culture]], which promises higher yields, less cost, better quality and surge capacity.<ref>{{cite journal |author=Bardiya N, Bae J |title=Influenza vaccines: recent advances in production technologies |url=http://www.springerlink.com/content/jdt26gc39v4bwk9q/ |journal=Appl Microbiol Biotechnol |volume=67 |issue=3 |pages=299–305 |year=2005 |pmid=15660212 | doi = 10.1007/s00253-004-1874-1}}</ref> 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<ref>{{cite journal |author=Neirynck S, Deroo T, Saelens X, Vanlandschoot P, Jou WM, Fiers W |title=A universal influenza A vaccine based on the extracellular domain of the M2 protein |journal=Nat. Med. |volume=5 |issue=10 |pages=1157–63 |year=1999 |month=October |pmid=10502819 |doi=10.1038/13484 |url=}}
</ref><ref>{{cite journal |author=Fiers W, Neirynck S, Deroo T, Saelens X, Jou WM |title=Soluble recombinant influenza vaccines |journal=Philos. Trans. R. Soc. Lond., B, Biol. Sci. |volume=356 |issue=1416 |pages=1961–3 |year=2001 |month=December |pmid=11779398 |pmc=1088575 |doi=10.1098/rstb.2001.0980 |url=}}</ref><ref>{{cite journal |author=Fiers W, De Filette M, Birkett A, Neirynck S, Min Jou W |title=A "universal" human influenza A vaccine |journal=Virus Res. |volume=103 |issue=1-2 |pages=173–6 |year=2004 |month=July |pmid=15163506 |doi=10.1016/j.virusres.2004.02.030 |url=}}</ref> and has now successfully concluded Phase I clinical trials.

The US government has purchased several million doses of vaccine from [[Sanofi Pasteur]] and [[Chiron Corporation]], meant to be used in case of an [[influenza pandemic]] of [[H5N1]] avian influenza and is conducting [[clinical trial]]s with these vaccines.<ref> [http://www.nytimes.com/2006/03/30/health/30vaccine.html?_r=1&oref=slogin New York Times article ""Doubt Cast on Stockpile of a Vaccine for Bird Flu""] by Denise Grady. Published: 30 March 2006. Accessed 19 Oct 06</ref> The UK government is also stockpiling millions of doses of antiviral drugs (oseltamivir (Tamiflu), zanimivir (Relanza)) to give to its citizens in the event of an outbreak; the UK [[Health Protection Agency]] has also gathered a limited amount of HPAI H5N1 vaccines for experimental purposes.{{facts|date=September 2007}}

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 pathway]]s like anti-viral drugs, but stimulate immune cells such as [[lymphocytes]], [[macrophages]], and/or [[antigen presenting cell]]s, 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.<ref>{{cite journal |quotes=no author= Gingerich, DA |year= 2008 |title=[Lymphocyte T-Cell Immunomodulator: Review of the ImmunoPharmacology of a new Veterinary Biologic] |journal= Journal of Applied Research in Veterinary Medicine |volume= 6 |issue= 2 |pages= 61–68 | url= http://jarvm.com/articles/Vol6Iss2/Vol6Iss2Gingerich61-68.pdf |language=English |format= |accessdate=2009-04-26}}</ref>

== Infection in other animals ==
{{H5N1}}{{further|[[Influenzavirus A]], [[H5N1]] and [[Transmission and infection of H5N1]]}}
Influenza infects many animal species, and transfer of viral strains between species can occur. [[Bird]]s are thought to be the main [[host (biology)|animal reservoirs]] of influenza viruses.<ref>{{cite journal |author=Gorman O, Bean W, Kawaoka Y, Webster R |title=Evolution of the nucleoprotein gene of influenza A virus |pmc=249282 |journal=J Virol |volume=64 |issue=4 |pages=1487–97 |year=1990 |pmid=2319644}}</ref> Sixteen forms of [[hemagglutinin]] and nine forms of [[neuraminidase]] have been identified. All known subtypes (HxNy) are found in birds, but many subtypes are endemic in humans, [[dog]]s, [[horse]]s, and [[pig]]s; populations of [[camel]]s, [[ferret]]s, [[cat]]s, [[pinniped|seals]], [[mink]], and [[whale]]s also show evidence of prior infection or exposure to influenza.<ref name=webster/> Variants of flu virus are sometimes named according to the species the strain is endemic in or adapted to. The main variants named using this convention are: [[Avian influenza|Bird Flu]], [[Human flu|Human Flu]], [[Swine flu|Swine Flu]], [[Horse flu|Horse Flu]] and [[Dog flu|Dog Flu]]. ([[Cat flu]] generally refers to [[Feline viral rhinotracheitis]] or [[Feline calicivirus]] and not infection from an influenza virus.) In pigs, horses and dogs, influenza symptoms are similar to humans, with cough, fever and [[Anorexia (symptom)|loss of appetite]].<ref name=webster/> The frequency of animal diseases are not as well-studied as human infection, but an outbreak of influenza in harbour seals caused approximately 500 seal deaths off the [[New England]] coast in 1979–1980.<ref>{{cite journal |author=Hinshaw V, Bean W, Webster R, Rehg J, Fiorelli P, Early G, Geraci J, St Aubin D |title=Are seals frequently infected with avian influenza viruses? |pmc=255856 |journal=J Virol |volume=51 |issue=3 |pages=863–5 |year=1984 |pmid=6471169}}</ref> On the other hand, outbreaks in pigs are common and do not cause severe mortality.<ref name=webster/>

===Bird flu===
Flu symptoms in birds are variable and can be unspecific.<ref>{{cite journal |author=Elbers A, Koch G, Bouma A |title=Performance of clinical signs in poultry for the detection of outbreaks during the avian influenza A (H7N7) epidemic in The Netherlands in 2003 |journal=Avian Pathol |volume=34 |issue=3 |pages=181–7 |year=2005 |pmid=16191700 | doi = 10.1080/03079450500096497}}</ref> The symptoms following infection with low-pathogenicity avian influenza may be as mild as ruffled feathers, a small reduction in egg production, or [[weight loss]] combined with minor [[respiratory disease]].<ref>Capua I, Mutinelli F. "Low pathogenicity (LPAI) and highly pathogenic (HPAI) avian inﬂuenza in turkeys and chicken." In: Capua I, Mutinelli F. (eds.), A Colour Atlas and Text on Avian Inﬂuenza, Papi Editore, Bologna, 2001, pp. 13–20</ref> Since these mild symptoms can make diagnosis in the field difficult, tracking the spread of [[avian flu|avian influenza]] requires laboratory testing of samples from infected birds. Some strains such as Asian [[H9N2]] are highly virulent to poultry and may cause more extreme symptoms and significant mortality.<ref>{{cite journal |author=Bano S, Naeem K, Malik S |title=Evaluation of pathogenic potential of avian influenza virus serotype H9N2 in chickens |journal=Avian Dis |volume=47 |issue=3 Suppl |pages=817–22 |year=2003 |pmid=14575070 |doi=10.1637/0005-2086-47.s3.817}}</ref> In its most highly pathogenic form, influenza in [[chicken]]s and [[turkey (bird)|turkeys]] produces a sudden appearance of severe symptoms and almost 100% mortality within two days.<ref>{{cite journal |author=Swayne D, Suarez D |title=Highly pathogenic avian influenza |journal=Rev Sci Tech |volume=19 |issue=2 |pages=463–82 |year=2000 |pmid=10935274}}</ref> As the virus spreads rapidly in the crowded conditions seen in the [[intensive farming]] of chickens and turkeys, these outbreaks can cause large economic losses to poultry farmers.

An avian-adapted, highly pathogenic strain of H5N1 (called HPAI A(H5N1), for "highly pathogenic avian influenza virus of type A of subtype H5N1") causes [[transmission and infection of H5N1|H5N1 flu]], commonly known as "avian influenza" or simply "bird flu", and is [[endemic (epidemiology)|endemic]] in many bird populations, especially in [[Southeast Asia]]. This Asian lineage strain of HPAI A(H5N1) is [[global spread of H5N1|spreading globally]]. It is [[epizootic]] (an epidemic in non-humans) and panzootic (a disease affecting animals of many species, especially over a wide area), killing tens of millions of birds and spurring the [[culling]] of hundreds of millions of other birds in an attempt to control its spread. Most references in the media to "bird flu" and most references to H5N1 are about this specific strain.<ref>{{cite journal |author=Li K, Guan Y, Wang J, Smith G, Xu K, Duan L, Rahardjo A, Puthavathana P, Buranathai C, Nguyen T, Estoepangestie A, Chaisingh A, Auewarakul P, Long H, Hanh N, Webby R, Poon L, Chen H, Shortridge K, Yuen K, Webster R, Peiris J |title=Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia |journal=Nature |volume=430 |issue=6996 |pages=209–13 |year=2004 |pmid=15241415 | doi = 10.1038/nature02746}}</ref><ref>Li KS, Guan Y, Wang J, Smith GJ, Xu KM, Duan L, Rahardjo AP, Puthavathana P, Buranathai C, Nguyen TD, Estoepangestie AT, Chaisingh A, Auewarakul P, Long HT, Hanh NT, Webby RJ, Poon LL, Chen H, Shortridge KF, Yuen KY, Webster RG, Peiris JS. [http://darwin.nap.edu/books/0309095042/html/116.html "The Threat of Pandemic Influenza: Are We Ready?" Workshop Summary] The National Academies Press (2005) "Today's Pandemic Threat: Genesis of a Highly Pathogenic and Potentially Pandemic H5N1 Influenza Virus in Eastern Asia", pages 116–130</ref>

At present, HPAI A(H5N1) is an avian disease, and there is no evidence suggesting efficient human-to-human transmission of HPAI A(H5N1). In almost all cases, those infected have had extensive physical contact with infected birds.<ref>{{cite journal |author=Liu J |title=Avian influenza—a pandemic waiting to happen? |url=http://jmii.org/content/pdf/v39n1p4.pdf |journal=J Microbiol Immunol Infect |volume=39 |issue=1 |pages=4–10 |year=2006 |pmid=16440117|format=PDF}}</ref> In the future, H5N1 may mutate or reassort into a strain capable of efficient human-to-human transmission. The exact changes that are required for this to happen are not well understood.<ref>{{cite journal |author=Salomon R, Webster RG |title=The influenza virus enigma |journal=Cell |volume=136 |issue=3 |pages=402–10 |year=2009 |month=February |pmid=19203576 |doi=10.1016/j.cell.2009.01.029}}</ref> However, due to the high lethality and [[virulence]] of H5N1, its [[endemic (epidemiology)|endemic]] presence, and its large and increasing biological host reservoir, the H5N1 virus was the world's pandemic threat in the 2006–07 flu season, and billions of dollars are being raised and spent researching H5N1 and preparing for a potential [[influenza pandemic]].<ref name=Rosenthal> Rosenthal, E. and Bradsher, K. [http://www.nytimes.com/2006/03/16/business/16bird.html?_r=1&oref=slogin Is Business Ready for a Flu Pandemic?] The New York Times 16-03-2006 Accessed 17-04-2006</ref>

===Swine flu===
{{Further|[[2009 swine flu outbreak]]}}
In 2009 an outbreak of [[swine flu]] occurred in Mexico. This was a variant of the [[H1N1]] strain responsible for the 1918 pandemic and was first identified in [[Mexico City]] and the surrounding area in March to April 2009.  
Seven deaths have been conclusively proved to be directly caused by this strain as they are the only ones officially recognized by the WHO as being clearly caused by this virus. The Mexican government introduced emergency measures, and sparked a coordinated international effort to contain the outbreak, which involved quarantine measures, restrictions in travel and stockpiling of treatments.<ref>{{cite web|url=http://www.who.int/csr/disease/avian_influenza/phase/en/index.html |title=WHO &#124; Current WHO phase of pandemic alert |publisher=Who.int |date= |accessdate=2009-04-27}}</ref><ref name="CDC-swineflu">{{cite web|url=http://www.cdc.gov/swineflu/|title=Swine Influenza (Flu)|publisher=CDC|date=2009-04-25|accessdate=2009-04-26}}</ref> This outbreak prompted the World Health Organization, on April 26, 2009 to declare the world one step closer to a pandemic, by raising the pandemic alert level from 3 to 4. Phase 4 refers to when there are small clusters -- e.g., <25 human cases lasting <2 weeks with limited human-to-human transmission, but when spread is highly localized, which suggests the virus has not adapted well to humans.<ref>[http://news.bbc.co.uk/2/hi/americas/8022437.stm More countries confirm swine flu] ''BBC News'' Tuesday, 28 April 2009</ref> On Wednesday 29 April the WHO raised the pandemic risk scale from 4 to 5, one below pandemic phase.

== Economic impact ==
{{further|[[Social impact of H5N1]]}}
Influenza produces [[variable cost|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.<ref>[http://www.whitehouse.gov/homeland/pandemic-influenza.html Statement from President George W. Bush on Influenza] Accessed 26 Oct 2006</ref> However, the economic impacts of past pandemics have not been intensively studied, and some authors have suggested that the [[Spanish flu|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 [[Recession|depressive]] effects.<ref>Brainerd, E. and M. Siegler (2003), “The Economic Effects of the 1918 Influenza Epidemic”, ''CEPR Discussion Paper'', no. 3791.</ref> Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the [[Economy of the United States|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.<ref>{{cite journal |author=Poland G |title=Vaccines against avian influenza—a race against time |url=http://content.nejm.org/cgi/content/full/354/13/1411 |journal=N Engl J Med |volume=354 |issue=13 |pages=1411–3 |year=2006 |pmid=16571885 | doi = 10.1056/NEJMe068047}}</ref>

Preventative costs are also high. Governments worldwide have spent billions of [[United States dollar|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 [[emergency management|disaster drills]] and strategies for improved [[border control]]s.<ref name=Rosenthal/> On 1 November 2005, [[President of the United States|United States President]] [[George W. Bush]] unveiled the National Strategy to Safeguard Against the Danger of Pandemic Influenza<ref>[http://www.whitehouse.gov/homeland/pandemic-influenza.html National Strategy for Pandemic Influenza] Whitehouse.gov Accessed 26 Oct 2006.</ref> backed by a request to [[United States Congress|Congress]] for $7.1 billion to begin implementing the plan.<ref>[http://usinfo.state.gov/gi/Archive/2005/Nov/01-432345.html Bush Outlines $7 Billion Pandemic Flu Preparedness Plan] State.gov. Accessed 26 Oct 2006</ref> 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.<ref>[http://www.ens-newswire.com/ens/jan2006/2006-01-18-02.asp Donor Nations Pledge $1.85 Billion to Combat Bird Flu] Newswire Accessed 26 Oct 2006.</ref>

== See also ==
{{commonscat|Influenza}}

<!-- Please do not add links already featured in the body of the article above -->
* [[Influenza-like illness]]
* [[List of epidemics]]
* [[List of viruses]]

;Information concerning flu research can be found at:
<div style="-moz-column-count:2; column-count:2;">
* [[Center for Biologics Evaluation and Research]]
* [[Cytokine storm]]
* [[H5N1 clinical trials]]
* [[H5N1 genetic structure]]
* [[ICEID]]
* [[Influenza Genome Sequencing Project]]
* [[Influenza research]]
* [[International Partnership on Avian and Pandemic Influenza]]
* [[National Influenza Centers]]
* [[Pandemic Preparedness and Response Act]]
</div>

== References and notes ==
{{reflist|2}}

== Further reading ==
{{Col-begin}}
{{Col-1-of-2}}
'''General'''
* {{cite journal |author=Beigel JH, Farrar J, Han AM, ''et al'' |title=Avian influenza A (H5N1) infection in humans |journal=N Engl J Med. |volume=353 |issue=13 |pages=1374–85 |year=2005 |month=September |pmid=16192482 |doi=10.1056/NEJMra052211 |url=http://content.nejm.org/cgi/content/full/353/13/1374}}
* [[Bernd Sebastian Kamps]], [[Christian Hoffmann]] and Wolfgang Preiser (Eds.) [http://www.InfluenzaReport.com/ Influenza Report 2006] Flying publisher 2006.
* {{cite book |author=Levine, Arnold J. |title=Viruses |publisher=Scientific American Library |location=New York |year=1992 |isbn=0-7167-5031-7 }}
* {{cite book |author=Baron, Samuel |title=Medical microbiology |publisher=University of Texas Medical Branch at Galveston |location=Galveston, Tex |year=1996 |isbn=0-9631172-1-1 |edition=4th |url=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed}}
* {{cite journal |author=Cox NJ, Subbarao K |title=Influenza |journal=Lancet |volume=354 |issue=9186 |pages=1277–82 |year=1999 |month=October |pmid=10520648 |doi=10.1016/S0140-6736(99)01241-6 }}
'''History'''
* {{cite journal |author=Kilbourne ED |title=Influenza pandemics of the 20th century |journal=Emerging Infect Dis. |volume=12 |issue=1 |pages=9–14 |year=2006 |month=January |pmid=16494710 |url=http://www.cdc.gov/ncidod/EID/vol12no01/05-1254.htm}}
* {{cite book |author=Collier, Richard |title=The plague of the Spanish lady: the influenza pandemic of 1918–1919 |publisher=Macmillan |location=New York |year=1974 |isbn=0-333-13864-3 }}
* {{cite book |author=Barry, John M. |title=The great influenza: the epic story of the deadliest plague in history |publisher=Viking |location=New York, N.Y |year=2004 |pages= |isbn=0-670-89473-7 }}
'''Microbiology'''
* {{cite journal |author=Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y |title=Evolution and ecology of influenza A viruses |journal=Microbiol Rev. |volume=56 |issue=1 |pages=152–79 |year=1992 |month=March |pmid=1579108 |pmc=372859 |url=http://mmbr.asm.org/cgi/pmidlookup?view=long&pmid=1579108 |day=01}}
* {{cite journal |author=Scholtissek C |title=Molecular epidemiology of influenza |journal=Arch Virol Suppl. |volume=13 |pages=99–103 |year=1997 |pmid=9413530 }}

{{Col-2-of-2}}
'''Pathogenesis'''
* {{cite journal |author=García-Sastre A |title=Antiviral response in pandemic influenza viruses |journal=Emerging Infect. Dis. |volume=12 |issue=1 |pages=44–7 |year=2006 |month=January |pmid=16494716 |url=http://www.cdc.gov/ncidod/EID/vol12no01/05-1186.htm}}
* {{cite journal |author=Zambon MC |title=The pathogenesis of influenza in humans |journal=Rev Med Virol. |volume=11 |issue=4 |pages=227–41 |year=2001 |pmid=11479929 |doi=10.1002/rmv.319}}

'''Epidemiology'''
* {{cite journal |author=Dowdle WR |title=Influenza pandemic periodicity, virus recycling, and the art of risk assessment |journal=Emerging Infect. Dis. |volume=12 |issue=1 |pages=34–9 |year=2006 |month=January |pmid=16494714 |url=http://www.cdc.gov/ncidod/EID/vol12no01/05-1013.htm}}
* {{cite journal |author=Horimoto T, Kawaoka Y |title=Pandemic threat posed by avian influenza A viruses |journal=Clin Microbiol Rev. |volume=14 |issue=1 |pages=129–49 |year=2001 |month=January |pmid=11148006 |pmc=88966 |doi=10.1128/CMR.14.1.129-149.2001 }}
* [http://www.who.int/wer/wer8126.pdf Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection]

'''Treatment and prevention'''
* {{cite journal |author=Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB |title=Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP) |journal=MMWR Recomm Rep |volume=54 |issue=RR-8 |pages=1–40 |year=2005 |month=July |pmid=16086456 }}
* {{cite journal |author=Monto AS |title=Vaccines and antiviral drugs in pandemic preparedness |journal=Emerging Infect. Dis. |volume=12 |issue=1 |pages=55–60 |year=2006 |month=January |pmid=16494718 |url=http://www.cdc.gov/ncidod/EID/vol12no01/05-1068.htm}}

'''Research'''
* {{cite journal |author=Palese P |title=Making better influenza virus vaccines? |journal=Emerging Infect. Dis. |volume=12 |issue=1 |pages=61–5 |year=2006 |month=January |pmid=16494719 |url=http://www.cdc.gov/ncidod/EID/vol12no01/05-1043.htm}}
* [http://www.who.int/csr/disease/avian_influenza/guidelines/recommendationvaccine.pdf WHO (PDF} contains latest Evolutionary "Tree of Life" for H5N1] article ''Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as pre-pandemic vaccines'' published 18 August 2006
* [http://www.who.int/csr/resources/publications/influenza/WHO_CDS_EPR_GIP_2006_3C.pdf WHO's assessment of Flu Research] as of November 2006.
{{Col-end}}

== External links ==
* [http://www.cdc.gov/flu/ Info on influenza] at [[Centers for Disease Control and Prevention|CDC]]
* [http://health.nytimes.com/health/guides/disease/the-flu/overview.html Summary of the disease] at the [[NYTimes]].
* [http://www.televisa.mobi/influenza/influenza-news.html News Influenza] 
* [http://www.outbreakalerts.com Outbreak Alerts] United States based communicable disease notification website. 
* [http://www.biohealthbase.org/influenza BioHealthBase Bioinformatics Resource Center] Database of influenza sequences and related information.
* [http://www.mayoclinic.com/health/influenza/DS00081 Influenza (Mayo Clinic)]
* [http://www.who.int/mediacentre/factsheets/fs211/en/index.html Fact Sheet] Overview of influenza at [[World Health Organization]]
* [http://http://origem.info/misms/index.php  The Multinational Influenza Seasonal Mortality Study (MISMS)] [[ Fogarty International Center]]
* [http://www.nhsdirect.nhs.uk/encyclopaedia/a-z/index.aspx Health encyclopedia entry] at [[NHS Direct]]
* [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/46000000.htm Orthomyxoviridae] The Universal Virus Database of the [[International Committee on Taxonomy of Viruses]]
* [http://www.ncbi.nlm.nih.gov/genomes/FLU/flubiology.html Influenza Virus Resource] from the [[National Center for Biotechnology Information|NCBI]]
* [http://www.eiss.org/ European Influenza Surveillance Scheme]
* [http://www.google.org/flutrends/ Flu Trends] &ndash; flu activity across the U.S.
* [https://www.nhsdirect.nhs.uk/Sat/Topics/ColdsAndFlu.aspx?Host=Nhsd&SyndicationPartnerGuid=d19370ea-a100-407d-9695-b73407f701c7&TopicGuid=8c903315-a302-412a-bfae-9cb576d4b4cd Cold and flu advice] (NHS Direct)
* [http://www.vega.org.uk/video/programme/6 Online video discussing influenza outbreaks and spread of other infectious diseases] (Vega Science Trust)

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{{Influenza}}
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[[Category:Poultry diseases]]
[[Category:Pulmonology]]
[[Category:Animal diseases]]
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