Influenza

Influenza virus nomenclature (for a Fujian flu virus)

Influenza viruses comprise four species. Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family Orthomyxoviridae. They are:[1][14]

• Influenza A virus (IAV), genus Alphainfluenzavirus
• Influenza B virus (IBV), genus Betainfluenzavirus
• Influenza C virus (ICV), genus Gammainfluenzavirus
• Influenza D virus (IDV), genus Deltainfluenzavirus

IAV 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 who have chronic health issues. Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls,[15][16] but the virus also circulates among mammals, including pigs, horses, and marine mammals. IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).[17] As of 2019, 18 H subtypes and 11 N subtypes have been identified. Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats. Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans,[17] the current IAV subtypes in circulation being H1N1 and H3N2.[2] IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.[1][9]

IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.[17] IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages,[1] or simply (B/)Victoria(-like) and (B/)Yamagata(-like).[17][2] Both lineages are in circulation in humans,[1] disproportionately affecting children.[9] IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.[17]

ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.[10][17] ICV infection primarily affects children and is usually asymptomatic[1][9] or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.[10] Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.[17] ICV is subclassified into six genetic/antigenic lineages.[10][18]

IDV 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.[17][18] IDV is distantly related to ICV. While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.[1][9][10] ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV. Because of this antigenic stability, relatively few novel lineages emerge.[18]

Structure of the influenza 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 ribonucleoproteins (RNP).

Influenza viruses have a 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).[8] IAV and IBV have eight genome segments that encode 10 major proteins. ICV and IDV have seven genome segments that encode nine major proteins.[10] Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.[19] The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).[1] For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV 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).[19] Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames[1][20] and which are important in host defense suppression, virulence, and pathogenicity.[21]

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 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.[22] The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope. There is a copy of the RdRp, all subunits included, bound to each RNP. The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs,[3] and the envelope contains HA and NA (or HEF[18]) proteins extending outward from the exterior surface of the envelope. HA and HEF[18] proteins have a distinct "head" and "stalk" structure. M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit. IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.[1]

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 evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.[1][15][3] 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 mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.[3] 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[20] to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.[21] 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.[20][3]

RNPs are then imported into the nucleus with the help of viral localization signals. There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template. The polymerase 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.[19] Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.[20] 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.[1][3] During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.[11]

Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.[19] HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins[21] to the cell membrane through the Golgi apparatus[19] 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.[1][21][3] PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.[16] 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.[1][3]

Progenic 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.[1][3] Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.[11] Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.[20]

Antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human influenza.

Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift. Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.[15] 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.[2][18] The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.[1][9] Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D.[18] Antigenic drift is a major cause of seasonal influenza,[23] 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 influenza viruses in swine and equines. In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.[1][9]

Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA. During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny. Since all influenza viruses have segmented genomes, all are capable of reassortment.[10][18] Antigenic shift, however, only occurs among influenza viruses of the same genus[19] and most commonly occurs among IAVs. 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.[24] Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential "mixing vessels" for reassortment.[17] If an animal strain reassorts with a human strain,[2] then a novel strain can emerge that is capable of human-to-human transmission. This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.[1][9]

People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air. A person susceptible to infection can then contract influenza by coming into contact with these particles.[13][25] 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 than respiratory droplets.[25][4] Inhalation of aerosols can lead to infection,[26] but most transmission is in the area about two meters around an infected person via respiratory droplets[8] that come into contact with mucosa of the upper respiratory tract.[26] Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces[8][25] since influenza viruses can survive for hours on non-porous surfaces.[4] If one's hands are contaminated, then touching one's face can cause infection.[27]

Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.[9] 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.[8] Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.[1][9] 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.[1] People who are 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 after it is introduced.[9] A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun,[26][28] and crowding.[25] 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.[8]

How the different sites of infection (shown in red) of H1N1 and H5N1 influences their transmission and lethality

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 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 cytokines.[13]

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.[1] Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.[15] In bacterial infections, early depletion of macrophages 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 glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.[13]

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,[1][15][3] such as respiratory and retinal epithelial cells.[20] AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells[1][15][3] and in humans in the lower respiratory tract.[29] Furthermore, cleavage of the HA protein into HA₁, the binding subunit, and HA₂, 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.[1][24][30]

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 also 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 phagocytizing viral particles and apoptotic cells. An exacerbated immune response, however, can harm the host organism through a cytokine storm.[1][11][20] 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.[1][21]

B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF[18]) and other proteins to a lesser degree. Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus. In humans, a sizeable antibody response occurs ~1 week after viral exposure.[31] This antibody response is typically robust and long-lasting, especially for ICV and IDV.[1][18] In other words, 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.[1] 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.[2]

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.[8][1][32] Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.[8][2] Two types of vaccines are in use: inactivated vaccines that contain "killed" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.[1] 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.[33] Most flu vaccines are inactivated and administered via intramuscular injection. LAIVs are sprayed into the nasal cavity.[1]

Vaccination recommendations vary by country. Some recommend vaccination for all people above a certain age, such as 6 months,[32] whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers,[1] people who come into contact with high-risk people, and people who transmit the virus easily.[9] Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.[34] Influenza vaccination also helps to reduce the probability of reassortment.[11]

In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.[8][2] Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.[2] Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.[8][3] Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.[2][35]

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 of age. Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.[8] Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.[8][9] It is recommended that it be offered to 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.[9]

Hand hygiene is important in reducing the spread of influenza. This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands. Covering one's nose and mouth when coughing or sneezing is important.[36] Other methods to limit influenza transmission include staying home when sick,[1] avoiding contact with others until one day after symptoms end,[9] and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.[1] Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.[8]

There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage. Likewise, the effectiveness of screening at points of entry into countries is not well researched.[36] Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission,[1][36] but these measures are often expensive, unpopular, and difficult to implement. Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform. Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.[37]

In health care settings, infected individuals may be cohorted or assigned to individual rooms. Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids. Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help,[8] but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.[4] In residential homes, new admissions may need to be closed until the spread of influenza is controlled. When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.[9]

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.[1] Closure of live poultry markets appears to the most effective measure[15] and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.[16] Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms,[38] changing clothes, disinfecting foot baths, and treating food and water.[1]

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.[1] Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.[15] In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy[24] if used in combination with other measures to limit transmission.[1] In pigs and horses, management of influenza is dependent on vaccination with biosecurity.[1]

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.[1][32] Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.[11] 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 IAV and IBV.[8][15][4]

NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions[1] so that viral release from infected cells and the rate of viral replication are impaired.[9] 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[1] and the duration of illness.[11][32][4] Additionally, the earlier NA inhibitors are provided, the better the outcome,[4] though late administration can still be beneficial in severe cases.[1][32] Other NA inhibitors include laninamivir[1] and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.[32]

The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel,[1] preventing viral uncoating.[4] These drugs are only functional against IAV[32] but are no longer recommended for use because of widespread resistance to them among IAVs.[4] 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,[1] especially the immunocompromised and young children.[4] Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.[1] 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 IBV and zanamivir against H1N1 pdm09. Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.[4]

The word influenza comes from the Italian word influenza, from medieval Latin influentia, originally meaning "visitation" or "influence". Terms such as influenza di freddo, meaning "influence of the cold", and 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 astrological conditions. As early as 1504, 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.[59][60][61] The shortened form of the word, "(the) flu", is first attested in 1839 as flue with the spelling flu first attested in 1893.[62] Other names that have been used for influenza include epidemic catarrh, la grippe from French, sweating sickness, and, especially when referring to the 1918 pandemic strain, Spanish fever.[63]

Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.[15][16] In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness. Symptoms of HPAI infection 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.[38]

The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens. At the genetic level, an AIV can be usually 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.[16][24] Most AIVs are LPAI. Notable HPAI viruses include HPAI H5N1 and HPAI 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 LPAI but became HPAI by acquiring the HA multibasic cleavage site. Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.[1]

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.[15][24] AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.[1] Ducks therefore act as key intermediates between wild and domestic birds.[24] 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,[1] cages, feed, and dead animals.[15] Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.[16]

AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.[1] Direction transmission from wild birds is rare.[24] 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.[16] The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.[15] 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.[1] Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred,[1][2] but sustained human-to-human transmission of AIVs has not occurred. Before 2013, H5N1 was the most common AIV to infect humans. Since then, H7N9 has been responsible for most human cases.[15]

Chinese inspectors checking airline passengers for fevers, 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 from infection within 3–7 days after symptoms appear. Prevention and control measures include inactivated vaccines and culling infected herds. The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.[68]

Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.[1] Furthermore, pigs, along with bats and quails,[17] 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, then reassortment is possible.[16] A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.[16][4] Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.[16]

Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals. Nearly all IAVs 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 IAVs, but they are still able to replicate in other mammals.[1] AIVs sometimes crossover into mammals. For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.[1]

Equine IAVs include H7N7 and two lineages[1] of H3N8. H7N7, however, has not been detected in horses since the late 1970s,[19] so it may have become extinct in horses.[16] H3N8 in equines spreads via aerosols and causes respiratory illness.[1] Equine H3N8 perferentially 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 IAVs 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.[16]

Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.[19] 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.[16]

IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.[17] Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.[10][17] IDV 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 IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.[17][18] Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660).[17]