Influenza is an infectious respiratory illness caused by an infection with a influenza virus. Flu has substantial incidence in children & adults <65 yrs. Not everyone gets sick when infected; the common symptoms include headache, fever, cough, sore throat, chills, fatigue and cold like symptoms. It is generally common in the infant and elderly as they are more susceptible to disease.
Influenza is known as orthomyxoviridae, it is an enveloped virus with a helical nucleocapsid. Influenza virus has segmented genomes, ssRNA with 8 different RNA molecules. Therefore various strains can be formed, each segment codes for one protein hence different strains of influenza.
Haemagglutinin binds to cell surface receptors. Neuraminidase is an enzyme that breaks down sialic acid and is involved in protein assembly. Both H and N are involved in immunity in regards to IgA.
There are three types of influenza A, B and C others are known to exist. Influenza A undergoes drift and shift. Influenza B only undergoes shift. Meaning antigenic shift is the re-assortment of gene segments from different strains and antigenic drift is the change of amino acid sequence of H and/or N from genetic mutations. Most changes occur through drift i.e. H3N2 Hong Kong flu may have been due to the change in H. Others known as H5N1, H9N2 also exist, however H1N1 and H3N2 (Sydney strain) are currently circulating.
MODE OF TRANSMISSION
Traditionally, influenza viruses have been thought to spread from person to person, primarily through large-particle respiratory droplet transmission (such as when an infected person coughs or sneezes near a susceptible person). Transmission via large-particle droplets requires close contact between the source and the recipient, because droplets generally travel only short distances (approximately ≤6 ft) through the air, but then settle out of the air. Indirect contact transmission via hand transfer of influenza virus from virus-contaminated surfaces or objects to mucosal surfaces of the face (nose, mouth) may also occur. Airborne transmission via small-particle aerosols in the vicinity of the infectious person may also occur; however, the relative contribution of the different modes of influenza transmission is unclear. All respiratory secretions and bodily fluids, including diarrheal stools, of patients with influenza should be considered infectious; however, the predominant source of infection is respiratory secretions. Viable influenza virus is rarely detected in blood or stool of infected patients. Most healthy adults who are ill with influenza may shed virus and be infectious to others from the day before symptom onset to 5–7 days after symptom onset; children, severely immunocompromised people, and more severely ill people, including those who are hospitalized, may shed influenza virus for ≥10 days after the onset of symptoms.
The replication of influenza is similar to that of an animal viral replication. Influenza enters the host cell by haemagglutinin binding to sialic acid found on glycoprotein receptors of host cell. The cell endocytoses the virus. In the acidic environment of endosomes, virus changes shape and fuses its envelope with endosomal membrane. This is followed by a signal to release the viral nucleocapsid into host cell cytoplasm. The nucleocapsid travels to the host nucleus.
Once in the host nucleus, primary transcription produces proteins for replication. It involves cap snatching where viral endonuclease (PB2) cuts 5’ methylguanosine cap as well as 10-13 nucleotides from RNA. This is used as a primer for transcription of PB1, viral transcriptase. In influenza A and B, 10 proteins result from translation of 8 segments of genome including H, N, PB1, PB2 etc...
Once the initial proteins are made, the 8 + cRNA sense are made from 8 – cRNA sense. These lack 5’ capped primer as well as 3’ poly (A) tail found in mRNA. From cRNA, - RNA sense is produced. Various proteins help – RNA to exit the nucleus and enter into the cytoplasm of host cell.
Meanwhile in the cytoplasm, H and N have undergone glycosylation, polymerisation and acylation. H, N and M2 travel together to the plasma membrane. There it meets with other matrix protein, M1 and begin the budding process, where the viral particle buds. N finally destroys the sialic acid receptors on the membrane thus allowing the viral particle to leave the cell.
EPIDEMIOLOGY
Seasonal Influenza
Infection with seasonal influenza viruses is common. In temperate climates, most cases occur during the winter months. The influenza season in the Northern Hemisphere may begin as early as October and can extend until May, and the influenza season in the Southern Hemisphere may begin in April and last through September. In tropical and subtropical areas, infection with influenza virus may occur throughout the year.
CDC estimates that from 1976 through 2006, annual seasonal influenza-associated deaths in the United States ranged from a low of approximately 3,000 people to a high of approximately 49,000 people; about 90% of these deaths occur among people aged ≥65 years. Influenza virus infections can cause disease in all age groups. Infection rates are highest among infants and children, while rates of severe illness (including death) are highest among people aged ≥65 and people of any age who have underlying medical conditions that place them at increased risk for complications. Children aged <2 years have rates of influenza-related hospitalization that are as high as those in the elderly.
Zoonotic Influenza
Influenza A viruses circulate in many different animal populations. The primary reservoirs for influenza A viruses of all subtypes are wild birds. Influenza viruses found in birds are typically referred to as avian influenza viruses. Influenza A viruses are also endemic in pigs globally and in horses in many countries. Other animal species may also become infected with influenza A viruses, including domestic poultry and marine mammals. During the 2009 pandemic, infections of domesticated cat and dogs, ferrets, turkeys, a cheetah, and other animals were also reported.
Human infections with animal-origin viruses are uncommon, but they occur. Before the 2009 H1N1 pandemic, occasional swine influenza infections among humans were reported in the United States and elsewhere. In addition, more than 500 human infections with highly pathogenic avian influenza A H5N1 (HPAI-H5N1) have been reported globally since 2003. Human infections with HPAI-H5N1 are particularly concerning because of the high case-fatality ratio of approximately 60% and because this virus is widespread among poultry in some countries in Asia and the Middle East. Thus far, however, the spread of HPAI-H5N1 viruses from one ill person to another has been reported rarely and has thus far been limited, inefficient, and unsustained. Human infections with other avian influenza viruses have also included avian H7N7, H7N2, and H9N2. No sustained transmission of these other avian influenza viruses has been documented, but these viruses, along with H5N1, still have the potential to result in a pandemic.
In addition, a lot of people continue to be infected by a particular subtype of influenza (H7N9) Avian influenza A. It was found in China on March 2013. It previously detected in birds in the past but was not observed in animals nor humans like in 2013. The World Health Organisation on January 2015 performed a risk assessment and have ultimately discovered that public health risk has not been altered since the initial assessment that took place on October 2014. To see the report for October 2014. Here is information below:
http://www.who.int/influenza/human_animal_interface/influenza_h7n9/riskassessment_h7n9_2Oct14.pdf?ua=1
However, since then, infections in both humans and birds have been observed. The disease is of concern because most patients have become severely ill. Most of the cases of human infection with this avian H7N9 virus have reported recent exposure to live poultry or potentially contaminated environments, especially markets where live birds have been sold. This virus does not appear to transmit easily from person to person, and sustained human-to-human transmission has not been reported.
Pandemic Influenza
A global pandemic was declared by the World Health Organization after 30,000 confirmed cases of 2009 pandemic influenza A (H1N1) virus had been reported from 74 countries. The virus spread from North America to the rest of the world. Severe illness resulting from infection with this virus was associated with risk factors such as chronic medical conditions, immunosuppression, pregnancy, young age, morbid obesity, and being a member of an indigenous population. However, in contrast to the epidemiology of seasonal influenza, CDC estimates that almost 90% of deaths from this virus occurred among people aged <65 years. The 2009 pandemic influenza A (H1N1) virus continues to circulate and was included as a component of the 2010–11 seasonal influenza vaccine.
The H5N1 avian influenza outbreak in Hong Kong 1997
In the latter half of 1997, an outbreak occurred in Hong Kong whereby 18 persons were infected by an avian influenza A, serotype H5N1. Of these 6 died, and 3 others were severely ill. The source of the outbreak was infected chickens and the outbreak stopped after all the chickens were slaughtered in the territory. Large-scale serological studies carried out showed that workers in the poultry industry were particularly at risk of infection although none complained of any symptoms. There was evidence of limited human to human transmission. It was postulated that the strain of avian influenza involved was unusually virulent; it had multiple basic amino acids near the cleavage site of the haemagglutinin protein, which as a result may render the haemagglutinin susceptible to a wider range of proteases. Since that outbreak, no more cases have occurred. In 1999, there were reports of human infections by avian influenza A H9N2 in Hong Kong and in Mainland China. However, all these cases were very mild and it is thought that the virus was unlikely to pose a large public health risk.
TREATMENT
Influenza epidemics are responsible for massive disruption to industry, and for a significant number of deaths, particularly in the elderly and the very young. At present, treatment of influenza is entirely symptomatic. Salicylates should be avoided in children because of the link with Reye's syndrome. 2 compounds, amantidine and ribavirin, with antiviral activity against influenza have been identified and may be of value.
Amantidine - this compound inhibit the growth of influenza viruses in cell culture and in experimental animals. Amantidine is only effective against influenza A, and some naturally occurring strains of influenza A are resistant to it. The mechanism of action of amantadine is not known. It is thought to act at the level of virus uncoating. The compound has been shown to have both therapeutic and prophylactic effects. Amantidine significantly reduced the duration of fever (51 hours as opposed to 74 hours) and illness. The compound also conferred 70% protection against influenza A when given prophylactically. Amantidine can occasionally induce mild neurological symptoms such as insomnia, loss of concentration and mental disorientation. However, these symptoms quickly developed in susceptible individuals and cease when treatment is stopped. The therapeutic and prophylactic activity of amantidine is now generally accepted and numerous analogues of this compound have been prepared. Rimantadine is not as effective as amantadine but is less toxic. Prophylaxis with 200mg of amantadine per day for 5 to 6 weeks or for the duration of the influenza A outbreak is not recommended for all persons. However, elderly persons with chronic underlying disease, institutionalized persons, staff and patients in hospital, close contacts of an index case, and patients who cannot receive influenza A vaccine due to sensitivity to egg protein may benefit from prophylaxis. Amantadine can also be used for therapy of uncomplicated influenza A infections. The recommended dose is 200mg for 5 days. Rimantadine may be used in place of amantadine for prophylaxis and the treatment of uncomplicated influenza A infections.
Rimantidine - this compound is similar to amantidine but has fewer side effects. It is approved by the FDA for the treatment and prophylaxis of influenza A infection in persons one year or older. It should be used for uncomplicated influenza A infections only since it is thought to be less effective than amantidine. Amantadine and rimantadine resistant viruses are readily generated in the laboratory. Resistance has been linked to changes in the M2 protein. To date, the emergence of resistant influenza A has been documented primarily in young children undergoing therapy with rimantadine. The resistant viruses had been transmitted and caused influenza. The universal susceptibility of all types of naturally occuring influenza A isolated from man and animals suggests that resistance will be found only in individuals treated with the drug. The reason for the natural selection of the susceptible phenotype of influenza A in nature is not known.
Zanamivir - the rational approach to drug design has led to the design of several potent inhibitors of influenza neuraminidase. Zanamivir was the first neuraminidase inhibitor available for clinical use and is effective against both influenza A and B. Because of its poor bioavailability, zanamivir must be administered by inhalation. Zanamivir had been shown to be effective and devoid of significant side effects in clinical trials. It is now approved by the FDA for use as treatment for influenza A and B in persons 12 years or older but not for prophylaxis.
Oseltamivir - oseltamivir is another neuraminidase inhibitor but unlike zanamivir, it can be given orally. Like zanamivir, it had been shown to be effective and devoid of significant side effects in clinical trials. It is approved by the FDA for use as treatment for influenza A and B in persons 18 years or older. It is also approved for prophylaxis in persons 13 years or older. Its lack of side effects would make particularly attractive in a family setting although its higher cost compared to amantidine and rimantidine should be taken into account.
Influenza is known as orthomyxoviridae, it is an enveloped virus with a helical nucleocapsid. Influenza virus has segmented genomes, ssRNA with 8 different RNA molecules. Therefore various strains can be formed, each segment codes for one protein hence different strains of influenza.
Haemagglutinin binds to cell surface receptors. Neuraminidase is an enzyme that breaks down sialic acid and is involved in protein assembly. Both H and N are involved in immunity in regards to IgA.
There are three types of influenza A, B and C others are known to exist. Influenza A undergoes drift and shift. Influenza B only undergoes shift. Meaning antigenic shift is the re-assortment of gene segments from different strains and antigenic drift is the change of amino acid sequence of H and/or N from genetic mutations. Most changes occur through drift i.e. H3N2 Hong Kong flu may have been due to the change in H. Others known as H5N1, H9N2 also exist, however H1N1 and H3N2 (Sydney strain) are currently circulating.
MODE OF TRANSMISSION
Traditionally, influenza viruses have been thought to spread from person to person, primarily through large-particle respiratory droplet transmission (such as when an infected person coughs or sneezes near a susceptible person). Transmission via large-particle droplets requires close contact between the source and the recipient, because droplets generally travel only short distances (approximately ≤6 ft) through the air, but then settle out of the air. Indirect contact transmission via hand transfer of influenza virus from virus-contaminated surfaces or objects to mucosal surfaces of the face (nose, mouth) may also occur. Airborne transmission via small-particle aerosols in the vicinity of the infectious person may also occur; however, the relative contribution of the different modes of influenza transmission is unclear. All respiratory secretions and bodily fluids, including diarrheal stools, of patients with influenza should be considered infectious; however, the predominant source of infection is respiratory secretions. Viable influenza virus is rarely detected in blood or stool of infected patients. Most healthy adults who are ill with influenza may shed virus and be infectious to others from the day before symptom onset to 5–7 days after symptom onset; children, severely immunocompromised people, and more severely ill people, including those who are hospitalized, may shed influenza virus for ≥10 days after the onset of symptoms.
The replication of influenza is similar to that of an animal viral replication. Influenza enters the host cell by haemagglutinin binding to sialic acid found on glycoprotein receptors of host cell. The cell endocytoses the virus. In the acidic environment of endosomes, virus changes shape and fuses its envelope with endosomal membrane. This is followed by a signal to release the viral nucleocapsid into host cell cytoplasm. The nucleocapsid travels to the host nucleus.
Once in the host nucleus, primary transcription produces proteins for replication. It involves cap snatching where viral endonuclease (PB2) cuts 5’ methylguanosine cap as well as 10-13 nucleotides from RNA. This is used as a primer for transcription of PB1, viral transcriptase. In influenza A and B, 10 proteins result from translation of 8 segments of genome including H, N, PB1, PB2 etc...
Once the initial proteins are made, the 8 + cRNA sense are made from 8 – cRNA sense. These lack 5’ capped primer as well as 3’ poly (A) tail found in mRNA. From cRNA, - RNA sense is produced. Various proteins help – RNA to exit the nucleus and enter into the cytoplasm of host cell.
Meanwhile in the cytoplasm, H and N have undergone glycosylation, polymerisation and acylation. H, N and M2 travel together to the plasma membrane. There it meets with other matrix protein, M1 and begin the budding process, where the viral particle buds. N finally destroys the sialic acid receptors on the membrane thus allowing the viral particle to leave the cell.
EPIDEMIOLOGY
Seasonal Influenza
Infection with seasonal influenza viruses is common. In temperate climates, most cases occur during the winter months. The influenza season in the Northern Hemisphere may begin as early as October and can extend until May, and the influenza season in the Southern Hemisphere may begin in April and last through September. In tropical and subtropical areas, infection with influenza virus may occur throughout the year.
CDC estimates that from 1976 through 2006, annual seasonal influenza-associated deaths in the United States ranged from a low of approximately 3,000 people to a high of approximately 49,000 people; about 90% of these deaths occur among people aged ≥65 years. Influenza virus infections can cause disease in all age groups. Infection rates are highest among infants and children, while rates of severe illness (including death) are highest among people aged ≥65 and people of any age who have underlying medical conditions that place them at increased risk for complications. Children aged <2 years have rates of influenza-related hospitalization that are as high as those in the elderly.
Zoonotic Influenza
Influenza A viruses circulate in many different animal populations. The primary reservoirs for influenza A viruses of all subtypes are wild birds. Influenza viruses found in birds are typically referred to as avian influenza viruses. Influenza A viruses are also endemic in pigs globally and in horses in many countries. Other animal species may also become infected with influenza A viruses, including domestic poultry and marine mammals. During the 2009 pandemic, infections of domesticated cat and dogs, ferrets, turkeys, a cheetah, and other animals were also reported.
Human infections with animal-origin viruses are uncommon, but they occur. Before the 2009 H1N1 pandemic, occasional swine influenza infections among humans were reported in the United States and elsewhere. In addition, more than 500 human infections with highly pathogenic avian influenza A H5N1 (HPAI-H5N1) have been reported globally since 2003. Human infections with HPAI-H5N1 are particularly concerning because of the high case-fatality ratio of approximately 60% and because this virus is widespread among poultry in some countries in Asia and the Middle East. Thus far, however, the spread of HPAI-H5N1 viruses from one ill person to another has been reported rarely and has thus far been limited, inefficient, and unsustained. Human infections with other avian influenza viruses have also included avian H7N7, H7N2, and H9N2. No sustained transmission of these other avian influenza viruses has been documented, but these viruses, along with H5N1, still have the potential to result in a pandemic.
In addition, a lot of people continue to be infected by a particular subtype of influenza (H7N9) Avian influenza A. It was found in China on March 2013. It previously detected in birds in the past but was not observed in animals nor humans like in 2013. The World Health Organisation on January 2015 performed a risk assessment and have ultimately discovered that public health risk has not been altered since the initial assessment that took place on October 2014. To see the report for October 2014. Here is information below:
http://www.who.int/influenza/human_animal_interface/influenza_h7n9/riskassessment_h7n9_2Oct14.pdf?ua=1
However, since then, infections in both humans and birds have been observed. The disease is of concern because most patients have become severely ill. Most of the cases of human infection with this avian H7N9 virus have reported recent exposure to live poultry or potentially contaminated environments, especially markets where live birds have been sold. This virus does not appear to transmit easily from person to person, and sustained human-to-human transmission has not been reported.
Pandemic Influenza
A global pandemic was declared by the World Health Organization after 30,000 confirmed cases of 2009 pandemic influenza A (H1N1) virus had been reported from 74 countries. The virus spread from North America to the rest of the world. Severe illness resulting from infection with this virus was associated with risk factors such as chronic medical conditions, immunosuppression, pregnancy, young age, morbid obesity, and being a member of an indigenous population. However, in contrast to the epidemiology of seasonal influenza, CDC estimates that almost 90% of deaths from this virus occurred among people aged <65 years. The 2009 pandemic influenza A (H1N1) virus continues to circulate and was included as a component of the 2010–11 seasonal influenza vaccine.
The H5N1 avian influenza outbreak in Hong Kong 1997
In the latter half of 1997, an outbreak occurred in Hong Kong whereby 18 persons were infected by an avian influenza A, serotype H5N1. Of these 6 died, and 3 others were severely ill. The source of the outbreak was infected chickens and the outbreak stopped after all the chickens were slaughtered in the territory. Large-scale serological studies carried out showed that workers in the poultry industry were particularly at risk of infection although none complained of any symptoms. There was evidence of limited human to human transmission. It was postulated that the strain of avian influenza involved was unusually virulent; it had multiple basic amino acids near the cleavage site of the haemagglutinin protein, which as a result may render the haemagglutinin susceptible to a wider range of proteases. Since that outbreak, no more cases have occurred. In 1999, there were reports of human infections by avian influenza A H9N2 in Hong Kong and in Mainland China. However, all these cases were very mild and it is thought that the virus was unlikely to pose a large public health risk.
TREATMENT
Influenza epidemics are responsible for massive disruption to industry, and for a significant number of deaths, particularly in the elderly and the very young. At present, treatment of influenza is entirely symptomatic. Salicylates should be avoided in children because of the link with Reye's syndrome. 2 compounds, amantidine and ribavirin, with antiviral activity against influenza have been identified and may be of value.
Amantidine - this compound inhibit the growth of influenza viruses in cell culture and in experimental animals. Amantidine is only effective against influenza A, and some naturally occurring strains of influenza A are resistant to it. The mechanism of action of amantadine is not known. It is thought to act at the level of virus uncoating. The compound has been shown to have both therapeutic and prophylactic effects. Amantidine significantly reduced the duration of fever (51 hours as opposed to 74 hours) and illness. The compound also conferred 70% protection against influenza A when given prophylactically. Amantidine can occasionally induce mild neurological symptoms such as insomnia, loss of concentration and mental disorientation. However, these symptoms quickly developed in susceptible individuals and cease when treatment is stopped. The therapeutic and prophylactic activity of amantidine is now generally accepted and numerous analogues of this compound have been prepared. Rimantadine is not as effective as amantadine but is less toxic. Prophylaxis with 200mg of amantadine per day for 5 to 6 weeks or for the duration of the influenza A outbreak is not recommended for all persons. However, elderly persons with chronic underlying disease, institutionalized persons, staff and patients in hospital, close contacts of an index case, and patients who cannot receive influenza A vaccine due to sensitivity to egg protein may benefit from prophylaxis. Amantadine can also be used for therapy of uncomplicated influenza A infections. The recommended dose is 200mg for 5 days. Rimantadine may be used in place of amantadine for prophylaxis and the treatment of uncomplicated influenza A infections.
Rimantidine - this compound is similar to amantidine but has fewer side effects. It is approved by the FDA for the treatment and prophylaxis of influenza A infection in persons one year or older. It should be used for uncomplicated influenza A infections only since it is thought to be less effective than amantidine. Amantadine and rimantadine resistant viruses are readily generated in the laboratory. Resistance has been linked to changes in the M2 protein. To date, the emergence of resistant influenza A has been documented primarily in young children undergoing therapy with rimantadine. The resistant viruses had been transmitted and caused influenza. The universal susceptibility of all types of naturally occuring influenza A isolated from man and animals suggests that resistance will be found only in individuals treated with the drug. The reason for the natural selection of the susceptible phenotype of influenza A in nature is not known.
Zanamivir - the rational approach to drug design has led to the design of several potent inhibitors of influenza neuraminidase. Zanamivir was the first neuraminidase inhibitor available for clinical use and is effective against both influenza A and B. Because of its poor bioavailability, zanamivir must be administered by inhalation. Zanamivir had been shown to be effective and devoid of significant side effects in clinical trials. It is now approved by the FDA for use as treatment for influenza A and B in persons 12 years or older but not for prophylaxis.
Oseltamivir - oseltamivir is another neuraminidase inhibitor but unlike zanamivir, it can be given orally. Like zanamivir, it had been shown to be effective and devoid of significant side effects in clinical trials. It is approved by the FDA for use as treatment for influenza A and B in persons 18 years or older. It is also approved for prophylaxis in persons 13 years or older. Its lack of side effects would make particularly attractive in a family setting although its higher cost compared to amantidine and rimantidine should be taken into account.
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