Influenza: The Past and Future Threat

The following article is a transcript of a lecture by Professor Barry C. Fox, M.D.

“Of all the health disasters over time, the Spanish flu ranks near the top of the list. It was one of the worst pandemics in history. Between 5 and 10 percent of the 500 million people who were infected died. No one knows the final actual death toll, but more people died from the flu than the total number of people killed in WWI.”

Image of lady surrounded by influenza germs and H1N1 llogo

Today we are going to take a look at one of the deadliest flu episodes ever—The Influenza Pandemic of 1918. The attacks of flu occurred in waves, in mid-1918, then again in the spring of 1919. Between 30 and 50 million people died worldwide, including 43,000 U.S. servicemen who, ironically, had survived the First World War but couldn’t fight off the flu.

Learn more: Viruses: Hijackers of Your Body’s Cells

The 1918 influenza had a designation as a “swine flu” variety, with the letters H1N1, which I’ll explain in a few minutes.

Why was it also called the Spanish flu? No one truly knows exactly where the flu started, but in Spain in 1918, there was an epidemic of influenza that actually left the country’s population growth in the negative direction. Although some people believe the Spanish outbreak was the beginning of the pandemic, the origin still remains speculative among virologists.

The Spanish Flu is Born

Most physicians at the time believed that influenza was caused by a bacterium, not a virus, but autopsies had continually failed to produce identification of a bacterial germ. They did, however understand germ theory by then, that influenza was spread through coughing, sneezing, and close personal contact. Unfortunately, there was no flu vaccine in those days, and efforts to develop one at the time failed. Instead, quarantines were put in place and bans were placed on public gatherings as a deterrent to contagion.

Health officials tried to control the spread of influenza by insisting that people wear masks. However, they didn’t realize that the masks were made from gauze, and they could not prevent the viruses from passing through because the holes in the mask were too large to halt a virus.

Public officials tried to limit the spread of influenza by banning spitting in public places and demanding that everyone cover their mouths and noses while sneezing. In addition, there was a shortage of physicians due to the First World War, so nurses and medical students often were left to staff emergency clinics. Health officials tried to control the spread of influenza by insisting that people wear masks. However, they didn’t realize that the masks were made from gauze, and they could not prevent the viruses from passing through because the holes in the mask were too large to halt a virus. In other efforts to control influenza, the public health departments declared it one of the “reportable” diseases to track its spread; however, the rate of spread was so rapid, it was virtually impossible to keep accurate records.

Learn more: Antibiotics: A Modern Miracle Lost?

So what exactly is the difference between an epidemic and a pandemic? An epidemic arises when a disease spreads rapidly to many people in a limited geographic region, so influenza in the U.S. on a yearly basis is an epidemic. A pandemic means there is global spread of the disease.

Returning to our pandemic, shysters trying to make a buck ran advertisements in the newspapers, claiming they had a cure—similar to selling snake oil to cure ailments. Others claimed influenza was cured by drinking alcohol, and there were runs on the liquor stores. Folk medicine practitioners recommended wearing a specific amulet or a small bag of camphor for protection. This practice was taken from the Middle Ages, when people were trying to protect themselves from the plague. But of course, none of these worked. Influenza started spreading worldwide, with no effective treatments.

An epidemic arises when a disease spreads rapidly to many people in a limited geographic region. A pandemic means there is global spread of the disease.

Of all the health disasters over time, the Spanish flu ranks near the top of the list. It was one of the worst pandemics in history. Between 5 and 10 percent of the 500 million people who were infected died. No one knows the final actual death toll, but more people died from the flu than the total number of people killed in WWI.

Seasonal flus are caused by influenzas types A and B. Influenza A can affect both humans and animals. It has the highest pandemic potential due the possibility for mixing animal and human genes, leading to surface protein mutations. Influenza B is a human virus only, has much less mutational capacity than type A, and has only one set of surface proteins, hence there’s only one species. But, with influenza B, there are slight variations of the structure, similar to flavors of ice cream, that give influenza B strain various numbers. The strains are determined in the city and the year in which it originated, such as B/Shanghai/361/2002.

Influenza C is a human flu that causes a very mild respiratory illness, and often is not even recognized as a classical clinical influenza illness. Importantly, neither Flu B nor C is associated with pandemics.

The Influenza Virus – A Closer Look

Let’s learn a little more about the actual influenza virus and how it causes human disease. Influenza virus is an RNA virus in the Orthomyxovirus family. Like all viruses, it can’t replicate by itself. It needs to take over the protein machinery of a living cell and reprogram the cell to create more virus particles, which usually results in cell death.

Type A virus is covered on its envelope, or outer surface, with two types of foreign proteins spikes known by the letters H and N. H is an abbreviation of the word hemagglutinin, and N is an abbreviation for neuraminidase.

Illustration of the Influenza Virus

The H spike is used like a hook by the virus to attach itself to the outside of a host cell.

Illustration of The Mechanics of The Influenza Virus

The cytoplasmic membrane of the cell next engulfs the virus and pulls it inside.

Illustration of The Mechanics of The Influenza Virus

Through a complicated series of maneuvers, including uncoating of the virus—where the RNA slips out of its viral coating…

Illustration of The Mechanics of The Influenza Virus

…the virus tricks the host cell to let the viral RNA into the cell, and once this occurs, the virus is in control.

Illustration of The Mechanics of The Influenza VirusRemarkably, within about 12 hours of hijacking the cell, the influenza virus can release up to one million new viruses. With such a rapid rate, there is a high possibility for genetic mutations.

Illustration of The Mechanics of The Influenza Virus

The antiviral medications Amantadine and Rimantadine were effective for influenza A virus for years. Both medications inhibited virus replication by interfering with the viral uncoating process heading inside the cell. Importantly, the high rate of mutations of influenza A has led to the emergence of widespread resistance to both of these antiviral medications, so much so that neither are used for treatment anymore.

The N, or neuraminidase, is essential for the virus to break out of its host cell, essentially performing the opposite of the H, cutting holes in the cell membrane from the inside to allow the virus to escape and infect other cells.

Learn more: Outbreak! Contagion! The Next Pandemic!

Antiviral medications known as neuraminidase inhibitors are fortunately still effective in shutting down virus replication. Oseltamivir and Zanamivir are two of these antivirals, and others are being developed. They work against both influenza A and B and so far, the viruses have shown a very low mutation rate against them. The antivirals inhibit the release of the virus from the host cell by blocking neuraminidase, so the viruses are trapped inside. When these antivirals are given within the first 72 hours of influenza illness, they can shorten the duration of clinical illness by one or two days. They have been shown to reduce the rate of secondary bacterial infections of the lung as well.

During the 1918 Spanish flu, while most patients subsequently recovered, some had a relapsing respiratory problem. Ironically, many victims died from a secondary bacterial infection rather than from the actual influenza.

Antiviral medications are also deemed to be helpful in those unfortunate enough to be hospitalized for influenza, even when the 72-hour window has expired. In general, the earlier they’re given, the more clinical benefit antivirals are likely to have. They can also judiciously be used for prophylaxis or prevention of flu when there are outbreak circumstances in a closed institution, such as a nursing home. As always, this use would need to be balanced against the risk of creating viral mutants, since the prophylaxis dose is half of the treatment dose.

Researching The Original Spanish Flu Virus

So back to the 1918 flu: Why was the Spanish flu virus so virulent? The National Institute of Allergies and Infectious Diseases have been researching the answer to this question. They even retrieved gene sequences of the 1918 flu virus from victims buried in Alaska’s permafrost. Note that this work was done in a very high-level biosafety lab to ensure the virus was well contained so as to not start another pandemic.

Image of Scientist in bio-safety lab
Scientists working within a biosafety lab must wear protective garments that are air-tight, thereby protecting the technician from exposure to highly-infectious pathogenic organisms.

Using 8 of the original genes, researchers genetically reverse-engineered the virus, then injected it into mice. They found that the virus was much more lethal than usual to mice, but this did not explain the mechanism of extreme virulence. Using current studies of bird, or avian influenza, one of the mechanisms of lethality may have been discovered. A receptor protein of the 1918 flu virus was very similar to a modern version of the avian flu, which may help explain its virulence.

Let me explain a little further. An unusual quality of avian influenza is that the bird virus proteins are not usually able to bind well to the human throat receptors.

Scientists believe that in order for the virus to leap from birds to humans, they have to pass through an intermediate animal that contains both bird and human receptors, like a pig, for example. However, the 1997 avian bird flu outbreak showed that an intermediate host might not be needed since that virus could jump directly to humans.

illustration of the avian flu cycle

A similar type of strong attachment protein for human throat receptors may be the virulence story of the Spanish flu. I’ll tell you more about this hypothesis later.

This is a transcript from the video series An Introduction to Infectious Diseases. It’s available for audio and video download here.

Why is a virus called H1N1? Well, the virus has hemagglutinin type 1 protein—for example, the H1—and neuraminidase 1 for the N1 protein. There are 16 versions of hemagglutinin, and 9 of neuraminidase, so you can expect to see many combinations of influenza viruses in the future.

We also need to introduce two important biological aspects of influenza: antigenic drift and antigenic shift, to understand why changes in viruses can have such a huge impact on disease prevalence. Antigenic drift is a process in which mutations to the virus genome produce changes in the viral H or N proteins. This drift results in the emergence of new strains when either the H or the N protein undergoes minor changes, for example H1N1 to H1N2, or even a tiny change in the structure of H1N1.

Image of influenza virus
Influenza virus, magnified approximately 100,000 times

This is why the flu vaccine contains a different mix of viruses each year, and must be updated annually. Because this is a single mutation, however, usually our bodies recognize at least one of the two proteins. We still experience a partial immune response that helps us fight the virus.

Antigenic shift, on the other hand, is the reason that pandemic viruses arise. Instead of modifying the existing H and N proteins, the proteins are replaced by significantly different Hs and Ns, for example, H1N1 to H5N2. This means that our bodies do not recognize either of these new Hs and Ns and therefore, we don’t have any preexisting antibody to protect against them.

The Creation of A Pandemic

A pandemic is usually caused by a new strain of the virus, or a reappearing one. These viruses either have never circulated among humans before, or they circulated many years ago. So either humans have no immunity against it, or very little. This makes the virus easy to spread.

All influenza pandemics since 1918 have been caused by viruses with RNA genetic remnants of the 1918 virus. In addition, all of them also contained RNA from swine. Importantly, the internal RNA genetic composition of influenza viruses is only loosely correlated with the nomenclature of the H and N proteins. So in a way, the 1918 pandemic earned the right to be called the mother of all pandemics. So far there have been 4 influenza pandemics in the last century, which spread to all countries within 6 to 9 months. The other 3 were the 1957 Asian flu, 1968 Hong Kong flu, and the 2009 Mexican flu. Since the speed and frequency of air travel has significantly increased since the 1960s, a much faster spread of influenza was seen in the 2009 pandemic.

Pandemic viruses can also originate when some of the genes from animal flu viruses mix with genes from human flu viruses to create a whole new hybrid.

This happens when an animal or person is co-infected by both a human virus and an avian flu virus at the same time. The process of combining viruses is called reassortment. The 2009 Mexican flu virus was actually a combination of swine, bird, and human flu viruses.

It’s a little hard to believe that descendants of the 1918 virus still persist in pigs today. After the 1957 Asian flu, the H1N1 descendants of the 1918 strain had seemingly disappeared from human circulation until a mysterious event happened in 1977. Human H1N1 viruses suddenly reappeared. The 1977 swine flu first emerged at Fort Dix, New Jersey, and killed several soldiers.

This was the impetus for the urgent creation of a swine flu vaccine that 40 million U.S. citizens received in record time. This vaccination effort was shrouded in controversy because it may have caused a slight increase in the incidence of a very rare neurologic disorder, Guillain-Barré syndrome. Also, the pandemic never materialized. So the side effects of the vaccination overshadowed the positive aspects of the rapid vaccine development and a mass public health response. It made many people reluctant to get the routine flu vaccinations for years to come after that event.

Image of the influenza pandemic timeline
The H1N1 Virus continues to mutate as it finds new hosts to infect

Clinical Illness Caused by The Flu

Let’s talk now about clinical illness with the flu: What makes influenza stand out from other respiratory illnesses? Well, the term influenza-like illness, or ILI, is used to describe the symptom complex. There is usually an incubation period of 1 to 4 days between the time the virus is acquired and the time the illness begins.

Image of Woman in bed suffering from the fluNot everyone with ILI has true influenza. In fact, there are many viruses that can mimic influenza, and several go by the strains of virus known as para-influenza 1, 2, and 3. There are also others. Usually ILI begins with a runny nose and upper respiratory congestion for 24 hours. This is while the virus is gaining entry into the surface lining of the nose and mucous membranes of the head. In the next 24 hours, a sore throat and headache symptoms begin. The headache of true influenza seems to be relatively distinctive compared with other ILI, usually towards the front of the head and with the distinction that moving your eyes back and forth in the sockets elicits discomfort in your eyes. Fever usually begins during the second day.

But this is just the beginning. Within the next 24 hours, the virus invades the bloodstream, breaking through the respiratory linings. True influenza virus has a propensity to invade muscles, sometimes leading to the agonizing muscle aches, and feeling of inability to move.

True influenza virus has a propensity to invade muscles, sometimes leading to the agonizing muscle aches, and feeling of inability to move.

In France, influenza was known as “la grippe,” referred to a gripping sensation in the muscles. The virus also descends into the upper airways of the lung, usually causing a dry, non-productive cough with white phlegm. Primary influenza, though, is unusual, but it can occur in very young children, elderly adults, or patients with compromised immune systems.
In order to fight the virus, the body now starts to mount a higher fever—trying to kill the virus—usually of about 102 to 103 degrees. The resetting of the body’s thermostat can often lead to episodes of shaking chills that may feel uncontrollable.

Learn more: Emerging and Reemerging Diseases

Even three days into the illness, relief does not come quickly. The main symptoms persist for up to another 72 hours, before finally scaling down on the 7th day of the illness. It may still take 3 to 5 days to get back to feeling “normal.”

While most of us will recover, presently influenza leads to the hospitalization of more than 200,000 people yearly and results in 30,000 to 50,000 deaths from flu or flu-related complications in the United States.

Just a side note—are you wondering about the so-called stomach flu that some of us grew up with? This is actually a misnomer since the flu doesn’t usually have intestinal symptoms. Most likely, the stomach flu of the ’50s and ’60s was really the norovirus.

The Flu Vaccine

Image of a band-aid on a vaccination arm

Getting back to influenza, with all of these miserable symptoms, who wouldn’t want to prevent this illness with vaccination? While we are talking about vaccination, it’s worth mentioning that there has been an advance in the vaccine, moving from two flavors of type A strains and one flavor of type B, to a vaccine with two strains of both A and B. We call this a quadrivalent vaccine, and it has had more opportunity for successful protection.

Other changes to prior vaccination policy include allowing most patients with egg allergies to still be vaccinated, recommending that children ages 2 to 8 receive the live, rather than killed, flu vaccine, and preferring a “high dose” vaccine for those over the age of 65, possibly for better prevention efficacy.

You might be wondering since the manufacturing of the vaccine obviously takes several months, how the World Health Organization determines which strains of influenza will be targeted in the vaccine for the fall? This is an important decision and involves influenza experts from all over the world. If the wrong strain is chosen for production, the efficacy of the vaccine may be more limited. In general, the northern hemisphere takes its cue from the vaccine composition from the southern hemisphere, and vice versa since the seasons are reversed.

In February, they decide on the vaccine for the northern hemisphere for the next season based on information gathering from influenza centers in 100 countries and other partners who conduct global surveillance year round.

The exact reason for the seasonality of most strains of influenza in temperate climates has been studied in detail but is not definitively known. Influenza exists at a low level throughout the year, but exhibits a marked seasonal increase during the winter months. This is probably a combination of factors, including cooler temperatures and lower humidity, which favors virus survival outside of humans. Also, more crowded indoor environments in the winter play a role in this increase. Influenza occurs in tropical areas as well, but not typically with the same seasonality.

Learn more: Which Germs in Your Daily Life Matter?

The Future of Influenza

Well, what’s in store for us with influenza? Conceptually scientists believe that history will repeat itself, and it’s not a matter of whether there will be another pandemic, but a matter of when it will be, and what strain of the virus. At the University of Wisconsin, our infectious disease department feels like we might be the gatekeepers of the next flu pandemic.

Conceptually scientists believe that history will repeat itself, and it’s not a matter of whether there will be another pandemic, but a matter of when it will be, and what strain of the virus

Let me explain further. Researchers in Madison have carefully studied genetic databases of avian flu that most closely contained proteins that resemble the 1918 Spanish flu. They use an animal model—ferrets—that have the capacity to contract and transmit influenza, and are a close model of human transmission.

The researchers intentionally altered the genetic code of the virus to within 3 percent relatedness of the 1918 Spanish flu. This enabled the virus to have receptors that would allow direct respiratory droplet transmission of influenza from ferret to ferret. These mutations involved only 7 tweaks of the virus.

This creation of an artificially virulent strain of avian flu generated tremendous international scrutiny. The Wisconsin researchers claimed that we needed to know this information to advance our knowledge of how pandemics begin, with the hope of designing better vaccines. They argued that the pandemic risk was already present in nature, and that it was more important to understand the viral properties, especially of H5N1 avian flu. Since 2003, H5N1 has infected nearly 1000 people in 20 countries with a 50 percent mortality rate.

Since 2003, H5N1 has infected nearly 1000 people in 20 countries with a 50 percent mortality rate.

They did test the antiviral oseltamivir against the mutant strain, and they fortunately found the drug was effective. This supports the pandemic preparedness belief in stockpiling anti-influenza drugs is important.

The opposing view was the obvious concern that the virus would escape and actually cause a pandemic, or that terrorists might steal the virus and use it as a biological weapon. For more than a year, there was a worldwide moratorium on this type of flu research until the scientific community had a chance to discuss the risk/benefit ratio in more detail. Our own National Institutes of Health, or NIH, debated these issues and eventually issued a supporting statement for ongoing research and demonstrated that appropriate biosafety measures were taken. The moratorium was lifted.

Other emerging avian flu viruses have been seen worldwide. For example, the H7N9 avian flu also reappeared in China with a 25 percent mortality rate.

However, careless handling of avian flu specimens at the CDC in 2014 and the Ebola outbreak reopened the debate. The momentum has shifted towards shutting down these experiments.

Well, since I’m teaching and practicing infectious diseases at the University of Wisconsin, now I know what Pandora felt like before she opened her box.

Our infectious disease group is on the front line with the university and the public health department if there is ever an accidental release or exposure of the virus. Facilitated by the Ebola outbreak, proactive plans are in place should this horrible event ever occur.

From the Lecture Series An Introduction to Infectious Diseases
Taught by Professor Barry C. Fox, M.D., University of Wisconsin