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As it is known to everyone, the influenza is a worldwide infectious disease and very familiar to those people who are living in small villages or in very big cities. The influenza or the flu as it usually referred is caused by RNA viruses which belong to Orthomyxoviridae family. These viruses affect mammals and birds as well. The influenza is typically transmitted through the air by sneezes or coughs creating virus containing aerosols. This is not the only way for influenza transmission but it could be also transmitted by nasal secretions or bird droppings if directly contact.
"influential " is a Latin word from where the virus gets the name and it means influence, as in the fourteenth century some Italians consider the distemper as flu was also known due to the adverse influence of the stars. Since more than two and half thousand years ago the ancient Greeks recognized it and this is according the available records.
In 419 BC, the forefather of the modern medicine (Hippocrates) described the flu symptoms. Some of the scientist believe that the influenza was caused by a bacterium originally but when the three English scientists came in 1933 Smith, Andrewes and Laidlaw, the thought was completely changed as they proved that this infection was instead caused by a virus.
Hundreds of thousands deaths are occurring worldwide every year because of influenza as it spreading in seasonal epidemics and millions of people in pandemic years.
They are three influenza viruses out of five genera of the family Orthomyxoviridae, influenza virus A, influenza virus B and influenza virus C which are only related to the human parainfluenza viruses and very common cause of respiratory infections in adults and children as they are RNA viruses belonging to the paramyxovirus family. Influenza virus C usually produces milder symptoms than influenza virus type A or B which are more sever and identical diseases essentially.
Influenza A is a genus of the Orthomyxoviridae family of viruses and it has only one species that is Influenza A virus which is single stranded, negative sense and encodes for 10 proteins at least. Several subtypes are there labelled according to H number (hemagglutinin) 16 different antigens (H1 to H16) and N number (neuraminidase) 9 different antigens (N1 to N9). From the wild birds, the strains of all influenza A subtypes have been isolated although the disease is not very common. Some of these isolates can cause very severe disease both in domestic poultry and quite rarely in the human beings. Sometimes the viruses which are transmitted from wild aquatic birds to the domestic poultry can ultimately cause an outbreak to the human beings influenza pandemics. Whereas, the influenza viruses of both human beings and avian can infect the swine populations.
Sometimes the variants are named according to the (host) the strain is adapted to or endemic in. Using this convention the main variants named are:
In chickens, the variants could be also name according to their deadliness in poultry,
Low Pathogenic Avian Influenza (LPAI).
Highly Pathogenic Avian Influenza or death flu (HPAI).
The virion of the influenza A (Figure 1) is
about 100 nm in diameter a globular particle
lipid bilayer sheathed
two integral membrane proteins in the lipid bilayer
some 500 molecules of hemagglutinin ("H") and
some 100 molecules of neuraminidase ("N")
Within the lipid bilayer are
8 pieces of RNA
around 3000 molecules of matrix protein
Each one of the 8 RNA molecules is associated with
some "non-structural" protein molecules of uncertain function
several nucleoprotein copies
many molecules of the three subunits of its RNA polymerase
Figure 1: Influenza A virion
Adapted from: http://www.virology.ws/2009/09/22/the-a-b-and-c-of-influenza-virus
In November 2009 several countries were exposed to very high pandemic activity of Influenza A virus like Italy. Norway, the Republic of Moldova, the Russian Federation (Urals region) and Sweden also reported very high activity. Bulgaria, Denmark, Finland, Germany, Iceland, Ireland, Lithuania, Luxembourg, Poland, Portugal, the Russian Federation, Serbia, Turkey and Ukraine reported high pandemic activity during this period. Although still high in some instances, influenza activity has passed its peak in Belgium, Iceland, Ireland and parts of the United Kingdom (England and Northern Ireland). In addition, 181 deaths in 21 countries were associated with laboratory-confirmed pandemic (H1N1) 2009 virus infection. This raises the total number of deaths reported in the WHO European Region since April 2009 from 471 to 652 (WHO 2009)C:\Users\Naji.Naji-PC\Desktop\transmission_swine_influenza_flu_virus_a_h1n1_through_species.jpg
Figure 2: Transmission of the influenza flu A virus through species
Adapted from: www.aht.org.uk/science_eqflu.html
As I've mentioned in the introduction, the virus can spread from one person to another via the aerosols which can get into the respiratory tract, and since it can survive for a short time it can be spread also via formats if the virus before loses its infectivity introduced into the nasal mucosa.
HA (haemagglutinin) protein
The virus protects its self by core of receptor binding site that is not exposed to the immune system. This protein structure is involved in attachment and membrane fusion in the infected cell. Combined with antigenic domains found on the surface the virus is able to alter these structures. These changes provide protective measure for the virus from specific immune response without affecting its ability to bind to the receptor.
Figure 3: HA (haemagglutinin) protein
Adapted from: www.medscape.com/viewarticle/551236_2
NA (neuraminidase) protein
The neuraminidase protein breaks down the cells surface particles sialic acid come and (part of the virus receptor) also it is involved in penetration of the mucus layer in the respiratory tract. Once bind to cells it will be internalized by late in infection, the sialic acid will have been removed from the infected cell surface by the neuraminidase making it is easier for the progeny virions to diffuse away once they exit the cell. Neuraminidase is also involved in penetration of the mucus layer in the respiratory tract.C:\Users\Naji.Naji-PC\Desktop\nri2054-f1.jpg
Figure 4: NA (neuraminidase) protein
Adapted from: www.nature.com /nri2054_F1.html
Antibodies to the HA protein are the most important in protection, although those to NA also play a role, both proteins undergo antigenic drift (i.e. accumulate mutations) and accumulate changes such that an individual immune to the original strain is not immune to the drifted one. The mutational Antigenic drift results in sporadic (occasional) outbreaks and limited epidemics (worldwide).
Figure 5: Antigenic drift
Adapted from: www.euro.who.int/influenza/AH1N1
Antigenic shift is due to reassortment for example in the case of influenza A, antigenic shift periodically occurs whereas the new HA and/or NA are exist in the circulating viral strains. There is little immunity (particularly if both proteins change, or if new HA is present) and an epidemic/pandemic is seen.C:\Users\Naji.Naji-PC\Desktop\Influenza_geneticshift.jpg
Figure 6: Antigenic shift
Adapted from: http://www.euro.who.int/influenza/AH1N1
The incubation period is quite short as it lasts for about 18 to 72 hours and for about one or two days after symptoms the concentrations of the virus will remain high in the nasal tracheal secretions. One small droplet of the aerosols can cause a new infection as the titration is very high usually.
The epithelial cells of the respiratory tract die due to the effects of the influenza virus or could be due to the effect of the interferon. This death could be also due to cytotoxic T-cells actions.
Symptoms and complications:
1. Uncomplicated influenza
Fever (38 - 40 degrees C)
Nasal discharge, dry cough
Tears, ocular symptoms - photophobia, ache
Vomiting, diarrhoea as in H1N1 strain "swine flu" in 2009
2. Pulmonary complications, sequelae:
acute laryngotracheobronchitis "Croup" in young children - symptoms include difficulty breathing, stridor, cough (like a barking seal)
Primary influenza virus pneumonia
Secondary bacterial infection: This involves Staphylococcus aureus, Hemophilus influenza, and Streptococcus pneumonia.
3. Non-pulmonary complications of influenza
Myositis , although it is quite rare and likely to be seen in children after influenza virus B infection
The table below shows some of the differences in symptoms between the common cold and the flu
Usually 100°F to 102°F, but can go higher and usually lasts three to four days
Usual, and often severe
Tiredness and weakness
Can last two or more weeks
Usual, at the beginning of the illness
Usual, and can become severe
Mild, hacking cough
Bronchitis, pneumonia; can be life-threatening
Sinus congestion, middle ear infection, asthma flare-up
Annual vaccination; antiviral medicines & see your doctor
Wash your hands often; avoid close contact with anyone with a cold
Adapted from: http://www.flumist.com/Understand-Flu/Cold-Flu-Symptoms
They are many factors which determine the influenza A virus pathogenicity and virulence and these factors are:
Host cells target receptors.
The immune system ability of control replication of the virus.
Presence of the enzyme in the host cells which is important for entry of the virus and for replication as well.
Individual host immunocompetence state
Individual host and target population viral epitopes Specific immunity
B. Viral factors:
Binding to host cells ability
Virus shedding ability.
Cytopathogenic effects restriction to ensure the balance between replication of the virus and control by the host.
Escape from immunosurveillance by evolution of antigenic variation driven by selective pressure of the immune response
Escape from immunosurveillance by recombination with different virus strains from zoonotic disease
Modulation of the immune response to attenuate effective host defense mechanisms
Influenza (flu) will go away within five to seven days in most healthy people. Home treatment is very important to prevent the complications and make the symptoms milder as the worst symptoms last for not more than 4 days usually.
Antiviral medication can help influenza A virus patients to:
Reduce the duration and the severity of the infection with influenza A virus.
Make the length of the illness shorter.
Reduce the flue complications.
Reduce the outbreaks of the flu.
Reduce the spread of the virus among high risk group.
As we have four drugs which currently available in treating influenza A virus infection, all of them are very active if taken within the first few hours of the symptoms onset. That is mean the sooner the better and this also will help in shorten the length of the illness and to modify the severity as well.
This antiviral is effective against influenza A virus only and it can significantly shorten the duration of the illness and the fever. This compound can give around 70 % protections against influenza A if given prophylactcally. Amantidine could induce mild neurological symptoms in some cases such as loss of concentration, mental disorientation or even insomnia occasionally. In addition to that, 200 mg Amantidine can be used as therapy for uncomplicated infections and the dose should be given for 5 days.
This antiviral is similar to Amantidine and it can be used for one year or older influenza A infection patients. Rimandtidine is recommended to be use to treat uncomplicated cases of influenza A patients as it is less effective than Amantidine.
This drug is very effective against both influenza A and B and it was the first clinical use neuraminidase inhibitor. Zanamivir should always be administrated by inhalation because of its weak bioavailability. In the clinical trials of this medication, Zanamivir had been shown to be free of significant side effects and effective drug also. However, this medication is approved to be used for 12 years old patients or older.
This medication is also neuraminidase inhibitor but it can be given orally. It has no significant side effects and also very effective medication just like Zanamivir. Therefore, it approved to be used as a treatment for 18 years old patients and above. Again this medication is attractive to the families as it is free of side effects and cheaper than Amantidine and Rimantidine.
According to all that, antiviral drugs could play a very essential role in the early stages of the diseases especially if the vaccine is not yet available or it is in short supply.
Laboratory Diagnosis of Human Influenza
Appropriate Specimen Collection
Pharyngeal swabs, nasopharyngeal aspirates and nasal washes are the main respiratory specimens to be used. The collection time of the specimens is very important and should also be transported in appropriate virus transport medium if the specimen is a swab and this to prevent desiccation of the specimen. If any transportation delay is expected, it is always recommended to transport on ice or (2-8) ËšC refrigeration.C:\Users\Naji.Naji-PC\Pictures\UTM_SidebySide_Swabs.jpg
Figure 7: Virus transport media
Adapted from: www.copanswabs.com
To determine the presence of influenza antibodies, blood specimen are collected for serology testing. It is always recommended to collect convalescent and acute samples to detect any significant rise in antibody titre.
They are many factors should be taken in consideration to decide which tests should be done. For example, test specificity, sensitivity, repeatability, and the time. According to the lab scientists the RT-PCR (Reverse transcription polymerase chain reaction) is more sensitive than culture and serology but the combination of the serology and RT-PCR is more and more sensitive than any other two methods (Zambon 2001).
They are many methods are available to detect influenza viruses directly such as Immunofluorescence, Enzyme immunoassays / Immunochromatography assays or RT-PCR. The only direct method which differentiates between the subtypes (neuraminidase and haemagglutinin) is the RT-PCR whereas all other direct techniques can detect the differences between influenza A and B types only.
If sufficient epithelial cells are present the respiratory specimen, then this technique will allows rapid diagnosis.
Enzyme immunoassays or Immunochromatography assays
These sorts of technique are taking short time 10 - 30 minutes and allow for bed side testing but it is generally more expensive.
RT-PCR (Reverse transcription polymerase chain reaction)
In this process, RNA is converted to cDNA(complementary DNA) and then amplification of section of the genome will takes place by using a primers which then bind specifically to this target area. This allows for exponential amplification of tiny amounts of nucleic acid, via the thermo stable DNA polymerase enzyme action, which off course enables a very high sensitive detection of very small amount of viral genomes. The specimen should be proceeds as soon as possible after collection to avoid any sort of RT-PCR sensitivity decrease due to RNN degradation of archival samples.
In this technique, the specimen is inoculated in a culture to detect the presence of the virus infection. As the culture is amplifying the amount of the virus so that it is mean it is more sensitive than direct method except than RT-PCR. Again the isolation needs rapid transport of the specimen to obtain better result.
Embryonated egg culture
This technique is no longer used for influenza virus diagnosis as it a special incubators and fertilized chicken eggs supply. However, reference laboratory still using this system to produce virus stocks for the purpose of epidemiological monitoring.
Conventional culture: This culture has very high sensitivity but it takes up to two weeks. (Weinberg 2005).
Shell vial culture: allows the diagnosis within two weeks but it is less sensitive than Conventional culture (Weinberg 2005).
As I mentioned earlier, serological techniques are usually used to detect influenza virus specific antibodies in serum or in any other fluids. It can either detect the total antibodies or specific class (IgM, IgG, or IgA).
For diagnosis of influenza there are several serological techniques such as compliment fixation (CF), haemagglutination inhibition (HI), indirect Immunofluorescence and enzyme immunoassays (EIA). On the other hand, serological diagnosis doesn't have much value in acute influenza diagnosis but it so important in determination the response of influenza vaccination (Prince 2003). In addition to that, serological techniques have amazing clinical value in paediatric patients (Steininger 2002).
Although the first diagnostic tests for influenza virus infection were virus isolation and serological tests, but still they are taking quite long turnaround time. Shell vial tests have reduced this time but absolutely they are not as quick as rapid tests.
Immunofluorescence is a good example for direct test as it only takes few hours to obtain the result but it needs a very skilled laboratory technologist and Immunofluorescence microscope. The diagnosis of influenza takes only 10 - 30 minutes after the development of the rapid antigen assays which are mainly using the principle of Immunochromatography or EIA. In addition to that, some of them not required a lab trained people to do it as it so easy and can be done in the clinic (bedside) testing.
Antigen assays are the friendliest techniques for the users, but they are not as sensitive as RT-PCR, isolation or Immunofluorescence. Table (2) shows the comparison of tests characteristics
Ease of performance
Rapid tests (EIA / chromatography)
Gel electrophoresis RT-PCR
Routine viral culture
Shell vial culture
Table 2 compares the characteristics of the different test methods available for influenza diagnosis.
Prevention and control
Immunity to Influenza
According to the studies, the human being immunity is induced to the virus (HA) and (NA) by the host responses. HA antibody is the most important component in the protection process against influenza virus.
Influenza vaccine must consist of both HA and NA antigens to stimulate the production of local IgA antibody, neutralizing antibody and cellular immunity maybe.
Types of vaccine
Mainly they are four types of vaccines in the market:
Whole virus vaccines - whole inactivated virus vaccines were the first influenza vaccines to be produced. Whole virus vaccine should not be used in children.
Split virus vaccines - This vaccine has few side effects that appear on the vaccinated people, but it is very similar in principle to the whole virus vaccine
Subunit virus vaccines - These vaccines prepared to contain HA and NA antigens only and are used in aqueous suspension or absorbed to carriers like alhydrogel for example. The aqueous subunit vaccines consider as the best available vaccines at the present.
Live attenuated vaccines - It has been experimentally proved that the immunization using attenuated live influenza virus vaccines induce more solid immunity than inactivated vaccines. Although there is no live attenuated vaccine available at all for general use.
Vaccination is mainly recommended for the individuals who are at risk of severe infection or for elderly and the vaccine usually confer protection in 60 - 90 % of vaccinated people. However, the influenza vaccination is recommended strongly for the children and adults who are suffering from following conditions.
1. Diabetes mellitus and other endocrine disorders
2. Immunosuppressant due to disease or treatment
3. Chronic heart disease.
4. Chronic renal failure.
5. Chronic respiratory disease.
Residents of nursing homes and other long stay facilities and old are also recommended to take the vaccines. They are two types of vaccines are available in the UK and both of them are suitable for children, surface antigen vaccines and spilt virus vaccines.
Conclusion and future outlook:
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. However, there is much more that is needed so that people who are at risk for influenza and its complications and those who come in contact with at-risk individuals receive the vaccine. Improving immunization protection will require APNs and other healthcare professionals to educate their clients and peers about their susceptibility to influenza and the severity of illness that influenza can cause. APNs need to assess their clients' beliefs, attitudes, and perceptions about influenza and the vaccine and plan interventions to make the vaccine and delivery of the influenza vaccine attractive so the morbidity and mortality associated with influenza can be reduced
Some side effects should be expected. Some people get a slight temperature and aching muscles for a couple of days and their arm may feel a bit sore where they were injected. Any other reactions are very rare.