See CDC.  Influenza Antiviral Medicines (CDC)   FDA (drugs approved for influenza)

See also Respiratory viruses

Introduction:

The flu is a contageious respiratory illness caused by influenza viruses. It causes mild to severe illness and at times can lead to death. Annually in the US, influenza is contracted by 5-20% of the population, hospitalizing about 200k and causing deaths of about 36K (WO2007/134327).

Structure:

Influenza viruses belong to the Orthomyxoviridae family and are enveloped single-stranded RNA virruses, that occur in 3 distinct antigenic types (A,B and C). Types A and B are responsible for epidemics, while type C causes mild respirtoary illness. The lipid bilayer coating the influenza virus contains specific hemagglutinin (H) and neuraminidase (N) protein spikes that define distinct viral subtypes. Hemagglutinin (H) contribues to infectivity by binding to host cell receptors of the respiratory mucosa. Neuraminidase (N) breaks down the protective mucous coating of the respiratory tract, assists in viral budding and release, keeps viruses form sticking together and participates in host cell fusion.

The genomes of all influenza viruses are composed of eight single-stranded RNA segments. These RNAs are negative-sense molecules, meaning that they must be copied into positive-sense molecules in order to direct the production of proteins. Scitable by Nature

The ssRNA genomes of the influenza virus is known for its extreme variability. It is subject to constant genetic changes that alter the structure of its envelope glycoproteins. This constant mutation of the glycoporteins is called antigenic drift; the antigens gradually change their amino acid composition, resulting in decreased ability of host memory cells to recognize them. Antigenic drift is the reason that a new vaccine is required each year.

An even more serious problem is called antigenic shift. Antigenic shift is the swapping out of one of the 10 genes of the virus, which are coded on 8 separate RNA strands, with a gene or strand from a different influenza virus. For example, where ducks and swine and humans live close together, the swine can serve as a melting pot for creating hybrid influenza viruses that are not recognized by the human immune system. Experts have traced the flu pandemics of 1918, 1957, 1968, 1977 and 2009 to strains of a virus that came from pigs (swing flu). In 2009, a swine flu called H1N1 caused a limited pandmeic. It reappeared in 2014.

People at Risk:

Epedemic influenza occurs annually and is a cause of significant morbidity and mortality worldwide. Children have the highest attack rate and are largely responsible for transmission of influenza virus in the human community. The elderly and persons with underlying health problems are at an increased risk for complications and hospitalization from influenza infection.  The flu and associated complications, including bacterial pneumonia, are the sixth leading cause of death in the world and the leading infectious cause of death.

Each year CDC estimates the burden of influenza in the U.S. CDC uses modeling to estimate the number of influenza illnesses, medical visits, flu-associated hospitalizations, and flu-associated deaths that occur in the U.S. in a given season. See CDC

Antigenic Drift: In the United States, seasonal influenza epidemics typically claim the lives of about 30,000 people each year and cause hospitalization of more than 100,000 (Reid & Tautenberger, 2003). Every two or three years, more virulent strains circulate, increasing death tolls by approximately 10,000 to 15,000 individuals. These seasonal epidemics are the result of antigenic drift, a phenomenon caused by mutations in two key viral genes due to an error-prone RNA polymerase. The high mutation rate leads to antigenic drift in the HA and NA genes. Antigenic drift refers to small changes in the HA and NA prtoeins such that previous vaccine induced immunity is no longer protective. Becasue antigenic drift is due to random mutations, it is impossible to predict precisely which viral strains will emerge each year. Immunologists and epidemiologists at the CDC use information on circualting strains to make the best possible predicitons which which strains to use for the upcoming sason.

Antigenic Shift: Less frequently, however, new and particularly virulent strains of influenza arise, which cause worldwide pandemics that are accompanied by greatly increased death tolls. These strains occur because of the phenomenon known as antigenic shift in which humans are infected with avian influenza viruses or viruses that contain a combination of genes from human and avian sources. In other words, antigenic shift occurs when an individual is infected with more than one virus, and the viral genomes are reassorted druing infection. Antigenic shift prodcues new HA-NA combinations. Since 1900, three of these pandemics have occurred. The first, which took place in 1918 and was referred to as “Spanish” influenza, was the deadliest, claiming an estimated 40 million lives worldwide in less than a year. Unlike weaker flu strains that are more of a threat to the elderly, this flu claimed the lives of many young people, including children and young adults. In fact, people under age 65 accounted for 99% of the deaths attributed to this strain, whereas subsequent pandemics claimed many fewer people from this age group. Later epidemics occurred in 1957, when the “Asian” flu killed 70,000 people in the United States, and in 1968, when the “Hong Kong” strain killed 30,000 Americans (Reid & Tautenberger, 2003).  Scitable by Nature

Antigenic shift proudcing new HA-NA combinations was responsible for the three major flu pandemics of the 20th centure: The “Spanish flue” of 1918, A(H1N1) killed 50-100 million people worldwidse, the Asian flue of 1957, A(H2N2) killsed over 100k Americans and the Hong Kong flue of 1968 A(H3N2) infected 50 million people in the US with 70k deaths. In the 1990s, 3 indfluenza virsues infected pigs: a classical swine flue virus, a North American avian influenza virus and a human H3N2 virus. When all 3 viruses infect the same cell, the 8 genomic segments form each virus are all replcated. When new viruses are assembled, the 8 genomic segments are slected randomly, which can shuffle the genomes form different viruses to produce new combinations of genome segments. Becasue the HA adn NA genes are on different genome segmetns, this can produce viruses with new combiantions of HA and NA prtoeins. Such a recombined virus circulated in swine herds in North America, but could not be transmitted to human. Soemtimes later, pigs harboring teh new virus were infected by an avian like influenza virus. This allwoed a second round of reassortment in the pigs, to create a new virus called H1N1/09 (“swine flue”) which could now infect humans and cause diase. This reassortment created a virus with an HA prtoein much better suited to binding to human respiratory epithelia.

How Influenza spreads (transmission): 

Influenza speads from person to person via airborne droplets or coughs. Influenza viruses generally enter the body through mucous membranes like the eyes, nose and mouth. It is highly contagious and affects people of all ages.

Transmission is greatly facilitated by crowding and poor ventilation in classrooms, barracks, nursing homes, dormitories and military installations in the late fall and winter. The dry air of winter facilitates the spread of the virus as the the moist particles expcelled by sneezes and coughs become dry very quickly, helping the virus remain airborn for longer periods of time. In addition, the dry cold air makes respiratory tract mucous membranes more brittle, with microscopic cracks that facilitate invasion by viruses.

Symptoms: 

Although the flu is conisdered to be an infection of the respiratory tract, people suffering the flu usually become acutely ill with high fever (usually 100-103F in an adult and possibly hihger in children) , chills, headache, weakness, loss of appetite and aching joints. The suddenness with which these symptoms develop usually aid in distinguishing between influenza and other viral respiratory infectious such as the common cold, which are generally characterized by a slower onset of symptoms. The typical lenght of time form when a perosn is exposed to influenza virus to when symptoms first occur ranges between 1 and 3 days, with an average of 2 days. Adults can be infectious (i.e., shedding virus) starting the day before the onset of symptoms begin until about 3 days after the onset of illness. Children can be infectious for longer periods of time.

Infection initiation/Entry:

The role of hemagglutinin in the lipid bilyer is to initiate infection of a host cell by binding to sialic acid residues present on cell surface molecules of a respiratory epithelial cell. The host cell then encloses the virus in an endosome, and the viral and cell membranes subsequently fuse. At a later stage of infection the neuraminidase functions to cleave the bonds between the nascent (newly replicated) viral particles which emerge form the infected host cell coated with a lipid bilayer aquired form the host cell plasma membrane. Neuraminidase is thus an essential enzyme for the replication of influenza virus and it has been described as a “molecular scissors” which cut the nascent viruses free. More specifically, neuraminidase cleaves terminal nueraminic (sialic) acid residues from carbohydrate moieties on host epithelial cell membrane proteins, and on viral enveope glycoprotein spikes of newly synthesized virions.

Influenza virions attach to a specific surface carbohydrate on respiratory epithelia cells, using a viral envelope protein called hemagglutin (HA). The virus is then endocytosed into the host cell’s cytoplasm. The eight seignts of the viral genome are released for the capsid and transproted into the nucleus. The viral genome is replicated and used to make mRNA from which viral proteins are translated. Viral capsids containing the genomic segments are assembled at the cell membrane and a virion buds form the cell surface. The viral envelope is created from the host cell membrane. Release of the virus from the cell surface depends on a viral protein embedded in the host cell membrane called neurominidase (NA).

How Influenza Causes Disease:

Disease is partly due to tissue damage caused by the virus itself and mainly due to the inflammatory response of the host. HA adn NA is the iral envelope are the two viral proteins most commonly recognized by the immune system. As inflammatory cells of the immune system respond to the virus, infected cells are killed and this contributes to tissue damage. Most cases resolve without intervention. However, in immunocompromised persons, disease can be severe, leading to respiratory failure and death. Ironically, a very strong immunoglogical response can be as dangerous as a weak one. For example, the strenght of the immune response triggered by the 1918 infleunza A virus may explain its high mortality rate.

Treatment:

Even an uncomplicated case of acute influenza is likely to require days of bed rest.

Antivirals:

Patients who present with suspected influenzy might benefit from treatment with antiviral agents.

—Amantadine and rimandtadine are available for both the prevention and treatment of influenza A disease only.

–Zanamivir and oseltamivir are available for the treatment of both influenza A and B disease. In adults, therapy with these agents may reduce the severity and duration of illness if given with the first 48 h of onset of illsness.

–Oseltamivir (Tamiflu) is available in capsules or as a powdered mix to be made into a drink. It can also be used for prevention of influenza A and B.

–Anamivir is approved for treatment of uncomplicated acute influenza in people over 12 who have been symptomatic for no more than 2 days. it is most effective if administered within 30-36 hrs of symptoms onset.

–Oseltamivir (Tamiflu): is approved for treatment of uncomplicated influenza in adults over 18 who have been symptomatic for no more than 2 days. Oseltamivir is a long acting oral agent with a systemic bioavailability of 80% and a half life of 6 to 10 hours. The proposed mechanism of action of oseltamivir is inhibition of influenza virus neuraminidase and prevention of viral budding from infected cells (US 2004/0248825).

–Relenza (zanamivir) is an inhalation powder approved for treatment of uncomplicated illness due to influenza A and B virus. It is indicative for preventitive (prophylaxis)in adults and pediatrics (5 years and older). Zanamivir is poorly absorbed in the gastroinestinal tract and formulated as a dry powder for inhalation. Most of the drug is deposited in the throat and about 20% of the inhaled drug reaches the lungs. It has a half-life of 2.5 to 5 hrs.

Vaccination for Influenza & associated Disease:

Although influenza vaccines are available, because an antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype of influenza, it is necessary to incorporate one or more new strains in each year’s influenza vaccine.

Influenza vaccines are usually trivalent vaccines. They generally contain antigens derived from two influenza A virus strains and one influenza B strain. The efficacy of such vaccines in preventing respiratory disease and influenza complications ranges from 75% in healthy adults to less than 50% in the elderly. Persons between the ages of 25-64 with health conditions associated with higher risk of medical complications from influenza, including HIV infection, should be vaccinated. Additional groups include ages 6 months-24 years, Healthcare personnel, pregnant woman household contacts and caregivers for children younger then 6 months.

Influenza predisposes people to developing community-acquired pneumonia. (pneumococcus) is the most common. S. pneumoniae is a illness and such vaccines can be useful in preventing secondary pneumococcal infections and reducing death among those infected with influenza viruses. CDC recommends a single dose of the pneumococcal polysaccharide vaccine (PPSV) for all people over 65 and for persons 2-64 with high risk conditions.

How Influenza Viruses Evade the Immune System: 

Influenza viruses evade infection fighting antibodies by constantly changing the shape of their marjor surface protein. This shape-shifting is called antigenic drift. It is why invluenza vaccines which are designed to elicity antibodies much be reformulated annually to match each year’s circulating virus strains.