Back in April 2020, Bill Gates described the novel coronavirus behind the ongoing pandemic as the "once-in-a-century pathogen we’ve been worried about.” He was, of course, making reference to the especially nasty strain of flu that took hold of the world just over 100 years ago during the 1918 influenza pandemic.

Of all plagues great and small, few disease outbreaks have ever been more deadly than this one. Known as the "Spanish flu", the pandemic is thought to have wiped out over 50 million people, with some estimates going as high as 100 million – that’s way, way more than the number of deaths seen during the human-made horror of World War I, which had only just concluded in 1918.

But what made this outbreak so aggressive, widespread, and deadly?

The outbreak was caused by a strain of influenza A virus subtype H1N1. Other versions of H1N1 have appeared since, most notably the so-called “swine flu” epidemic of 2009, but none have reached the immensity of the 1918 outbreak.

Despite its common name, it most likely didn’t start in Spain. Unlike many other European powers at the time, Spain remained neutral during WWI, meaning the Spanish media was not subjected to wartime censorship and free to report on the outbreak in detail. This gave the impression the outbreak was more prevalent there, but it most likely originated elsewhere, perhaps the UK, France, China, or the US. 

Perfect Timing

The timing was ideal (for the virus, at least). It had never been easier for a pathogen to hop between cities, countries, and continents. The First World War had just seen the widespread movement of large numbers of troops across the globe. Paired with this, the start of the 20th century experienced a wider trend of increasing intercontinental travel and globalization. The planet’s inhabitants were coming into increasing contact with one another, often with little-to-no immunity of each other's "local brand" of lurgies.

However, science and technological advancement had not kept up in other respects. There were no vaccines to help prevent flu infection, nor antibiotics to help treat secondary infections like pneumonia. There were also no lab tests to detect or characterize these viruses, so knowledge about the virus was slim.  

The Virus Was The Perfect Killer

Something else important happened around this time, albeit on a much smaller scale. A major study from 2014 led by Professor Michael Worobey found that the H1 flu virus had entered the human population just 10 or 15 years prior to 1918. Then, suddenly, something big happened. Around Autumn 1918, it appears the virus managed to pick up genetic material from a bird flu virus. 

Other researchers have suggested that this, along with other mutations, “enhanced its ability to bind human airway receptors, presumably gaining transmissibility.” Something, although scientists still aren’t precisely sure what, happened to the virus that made it all the more potent, aggressive, and nimble. 

"It sounds like a modest little detail, but it may be the missing piece of the puzzle. Once you have that clue, many other lines of evidence that have been around since 1918 fall into place," explained Worobey.

Deaths were terrifyingly rapid, with many people falling ill and dying within a day or two. There’s one anecdotal account of four women meeting up in the evening, apparently feeling fit and well, and playing bridge together late into the night. By morning, three of them were dead from the infection. Being a quick killer is actually a pretty bad strategy for a virus as they need a live host to survive, spread, and thrive. Typically, most viruses evolve to become less lethal over time, but this strain of H1N1 was still young and reckless. 

Nobody Was Safe – Not Even The Young And Healthy

Unlike other influenza outbreaks, the 1918 strain wasn’t picky about who it infected either. Flu epidemics typically hit young children and the elderly the hardest, but the "Spanish flu" deeply affected young adults aged between 20 and 40. According to the CDC, the average age of those who died during the pandemic was just 28 years old.

While it’s unclear why the young and healthy were hit so hard, it’s most likely to do with the strains of flu they encountered as children when their immune system was building up. Young adults in 1918 were fairly likely to have encountered an H3N8 flu virus that was common between 1889 and 1900 during their childhood. It’s been suggested that exposure to this type of the flu may have resulted in their immune system “misreading” the H1N1 strain when it came around later in life. 

“A person with an antibody arsenal directed against the H3 protein would not have fared well when faced with flu viruses studded with H1 protein,” Worobey explained. “And we believe that that mismatch may have resulted in the heightened mortality in the age group that happened to be in their late 20s during the 1918 pandemic." 

What Does This Mean For Today's COVID-19 Outbreak? 

Any comparisons between disease outbreaks should be taken with a pinch of salt as outbreaks are always full of surprises, immensely complex, and tough to predict. Equally, the "flu bug" responsible for the 1918 outbreak is different from the coronavirus SARS-CoV-2 responsible for the global cases of COVID-19 at the moment. Not only is the pathogen vastly different, but it's also infecting an unrelated population, armed with new biomedical know-how and different immune systems. 

With that said, it would be naive to ignore the warning calls from the 1918 influenza outbreak.

“With Covid-19, are we seeing a replay of 1918?" question a team of virologists wrote in the New England Journal of Medicine in April 2020. 

“With luck, public health control measures may be able to put the demons back in the jar."

“If they do not," they added, "we face a daunting challenge equal to or perhaps greater than that posed by the influenza pandemic of a century ago.”