If I were to tell you that the single most deadly event in recorded human history took place in the 1900’s, what would you think it was? Probably one of the Great Wars – which would be close, but not quite right. The event took place from 1918 to 1919, but the killer was no human; the weapon neither bullets or gas. It was an enemy so small it cannot be seen by the naked eye: the 1918 Spanish Influenza virus, also known as “La Grippe.” During its year-long reign, this tiny virus killed between 50 and 100 million people across the globe. It killed more people in a single year than the Black Death did in the entire 14th century, more than either World War, and well over 6 times the population of New York City. Some even say that more Americans were buried in France having died of influenza than had been killed fighting on the battlefield. We get outbreaks of the flu every year without batting an eyelash, so what went so terribly wrong in 1918?
Meet the Microbe: 1918 Influenza A H1N1
The flu is caused by a virus: a tiny pathogen that reproduces in the cells of other organisms such as you or me. The influenza virus is made up of RNA (a nucleic acid like DNA) and belongs to the Orthomyxoviridae family, which probably tells you absolutely nothing but looks impressively unpronounceable. The viral RNA encodes all the information necessary for the virus to make proteins to invade the cells of other living creatures. Inside a host cell such as ours, the influenza virus hijacks our cellular machinery to create swarms of homicidal offspring. The virus replicates inside our cell and then new viral RNAs and proteins are packaged to form a virion as it exits the cell. These virions then invade other cells and hijack those as well, resulting in a cascade of replication and infection.
There are three types of influenza: A, B, and C. The 1918 influenza is a type A influenza, the most virulent type that is typically found in wild aquatic bird species – the 1918 flu was recently confirmed to have originated in birds[22, 16]. These viruses pass into other species and cause disease outbreaks. In humans, influenza A typically causes respiratory illness. Influenza viruses also have different subtypes, called serotypes. The 1918 flu is serotype H1N1; the H and N come from the viral proteins known as HA (hemagglutinin) and NA (neuraminidase) and the numbers correlate to subtypes of these proteins. These proteins are what your antibodies recognize in order to fight the virus.
Influenza & The Spanish Flu of 1918
The term “influenza” has been around for centuries. Influenza derives from the Latin for ‘influence of stars,’ suggesting that, back in the day, people believed the disease was a disaster sent from heaven . Today, we casually refer to this disease as “the flu” and, if we’re lucky, we associate it with an annoying annual shot and a potentially miserable week of aches and a fever. For infants, the immunocompromised, and the elderly this illness can be far more serious: 3 to 5 million people are infected each year and up to half a million of these cases result in death.
Unfortunately, larger, worldwide outbreaks of the flu can occur that result in over a million deaths. One of these larger outbreaks was our very own 1918 influenza, and it managed to shatter the mortality records. While the 1918 influenza virus was not more transmissible than other pandemic influenza strains, and whilst most of the infected individuals survived, the sheer breadth of the outbreak and the mortality curve set this outbreak apart from the rest[2,3]. This virus had a distinct, and disturbing trend: it targeted the young and healthy. The 1918 pandemic had such an impact that it actually decreased the overall life expectancy in the United States by 10-12 years (from 51 in 1917 to 39 in 1919) and the death rate for people aged 15-34 increased an incredible 2000% in 1918 from the previous year.
Mortality curves are used to visualize the mortality rate for different ages. Most influenza outbreaks have their peaks at either end of the age range: vulnerable infants and elderly. The Spanish Flu has a distinct W-shaped mortality curve, with a third peak at 28 years of age. Young adults typically fare very well with the flu, as they are generally in good health and their immune systems can handle the infection, so this peak is quite unusual. We are still uncertain of exactly why healthy, young adults were so susceptible to death with this pandemic, although it has been hypothesized that it could be related to previous exposures to flu outbreaks[17, 19]. Your adaptive immune system has memory, in the form of long lived cells (T cells) that can specifically recognize a pathogen your body has previously encountered. This is the basis of vaccines – you expose your immune system to the pathogen (in a state where it can’t cause infection), and your body creates these memory cells so that the next time you encounter the pathogen, it is nearly instantly recognized and dealt with. The aforementioned hypothesis suggests that previous exposure to influenza viruses that are similar may help the immune response, and the unfortunate folks born around 1880-1900 were only exposed to circulating influenza viruses that were far too different from the Spanish Flu to offer any protection.
When you catch a cold from an acquaintance you might notice that you suffer for a shorter amount of time with less severe symptoms than the person who infected you. If you’re unlucky, maybe you’re stuck feeling terrible for twice as long, sniffling so hard it’s like you have an entirely different sickness while you plot the demise of the ex-friend who coughed in your vicinity. The Spanish flu worked a little like this – there was a lot of variation in the severity of the disease between individuals and entire populations. When we see this, it suggests that factors unique to each person or population plays an important role: specifically, their immune system and genetics[20, 35].
Normally, and luckily for us, human influenza viruses don’t survive and reproduce very well in our lungs. The 1918 influenza was an exception, with the virus rapidly spreading to the respiratory tract after infection[29, 32, 12]. The virus replication causes severe damage to the cells in the lungs as well as triggering the immune system to produce inflammatory cytokines and chemokines. Animal models have demonstrated that this damage leads to dramatic swelling and pus in the lungs, while the body’s immune system spirals out of control and attacks itself in an autoimmune reaction to the virus[9, 10, 28]. While damage to the lung tissue would normally be repaired, the viral infection and subsequent damage increases people’s susceptibility to other bacterial infections, especially people exposed to bacteria they haven’t previously been exposed to. People who, for example, were in new environments such as the new military recruits, soldiers on troop ships, patients in hospital wards, and the staff of military wards.
Additionally, the damage to the cells in the lung causes unusual amounts of bleeding in these organs. Bleeding symptoms, including nosebleeds, were unusually common in the 1918 flu outbreak. Another unique symptom was a discoloration of the skin due to lack of oxygen (and consequent build up of deoxygenated haemoglobin in the blood). While cyanotic skin is caused by many conditions, the symptom was characteristic enough to the Spanish influenza to garner its own term: heliotrope cyanosis, an oddly romantic description inspired by a deep blue-purple flower. This lack of oxygen was likely caused by extreme damage to the lining of the lung, resulting in the little alveoli (where oxygen exchange from air to your blood occurs) filling up with fluid. In most cases of pneumonia, for example, only parts of the lungs fill with liquid. In the case of the Spanish flu, it’s believed that the entire lung succumbed to damage and filled with liquid, resulting in the distinct blue discoloration and a rapid descent into death: 95% of people died within a day of turning blue.
For those that did not suffer heliotrope cyanosis but still succumbed to the illness, death generally occurred within 7 days. The massive amount of damage and bleeding in the lungs combined with a lack of antibiotics meant that if you didn’t die due to blood loss, swelling, or drowning from the fluid buildup in the lungs directly as a result of the virus, other bacteria seize the opportunity to grow in your ravaged lungs and worsen the pneumonia[1,26]. This secondary bacterial pneumonia was the major cause of death from the Spanish influenza, with the most common culprit being the bacterium Streptococcus pneumoniae.
As with many major diseases, our (rather abusive) relationship with influenza reaches back thousands of years; Hippocrates recorded the first known flu epidemic in 412 BCE and we have had a close relationship with the disease ever since. In the past century alone, four major outbreaks of flu have occurred in the form of pandemics: the Spanish Influenza H1N1 in 1918 and 1919, the Asian Influenza H2N2 in 1957, the Hong Kong Influenza H3N2 in 1968, and the H1N1 Influenza in 2009. Such pandemics occur when humans are exposed to an influenza with a hemagglutinin protein they’ve never been previously exposed to and thus have no immunological protection against.
In March 1918, cases of an illness in military camps in the USA were reported, but drew little interest. Annual flu cases were hardly unusual, but by summer the illness was widespread; a 3 day fever that affected people across the globe. The Spanish Influenza occurred in three (arguably four) distinct waves. This first wave began in early 1918 with a low mortality rate but wide reach, as nearly all living humans were susceptible to the strain type we now know to be Type A H1N1. By the fall, the second wave had begun with a much higher mortality rate continuing into 1919. This second wave, along with a smaller third wave in the winter of 1919, is believed to have affected 30% of the entire world’s population: around 500 million people. To give just a small glimpse into the spread of this disease, nearly a third of Americans were infected and over 675,000 died; almost 20 million people may have died in India, over 2.6 million across Europe, 390,000 in Japan, 300,000 in Brazil, and 400,000 in Ghana – and this is hardly a complete list!
We are still uncertain exactly where (and when) the Spanish Influenza originally broke out. While the name suggests a strong connotation with Spain, it is actually not believed to have originated there. Spain was neutral during the war, and as such its press was uncensored allowing for widespread coverage of the disease and its spread (especially after King Alfonso XIII became ill in late May, 1918). The first public news of the epidemic was a Madrid headline on May 22, 1918, six days before the king was taken ill. The open reporting of the influenza in Spain is thought to be the reason why the disease became known as the Spanish Influenza, a rather unfortunate connotation to come out of a good thing such as uncensored news. The disease was even jokingly referred to as Soldado de Napoles, the Naples Soldier, which was a popular song as catchy and contagious as the illness appeared to be. While some embraced this morbid humor, at the same time Spanish cities were running out of coffins and the army was conscripted to help transport and bury the dead as resources were unable to keep up with the spread of disease. In some villages, the church bells that tolled for the dead were actually banned in order to avoid inciting panic[1,6].
On October 17th, 1918, even General Ludendorff commented that “the fighting power of the Entente [Allies] has not been up to it’s previous level…the Americans are suffering severely from influenza.” Could this pandemic have actually influenced the path of the war? Historians and scientists have investigated the impact it had on the course of World War I, and while it appears that it likely had minimal overall impact on the outcome of the war, it definitely affected fighting strength, morale, and caused delays in offensives.
At the time, people had very little understanding of the true cause behind influenza. There was no technology to isolate or recognize viruses. It wasn’t until the 1930’s that US and British researchers came up with a method that could isolate swine (pig) and human influenza. In the 1950’s, researchers attempted to isolate the virus from people who had died and been buried in permafrost graves in Alaska, which would have helped preserve the pathogen, but they had no luck. It wasn’t until the late 1990’s when Taubenberger et al. isolated the viral genome from US army soldiers and a buried Alaskan Inuit woman while working with the US Armed Forced Institute of Pathology[15,24]. This work identified the virus as Influenza A H1N1. Since then, scientists have used reverse genetics to actually recreate this virus and study it in animal models to help us understand just what made this influenza outbreak so deadly[10, 28].
Luckily for us, there don’t appear to be any cases of purposeful misuse of this virus. By reverse genetics, we have recreated this virus in order to study it and help us prepare for a future event of this magnitude, as we will likely continue to suffer influenza pandemics for as long as our technology is shy of eradicating such an elusive foe. Granted, this also means that there’s a possible potential to misuse this virus. This is a calculated risk that researchers take, as reviving and studying a disease is one of the only ways we can learn about it and be able to combat it. Half a million people die every year to various strains of influenza across the globe, and in the era of genetic engineering the use of influenza as a bioterrorism is enough of a potential risk that there are quite a few published papers regarding this specific concern. For you and me, however, I’d just suggest remembering to get our annual flu injections and keeping as healthy as possible to mitigate the far more likely scenario of us suffering an episode of naturally occurring flu.
At the time, there was no effective treatment for the Spanish Influenza. They attempted to treat the symptoms, such as using codeine for coughs, and even tried experimental vaccines to no avail as they believed it was caused by bacteria rather than a virus. Incidentally, their experiments using bacterial vaccinations during an influenza pandemic could support vaccination use in modern times to help control secondary infections, but the vaccines had no effect whatsoever on the actual viral infection. Travellers, baggage, trains, churches, and other areas of social congregation were disinfected with phenolic oil or creolin, and in some Spanish cities they cleaned the streets with diluted sodium hypochlorite and banned spitting in hopes of containing the disease[1,6]. Unfortunately, these measures seemed to have little impact on the overall momentum of the pandemic.
Nowadays, the best measures for influenza in general are preventative (get your flu vaccines and wash your hands!). In the case of having a serious influenza infection, there are antiviral drugs that help control the infection. Additionally, antibiotics are available to help treat any secondary infections that may occur.
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