Gesundheit! Now go wash your hands before you spread that flu to everyone else

I had a little bird, And its name was Enza. I opened the window And in-flew-enza.

A skipping rhyme about the 1918 H1N1 flu pandemic, the most lethal influenza pandemic that killed more people than all the casualties from the then-recent World War I put together (estimates range from 20 to 100 million people). This virus was a result of an avian flu virus making the jump successfully into humans.

Influenza is a viral infection that generally affects the upper respiratory tract; that is to say, the mouth, nose and throat. Symptoms often last a week or so, and range from a sudden high fever, coughing, headache, muscle and joint pain, severe fatigue, to sore throat and runny nose. Although the virus can be transmitted at all times, it is typically a seasonal infection that peaks during winter in temperate countries, presumably because more people are packed closer together in winter; the influenza virus is also able to survive for longer outside the body in cold weather. Influenza is passed from person to person via aerosolized droplets i.e. by sneezing and coughing, and contact with contaminated surfaces. It is also able to infect people of all ages; however, the most vulnerable are the very young, the very old, and those with suppressed immune systems. Special care should be taken in these cases, as severe illness or death may result. ImageIn the United States, seasonal influenza epidemics have caused the deaths of more than 30,000 people yearly, and the hospitalization of more than 100,000. More virulent strains may claim the lives of 10,000 – 15,000 more people each year. Influenza pandemics are caused by strains that are so virulent that in the 1918 flu pandemic, more than 2.5% of those that fell ill died, compared to a case fatality rate of less than 0.05% for the more typical virus strain; these pandemic strains are also able to spread rapidly even in the summer, during what is supposedly their “off” season.

There are three types of influenza virus (A, B & C), but the one that we are most concerned about is the influenza A virus. When we’re talking about H1N1, H2N3, and H7N9, we are talking about the influenza A virus – an RNA virus of the orthomyxoviridae (influenza virus) family that is able to infect birds, pigs, and humans, amongst other animals. Variants of the virus that are endemic in birds are called avian influenza; variants that are endemic in pigs are called swine influenza.

In the naming of the subtypes of influenza A virus, ‘H’ stands for hemagglutinin, and ‘N’ for neuraminidase, both of which are antigens embedded on the lipid envelope surface of influenza A virus particles. HA is a protein that mediates binding of the virion to, and entry of the viral genome into, the host cell, while NA is involved in the release of new influenza virions from infected cells. There are 17a different known hemagglutinin (HA) antigens, and 11 different known neuraminidase (NA) antigens; therefore, there are 187 possible different combinations of HA and NA antigens that can theoretically be expressed on the surface of an influenza A virus particle. The genome of the influenza A virus is segmented; that is to say, the genome is broken up into different segments, and each segment codes for different parts of the viral particle.

Influenza A virus schematic

Influenza A virus schematic; M2 Ion channel is important for viral replication by controlling pH; RNP stands for ribonucleic protein and holds the RNA genome. Illustration by CDC.

Several small details are all that differentiate avian flu from human flu; for example, avian flu HA binds to alpha 2–3 sialic acid receptors on the avian cell surface, while human flu HA binds to alpha 2–6 sialic acid receptors on the human cell surface. Unfortunately, swine flu viruses have the ability to bind both types of sialic acid receptors on swine cell surfaces – this makes them dangerous because virulent avian flu viruses could jump into pigs, undergo reassortment and gain the ability to bind to alpha 2-6 sialic acid receptors, then jump into humans and consequently cause a pandemic. This sudden change in the genetic makeup of the influenza virus is known as antigenic shift.

The best way to prevent being infected by the influenza virus is, of course, by getting the flu vaccine. Typically available as a seasonal trivalent vaccine (that means that it is protective against three viruses, usually two influenza A viruses and one influenza B virus), the seasonal flu vaccine is recommended for people at high risk of getting flu, particularly during its peak season in the winter months. It is also only provides protection for one season (one year) because the surface protein antigens on the influenza viruses mutate over time such that the antibodies put out by our immune system against one year’s vaccine will no longer recognize next year’s viral antigens. In fact, the genes for an influenza virus evolve at a rate which is approximately a million times faster than that of animal (including human) genes. This gradual mutation of antigens is known as antigenic drift.

To decide which influenza viruses to include in each year’s trivalent vaccine, scientists study influenza viruses in the wild to determine which are the most predominant, or most likely to become predominant, in the following year; these viruses are then cultivated, then inactivated or attenuated, and included in the following year’s influenza vaccine. There are three types of inactivated vaccines (with decreasing risk of the virus regaining virulence if the inactivation is carried out improperly): whole virus vaccines, split virus vaccines, and subunit vaccines. Whole and split virus vaccines have names that are mostly self-explanatory, while subunit vaccines make use of only certain antigens from the influenza virus; in this case, primarily HA and NA. Live, attenuated influenza vaccines, on the other hand, are weaker and avirulent strains of the live influenza virus. Live, attenuated vaccines are the most effective, but they are also the ones that are most likely to revert to the virulent strain of influenza.

Influenza viruses that are suspected to be able to cause pandemics are used to create monovalent influenza vaccines; this is primarily to allow for control of manufacture, transport, and administration of the vaccine, so as to reduce the risk of the virus regaining its virulence and spreading throughout the population.

Deaths from pandemics were caused by both the virus (and the immune system’s reaction to the virus) as well as secondary infections that turned lethal when the infected person’s immune system was too busy fighting off the virus. When antibiotics were discovered, the mortality rate of pandemic influenza viruses fell as secondary bacterial pneumonia could now be treated effectively. Antivirals such as Tamiflu, a neuraminidase inhibitor, are a recent development, but they have been shown to be effective against influenza in the most recent 2009 H1N1 influenza pandemic, causing the case fatality rate to fall further to 0.03% – very close to the case fatality rate for seasonal influenza.

References

J. K. Taubenberger and D. M. Morens 1918 Influenza: the Mother of All Pandemics

Note a: An 18th hemagglutinin antigen was found recently in bats

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