Influenza

Influenza, commonly known as "the flu", is an

Influenza
infectious disease caused by influenza viruses.
Symptoms range from mild to severe and often include Other Flu, the flu, Grippe
fever, runny nose, sore throat, muscle pain, headache, names
coughing, and fatigue. These symptoms begin from
one to four days after exposure to the virus (typically
two days) and last for about 2–8 days. Diarrhea and
vomiting can occur, particularly in children. Influenza
may progress to pneumonia, which can be caused by
the virus or by a subsequent bacterial infection. Other
complications of infection 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, termed

influenza viruses A, B, C, and D. Aquatic birds 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 virus, magnified approximately
IAV and IBV circulate in humans and cause seasonal
100,000 times
epidemics, and ICV causes a mild infection, primarily
in children. IDV can infect humans but is not known to Specialty Infectious disease
cause illness. In humans, influenza viruses are primarily Symptoms Fever, runny nose, sore throat,
transmitted through respiratory droplets produced from muscle pain, headache,
coughing and sneezing. Transmission through aerosols coughing, fatigue
and intermediate objects and surfaces contaminated by
the virus also occur. Usual 1–4 days after exposure
onset
Frequent hand washing and covering one's mouth and Duration 2–8 days
nose when coughing and sneezing reduce transmission.
Annual vaccination can help to provide protection Causes Influenza viruses
against influenza. Influenza viruses, particularly IAV, Prevention Hand washing, flu vaccines
evolve quickly, so flu vaccines are updated regularly to Medication Antiviral drugs such as
match which influenza strains are in circulation.
oseltamivir
Vaccines currently in use provide protection against
IAV subtypes H1N1 and H3N2 and one or two IBV Frequency 3–5 million severe cases per
subtypes. Influenza infection is diagnosed with year[1][2]
laboratory methods such as antibody or antigen tests Deaths >290,000–650,000 deaths per
and a polymerase chain reaction (PCR) to identify viral year[3][4]
nucleic acid. The disease can be treated with supportive
measures and, in severe cases, with antiviral drugs such as oseltamivir. In healthy individuals, influenza is
typically self-limiting and rarely fatal, but it can be deadly in high-risk groups.
In a typical year, 5–15% of the population contracts influenza. There are 3–5 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
regions of the world, the number of influenza cases peaks during winter, whereas in the tropics influenza
can occur year-round. Since the late 1800s, large outbreaks of novel influenza strains that spread globally,
called pandemics, have occurred every 10–50 years. Five flu pandemics have occurred since 1900: the
Spanish flu in 1918–1920, which was the most severe flu pandemic, the Asian flu in 1957, the Hong Kong
flu in 1968, the Russian flu in 1977, and the swine flu pandemic in 2009.

Contents
Signs and symptoms
Virology
Types of virus
Genome and structure
Life cycle
Antigenic drift and shift
Mechanism
Transmission
Pathophysiology
Immunology
Prevention
Vaccination
Antiviral chemoprophylaxis
Infection control
Diagnosis
Treatment
Antivirals
Prognosis
Epidemiology
History
Etymology
Research
In animals
Birds
Pigs
Other animals
References

Signs and symptoms

The time between exposure to the virus and
development of symptoms, called the incubation
period, is 1–4 days, most commonly 1–2 days. Many
infections, however, are asymptomatic.[8] The onset of
symptoms is sudden, and initial symptoms are
predominately non-specific, including fever, chills,
headaches, muscle pain or aching, a feeling of
discomfort, loss of appetite, lack of energy/fatigue, and
confusion. These symptoms are usually accompanied
by respiratory symptoms such as a dry cough, sore or
dry throat, hoarse voice, and a stuffy or runny nose.
Coughing is the most common symptom.[1]
Gastrointestinal symptoms may also occur, including
nausea, vomiting, diarrhea,[9] and gastroenteritis,[10]
especially in children. The standard influenza Symptoms of influenza,[5][6] with fever and cough
symptoms typically last for 2–8 days.[11] A 2021 study the most common symptoms[7]
suggests influenza can cause long lasting symptoms in
a similar way to long COVID.[12]

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 by a
secondary bacterial infection. Primary pneumonia is characterized by rapid progression of fever, cough,
labored breathing, and low oxygen levels that cause 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 1–3 weeks[13] followed by recurrent fever, sputum
production, and fluid buildup in the lungs,[1] but can also occur just a few days after influenza symptoms
appear.[13] 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.[8][1]

Virology

Types of 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 Influenza virus nomenclature (for a Fujian flu virus)
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]

Genome and structure

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
Structure of the influenza virion. The hemagglutinin
membrane protein (M2) share a segment, as do the
(HA) and neuraminidase (NA) proteins are shown on
non-structural protein (NS1) and the nuclear export
the surface of the particle. The viral RNAs that make
protein (NEP).[1] For IAV and IBV, hemagglutinin
up the genome are shown as red coils inside the
(HA) and neuraminidase (NA) are encoded on one particle and bound to ribonucleoproteins (RNP).
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]

Life cycle

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
Host cell invasion and replication by the influenza
envelope with the endosomal membrane.[21] At the
virus
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 drift and shift

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
Antigenic shift, or reassortment, can
among circulating strains. Antigenic evolution of influenza viruses
result in novel and highly pathogenic
of humans appears to be faster than influenza viruses in swine and
strains of human influenza.
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]

Mechanism

Transmission

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]

Pathophysiology

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
How the different sites of infection (shown in red) of
to during entry into cells. Mammalian influenza
H1N1 and H5N1 influences their transmission and
viruses preferentially bind to sialic acids connected to
lethality
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]

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 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]

Prevention

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 Giving an influenza vaccination
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]

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 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]

Infection control
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]

Diagnosis
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 breaking down of muscle tissue occur.[13] Because influenza is similar to other
viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation. Common ways of
collecting samples for testing include nasal and throat
swabs.[1] 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.[32]
Diagnostic methods that can identify influenza
include viral cultures, antibody- and antigen-
detecting tests, and nucleic acid-based tests.[39]

Viruses can be grown in a culture of mammalian

cells or embryonated eggs for 3–10 days to monitor X-ray of 29-year-old person with H1N1
cytopathic effect. Final confirmation can then be
done via antibody staining, hemadsorption using red
blood cells, 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.[1][32][39] 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.[1]

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.[1][39]

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 IAV and IBV but can't subtype IAV.[39] Rapid
influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce
results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV
and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.[1][39]

Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid. Most of these tests take a few
hours,[39] but rapid molecular assays are as fast as RIDTs.[32] Among NATs, reverse transcription
polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing
influenza[39] because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-
positives than cultures.[1] 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 next-generation methods that have greater sequencing speed and throughput.[39]

Treatment
Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications
such as acetaminophen and ibuprofen,[40] adequate fluid intake to avoid dehydration, and resting at
home.[9] Cough drops and throat sprays may be beneficial for sore throat. It is recommended to avoid
alcohol and tobacco use while sick with the flu.[40] Aspirin is not recommended to treat influenza in
children due to an elevated risk of developing Reye syndrome.[41] Corticosteroids likewise 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.[32] If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.[9]

Antivirals

Antiviral drugs[11]
Route of
Drug Approved age of use
administration
Oseltamivir Oral At least two weeks old
Zanamivir Inhalation At least five years old
Peramivir Intravenous injection At least 18 years old
40 milligrams (mg) dose for people at least 10 years
Laninamivir Inhalation [1] old,
20 mg for those under 10 [42]
Baloxavir
Oral[4] At least 12 years old [32]
marboxil

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]

Prognosis
In healthy individuals, influenza infection is usually self-limiting and rarely fatal.[8][9] Symptoms usually
last for 2–8 days.[11] 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,[1][9] which can progress to ARDS.[11]

Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid
buildup in the lungs, and exacerbation of chronic bronchitis and asthma. Middle ear infection and croup
may occur, most commonly in children.[8][1] 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.[1] Complications affecting the cardiovascular system are rare and include pericarditis, fulminant
myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular
disease.[8][9] 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.[1][9][13]

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.[9] Neurological complications have been
associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated
encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.[13] Additionally, febrile seizures and
Reye syndrome can occur, most commonly in children.[1][9] Influenza-associated encephalopathy can occur
directly from central nervous system infection from the presence of the virus in blood and presents as
suddent onset of fever with convulsions, followed by rapid progression to coma.[8] An atypical form of
encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely
occur sometime after infection.[1] In survivors of influenza-associated encephalopathy, neurological defects
may occur.[8] Primarily in children, in severe cases the immune system may rarely dramatically
overproduce white blood cells that release cytokines, causing severe inflammation.[8]

People who are at least 65 years of age,[9] 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[1] and lasts up to two weeks after childbirth.[9][32] 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,[8][1][9] as are people who are immunocompromised from chemotherapy, asplenia, prolonged
steroid treatment, splenic dysfunction, or HIV infection.[9] Current or past tobacco use also places a person
at risk.[32] The role of genetics in influenza is not well researched,[1] but it may be a factor in influenza
mortality.[11]

Epidemiology
Influenza is typically characterized by seasonal epidemics
and sporadic pandemics. Most of the burden of influenza
is a result of flu seasons caused by IAV and IBV. Among
IAV subtypes, H1N1 and H3N2 currently 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,[1] and the
immunocompromised.[4] In a typical year, influenza
viruses infect 5–15% of the global population,[3][39]
causing 3–5 million cases of severe illness annually[1][2]
and accounting for 290,000–650,000 deaths each year
due to respiratory illness.[3][4][44] 5–10% of adults and
20–30% of children contract influenza each year.[17] The
Influenza mortality in symptomatic cases in the
reported number of influenza cases is usually much lower
US for the 2018/2019 season.[43]
than the actual number of cases.[1][34]

During seasonal epidemics, it is estimated that about 80%

of otherwise healthy people who have a cough or sore throat have the flu.[1] 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 is one of the two most common causes of ARDS, the other being the respiratory syncytial
virus.[13] About 3–5% of children each year develop otitis media due to influenza.[8] Adults who develop
organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of
mortality.[13] 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.[11]

In temperate regions, the number of influenza cases

varies from season to season. Lower vitamin D
levels, presumably due to less sunlight,[28] 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[11]), and in
the southern hemisphere, this is from May to October
(more narrowly June to September[11]). There are Seasonal risk areas for influenza: November–April
therefore two distinct influenza seasons every year in (blue), April–November (red), and year-round (yellow)
temperate regions, one in the northern hemisphere
and one in the southern hemisphere.[1][9][2] 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.[1][45]
Influenza may therefore occur year-round in these regions.[11] Influenza epidemics in modern times have
the tendency to start in the eastern or southern hemisphere,[45] with Asia being a key reservoir of influenza
viruses.[11]

IAV and IBV co-circulate, so the two have the same patterns of transmission.[1] The seasonality of ICV,
however, is poorly understood. ICV infection is most common in children under the age of 2, and by
adulthood most people have been exposed to it. ICV-associated hospitalization most commonly occurs in
children under the age of 3 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, ICV appears to account for only a small percentage of such cases. Large
outbreaks of ICV infection can occur, so incidence varies significantly.[10]

Outbreaks of influenza caused by novel influenza viruses are common.[19] 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 IAVs, 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.[1][9][32] Pandemic strains tend to be associated with higher rates of pneumonia in
otherwise healthy individuals.[13] Generally after each influenza pandemic, the pandemic strain continues
to circulate as the cause of seasonal influenza, replacing prior strains.[1] 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.[45]

History
It is impossible to know when an influenza
virus first infected humans or when the first
influenza pandemic occurred.[47] Possibly the
first influenza epidemic occurred around 6,000
BC in China,[48] and possible descriptions of
influenza exist in Greek writings from the 5th
century BC.[45][49] In both 1173–1174 AD
and 1387 AD, epidemics occurred across The main types of influenza viruses in humans. Solid
Europe that were named "influenza". Whether squares show the appearance of a new strain, causing
these epidemics and others were caused by recurring influenza pandemics. Broken lines indicate
influenza is unclear since there was no uncertain strain identifications.[46]
consistent naming pattern for epidemic
respiratory diseases at that time, and
"influenza" didn't become completely attached to respiratory disease until centuries later.[50] 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.[51][52]

The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before
spreading to North Africa and then Europe.[47] Following the pandemic, seasonal influenza occurred, with
subsequent pandemics in 1557 and 1580.[50] The flu pandemic in 1557 was potentially the first time
influenza was connected to miscarriage and death of pregnant women.[53] The 1580 flu pandemic
originated in Asia during summer, spread to Africa, then Europe, and finally America.[45] By the end of the
16th century, influenza was likely beginning to become understood as a specific, recognizable disease with
epidemic and endemic forms.[50] In 1648, it was discovered that horses also experience influenza.[47]

Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each
of which incrementally increased understanding of influenza.[54] 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. The second flu pandemic of the 18th century was in 1781–1782, starting in
China in autumn.[45] From this pandemic, influenza became associated with sudden outbreaks of febrile
illness.[54] 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.[23][45]
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.[54] Highly pathogenic avian influenza was recognized in 1878[54] and
was soon linked to transmission to humans.[47] By the time of the 1889 pandemic, which may have been
caused by an H2N2 strain,[55] the flu had become an easily recognizable disease.[47]

Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer
as the bacteria species Haemophilus influenzae, which retains "influenza" in its name.[47][54] In the
following years, the field of virology began to form as viruses were identified as the cause of many
diseases. From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then
called "fowl plague",[24] 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.[54]

From 1918 to 1920, the Spanish flu pandemic became the most
devastating influenza pandemic and one of the deadliest pandemics
in history. The pandemic, probably caused by H1N1, likely began
in the USA before spreading worldwide by 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,[45]
accounting for most deaths. A third wave with lower mortality
occurred in many places a few months after the second.[23] By the
The difference between the influenza
end of 1920, it is estimated that about a third[11] to half of all
mortality age distributions of the
people in the world had been infected, with tens of millions of
1918 epidemic and normal
deaths, disproportionately young adults.[45] During the 1918
epidemics. Deaths per 100,000
pandemic, the respiratory route of transmission was clearly persons in each age group, United
identified[23] and influenza was shown to be caused by a "filter States, for the interpandemic years
passer", not a bacterium, but there remained a lack of agreement 1911–1917 (dashed line) and the
about influenza's cause for another decade and research on pandemic year 1918 (solid line).[56]
influenza declined.[54] After the pandemic, H1N1 circulated in
humans in seasonal form[1] up until the next pandemic.[54]

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 first characterized during the second wave of the 1918
pandemic.[53][54] 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.[54] Just two years after influenza viruses were discovered, in 1933, IAV was
identified as the agent responsible for human influenza.[53][57] Subtypes of IAV were discovered
throughout the 1930s,[54] and IBV was discovered in 1940.[17]

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.[1] ICV was
discovered two years later in 1947.[17] In 1955, avian influenza was confirmed to be caused by IAV.[24]
Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic. The first of
these was the Asian flu from 1957 to 1958, caused by an H2N2 strain[1][37] and beginning in China's
Yunnan province. The number of deaths probably exceeded one million, mostly among the very young and
very old.[45] Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global
surveillance system and laboratories able to study the novel influenza virus.[23] After the pandemic, H2N2
was the IAV subtype responsible for seasonal influenza.[1] The first antiviral drug against influenza,
amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.[4]
In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain
and an H2N2 strain that was circulating in humans. The novel H3N2 strain first 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.[3][23] H2N2 and H3N2 co-circulated after
the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.[3] In
1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident,
and caused a pseudo-pandemic.[23][54] Whether the 1977 "pandemic" deserves to be included in the natural
history of flu pandemics is debatable.[45] 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.[1] In 1980, the current classification system used to subtype influenza viruses was
introduced.[58]

At some point, IBV diverged into two lineages, named the

B/Victoria-like and B/Yamagata-like lineages, both of which have
been circulating in humans since 1983.[17] In 1996, HPAI H5N1
was detected in Guangdong, China[24] 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,[30] and sporadic human cases have occurred since 1997,
carrying a high case fatality rate.[15][39] The most recent flu
pandemic was the 2009 swine flu pandemic, which originated in
Mexico and resulted in hundreds of thousands of deaths.[23] It was Thermal imaging camera and screen,
caused by a novel H1N1 strain that was a reassortment of human, photographed in an airport terminal in
swine, and avian influenza viruses.[16][4] The 2009 pandemic had Greece during the 2009 flu
the effect of replacing prior H1N1 strains in circulation with the pandemic. Thermal imaging can
novel strain but not any other influenza viruses. Consequently, detect elevated body temperature,
H1N1, H3N2, and both IBV lineages have been in circulation in one of the signs of swine flu.
seasonal form since the 2009 pandemic.[1][23][24]

In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary
reservoir of IDV.[10][17] In the same year,[39] avian H7N9 was detected in China and began to cause
human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China. HPAI H7N9
emerged sometime in 2016 and has occasionally infected humans incidentally. Other AIVs have less
commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8,[15]
and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the
world since the 2010s. Future flu pandemics, which may be caused by an influenza virus of avian
origin,[24] are viewed as almost inevitable, and increased globalization has made it easier for novel viruses
to spread,[23] so there are continual efforts to prepare for future pandemics[53] and improve the prevention
and treatment of influenza.[1]

Etymology

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]

Research
Influenza research is wide-ranging and includes efforts to understand how
influenza viruses enter hosts, the relationship between influenza viruses and
bacteria, how influenza symptoms progress, and what make some influenza
viruses deadlier than others.[64] Non-structural proteins encoded by influenza
viruses are periodically discovered and their functions are continually under
research.[21] Past pandemics, and especially the 1918 pandemic, are the subject
of much research to understand flu pandemics.[45] As part of pandemic
preparedness, the Global Influenza Surveillance and Response System is a
global network of laboratories that monitors influenza transmission and
epidemiology.[65] Additional areas of research include ways to improve the
Professional examining diagnosis, treatment, and prevention of influenza.
a laboratory-grown
reconstruction of the Existing diagnostic methods have a variety of limitations coupled with their
1918 Spanish flu virus advantages. For example, NATs have high sensitivity and specificity but are
in a biosafety level 3 impractical in under-resourced regions due to their high cost, complexity,
environment maintenance, and training required. Low-cost, portable RIDTs can rapidly
diagnose influenza but have highly variable sensitivity and are unable to subtype
IAV. As a result of these limitations and others, research into new diagnostic
methods revolves around producing new methods that are cost-effective, less labor-intensive, and less
complex than existing methods while also being able to differentiate influenza species and IAV subtypes.
One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety
of diagnostic tests, such as RT-PCR and serological assays, in microchip form. These chips have many
potential advantages, including high reaction efficiency, low energy consumption, and low waste
generation.[39]

New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and
concerns over oseltamivir resistance. These include: NA inhibitors that can be injected intravenously, such
as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several
RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide,
which inhibits HA maturation.[1][11] Reducing excess inflammation in the respiratory tract is also subject to
much research since this is one of the primary mechanisms of influenza pathology.[11][13] Other forms of
therapy in development include monoclonal and polyclonal antibodies that target viral proteins,
convalescent plasma, different approaches to modify the host antiviral response,[32][66] and stem cell-based
therapies to repair lung damage.[11]

Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless
influenza viruses in vaccines that still confer immunity.[21] The high variability and rapid evolution of
influenza virus antigens, however, is a major obstacle in developing effective vaccines. Furthermore, it is
hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient
quantity of flu vaccines for the next season is difficult,[2] LAIVs have limited efficacy, and repeated annual
vaccination potentially has diminished efficacy.[1] For these reasons, "broadly-reactive" or "universal" flu
vaccines are being researched that can provide protection against many or all influenza viruses. Approaches
to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but
different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens,
anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.[2][66]
mRNA vaccines to provide protection against influenza are also under research.[67]

In animals

Birds

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]

Pigs
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
Chinese inspectors
influenza viruses usually responsible for swine flu are IAV subtypes H1N1,
checking airline passengers
H1N2, and H3N2.[68]
for fevers, a common
symptom of swine flu
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]

Other animals

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]

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