The influenza or flu infection is caused by a highly infectious virus. It spreads through the air, multiplies in cells lining the airways. Influenza is viral infections which can affect both the upper and lower respiratory tract and it mainly affect the nose, throat and bronchi. Influenza is highly contagious respiratory disease that spreads from person to person by sneezing and coughing. Comparison to the most viral respiratory infections, it is found that the symptoms of influenza infection are very severe. It is a seasonal infection; the spread of infection is usually in the winter and will last several weeks. It infects an estimated 100 million people in America, Europe, and Japan (approximately 10% of the population). About 600 people per year die in UK from seasonal flu and this number rises toÂ around 13,000Â during an epidemic (www.nhs.uk).In addition to that, it prevents millions of people from performing their jobs or going to the schools.
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All influenza viruses are same among the viruses which cause respiratory infection with regard to their antigenic variability, seasonality and impact on the general population. They can cause explosive outbreaks of respiratory illness across all age groups (Richman et al., 2009)
Influenza infection is caused by a member of viruses which belong to the family Orthomyxoviride, (orthos in Greek means straight and myxa in Greek means mucus). Influenza is an extremely changeable, fast-mutating virus. There are three main types, or genera: Influenza virus A, Influenza virus B, Influenza virus C and 'thogoto-like viruses' which do not infect human. Influenza A is considered here which is also known as avian influenza (Collier et al., 2006).
Influenza virus A causes the most severe form of influenza. It mutates 2-3 times faster than Influenza virus B and is responsible for most large pandemics. Influenza A virus is characterized by eight-segmented, negative (-) strand RNA genome. These virions are roughly 100-200 microns in diameter and are more or less spherical. The classification of influenza virus A based on variations on two proteins found on the virus surface. Hemagglutinin, a glycoprotein present on the viral surface as rod-shaped projections, abbreviated HA and has 16 types. It has the ability to agglutinate erythrocytes and enhance the attachment and penetration of the virus to the receptor of the cells, the other type of glycoprotein is neuraminidase, abbreviated NA and has 9 subtypes. About 80% of them are HA and the ratio of HA to NA is about 4-5 to 1. The most significant subtypes that can cause extensive outbreaks in human are H1N1, H1N2, and H3N2 viruses (Richman et al., 2009)
The sub-types of viruses that cause avian influenza, which has infected human and resulted in the numbers of deaths:
1 - 1918 (H1N1), which caused the Spanish flu.
2 - 1957 (H2N2), which has caused the Asian influenza.
3 - 1968 (H3N2), flu, which has caused Hong Kong.
4 - 1976 (H1N1), swine flu episode
5 - 1977 (H1N1), Russian flu
6 - 1997 (H5N1), South-East Asia, died tens of millions of birds caused by this strain.
7 - 1999 (H9N2), bird flu in Hong Kong.
8 - 2003 (H7N7), bird flu in Netherland
9 - 2004 (H5N1), bird flu in South-East Asia
10 - 2009 (H1N1) virus, which is a pandemic in our times (H1) derived from the swine flu of 1930 (and related to the H1 of the great 1918 Spanish flu) and (N1) from a virus that had been circulating in the pigs of Europe and Asia since 1979 along with the M gene from that virus (Riel et al., 2007).
The natural hosts for influenza a virus are the birds that live in water or they are called aquatic birds. Also different mammals can be hosts for this virus such as humans, horses and pigs.
Antigenic variation is the mechanism by which the influenza changes the hemagglutinin (HA) and neuraminidase (NA) proteins in order to evade the immune system and cause re-infection as the immune system will not recognize them. This process occurs in two ways as either antigenic drift or antigenic shift.
Antigenic shift is the genetic change between two different strains of influenza a, and results in a new strain. This change leads to change in pathogen, which results in modification of antigenic epitope. Antigenic shift enables the influenza strain to jump or spread from one animal to another, including the humans. For example, if one strain can infect humans only and another can infect birds only, the genetic change between these two strains will result in a new strain which can infect both humans and birds. The HA antigen is always involved in antigenic shift as it is responsible for eliciting virus-neutralizing antibodies. It causes a pandemic because there is no pre-existing immunity in humans. (Schweiger et al., 2002).
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Antigenic drift is a gradual and small change that happen through the mutation in the two genes which contain the genetic materials in order to produce the surface proteins (HA & NA). This occurs continually over time and results in minor changes to the surface proteins. This change can produce new strain of influenza a virus which may not be recognized by the body immune system. This is one of the main reasons why people can get the flu more than one time. This causes the seasonal epidemics (Schweiger et al., 2002).
The influenza A virus contains eight-segmented, negative (-) RNA as its hereditary materials. It replicates by entering the host cells (adsorption) and using this cells as resources to produce hundreds copies of viral RNA.
After attachment to the specific receptors on the surface of the host cells, the hemagglutinin (HA) binds to the sialic acid (important part of the receptor) on the receptors surface and the virions enter into the cells by endocytosis. The neuraminidase plays a critical role in viral replication by removing sialic acid which also known as neuraminic acid from the surface of cell. That makes the cell do not have functional receptors, that allows the virions not to stick to each other or to the cells that they have invaded. Therefore, they will be able to spread away from the cell and invade anther cell. Viral multiplication starts in the cytoplasm. The virions are transported to endosome due to the acidic environment of the host cell. In this low pH environment, the ribonucleoprotein (RNP) is released from antigenic protein which lines the inside of the envelope, it is called the matrix protein (MP 1). So the viral RNP is released into the cytoplasm by the viral lipoprotein envelope and it is transported into the nucleus (Collier et al., 2006).
The mRNA synthesis and replication take place in the nucleus with assistance of the viral RNA-dependent RNA polymerase. The viral RNA polymerase uses the nucleocapsids as a template and it does not need a fully uncoated nucleocapsids. Since this virus is a negative-strand RNA, RNA modification enzymes and RNA polymerase are packaged in the virion. So the viral genes are transcribed and translated (to give viral proteins) by the cell's enzymes and ribosome, that makes the viruses take over the cell productivity and instead of producing the cellular materials only, the cell will produce hundreds copies of viruses. These viruses will be released out from the host cell and they start invading a new host cell by their own (Korteweg et al., 2008).
Influenza infection is seasonal infection because the spread of infection usually occurs in the winter and will last for weeks. Influenza A infection is a significant cause of morbidity and mortality. Global epidemiology of influenza occurs unexpectedly, and is infected 50% of the population, leaving millions of dead in the world. Epidemiology global event in 1918 caused the death of 20-40 million people around the world which more than people who killed in world war I (Kleinman et al., 2008).
As known, influenza A virus is the most serious type which characterized by the most acute symptoms. It is also the most common form, because it usually breaking out every two or three years. Influenza virus type A spread among the many animals, including ducks, chickens, pigs, whales, and horses. Somehow, some minor species of the virus strains are limited to animals alone, but in the offspring of birds and subjected to infection with all kinds of influenza virus A (Richman et al., 2009). Avian influenza type A can be transmitted to humans in two ways: Directly from birds or contaminated environments to humans and through an intermediary host such as pigs (Collier et al., 2006).
Influenza A virus can be transmitted between humans in three different ways: through contact with infected persons, by contact with contaminated object and inhalation aerosol contains virus. The virus is inhaled through the nose or mouth and reaches the respiratory tract cells, which begins to multiply. The patients with influenza can infect other people, one day before they develop any symptoms and up to 5 days after becoming sick. That means these patients may infect or pass the influenza infection to someone else before they know that they are infected or sick (www.cdc.gov)
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The exact details of the pathogencity of influenza virus in human are not completely understood. The hemagglutinin glycoprotein is the major determinate of virulence and plays a critical role in pathogenesis of influenza.
The initial site of influenza infection is the upper respiratory tract mucosa. The virus multiplies in the epithelial cells in the nose and sinus passages and destroys the most important element in defence which are the cilia. The virus replicates in both upper and lower respiratory tracts (Greenwood et al,. 2007).
The time between the real infection and the appearance of symptoms is known as the incubation period. The duration of virus shedding in respiratory secretions is generally 2 to 3 days during uncomplicated influenza in adult and older children. Longer period of virus shedding which takes 1 to 2 weeks, are commonly seen in infants and children and prolonged period of virus shedding can be seen in patients with immunodeficiency (Richman et al., 2009).
The virulence and pathogencity of the influenza virus can be identified by two major factors which are host and viral factors.
Enzymes should be available in the cell host in order to help the viral entry and replication.
The target receptors must be present on the surface of the host cell.
Immunocompetence State of each host.
Specific immunity against certain viral epitopes in the host.
Ability of the immune system to control the viral replication effectively without causing serious damage for the host by its inflammatory response (Nagata et al., 2008)
Following the incubation period of 2-3 days, the typical symptoms of influenza start to appear. The flu is characterised by rapid onset of respiratory and generalised symptoms and sings including, myalgia (pain in muscle), shivering, marked fever, limbs and back pain, dry cough, malaise and dry tickling throat. In addition to that, the patient also may have abdominal cramps, diarrhoea and vomiting (more common among children than adult) (Collier et al., 2006)
During pandemic influenza, these symptoms can be caused by either a pandemic influenza or seasonal flu (non-pandemic). Most patients who get the influenza recover completely in one to two weeks, but some people develop serious medical complications, such as pneumonia (Walsh et al., 2002)
The infection with influenza a viruses, makes the immune system of the human body to produce antibodies against the strain of virus that has invaded the body. This immunity is stimulated by the responses of the host cell against virus hemagglutinin (HA) and neuraminidase (NA). So the antibody (anti-NA) produced against HA, is the most important molecules in defending or protection against the influenza viruses. The anti-NA prevents the release of new virus from the host cell. In addition to that, the hemagglutinin inhibition (HI) decrease the spreading of the virus and reduce the infection severity and that makes it more important in determining immunity than anti-NA (Kash et al., 2005). Following the primary infection in children, the hemagglutinin inhibition (HI) and anti-NA antibodies develop within 10 day and persist for years and in adult the antibodies are present within the first week (Richman et al., 2009).
During the vaccination, the vaccine must contain both HA and NA antigens which will stimulate the immune system to produce the neutralizing antibodies in order to provide a good protection against influenza a infection (Kash et al., 2005)..
The differentiation between flu and cold is very difficult on the basis of the symptoms alone because symptoms of cold are nearly same to those of flu but it always less severe than those of the flu. In this case the doctor examination is needed in order to tell whether the patient has developed flu or a flu complication. So the diagnosis of influenza infection is made on the evidence of the characteristic clinical picture, backed up by the knowledge that an outbreak is in progress (Majury et al., 2006)
Virus culture, is one of very useful method used in the diagnosis of influenza A and it provides results in 2 to 10 days. That is done by isolating the influenza viruses and that can be done using different specimens such as sputum, nose swab, throat swab and nasal aspirate. It is reported that nasal washing is the best specimens for isolation of virus. Two types of viral cultures are used which are embryonated egg culture and cell culture (Dwyer et al., 2006).
Rapid test (antigen detection) is used to detect the influenza antigens in the respiratory secretion within hours, but it will not differentiate between the types of influenza. There are several types of rapid tests which can be used to detect the influenza and these tests are very helpful in ruling out or confirming the influenza . Many of these tests can give results in less time, but they vary on the specific strains of influenza viruses and they are not accurate as a viral culture. This method has been accomplished by enzyme immunoassay (EIA), radioimmunoassay, immunofluorescence (IF) and time-resolved fluoroimmunoassay (Richman et al., 2009). The viruses can be identified by using the immunofluorescence staining to stain the cells present in the nasopharyngeal aspirate specimen
Reverse transcription polymerase chain reaction (RT-PCR) is a very powerful technique used to identify the genome of the virus. Since the influenza a virus genome is single-stranded RNA, it should be converted to complementary DNA (cDNA) in order to start the amplification of the viral genome. This is done by using reverse transcriptase (RT) polymerase and primers of known HA sequence. PCR allows the exponential amplification of small amounts of nucleic acid and that gives a highly sensitive detection of very small amounts of virus genome (Steininger et al., 2003).
Serology tests are used to detect the antibodies produced against influenza viruses in the serum or other body fluids. These tests can detect the total antibodies or specific antibodies like IgG, IgA and IgM. The detection of influenza-specific IgG antibody is not diagnostic of recent infection (Dwyer et al., 2006)
Influenza types detected
Time for results
A & B
NP swab, throat swab, nasal wash, bronchial wash, nasal aspirate, sputum
DFA Antibody Staining
A and B
NP swab2, nasal wash, bronchial wash, nasal aspirate, sputum
A and B
NP swab, throat swab, nasal wash, bronchial wash, nasal aspirate, sputum
A and B
paired acute and convalescent serum samples6
2 weeks or more
Enzyme Immuno Assay (EIA)
A and B
NP swab2 , throat swab, nasal wash, bronchial wash
Different types of avian influenza virus may cause different symptoms and that makes the treatment vary for each type according to the symptoms. There is no effective treatment for influenza A because the antibiotics (antiviral) do not kill the viruses, but it may make the disease less severe.
The drugs or the antibiotics that are used in influenza A infection are two types Adamantanes (amantadine and rimantadine) and Neuraminidase Inhibitors (zanamivir and oseltamivir):
Amantadine (Symmetrel, trade name) is type of adamantanes and is effective against influenza A only, and some of the influenza A strains which are naturally occurring like H5N1, are resistant to this antibiotic. The exact mechanism of action of amantadine is not known and it is thought that it interferes with viral uncoating inside the cell (Jefferson et al., 2006).
Rimantadine (Flumadine, trade name) is similar to amantadine but it has less side effect (less toxic). Rimantadine is not more effective like amantadine, so it can be used only for uncomplicated influenza A (Moscona, A. 2005).
Zanamivir (Relenza, trade name) is known as neuraminidase inhibitors that help to prevent influenza A and B from multiplying, by interfering with the release of progeny (new release of virus) influenza virus from infected host cells, this process will prevent new host cells from the infection and thereby stops the spread of infection in the respiratory tract, airways and lungs. Zanamivir was the first neuraminidase inhibitor available for clinical use and it must be given to the patient by inhalation. This type of drugs should be given as early as possible because the influenza virus replication in the respiratory tract reaches its peak between 24 and 72 hours after the onset of the illness and this drugs work or act at this stage (Moscona, A. 2005).
Oseltamivir (Tamiflu, trade name) is another type of neuraminidase inhibitors and it is similar to zanamivir. The only difference is that oseltamivir can be given orally (Moscona, A. 2005).
PREVENTION AND CONTROL
Influenza A is one of the highly infectious diseases that cause respiratory disease and death every year. It is preventable. There are three possible ways to control or prevent influenza infection: vaccination, anti-viral and non-medical interventions. The single best way to protect against influenza is to get vaccination. Also infection can be prevented by disease control steps that to be followed by everyone during pandemic influenza or seasonal influenza (Collier et al., 2006).
Washing hands by using water and soap or alcohol swap.
Covering nose and mouth while coughing.
Discard the tissue after use in dust pin and wash hands.
Avoid close contact with people with influenza symptoms.
Avoid being in poorly ventilated and crowded places for long time.
Maintaining good health by eating nutritious food .
Avoid sharing things with other people like glass, napkins, handkerchiefs and towels (www.cdc.gov).
influenza a virus infection is one of the most dangerous disease and it leads to the acute development of a febrile respiratory illness. It is a major public health threat which kill hundred thousands of people every year and sickening millions of people. Novel influenza virus strains appear periodically to which humans have little immunity, resulting in devastating pandemics. There have been many achievements in the development of influenza vaccines and antiviral medications to prevent and treat influenza, and there are systems in place to give early warning for the occurrence of pandemic viruses.