This week’s entry brings us to the conclusion of my three part series on the flu. If you want to start at the beginning here are the links for Part I and Part II. The flu, with its predictable yearly visits, has become so familiar to us that we tend to forget that it is a truly serious disease. Each year 10 to 20 percent of the world’s population gets the flu, resulting in 500,000 to 1,000,000 deaths per year. Least we think this is just a problem for others, the United States an average of around 40,000 people die from the flu each year. 

At the top of the page is a picture of the influenza virus. You may recall from Part I that two types of antigens on the surface were called hemagglutinin and neuraminidase. Note that the names of these antigens start with H and N, which forms the basis for the naming system for the flu. There are 16 types of hemagglutinin and 9 types of neuraminidase. A flu virus with type 2 hemagglutinin and type 3 neuraminidase would be called H2N3 and so on. All told there are 144 types of the flu, the number of combinations between the 16 H’s and 9 N’s. Each of the 144 types can have many, many sub variations. As an example, the H1N1 virus from the recent 2009 pandemic was not the same as the most famous H1N1 influenza virus of all, the Spanish Flu of 1918. 
A distinguishing, and pernicious, characteristic of the flu is its tendency to mutate. As the flu creates copies of itself, it sometimes makes mistakes. This process creates relatively small changes in the virus and is called antigen drift. Antigen drift causes the year-over-year changes in the flu virus that require that we get new flu shots every year. If the change in the virus is not particularly significant, your antibodies from the pre-mutated strain will still have least some utility in fending off the new version.
There are two peak flu seasons around the globe each year, the southern and northern hemisphere winters.   The World Health Organization (WHO) monitors these alternating flu seasons to determine which three strains of virus will be used for the upcoming flu season vaccine. Since there are only 3 strains in the virus included in the vaccine, is it still quite possible for an immunized person to get the flu from a strain not included in the vaccine.  
Although there are 144 types of influenza, humans tend only to become infected with 6 types which result from combinations of H1, H2, and H3 with N1 and N2. This background is important to understand the extreme concern surrounding the Avian Flu which began in 2004. This was an H5N1 virus that acquired the ability to spread from poultry to people. Since humans don’t typically get H5 viruses we don’t have any antibodies against them. Secondly, and more importantly, 50 to 60% of people who get infected with H5N1 die. Contrast this to the mortality rate of 0.1% for seasonal flu and you can start to see the basis for a little hysteria. Fortunately this virus proved to not be effective in spreading from human to human, which prevented the feared global pandemic, at least for now (more on that below). The content of this paragraph does not make the cut for a typical news article about the flu. This is unfortunate since the presence and novelty of H5 is important for the reader to understand the risks of this particular virus.
Things get interesting, and scary, for influenza when a phenomenon called antigen shift occurs instead to antigen drift. Antigen shift can occur when a single host cell is concurrently infected with two different types of virus. The viruses within the cell can swap DNA strands to create a novel virus that no human being has ever had before. The disaster scenario would play out as follows. Someone gets a seasonal flu which is particularly efficient in spreading from person to person. This same person contracts H5N1. The two viruses swap DNA and create a virus which can spread like seasonal flu and kill like 2004 H5N1 Avian Flu.  A scenario like this one could result in a global pandemic not dissimilar to the one portrayed in the recent movie Contagion. It also explains why, despite the small number of human cases of H5N1, the WHO devoted significant resources to containment and why millions and millions of poultry were euthanized to prevent the spread among birds. Given the short attention span in the media you might be surprised to see, as shown in the graph below, that the number of human H5N1 cases was the same in 2010 as it was in the year 2004 when we had the panic. 
The most famous flu pandemic began on March 4, 1918 when US Army company cook Albert Gitchell reported sick at Fort Riley in Kansas. Within several days 522 men at the camp reported sick and within a week the flu, an H1N1 type, had reached New York City. Later studies showed that this flu was the combination of a human and pig virus, hence it is often called the swine flu. This flu pandemic infected more than one quarter of all people on the globe and had a mortality rate of 10-20%. It killed somewhere between 50 and 100 million people worldwide in only a few months.   As a contrast, consider that AIDS has killed 25 million people over 25 years.  Many countries around the world in 1918 had news censorship as a result of being involved in World War I. Spain, not being involved in the war, had no such black out, so its newspapers reported on the devastation of the disease. As a result, this flu pandemic came to be known as the Spanish Flu.
The Spanish Flu was very unusual in its profile of victims. Normally the flu is deadly to the young, the old, and the infirm. In contrast to this, many of the victims of Spanish Flu were between 20 and 40 years old. In a bit of macabre irony, many these people in the prime of their lives were killed by their own immune systems in what is called a “cytokine storm.” Recall from Part II that infected cells in your body release chemical signals called cytokines which call in an array of different types of white blood cells to come fend off disease. Your white blood cells come to the site of infection and kill infected cells and clear dead matter. If the infection spreads very rapidly, which was the case for Spanish Flu, the production of cytokines is very fast as well.  In this circumstance, a person with a strong immune system will rapidly send in a large concentration of white blood cells. Recall from Part I that the flu primarily infects cells in your lungs.   The white blood cells start doing such an effective job of killing and removing the infected cells that the inside of your lungs begin to bleed and become inflamed. In strong Spanish Flu victims the self-reinforcing effects of this cytokine storm effectively dissolved the inside of their lungs causing death often within 24 hours of the onset of symptoms.
To properly understand the mortality rates of the Spanish Flu, it’s important to remember that this pandemic occurred prior to the age of antibiotics. It’s estimated that more than half of the deaths were not from the influenza itself but from opportunistic bacterial infections, pneumonia, in the flu-damaged lungs in people who survive the initial onslaught from the virus. Today we can prevent the pneumonia deaths with simple antibiotics. In fact the next three global pandemics, 1957 Asian Flu, 1968 Hong Kong Flu, and the recent 2009 H1N1 flu were less severe, partly from their inherent characteristics and partly because we did not let their victims get pneumonia.
 I was critical of the WHO in “Is Your Cell Phone Going to Kill You?” so I feel compelled to note that the WHO was unfairly criticized as alarmist during the 2009 H1N1 outbreak. The public and the news media incorrectly interpret the word pandemic to relate to virulence not spread. The WHO classifies pandemics on degree of spread.   H1N1 spread to the entire world and fit all criteria for a stage 6 pandemic. 
The recent movie Contagion depicts a global pandemic and our societal response. The depiction of the pandemic and the efforts to develop a vaccine are quite accurately portrayed. As for the accuracy of the portrayal of societal response, time will tell. Pandemics will continue to happen. Those that stay within the typical arena of H1-3, N1-2 will likely be similar to those from 1957, 1968, and 2009 since we all have antibodies in that range. The chance for a Contagion-like disaster is a race against time. On the one side is a novel virus, like H5N1, which is very deadly and to which we have no antibodies. This novel virus is just waiting to splice DNA with a flu which can spread quickly in humans. If this happened today we could have an experience just like portrayed in Contagion. On the other side are scientists and engineers trying to change the way we make vaccines, from the old, slow way of growing them in chicken eggs to a more modern biotech method of manipulating cells which are in a chemical reactor to have them make the antibodies. The cell-based method is an order of magnitude faster than making vaccines in chicken eggs. Once this method is available, which likely will be within the next 5 to 10 years, the time required to make a vaccine to fend off a new pandemic virus will drop from months to weeks. Having the vaccine available this quickly would stop the pandemic in its tracks.
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