I had a little bird,

Its name was Enza.

I opened the window,

And in-flu-enza. ~ Children's Skipping Rhyme, 1918

Like most rhymes that one learns as a child, I had no idea at the time what this one meant, nor did I ponder its possible meaning as I grew older. But one afternoon, this poem's significance became startlingly clear to me. As I sat in a large university lecture hall where I was working towards my microbiology degree, these words abruptly popped into my mind during lecture. I was surprised by this unexpected and noisy mental guest; my life had changed in almost every conceivable way since early childhood and I hadn't thought about that rhyme in many years.

Having earned part of my tuition by working in a hospital microbiology lab, I found microbiology fascinating, but this particular lecture riveted me like no other because it shook my worldview. This was the lecture about influenza, including a discussion of the pandemic of 1918-1919. This worldwide disease outbreak had unparalleled deadliness, claiming more lives than did any of the plague pandemics, yet I had never even heard about it.

It sounded like science fiction rather than science fact to hear that between 50 and 100 million people (3-6% of the world's population at the time) perished in less than 18 months' time -- the greatest number of human deaths due to infectious disease ever recorded.

This particular strain of influenza popped up during World War I, "The Great War" as it was known in those brief years before the conclusion of the Second World War. At the time, this influenza variant was commonly known as the "Spanish flu" because neutral Spain's media, which enjoyed relative freedom from censorship, openly reported this nation's influenza woes, which made its situation appear more dire than anywhere else.

Despite their comparative silence on the matter, France, Great Britain, and the United States all suffered greatly, too. Their influenza deaths were much higher than those caused by the war itself. Much later, archival records revealed that influenza probably struck German and Austrian troops first, and it struck them very hard before expanding into their civilian populations and spilling over into Allied troops. The resulting losses on both sides were so terrible that many historians think influenza contributed significantly to an early conclusion to the war.

During that last summer of The Great War, flu continued its exceptional rampage, hitchhiking everywhere that people traveled: even the remotest corners of the globe were not safe. Ninety percent of Western Samoa's population became infected and twenty percent died in just two months. Entire villages in Alaska perished. Even my professor, whose PhD was the result of her studies of Yersinia pestis -- the Black Death, another major killer of humanity -- was openly awestruck by influenza's deadly efficiency.

The 1918 influenza virus's style of killing was unlike that seen for most other influenza strains known. Airborne, it was highly infectious, causing illness in 50 percent or more of those exposed to it, and its morbidity and mortality rates were peculiar, too: it had an estimated mortality rate of 20 percent, whereas other strains of influenza normally kill just 0.1 percent of their victims. Its patterns of lethality were unique, preferentially killing healthy young people between 20 and 40 years of age whilst leaving older people relatively unharmed. Additionally, it was an especially efficient killer of pregnant women, whose mortality rate ranged between 23 and 71 percent.

Where did this supervirus come from? How could such a potent disease pop up without warning? How did it kill so many people? And perhaps the cruelest injustice of all, why did its deadliest rampage occur just as The Great War was finally ending?

Mysterious origins and unanticipated allies

A lot of scientific, medical and historical detective work has been published over the decades, but it still is not known with certainty where this viral strain originated. A number of scientists argue that it came from China (doi:10.1126/science.1093155), a country where even today, ducks, pigs and humans often live in close proximity to each other -- the perfect biological mixing bowl whereby novel influenza viruses evolve the ability to "jump" from animal hosts into humans, causing severe illness against which no humans have established any prior immunity. Military historian Mark Osborne Humphries came to the same conclusion, extensively referencing archival materials documenting that this influenza strain arose in 1917 in China, and showing how military pathways carved across the globe to sustain the war effort facilitated its rapid spread on the Western Front (doi:10.1177/0968344513504525). Several historians, particularly John Barry, argued that the virus originated on a pig farm in Kansas, in the central United States (doi:10.1186/1479-5876-2-3; also see his book [2009]) whilst Austrian documents led political scientist Andrew Price-Smith to propose that it originated in Austria in 1917 (2008).

Regardless of where it originated, the 1918 influenza virus quickly mutated into an efficient killer of humanity.

In fact, the increased lethality of the 1918 flu virus was the trait that became most inexplicable to me, as I sat transfixed in that university lecture hall. All the pathogens we'd learned about thus far had mutated towards becoming less virulent. This is due to several evolutionary reasons. Most pathogens exist in a precarious balance between maximizing their ability to be transmitted to new hosts and to appropriate host resources for rapid replication, with virulence. Pathogens don't "want" to kill their hosts (this is not in its best interests), but when increased dispersal and replication capabilities don't reduce virulence, the resulting pathogen typically does become more lethal. However, if a pathogen becomes so deadly that it kills its current host before infecting new hosts, the epidemic quickly burns out and that particular viral strain is replaced by less lethal variants.

This scenario is precisely what was observed when Australians, desperate to rid the continent of hundreds of millions of invasive feral rabbits, introduced the potent rabbit-killing virus, myxomatosis, in 1950. Over the ensuing years, not only were the few surviving feral rabbits capable of developing immunity to the virus (a trait they passed on to their offspring), but the virus itself evolved to be less lethal.

The 1918 strain of influenza became a mass killer partly due to the influence of an accidental ally: the victim's own immune system. Although the mechanistic and biochemical details are poorly understood, scientists found that the 1918 influenza virus can trigger a localised positive feedback loop known by the picturesque term, "cytokine storm" (doi:10.1056/NEJMp058068). A cytokine storm is an increasingly robust expression of an otherwise normal immune response, but it quickly escalates until it is out of control, causing biological inflammatory factors, immune cells and body fluids to accumulate in the affected area. This produces lasting damage to the tissues under attack. If this immune response is not brought under control, it can spread throughout the entire body, attacking all organs and causing death.

Whilst those patients who lingered for a week or more succumbed to secondary infections by bacterial pneumonia, the most rapid deaths resulted from a cytokine storm in the lungs that caused the victim to drown in his own body fluids within mere hours. This out-of-control immune response is reflected by the demographics of those who died: young adults produce the most robust immune responses to infections, and death-by-cytokine-storm is consistent with the high mortality in this age group. Subsequently, it has been found that cytokine storms can be triggered by other viral infections, including several more recent influenza strains.

How the Great War helped create a supervirus

When stressed people are crowded together, as are students in university dorms, and residents of refugee camps, prisons and hospitals, their close proximity and compromised immune systems provide the perfect opportunity for a pathogen to enhance its virulence. Unlike people, pathogens have a high mutation rate, a very rapid generation time and they produce immense numbers of progeny. Individual pathogens carrying mutations that improve replication or dispersal abilities quickly win the infection competition, but when immunologically-naïve hosts are so plentiful and so readily available, there is no selection pressure against developing increased virulence as well.

Influenza, a virus that seems to cultivate its especially high mutation rate, found itself in a perfect supervirus testing ground when it infected stressed-out and often malnourished soldiers crowded together in trenches and in hospitals. The most virulent influenza strains became widespread when sick soldiers were transported -- sometimes long distances -- to military hospitals for more intensive treatment, whilst those infected with less debilitating strains remained entrenched.

As is the case for most influenza pandemics, the 1918 strain passed through the human population in three or four pandemic waves, each more lethal than the previous. The first wave was highly contagious but its symptoms were mild -- so mild that the medical establishment argued that it really wasn't influenza at all. Yet fortunately for those infected in the first wave, they developed immunity to what was to come. The second wave, which may have popped up in several locations simultaneously in August 1918, was just as contagious as the first wave, but much more virulent, particularly at the beginning. By November 1918, the second wave had run its course by evolving into a less virulent virus. As people celebrated the end of the war and welcomed their soldiers home again, the third wave of influenza popped up. The third wave was also very contagious and virulent but since it didn't reach some areas, and because it overlapped with the second wave in other locales, it is difficult in retrospect to distinguish and characterise.

Nearly 100 years have elapsed since this most deadly of all documented pandemics roared around the planet. This pandemic benefitted from conditions created by the Great War, but to this day, thousands of important questions about the nature of the 1918 influenza pandemic remain unanswered; did this virus originate in animals? Since this virus also was the source of an overlapping pandemic in swine, was this the entry point for influenza virus into the global pig population? What gave this virus its (so far) unique ability to generate three waves in just a single year? Why were so many 5-14 year old children infected by flu, yet so few died?

Despite our modern antiviral and antibacterial drugs, vaccines, and prevention knowledge, we are not immune to another pandemic virus. Even today, we can still hear the ghostly echoes of the 1918 influenza pandemic when we read news reports about the emergent ebola virus and its deadly outbreak in several African nations. With the advent of ever faster travel options and as more people travel ever greater distances for work and for pleasure, the possibility exists that another great pandemic awaits, just on the horizon. Only by gaining a clearer understanding of the historic, epidemiologic, and biologic aspects of the 1918 influenza pandemic will we be able to better prepare for what lies ahead.

Sources:

Taubenberger J.K. (2006). 1918 Influenza: the Mother of All Pandemics, Emerging Infectious Diseases, 12 (1) 15-22. doi:10.3201/eid1201.050979 [OA]

Gamblin S.J. (2004). The Structure and Receptor Binding Properties of the 1918 Influenza Hemagglutinin, Science, 303 (5665) 1838-1842. doi:10.1126/science.1093155 [$]

Barry J.M. (2004). The site of origin of the 1918 influenza pandemic and its public health implications (Commentary), Journal of Translational Medicine, 2 (3) doi:10.1186/1479-5876-2-3 [OA]

Humphries M.O. (2014). Paths of Infection: The First World War and the Origins of the 1918 Influenza Pandemic, War in History, 21 (1) 55-81. doi:10.1177/0968344513504525 [OA]

Osterholm M.T. (2005). Preparing for the Next Pandemic, New England Journal of Medicine, 352 1839-1842. doi:10.1056/NEJMp058068 [OA; also includes a podcast interview and useful images]

The United States Department of Health and Human Services' superb dedicated site, The Great Pandemic 1918-1919

Books:

Barry, John. The Great Influenza: The Epic Story of the Deadliest Plague in History [Penguin Books, revised 2009; Amazon UK; Amazon US/kindle US/audiobook CD US]

Price-Smith, Andrew T. Contagion and Chaos: Disease, Ecology, and National Security in the Era of Globalization [The MIT Press, 2008; Amazon UK/kindle UK; Amazon US/kindle US]

.. .. .. .. .. .. .. .. .. .. ..

When reading about influenza has not got her sitting on the edge of her chair, GrrlScientist can be found here: Maniraptora. She's very active on twitter @GrrlScientist and sometimes lurks on social media: facebook, G+, LinkedIn, and Pinterest.