About of Influenza | Definition of Influenza

Source:  About of Influenza | Definition of Influenza    Tag:  influenza rna virus
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 most common symptoms of the disease are chills, fever, sore throat, muscle pains, severe headache, coughing, weakness/fatigue and general discomfort. Although it is often confused with other influenza-like illnesses, especially the common cold, influenza is a 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 inaccurately "stomach flu."

In occasional cases, even for healthy young adults, flu can cause either respiratory distress syndrome or pneumonia, which are manifest with a difficulty in breathing. In addition, there is a pattern in which a child (or presumably an adult) seems to be recovering and then relapses with high fever. This relapse can be bacterial pneumonia. And in general, in occasional cases, flu can cause either direct viral pneumonia and/or secondary bacterial pneumonia.

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 epidemics, resulting in the deaths of between 250,000 and 500,000 people every year, up to millions in some pandemic years. On average 41,400 people died each year in the United States between 1979 and 2001 from influenza. In 2010 the Centers for Disease Control and Prevention (CDC) in the United States changed the way it reports the 30 year estimates for deaths. Now they are reported as a range from a low of about 3,300 deaths to a high of 49,000 per year.

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, the strain actually having a lower mortality rate than common flu outbreaks.

Vaccinations against influenza are usually made available to people in developed countries Farmed poultry is often vaccinated to avoid decimation of the flocks. The most common human vaccine is the trivalent influenza vaccine (TIV) that contains purified and inactivated antigens against 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.

In virus classification influenza viruses are RNA viruses that make up three of the five genera of the family Orthomyxoviridae:
  • Influenzavirus A
  • Influenzavirus B
  • Influenzavirus C
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.

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: 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 16 H and 9 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.

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 either is 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.

Influenza virus shedding (the time during which a person might be infectious to another person) begins the day before symptoms appear and virus is then released for between 5 to 7 days, although some people may shed virus for longer periods. People who contract influenza are most infective between the second and third days after infection. The amount of virus shed appears to correlate with fever, with higher amounts of virus shed when temperatures are highest. 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 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 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 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'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 has been believed to also be a rare side effect of influenza vaccines. Although one review gives an incidence of about one case per million vaccinations, a large study in China, reported in the NEJM covering close to 100 million doses of vaccine against the 2009 H1N1 "swine" flu found only eleven cases of Guillain-Barre syndrome, (0.1%) total incidence in persons vaccinated, actually lower than the normal rate of the disease in China, and no other notable side effects; "The risk-benefit ratio, which is what vaccines and everything in medicine is about, is overwhelmingly in favor of vaccination." 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).

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 to refer to the disease we know today in 1703 by J. Hugger of the University of Edinburgh in his thesis De Catarrho epidemio, vel Influenza, prout in India occidentali sese ostendit. Archaic terms for influenza include epidemic catarrh, grippe (from the French, first used by Molyneaux in 1694 ), sweating sickness, and Spanish fever (particularly for the 1918 flu pandemic strain).

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.