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Influenza or flu as commonly known is one of the emerging infectious diseases. It is a contagious respiratory disease caused by influenza virus which is an RNA virus. New strains of the influenza virus are continuing to appear giving rise to yearly epidemics. Some of the suddenly appearing strains are totally new to human's immune system and that is the cause of the pandemics which may sometimes be disastrous. (Robert,1998, Online). The most serious human pandemics are caused by influenza A virus. It causes the most virulent infection in humans.
The Influenza Virus
Influenza is caused by an RNA virus from the family Orthomyxoviridae. This family includes 4 genera: influenza A, B, C and Thogovirruses (Greenwood, 2002). We are going to talk about the genus influenza A, as this is the one that causes pandemics in addition to epidemics. This genus comprises of one specie, Influenza A virus. This specie infects many host species including birds and mammals like swine, horses, dogs, cats and humans.
Figure structure of influenza virus virion. Adopted from/www.wvdhhr.org/The virion of the influenza A may be either spherical measuring 80-120 nm in diameter or filamentous but the spherical shape is more common. The genom is found in the centre of the virion. It consists of 8 segments of single stranded RNA. All these are surrounded by an M1 protein capsid which is then enveloped by a lipid layer derived from the host cell. There are three projections on the surface of the envelope. From the M2 protein projects some iron channels allowing changes in the endosome. The other two spikes project from the envelope itself and these are haemagglutinin and neuraminidase. These are type determining antigens used to specify different strains of influenza A virus. There are 16 different H antigens starting from H1 to H16, and 9 different N antigens (N1- N9). Different combinations of H and N antigen give the different strain names like H3N2, H1N1 and H1N2. There are other factors which are important in the full nomenclature. These include influenza group, the place and year first isolated and finally the strain. For example, A/Phillipines/82/H3N2 .(Mims,2004, p227)influenza_projections.jpg
Like all other influenza viruses, this virus undergoes genetic changes while spreading from host specie to another. These are known as;
Antigenic drift; this is slow series of mutations happening over a long period of time leading to gradual change of the virus. These mutations take place in the antigenic binding site resulting in a new strain of virus that can't be inhibited by the antibody produced against the previous strain. This is a common feature between influenza A and influenza B. (Richman et al.,2002,p.899).
Antigenic shift; this feature is the one that makes Influenza A virus unique in the way it causes sudden pandemics. This is a sudden major change in the H and N antigens. It occurs when two different strains infect the same cell then a recombination between the strains take place. The resulting strain is totally new to the immune system and may lead to pandemic spread.(Mims et al, 2004, p227)
Influenza virus is transmitted by direct contact with an infected person, touching objects contaminated by the virus or by inhaling aerosols carrying the virus.
Figure world map with cases of H1N1. adopted from gamapserver.who.int/mapLibrary/app/searchResults.aspxBecause of the complex genetic changes that occur in influenza, epidemics happen every year especially in the winter and autumn. The severity and spread of the epidemic differ according to the subtype causing it. In a year three to five million people develop the infection and 2500000- 500000 deaths are recorded worldwide (WHO,2010) According to the Canters of Disease Control and prevention, in the United States of America alone an average of 5-20% of the population gets flu each year. 200000 and more people get hospitalized because of flue and its complications.36000 people die for the same reason. (CDC,2010).Influenza causes pandemics also. One of the most serious pandemics of influenza A virus was the Spanish influenza that take place in the years 1918 and 1918. At that time 40-50 million people died to from the disease worldwide. This was caused by subtype H1N1. Another major pandemic was the Asian flu caused by H2N2 between the years 1954 and 1958. It caused deaths of about 69800 worldwide.(Green,2006). The last one is the 2009 flu or what was named as swine flu. This was first recognized in March 2009 in Mexico and the new strain of H1N1 caused the pandemic was first identified in April the same year. According to the World Health Organization weekly update report published at 11th of December 2009, more than 208 countries around the word reported laboratory confirmed cases and the total number of the deaths were 9596 worldwide. The last report from the WHO at 3rd of March 2010 showed the map in figure2. The map well shows that this pandemic affected almost the whole world and no less than one death was reported from most of the countries.GlobalSubnationalMasterGradcolour_20100103_weekly.png
This virus differs in the way it attaches to the host cell according to the strain and the host that it infects. The human influenza A virus recognizes receptors that contain sialic acid which are linked to penultimate sugar with an alpha2,6 linkage. In avian influenza strains the receptors contain alpha 2,3 linkage but in pigs both are present. The virus attaches to the cell receptors by its haemagglutinin and by the process of endocytosis it enters the cell. Once inside the cell, the change in the surrounding pH leads to the fusion of the haemagglutinin with the cell membrane. After that the virus releases its RNA and RNP to the cytoplasm of the infected cell then they are transported to the cell nucleus. In the nucleus, transcription of the viral RNA mulecules takes place and mRNA molecules are produced. New viral protein and viral RNA are then produced and these are then transported to the cell membrane and joined by H and N glycoprotein. At this stage, new viral particles are assembled and then released out of the cell by budding with the help of neuraminidase. Then these new viral particles are ready to infect new cells. (Greenwood, 2002)flu2life (1).gif
Figure . Influenza viral replication. Adopted from http://web.uct.ac.za
Transmission & Incubation Period
This virus is easily transmitted from person to person through the droplets emitted by an infected person when sneezing or coughing. Another person in the surrounding area will inhale the infected droplet. The fact that this person will get the infection depends on many things including the size of the droplet or aerosol he inhaled. Small sized droplets most of the times precipitate in the small airways and don't reach the alveoli.(influenza report, 2009). Close contact is required as this virus will not remain suspended in air. Transmission can also be by direct skin to skin contact or by touching contaminated surfaces. This is possible because this virus can survive in the environment for a long time especially in cold weathers. The incubation period for this virus ranges from 2 days up to 5 days and the patient can still be able to pass the virus to other people during these days. Children are more infectious and can spread the virus for a longer period of time. (Fabrice Carrat,et all ,2006)huge_23_116043.jpg
Entrance of the viral particles to the host; this starts when a person inhales the contaminated droplet, it enters its respiratory tract, and the virus starts to act on the columnar epithelial cells there. This will take place unless the viral particle passes all the defence mechanisms of the host. They include the mucus layer, the mucus producing glands and the cilia that cover the tract.
Binding to the host cells; the binding will take place between the receptors on the host cell and the haemagglutinin biding site
Viral replication; once the virus finds the correct receptor on the host cell it enters the cell and starts to replicate and make copies of it. The new viruses then do the same with the neighbouring cells.
Hypersensitivity; in the process of replication and when new influenza viruses are produced the infected cells get ruptured. When the lyses take place in the epithelial of the upper respiratory system, it causes the mucosal cells to become vacuolated and swollen leading to the hypersensitivity of the respiratory tract cells and production of more mucus. This is the cause of the common symptoms of runny nose, nasal congestion and cough.(Wilschut, et all, 2006,
Figure immune rsponse after influenza infection. adopted from www.influenzareport.com After the iterance of the virus to the body, two types of immune response take place. One is cellular immune response and the other is the more specific humeral immune response.image27.jpg
Cellular immune response; at the site of inoculation macrophages engulf the viral particle and after that represent some of the antigens of the virus to lymphocytes. Cytotoxic T lymphocytes are one of the cells that recognize the viral anrigens presented by the dendritic cells then they are activated. When cytotoxic T lymphocytes are activated, they lead to the process of killing of the infected cells. T helper lymphocytes also recognise the viral antigens on the surface of the dendritic cells and get activated. The activation of these cells lead to the production of cytokines which then help in humoral immune response.
Humoral immune response; B lymphocytes will also identify the viral antigens directly from the site of inoculation. Then with the help of the T lymphocytes and the cytokines produced from cellular immune response B cells will be activated hence produce specific antibodies against the invading influenza virus.
All these procedures will work together to stop the virus from spreading and start the healing process.
Usually influenza A causes upper or lower respiratory infections but sometimes may cause other complications due to secondary infections. The complications may be very serious in some group of people like the elderly, children, and people with other diseases. (Richman.et, al.2002, p.905). it is thought that the reason behind the increase number of deaths from heart disease is due to the fact that influenza is more at those times. The most common complication of influenza is Pneumonia. This may be caused by the virus itself or a secondary bacterial infection due to the weekend immune system of the patient. The viral pneumonia occurs usually after 5 days of infection. Some other less common complications include otitis media, toxic shock syndrome, inflammation of the heart muscle and convulsion resulting from fever. (Richman.et, al.2002, p.905). The normal symptoms of influenza A infection is always confused with common colds especially at the early stages. Influenza infection causes a sudden illness with systemic symptoms like;
Fever - Chills - Headache - Myalgia - Anorexia
The best samples for testing Influenza A virus are, nasopharyngeal swab, nasal swab and nasal wash or aspiration and the choice depends on the method of testing to be used. Sample must be collected within the first 4 days of illness.(CDC, 10) Some of the tests done to detect the disease include;
Viral culture; results from this test will be ready within 3-10 days
Immunofluorescence Antibody Staining. This is done to identify the virus on tissue culture or can also be performed directly on the sample.
Serology test to detect the specific strain causeing an outbreak. This is useful in epidemiology and vaccine production but this method may be not very sensitive. First, compliment fixation test are usually done to detect that the infection is A, B or C infection. Then other methods like neutralization assays or strain specific compliment fixation tests are used to identify the strain.(Greenwood, et all, 2004, p 472)
Reverse transcriptase-PCR to detect Influenza RNA. This method maybe very useful but is not available in most diagnostic laboratories.
Figure Influenza A antigen rapid test kit. Adopted from quicking.en.alibaba.comRapid diagnostic test for influenza. These are commercially available test kits used to detect the results within few minutes. They are immunoassays detecting the viral antigen. The type of specimens used and the time needed to get the results depend on the kit used. These test are useful in places with allot people like hospitals where results are needed quickly to take actions like isolation of the patient from other patients.Influenza_A_Antigen_Rapid_Test_Kit.jpg
Adamantanes (amantadine and remantadine); these oral drugs are widely used as treatment and prophylactic agent against Influenza A virus. These drugs act on the viral envelop by blocking the ion channel and hence prevent the pH change. Subsequently, the viral particle will not be uncoated after the endocytosis to the cell. This drug is strictly used to treat Influenza A not B or C but it can also show resentence against some strains of A
Neuraminidase Inhibitors; these drugs inhibit the action of neuraminidase and thus prevent the virus from getting out of the cell by budding after reproduction. They can reduce the duration of the disease by 1-3 days if given in the early days of the onset of disease. .(Greenwood, et all, 2004, p 474) There are two forms of these drugs;
Zanamivir. This is given as dry powder to be inhaled for 5 days.
Oseltamivir. This is what is known as Tamiflu and its an oral drug given twice daily for 5-7 days.
These drugs were proved to be used for treatment and as prophylaxis but some mutated strains showed resistance to them. For example, it was reported in the Pandemic H1N1 briefing of the WHO published on December 2009 that two clusters of patients infected with Oseltamivir resistant H1N1 were found. One was from Wales UK and the other from North Carolina in the US. Both clusters were from hospital words with immune-compromised patients.(WHO,2010)
Prevention and control
Influenza Vaccines. The seasonal vaccine is an annual vaccine that it produced from a combination of two influenza (H1N1 and H3N2) viruses and one influenza B. The strains to be used each year are recommended by WHO Global Influenza Surveillance Centre and 250 million doses of influenza are produced annually.(WHO,2010) The vaccine is made in two forms;FLUMIST.jpg
Flu Shot; this is made by using killed form of the three virus strains and given as injections.
Figure ;Flu nasal spray. Adopted from www.stuttgart.army.milNasal spray; in this one the virus strains are alive but weakened so that they don't cause much flu symptoms.
The annual influenza vaccine is recommended for certain groups of people which include elderly, young children and people with low immunity and who have a chance of developing serious complications if they caught influenza.
Both these vaccines and what is known as pre-pandemic vaccines are different from the vaccines made for the pandemic causing influenza viruses. The pandemic influenza vaccine is made only after the pandemic have started and the virus is isolated. The period from the start of the pandemic to the day when the vaccine might be ready may be between 4 to 6 months.(WHO,2007)
Non-pharmacologic interventions; these may include simple hygiene measures like appropriate hand washing and improved respiratory hygiene all the times to avoid spread from one person to another. In cases of pandemics CDC recommended some other means of reducing the spread such as closing schools, using respiratory protectors like masks and avoiding gathering and crowded places.(CDC, 2007)
Conclusion and future outlook
Influenza is one of the major causes of mortality and morbidity worldwide for many years now. The virus continues to evolve and new strains appear each year resulting in epidemics and sometimes pandemics. It remains a serious disease despite the availability of antivirals and diffirent vaccines, which are effective for most people. Although the vaccines used are helpful most of the times, new approaches are being developed. Specifically, cold-adapted live-virus vaccines, which have been used in millions of people outside the US, are now being considered for approval by the FDA. Other second-generation live-virus vaccines are being designed and tested in animals and are waiting to be studied in humans. Major improvements, based on novel adjuvants and recombinant DNA techniques, are looking forward to change the view of vaccinology against influenza.