Influenza

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Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae (the influenza viruses), that affects birds and mammals. The name influenza is Italian and means "influence" (Latin: influentia). The most common symptoms of the disease are chills, fever, sore throat, muscle pains, severe headache, coughing, weakness/fatigue and general discomfort.^[1] Sore throat, fever and coughs are the most frequent symptoms. In more serious cases, influenza causes pneumonia, which can be fatal, particularly for the young and the elderly. Although it is often confused with other influenza-like illnesses, especially the common cold, influenza is a much more severe disease than the common cold and is caused by a different type of virus.^[2] Influenza may produce nausea and vomiting, particularly in children,^[1] but these symptoms are more common in the unrelated gastroenteritis, which is sometimes called "stomach flu" or "24-hour flu".^[3]
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.^[4] Influenza viruses can be inactivated by sunlight, disinfectants and detergents.^[5][6] 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 hundreds of thousands worldwide annually, and millions in pandemic years. On average 41,400 people died each year in the United States between 1979 and 2001 from influenza.^[7] 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.^[8] 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.^[9]
Vaccinations against influenza are usually given to people in developed countries^[10] and to farmed poultry.^[11] The most common human vaccine is the trivalent influenza vaccine (TIV) that contains purified and inactivated material from three viral strains. Typically, this vaccine includes material from two influenza A virus subtypes and one influenza B virus strain.^[12] The TIV carries no risk of transmitting the disease, and it has very low reactivity. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus evolves rapidly, and new strains quickly replace the older ones. Antiviral drugs can be used to treat influenza, with neuraminidase inhibitors being particularly effective.

Classification

 

Types of influenza virus

 

In virus classification influenza viruses are RNA viruses that make up three of the five genera of the family Orthomyxoviridae:^[13]

• 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,^[14] but can also cause a disease similar to influenza in adults.^[15]

Influenzavirus A

This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics.^[16] The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses.^[17] The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

• H1N1, which caused Spanish flu in 1918, and the 2009 flu pandemic
• H2N2, which caused Asian Flu in 1957
• H3N2, which caused Hong Kong Flu in 1968
• H5N1, a current pandemic threat
• H7N7, which has unusual zoonotic potential^[18]
• H1N2, endemic in humans and pigs
• H9N2
• H7N2
• H7N3
• H10N7
  

Influenzavirus B

This genus has one species, influenza B virus. Influenza B almost exclusively infects humans^[17] and is less common than influenza A. The only other animals known to be susceptible to influenza B infection are the seal^[19] and the ferret.^[20] This type of influenza mutates at a rate 2–3 times lower than type A^[21] and consequently is less genetically diverse, with only one influenza B serotype.^[17] 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.^[22] 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.^[23]

Influenzavirus C

This genus has one species, influenza C virus, which infects humans, dogs and pigs, sometimes causing both severe illness and local epidemics.^[24][25] However, influenza C is less common than the other types and usually only causes mild disease in children.^[26

Structure, properties, and subtype nomenclature

Influenzaviruses A, B and C are very similar in overall structure.^[28] The virus particle is 80–120 nanometres in diameter and usually roughly spherical, although filamentous forms can occur.^[29][30] 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.^[31] However, despite these varied shapes, the viral particles of all influenza viruses are similar in composition.^[31] 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.^[30] 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.^[31] For example, the influenza A genome contains 11 genes on eight pieces of RNA, encoding for 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1, PB1-F2 and PB2.^[32]
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.^[33] Thus, these proteins are targets for antiviral drugs.^[34] 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.^[35] 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.^[36]

Replication

Viruses can only replicate in living cells.^[37] Influenza infection and replication is a multi-step process: firstly the virus has to bind to and enter the cell, then deliver its genome to a site where it can produce new copies of viral proteins and RNA, assemble these components into new viral particles and finally exit the host cell.^[31]
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).^[38] After the hemagglutinin is cleaved by a protease, the cell imports the virus by endocytosis.^[39]
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.^[31] The viral RNA (vRNA) molecules, accessory proteins and RNA-dependent RNA polymerase are then released into the cytoplasm (Stage 2).^[40] The M2 ion channel is blocked by amantadine drugs, preventing infection.^[41]
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).^[42] The vRNA is either exported into the cytoplasm and translated (step 4), or remains in the nucleus. Newly synthesised viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell mRNAs.^[43]
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).^[44] 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.^[38] Drugs that inhibit neuraminidase, such as oseltamivir, therefore prevent the release of new infectious viruses and halt viral replication.^[34] 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.^[45] 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.^[35] This is important in the emergence of pandemics, as discussed below in the section on Epidemiology.

Signs and symptoms

Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from 38-39 °C (approximately 100-103 °F).^[48] 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.^[1] Symptoms of influenza may include:

• Fever and extreme coldness (chills, shivering, shaking (rigor))
• Cough
• Nasal congestion
• Body aches, especially joints and throat
• Fatigue
• Headache
• Irritated, watering eyes
• Reddened eyes, skin (especially face), mouth, throat and nose
• In children, gastrointestinal symptoms such as diarrhea and abdominal pain,^[49][50] (may be severe in children with influenza B)^[51]

It can be difficult to distinguish between the common cold and influenza in the early stages of these infections,^[2] but a flu can be identified by a high fever with a sudden onset and extreme fatigue. Diarrhea is not normally a symptom of influenza in adults,^[46] although it has been seen in some human cases of the H5N1 "bird flu"^[52] and can be a symptom in children.^[49] The symptoms most reliably seen in influenza are shown in the table to the right.^[46]
Since antiviral drugs are effective in treating influenza if given early (see treatment section, below), it can be important to identify cases early. Of the symptoms listed above, the combinations of fever with cough, sore throat and/or nasal congestion can improve diagnostic accuracy.^[53] Two decision analysis studies^[54][55] suggest that during local outbreaks of influenza, the prevalence will be over 70%,^[55] and thus patients with any of these combinations of symptoms may be treated with neuraminidase inhibitors without testing. Even in the absence of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the prevalence is over 15%.^[55]
The available laboratory tests for influenza continue to improve. The United States Centers for Disease Control and Prevention (CDC) maintains an up-to-date summary of available laboratory tests.^[56] According to the CDC, rapid diagnostic tests have a sensitivity of 70–75% and specificity of 90–95% when compared with viral culture. These tests may be especially useful during the influenza season (prevalence=25%) but in the absence of a local outbreak, or peri-influenza season (prevalence=10%^[55]).

Mechanism

 

Transmission

 

People who contract influenza are most infective between the second and third days after infection, and infectivity lasts for around ten days.^[57] Children are much more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection.^[57][58] The transmission of influenza can be modeled mathematically, which helps predict how the virus will spread in a population.^[59]
Influenza can be spread in three main ways:^[60][61] 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.^[4][62] 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.^[60] Although a single sneeze releases up to 40,000 droplets,^[63] most of these droplets are quite large and will quickly settle out of the air.^[60] How long influenza survives in airborne droplets seems to be influenced by the levels of humidity and UV radiation: with low humidity and a lack of sunlight in winter probably aiding its survival.^[60]
As the influenza virus can persist outside of the body, it can also be transmitted by contaminated surfaces such as banknotes,^[64] doorknobs, light switches and other household items.^[1] 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.^[65] However, if the virus is present in mucus, this can protect it for longer periods (up to 17 days on banknotes).^[60][64] Avian influenza viruses can survive indefinitely when frozen.^[66] They are inactivated by heating to 56 °C (133 °F) for a minimum of 60 minutes, as well as by acids (at pH <2).^[66]

Prevention

Vaccination

Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as children and the elderly, or in people who have asthma, diabetes, heart disease, or are immuno-compromised. Influenza vaccines can be produced in several ways; the most common method is to grow the virus in fertilized hen eggs. After purification, the virus is inactivated (for example, by treatment with detergent) to produce an inactivated-virus vaccine. Alternatively, the virus can be grown in eggs until it loses virulence and the avirulent virus given as a live vaccine.^[35] The effectiveness of these influenza vaccines are variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. Every year, the World Health Organization predicts which strains of the virus are most likely to be circulating in the next year, allowing pharmaceutical companies to develop vaccines that will provide the best immunity against these strains.^[79] 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.^[80]
It is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few specific flu strains but cannot possibly include all the strains actively infecting people in the world for that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003–2004 flu season).^[81] It is also possible to get infected just before vaccination and get sick with the very strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.^[82]
The 2006–2007 season was the first in which the CDC had recommended that children younger than 59 months receive the annual influenza vaccine.^[83] Vaccines can cause the immune system to react as if the body were actually being infected, and general infection symptoms (many cold and flu symptoms are just general infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza. The most dangerous side-effect is a severe allergic reaction to either the virus material itself or residues from the hen eggs used to grow the influenza; however, these reactions are extremely rare.^[84]
In addition to vaccination against seasonal influenza, researchers are working to develop a vaccine against a possible influenza pandemic. The rapid development, production, and distribution of pandemic influenza vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame between identification of a pandemic strain and need for vaccination, researchers are looking at non-egg-based options for vaccine production. Live attenuated (egg-based or cell-based) technology and recombinant technologies (proteins and virus-like particles) could provide better "real-time" access and be produced more affordably, thereby increasing access for people living in low- and moderate-income countries, where an influenza pandemic may likely originate. As of July 2009, more than 70 known clinical trials have been completed or are ongoing for pandemic influenza vaccines.^[85] In September 2009, the US Food and Drug Administration approved four vaccines against the 2009 H1N1 influenza virus (the current pandemic strain), and expect the initial vaccine lots to be available within the following month.^[86]

Infection control

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^[87]; frequent hand washing (with soap and water, or with alcohol-based hand rubs)^[88]; covering coughs and sneezes; avoiding close contact with sick people; and staying home yourself if you are sick. Avoiding spitting is also recommended.^[89]
Although face masks might help prevent transmission when caring for the sick,^[90][91] there is mixed evidence on beneficial effects in the community.^[89][92] Smoking raises the risk of contracting influenza, as well as producing more severe disease symptoms.^{[93][94][95][96][97]} Thus, according to the laws of mathematical modelling of infectious diseases, smokers raise the exponential growth rates of influenza epidemics and may indirectly be responsible for a large percentage of influenza cases.
Since influenza spreads through both aerosols and contact with contaminated surfaces, surface sanitizing may help prevent some infections.^[98] 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.^[99] In hospitals, quaternary ammonium compounds and bleach are used to sanitize rooms or equipment that have been occupied by patients with influenza symptoms.^[99] At home, this can be done effectively with a diluted chlorine bleach.^[100]
During past pandemics, closing schools, churches and theaters slowed the spread of the virus but did not have a large effect on the overall death rate.^[101][102] 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.^[89] When small numbers of people are infected, isolating the sick might reduce the risk of transmission.^[89]