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Influenza is a life threatening disease caused by influenza virus. Structure of the virus is spherical and the subtypes can be distinguished by the placing of RNA's. influenza virus has created many disastral events during twentieth century. Especially in 1918 the spanish flu has taken upto 60 billion lives only in USA. After 1918 it has shown its power again in 1957 and 1968 but these were not such horrible as 1918. These threats occuring frequently is due to mutational changes in the virus. Currently another threat, swine flu is creating pandemics and high mortality among all the people. To overcome these some powerful vaccine or drug has to be produced by our scientists.
Influenza is a common disease which can be seen commonly in the villages and small cities all over the world. Influenza got its name from Latin word 'Influentia' which means 'Influence'. Influenza is a highly acute infectious human pathogen mainly affects the respiratory tract in the upper part and is transmitted mainly by airborne respiratory droplets. It is caused by influenza virus which belongs to the family orthomyxoviridae. Globally every year 250,000 to 500,000 deaths are occurring due to influenza. It is bothering more than 60 billion Americans every year. It is affecting people of all ages and had a severe outbreak in the twentieth century (pandemics) resulting in the death of billions of people . Influenza firstly infects animals then mammals got affected easily due to less immunity towards it. Influenza virus is mainly divided into three types: A, B, C Ex: swine flu, seasonal flu, Avian (bird) flu. Influenza A virus infects mammals and animals like pigs, horses, birds etc., and causes disease. Influenza B virus cause disease by infecting only mammals but not animals where as Influenza C virus attacks only mammals and cause disease very rare.
The Orthomyxovirus means the affinity of viruses towards mucins. These viruses are pleomorphic, febrile and have an ability to adsorb mucoprotein receptors of RBC and causes hemagglutination. Influenza virus is spherical shaped and has a diameter of 80 to 120 nm . It is enveloped with a helical nucleocapsid and the outer envelope is made up of lipoprotein. It mainly differs from paramyxoviruses in their RNA genome (segmented into eight pieces) . RNA of these viruses is single stranded with negative polarity. It contains RNA-dependent RNA polymerase. Tetrameric neuraminidase (NA) and hemagglutinin (HA) are the two types of spikes inserted into the lipid layer which are glycoproteins.
Fig.1: Influenza virus 
These proteins are situated at RNA4 and RNA6 and are mainly responsible to distinguish the types of influenza. Matrix protein, M1 is present below the lipid protein which gives strength and rigidity for the envelope. The RNA segments are the genes of influenza virus. These segments consist of proteins: PA, HA, PB1, NA, B1, PB2, NP, M1, M2 and NS1, NS2 . Sialic acid of the glycoproteins determines the type of influenza acting on it and can be explained by the amino acid presence on hemagglutinin protein at 226 position . Virus has an ability to undergo mutations by antigenic shifts and antigenic drifts and hence able to produce pandemics and epidemics.
Influenza is caused mainly by the influenza virus and it has an ability to mutate and develop different strains. Due to this, in the past even exposure to the same strains may not defend the new one. Recently a research was made by scientist Darwyn Kobasa in which H1N1 virus has been extracted from a dead person and resuspended into the monkeys. The results were quite unpleasant. Monkeys developed symptoms within 24 hrs and died of lungs damage . Actual cause for this situation is not the virus but the response of the body to infection. Immune system proteins and also RIG-1 gene are responsible for damage in the infected tissue and are found to be high in number after the H1N1 viral infection . After this experiment it is more worrying if changes in virus are seen, more lethal the situation will be.
Symptoms depend upon the severity of complications. Patients seem to be sick but it will be rarely complicated. Complication that is common in influenza is pneumonia.
For non-complicated influenza: Fever of 30-40°C. Myalgias, malaise, dry cough and headache . Ocular symptoms like tears, photophobia. Gastro-intestinal symptoms like vomiting and diarrhoea can be seen in H1N1 viral infection.
For pulmonary complications of influenza: Pneumonia caused by staphylococcus aureus. In young children Croup (acute laryngotracheobronchitis) is observed, which includes symptoms like cough and stridor . Patients with pulmonary or heart disease can easily show these complications (pericarditis).
For non-pulmonary complications: Reye's-syndrome-vomiting, sometimes result in coma. In children after influenza B virus myositis can be seen. Encephalopathy (Parkinson's disease). Guillain-Barre syndrome which is also called as acute idiopathic polyneuritis . Most of the deaths occurred are in the people aged over 65 and are due to cardiac and pulmonary failure. Substernal burning, otitis media are some of the symptoms.
As the symptoms of both cold and flu are similar, differentiation has to be done carefully for the further diagnosis and treatment. Specimens for laboratory diagnosis are throat or nasal swabs, sputum, throat or nasal swabs. Rapid diagnosis tests such as polymerase chain reaction (PCR) or cell culture-based tests, direct fluorescent antibody are performed. H7N7 viruses are diagnosed by PCR tests. Upper respiratory viruses and types of influenza affecting are differentiated by the fluorescent antibody tests and the strains can be differentiated by the viral cultures . Antigen detection can be done by two tests using monoclonal antibodies (QUICKVUE and FLU QIA influenza tests). For the detection of viral neuraminidase ZSTATFLU test is used . New techniques are mainly based on separation-free bio affinity assay technique in which competitive binding assay, serum antibodies and antigens are detected [21, 22]. Assay of antibody titer can be done by using complement fixation (CF) and hemagglutination inhibition .
Influenza virus is hard to control as it affects not only humans but also animals. 10,000 years ago at the ice age end influenza A virus was emerged . Pigs and chicken sometimes gets infected by more than one type of virus, a new virus strain is created by sharing the genetic information. This may lead to adverse effects on human because newer the strains, lesser immunity towards it . Most of the influenza epidemics seem to begin in the Asia; it is because of the closer contact of humans with the animals in the farms of rural areas. This close contact will transfer the virus between species and leads to a new form of virus. First pandemic influenza was occurred in 1580, which was originated from Asia then spread to Africa and Europe  where as the first influenza epidemic report was happened in 1173-4. Many reports showed that it is caused in the 14 and 15 century but the first report given by Molineux in 1964 was convincing . At early 18 century hike in the data is observed both in its quantity and quality. From the past two and half centuries 10-20 pandemics of influenza have occurred. Changes in the virus are due to the antigenic shift which creates a new subtype and results in the epidemics . In 1931 shope has isolated swine influenza A virus but the human influenza A virus has been discovered in 1933. This discovery led to enormous progress in the fields of virology and immunology .
Flu raises its activity between December and march and its activity is more in February month because of cold weather which is suitable for the survival of viruses and also easy spreading (fig.2). In fig.2 over past 21 years February is the peak time for flu activity for 9 years .
Fig.2: peak months for the activity of Flu 
In the last century three influenza pandemics has occurred. In 1918, Spanish influenza (caused by unusual virulent H1N1 virus) showed adverse effects on the people (fig.3). 675,000 people lost their lives within a year due to this virus in USA (fig.4) and the total toll death was 50 million . In US during 1918 influenza pandemic mortality of infants (age 1-4) and the old people who are above 80 is more. Fluctuations in the peaks of the graph are observed because people who got affected by 1918 influenza already have a partial immunity towards it as already they got infected to the 1889 pandemic. If not, in this situation mortality of the adults has to be more. In the recent cases infectious diseases like Human Immunodeficiency Virus are devastating over a long period.
Transmissibility of 1918 virus:
Influenza HA virus from the isolate of 1918 Southcarolina (SC18) binds to human receptor preferentially. An additional mutation to the avian consensus (AV18) of HA will reduce the binding ability of HA to the sialic acid linkage in human. While New York (NA18) amino acid differs by a single amino acid, it binds to avian and human receptors. SC18 is readily transmitted rather than AV18.
After 1918 the isolate of the virus is almost absent but in 1957, Asian influenza with two new proteins on the surface are observed (fig.3) . The N2 subtype neuraminidase has 37% of the overall affect on N1 subtype neuraminidase. After 39 years of H1N1 virus infection a little immune response in the humans has been observed. This cellular immunity is not enough for the new virus (H2N2 virus) which has affected several Americans in United States alone and killed up to 70,000 people .
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Fig.3:Â subtypes of influenza A virus present in human population
Three different hemagglutinin subtypes (H1, H2 or H3) and two neuraminidase subtypes (N1 or N2) of viruses are identified in humans. Introduction of the pandemic strains in different years are indicated by squares respectively. Similar strains of H1N1 virus (1950) are reintroduced in 1977. Broken lines indicate the absence of viral isolate absence and indirect evidence of strains that are circulated .
Life expectancy in both the races is increased along with age (fig.4). The graph shows that the life expectancy in 1900 was about 47 years and has increased gradually to76 in 2001 with respect to United states. Whereas a major dip in the life expectancy is observed at 1918, which was a result of 1918 pandemic.
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Fig.4:Â Life expectancy from 1900 to 2001 showing the impact of the 1918 influenza pandemic .
In 1968, virus (H3N3 virus) has changed its surface glycoprotein's and resulted in another high mortality. In this the HA gene encoding PB1 gene has been changed . Asian flu of 1957 and Hong Kong flu of 1968 are less severe compared to Spanish flu. Reappearance of H1N1 virus in 1977 has resulted death of people less than 25 years, as they lack immunity in prior. Avian flu in 1997 is spread to children from the chicken. Most of the chicken are slaughter but due to mutations it has recurred in 1999 . In 2007 antigenic drifts are only seen with respect to influenza B virus. Between 2006 and 2007 vaccines are created for the H1 and H3 strains which are trivalent.
National institute of health has funded a collaborative work of studies which led to a better understanding of 1918 and 1919 virus. This has done in collaboration with Mount Sinai school of medicine, Armed forces institute of pathology (samples from soldiers who died), CDC Atlanta, TSRI, Southeast poultry research laboratory, University of Washington. They have used reverse genetics to reconstruct the 1918 virus. 8 plasmids of viral RNA expression and 4 plasmids of protein expression are transfected together to form a recombinant influenza virus and are characterized .
In 2004 eight countries in Asia has reported H5N1 HPAI (Avian influenza) in poultry. By 2006 more than 60 countries has reported the cases of H5N1 virus. This virus has not only affected chicken but also wild birds and humans. In 2005 outbreak of H7N7 has been reported in Netherlands . Human H5N1 cases which are updated on January 12, 2007 have confirmed 159 deaths out of 265 cases and the fatality ratio was 50% [World Health Organisation].
Fig.5: mortality rate of influenza from 2003 to 2008 
The recent data regarding the cases, deaths and mortality rate of influenza are given in the fig.5. It explains that in 2006 the number of cases of influenza is more when compared to rest of the years.
Influenza A virus has 16 different subtypes which are observed and their ability to create epidemics are not known. Due to antigenic drift and shift re-infection has occurred in the 2006, 2007 years. Reoccurrence was happened with many other viruses such as: severe acute respiratory syndrome (SARS), West Nile, Nipah and Hendra . Current threat going on is because of the new strain of influenza H1N1 (swine flu) virus. WHO has given high alert phase of need of response in 2009 phase revisions . On May 4, 2009 WHO has confirmed that in 20 countries 286 cases are seen and this has come from Mexico. Current outbreak of influenza H1N1 virus (avian in origin) is alarming because gene segments of the virus are combined uniquely, which is not reported before in any swine cases . This swine virus is effectively transmitting between humans and the outbreaks in the community level are seen . Even the vaccine developed is not much effective as before and the people are partially protected as H1 viruses are still circulating.
Calculated data of WHO and the data from the official sources of pandemic Influenza viruses are shown in the table 1. Nationwide data has been taken from Australia, Canada and New Zealand regions .
Table.1: confirmed cases, deaths and rates of pandemic influenza per 100.000 inhabitants, 2009 
In the recent years 2009 and 2010 the activity of the influenza seems to get decreased gradually during the week 1 was almost 0% and is clearly explained in the graph (fig.6) . But in week 43 i.e., in 2009 end the test which are positive to influenza arealmost 55%.
INFLUENZA Virus Isolated
Fig.6: Reports of the positive tests done in the laboratories 
Apart from all these to overcome this outbreak WHO is organising a surveillance programme to detect new strains which are dangerous at the early moments. New isolates are submitted for further analysis. Normally a trivalent vaccine is used, which consists of: H3N2, H1N1 and a subtype of influenza A. Subtypes used are mainly antigenic diverse strains . Even pandemic plans are developed by WHO, most of the European countries has prepared objectives to alert medical, scientific groups in order to decrease the mortality and morbidity.
But the immunization strategies are not developed widely by any country because of two reasons. First, production capacity of the vaccine for the world is not enough to cover the antigenic changes of the virus. Second, production of vaccines in large scale may result in fast antigenic changes. New ranges of antiviral drugs are developed for the virus by X-Ray crystallography .
Within three or four days most of the people will recover from infection. If any symptoms as following observe, treatment is needed: Difficulty in breath taking, Pain in the chest region, lips discolouration, dehydration, vomiting. Duration of Flu is shortened by using:
Acetaminophen- gives relief for fever, headache and muscle pains.
Antiviral drugs like Oseltamivir (Tami flu), Rimantadine (Flumadine), Amantadine (Symmetrel) and Zanamivir (Relenza) are approved by FDA and can be used as they reduce the span and severity. First three are taken orally whereas Relenza has to be inhaled.
Recent studies on mice show that Oseltamivir protects it from the lethal 1918 viral challenge.
Aspirin and also medicines that include aspirin are avoided, as they may cause severe effects.
Zanamivir and Oseltamivir may cause side effects like difficulty in breathing and vomiting.
Antibiotics are not used except in the case of bacterial pneumonia and sinusitis.
Other than these many alternative treatments are present like homeopathy and herbal. Oscillococcinum is one of the homeopathic remedy which can reduce the duration of the virus .
Avoiding contact with new and infected people will primarily prevent flu infection. 500mg intake of vitamin c will also helps in preventing flu by strengthening immune system . Vaccination is the most important way to prevent viral infection. Flu vaccine can be administered in two forms: injection (Flu-shot: inactivated virus) and nasal spray (made of live attenuated influenza vaccine, LIAV) . Spray is used for the children aged 24 months and injection is used for adults
Seasonal vaccine for influenza- it is suitable for the people above age 50, pregnant, children and adults who have chronic conditions.
H1N1 swine influenza vaccine- pregnant women, health care workers are preferably vaccinated first as they are more susceptible to H1N1 swine flu. Generally vaccination is done at September of every year due to vary of levels in timing . H1 vaccine works by using neuraminidase and hemagglutinin of 1918 virus. Immunization is done by challenging mice with 100LD50.
Mammalian cells like Vero and MDCK are utilized to produce vaccines by new technologies .
But the vaccines will have side effect like soreness at injecting site.
Influenza has created many disastrous events in 1918, 1957 and 1968. It clearly explains that the chance of reoccurrence of the virus is more and vaccines or anti-virals which are effective against the virus has to be produced within a short span of time, as there is a threat coming on in the future. Scientists approach towards the virus seems to be poor where as molecular virology has reached its maximum by using reverse genetics. But the information givn by human genome project reveals that almost 30,000 genes are present in producing acquired and innate immunity which may assure that some kind of protection can be created against viruses. Observations from the threatening viruses inform us to broaden the vigilance epidemiologically by building infrastructure regarding health of the public. Influenza is said to be a weapon for the bio war, as it may create disastrous events than First World War and an atomic bomb can. But greatest bioterrorist of our world is nature and many efforts have to be expanded for public health. From a saying of Yogi Berra, "It is very hard to make predictions, specifically about future". Many people are still putting their efforts to develop new antivirals, vaccines which are not only against seasonal influenza but also on the potential threat of pandemic influenza. Hopefully in the next couple of years or decades virus of influenza are cured.