View source for Influenza

{{Short description|Infectious disease}}
{{Redirect2|Flu|Grippe|other uses|Flu (disambiguation)|and|Grippe (disambiguation)|and|Influenza (disambiguation)}}
{{Redirect|Flus|the diagnostic class of thyroid nodules|FLUS}}
{{Distinguish|Flue}}
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{{Infobox medical condition (new)
| name          = Influenza
| synonyms      = flu, grippe (French for flu)
| image         = EM of influenza virus.jpg
| caption       = Influenza virus
| field         = [[Infectious disease (medical specialty)|Infectious disease]]
| symptoms      = [[Fever]], [[rhinorrhea|runny nose]], [[sore throat]], [[Myalgia|muscle pain]], [[headache]], [[cough]]ing, [[fatigue]]
| complications =
| onset         = 1–4 days after exposure
| duration      = 2–8 days
| causes        = Influenza viruses
| risks         =
| diagnosis     =
| differential  =
| prevention    = [[Hand washing]], [[flu vaccine]]s
| treatment     =
| medication    = [[Antiviral drug]]s such as [[oseltamivir]]
| prognosis     =
| frequency     = 3–5 million severe cases per year<ref name=krammer /><ref name=sautto />
| deaths        = >290,000–650,000 deaths per year<ref name=allen /><ref name=lampejo />
| alt           =
}}

'''Influenza''', commonly known as the '''flu''', is an [[infectious disease]] caused by [[influenza viruses]]. Symptoms range from mild to severe and often include [[fever]], [[Rhinorrhea|runny nose]], [[sore throat]], [[Myalgia|muscle pain]], [[headache]], [[cough]]ing, and [[fatigue]]. These symptoms begin one to four (typically two) days after exposure to the virus and last for about two to eight days. [[Diarrhea]] and [[vomiting]] can occur, particularly in children. Influenza may progress to [[pneumonia]] from the virus or a subsequent [[bacterial infection]]. Other complications include [[acute respiratory distress syndrome]], [[meningitis]], [[encephalitis]], and worsening of pre-existing health problems such as [[asthma]] and [[cardiovascular disease]].

There are four types of influenza virus: types A, B, C, and D. [[Aquatic bird]]s are the primary source of [[influenza A virus]] (IAV), which is also widespread in various mammals, including humans and pigs. [[Influenza B virus]] (IBV) and [[influenza C virus]] (ICV) primarily infect humans, and [[influenza D virus]] (IDV) is found in cattle and pigs. Influenza A virus and influenza B virus circulate in humans and cause seasonal [[epidemic]]s, and influenza C virus causes a mild infection, primarily in children. Influenza D virus can infect humans but is not known to cause illness. In humans, influenza viruses are primarily [[disease transmission|transmit]]ted through [[respiratory droplet]]s from coughing and sneezing. Transmission through [[aerosol]]s and surfaces contaminated by the virus also occur.

Frequent [[hand washing]] and covering one's mouth and nose when coughing and sneezing reduce transmission, as does wearing a mask. [[Influenza vaccination|Annual vaccination]] can help to provide protection against influenza. Influenza viruses, particularly influenza A virus, evolve quickly, so flu vaccines are updated regularly to match which influenza strains are in circulation. Vaccines provide protection against influenza A virus subtypes [[H1N1]] and [[H3N2]] and one or two influenza B virus subtypes. Influenza infection is diagnosed with laboratory methods such as [[antibody]] or [[antigen]] tests and a polymerase chain reaction ([[Polymerase chain reaction|PCR]]) to identify viral [[nucleic acid]]. The disease can be treated with [[supportive measures]] and, in severe cases, with [[antiviral drug]]s such as [[oseltamivir]]. In healthy individuals, influenza is typically [[Self-limiting (biology)|self-limiting]] and rarely fatal, but it can be deadly in high-risk groups.

In a typical year, five to 15 percent of the population contracts influenza. There are 3 to 5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year. Deaths most commonly occur in high-risk groups, including young children, the elderly, and people with chronic health conditions. In [[temperate region]]s, the number of influenza cases peaks during winter, whereas in the [[tropics]], influenza can occur year-round. Since the late 1800s, [[pandemic]] outbreaks of novel influenza strains have occurred every 10 to 50 years. Five [[Influenza pandemic|flu pandemics]] have occurred since 1900: the [[Spanish flu]] from 1918 to 1920, which was the most severe; the [[Asian flu]] in 1957; the [[Hong Kong flu]] in 1968; the [[1977 Russian flu|Russian flu]] in 1977; and the [[2009 swine flu pandemic|swine flu pandemic]] in 2009.

==Signs and symptoms==
[[File:Symptoms of influenza.svg|thumb|upright=1.35|Symptoms of influenza,<ref>{{cite web | title=Flu Symptoms & Diagnosis | website=U.S. [[Centers for Disease Control and Prevention]] (CDC) | date=10 July 2019 | url=https://www.cdc.gov/flu/symptoms/index.html | access-date=24 January 2020 | archive-date=27 December 2019 | archive-url=https://web.archive.org/web/20191227211854/https://www.cdc.gov/flu/symptoms/index.html | url-status=live }}</ref><ref>{{cite web | title = Flu Symptoms & Complications | publisher = U.S. [[Centers for Disease Control and Prevention]] (CDC) | date = 26 February 2019 | url = https://www.cdc.gov/flu/symptoms/symptoms.htm | access-date = 6 July 2019 | archive-date = 1 August 2020 | archive-url = https://web.archive.org/web/20200801071343/https://www.cdc.gov/flu/symptoms/symptoms.htm | url-status = live }}</ref> with fever and cough the most common symptoms<ref name="pmid15728170">{{cite journal | vauthors = Call SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP | title = Does this patient have influenza? | journal = JAMA | volume = 293 | issue = 8 | pages = 987–997 | date = February 2005 | pmid = 15728170 | doi = 10.1001/jama.293.8.987 }}</ref>]]

The symptoms of influenza are similar to those of a cold, although usually more severe and less likely to include a [[runny nose]].<ref name=CMAJ2014>{{cite journal |vauthors=Allan GM, Arroll B |title=Prevention and treatment of the common cold: making sense of the evidence |journal=CMAJ |volume=186 |issue=3 |pages=190–9 |date=February 2014 |pmid=24468694 |pmc=3928210 |doi=10.1503/cmaj.121442}}</ref><ref>{{cite web |title=Cold Versus Flu |date=11 August 2016 |url=https://www.cdc.gov/flu/about/qa/coldflu.htm |access-date=5 January 2017 |url-status=dead |archive-url=https://web.archive.org/web/20170106173600/https://www.cdc.gov/flu/about/qa/coldflu.htm |archive-date=6 January 2017}}</ref> The time between exposure to the virus and development of symptoms (the [[incubation period]]) is one to four days, most commonly one to two days. Many infections are asymptomatic.<ref name=dharmapalan >{{cite journal | vauthors = Dharmapalan D | title = Influenza | journal = Indian Journal of Pediatrics | volume = 87 | issue = 10 | pages = 828–832 | date = October 2020 | pmid = 32048225 | pmc = 7091034 | doi = 10.1007/s12098-020-03214-1 }}</ref> The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, [[Myalgia|muscle pain]], [[malaise]], [[Anorexia|loss of appetite]], lack of energy, and confusion. These are usually accompanied by respiratory symptoms such as a [[dry cough]], [[pharyngitis|sore or dry throat]], [[hoarseness|hoarse voice]], and a [[nasal congestion|stuffy]] or [[rhinorrhea|runny nose]]. Coughing is the most common symptom.<ref name=krammer >{{cite journal | vauthors = Krammer F, Smith GJ, Fouchier RA, Peiris M, Kedzierska K, Doherty PC, Palese P, Shaw ML, Treanor J, Webster RG, García-Sastre A | title = Influenza | journal = Nature Reviews. Disease Primers | volume = 4 | issue = 1 | pages = 3 | date = June 2018 | pmid = 29955068 | pmc = 7097467 | doi = 10.1038/s41572-018-0002-y }}</ref> Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea,<ref name=ghebrehewet >{{cite journal | vauthors = Ghebrehewet S, MacPherson P, Ho A | title = Influenza | journal = BMJ | volume = 355 | pages = i6258 | date = December 2016 | pmid = 27927672 | pmc = 5141587 | doi = 10.1136/bmj.i6258 }}</ref> and gastroenteritis,<ref name=sederdahl >{{cite journal | vauthors = Sederdahl BK, Williams JV | title = Epidemiology and Clinical Characteristics of Influenza C Virus | journal = Viruses | volume = 12 | issue = 1 | pages = 89 | date = January 2020 | pmid = 31941041 | pmc = 7019359 | doi = 10.3390/v12010089 | doi-access = free | title-link = doi }}</ref> especially in children. The standard influenza symptoms typically last for two to eight days.<ref name=peteranderl >{{cite journal | vauthors = Peteranderl C, Herold S, Schmoldt C | title = Human Influenza Virus Infections | journal = Seminars in Respiratory and Critical Care Medicine | volume = 37 | issue = 4 | pages = 487–500 | date = August 2016 | pmid = 27486731 | pmc = 7174870 | doi = 10.1055/s-0036-1584801 }}</ref> Some studies suggest influenza can cause long-lasting symptoms in a similar way to [[long COVID]].<ref>{{cite web | vauthors = Triggle N | title=People also suffer 'long flu', study shows | website=BBC News Online | date=28 September 2021 | url=https://www.bbc.com/news/health-58726775 | access-date=10 June 2024 | archive-url=https://web.archive.org/web/20220325040953/https://www.bbc.co.uk/news/health-58726775 | archive-date=25 March 2022 | url-status=live }}</ref><ref>{{cite press release | vauthors = Sauerwein K | title='Long flu' has emerged as a consequence similar to long COVID | website=Washington University School of Medicine in St. Louis | date=14 December 2023 | url=https://medicine.wustl.edu/news/long-flu-has-emerged-as-a-consequence-similar-to-long-covid-19/ | access-date=10 June 2024 | archive-date=10 June 2024 | archive-url=https://web.archive.org/web/20240610052844/https://medicine.wustl.edu/news/long-flu-has-emerged-as-a-consequence-similar-to-long-covid-19/ | url-status=live }}</ref><ref>{{cite journal | vauthors = Xie Y, Choi T, Al-Aly Z | title = Long-term outcomes following hospital admission for COVID-19 versus seasonal influenza: a cohort study | journal = The Lancet. Infectious Diseases | volume = 24 | issue = 3 | pages = 239–255 | date = March 2024 | pmid = 38104583 | doi = 10.1016/S1473-3099(23)00684-9 }}</ref>

Symptomatic infections are usually mild and limited to the [[upper respiratory tract]], but progression to pneumonia is relatively common. Pneumonia may be caused by the primary viral infection or a [[secondary infection|secondary bacterial infection]]. Primary pneumonia is characterized by rapid progression of fever, cough, [[dyspnea|labored breathing]], and [[Hypoxia (medical)|low oxygen level]]s that cause [[cyanosis|bluish skin]]. It is especially common among those who have an underlying [[cardiovascular disease]] such as [[rheumatic heart disease]]. Secondary pneumonia typically has a period of improvement in symptoms for one to three weeks<ref name=kalil >{{cite journal | vauthors = Kalil AC, Thomas PG | title = Influenza virus-related critical illness: pathophysiology and epidemiology | journal = Critical Care | volume = 23 | issue = 1 | pages = 258 | date = July 2019 | pmid = 31324202 | pmc = 6642581 | doi = 10.1186/s13054-019-2539-x | doi-access = free | title-link = doi }}</ref> followed by recurrent fever, [[sputum]] production, and [[pulmonary effusion|fluid buildup in the lungs]],<ref name=krammer /> but can also occur just a few days after influenza symptoms appear.<ref name=kalil /> About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria ''[[Streptococcus pneumoniae]]'' and ''[[Staphylococcus aureus]]''.<ref name=dharmapalan /><ref name=krammer />

==Virology==
===Types of virus===
[[File:Influenza nomenclature.svg|thumb|upright=1.4|Influenza virus [[International Committee on Taxonomy of Viruses|nomenclature]] (for a [[Fujian flu]] virus)]]
Influenza viruses comprise four species, each the sole member of its own genus. The four influenza genera comprise four of the seven genera in the family ''[[Orthomyxoviridae]]''. They are:<ref name=krammer /><ref name=ictv >{{cite web |url=https://ictv.global/taxonomy |title=Virus Taxonomy: 2019 Release |author=<!--Not stated--> |publisher=International Committee on Taxonomy of Viruses |access-date=9 March 2021 |archive-date=20 March 2020 |archive-url=https://web.archive.org/web/20200320103754/https://talk.ictvonline.org/taxonomy |url-status=live }}</ref>
* ''[[Influenza A virus]]'', genus ''Alphainfluenzavirus''
* ''[[Influenza B virus]]'', genus ''Betainfluenzavirus''
* ''[[Influenza C virus]]'', genus ''Gammainfluenzavirus''
* ''[[Influenza D virus]]'', genus ''Deltainfluenzavirus''

Influenza A virus is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics. It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those with chronic health issues. Birds are the primary reservoir of influenza A virus, especially aquatic birds such as ducks, geese, shorebirds, and gulls,<ref name=li >{{cite journal | vauthors = Li YT, Linster M, Mendenhall IH, Su YC, Smith GJ | title = Avian influenza viruses in humans: lessons from past outbreaks | journal = British Medical Bulletin | volume = 132 | issue = 1 | pages = 81–95 | date = December 2019 | pmid = 31848585 | pmc = 6992886 | doi = 10.1093/bmb/ldz036 }}</ref><ref name=joseph >{{cite journal | vauthors = Joseph U, Su YC, Vijaykrishna D, Smith GJ | title = The ecology and adaptive evolution of influenza A interspecies transmission | journal = Influenza and Other Respiratory Viruses | volume = 11 | issue = 1 | pages = 74–84 | date = January 2017 | pmid = 27426214 | pmc = 5155642 | doi = 10.1111/irv.12412 }}</ref> but the virus also circulates among mammals, including pigs, horses, and marine mammals.

Subtypes of Influenza A are defined by the combination of the antigenic viral proteins [[Hemagglutinin (influenza)|haemagglutinin]] (H) and [[neuraminidase]] (N) in the [[viral envelope]]; for example, "[[Influenza A virus subtype H1N1|H1N1]]" designates an IAV subtype that has a type-1 hemagglutinin (H) protein and a type-1 neuraminidase (N) protein.<ref name=":112">{{Cite web |last=CDC |date=1 February 2024 |title=Influenza Type A Viruses |url=https://www.cdc.gov/flu/avianflu/influenza-a-virus-subtypes.htm |access-date=3 May 2024 |website=Centers for Disease Control and Prevention |language=en-us}}</ref> Almost all possible combinations of H (1 thru 16) and N (1 thru 11) have been isolated from wild birds.<ref>{{Cite web |title=FluGlobalNet – Avian Influenza |url=https://science.vla.gov.uk/fluglobalnet/about_ai.html |access-date=5 June 2024 |website=science.vla.gov.uk}}</ref><ref name="asha">{{cite journal | vauthors = Asha K, Kumar B | title = Emerging Influenza D Virus Threat: What We Know so Far! | journal = Journal of Clinical Medicine | volume = 8 | issue = 2 | pages = 192 | date = February 2019 | pmid = 30764577 | pmc = 6406440 | doi = 10.3390/jcm8020192 | doi-access = free | title-link = doi }}</ref> In addition H17, H18, N10 and N11 have been found in bats.<ref>{{Cite web |date=17 June 2024 |title=Influenza A Subtypes and the Species Affected {{!}} Seasonal Influenza (Flu) {{!}} CDC |url=https://www.cdc.gov/flu/other/animal-flu.html |access-date=18 June 2024 |website=Centers for Disease Control and Prevention |language=en-us}}</ref><ref name="asha" /> The influenza A virus subtypes in circulation among humans {{as of|2018|lc=y}} are H1N1 and H3N2.<ref name="sautto">{{cite journal | vauthors = Sautto GA, Kirchenbaum GA, Ross TM | title = Towards a universal influenza vaccine: different approaches for one goal | journal = Virology Journal | volume = 15 | issue = 1 | pages = 17 | date = January 2018 | pmid = 29370862 | pmc = 5785881 | doi = 10.1186/s12985-017-0918-y | doi-access = free | title-link = doi }}</ref>

Influenza B virus mainly infects humans but has been identified in seals, horses, dogs, and pigs.<ref name=asha /> Influenza B virus does not have subtypes like influenza A virus but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages,<ref name=krammer /> or simply (B/)Victoria(-like) and (B/)Yamagata(-like).<ref name=asha /><ref name=sautto /> Both lineages are in circulation in humans,<ref name=krammer /> disproportionately affecting children.<ref name=ghebrehewet /> However, the B/Yamagata lineage might have become extinct in 2020/2021 due to [[COVID-19 pandemic]] measures.<ref name="Koutsakos2021">{{cite journal |vauthors=Koutsakos M, Wheatley AK, Laurie K, Kent SJ, Rockman S |date=December 2021 |title=Influenza lineage extinction during the COVID-19 pandemic? |journal=Nature Reviews. Microbiology |volume=19 |issue=12 |pages=741–742 |doi=10.1038/s41579-021-00642-4 |pmc=8477979 |pmid=34584246}}</ref> Influenza B viruses contribute to seasonal epidemics alongside influenza A viruses but have never been associated with a pandemic.<ref name=asha />

Influenza C virus, like influenza B virus, is primarily found in humans, though it has been detected in pigs, feral dogs, [[dromedary]] camels, cattle, and dogs.<ref name=sederdahl /><ref name=asha /> Influenza C virus infection primarily affects children and is usually asymptomatic<ref name=krammer /><ref name=ghebrehewet /> or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.<ref name=sederdahl /> Unlike influenza A virus and influenza B virus, influenza C virus has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.<ref name=asha /> Influenza C virus is subclassified into six genetic/antigenic lineages.<ref name=sederdahl /><ref name=su >{{cite journal | vauthors = Su S, Fu X, Li G, Kerlin F, Veit M | title = Novel Influenza D virus: Epidemiology, pathology, evolution and biological characteristics | journal = Virulence | volume = 8 | issue = 8 | pages = 1580–1591 | date = November 2017 | pmid = 28812422 | pmc = 5810478 | doi = 10.1080/21505594.2017.1365216 }}</ref>

Influenza D virus has been isolated from pigs and cattle, the latter being the natural reservoir. Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.<ref name=asha /><ref name=su /> Influenza D virus is distantly related to influenza C virus. While cattle workers have occasionally tested positive to prior influenza D virus infection, it is not known to cause disease in humans.<ref name=krammer /><ref name=ghebrehewet /><ref name=sederdahl /> Influenza C virus and influenza D virus experience a slower rate of antigenic evolution than influenza A virus and influenza B virus. Because of this antigenic stability, relatively few novel lineages emerge.<ref name=su />

==== Influenza virus nomenclature ====
[[File:InfluenzaNomenclatureDiagram.svg|right|thumb|Diagram of influenza nomenclature]]
Every year, millions of influenza virus samples are analysed to monitor changes in the virus' [[Antigenic variation|antigenic]] properties, and to inform the development of vaccines.<ref name=":022">{{Cite web |date=19 September 2022 |title=70 years of GISRS – the Global Influenza Surveillance & Response System |url=https://www.who.int/news-room/feature-stories/detail/seventy-years-of-gisrs---the-global-influenza-surveillance---response-system |access-date=13 June 2024 |website=World Health Organization |language=en}}</ref>

To unambiguously describe a specific [[Isolation (microbiology)|isolate]] of virus, researchers use the internationally accepted influenza virus nomenclature,<ref>{{Cite journal |date=1980 |title=A revision of the system of nomenclature for influenza viruses: a WHO Memorandum |journal=Bull World Health Organ |volume=58 |issue=4 |pages=585–591 |pmc=2395936 |pmid=6969132 |quote=This Memorandum was drafted by the signatories listed on page 590 on the occasion of a meeting held in Geneva in February 1980. }}</ref> which describes, among other things, the species of animal from which the virus was isolated, and the place and year of collection. As an example – '''A/chicken/Nakorn-Patom/Thailand/CU-K2/04(H5N1)''':

* '''A''' stands for the genus of influenza ([[Influenzavirus A|A]], [[Influenzavirus B|B]], [[Influenzavirus C|C]] or [[Influenza D virus|D]]).
* '''chicken''' is the animal species the isolate was found in (note: human isolates lack this component term and are thus identified as human isolates by default)
* '''Nakorn-Patom/Thailand''' is the place this specific virus was isolated
* '''CU-K2''' is the laboratory reference number that identifies it from other influenza viruses isolated at the same place and year
* '''04''' represents the year of isolation 2004
* '''H5''' stands for the fifth of several known types of the protein [[Hemagglutinin (influenza)|hemagglutinin]].
* '''N1''' stands for the first of several known types of the protein [[Viral neuraminidase|neuraminidase]].<ref name="PAHO">{{cite report |url=https://www.paho.org/en/documents/technical-note-influenza-virus-nomenclature |title=Technical note: Influenza virus nomenclature |date=22 November 2022 |access-date=27 May 2024 |archive-url=https://web.archive.org/web/20230810004651/http://www.paho.org/en/documents/technical-note-influenza-virus-nomenclature |archive-date=10 August 2023 |url-status=live |website=Pan American Health Organization}}</ref>

The nomenclature for influenza B, C and D, which are less variable, is simpler. Examples are B/Santiago/29615/2020 and C/Minnesota/10/2015.<ref name="PAHO" />

===Genome and structure===
[[File:3D Influenza virus.png|thumb|upright=1.4|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 [[Influenza virus nucleoprotein|ribonucleoproteins]] (RNP).]]
Influenza viruses have a [[Sense (molecular biology)|negative-sense]], single-stranded RNA genome that is segmented. The negative sense of the genome means it can be used as a template to synthesize [[messenger RNA]] (mRNA).<ref name=dharmapalan /> Influenza A virus and influenza B virus have eight genome segments that encode 10 major proteins. Influenza C virus and influenza D virus have seven genome segments that encode nine major proteins.<ref name=sederdahl />

Three segments encode three subunits of an [[RNA-dependent RNA polymerase]] (RdRp) complex: PB1, a transcriptase, PB2, which recognizes [[Five-prime cap|5' caps]], and PA (P3 for influenza C virus and influenza D virus), an [[endonuclease]].<ref name="mccauley">{{cite web |url=https://ictv.global/report_9th/RNAneg/Orthomyxoviridae |title=Orthomyxoviridae |vauthors=McCauley JW, Hongo S, Kaverin NV, Kochs G, Lamb RA, Matrosovich MN, Perez DR, Palese P, Presti PM, Rimstad E, Smith GJ |year=2011 |publisher=International Committee on Taxonomy of Viruses |access-date=9 March 2021 |archive-date=8 August 2022 |archive-url=https://web.archive.org/web/20220808050352/https://ictv.global/report_9th/RNAneg/Orthomyxoviridae |url-status=live }}</ref> The [[Viral matrix protein|M1 matrix protein]] and [[M2 proton channel]] share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).<ref name="krammer" /> For influenza A virus and influenza B virus, [[hemagglutinin (influenza)|hemagglutinin]] (HA) and [[neuraminidase]] (NA) are encoded on one segment each, whereas influenza C virus and influenza D virus encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA. The final genome segment encodes the viral nucleoprotein (NP).<ref name="mccauley" /> Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are [[Gene expression|expressed]] through alternative [[open reading frame]]s<ref name="krammer" /><ref name="shim">{{cite journal | vauthors = Shim JM, Kim J, Tenson T, Min JY, Kainov DE | title = Influenza Virus Infection, Interferon Response, Viral Counter-Response, and Apoptosis | journal = Viruses | volume = 9 | issue = 8 | pages = 223 | date = August 2017 | pmid = 28805681 | pmc = 5580480 | doi = 10.3390/v9080223 | doi-access = free | title-link = doi }}</ref> and which are important in host defense suppression, virulence, and pathogenicity.<ref name="hao">{{cite journal | vauthors = Hao W, Wang L, Li S | title = Roles of the Non-Structural Proteins of Influenza A Virus | journal = Pathogens | volume = 9 | issue = 10 | pages = 812 | date = October 2020 | pmid = 33023047 | pmc = 7600879 | doi = 10.3390/pathogens9100812 | doi-access = free | title-link = doi }}</ref>

The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape. Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions. Filamentous virions are about 250 nanometers (nm) by 80&nbsp;nm, bacilliform 120–250 by 95&nbsp;nm, and spherical 120&nbsp;nm in diameter.<ref name=dadonaite >{{cite journal | vauthors = Dadonaite B, Vijayakrishnan S, Fodor E, Bhella D, Hutchinson EC | title = Filamentous influenza viruses | journal = The Journal of General Virology | volume = 97 | issue = 8 | pages = 1755–1764 | date = August 2016 | pmid = 27365089 | pmc = 5935222 | doi = 10.1099/jgv.0.000535 }}</ref>

The core of the virion comprises one copy of each segment of the genome bound to NP nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment. There is a copy of the RdRp, all subunits included, bound to each RNP. The genetic material is [[Capsid|encapsulated]] by a layer of M1 matrix protein which provides structural reinforcement to the outer layer, the [[viral envelope]].<ref name="allen">{{cite journal |vauthors=Allen JD, Ross TM |year=2018 |title=H3N2 influenza viruses in humans: Viral mechanisms, evolution, and evaluation |journal=Human Vaccines & Immunotherapeutics |volume=14 |issue=8 |pages=1840–1847 |doi=10.1080/21645515.2018.1462639 |pmc=6149781 |pmid=29641358}}</ref> The envelope comprises a [[lipid bilayer]] membrane incorporating HA and NA (or HEF<ref name="su" />) proteins extending outward from its exterior surface. HA and HEF<ref name="su" /> proteins have a distinct "head" and "stalk" structure. M2 proteins form [[M2 proton channel|proton channels]] through the viral envelope that are required for viral entry and exit. Influenza B viruses contain a surface protein named NB that is anchored in the envelope, but its function is unknown.<ref name="krammer" />

===Life cycle===
[[File:Virus Replication large.svg|thumb|upright=1.4|Host cell invasion and replication by the influenza virus]]

The viral life cycle begins by binding to a target cell. Binding is mediated by the viral HA proteins on the surface of the envelope, which bind to cells that contain [[sialic acid]] receptors on the surface of the cell membrane.<ref name=krammer /><ref name=li /><ref name=allen /> For N1 subtypes with the "G147R" mutation and N2 subtypes, the NA protein can initiate entry. Prior to binding, NA proteins promote access to target cells by degrading mucus, which helps to remove extracellular decoy receptors that would impede access to target cells.<ref name=allen /> After binding, the virus is internalized into the cell by an [[endosome]] that contains the virion inside it. The endosome is acidified by cellular vATPase<ref name=shim /> to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.<ref name=hao /> At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's [[cytosol]]. The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.<ref name=shim /><ref name=allen />

RNPs are then imported into the nucleus with the help of viral localization signals. There, the viral RNA polymerase [[Transcription (biology)|transcribes]] mRNA using the genomic negative-sense strand as a template. The polymerase [[Cap snatching|snatches 5' caps]] for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.<ref name=mccauley /> Once viral mRNA is transcribed, it is exported out of the nucleus and [[Translation (biology)|translated]] by host ribosomes in a cap-dependent manner to synthesize viral proteins.<ref name=shim /> RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.<ref name=krammer /><ref name=allen /> During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.<ref name=peteranderl />

Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.<ref name=mccauley /> HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins<ref name=hao /> to the cell membrane through the [[Golgi apparatus]]<ref name=mccauley /> and inserted into the cell's membrane. Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.<ref name=krammer /><ref name=hao /><ref name=allen /> PB1-F2 also interacts with PB1 to keep polymerases in the nucleus longer.<ref name=joseph /> M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.<ref name=krammer /><ref name=allen />

Progeny viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane. The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins. At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins. The virion is then released from the cell. The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.<ref name=krammer /><ref name=allen /> Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.<ref name=peteranderl /> Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis (programmed cell death), which is initiated by cellular factors to restrict viral replication.<ref name=shim />

===Antigenic drift and shift===
[[File:Viruses-10-00497-g003.png|thumb|Evolution mechanisms of IAV. (A) '''Antigenic Drift''': Gradual accumulation of mutations in the genome of IAVs leads to emergence of new virus variants. (B) '''Antigenic Shift''': The reassortment of genetic segments between two or more invading IAVs in a host cell can lead to emergence of an antigenically novel subtype.]]
Two key processes that influenza viruses evolve through are [[antigenic drift]] and [[antigenic shift]]. Antigenic drift is when an influenza virus' antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.<ref name=li /> This can occur in response to [[evolutionary pressure]] exerted by the host immune response. Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.<ref name=sautto /><ref name=su /> The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.<ref name=krammer /><ref name=ghebrehewet /> Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D.<ref name=su /> Antigenic drift is a major cause of seasonal influenza,<ref name=hastings >{{cite journal | vauthors = Saunders-Hastings PR, Krewski D | title = Reviewing the History of Pandemic Influenza: Understanding Patterns of Emergence and Transmission | journal = Pathogens | volume = 5 | issue = 4 | pages = 66 | date = December 2016 | pmid = 27929449 | pmc = 5198166 | doi = 10.3390/pathogens5040066 | doi-access = free | title-link = doi }}</ref> and requires that flu vaccines be updated annually. HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains. Antigenic evolution of influenza viruses of humans appears to be faster than in swine and equines. In wild birds, within-subtype [[antigenic variation]] appears to be limited but has been observed in poultry.<ref name=krammer /><ref name=ghebrehewet />

Antigenic shift is a sudden, drastic change in an influenza virus' antigen, usually HA. During antigenic shift, antigenically different strains that infect the same cell can [[Reassortment|reassort]] genome segments with each other, producing hybrid progeny. Since all influenza viruses have segmented genomes, all are capable of reassortment.<ref name=sederdahl /><ref name=su /> Antigenic shift only occurs among influenza viruses of the same genus<ref name=mccauley /> and most commonly occurs among influenza A viruses. In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.<ref name=lycett >{{cite journal | vauthors = Lycett SJ, Duchatel F, Digard P | title = A brief history of bird flu | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 374 | issue = 1775 | pages = 20180257 | date = June 2019 | pmid = 31056053 | pmc = 6553608 | doi = 10.1098/rstb.2018.0257 }}</ref> Pigs, bats, and quails have receptors for both mammalian and avian influenza A viruses, so they are potential "mixing vessels" for reassortment.<ref name=asha /> If an animal strain reassorts with a human strain,<ref name=sautto /> then a novel strain can emerge that is capable of human-to-human transmission. This has caused pandemics, but only a limited number, so it is difficult to predict when the next will happen.<ref name=krammer /><ref name=ghebrehewet />
The [[Global Influenza Surveillance and Response System]] of the [[World Health Organization]] (GISRS) tests several millions of specimens annually to monitor the spread and evolution of influenza viruses.<ref name="gisrs2">{{cite web |title=Global Influenza Surveillance and Response System (GISRS) |url=https://www.who.int/influenza/gisrs_laboratory/en/ |url-status=dead |archive-url=https://web.archive.org/web/20111003070329/http://www.who.int/influenza/gisrs_laboratory/en/ |archive-date=3 October 2011 |access-date=24 March 2021 |publisher=World Health Organization}}</ref><ref name="Leveraging">{{cite journal | vauthors = Broor S, Campbell H, Hirve S, Hague S, Jackson S, Moen A, Nair H, Palekar R, Rajatonirina S, Smith PG, Venter M, Wairagkar N, Zambon M, Ziegler T, Zhang W | title = Leveraging the Global Influenza Surveillance and Response System for global respiratory syncytial virus surveillance-opportunities and challenges | journal = Influenza and Other Respiratory Viruses | volume = 14 | issue = 6 | pages = 622–629 | date = November 2020 | pmid = 31444997 | pmc = 7578328 | doi = 10.1111/irv.12672 | doi-access = free | title-link = doi }}{{CC-notice|by4|url=https://onlinelibrary.wiley.com/doi/full/10.1111/irv.12672}}</ref><ref name=":022"/>

==Mechanism==

===Transmission===
People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread [[respiratory droplet]]s and [[aerosol]]s that contain virus particles into the air. A person susceptible to infection can contract influenza by coming into contact with these particles.<ref name=kalil /><ref name=kutter >{{cite journal | vauthors = Kutter JS, Spronken MI, Fraaij PL, Fouchier RA, Herfst S | title = Transmission routes of respiratory viruses among humans | journal = Current Opinion in Virology | volume = 28 | pages = 142–151 | date = February 2018 | pmid = 29452994 | pmc = 7102683 | doi = 10.1016/j.coviro.2018.01.001 }}</ref> Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces. Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further.<ref name=kutter /><ref name=lampejo >{{cite journal | vauthors = Lampejo T | title = Influenza and antiviral resistance: an overview | journal = European Journal of Clinical Microbiology & Infectious Diseases | volume = 39 | issue = 7 | pages = 1201–1208 | date = July 2020 | pmid = 32056049 | pmc = 7223162 | doi = 10.1007/s10096-020-03840-9 }}</ref> Inhalation of aerosols can lead to infection,<ref name=killingley >{{cite journal | vauthors = Killingley B, Nguyen-Van-Tam J | title = Routes of influenza transmission | journal = Influenza and Other Respiratory Viruses | volume = 7 | issue = Suppl 2 | pages = 42–51 | date = September 2013 | pmid = 24034483 | pmc = 5909391 | doi = 10.1111/irv.12080 }}</ref> but most transmission is in the area about two meters around an infected person via respiratory droplets<ref name=dharmapalan /> that come into contact with mucosa of the upper respiratory tract.<ref name=killingley /> Transmission through contact with a person, bodily fluids, or intermediate objects ([[fomite]]s) can also occur,<ref name=dharmapalan /><ref name=kutter /> since influenza viruses can survive for hours on non-porous surfaces.<ref name=lampejo /> If one's hands are contaminated, then touching one's face can cause infection.<ref name=weber >{{cite journal | vauthors = Weber TP, Stilianakis NI | title = Inactivation of influenza A viruses in the environment and modes of transmission: a critical review | journal = The Journal of Infection | volume = 57 | issue = 5 | pages = 361–373 | date = November 2008 | pmid = 18848358 | pmc = 7112701 | doi = 10.1016/j.jinf.2008.08.013 }}</ref>

Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.<ref name=ghebrehewet /> In healthy adults, the virus is shed for up to 3–5 days. In children and the immunocompromised, the virus may be transmissible for several weeks.<ref name=dharmapalan /> Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.<ref name=krammer /><ref name=ghebrehewet /> Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.<ref name=krammer /> People at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza. In long-term care facilities, the flu can spread rapidly.<ref name=ghebrehewet /> A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative [[humidity]], less [[ultraviolet]] radiation from the sun,<ref name=killingley /><ref name=moriyama >{{cite journal | vauthors = Moriyama M, Hugentobler WJ, Iwasaki A | title = Seasonality of Respiratory Viral Infections | journal = Annual Review of Virology | volume = 7 | issue = 1 | pages = 83–101 | date = September 2020 | pmid = 32196426 | doi = 10.1146/annurev-virology-012420-022445 | doi-access = free | title-link = doi }}</ref> and crowding.<ref name=kutter /> Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like [[H5N1]] tend to cause more severe illness but are less contagious.<ref name=dharmapalan />

===Pathophysiology===
[[File:H1N1 versus H5N1 pathology.png|thumb|upright=1.4|How the different sites of infection (shown in red) of H1N1 and H5N1 influences their transmission and lethality<ref name=":1">{{cite journal | vauthors = Yoo E | title = Conformation and Linkage Studies of Specific Oligosaccharides Related to H1N1, H5N1, and Human Flu for Developing the Second Tamiflu | journal = Biomolecules & Therapeutics | volume = 22 | issue = 2 | pages = 93–99 | date = February 2014 | pmid = 24753813 | pmc = 3975476 | doi = 10.4062/biomolther.2014.005 }}</ref>]]

In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract. Illness during infection is primarily the result of lung [[inflammation]] and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection. Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown. Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of [[Pulmonary alveolus|alveolar]] structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure. In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory [[cytokine]]s.<ref name=kalil />

Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a [[cytokine storm]].<ref name=krammer /> Infection with H5N1 or [[H7N9]] especially produces high levels of pro-inflammatory cytokines.<ref name=li /> In bacterial infections, early depletion of [[macrophage]]s during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection. Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection. Infection also induces production of systemic [[glucocorticoid]]s that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.<ref name=kalil />

The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells. Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells,<ref name=krammer /><ref name=li /><ref name=allen /> such as respiratory and retinal epithelial cells.<ref name=shim /> AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells<ref name=krammer /><ref name= li /><ref name=allen /> and in humans in the lower respiratory tract.<ref name=shao >{{cite journal | vauthors = Shao W, Li X, Goraya MU, Wang S, Chen JL | title = Evolution of Influenza A Virus by Mutation and Re-Assortment | journal = International Journal of Molecular Sciences | volume = 18 | issue = 8 | pages = 1650 | date = August 2017 | pmid = 28783091 | pmc = 5578040 | doi = 10.3390/ijms18081650 | doi-access = free | title-link = doi }}</ref> [[Proteolysis|Cleavage]] of the HA protein into HA{{sub|1}}, the binding subunit, and HA{{sub|2}}, the fusion subunit, is performed by different proteases, affecting which cells can be infected. For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.<ref name=krammer /><ref name=lycett /><ref name=steinhauer >{{cite journal | vauthors = Steinhauer DA | title = Role of hemagglutinin cleavage for the pathogenicity of influenza virus | journal = Virology | volume = 258 | issue = 1 | pages = 1–20 | date = May 1999 | pmid = 10329563 | doi = 10.1006/viro.1999.9716 | doi-access = free | title-link = doi }}</ref>

===Immunology===
Cells possess sensors to detect viral RNA, which can then induce [[interferon]] production. Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they notify nearby uninfected cells of infection. Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection. Immune cells control viral infection by killing infected cells and [[Phagocytosis|phagocytizing]] viral particles and apoptotic cells. An exacerbated immune response can harm the host organism through a cytokine storm.<ref name=krammer /><ref name=peteranderl /><ref name=shim /> To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.<ref name=krammer /><ref name=hao />

[[B cell]]s, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF<ref name=su />) and other proteins to a lesser degree. Once bound to these proteins, antibodies block virions from binding to cellular receptors, [[Neutralizing antibody|neutralizing]] the virus. In humans, a sizeable antibody response occurs about one week after viral exposure.<ref>{{cite journal | vauthors = Einav T, Gentles LE, Bloom JD | title = SnapShot: Influenza by the Numbers | journal = Cell | volume = 182 | issue = 2 | pages = 532–532.e1 | date = July 2020 | pmid = 32707094 | doi = 10.1016/j.cell.2020.05.004 | s2cid = 220715148 | doi-access = free | title-link = doi }}</ref> This antibody response is typically robust and long-lasting, especially for influenza C virus and influenza D virus.<ref name=krammer /><ref name=su /> People exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.<ref name=krammer /> There is, however, an "[[original antigenic sin]]", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.<ref name=sautto />

==Prevention==
{{Further|Prevention of influenza}}

===Vaccination===
{{Main|Influenza vaccine}}
[[File:Defense.gov News Photo 041028-N-9864S-021.jpg|thumb|upright=1.4|Giving an influenza vaccination]]
Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.<ref name=dharmapalan /><ref name=krammer /><ref name=chow >{{cite journal | vauthors = Chow EJ, Doyle JD, Uyeki TM | title = Influenza virus-related critical illness: prevention, diagnosis, treatment | journal = Critical Care | volume = 23 | issue = 1 | pages = 214 | date = June 2019 | pmid = 31189475 | pmc = 6563376 | doi = 10.1186/s13054-019-2491-9 | doi-access = free | title-link = doi }}</ref> Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two influenza B virus strains corresponding to the two influenza B virus lineages.<ref name=dharmapalan /><ref name=sautto /> Two types of vaccines are in use: inactivated vaccines that contain "killed" (i.e. inactivated) viruses and [[live attenuated influenza vaccine]]s (LAIVs) that contain weakened viruses.<ref name=krammer /> There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.<ref name=tregoning >{{cite journal | vauthors = Tregoning JS, Russell RF, Kinnear E | title = Adjuvanted influenza vaccines | journal = Human Vaccines & Immunotherapeutics | volume = 14 | issue = 3 | pages = 550–564 | date = March 2018 | pmid = 29232151 | pmc = 5861793 | doi = 10.1080/21645515.2017.1415684 }}</ref> Most flu vaccines are inactivated and administered via intramuscular injection. LAIVs are sprayed into the nasal cavity.<ref name=krammer />

Vaccination recommendations vary by country. Some recommend vaccination for all people above a certain age, such as 6 months,<ref name=chow /> whereas other countries limit recommendations to high-risk groups.<ref name=krammer /><ref name=ghebrehewet /> Young infants cannot receive flu vaccines for safety reasons, but they can inherit [[passive immunity]] from their mother if vaccinated during pregnancy.<ref name=principi >{{cite journal | vauthors = Principi N, Esposito S | title = Protection of children against influenza: Emerging problems | journal = Human Vaccines & Immunotherapeutics | volume = 14 | issue = 3 | pages = 750–757 | date = March 2018 | pmid = 28129049 | pmc = 5861800 | doi = 10.1080/21645515.2017.1279772 }}</ref> Influenza vaccination helps to reduce the probability of reassortment.<ref name=peteranderl />

[[File:COVID-19-Antigen-with-Influenza-A-B-Rapid-Antigen-Combo.jpg|thumb|An Influenza A&B Antigen Test (bottom) showing negative results for both Influenza A and B)]]

In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.<ref name=dharmapalan /><ref name=sautto /> Most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.<ref name=sautto /> Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, once for each hemisphere, to discuss [[Historical annual reformulations of the influenza vaccine|which strains should be included]] based on observation from HA inhibition assays.<ref name=dharmapalan /><ref name=allen /> Other manufacturing methods include an [[Madin-Darby Canine Kidney cells|MDCK cell]] culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from [[baculovirus]] overexpression in insect cells.<ref name=sautto /><ref name=barr >{{cite journal | vauthors = Barr IG, Donis RO, Katz JM, McCauley JW, Odagiri T, Trusheim H, Tsai TF, Wentworth DE | title = Cell culture-derived influenza vaccines in the severe 2017–2018 epidemic season: a step towards improved influenza vaccine effectiveness | journal = npj Vaccines | volume = 3 | pages = 44 | date = October 2018 | pmid = 30323955 | pmc = 6177469 | doi = 10.1038/s41541-018-0079-z }}</ref>

===Antiviral chemoprophylaxis===
Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs [[oseltamivir]], which can be taken orally by those at least three months old, and [[zanamivir]], which can be inhaled by those above seven years. [[Chemoprophylaxis]] is most useful for individuals at high risk for complications and those who cannot receive the flu vaccine.<ref name=dharmapalan /> Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected case and zanamivir within 36 hours.<ref name=dharmapalan /><ref name=ghebrehewet /> It is recommended for people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.<ref name=ghebrehewet />

===Infection control===

{{further|Influenza prevention}}
These are the main ways that influenza spreads
* by direct transmission (when an infected person sneezes mucus directly into the eyes, nose or mouth of another person);
* the airborne route (when someone inhales the [[Particulate|aerosols]] produced by an infected person coughing, sneezing or spitting);
* through hand-to-eye, hand-to-nose, or hand-to-mouth transmission, either from contaminated surfaces or from direct personal contact such as a hand-shake.

When vaccines and antiviral medications are limited, non-pharmaceutical interventions are essential to reduce transmission and spread. The lack of [[controlled studies]] and rigorous evidence of the effectiveness of some measures has hampered planning decisions and recommendations. Nevertheless, strategies endorsed by experts for all phases of flu outbreaks include hand and respiratory hygiene, self-isolation by symptomatic individuals and the use of face masks by them and their caregivers, surface disinfection, rapid testing and diagnosis, and [[contact tracing]]. In some cases, other forms of [[social distancing]] including school closures and travel restrictions are recommended.<ref name="Aledort" />

Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene habits such as: not touching the eyes, nose or mouth;<ref name="CDCQA">{{cite web | url=https://www.cdc.gov/H1N1flu/qa.htm | title=2009 H1N1 Flu ("Swine Flu") and You | publisher=[[Centers for Disease Control and Prevention]] (CDC) | date=10 February 2010 | archive-url=https://web.archive.org/web/20100304031110/https://www.cdc.gov/h1n1flu/qa.htm | archive-date=4 March 2010 | url-status=live | access-date=2 December 2019}}</ref> frequent [[hand washing]] (with soap and water, or with alcohol-based hand rubs);<ref>{{cite journal | vauthors = Grayson ML, Melvani S, Druce J, Barr IG, Ballard SA, Johnson PD, Mastorakos T, Birch C | display-authors = 6 | title = Efficacy of soap and water and alcohol-based hand-rub preparations against live H1N1 influenza virus on the hands of human volunteers | journal = Clinical Infectious Diseases | volume = 48 | issue = 3 | pages = 285–91 | date = February 2009 | pmid = 19115974 | doi = 10.1086/595845 | doi-access = free }}</ref> covering coughs and sneezes with a tissue or sleeve; avoiding close contact with sick people; and staying home when sick. Avoiding spitting is also recommended.<ref name="Aledort">{{cite journal | vauthors = 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 | pages = 208 | date = August 2007 | pmid = 17697389 | pmc = 2040158 | doi = 10.1186/1471-2458-7-208 | doi-access = free }}</ref> Although [[Surgical mask|face masks]] might help prevent transmission when caring for the sick,<ref>{{cite journal | vauthors = MacIntyre CR, Cauchemez S, Dwyer DE, Seale H, Cheung P, Browne G, Fasher M, Wood J, Gao Z, Booy R, Ferguson N | display-authors = 6 |title=Face mask use and control of respiratory virus transmission in households |journal=[[Emerging Infectious Diseases (journal)|Emerging Infectious Diseases]] |volume=15 | issue = 2 | pages = 233–41 | date = February 2009 | pmid = 19193267 | pmc = 2662657 | doi = 10.3201/eid1502.081167 | df = dmy-all }}</ref><ref>{{cite journal | vauthors = Bridges CB, Kuehnert MJ, Hall CB | title = Transmission of influenza: implications for control in health care settings | journal = Clinical Infectious Diseases | volume = 37 | issue = 8 | pages = 1094–101 | date = October 2003 | pmid = 14523774 | doi = 10.1086/378292 | doi-access = free }}</ref> there is mixed evidence on beneficial effects in the community.<ref name="Aledort" /><ref>{{cite web | url=https://www.cdc.gov/flu/professionals/infectioncontrol/maskguidance.htm | title=Interim Guidance for the Use of Masks to Control Seasonal Influenza Virus Transmission | publisher=[[Centers for Disease Control and Prevention]] (CDC) | date=5 March 2019 | archive-url=https://web.archive.org/web/20191202233328/https://www.cdc.gov/flu/professionals/infectioncontrol/maskguidance.htm | archive-date=2 December 2019 | url-status=live | access-date=2 December 2019 }}</ref> Smoking raises the risk of contracting influenza, as well as producing more severe disease symptoms.<ref name="pmid16231688">{{cite journal | vauthors = Murin S, Bilello KS | title = Respiratory tract infections: another reason not to smoke | journal = Cleveland Clinic Journal of Medicine | volume = 72 | issue = 10 | pages = 916–20 | date = October 2005 | pmid = 16231688 | doi = 10.3949/ccjm.72.10.916 }}</ref><ref>{{cite journal | vauthors = Kark JD, Lebiush M, Rannon L | title = Cigarette smoking as a risk factor for epidemic a(h1n1) influenza in young men | journal = New England Journal of Medicine | volume = 307 | issue = 17 | pages = 1042–46 | date = October 1982 | pmid = 7121513 | doi = 10.1056/NEJM198210213071702 }}</ref>

Since influenza spreads through both [[particulate|aerosols]] and contact with contaminated surfaces, surface sanitizing may help prevent some infections.<ref>{{cite journal | vauthors = Hota B | title = Contamination, disinfection, and cross-colonization: are hospital surfaces reservoirs for nosocomial infection? | journal = Clinical Infectious Diseases | volume = 39 | issue = 8 | pages = 1182–89 | date = October 2004 | pmid = 15486843 | doi = 10.1086/424667 | pmc = 7107941 | doi-access = free }}</ref> [[Rubbing alcohol|Alcohol]] is an effective sanitizer against influenza viruses, while [[Quaternary ammonium cation|quaternary ammonium compounds]] can be used with alcohol so that the sanitizing effect lasts for longer.<ref name=McDonnell>{{cite journal | vauthors = McDonnell G, Russell AD | title = Antiseptics and disinfectants: activity, action, and resistance | journal = Clinical Microbiology Reviews | volume = 12 | issue = 1 | pages = 147–79 | date = January 1999 | pmid = 9880479 | pmc = 88911 | doi = 10.1128/CMR.12.1.147 | doi-access=free }}</ref> In hospitals, quaternary ammonium compounds and [[bleach]] are used to sanitize rooms or equipment that have been occupied by people with influenza symptoms.<ref name=McDonnell/> At home, this can be done effectively with a diluted chlorine bleach.<ref>{{cite web |url=http://www.waterandhealth.org/newsletter/new/winter_2005/chlorine_bleach.html |title=Chlorine Bleach: Helping to Manage the Flu Risk |publisher=Water Quality & Health Council |date=April 2009 |access-date=12 May 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090607164343/http://www.waterandhealth.org/newsletter/new/winter_2005/chlorine_bleach.html |archive-date=7 June 2009 }}</ref>

Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important. [[Water treatment]], indoor raising of animals, quarantining sick animals, vaccination, and [[biosecurity]] are the primary measures used. Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.<ref name=krammer /> Closure of live poultry markets appears to the most effective measure<ref name=li /> and has shown to be effective at controlling the spread of H5N1, H7N9, and [[H9N2]].<ref name=joseph /> Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms,<ref name=avian >{{cite web |url=https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/nvap/NVAP-Reference-Guide/Poultry/Avian-Influenza |title=Avian Influenza (AI) |author=<!--Not stated--> |publisher=U.S. Department of Agriculture, Animal and Plant Health Inspection Service |access-date=9 March 2021 |archive-date=23 March 2021 |archive-url=https://web.archive.org/web/20210323183930/https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/nvap/NVAP-Reference-Guide/Poultry/Avian-Influenza |url-status=live }}</ref> changing clothes, disinfecting foot baths, and treating food and water.<ref name=krammer />

If live poultry markets are not closed, then "clean days" when unsold poultry is removed and facilities are disinfected and "no carry-over" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses. If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.<ref name=krammer /> Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.<ref name=li /> In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy<ref name=lycett /> if used in combination with other measures to limit transmission.<ref name=krammer /> In pigs and horses, management of influenza is dependent on vaccination with biosecurity.<ref name=krammer />

==Diagnosis==
[[File:X-ray of 29-year-old person with H1N1.jpg|thumb|upright=1.4|X-ray of 29-year-old person with H1N1]]
Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), [[sepsis]], or if encephalitis, [[myocarditis]], or [[Rhabdomyolysis|breakdown of muscle tissue]] occur.<ref name=kalil /> Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation. Common sample collection methods for testing include nasal and throat swabs.<ref name=krammer /> Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract. Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case. For severe cases, earlier diagnosis improves patient outcome.<ref name=chow /> Diagnostic methods that can identify influenza include [[viral culture]]s, antibody- and antigen-detecting tests, and nucleic acid-based tests.<ref name=vemula >{{cite journal | vauthors = Vemula SV, Zhao J, Liu J, Wang X, Biswas S, Hewlett I | title = Current Approaches for Diagnosis of Influenza Virus Infections in Humans | journal = Viruses | volume = 8 | issue = 4 | pages = 96 | date = April 2016 | pmid = 27077877 | pmc = 4848591 | doi = 10.3390/v8040096 | doi-access = free | title-link = doi }}</ref>

Viruses can be grown in a culture of mammalian cells or [[embryonated]] eggs for 3–10 days to monitor cytopathic effect. Final confirmation can then be done via antibody staining, hemadsorption using [[red blood cell]]s, or [[immunofluorescence]] microscopy. Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.<ref name=krammer /><ref name=chow /><ref name=vemula /> Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.<ref name=krammer />

Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination. Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays. These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.<ref name=krammer /><ref name=vemula />

Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope. They can differentiate between influenza A virus and influenza B virus but can not subtype influenza A virus.<ref name=vemula /> [[Rapid influenza diagnostic test]]s (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results in less than 30 minutes, so they are commonly used, but they can not distinguish between influenza A virus and influenza B virus or between influenza A virus subtypes and are not as sensitive as nucleic-acid based tests.<ref name=krammer /><ref name=vemula />

[[Nucleic acid test|Nucleic acid-based tests]] (NATs) amplify and detect viral nucleic acid. Most of these tests take a few hours,<ref name=vemula /> but rapid molecular assays are as fast as RIDTs.<ref name=chow /> Among NATs, [[reverse transcription polymerase chain reaction]] (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza<ref name=vemula /> because it is fast and can subtype influenza A virus, but it is relatively expensive and more prone to false-positives than cultures.<ref name=krammer /> Other NATs that have been used include [[loop-mediated isothermal amplification]]-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification. Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance. The traditional method is [[Sanger sequencing]], but it has been largely replaced by [[Massive parallel sequencing|next-generation methods]] that have greater sequencing speed and throughput.<ref name=vemula />

==Management==
{{Main|Treatment of influenza}}

Treatment in cases of mild or moderate illness is supportive and includes anti-fever medications such as [[acetaminophen]] and [[ibuprofen]],<ref name=MLP2010 >{{cite web |url=https://www.nlm.nih.gov/medlineplus/ency/article/000080.htm |title=Flu: MedlinePlus Medical Encyclopedia |publisher=U.S. National Library of Medicine |access-date=7 February 2010 |url-status=live |archive-url=https://web.archive.org/web/20100214213310/http://www.nlm.nih.gov/medlineplus/ency/article/000080.htm |archive-date=14 February 2010}}</ref> adequate fluid intake to avoid dehydration, and rest.<ref name=ghebrehewet /> Cough drops and throat sprays may be beneficial for sore throat. It is recommended to avoid alcohol and tobacco use while ill.<ref name=MLP2010 /> [[Aspirin]] is not recommended to treat influenza in children due to an elevated risk of developing [[Reye syndrome]].<ref name=banday >{{cite journal | vauthors = Banday AZ, Arul A, Vignesh P, Singh MP, Goyal K, Singh S | title = Kawasaki disease and influenza-new lessons from old associations | journal = Clinical Rheumatology | volume = 40 | issue = 7 | pages = 2991–2999 | date = July 2021 | pmid = 33387094 | pmc = 7778392 | doi = 10.1007/s10067-020-05534-1 }}</ref> [[Corticosteroid]]s are not recommended except when treating [[septic shock]] or an underlying medical condition, such as [[chronic obstructive pulmonary disease]] or asthma exacerbation, since they are associated with increased mortality.<ref name=chow /> If a secondary bacterial infection occurs, then antibiotics may be necessary.<ref name=ghebrehewet />

===Antivirals===
{| class="wikitable" style="text-align:center; margin-left: auto; margin-right: auto; border: none;"
|+ Antiviral drugs<ref name=peteranderl /><!--Oseltamivir, Zanamivir, and Peramivir are sourced to Peteranderl, et al.-->
! Drug || Route of administration || Approved age of use
|-
| [[Oseltamivir]] || Oral || At least two weeks old
|-
| [[Zanamivir]] || Inhalation || At least five years old
|-
| [[Peramivir]] || Intravenous injection || At least 18 years old
|-
| [[Laninamivir]] || Inhalation<ref name=krammer /> || 40 milligrams (mg) dose for people at least 10 years old,<br /> 20&nbsp;mg for those under 10<ref name=lanina >{{cite web |url=https://drugs.ncats.io/drug/B408IW3GL5 |title=Laninamivir |author=<!--Not stated--> |publisher=National Center for Advancing Translational Sciences |access-date=9 March 2021 |archive-date=28 August 2021 |archive-url=https://web.archive.org/web/20210828124317/https://drugs.ncats.io/drug/B408IW3GL5 |url-status=live }}</ref>
|-
| [[Baloxavir marboxil]] || Oral<ref name=lampejo /> || At least 12 years old<ref name=chow />
|}

Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems. Antivirals are most effective when started in the first 48 hours after symptoms appear. Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus. Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.<ref name=krammer /><ref name=chow /> Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.<ref name=peteranderl /> Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for influenza A virus and influenza B virus.<ref name=dharmapalan /><ref name=li /><ref name=lampejo />

NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on influenza A virus and influenza B virus virions<ref name=krammer /> so that viral release from infected cells and the rate of viral replication are impaired.<ref name=ghebrehewet /> NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally. Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality<ref name=krammer /> and the duration of illness.<ref name=peteranderl /><ref name=chow /><ref name=lampejo /> Additionally, the earlier NA inhibitors are provided, the better the outcome,<ref name=lampejo /> though late administration can still be beneficial in severe cases.<ref name=krammer /><ref name=chow /> Other NA inhibitors include laninamivir<ref name=krammer /> and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.<ref name=chow />

The [[adamantane]]s [[amantadine]] and [[rimantadine]] are orally administered drugs that block the influenza virus' M2 ion channel,<ref name=krammer /> preventing viral uncoating.<ref name=lampejo /> These drugs are only functional against influenza A virus<ref name=chow /> but are no longer recommended for use because of widespread resistance to them among influenza A viruses.<ref name=lampejo /> Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008. Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation. Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy,<ref name=krammer /> especially the immunocompromised and young children.<ref name=lampejo /> Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and influenza B viruss less commonly.<ref name=krammer /> Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and influenza B virus and zanamivir against H1N1 pdm09. Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.<ref name=lampejo />

==Prognosis==
In healthy individuals, influenza infection is usually self-limiting and rarely fatal.<ref name=dharmapalan /><ref name=ghebrehewet /> Symptoms usually last for 2–8 days.<ref name=peteranderl /> Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence. Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve. Complications and mortality primarily occur in high-risk populations and those who are hospitalized. Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection,<ref name=krammer /><ref name=ghebrehewet /> which can progress to ARDS.<ref name=peteranderl />

Other respiratory complications that may occur include [[sinusitis]], [[bronchitis]], [[bronchiolitis]], excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma. [[Otitis media|Middle ear infection]] and [[croup]] may occur, most commonly in children.<ref name=dharmapalan /><ref name=krammer /> Secondary ''S. aureus'' infection has been observed, primarily in children, to cause [[toxic shock syndrome]] after influenza, with hypotension, fever, and reddening and peeling of the skin.<ref name=krammer /> Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a [[Arrythmia|fast, slow, or irregular heartbeat]], and exacerbation of pre-existing cardiovascular disease.<ref name=dharmapalan /><ref name=ghebrehewet /> [[Myositis|Inflammation or swelling of muscles]] accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.<ref name=krammer /><ref name=ghebrehewet /><ref name=kalil />

Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.<ref name=ghebrehewet /> Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and [[Guillain–Barré syndrome]].<ref name=kalil /> Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.<ref name=krammer /><ref name=ghebrehewet /> Influenza-associated encephalopathy can occur directly from central nervous system infection from [[Viremia|the presence of the virus in blood]] and presents as sudden onset of fever with convulsions, followed by rapid progression to coma.<ref name=dharmapalan /> An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.<ref name=krammer /> In survivors of influenza-associated encephalopathy, neurological defects may occur.<ref name=dharmapalan /> Primarily in children, in severe cases the immune system may rarely [[hemophagocytic lymphohistiocytosis|dramatically overproduce white blood cells]] that release cytokines, causing severe inflammation.<ref name=dharmapalan />

People who are at least 65 years of age,<ref name=ghebrehewet /> due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times. Pregnant women are at an elevated risk, which increases by trimester<ref name=krammer /> and lasts up to two weeks after childbirth.<ref name=ghebrehewet /><ref name=chow /> Obesity, in particular a [[body mass index]] greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy. People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. [[diabetes]]) disorders,<ref name=dharmapalan /><ref name=krammer /><ref name=ghebrehewet /> as are people who are immunocompromised from chemotherapy, [[asplenia]], prolonged steroid treatment, splenic dysfunction, or [[HIV]] infection.<ref name=ghebrehewet /> Tobacco use, including past use, places a person at risk.<ref name=chow /> The role of genetics in influenza is not well researched,<ref name=krammer /> but it may be a factor in influenza mortality.<ref name=peteranderl />

==Epidemiology==
{{further|Flu season|Flu pandemics}}
[[File:InfluenzaCaseMortality.svg|thumb|upright=1.25|Influenza mortality in symptomatic cases in the US for the 2018/2019 season<ref>{{cite web |title=Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths in the United States – 2018–2019 influenza season |url=https://www.cdc.gov/flu/about/burden/2018-2019.html |website=U.S. [[Centers for Disease Control and Prevention]] (CDC) |access-date=5 March 2020 |date=9 January 2020 |archive-date=9 December 2020 |archive-url=https://web.archive.org/web/20201209004454/https://www.cdc.gov/flu/about/burden/2018-2019.html |url-status=live }}</ref>]]
Influenza is typically characterized by seasonal epidemics and sporadic pandemics. Most of the burden of influenza is a result of flu seasons caused by influenza A virus and influenza B virus. Among influenza A virus subtypes, H1N1 and H3N2 circulate in humans and are responsible for seasonal influenza. Cases disproportionately occur in children, but most severe causes are among the elderly, the very young,<ref name=krammer /> and the immunocompromised.<ref name=lampejo /> In a typical year, influenza viruses infect 5–15% of the global population,<ref name=allen /><ref name=vemula /> causing 3–5 million cases of severe illness annually<ref name=krammer /><ref name=sautto /> and accounting for 290,000–650,000 deaths each year due to respiratory illness.<ref name=allen /><ref name=lampejo /><ref>{{cite news |author=<!--Staff writer(s)/no by-line.--> |title=Up to 650 000 people die of respiratory diseases linked to seasonal flu each year |url=https://www.who.int/news/item/13-12-2017-up-to-650-000-people-die-of-respiratory-diseases-linked-to-seasonal-flu-each-year |publisher=World Health Organization |location=Geneva |date=13 December 2017 |access-date=16 June 2021 |archive-date=3 May 2021 |archive-url=https://web.archive.org/web/20210503135205/https://www.who.int/news/item/13-12-2017-up-to-650-000-people-die-of-respiratory-diseases-linked-to-seasonal-flu-each-year |url-status=live }}</ref> 5–10% of adults and 20–30% of children contract influenza each year.<ref name=asha /> The reported number of influenza cases is usually much lower than the actual number.<ref name=krammer /><ref name=principi />

During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.<ref name=krammer /> Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults. In children, influenza and [[respiratory syncytial virus]] are the two most common causes of ARDS.<ref name=kalil /> About 3–5% of children each year develop otitis media due to influenza.<ref name=dharmapalan /> Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.<ref name=kalil /> During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.<ref name=peteranderl />

[[File:Influenza Seasonal Risk Areas.svg|thumb|upright=1.4|Seasonal risk areas for influenza: November–April (blue), April–November (red), and year-round (yellow)]]

In temperate regions, the number of influenza cases varies from season to season. Lower [[vitamin D]] levels, presumably due to less sunlight,<ref name=moriyama /> lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season. In the northern hemisphere, this is from October to May (more narrowly December to April<ref name=peteranderl />), and in the southern hemisphere, this is from May to October (more narrowly June to September<ref name=peteranderl />). There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.<ref name=krammer /><ref name=ghebrehewet /><ref name=sautto /> In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.<ref name=krammer /><ref name=potter >{{cite journal | vauthors = Potter CW | title = A history of influenza | journal = Journal of Applied Microbiology | volume = 91 | issue = 4 | pages = 572–579 | date = October 2001 | pmid = 11576290 | doi = 10.1046/j.1365-2672.2001.01492.x | s2cid = 26392163 }}</ref> Influenza may therefore occur year-round in these regions.<ref name=peteranderl /> Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere,<ref name=potter /> with Asia being a key reservoir.<ref name=peteranderl />

Influenza A virus and influenza B virus co-circulate, so have the same patterns of transmission.<ref name=krammer /> The seasonality of influenza C virus, however, is poorly understood. Influenza C virus infection is most common in children under the age of two, and by adulthood most people have been exposed to it. Influenza C virus-associated hospitalization most commonly occurs in children under the age of three and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease. When considering all hospitalizations for respiratory illness among young children, influenza C virus appears to account for only a small percentage of such cases. Large outbreaks of influenza C virus infection can occur, so incidence varies significantly.<ref name=sederdahl />

Outbreaks of influenza caused by novel influenza viruses are common.<ref name=mccauley /> Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths. These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses. To date, all known flu pandemics have been caused by influenza A viruses, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.<ref name=krammer /><ref name=ghebrehewet /><ref name=chow /> Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.<ref name=kalil /> Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.<ref name=krammer /> From 1700 to 1889, influenza pandemics occurred about once every 50–60 years. Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.<ref name=potter />

==History==
[[File:Influenza subtypes.svg|thumb|upright=1.6|The main types of influenza viruses in humans. Solid squares show the appearance of a new strain, causing recurring influenza pandemics. Broken lines indicate uncertain strain identifications.<ref name=Palese>{{cite journal | vauthors = Palese P | title = Influenza: old and new threats | journal = Nature Medicine | volume = 10 | issue = 12 Suppl | pages = S82–S87 | date = December 2004 | pmid = 15577936 | doi = 10.1038/nm1141 | s2cid = 1668689 | doi-access = free | title-link = doi }}</ref>]]
The first influenza epidemic may have occurred around 6,000 BC in China,<ref name=mordini >{{cite book |veditors=Mordini E, Green M |title=Internet-Based Intelligence in Public Health Emergencies: Early Detection and Response in Disease Outbreak Crises |publisher=IOS Press |year=2013 |page=67 |isbn=978-1614991755}}</ref> and possible descriptions of influenza exist in Greek writings from the 5th century BC.<ref name=potter /><ref name=martin >{{cite journal | vauthors = Martin PM, Martin-Granel E | title = 2,500-year evolution of the term epidemic | journal = Emerging Infectious Diseases | volume = 12 | issue = 6 | pages = 976–980 | date = June 2006 | pmid = 16707055 | pmc = 3373038 | doi = 10.3201/eid1206.051263 }}</ref> In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named "influenza". Whether these epidemics or others were caused by influenza is unclear since there was then no consistent naming pattern for epidemic respiratory diseases, and "influenza" did not become clearly associated with respiratory disease until centuries later.<ref name=morens1 >{{cite journal | vauthors = Morens DM, North M, Taubenberger JK | title = Eyewitness accounts of the 1510 influenza pandemic in Europe | journal = Lancet | volume = 376 | issue = 9756 | pages = 1894–1895 | date = December 2010 | pmid = 21155080 | pmc = 3180818 | doi = 10.1016/S0140-6736(10)62204-0 }}</ref> Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the [[Antilles]].<ref name=guerra1988 >{{cite journal | vauthors = Guerra F | title = The earliest American epidemic. The influenza of 1493 | journal = Social Science History | volume = 12 | issue = 3 | pages = 305–325 | year = 1988 | pmid = 11618144 | doi = 10.2307/1171451 | jstor = 1171451 }}<!-- (only the first page can be read for free, but that has enough information about influenza being the main disease brought by Columbus killing 90 % of the indigenous population) --></ref><ref name=guerra1993 >{{cite journal | vauthors = Guerra F | title = The European-American exchange | journal = History and Philosophy of the Life Sciences | volume = 15 | issue = 3 | pages = 313–327 | year = 1993 | pmid = 7529930 }}</ref>

The first convincing record of an influenza pandemic was [[1510 influenza pandemic|in 1510]]. It began in East Asia before spreading to North Africa and then Europe.<ref name=morens2 >{{cite journal | vauthors = Morens DM, Taubenberger JK, Folkers GK, Fauci AS | title = Pandemic influenza's 500th anniversary | journal = Clinical Infectious Diseases | volume = 51 | issue = 12 | pages = 1442–1444 | date = December 2010 | pmid = 21067353 | pmc = 3106245 | doi = 10.1086/657429 }}</ref> Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.<ref name=morens1 /> The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.<ref name=knobler >{{cite book |veditors=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 |chapter-url=http://books.nap.edu/openbook.php?record_id=11150&page=61 |publisher=The National Academies Press |location=Washington, DC |doi=10.17226/11150 |pmid=20669448 |year=2005 |isbn=978-0-309-09504-4 |author1=Institute of Medicine (US) Forum on Microbial Threats |access-date=10 March 2021 |archive-date=10 June 2024 |archive-url=https://web.archive.org/web/20240610052848/https://nap.nationalacademies.org/read/11150/chapter/3#63 |url-status=live }}</ref> The [[1580 influenza pandemic]] originated in Asia during summer, spread to Africa, then Europe, and finally America.<ref name=potter /> By the end of the 16th century, influenza was beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.<ref name=morens1 /> In 1648, it was discovered that horses also experience influenza.<ref name=morens2 />

Influenza data after 1700 is more accurate, so it is easier to identify flu pandemics after this point.<ref name=taubenberger >{{cite journal | vauthors = Taubenberger JK, Hultin JV, Morens DM | title = Discovery and characterization of the 1918 pandemic influenza virus in historical context | journal = Antiviral Therapy | volume = 12 | issue = 4 Pt B | pages = 581–591 | year = 2007 | pmid = 17944266 | pmc = 2391305 | doi = 10.1177/135965350701200S02.1 }}</ref> The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal. Another flu pandemic occurred in 1781–1782, starting in China in autumn.<ref name=potter /> From this pandemic, influenza became associated with sudden outbreaks of febrile illness.<ref name=taubenberger /> The next flu pandemic was from 1830 to 1833, beginning in China in winter. This pandemic had a high attack rate, but the mortality rate was low.<ref name=hastings /><ref name=potter />

A minor influenza pandemic occurred from 1847 to 1851 at the same time as the [[third cholera pandemic]] and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.<ref name=taubenberger /> Fowl plague (now recognised as highly pathogenic avian influenza) was recognized in 1878<ref name=taubenberger /> and was soon linked to transmission to humans.<ref name=morens2 /> By the time of the [[1889–1890 pandemic|1889 pandemic]], which may have been caused by an H2N2 strain,<ref name=vijgen >{{cite journal | vauthors = Vijgen L, Keyaerts E, Moës E, Thoelen I, Wollants E, Lemey P, Vandamme AM, Van Ranst M | title = Complete genomic sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event | journal = Journal of Virology | volume = 79 | issue = 3 | pages = 1595–1604 | date = February 2005 | pmid = 15650185 | pmc = 544107 | doi = 10.1128/JVI.79.3.1595-1604.2005 }}</ref> the flu had become an easily recognizable disease.<ref name=morens2 />

The microbial agent responsible for influenza was incorrectly identified in 1892 by [[Richard Friedrich Johannes Pfeiffer|R. F. J. Pfeiffer]] as the bacteria species ''[[Haemophilus influenzae]]'', which retains "influenza" in its name.<ref name=morens2 /><ref name=taubenberger /> From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called "fowl plague",<ref name=lycett /> was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through. The fundamental differences between viruses and bacteria, however, were not yet fully understood.<ref name=taubenberger />

[[File:W curve.png|thumb|upright=1.3|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=Taubenberger2 >{{cite journal | vauthors = Taubenberger JK, Morens DM | title = 1918 Influenza: the mother of all pandemics | journal = Emerging Infectious Diseases | volume = 12 | issue = 1 | pages = 15–22 | date = January 2006 | pmid = 16494711 | pmc = 3291398 | doi = 10.3201/eid1201.050979 }}</ref>]]

From 1918 to 1920, the [[Spanish flu]] pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history. The pandemic, caused by an H1N1 strain of influenza A,<ref name="taubenberger2">{{cite journal |vauthors=Taubenberger JK, Hultin JV, Morens DM |year=2007 |title=Discovery and characterization of the 1918 pandemic influenza virus in historical context |journal=Antiviral Therapy |volume=12 |issue=4 Pt B |pages=581–591 |doi=10.1177/135965350701200S02.1 |pmc=2391305 |pmid=17944266}}</ref> likely began in the United States before spreading worldwide via soldiers during and after the [[First World War]]. The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate.<ref name=potter /> A third wave with lower mortality occurred in many places a few months after the second.<ref name=hastings /> By the end of 1920, it is estimated that about a third<ref name=peteranderl /> to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.<ref name=potter /> During the 1918 pandemic, the respiratory route of transmission was clearly identified<ref name=hastings /> and influenza was shown to be caused by a "filter passer", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.<ref name=taubenberger /> After the pandemic, H1N1 circulated in humans in seasonal form<ref name=krammer /> until the next pandemic.<ref name=taubenberger />

In 1931, [[Richard Shope]] published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was characterized during the second wave of the 1918 pandemic.<ref name=knobler /><ref name=taubenberger /> Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.<ref name=taubenberger /> Just two years after influenza viruses were discovered, in 1933, influenza A virus was identified as the agent responsible for human influenza.<ref name=knobler /><ref name=smith >{{cite journal |vauthors=Smith W, Andrewes CH, Laidlaw PP |year=1933 |title=A virus obtained from influenza patients |journal=Lancet |volume=2 |issue=5732 |pages=66–68 |doi=10.1016/S0140-6736(00)78541-2 | doi-access = free | title-link = doi }}</ref> Subtypes of influenza A virus were discovered throughout the 1930s,<ref name=taubenberger /> and influenza B virus was discovered in 1940.<ref name=asha />

During the [[Second World War]], the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.<ref name=krammer /> Influenza C virus was discovered two years later in 1947.<ref name=asha /> In 1955, avian influenza was confirmed to be caused by influenza A virus.<ref name=lycett /> Four influenza pandemics have occurred since WWII. The first of these was the [[Asian flu]] from 1957 to 1958, caused by an H2N2 strain<ref name=krammer /><ref name=saunders >{{cite journal | vauthors = Saunders-Hastings P, Crispo JA, Sikora L, Krewski D | title = Effectiveness of personal protective measures in reducing pandemic influenza transmission: A systematic review and meta-analysis | journal = Epidemics | volume = 20 | pages = 1–20 | date = September 2017 | pmid = 28487207 | doi = 10.1016/j.epidem.2017.04.003 | doi-access = free | title-link = doi | hdl = 10393/38995 | hdl-access = free }}</ref> and beginning in China's [[Yunnan]] province. The number of deaths probably exceeded one million, mostly among the very young and very old.<ref name=potter /> This was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.<ref name=hastings /> After the pandemic, H2N2 was the influenza A virus subtype responsible for seasonal influenza.<ref name=krammer /> The first antiviral drug against influenza, [[amantadine]], was approved in 1966, with additional antiviral drugs being used since the 1990s.<ref name=lampejo />

In 1968, H3N2 was introduced into humans through a rearrangement between an avian H3N2 strain and an H2N2 strain that was circulating in humans. The novel H3N2 strain emerged in Hong Kong and spread worldwide, causing the [[Hong Kong flu]] pandemic, which resulted in 500,000–2,000,000 deaths. This was the first pandemic to spread significantly by air travel.<ref name=allen /><ref name=hastings /> H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.<ref name=allen /> In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused [[1977 Russian flu|a pseudo-pandemic]].<ref name=hastings /><ref name=taubenberger /> This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957. Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.<ref name=krammer /> In 1980, the classification system used to subtype influenza viruses was introduced.<ref name=heinen >{{cite journal |vauthors=Heinen PP |date=15 September 2003 |title=Swine influenza: a zoonosis |journal=Veterinary Sciences Tomorrow |issn=1569-0830 |url=http://www.col.ops-oms.org/prevencion/influenza/docsgenerales/Swine_Influenza.htm |access-date=28 December 2016 |url-status=dead |archive-url=https://web.archive.org/web/20070211211419/http://www.col.ops-oms.org/prevencion/influenza/docsgenerales/Swine_Influenza.htm |archive-date=11 February 2007}}</ref>

[[File:Airport Thermographic Camera.jpg|thumb|Thermal imaging camera and screen, photographed in an airport terminal in [[Greece]] during the 2009 flu pandemic. Thermal imaging can detect elevated body temperature, one of the signs of swine flu.]]

At some point, influenza B virus diverged into two strains, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.<ref name=asha />

In 1996, a highly pathogenic H5N1 subtype of influenza A was detected in geese in [[Guangdong]], China<ref name="lycett" /> and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there. A small H5N1 outbreak in humans in Hong Kong occurred then,<ref name="steinhauer" /> and sporadic human cases have occurred since 1997, carrying a high case fatality rate.<ref name="li" /><ref name="vemula" />

The most recent flu pandemic was the [[2009 swine flu pandemic]], which originated in Mexico and resulted in hundreds of thousands of deaths.<ref name="hastings" /> It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.<ref name="joseph" /><ref name="lampejo" /> The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses. Consequently, H1N1, H3N2, and both influenza B virus lineages have been in circulation in seasonal form since the 2009 pandemic.<ref name="krammer" /><ref name="hastings" /><ref name="lycett" />

In 2011, influenza D virus was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of influenza D virus.<ref name="sederdahl" /><ref name="asha" />

In the same year,<ref name="vemula" /> avian H7N9 was detected in China and began to cause human infections in 2013, starting in [[Shanghai]] and [[Anhui]] and remaining mostly in China. Highly pathogenic H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally. Other avian influenza viruses have less commonly infected humans since the 1990s, including H5N1, H5N5, [[H5N6]], [[H6N1|H5N8]], [[H6N1]], [[Influenza A virus subtype H7N2|H7N2]], [[H7N7]], and [[Influenza A virus subtype H10N7|H10N7]], and have begun to spread throughout much of the world since the 2010s.<ref name="li" /> Future flu pandemics, which may be caused by an influenza virus of avian origin,<ref name="lycett" /> are viewed as almost inevitable, and increased [[globalization]] has made it easier for a pandemic virus to spread,<ref name="hastings" /> so there are continual efforts to prepare for future pandemics<ref name="knobler" /> and improve the prevention and treatment of influenza.<ref name="krammer" />

===Etymology===
The word ''influenza'' comes from the [[Italian language|Italian]] word {{Lang|it|influenza}}, from medieval [[Latin]] {{Lang|la|influentia}}, originally meaning 'visitation' or 'influence'. Terms such as {{Lang|it|influenza di freddo}}, meaning 'influence of the cold', and {{Lang|it|influenza di stelle}}, meaning 'influence of the stars' are attested from the 14th century. The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable [[Astrology|astrological]] conditions. As early as 1504, {{Lang|it|influenza}} began to mean a 'visitation' or 'outbreak' of any disease affecting many people in a single place at once. During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation. Since the mid-1800s, ''influenza'' has also been used to refer to severe colds.<ref name=espinosa >{{cite journal | vauthors = Vázquez-Espinosa E, Laganà C, Vázquez F | title = The Spanish flu and the fiction literature | journal = Revista Espanola de Quimioterapia | volume = 33 | issue = 5 | pages = 296–312 | date = October 2020 | pmid = 32633114 | pmc = 7528412 | doi = 10.37201/req/049.2020 }}</ref><ref name=etymonline >{{cite web |url=https://www.etymonline.com/word/influenza#etymonline_v_6456 |title=influenza (n.) |author=<!--Not stated--> |publisher=Online Etymology Dictionary |access-date=9 March 2021 |archive-date=28 January 2021 |archive-url=https://web.archive.org/web/20210128213116/https://www.etymonline.com/word/influenza#etymonline_v_6456 |url-status=live }}</ref><ref name=oed >{{cite web |url=https://www.oed.com/oed2/00116459;jsessionid=03BCFDCDE17AD6089AD4ED9040E2B58F |title=influenza |author=<!--Not stated--> |publisher=Oxford English Dictionary |access-date=9 March 2021 |archive-date=16 October 2021 |archive-url=https://web.archive.org/web/20211016025857/https://www.oed.com/oed2/00116459;jsessionid=03BCFDCDE17AD6089AD4ED9040E2B58F |url-status=dead }}</ref> The shortened form of the word, "flu", is first attested in 1839 as ''flue'' with the spelling ''flu'' confirmed in 1893.<ref name=etymflu >{{cite web |url=https://www.etymonline.com/word/flu#etymonline_v_8928 |title=flu (n.) |author=<!--Not stated--> |publisher=Online Etymology Dictionary |access-date=20 July 2021 |archive-date=21 July 2021 |archive-url=https://web.archive.org/web/20210721010327/https://www.etymonline.com/word/flu#etymonline_v_8928 |url-status=live }}</ref> Other names that have been used for influenza include ''epidemic catarrh'', ''la grippe'' from [[French language|French]], ''sweating sickness'', and, especially when referring to the 1918 pandemic strain, ''Spanish fever''.<ref name=calisher >{{cite journal | vauthors = Calisher CH | title = Swine flu | journal = Croatian Medical Journal | volume = 50 | issue = 4 | pages = 412–415 | date = August 2009 | pmid = 19673043 | pmc = 2728380 | doi = 10.3325/cmj.2009.50.412 | author1-link = Charles Calisher }}</ref>

==In animals==
===Birds===
Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of influenza A viruses (IAVs).<ref name=li /><ref name=joseph />

Because of the impact of avian influenza on economically important chicken farms, a classification system was devised in 1981 which divided avian virus strains as either highly pathogenic (and therefore potentially requiring vigorous control measures) or low pathogenic. The test for this is based solely on the effect on chickens – a virus strain is '''highly pathogenic avian influenza''' (HPAI) if 75% or more of chickens die after being deliberately infected with it. The alternative classification is '''low pathogenic avian influenza''' (LPAI) which produces mild or no symptoms.<ref name=":AA6">{{cite journal | vauthors = Alexander DJ, Brown IH | title = History of highly pathogenic avian influenza | journal = Revue Scientifique et Technique | volume = 28 | issue = 1 | pages = 19–38 | date = April 2009 | pmid = 19618616 | doi = 10.20506/rst.28.1.1856 | doi-access = }}</ref> This classification system has since been modified to take into account the structure of the virus' haemagglutinin protein.<ref>{{Cite web |date=15 June 2017 |title=Factsheet on A(H5N1) |url=https://www.ecdc.europa.eu/en/zoonotic-influenza/facts/factsheet-h5n1 |access-date=21 May 2024 |website=www.ecdc.europa.eu |archive-date=21 May 2024 |archive-url=https://web.archive.org/web/20240521183049/https://www.ecdc.europa.eu/en/zoonotic-influenza/facts/factsheet-h5n1 |url-status=live }}</ref> At the genetic level, an AIV can be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.<ref name="joseph" /><ref name="lycett" /> Other species of birds, especially water birds, can become infected with HPAI virus without experiencing severe symptoms and can spread the infection over large distances; the exact symptoms depend on the species of bird and the strain of virus.<ref name=":AA6" /> Classification of an avian virus strain as HPAI or LPAI does not predict how serious the disease might be if it infects humans or other mammals.<ref name=":AA6" /><ref>{{Cite web |last=CDC |date=5 April 2024 |title=Current U.S. Bird Flu Situation in Humans |url=https://www.cdc.gov/flu/avianflu/inhumans.htm |access-date=22 May 2024 |website=U.S. [[Centers for Disease Control and Prevention]] (CDC) |archive-date=22 May 2024 |archive-url=https://web.archive.org/web/20240522125455/https://www.cdc.gov/flu/avianflu/inhumans.htm |url-status=live }}</ref>

Symptoms of HPAI infection in chickens include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea; birds infected with an HPAI virus may also die suddenly without any signs of infection.<ref name="avian" /> Notable HPAI viruses include influenza A (H5N1) and A (H7N9). HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds. In H7N9's case, some circulating strains were originally low pathogenic but became high pathogenic by mutating to acquire the HA multibasic cleavage site. Avian H9N2 is also of concern because although it is low pathogenic, it is a common donor of genes to H5N1 and H7N9 during reassortment.<ref name=krammer />

[[Bird migration|Migratory birds]] can spread influenza across long distances. An example of this was when an H5N1 strain in 2005 infected birds at [[Qinghai Lake]], China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.<ref name= li /><ref name=lycett /> AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.<ref name=krammer /> Ducks therefore act as key intermediates between wild and domestic birds.<ref name=lycett /> Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other. From there, AIVs can spread to poultry farms in the absence of adequate biosecurity. Among poultry, HPAI transmission occurs through aerosols and contaminated feces,<ref name=krammer /> cages, feed, and dead animals.<ref name=li /> Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.<ref name=joseph />

AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.<ref name=krammer /> Direction transmission from wild birds is rare.<ref name=lycett /> Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.<ref name=joseph /> The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.<ref name=li /> Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days. H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.<ref name=krammer /> Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.<ref name=krammer /><ref name=sautto />

===Pigs===
[[File:ChineseFluInspectors.JPG|thumb|Chinese inspectors checking airline passengers for fever, a common symptom of swine flu]]
Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide. Asymptomatic infections are common. Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge. In sows, pregnancy may be aborted. Complications include secondary infections and potentially fatal [[bronchopneumonia]]. Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd. Pigs usually recover within 3–7 days after symptoms appear. Prevention and control measures include inactivated vaccines and culling infected herds. Influenza A virus subtypes H1N1, [[H1N2]], and H3N2 are usually responsible for swine flu.<ref name=swine >{{cite web |url=https://www.oie.int/en/animal-health-in-the-world/animal-diseases/Swine-influenza/ |title=Swine influenza |author=<!--Not stated--> |publisher=World Organisation for Animal Health |access-date=9 March 2021 |archive-date=4 March 2021 |archive-url=https://web.archive.org/web/20210304222929/https://www.oie.int/en/animal-health-in-the-world/animal-diseases/Swine-influenza/ |url-status=live }}</ref>

Some influenza A viruses can be transmitted via aerosols from pigs to humans and vice versa.<ref name=krammer /> Pigs, along with bats and quails,<ref name=asha /> are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract. Because of that, both avian and mammalian influenza viruses can infect pigs. If co-infection occurs, reassortment is possible.<ref name=joseph /> A notable example of this was the reassortment of a swine, avian, and human influenza virus that caused the 2009 flu pandemic.<ref name=joseph /><ref name=lampejo /> Spillover events from humans to pigs appear to be more common than from pigs to humans.<ref name=joseph />

===Other animals===
Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals. Nearly all influenza A viruses are apparently descended from ancestral viruses in birds. The exception are bat influenza-like viruses, which have an uncertain origin. These bat viruses have HA and NA subtypes H17, H18, N10, and N11. [[H17N10]] and [[H18N11]] are unable to reassort with other influenza A viruses, but they are still able to replicate in other mammals.<ref name=krammer />

Equine influenza A viruses include H7N7 and two lineages<ref name=krammer /> of [[H3N8]]. H7N7, however, has not been detected in horses since the late 1970s,<ref name=mccauley /> so it may have become extinct in horses.<ref name=joseph /> H3N8 in equines spreads via aerosols and causes respiratory illness.<ref name=krammer /> Equine H3N8 preferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment. In canines, the only influenza A viruses in circulation are equine-derived H3N8 and avian-derived H3N2. Canine H3N8 has not been observed to reassort with other subtypes. H3N2 has a much broader host range and can reassort with H1N1 and H5N1. An isolated case of H6N1, likely from a chicken, was found infecting a dog, so other AIVs may emerge in canines.<ref name=joseph />

[[List of mammals that can get H5N1|A wide range of other mammals]] have been affected by avian influenza A viruses, generally due to eating birds which had been infected.<ref>{{Cite news |date=2 February 2023 |title=Bird flu 'spills over' to otters and foxes in UK |url=https://www.bbc.com/news/science-environment-64474594 |access-date=11 June 2024 |work=BBC News |language=en-GB}}</ref> There have been instances where transmission of the disease between mammals, including seals and cows, may have occurred.<ref>{{Cite web |date=15 March 2023 |title=Study of H5N1 avian flu seal deaths reveals multiple lineages {{!}} CIDRAP |url=https://www.cidrap.umn.edu/avian-influenza-bird-flu/study-h5n1-avian-flu-seal-deaths-reveals-multiple-lineages |access-date=13 June 2024 |website=Center for Infectious Disease Research and Policy |language=en}}</ref><ref name=":B22">{{cite journal | vauthors = Kozlov M | title = Huge amounts of bird-flu virus found in raw milk of infected cows | journal = Nature | date = June 2024 | pmid = 38840011 | doi = 10.1038/d41586-024-01624-1 }}</ref><ref name=mccauley /> Various mutations have been identified that are associated with AIVs adapting to mammals. Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals. Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.<ref name=joseph />

Influenza B virus is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.<ref name=asha /> Likewise, influenza C virus primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.<ref name=sederdahl /><ref name=asha /> Influenza D virus causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown. It may cause respiratory disease resembling human influenza on its own, or it may be part of a [[bovine respiratory disease]] (BRD) complex with other pathogens during co-infection. BRD is a concern for the cattle industry, so influenza D virus' possible involvement in BRD has led to research on vaccines for cattle that can provide protection against influenza D virus.<ref name=asha /><ref name=su /> Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660).<ref name=asha />

== References ==
{{Reflist}}

==Further reading==
{{external media| float = right| video1 = [https://www.c-span.org/video/?458488-1/influenza Presentation by Brown on ''Influenza'', March 5, 2019], [[C-SPAN]]}}
* {{cite book | vauthors=Brown J |title=Influenza: The Hundred Year Hunt to Cure the Deadliest Disease in History|publisher=Atria|location=New York |year=2018 |isbn=978-1501181245}}
* {{cite book|author-link=Arthur Albert St. Mouritz | vauthors = St Mouritz AA |date=1921 |title=The Flu: A Brief History of Influenza in U.S. America, Europe, Hawaii |url=https://collections.nlm.nih.gov/bookviewer?PID=nlm:nlmuid-101283076-bk#page/3/mode/1up/ |location=Honolulu, Hawaii, U.S. America |publisher=Advertiser Publishing Co. }}

{{Medical condition classification and resources
|DiseasesDB=6791
|ICD10={{ICD10|J|10||j|09}}, {{ICD10|J|11||j|09}}
|ICD9={{ICD9|487}}
|OMIM=614680
|MedlinePlus=000080
|eMedicineSubj=med
|eMedicineTopic=1170
|eMedicine_mult={{eMedicine2|ped|3006}}
|MeshID=D007251
}}
{{Influenza}}
{{Respiratory pathology}}
{{Viral diseases}}
{{Subject bar|Medicine|Viruses|b = y|b-search = |commons = y|commons-search = |d = y|d-search = |n = y|n-searc h =|q = y|q-search = |s = y|s-search = |species = y|species-search = |v = y|v-search = |voy = y|voy-search = |wikt = y|wikt-search = }}
{{Authority control}}

[[Category:Influenza| ]]
[[Category:Airborne diseases]]
[[Category:Animal viral diseases]]
[[Category:Healthcare-associated infections]]
[[Category:Vaccine-preventable diseases]]
[[Category:Wikipedia emergency medicine articles ready to translate]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Zoonoses]]