Influenza, commonly known as the flu, is an infectious disease caused by an influenza virus. Symptoms can be mild to severe. The most common symptoms include: high fever, runny nose, sore throat, muscle pains, headache, coughing, sneezing, and feeling tired. These symptoms typically begin two days after exposure to the virus and most last less than a week. The cough, however, may last for more than two weeks. In children, there may be diarrhea and vomiting, but these are not common in adults. Diarrhea and vomiting occur more commonly in gastroenteritis, which is an unrelated disease and sometimes inaccurately referred to as "stomach flu" or the "24-hour flu". Complications of influenza may include viral pneumonia, secondary bacterial pneumonia, sinus infections, and worsening of previous health problems such as asthma or heart failure.
Three of the four types of influenza viruses affect humans: Type A, Type B, and Type C. Type D has not been known to infect humans, but is believed to have the potential to do so. Usually, the virus is spread through the air from coughs or sneezes. This is believed to occur mostly over relatively short distances. It can also be spread by touching surfaces contaminated by the virus and then touching the mouth or eyes. A person may be infectious to others both before and during the time they are showing symptoms. The infection may be confirmed by testing the throat, sputum, or nose for the virus. A number of rapid tests are available; however, people may still have the infection even if the results are negative. A type of polymerase chain reaction that detects the virus's RNA is more accurate.
Frequent hand washing reduces the risk of viral spread. Wearing a surgical mask is also useful. Yearly vaccinations against influenza are recommended by the World Health Organization for those at high risk. The vaccine is usually effective against three or four types of influenza. It is usually well-tolerated. A vaccine made for one year may not be useful in the following year, since the virus evolves rapidly. Antiviral drugs such as the neuraminidase inhibitor oseltamivir, among others, have been used to treat influenza. The benefit of antiviral drugs in those who are otherwise healthy do not appear to be greater than their risks. No benefit has been found in those with other health problems.
Influenza spreads around the world in yearly outbreaks, resulting in about three to five million cases of severe illness and about 250,000 to 500,000 deaths. About 20% of unvaccinated children and 10% of unvaccinated adults are infected each year. In the northern and southern parts of the world, outbreaks occur mainly in the winter, while around the equator, outbreaks may occur at any time of the year. Death occurs mostly in the young, the old, and those with other health problems. Larger outbreaks known as pandemics are less frequent. In the 20th century, three influenza pandemics occurred: Spanish influenza in 1918 (~50 million deaths), Asian influenza in 1957 (two million deaths), and Hong Kong influenza in 1968 (one million deaths). The World Health Organization declared an outbreak of a new type of influenza A/H1N1 to be a pandemic in June 2009. Influenza may also affect other animals, including pigs, horses, and birds.
|Other names||Flu, the flu|
|Influenza virus, magnified approximately 100,000 times|
|Symptoms||Fever, runny nose, sore throat, muscle pains, headache, coughing, sneezing, feeling tired|
|Usual onset||Two days after exposure|
|Prevention||Handwashing, surgical mask, influenza vaccine|
|Medication||Antiviral drugs such as oseltamivir|
|Frequency||3–5 million per year|
|Deaths||~375,000 per year|
Approximately 33% of people with influenza are asymptomatic.
Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills and body aches, but fever is also common early in the infection, with body temperatures ranging from 38 to 39 °C (approximately 100 to 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.
It can be difficult to distinguish between the common cold and influenza in the early stages of these infections. Influenza symptoms are a mixture of symptoms of common cold and pneumonia, body ache, headache, and fatigue. Diarrhea is not usually 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 adjacent table.
The specific combination of fever and cough has been found to be the best predictor; diagnostic accuracy increases with a body temperature above 38°C (100.4°F). Two decision analysis studies suggest that during local outbreaks of influenza, the prevalence will be over 70%. Even in the absence of a local outbreak, diagnosis may be justified in the elderly during the influenza season as long as the prevalence is over 15%.
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 50–75% and specificity of 90–95% when compared with viral culture.
Occasionally, influenza can cause severe illness including primary viral pneumonia or secondary bacterial pneumonia. The obvious symptom is trouble breathing. In addition, if a child (or presumably an adult) seems to be getting better and then relapses with a high fever, that is a danger sign since this relapse can be bacterial pneumonia.
Sometimes, influenza may have abnormal presentations, like confusion in the elderly and a sepsis-like syndrome in the young. Encephalitis due to the flu is rare but not unheard of.
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.
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 four influenza types and cause the severest 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:
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 slower 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.
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.
This genus has only one species, influenza D virus, which infects pigs and cattle. The virus has the potential to infect humans, although no such cases have been observed yet. This virus has not been found to be responsible for any major epidemics.
Influenzaviruses A, B, C, and D are very similar in overall structure. The virus particle (also called the virion) is 80–120 nanometers in diameter such that the smallest virions adopt an elliptical shape. The length of each particle varies considerably, owing to the fact that influenza is pleomorphic, and can be in excess of many tens of micrometers, producing filamentous virions. 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, which code for a gene product (protein). 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 (matrix 1 protein), M2, NS1 (non-structural protein 1), NS2 (other name is NEP, nuclear export protein), PA, PB1 (polymerase basic 1), 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 18 H and 11 N subtypes known, but only H 1, 2 and 3, and N 1 and 2 are commonly found in humans.
Viruses can replicate only in living cells. Influenza infection and replication is a multi-step process: First, 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, last, 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.
The intracellular details are still being elucidated. It is known that virions converge to the microtubule organizing center, interact with acidic endosomes and finally enter the target endosomes for genome release.
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 disassemble 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 either is exported into the cytoplasm and translated (step 4) or remains in the nucleus. Newly synthesized 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. 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.
When an infected person sneezes or coughs more than half a million virus particles can be spread to those close by. In otherwise healthy adults, influenza virus shedding (the time during which a person might be infectious to another person) increases sharply one-half to one day after infection, peaks on day 2 and persists for an average total duration of 5 days—but can persist as long as 9 days. In those who develop symptoms from experimental infection (only 67% of healthy experimentally infected individuals), symptoms and viral shedding show a similar pattern, but with viral shedding preceding illness by one day. Children are much more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection. In immunocompromised people, viral shedding can continue for longer than two weeks.
Influenza can be spread in three main ways: by direct transmission (when an infected person sneezes mucus directly into the eyes, nose or mouth of another person); the airborne route (when someone inhales the aerosols produced by an infected person coughing, sneezing or spitting) and through hand-to-eye, hand-to-nose, or hand-to-mouth transmission, either from contaminated surfaces or from direct personal contact such as a handshake. 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 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).
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. Influenza appear to trigger programmed cell death (apoptosis).
The influenza vaccine is recommended by the World Health Organization and United States Centers for Disease Control and Prevention for high-risk groups, such as children, the elderly, health care workers, and people who have chronic illnesses such as asthma, diabetes, heart disease, or are immuno-compromised among others. In healthy adults it is modestly effective in decreasing the amount of influenza-like symptoms in a population. In healthy children over the age of 2, the vaccine reduces the chances of getting influenza by around two-thirds, while it has not been well studied in children under 2. In those with chronic obstructive pulmonary disease vaccination reduces exacerbations, it is not clear if it reduces asthma exacerbations. Evidence supports a lower rate of influenza-like illness in many groups who are immunocompromised such as those with: HIV/AIDS, cancer, and post organ transplant. In those at high risk immunization may reduce the risk of heart disease. Whether immunizing health care workers affects patient outcomes is controversial with some reviews finding insufficient evidence and others finding tentative evidence.
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 (see Historical annual reformulations of the influenza vaccine), allowing pharmaceutical companies to develop vaccines that will provide the best immunity against these strains. The vaccine is reformulated each season for a few specific flu strains but does not include all the strains active in the world during 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. It is also possible to get infected just before vaccination and get sick with the strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.
Vaccines can cause the immune system to react as if the body were actually being infected, and general infection symptoms (many cold and flu symptoms are just general infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza. The most dangerous adverse effect 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.
A 2018 Cochrane review of children in good general health found that the live immunization seemed to lower the risk of getting influenza for the season from 18% to 4%. The inactivated vaccine seemed to lower the risk of getting flu for the season from 30% to 11%. Not enough data was available to draw definite conclusions about serious complications such as pneumonia or hospitalization.
For healthy adults, a 2018 Cochrane review showed that vaccines reduced the incidence of lab-confirmed influenza from 2.3% to 0.9%, which constitutes a reduction of risk of approximately 60%. However, for influenza-like illness which is defined as the same symptoms of cough, fever, headache, runny nose, and bodily aches and pains, vaccine reduced the risk from 21.5% to 18.1%. This constitutes a much more modest reduction of risk of approximately 16%. The difference is most probably explained by the fact that over 200 viruses cause the same or similar symptoms as the flu virus.
The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings. It has generally been found to be a cost-effective intervention, especially in children and the elderly, however the results of economic evaluations of influenza vaccination have often been found to be dependent on key assumptions.
These are the main ways that influenza spreads
Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene habits such as: not touching your eyes, nose or mouth; frequent hand washing (with soap and water, or with alcohol-based hand rubs); covering coughs and sneezes; avoiding close contact with sick people; and staying home yourself if you are sick. Avoiding spitting is also recommended. 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.
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 people with influenza symptoms. At home, this can be done effectively with a diluted chlorine bleach.
Social distancing strategies used during past pandemics, such as 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.
There are a number of rapid tests for the flu. One is called a Rapid Molecular Assay, when an upper respiratory tract specimen (mucus) is taken using a nasal swab or a nasopharyngeal swab. It should be done within 3–4 days of symptom onset, as upper respiratory viral shedding takes a downward spiral after that.
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. They are also advised to avoid close contact with others to prevent spread of infection. 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 may be effective, if given early (within 48 hours to first symptoms), but some strains of influenza can show resistance to the standard antiviral drugs and there is concern about the quality of the research. High-risk individuals such as young children, pregnant women, the elderly, and those with compromised immune systems should visit the doctor for antiviral drugs. Those with the emergency warning signs should visit the emergency room at once.
Overall the benefits of neuraminidase inhibitors in those who are otherwise healthy do not appear to be greater than the risks. There does not appear to be any benefit in those with other health problems. In those believed to have the flu, they decreased the length of time symptoms were present by slightly less than a day but did not appear to affect the risk of complications such as needing hospitalization or pneumonia. Increasingly prevalent resistance to neuraminidase inhibitors has led to researchers to seek alternative antiviral drugs with different mechanisms of action.
The antiviral drugs amantadine and rimantadine inhibit a viral ion channel (M2 protein), thus inhibiting replication of the influenza A virus. These drugs are sometimes effective against influenza A if given early in the infection but are ineffective against influenza B viruses, which lack the M2 drug target. 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. The CDC recommended against using M2 inhibitors during the 2005–06 influenza season due to high levels of drug resistance.
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). Thus, influenza can be deadly, especially for the weak, young and old, those with compromised immune systems, or the chronically ill. People with a weak immune system, such as people with advanced HIV infection or transplant people (whose immune systems are medically suppressed to prevent transplant organ rejection), suffer from particularly severe disease. Pregnant women and young children are also at a high risk for complications.
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 65 years old, pregnant women, 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 has been believed to also be a rare side effect of influenza vaccines. One review gives an incidence of about one case per million vaccinations. Getting infected by influenza itself increases both the risk of death (up to 1 in 10,000) and increases the risk of developing GBS to a much higher level than the highest level of suspected vaccine involvement (approx. 10 times higher by recent estimates).
According to cdc.gov, "Children of any age with neurologic conditions are more likely than other children to become very sick if they get the flu. Flu complications may vary and for some children, can include pneumonia and even death.
Neurological conditions can include:
These conditions can impair coughing, swallowing, clearing the airways, and in the worst cases, breathing. Therefore, they worsen the flu symptoms.
Encephalitis is a rare but not unheard of, and can occur in the elderly and present as confusion and slurred speech.
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.
A long-standing puzzle has been 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 particles. Dry particles are lighter and can thus remain airborne for a longer period. The virus also survives longer on surfaces at colder temperatures and aerosol transmission of the virus is highest in cold environments (less than 5 °C) with low relative humidity. The lower air humidity in winter seems to be the main cause of seasonal influenza transmission in temperate regions.
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.
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 around 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. One method of calculating influenza mortality produced an estimate of 41,400 average deaths per year in the United States between 1979 and 2001. Different methods in 2010 by the Centers for Disease Control and Prevention (CDC) reported a range from a low of about 3,300 deaths to a high of 49,000 per year.
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 pandemics section). 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.
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.
From a public health point of view, flu epidemics spread rapidly and are very difficult to control. Most influenza virus strains are not very infectious and each infected individual will only go on to infect one or two other individuals (the basic reproduction number for influenza is generally around 1.4). However, the generation time for influenza is extremely short: the time from a person becoming infected to when he infects the next person is only two days. The short generation time means that influenza epidemics generally peak at around 2 months and burn out after 3 months: the decision to intervene in an influenza epidemic therefore has to be taken early, and the decision is therefore often made on the back of incomplete data. Another problem is that individuals become infectious before they become symptomatic, which means that putting people in quarantine after they become ill is not an effective public health intervention. For the average person, viral shedding tends to peak on day two, whereas symptoms peak on day three.
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. It was introduced into English in the mid-eighteenth century during a pan-European epidemic. Archaic terms for influenza include epidemic catarrh, la grippe (from the French, first used by Molyneaux in 1694), sweating sickness, and Spanish fever (particularly for the 1918 flu pandemic strain).
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 respiratory diseases. The disease may 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 50 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. 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 was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between two and twenty percent 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.
|Name of pandemic||Date||Deaths||Case fatality rate||Subtype involved||Pandemic Severity Index|
|1889–1890 flu pandemic
(Asiatic or Russian Flu)
|1889–1890||1 million||0.15%||possibly H3N8
|1918 flu pandemic
|1918–1920||20 to 100 million||2%||H1N1||5|
|Asian Flu||1957–1958||1 to 1.5 million||0.13%||H2N2||2|
|Hong Kong Flu||1968–1969||0.75 to 1 million||<0.1%||H3N2||2|
|Russian flu||1977–1978||no accurate count||N/A||H1N1||N/A|
|2009 flu pandemic||2009–2010||105,700–395,600||0.03%||H1N1||N/A|
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 virus family Orthomyxoviridae, 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.
Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, seasonal influenza is estimated to result in a total average annual economic cost of over $11 billion, with direct medical costs estimated to be over $3 billion annually. 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 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. There has been some research success towards a "universal flu vaccine" that produces antibodies against proteins on the viral coat which mutate less rapidly, and thus a single shot could potentially provide longer-lasting protection.
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. Influenza 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.
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 harbor seals caused approximately 500 seal deaths off the New England coast in 1979–1980. However, outbreaks in pigs are common and do not cause severe mortality. 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.
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.
In March 2013, the Chinese government reported three cases of H7N9 influenza infections in humans. Two of whom had died and the third was critically ill. Although the strain of the virus is not thought to spread efficiently between humans, by mid-April, at least 82 persons had become ill from H7N9, of which 17 had died. These cases include three small family clusters in Shanghai and one cluster between a neighboring girl and boy in Beijing, raising at least the possibility of human-to-human transmission. WHO points out that one cluster did not have two of the cases lab confirmed and further points out, as a matter of baseline information, that some viruses are able to cause limited human-to-human transmission under conditions of close contact but are not transmissible enough to cause large community outbreaks.
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.
The regression model attributes an annual average of 41,400 (95% confidence interval: 27,100, 55,700) deaths to influenza over the period 1979–2001
Instead of the estimated 36,000 annual flu deaths in the United States ... the actual number in the past 30 years has ranged from a low of about 3,300 deaths to a high of nearly 49,000, the CDC said on Thursday
Treatment and prevention
The 2009 flu pandemic or swine flu was an influenza pandemic that lasted from early 2009 to late 2010, and the second of the two pandemics involving H1N1 influenza virus (the first of them being the 1918 flu pandemic), albeit in a new version. First described in April 2009, the virus appeared to be a new strain of H1N1 which resulted when a previous triple reassortment of bird, swine and human flu viruses further combined with a Eurasian pig flu virus, leading to the term "swine flu".Unlike most strains of influenza, H1N1 does not disproportionately infect adults older than 60 years; this was an unusual and characteristic feature of the H1N1 pandemic. Even in the case of previously very healthy people, a small percentage will develop pneumonia or acute respiratory distress syndrome (ARDS). This manifests itself as increased breathing difficulty and typically occurs 3–6 days after initial onset of flu symptoms. The pneumonia caused by flu can be either direct viral pneumonia or a secondary bacterial pneumonia. In fact, a November 2009 New England Journal of Medicine article recommended that flu patients whose chest X-ray indicates pneumonia receive both antivirals and antibiotics. In particular, it is a warning sign if a child (and presumably an adult) seems to be getting better and then relapses with high fever, as this relapse may be bacterial pneumonia.Amantadine
Amantadine (trade name Symmetrel, by Endo Pharmaceuticals) is a medication that has U.S. Food and Drug Administration approval for use both as an antiviral and an antiparkinsonian medication. It is the organic compound 1-adamantylamine or 1-aminoadamantane, meaning it consists of an adamantane backbone that has an amino group substituted at one of the four methyne positions. Rimantadine is a closely related derivative of adamantane with similar biological properties.
Apart from medical uses, this compound is useful as a building block in organic synthesis, allowing the insertion of an adamantyl group.
According to the U.S. Centers for Disease Control and Prevention (CDC) 100% of seasonal H3N2 and 2009 pandemic flu samples tested showed resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza in the United States. Additionally, its effectiveness as an antiparkinsonian drug is undetermined, with a 2003 Cochrane Review concluding that there was insufficient evidence in support of or against its efficacy and safety.Avian influenza
Avian influenza—known informally as avian flu or bird flu is a variety of influenza caused by viruses adapted to birds. The type with the greatest risk is highly pathogenic avian influenza (HPAI). Bird flu is similar to swine flu, dog flu, horse flu and human flu as an illness caused by strains of influenza viruses that have adapted to a specific host. Out of the three types of influenza viruses (A, B, and C), influenza A virus is a zoonotic infection with a natural reservoir almost entirely in birds. Avian influenza, for most purposes, refers to the influenza A virus.
Though influenza A is adapted to birds, it can also stably adapt and sustain person-to person transmission. Recent influenza research into the genes of the Spanish flu virus shows it to have genes adapted from both human and avian strains. Pigs can also be infected with human, avian, and swine influenza viruses, allow for mixtures of genes (reassortment) to create a new virus, which can cause an antigenic shift to a new influenza A virus subtype which most people have little to no immune protection.Avian influenza strains are divided into two types based on their pathogenicity: high pathogenicity (HP) or low pathogenicity (LP). The most well-known HPAI strain, H5N1, appeared in China in 1996, and also has low pathogenic strains found in North America. Companion birds in captivity are unlikely to contract the virus and there has been no report of a companion bird with avian influenza since 2003. Pigeons can contract avian strains, but rarely become ill and are incapable of transmitting the virus efficiently to humans or other animals.Between early 2013 and early 2017, 916 lab-confirmed human cases of H7N9 were reported to the World Health Organization (WHO). On 9 January 2017, the National Health and Family Planning Commission of China reported to WHO 106 cases of H7N9 which occurred from late November through late December, including 35 deaths, 2 potential cases of human-to-human transmission, and 80 of these 106 persons stating that they have visited live poultry markets. The cases are reported from Jiangsu (52), Zhejiang (21), Anhui (14), Guangdong (14), Shanghai (2), Fujian (2) and Hunan (1). Similar sudden increases in the number of human cases of H7N9 have occurred in previous years during December and January.Haemophilus influenzae
Haemophilus influenzae (formerly called Pfeiffer's bacillus or Bacillus influenzae) is a Gram-negative, coccobacillary, facultatively anaerobic pathogenic bacterium belonging to the Pasteurellaceae family. H. influenzae was first described in 1892 by Richard Pfeiffer during an influenza pandemic.The bacterium was mistakenly considered to be the cause of influenza until 1933, when the viral cause of influenza became apparent, and is still colloquially known as bacterial influenza. H. influenzae is responsible for a wide range of localized and invasive infections. This species was the first free-living organism to have its entire genome sequenced.Influenza-like illness
Influenza-like illness (ILI), also known as flu-like syndrome/symptoms, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms.
Symptoms commonly include fever, shivering, chills, malaise, dry cough, loss of appetite, body aches, and nausea, typically in connection with a sudden onset of illness. In most cases, the symptoms are caused by cytokines released by immune system activation, and are thus relatively non-specific.
Common causes of ILI include the common cold and influenza, which tends to be less common but more severe than the common cold. Less-common causes include side effects of many drugs and manifestations of many other diseases.Influenza A virus
Influenza A virus causes influenza in birds and some mammals, and is the only species of the Alphainfluenzavirus genus of the Orthomyxoviridae family of viruses. Strains of all subtypes of influenza A virus have been isolated from wild birds, although disease is uncommon. Some isolates of influenza A virus cause severe disease both in domestic poultry and, rarely, in humans. Occasionally, viruses are transmitted from wild aquatic birds to domestic poultry, and this may cause an outbreak or give rise to human influenza pandemics.Influenza A viruses are negative-sense, single-stranded, segmented RNA viruses.
The several subtypes are labeled according to an H number (for the type of hemagglutinin) and an N number (for the type of neuraminidase). There are 18 different known H antigens (H1 to H18) and 11 different known N antigens (N1 to N11). H17N10 was isolated from fruit bats in 2012. H18N11 was discovered in a Peruvian bat in 2013.Each virus subtype has mutated into a variety of strains with differing pathogenic profiles; some are pathogenic to one species but not others, some are pathogenic to multiple species.
A filtered and purified influenza A vaccine for humans has been developed, and many countries have stockpiled it to allow a quick administration to the population in the event of an avian influenza pandemic. Avian influenza is sometimes called avian flu, and colloquially, bird flu. In 2011, researchers reported the discovery of an antibody effective against all types of the influenza A virus.Influenza A virus subtype H1N1
Influenza (H1N1) virus is the subtype of influenza A virus that was the most common cause of human influenza (flu) in 2009, and is associated with the 1918 outbreak known as the Spanish flu.
It is an orthomyxovirus that contains the glycoproteins haemagglutinin and neuraminidase. For this reason, they are described as H1N1, H1N2 etc. depending on the type of H or N antigens they express with metabolic synergy. Haemagglutinin causes red blood cells to clump together and binds the virus to the infected cell. Neuraminidase is a type of glycoside hydrolase enzyme which helps to move the virus particles through the infected cell and assist in budding from the host cells.Some strains of H1N1 are endemic in humans and cause a small fraction of all influenza-like illness and a small fraction of all seasonal influenza. H1N1 strains caused a small percentage of all human flu infections in 2004–2005. Other strains of H1N1 are endemic in pigs (swine influenza) and in birds (avian influenza).
In June 2009, the World Health Organization (WHO) declared the new strain of swine-origin H1N1 as a pandemic. This strain is often called swine flu by the public media. This novel virus spread worldwide and had caused about 17,000 deaths by the start of 2010. On August 10, 2010, the World Health Organization declared the H1N1 influenza pandemic over, saying worldwide flu activity had returned to typical seasonal patterns.Influenza A virus subtype H5N1
Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species. A bird-adapted strain of H5N1, called HPAI A(H5N1) for highly pathogenic avian influenza virus of type A of subtype H5N1, is the highly pathogenic causative agent of H5N1 flu, commonly known as avian influenza ("bird flu"). It is enzootic (maintained in the population) in many bird populations, especially in Southeast Asia. One strain of HPAI A(H5N1) is spreading globally after first appearing in Asia. It is epizootic (an epidemic in nonhumans) and panzootic (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 others to stem its spread. Many references to "bird flu" and H5N1 in the popular media refer to this strain.According to the World Health Organization and United Nations Food and Agriculture Organization, H5N1 pathogenicity is gradually continuing to rise in endemic areas, but the avian influenza disease situation in farmed birds is being held in check by vaccination, and so far there is "no evidence of sustained human-to-human transmission" of the virus. Eleven outbreaks of H5N1 were reported worldwide in June 2008 in five countries (China, Egypt, Indonesia, Pakistan and Vietnam) compared to 65 outbreaks in June 2006, and 55 in June 2007. The global HPAI situation significantly improved in the first half of 2008, but the FAO reports that imperfect disease surveillance systems mean that occurrence of the virus remains underestimated and underreported. In July 2013, the WHO announced a total of 630 confirmed human cases which resulted in the deaths of 375 people since 2003.Several H5N1 vaccines have been developed and approved, and stockpiled by a number of countries, including the United States (in its National Stockpile), Britain, France, Canada, and Australia, for use in an emergency.Research has shown that a highly contagious strain of H5N1, one that might allow airborne transmission between mammals, can be reached in only a few mutations, raising concerns about a pandemic and bioterrorism.Influenza B virus
Influenza B virus is the only species in the genus Betainfluenzavirus in the virus family Orthomyxoviridae.
Influenza B virus is only known to infect humans and seals with influenza.. This limited host range is apparently responsible for the lack of associated influenza pandemics in contrast with those caused by the morphologically similar influenza A virus as both mutate by both antigenic drift and reassortment. There are two known circulating lineages of Influenza B virus based on the antigenic properties of the surface glycoprotein hemagglutinin. The lineages are termed B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. The quadrivalent influenza vaccine licensed by the CDC is currently designed to protect against both co-circulating lineages and has been shown to have greater effectiveness in prevention of influenza caused by Influenza B virus than the previous trivalent vaccine.Further diminishing the impact of this virus, "in humans, influenza B viruses evolve slower than A viruses and faster than C viruses". Influenzavirus B mutates at a rate 2 to 3 times slower than type A. Nevertheless, it is accepted that Influenza B virus cause significant morbidity and mortality worldwide, and significantly impacts adolescents and schoolchildren.Influenza C virus
Influenza C virus is the species in the genus Influenzavirus C, in the virus family Orthomyxoviridae, which like other influenza viruses, causes influenza.
Influenza C viruses are known to infect humans and pigs.Flu due to the Type C species is rare compared to Types A or B, but can be severe and can cause local epidemics. Type C has 7 RNA segments and encodes 9 proteins, while Types A and B have 8 RNA segments and encode at least 10 proteins.Influenza pandemic
An influenza pandemic is an epidemic of an influenza virus that spreads on a worldwide scale and infects a large proportion of the world population. In contrast to the regular seasonal epidemics of influenza, these pandemics occur irregularly – there have been about 9 influenza pandemics during the last 300 years. Pandemics can cause high levels of mortality, with the 1918 Spanish influenza pandemic being the worst in recorded history; this pandemic was estimated to be responsible for the deaths of approximately 50–100 million people. There have been about three influenza pandemics in each century for the last 300 years, the most recent one being the 2009 flu pandemic.Influenza pandemics occur when a new strain of the influenza virus is transmitted to humans from another animal species. Species that are thought to be important in the emergence of new human strains are pigs, chickens and ducks. These novel strains are unaffected by any immunity people may have to older strains of human influenza and can therefore spread extremely rapidly and infect very large numbers of people. Influenza A viruses can occasionally be transmitted from wild birds to other species causing outbreaks in domestic poultry and may give rise to human influenza pandemics. The propagation of influenza viruses throughout the world is thought in part to be by bird migrations, though commercial shipments of live bird products might also be implicated, as well as human travel patterns.
The World Health Organization (WHO) has produced a six-stage classification that describes the process by which a novel influenza virus moves from the first few infections in humans through to a pandemic. This starts with the virus mostly infecting animals, with a few cases where animals infect people, then moves through the stage where the virus begins to spread directly between people, and ends with a pandemic when infections from the new virus have spread worldwide.One strain of virus that may produce a pandemic in the future is a highly pathogenic variation of the H5N1 subtype of influenza A virus. On 11 June 2009, a new strain of H1N1 influenza was declared to be a global pandemic (Stage 6) by the WHO after evidence of spreading in the southern hemisphere. The 13 November 2009 worldwide update by the WHO stated that "[a]s of 8 November 2009, worldwide more than 206 countries and overseas territories or communities have reported [503,536] laboratory confirmed cases of pandemic influenza H1N1 2009, including over 6,250 deaths."Influenza vaccine
Influenza vaccines, also known as flu shots or flu jabs, are vaccines that protect against infection by influenza viruses. A new version of the vaccine is developed twice a year, as the influenza virus rapidly changes. While their effectiveness varies from year to year, most provide modest to high protection against influenza. The United States Centers for Disease Control and Prevention (CDC) estimates that vaccination against influenza reduces sickness, medical visits, hospitalizations, and deaths. When an immunized worker does catch the flu, they are on average back at work a half day sooner. Vaccine effectiveness in those under two years old and over 65 years old remains unknown due to the low quality of the research. Vaccinating children may protect those around them.The World Health Organization (WHO) and the CDC recommend yearly vaccination for nearly all people over the age of six months, especially those at high risk. The European Centre for Disease Prevention and Control also recommends yearly vaccination of high risk groups. These groups include pregnant women, the elderly, children between six months and five years of age, those with other health problems, and those who work in healthcare.The vaccines are generally safe. Fever occurs in five to ten percent of children vaccinated. Temporary muscle pains or feelings of tiredness may occur as well. In certain years, the vaccine has been linked to an increase in Guillain–Barré syndrome among older people at a rate of about one case per million doses. It should not be given to those with severe allergies to previous versions of the vaccine. Although most influenza vaccines are produced using egg-based techniques, influenza vaccines are nonetheless recommended for people with egg allergies, even if severe. The vaccines come in both inactive and weakened viral forms. The inactive version should be used for those who are pregnant. They come in forms that are injected into a muscle, sprayed into the nose, or injected into the middle layer of the skin.Vaccination against influenza began in the 1930s with large scale availability in the United States beginning in 1945. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale price in the developing world is about $5.25 USD per dose as of 2014. In the United States, the vaccine costs less than $25 USD per dose, as of 2015.Live attenuated influenza vaccine
Live attenuated influenza vaccine (LAIV) is a type of influenza vaccine in the form of a nasal spray that is recommended for the prevention of influenza. In June 2016 the CDC stopped recommending the use of LAIV as its effectiveness has appeared to have decreased between 2013 and 2016, but this recommendation was reversed in February 2018 for the 2018-2019 influenza season.It is an attenuated vaccine, unlike most influenza vaccines, which are inactivated vaccines. LAIV is administered intranasally, while inactivated vaccines are administered by intramuscular injection. LAIV is sold under the trade name FluMist in the United States and Canada, and Fluenz in Europe. FluMist is manufactured by MedImmune and was first introduced in 2003.Orthomyxoviridae
Orthomyxoviridae (ὀρθός, orthós, Greek for "straight"; μύξα, mýxa, Greek for "mucus") is a family of RNA viruses. It includes seven genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Influenzavirus D, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in vertebrates, including birds (see also avian influenza), humans, and other mammals. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates, such as ticks and mosquitoes.The four genera of Influenza virus, which are identified by antigenic differences in their nucleoprotein and matrix protein, infect vertebrates as follows:
Influenzavirus A infects humans, other mammals, and birds, and causes all flu pandemics
Influenzavirus B infects humans and seals
Influenzavirus C infects humans, pigs, and dogs.
Influenzavirus D infects pigs and cattleOseltamivir
Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B (flu). Many medical organizations recommend it in people who have complications or are at high risk of complications within 48 hours of first symptoms of infection. They recommend it to prevent infection in those at high risk, but not the general population. The CDC recommends that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection. It is taken by mouth, either as a pill or liquid.Recommendations regarding oseltamivir are controversial as are criticisms of the recommendations. A 2014 Cochrane review concluded that oseltamivir does not reduce hospitalizations, and that there is no evidence of reduction in complications of influenza. Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks. They also found little evidence regarding whether treatment changes the risk of hospitalization or death in high risk populations. However, another meta-analysis found that oseltamivir was effective for prevention of influenza at the individual and household levels.Common side effects include vomiting, diarrhea, headache, and trouble sleeping. Other side effects may include psychiatric symptoms and seizures. In the United States it is recommended for influenza infection during pregnancy. It has been taken by a small number of pregnant women without signs of problems. Dose adjustment may be needed in those with kidney problems.Oseltamivir was approved for medical use in the US in 1999. It was the first neuraminidase inhibitor available by mouth. It is on the complementary list of World Health Organization's List of Essential Medicines, indicating a lower cost-benefit ratio. A generic version was approved in the US in 2016. As of 2014 the wholesale cost in the developing world was about US$4.27 per day. The wholesale cost for a course of treatment in the United States is about US$54.00 as of 2019. In 2016 it was the 249th most prescribed medication in the United States with more than a million prescriptions.Pandemic
A pandemic (from Greek πᾶν pan "all" and δῆμος demos "people") is an epidemic of disease that has spread across a large region; for instance multiple continents, or even worldwide.
A widespread endemic disease that is stable in terms of how many people are getting sick from it is not a pandemic. Further, flu pandemics generally exclude recurrences of seasonal flu. Throughout history, there have been a number of pandemics, such as smallpox and tuberculosis. One of the most devastating pandemics was the Black Death, which killed over 75 million people in 1350. The most recent pandemics include the HIV pandemic as well as the 1918 and 2009 H1N1 pandemics.Spanish flu
The 1918 influenza pandemic (January 1918 – December 1920; colloquially known as Spanish flu) was an unusually deadly influenza pandemic, the first of the two pandemics involving H1N1 influenza virus. It infected 500 million people around the world, including people on remote Pacific islands and in the Arctic, and resulted in the deaths of 50 to 100 million (three to five percent of the world's population), making it one of the deadliest natural disasters in human history.Infectious disease already limited life expectancy in the early 20th century. But in the first year of the pandemic, life expectancy in the United States dropped by about 12 years. Most influenza outbreaks have a U-shaped mortality rate, disproportionately killing the very young and the very old, with higher survival rate for those inbetween, but the 1918 pandemic had a W-shaped mortality rate, with a higher than expected mortality rate for young adults.To maintain morale, wartime censors minimized early reports of illness and mortality in Germany, the United Kingdom, France, and the United States. Papers were free to report the epidemic's effects in neutral Spain (such as the grave illness of King Alfonso XIII). This created a false impression of Spain as especially hard hit, thereby giving rise to the pandemic's nickname, "Spanish flu".Scientists offer several possible explanations for the high mortality rate of the 1918 influenza pandemic. Some research suggests that the specific variant of the virus was unusually aggressive. One group of researchers recovered the virus from the bodies of frozen victims, and transfected animals with it, causing a rapidly progressive respiratory failure and death through a cytokine storm (overreaction of the body's immune system). It was postulated that the strong immune reactions of young adults ravaged the body, whereas the weaker immune systems of children and middle-aged adults resulted in fewer deaths among those groups.In 2007, analysis of medical journals from the period of the pandemic found that the viral infection itself was not more aggressive than any previous influenza, but that the special circumstances of the epidemic (malnourishment, overcrowded medical camps and hospitals, poor hygiene) promoted bacterial superinfection that killed most of the victims, typically after a somewhat prolonged death bed.Historical and epidemiological data are inadequate to identify the pandemic's geographic origin. It was implicated in the outbreak of encephalitis lethargica in the 1920s.Swine influenza
Swine influenza is an infection caused by any one of several types of swine influenza viruses. Swine influenza virus (SIV) or swine-origin influenza virus (S-OIV) is any strain of the influenza family of viruses that is endemic in pigs. As of 2009, the known SIV strains include influenza C and the subtypes of influenza A known as H1N1, H1N2, H2N1, H3N1, H3N2, and H2N3.
The Swine flu was initially seen in humans in Mexico in 2009, where the strain of the particular virus was a mixture from 3 types of strains. Six of the genes are very similar to the H1N2 influenza virus that was found in pigs around 2000.Swine influenza virus is common throughout pig populations worldwide. Transmission of the virus from pigs to humans is not common and does not always lead to human flu, often resulting only in the production of antibodies in the blood. If transmission does cause human flu, it is called zoonotic swine flu. People with regular exposure to pigs are at increased risk of swine flu infection.
Around the mid-20th century, identification of influenza subtypes became possible, allowing accurate diagnosis of transmission to humans. Since then, only 50 such transmissions have been confirmed. These strains of swine flu rarely pass from human to human. Symptoms of zoonotic swine flu in humans are similar to those of influenza and of influenza-like illness in general, namely chills, fever, sore throat, muscle pains, severe headache, coughing, weakness, shortness of breath, and general discomfort.
In August 2010, the World Health Organization declared the swine flu pandemic officially over.Cases of swine flu have been reported in India, with over 31,156 positive test cases and 1,841 deaths up to March 2015.Viral neuraminidase
Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins and are required for influenza virus replication.
When influenza virus replicates, it attaches to the interior cell surface using hemagglutinin, a molecule found on the surface of the virus that binds to sialic acid groups. Sialic acids are found on various glycoproteins at the host cell surface, and the virus exploits these groups to bind the host cell. In order for the virus to be released from the cell, neuraminidase must enzymatically cleave the sialic acid groups from host glycoproteins.
Since the cleavage of the sialic groups is an integral part of influenza replication, blocking the function of neuraminidase with neuraminidase inhibitors is an effective way to treat influenza.
A single hemagglutinin-neuraminidase protein can combine neuraminidase and hemagglutinin functions, such as in mumps virus and human parainfluenza virus.
Influenza A virus
Diseases of the respiratory system (J, 460–519)
|Lower RT/lung disease|
acute viral nasopharyngitis/
|Human digestive system|