Influenza, commonly referred to as the
flu, is an
infectious disease caused by
RNA viruses of the
family Orthomyxoviridae (the influenza viruses),
that affects
birds and
mammals. The name
influenza is
Italian and means "influence" ( ). The most
common symptoms of the disease are
chills,
fever,
sore throat,
muscle pains, severe
headache,
coughing,
weakness and
general
discomfort. Sore throat, fever and coughs are the most frequent
symptoms. In more serious cases, influenza
causes pneumonia, which can
be fatal, particularly for the young and the elderly. Although it
is often confused with other
influenza-like illnesses, especially
the
common cold, influenza is a much
more severe disease than the common cold and is caused by a
different type of virus. Influenza may produce
nausea and
vomiting,
particularly in children, but these symptoms are more common in the
unrelated
gastroenteritis, which is
sometimes called "stomach flu" or "24-hour flu".
Typically, influenza is transmitted through the air by coughs or
sneezes, creating
aerosols containing the
virus. Influenza can also be transmitted by direct contact with
bird droppings or
nasal secretions, or through
contact with contaminated surfaces. Airborne aerosols have been
thought to cause most infections, although which means of
transmission is most important is not absolutely clear. Influenza
viruses can be inactivated by
sunlight,
disinfectants and
detergents. As the virus can be inactivated by
soap, frequent hand washing reduces the risk of infection.
Influenza spreads around the world in
seasonal epidemic, resulting in the deaths of
hundreds of thousands worldwide annually, and millions in
pandemic years.
On average 41,400 people died each year in
the United
States
between 1979 and 2001 from influenza. Three
influenza pandemics occurred in the 20th century and killed tens of
millions of people, with each of these pandemics being caused by
the appearance of a new
strain of
the virus in humans. Often, these new strains appear when an
existing flu virus spreads to humans from other animal
species, or when an existing human strain picks up
new
genes from a virus that usually infects
birds or pigs. An avian strain named
H5N1
raised the concern of a new
influenza
pandemic, after it emerged in Asia in the 1990s, but it has not
evolved to a form that spreads easily
between people. In April 2009 a novel flu strain evolved that
combined genes from human, pig, and bird flu, initially dubbed
"
swine flu" and also known as
influenza A/H1N1, emerged in
Mexico, the United States, and several other nations. The
World Health Organization
officially declared the outbreak to be a "
pandemic" on June 11, 2009 (see
2009 flu pandemic). The WHO's declaration
of a pandemic level 6 was an indication of spread, not
severity.
Vaccinations against influenza are
usually given to people in
developed
countries and to farmed poultry. The most common human vaccine
is the trivalent
influenza vaccine
(TIV) that contains purified and inactivated material from three
viral strains. Typically, this vaccine includes material from two
influenza A virus subtypes and one
influenza B virus strain. The TIV
carries no risk of transmitting the disease, and it has very low
reactivity. A vaccine formulated for one year may be ineffective in
the following year, since the influenza virus evolves rapidly, and
new strains quickly replace the older ones.
Antiviral drugs can be used to treat
influenza, with
neuraminidase
inhibitors being particularly effective.
Classification
Types of influenza virus
In
virus classification
influenza viruses are
RNA viruses that
make up three of the five
genera of the
family
Orthomyxoviridae:
These viruses are only distantly related to the
human parainfluenza viruses,
which are RNA viruses belonging to the
paramyxovirus family that are a common cause
of respiratory infections in children such as
croup, but can also cause a disease similar to
influenza in adults.
Influenzavirus A
This genus has one species, influenza A virus. Wild aquatic birds
are the natural hosts for a large variety of influenza A.
Occasionally, viruses are transmitted to other species and may then
cause devastating outbreaks in domestic poultry or give rise to
human influenza
pandemics.The type A
viruses are the most virulent human pathogens among the three
influenza types and cause the most severe disease. The influenza A
virus can be subdivided into different
serotypes based on the
antibody response to these viruses. The serotypes
that have been confirmed in humans, ordered by the number of known
human pandemic deaths, are:
Influenzavirus B
This genus has one species, influenza B virus. Influenza B almost
exclusively infects humans and is less common than influenza A. The
only other animals known to be susceptible to influenza B infection
are the
seal and the
ferret. This type of influenza mutates at a rate 2–3
times lower than type A and consequently is less genetically
diverse, with only one influenza B serotype. As a result of this
lack of
antigenic diversity, a degree of
immunity to influenza B is
usually acquired at an early age. However, influenza B mutates
enough that lasting immunity is not possible. This reduced rate of
antigenic change, combined with its limited host range (inhibiting
cross species
antigenic shift),
ensures that pandemics of influenza B do not occur.
Influenzavirus C
This genus has one species, influenza C virus, which infects
humans, dogs and pigs, sometimes causing both severe illness and
local epidemics. However, influenza C is less common than the other
types and usually only causes mild disease in children.
Structure, properties, and subtype nomenclature
Influenzaviruses A, B and C are very similar in overall structure.
The virus particle is 80–120
nanometres in
diameter and usually roughly spherical, although filamentous forms
can occur. These filamentous forms are more common in influenza C,
which can form cordlike structures up to 500
micrometres long on the surfaces of infected
cells. However, despite these varied shapes, the viral particles of
all influenza viruses are similar in composition. These are made of
a
viral envelope containing two main
types of
glycoproteins, wrapped around
a central core. The central core contains the viral
RNA genome and other viral
proteins that package and protect this RNA. RNA tends to be single
stranded but in special cases it is double. Unusually for a virus,
its genome is not a single piece of
nucleic
acid; instead, it contains seven or eight pieces of segmented
negative-sense RNA, each piece of RNA
containing either one or two
genes. For
example, the influenza A genome contains 11 genes on eight pieces
of RNA, encoding for 11
proteins:
hemagglutinin (HA),
neuraminidase (NA), nucleoprotein (NP),
M1,
M2,
NS1, NS2(NEP), PA, PB1, PB1-F2
and PB2.
Hemagglutinin (HA) and neuraminidase (NA) are the two large
glycoproteins on the outside of the viral particles. HA is a
lectin that mediates binding of the virus to
target cells and entry of the viral genome into the target cell,
while NA is involved in the release of progeny virus from infected
cells, by cleaving sugars that bind the mature viral particles.
Thus, these proteins are targets for
antiviral drugs. Furthermore, they are
antigens to which
antibodies can be raised. Influenza A viruses are
classified into subtypes based on antibody responses to HA and NA.
These different types of HA and NA form the basis of the
H
and
N distinctions in, for example,
H5N1. There
are 16 H and 9 N subtypes known, but only H 1, 2 and 3, and N 1 and
2 are commonly found in humans.
Replication
Host cell invasion and replication by
the influenza virus.
The steps in this process are discussed in the text.
Viruses can only replicate in living cells. Influenza infection and
replication is a multi-step process: firstly the virus has to bind
to and enter the cell, then deliver its genome to a site where it
can produce new copies of viral proteins and RNA, assemble these
components into new viral particles and finally exit the host
cell.
Influenza viruses bind through
hemagglutinin onto
sialic acid sugars on the surfaces of
epithelial cells; typically in the nose, throat
and
lungs of mammals and
intestines of birds (Stage 1 in infection figure).
After the hemagglutinin is
cleaved by a
protease, the cell imports the virus by
endocytosis.
Once inside the cell, the acidic conditions in the
endosome cause two events to happen: first part of
the hemagglutinin protein fuses the
viral
envelope with the vacuole's membrane, then the M2
ion channel allows
protons
to move through the viral envelope and acidify the core of the
virus, which causes the core to dissemble and release the viral RNA
and core proteins. The viral RNA (vRNA) molecules, accessory
proteins and
RNA-dependent
RNA polymerase are then released into the
cytoplasm (Stage 2). The M2 ion channel is blocked
by
amantadine drugs, preventing
infection.
These core proteins and vRNA form a complex that is transported
into the
cell nucleus, where the
RNA-dependent RNA polymerase begins transcribing complementary
positive-sense vRNA (Steps 3a and b). The vRNA is either exported
into the cytoplasm and translated (step 4), or remains in the
nucleus. Newly synthesised viral proteins are either secreted
through the
Golgi apparatus onto the
cell surface (in the case of neuraminidase and hemagglutinin, step
5b) or transported back into the nucleus to bind vRNA and form new
viral genome particles (step 5a). Other viral proteins have
multiple actions in the host cell, including degrading cellular
mRNA and using the released
nucleotides for vRNA synthesis and also
inhibiting
translation of
host-cell mRNAs.
Negative-sense vRNAs that form the
genomes of
future viruses, RNA-dependent RNA polymerase, and other viral
proteins are assembled into a virion. Hemagglutinin and
neuraminidase molecules cluster into a bulge in the cell membrane.
The vRNA and
viral core proteins leave the
nucleus and enter this membrane protrusion (step 6). The mature
virus buds off from the cell in a sphere of host
phospholipid membrane, acquiring hemagglutinin
and neuraminidase with this membrane coat (step 7). As before, the
viruses adhere to the cell through hemagglutinin; the mature
viruses detach once their
neuraminidase has cleaved sialic acid residues
from the host cell. Drugs that inhibit neuraminidase, such as
oseltamivir, therefore prevent the
release of new infectious viruses and halt viral replication. After
the release of new influenza viruses, the host cell dies.
Because of the absence of RNA
proofreading enzymes, the
RNA-dependent RNA polymerase that copies the viral genome makes an
error roughly every 10 thousand nucleotides, which is the
approximate length of the influenza vRNA. Hence, the majority of
newly manufactured influenza viruses are mutants; this causes
"antigenic drift", which is a slow change in the antigens on the
viral surface over time. The separation of the genome into eight
separate segments of vRNA allows mixing or
reassortment of vRNAs if more than one type of
influenza virus infects a single cell. The resulting rapid change
in viral genetics produces
antigenic
shifts, which are sudden changes from one antigen to another.
These sudden large changes allow the virus to infect new host
species and quickly overcome protective immunity. This is important
in the emergence of pandemics, as discussed below in the section on
Epidemiology.
Signs and symptoms
sensitive]] symptoms for diagnosing
influenza
| Symptom: |
sensitivity |
specificity |
| Fever |
68-86% |
25-73% |
| Cough |
84-98% |
7-29% |
| Nasal congestion |
68–91% |
19–41% |
- All three findings, especially fever, were less
sensitive in patients over 60 years of age.
|
Symptoms of influenza,, with fever and
cough the most common symptoms.
Symptoms of influenza can start quite suddenly one to two days
after infection. Usually the first symptoms are chills or a chilly
sensation, but fever is also common early in the infection, with
body temperatures ranging from 38-39 °C (approximately 100-103 °F).
Many people are so ill that they are confined to bed for several
days, with aches and pains throughout their bodies, which are worse
in their backs and legs. Symptoms of influenza may include:
It can be difficult to distinguish between the
common cold and influenza in the early stages of
these infections, but a flu can be identified by a high fever with
a sudden onset and extreme fatigue. Diarrhea is not normally a
symptom of influenza in adults, although it has been seen in some
human cases of the
H5N1 "bird flu" and can be a
symptom in children. The symptoms most reliably seen in influenza
are shown in the table to the right.
Since
antiviral drugs are effective
in treating influenza if given early (see treatment section,
below), it can be important to identify cases early. Of the
symptoms listed above, the combinations of fever with cough, sore
throat and/or nasal congestion can improve diagnostic accuracy. Two
decision analysis studies suggest
that
during local outbreaks of influenza, the
prevalence will be over 70%, and thus patients
with any of these combinations of symptoms may be treated with
neuraminidase inhibitors
without testing. Even in the absence of a local outbreak, treatment
may be justified in the elderly during the influenza season as long
as the prevalence is over 15%.
The available laboratory tests for influenza continue to improve.
The United States
Centers for Disease
Control and Prevention (CDC) maintains an up-to-date summary of
available laboratory tests. According to the CDC, rapid diagnostic
tests have a sensitivity of 70–75% and specificity of 90–95% when
compared with
viral culture. These
tests may be especially useful during the influenza season
(prevalence=25%) but in the absence of a local outbreak, or
peri-influenza season (prevalence=10%).
Mechanism
Transmission
People who contract influenza are most infective between the second
and third days after infection and infectivity lasts for around ten
days. Children are much more infectious than adults and shed virus
from just before they develop symptoms until two weeks after
infection. The transmission of influenza can be
modeled
mathematically, which helps predict how the virus will spread
in a population.
Influenza can be spread in three main ways: by direct transmission
when an infected person sneezes mucus into the eyes, nose or mouth
of another person; through people inhaling the
aerosols produced by infected people coughing,
sneezing and spitting; and through hand-to-mouth transmission from
either contaminated surfaces or direct personal contact, such as a
hand-shake. The relative importance of these three modes of
transmission is unclear, and they may all contribute to the spread
of the virus. In the airborne route, the droplets that are small
enough for people to inhale are 0.5 to 5
µm in diameter and inhaling just one droplet might
be enough to cause an infection. Although a single sneeze releases
up to 40,000 droplets, most of these droplets are quite large and
will quickly settle out of the air. How long influenza survives in
airborne droplets seems to be influenced by the levels of
humidity and
UV
radiation: with low humidity and a lack of sunlight in winter
probably aiding its survival.
As the influenza virus can persist outside of the body, it can also
be transmitted by contaminated surfaces such as banknotes,
doorknobs, light switches and other household items. The length of
time the virus will persist on a surface varies, with the virus
surviving for one to two days on hard, non-porous surfaces such as
plastic or metal, for about fifteen minutes from dry paper tissues,
and only five minutes on skin. However, if the virus is present in
mucus, this can protect it for longer periods (up to 17 days
on banknotes). Avian influenza viruses can survive indefinitely
when frozen. They are inactivated by heating to 56 °C (133 °F) for
a minimum of 60 minutes, as well as by acids (at pH
<2).></2).>
Pathophysiology
The mechanisms by which influenza infection causes symptoms in
humans have been studied intensively. One of the mechanisms is
believed to be the inhibition of adrenocorticotropic hormone (ACTH)
resulting in lowered cortisol levels.Knowing which genes are
carried by a particular strain can help predict how well it will
infect humans and how severe this infection will be (that is,
predict the strain's
pathophysiology).
For instance, part of the process that allows influenza viruses to
invade cells is the
cleavage of the
viral
hemagglutinin protein by any one
of several human
proteases. In mild and
avirulent viruses, the structure of the hemagglutinin means that it
can only be cleaved by proteases found in the throat and lungs, so
these viruses cannot infect other tissues. However, in highly
virulent strains, such as H5N1, the hemagglutinin can be cleaved by
a wide variety of proteases, allowing the virus to spread
throughout the body.
The viral hemagglutinin protein is responsible for determining both
which species a strain can infect and where in the human
respiratory tract a strain of influenza
will bind. Strains that are easily transmitted between people have
hemagglutinin proteins that bind to receptors in the upper part of
the respiratory tract, such as in the nose, throat and mouth. In
contrast, the highly-lethal H5N1 strain binds to receptors that are
mostly found deep in the lungs. This difference in the site of
infection may be part of the reason why the H5N1 strain causes
severe viral pneumonia in the lungs, but is not easily transmitted
by people coughing and sneezing.
Common symptoms of the flu such as fever, headaches, and fatigue
are the result of the huge amounts of proinflammatory
cytokines and
chemokines
(such as
interferon or
tumor necrosis factor) produced
from influenza-infected cells. In contrast to the
rhinovirus that causes the
common cold, influenza does cause tissue damage,
so symptoms are not entirely due to the
inflammatory response. This massive immune
response might produce a life-threatening
cytokine storm. This effect has been proposed
to be the cause of the unusual lethality of both the H5N1 avian
influenza, and the 1918 pandemic strain. However, another
possibility is that these large amounts of cytokines are just a
result of the massive levels of viral replication produced by these
strains, and the immune response does not itself contribute to the
disease.
Prevention
Vaccination
Giving an influenza vaccination.
Vaccination against influenza with an
influenza vaccine is often recommended for
high-risk groups, such as children and the elderly, or in people
who have
asthma,
diabetes,
heart
disease, or are immuno-compromised. Influenza vaccines can be
produced in several ways; the most common method is to grow the
virus in fertilized
hen eggs. After
purification, the virus is inactivated (for example, by treatment
with detergent) to produce an inactivated-virus vaccine.
Alternatively, the virus can be grown in eggs until it loses
virulence and the avirulent virus given as
a live vaccine. The effectiveness of these influenza vaccines are
variable. Due to the high
mutation
rate of the virus, a particular influenza vaccine usually
confers protection for no more than a few years. Every year, the
World Health Organization
predicts which strains of the virus are most likely to be
circulating in the next year, allowing
pharmaceutical companies to develop
vaccines that will provide the best immunity against these strains.
Vaccines have also been developed to protect
poultry from
avian
influenza. These vaccines can be effective against multiple
strains and are used either as part of a preventative strategy, or
combined with
culling in attempts to
eradicate outbreaks.
It is possible to get vaccinated and still get influenza. The
vaccine is reformulated each season for a few specific flu strains
but cannot possibly include all the strains actively infecting
people in the world for that season. It takes about six months for
the manufacturers to formulate and produce the millions of doses
required to deal with the seasonal epidemics; occasionally, a new
or overlooked strain becomes prominent during that time and infects
people although they have been vaccinated (as by the
H3N2 Fujian flu in the 2003–2004 flu season). It
is also possible to get infected just before vaccination and get
sick with the very strain that the vaccine is supposed to prevent,
as the vaccine takes about two weeks to become effective.
The 2006–2007 season was the first in which the CDC had recommended
that children younger than 59 months receive the annual influenza
vaccine. Vaccines can cause the
immune
system to react as if the body were actually being infected,
and general infection symptoms (many cold and flu symptoms are just
general infection symptoms) can appear, though these symptoms are
usually not as severe or long-lasting as influenza. The most
dangerous
side-effect is a severe
allergic reaction to either the virus
material itself or residues from the hen eggs used to grow the
influenza; however, these reactions are extremely rare.
In addition to vaccination against seasonal influenza, researchers
are working to develop a vaccine against a possible influenza
pandemic. The rapid development, production, and distribution of
pandemic influenza vaccines could potentially save millions of
lives during an influenza pandemic. Due to the short time frame
between identification of a pandemic strain and need for
vaccination, researchers are looking at non-egg-based options for
vaccine production. Live attenuated (egg-based or cell-based)
technology and recombinant technologies (proteins and virus-like
particles) could provide better "real-time" access and be produced
more affordably, thereby increasing access for people living in
low- and moderate-income countries, where an influenza pandemic may
likely originate. As of July 2009, more than 70 known clinical
trials have been completed or are ongoing for pandemic influenza
vaccines. In September 2009, the US Food and Drug Administration
approved four vaccines against the 2009 H1N1 influenza virus (the
current pandemic strain), and expect the initial vaccine lots to be
available within the following month.
Infection control
Since influenza is spread by both aerosols and direct contact, good
personal health and hygiene habits, like
hand washing, avoiding spitting, and
covering the nose and mouth when sneezing or coughing, can reduce
influenza transmission. In particular, hand-washing with soap and
water, or with alcohol-based hand rubs, is very effective at
inactivating influenza viruses. These simple personal hygiene
precautions are recommended as the main way of reducing infections
during pandemics. Although
face masks
might help prevent transmission when caring for the sick, there is
mixed evidence on beneficial effects in the community. Smoking
raises the risk of contracting influenza, as well as producing more
severe disease symptoms. Thus, according to the laws of
mathematical
modelling of infectious diseases, smokers raise the
exponential growth rates of influenza
epidemics and may indirectly be responsible for a large percentage
of influenza cases.
Since influenza spreads through both
aerosols and contact with contaminated surfaces,
surface sanitizing may help prevent some infections.
Alcohol is an effective sanitizer against influenza
viruses, while
quaternary
ammonium compounds can be used with alcohol so that the
sanitizing effect lasts for longer. In hospitals, quaternary
ammonium compounds and
bleach are used to
sanitize rooms or equipment that have been occupied by patients
with influenza symptoms. At home, this can be done effectively with
a diluted chlorine bleach.
During past pandemics, closing schools, churches and theaters
slowed the spread of the virus but did not have a large effect on
the overall death rate. It is uncertain if reducing public
gatherings, by for example closing schools and workplaces, will
reduce transmission since people with influenza may just be moved
from one area to another; such measures would also be difficult to
enforce and might be unpopular. When small numbers of people are
infected, isolating the sick might reduce the risk of
transmission.
Treatment
People with the flu are advised to get plenty of rest, drink plenty
of liquids, avoid using
alcohol
and
tobacco and, if necessary, take
medications such as acetaminophen (
paracetamol) to relieve the fever and muscle
aches associated with the flu. Children and teenagers with flu
symptoms (particularly fever) should avoid taking
aspirin during an influenza infection (especially
influenza type B), because doing so
can lead to
Reye's syndrome, a rare
but potentially fatal disease of the
liver.
Since influenza is caused by a virus,
antibiotics have no effect on the infection;
unless prescribed for
secondary
infections such as
bacterial
pneumonia. Antiviral medication can be effective, but some
strains of influenza can show resistance to the standard antiviral
drugs.
The two classes of antiviral drugs used against influenza are
neuraminidase inhibitors and
M2 protein
inhibitors (
adamantane derivatives).
Neuraminidase inhibitors are currently preferred for flu virus
infections since they are less toxic and more effective. The CDC
recommended against using M2 inhibitors during the 2005–06
influenza season due to high levels of
drug resistance. As pregnant women seem to
be more severely affected than the general population by the 2009
H1N1 influenza virus, prompt treatment with anti-influenza drugs
has been recommended.
Neuraminidase inhibitors
Antiviral drugs such as
oseltamivir
(trade name Tamiflu) and
zanamivir (trade
name Relenza) are
neuraminidase
inhibitors that are designed to halt the spread of the virus in
the body. These drugs are often effective against both influenza A
and B. The
Cochrane
Collaboration reviewed these drugs and concluded that they
reduce symptoms and complications. Different strains of influenza
viruses have differing degrees of resistance against these
antivirals, and it is impossible to predict what degree of
resistance a future pandemic strain might have.
M2 inhibitors (adamantanes)
The
antiviral drugs amantadine and
rimantadine block a viral
ion channel (
M2
protein) and prevent the virus from infecting cells. These
drugs are sometimes effective against influenza A if given early in
the infection but are always ineffective against influenza B
because B viruses do not possess M2 molecules. Measured resistance
to amantadine and rimantadine in American isolates of
H3N2 has increased to 91% in 2005. This high level of
resistance may be due to the easy availability of amantadines as
part of over-the-counter cold remedies in countries such as China
and Russia, and their use to prevent outbreaks of influenza in
farmed poultry.
Prognosis
Influenza's effects are much more severe and last longer than those
of the
common cold. Most people will
recover completely in about one to two weeks, but others will
develop life-threatening complications (such as
pneumonia). Influenza, thus, can be deadly,
especially for the weak, young and old, or chronically ill. People
with a
weak immune system, such as
people with advanced
HIV infection or transplant
patients (whose immune systems are medically suppressed to prevent
transplant organ rejection), suffer from particularly severe
disease. Other high-risk groups include pregnant women and young
children.
The flu can worsen chronic health problems. People with emphysema,
chronic bronchitis or asthma may experience
shortness of breath while they have the flu, and
influenza may cause worsening of
coronary heart disease or
congestive heart failure.
Smoking is another
risk factor associated with more serious disease
and increased mortality from influenza.
According to the
World Health
Organization: "Every winter, tens of millions of people get the
flu. Most are only ill and out of work for a week, yet the elderly
are at a higher risk of death from the illness. We know the
worldwide death toll exceeds a few hundred thousand people a year,
but even in developed countries the numbers are uncertain, because
medical authorities don't usually verify who actually died of
influenza and who died of a flu-like illness." Even healthy people
can be affected, and serious problems from influenza can happen at
any age. People over 50 years old, very young children and people
of any age with chronic
medical
conditions are more likely to get complications from influenza,
such as pneumonia,
bronchitis,
sinus, and
ear
infections.
In some cases, an
autoimmune response to
an influenza infection may contribute to the development of
Guillain-Barré
syndrome. However, as many other infections can increase the
risk of this disease, influenza may only be an important cause
during epidemics. This syndrome can also be a rare side-effect of
influenza vaccines, with an incidence of about one case per million
vaccinations.
Epidemiology
Seasonal variations
Influenza
reaches peak prevalence in winter, and because the Northern
and Southern Hemispheres
have winter at different times of the year, there
are actually two different flu seasons each year. This is
why the
World Health
Organization (assisted by the
National Influenza Centers) makes
recommendations for two different vaccine formulations every year;
one for the Northern, and one for the Southern Hemisphere.
It is not clear why outbreaks of the flu occur seasonally rather
than uniformly throughout the year. One possible explanation is
that, because people are indoors more often during the winter, they
are in close contact more often, and this promotes transmission
from person to person. Increased travel due to the Northern
Hemisphere winter holiday season may also play a role. Another
factor is that cold temperatures lead to drier air, which may
dehydrate mucus, preventing the body from effectively expelling
virus particles. The virus may also survive longer on exposed
surfaces at colder temperatures. Aerosol transmission of the virus
is highest in cold environments (less than 5 °C) with low
relative humidity. However, seasonal changes in infection rates
also occur in tropical regions, and in some countries these peaks
of infection are seen mainly during the rainy season. Seasonal
changes in contact rates from school terms, which are a major
factor in other
childhood
diseases such as
measles and
pertussis, may also play a role in the flu. A
combination of these small seasonal effects may be amplified by
dynamical resonance with the endogenous disease cycles.
H5N1 exhibits seasonality in both humans and
birds.
An alternative hypothesis to explain seasonality in influenza
infections is an effect of
vitamin D
levels on immunity to the virus. This idea was first proposed by
Robert Edgar Hope-Simpson
in 1965. He proposed that the cause of influenza epidemics during
winter may be connected to seasonal fluctuations of vitamin D,
which is produced in the skin under the influence of solar (or
artificial)
UV radiation. This could
explain why influenza occurs mostly in winter and during the
tropical rainy season, when people stay indoors, away from the sun,
and their vitamin D levels fall.
Epidemic and pandemic spread
As influenza is caused by a variety of species and strains of
viruses, in any given year some strains can
die out while others create
epidemics,
while yet another strain can cause a
pandemic. Typically, in a year's normal two
flu seasons (one per hemisphere), there
are between three and five million cases of severe illness and up
to 500,000 deaths worldwide, which by some definitions is a yearly
influenza epidemic. Although the incidence of influenza can vary
widely between years, approximately 36,000 deaths and more than
200,000 hospitalizations are directly associated with influenza
every year in the United States. Roughly three times per century, a
pandemic occurs, which infects a large proportion of the world's
population and can kill tens of millions of people (see history
section). Indeed, one study estimated that if a strain with similar
virulence to the
1918 influenza emerged today, it could
kill between 50 and 80 million people.
Antigenic shift, or reassortment, can
result in novel and highly pathogenic strains of human
influenza
New influenza viruses are constantly
evolving by
mutation or by
reassortment. Mutations can cause small
changes in the
hemagglutinin and
neuraminidase antigens on the surface of the virus. This is called
antigenic drift, which slowly
creates an increasing variety of strains until one evolves that can
infect people who are immune to the pre-existing strains. This new
variant then replaces the older strains as it rapidly sweeps
through the human population—often causing an epidemic. However,
since the strains produced by drift will still be reasonably
similar to the older strains, some people will still be immune to
them. In contrast, when influenza viruses reassort, they acquire
completely new antigens—for example by reassortment between avian
strains and human strains; this is called antigenic shift. If a
human influenza virus is produced that has entirely new antigens,
everybody will be susceptible, and the novel influenza will spread
uncontrollably, causing a pandemic. In contrast to this model of
pandemics based on antigenic drift and shift, an alternative
approach has been proposed where the periodic pandemics are
produced by interactions of a fixed set of viral strains with a
human population with a constantly changing set of immunities to
different viral strains.
History
Etymology
The word
Influenza comes from the
Italian language meaning "influence" and
refers to the cause of the disease; initially, this ascribed
illness to unfavorable
astrological
influences. Changes in medical thought led to its modification to
influenza del freddo, meaning "influence of the cold". The
word
influenza was first used in English in 1743 when it
was adopted, with an anglicized pronunciation, during an outbreak
of the disease in Europe. Archaic terms for influenza include
epidemic catarrh,
grippe (from the French),
sweating sickness, and
Spanish fever
(particularly for the
1918 pandemic
strain).
Pandemics
The difference between the influenza
mortality age distributions of the 1918 epidemic and normal
epidemics.
Deaths per 100,000 persons in each age group, United States,
for the interpandemic years 1911–1917 (dashed line) and the
pandemic year 1918 (solid line).
The symptoms of human influenza were clearly described by
Hippocrates roughly 2,400 years ago. Although
the virus seems to have caused epidemics throughout human history,
historical data on influenza are difficult to interpret, because
the symptoms can be similar to those of other diseases, such as
diphtheria,
pneumonic plague,
typhoid fever,
dengue,
or
typhus. The disease may even have spread
from Europe to the Americas as early as the
European colonization of
the Americas; since almost the entire indigenous population of
the Antilles was killed by an epidemic resembling influenza that
broke out in 1493, after the arrival of
Christopher Columbus.
The first convincing record of an influenza pandemic was of an
outbreak in 1580, which began in Russia and spread to Europe via
Africa. In
Rome,
over 8,000 people were killed, and several Spanish cities were
almost wiped out. Pandemics continued sporadically throughout the
17th and 18th centuries, with the pandemic of 1830–1833 being
particularly widespread; it infected approximately a quarter of the
people exposed.
The most famous and lethal outbreak was the
1918 flu pandemic (Spanish flu pandemic)
(
type A influenza,
H1N1 subtype), which lasted from 1918 to 1919. It is
not known exactly how many it killed, but estimates range from 20
to 100 million people. This pandemic has been described as "the
greatest medical holocaust in history" and may have killed as many
people as the
Black Death. This huge
death toll was caused by an extremely high infection rate of up to
50% and the extreme severity of the symptoms, suspected to be
caused by
cytokine storms. Indeed,
symptoms in 1918 were so unusual that initially influenza was
misdiagnosed as dengue,
cholera, or typhoid.
One observer wrote, "One of the most striking of the complications
was hemorrhage from
mucous
membranes, especially from the nose, stomach, and intestine.
Bleeding from the ears and
petechial
hemorrhages in the skin also occurred." The majority of deaths
were from
bacterial pneumonia, a
secondary infection caused by
influenza, but the virus also killed people directly, causing
massive
hemorrhages and
edema in the lung.
The 1918 flu pandemic (Spanish flu pandemic) was truly global,
spreading even to the
Arctic and remote
Pacific islands. The unusually
severe disease killed between 2 and 20% of those infected, as
opposed to the more usual flu epidemic
mortality rate of 0.1%. Another unusual
feature of this pandemic was that it mostly killed young adults,
with 99% of pandemic influenza deaths occurring in people under 65,
and more than half in young adults 20 to 40 years old. This is
unusual since influenza is normally most deadly to the very young
(under age 2) and the very old (over age 70). The total mortality
of the 1918–1919 pandemic is not known, but it is estimated that
2.5% to 5% of the world's population was killed. As many as 25
million may have been killed in the first 25 weeks; in contrast,
HIV/AIDS has killed 25 million in its first 25
years.
Later flu pandemics were not so devastating. They included the 1957
Asian Flu (type A,
H2N2 strain) and the 1968
Hong
Kong Flu (type A,
H3N2 strain), but even
these smaller outbreaks killed millions of people. In later
pandemics
antibiotics were available to
control secondary infections and this may have helped reduce
mortality compared to the Spanish Flu of 1918.
The first influenza virus to be isolated was from poultry, when in
1901 the agent causing a disease called "fowl plague" was passed
through
Chamberland filters,
which have pores that are too small for
bacteria to pass through. The
etiological cause of influenza, the
Orthomyxoviridae family of viruses, was first discovered in
pigs by
Richard
Shope in 1931.
This discovery was shortly followed by the
isolation of the virus from humans by a group headed by Patrick Laidlaw at the Medical Research Council of
the United
Kingdom
in 1933. However, it was not until
Wendell Stanley first crystallized
tobacco mosaic virus in 1935 that the
non-cellular nature of viruses was
appreciated.
The first significant step towards preventing influenza was the
development in 1944 of a killed-virus vaccine for influenza by
Thomas Francis, Jr.. This built
on work by Australian
Frank
Macfarlane Burnet, who showed that the virus lost virulence
when it was cultured in fertilized hen's eggs.
Application of this
observation by Francis allowed his group of researchers at the
University of
Michigan
to develop the first influenza vaccine, with support from the
U.S. Army. The Army was deeply involved in
this research due to its experience of influenza in
World War I, when thousands of troops were
killed by the virus in a matter of months. In comparison to
vaccines, the development of anti-influenza drugs has been slower,
with
amantadine being licensed in 1966
and, almost thirty years later, the next class of drugs (the
neuraminidase inhibitors)
being developed.
Society and culture
Influenza produces
direct costs due to
lost
productivity and associated
medical treatment, as well as
indirect
costs of preventative measures. In the United States, influenza
is responsible for a total cost of over $10 billion per year, while
it has been estimated that a future pandemic could cause hundreds
of billions of dollars in direct and indirect costs. However, the
economic impacts of past pandemics have not been intensively
studied, and some authors have suggested that the
Spanish influenza actually had a positive
long-term effect on per-capita income growth, despite a large
reduction in the working population and severe short-term
depressive effects. Other studies have attempted
to predict the costs of a pandemic as serious as the 1918 Spanish
flu on the
U.S.
economy, where 30% of all workers became ill, and 2.5% were
killed. A 30% sickness rate and a three-week length of illness
would decrease the
gross domestic
product by 5%. Additional costs would come from medical
treatment of 18 million to 45 million people, and total economic
costs would be approximately $700 billion.
Preventative costs are also high. Governments worldwide have spent
billions of
U.S. dollars
preparing and planning for a potential H5N1 avian influenza
pandemic, with costs associated with purchasing drugs and vaccines
as well as developing
disaster
drills and strategies for improved
border controls. On 1 November 2005,
United States President
George W. Bush unveiled the National Strategy to
Safeguard Against the Danger of Pandemic Influenza backed by a
request to
Congress for $7.1
billion to begin implementing the plan. Internationally, on 18
January 2006, donor nations pledged US$2 billion to combat bird flu
at the two-day International Pledging Conference on Avian and Human
Influenza held in China.
In an assessment of the 2009 H1N1 pandemic on selected countries in
the Southern Hemisphere, data suggest that all countries
experienced some time-limited and/or geographically-isolated
socio/economic effects and a temporary decrease in tourism most
likely due to fear of 2009 H1N1 disease. It is still too early to
determine whether the H1N1 pandemic has caused any long-term
economic impacts.
Research
Research on influenza includes studies on
molecular virology, how the virus
produces disease (
pathogenesis), host
immune responses,
viral genomics, and how the virus spreads (
epidemiology). These studies help in developing
influenza countermeasures; for example, a better understanding of
the body's immune system response helps
vaccine development, and a detailed picture of how
influenza invades cells aids the development of antiviral drugs.
One important
basic research program is the
Influenza Genome
Sequencing Project, which is creating a library of influenza
sequences; this library should help clarify which factors make one
strain more lethal than another, which genes most affect
immunogenicity, and how the virus
evolves over time.
Research into new vaccines is particularly important, as current
vaccines are very slow and expensive to produce and must be
reformulated every year. The sequencing of the influenza genome and
recombinant DNA technology may
accelerate the generation of new vaccine strains by allowing
scientists to substitute new antigens into a previously developed
vaccine strain. New technologies are also being developed to grow
viruses in
cell culture, which promises
higher yields, less cost, better quality and surge capacity.
Research
on a universal influenza A vaccine, targeted against the external
domain of the transmembrane viral M2
protein (M2e), is being done at the University of
Ghent
by Walter Fiers,
Xavier Saelens and their team and has
now successfully concluded Phase I clinical trials.
A number of
biologics, therapeutic
vaccines and immunobiologics are also being investigated for
treatment of infection caused by viruses. Therapeutic biologics are
designed to activate the immune response to virus or antigens.
Typically, biologics do not target
metabolic pathways like anti-viral drugs,
but stimulate immune cells such as
lymphocytes,
macrophages, and/or
antigen presenting cells, in an
effort to drive an immune response towards a
cytotoxic effect against the virus. Infuenza
models, such as murine influenza, are convenient models to test the
effects of prophylactic and therapeutic biologics. For example,
Lymphocyte T-Cell
Immune Modulator inhibits viral growth in the murine model of
influenza.
Infection in other animals
Influenza infects many animal species, and transfer of viral
strains between species can occur.
Birds are
thought to be the main
animal
reservoirs of influenza viruses. Sixteen forms of
hemagglutinin and nine forms of
neuraminidase have been identified. All known
subtypes (HxNy) are found in birds, but many subtypes are endemic
in humans,
dogs,
horses,
and
pigs; populations of
camels,
ferrets,
cats,
seals,
mink, and
whales also show
evidence of prior infection or exposure to influenza. Variants of
flu virus are sometimes named according to the species the strain
is endemic in or adapted to. The main variants named using this
convention are:
Bird Flu,
Human Flu,
Swine Flu,
Horse Flu and
Dog
Flu. (
Cat flu generally refers to
Feline viral
rhinotracheitis or
Feline
calicivirus and not infection from an influenza virus.) In
pigs, horses and dogs, influenza symptoms are similar to humans,
with cough, fever and
loss of
appetite.
The frequency of animal diseases are not as
well-studied as human infection, but an outbreak of influenza in
harbour seals caused approximately 500 seal deaths off the New England
coast in 1979–1980. On the other hand,
outbreaks in pigs are common and do not cause severe
mortality.
Bird flu
Flu symptoms in birds are variable and can be unspecific. The
symptoms following infection with low-pathogenicity avian influenza
may be as mild as ruffled feathers, a small reduction in egg
production, or
weight loss combined with
minor
respiratory disease. Since
these mild symptoms can make diagnosis in the field difficult,
tracking the spread of
avian influenza
requires laboratory testing of samples from infected birds. Some
strains such as Asian
H9N2 are highly virulent
to poultry and may cause more extreme symptoms and significant
mortality. In its most highly pathogenic form, influenza in
chickens and
turkeys produces a sudden appearance of severe
symptoms and almost 100% mortality within two days. As the virus
spreads rapidly in the crowded conditions seen in the
intensive farming of chickens and turkeys,
these outbreaks can cause large economic losses to poultry
farmers.
An avian-adapted, highly pathogenic strain of H5N1 (called HPAI
A(H5N1), for "highly pathogenic avian influenza virus of type A of
subtype H5N1") causes
H5N1 flu, commonly known
as "avian influenza" or simply "bird flu", and is
endemic in many bird populations,
especially in
Southeast Asia. This
Asian lineage strain of HPAI A(H5N1) is
spreading globally. It is
epizootic (an epidemic in non-humans) and
panzootic (a disease affecting animals of many species, especially
over a wide area), killing tens of millions of birds and spurring
the
culling of hundreds of millions of other
birds in an attempt to control its spread. Most references in the
media to "bird flu" and most references to H5N1 are about this
specific strain.
At present, HPAI A(H5N1) is an avian disease, and there is no
evidence suggesting efficient human-to-human transmission of HPAI
A(H5N1). In almost all cases, those infected have had extensive
physical contact with infected birds. In the future, H5N1 may
mutate or reassort into a strain capable of efficient
human-to-human transmission. The exact changes that are required
for this to happen are not well understood. However, due to the
high lethality and
virulence of H5N1, its
endemic presence, and its
large and increasing biological host reservoir, the H5N1 virus was
the world's pandemic threat in the 2006–07 flu season, and billions
of dollars are being raised and spent researching H5N1 and
preparing for a potential
influenza
pandemic.
Swine flu
Chinese inspectors on an airplane,
checking passengers for fevers, a common symptom of swine flu
In pigs
swine influenza produces
fever, lethargy, sneezing, coughing, difficulty breathing and
decreased appetite. In some cases the infection can cause abortion.
Although mortality is usually low, the virus can produce weight
loss and poor growth, causing economic loss to farmers. Infected
pigs can lose up to 12 pounds of body weight over a 3 to 4 week
period. Direct transmission of an influenza virus from pigs to
humans is occasionally possible (this is called
zoonotic swine flu). In all, 50 human cases are
known to have occurred since the virus was identified in the
mid-20th century, which have resulted in six deaths.
In 2009, a swine-origin
H1N1 virus strain
commonly referred to as "swine flu" caused the
2009 flu pandemic, but there is no
evidence that it is endemic to pigs (i.e. actually a swine flu) or
of transmission from pigs to people, instead the virus is spreading
from person to person. This strain is a reassortment of several
strains of H1N1 that are usually found separately, in
humans,
birds, and pigs.
See also
- Information concerning flu research can be found at:
References
Further reading
General
- Bernd Sebastian Kamps,
Christian Hoffmann and Wolfgang Preiser (Eds.) Influenza
Report, 225 pp, PDF, free download. Flying Publisher 2006.
- ISBN 9783211808924 The Influenza Viruses Hoyle L 1968 Springer
Verlag
History
Microbiology
Pathogenesis
Epidemiology
Treatment and prevention
Research
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