A Major Avian Influenza Outbreak Could Kill 62 Million People

“It’s just a matter of when it happens, how it happens, and how deadly it's going to be.”

Michelle Malia

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Pathogens love us—we offer them a whole host of ways to attack our bodies. We consider them "bad" because to exist they must invade our cells, but just like us, pathogens are organisms that evolve with one goal: survival.

In order to not die off, bacteria and viruses have to efficiently infect us and reproduce. Herpes and HPV spread best through sexual contact, Lyme disease and malaria through disease-carrying arthropods, and salmonella and E. coli in food. Respiratory illnesses like the common cold, the flu, and strep throat transmit best on tiny droplets in the air.

If a pathogen's purpose is to reproduce, it has to balance its virulence with its ability to infect host cells. In the more isolated world of the past, "it may have been more important not to kill your host too quickly" so the infected person had enough time to reach another person, or host, for the virus to attack, says Christopher Dye, director of strategy at the World Health Organization.

"The question is, how many secondary cases can you generate from that primary infected individual?" Dye says. "The more you can generate by whatever mechanism, then of course the more successful you're going to be as a pathogen."

Airborne illnesses in particular are a huge concern for scientists and researchers tasked with disease control and prevention. They recognize no geographic boundaries. They infect the young, the old, the healthy, and the immunocompromised alike. They spread through populations quickly, because you can't exactly keep people from breathing air.

For an infectious agent to evolve into an airborne pathogen, it must mutate in a way that makes that mode of transmission the most efficient. Viruses and bacteria are constantly mutating—it's the reason we get revaccinated for the seasonal flu each year, because the virus changes just enough to infect us again—so the transition is possible.

"When the right combination of changes takes place, then the virus that results from that mutation process is more strongly selected because it does better to infect hosts," Dye says.

People fear the prospect of pathogens going airborne and ravaging the population in pandemic proportions. But not all diseases pose this threat. Airborne pathogens need to be able to survive on air droplets and efficiently infect the lungs by recognizing and latching on to cell receptors in the throat.

That type of mutation is extremely unlikely for something like, say, malaria. "Part of its life cycle needs to be in a mosquito," says Janis Antonovics, a research professor of biology at the University of Virginia. "It's unlikely for vector-transmitted diseases to go airborne because they're basically reliant on an insect that feeds on a host."

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As a bloodborne disease, HIV has already swept the globe, killing 35 million people and counting—so the hell that would break loose if that virus went airborne is unimaginable. But thankfully, we can cross that off our list of worries. "There's no way HIV can leave the body via the lungs or go from the blood into the air," Antonovics says. "It kind of saves us in a way." The virus does survive in a fluid—blood—but it would have to become a totally different kind of virus for it to get into the air, survive on tiny droplets, and recognize and infect cells in the lungs.

The viruses scientists do worry could evolve into airborne agents are respiratory viruses coming from a surprising source: other animals. "That's likely to be where the biggest source of human mortality in a future pandemic is going to lie," Dye says.

Birds and pigs have caused fast-moving pandemics before. Take a look at the last century: A strain of the influenza virus containing both avian and swine genes caused the 1918 Spanish flu pandemic that killed up to 50 million people worldwide. The 1957 Asian flu originated in birds, wiping out up to four million people. In 1968, a similar strain killed about one million. And in 2009, the H1N1 swine flu infected 60 million people worldwide.

These influenza viruses started off being transmitted in birds and pigs via the fecal-oral route. People contract the virus by coming into close contact with the animals, and with the right random mutation, it evolves from simply infecting individuals to spreading effectively between humans.

It all lies in the details of the host cell: Influenza viruses depend on the virus's own proteins, called hemagglutinin proteins, to recognize and bind the virus to sugars, called glycans, in cells in the upper respiratory tract. The flu virus's proteins recognize a glycan called sialic acid. When sialic acid is linked to a sugar within a host cell at one position—"position A"—it's recognized by avian viruses. When it's linked to the sugar at another position—"position B"—it's recognized by human viruses.

"It's a very subtle difference, but it's the black and white between avian and human viruses," says James Paulson, a professor in the department of molecular medicine at The Scripps Research Institute. And it doesn't take much mutation for the virus to acquire human-type specificity, the ability to recognize human host cells.

Paulson and a team of researchers conducted mutation analyses on the H7N9 strain, which began infecting people in 2013. Their findings, published this month in PLoS Pathogens, show that just three mutations give the virus human-type specificity and airborne transmission in people.

Other strains of influenza also require just a handful of mutations to become airborne pathogens in human populations. In the 1918, 1957, and 1968 pandemics, the H1N1, H2N2, and H3N2 strains each made only two mutations to recognize human cells and lead to a pandemic, Paulson says. And research shows the H5N1 strain takes five amino acid changes to acquire airborne transmission in mammals.

It might seem odd that a simple flu can be so catastrophic—after all, many of us get the flu every year—but these avian-type influenzas are so distinct from the seasonal flu that causes uncomfortable but treatable congestion, fever, and chills. We have absolutely zero immunity to these distinct variations, also called serotypes, of the influenza virus, so when they enter the human population, they hit hard.

In fact, a 1918-type outbreak of an avian influenza has deadly potential: A similar pandemic today could kill 62 million people, according to research published in The Lancet. "That's why people are worried about a new avian virus coming in," Paulson says. "There's no human immunity, it'll spread very fast, and it'll cause severe illness."

A lot of coordination needs to happen between government, the research community, and the industry producing vaccines in order to control a flu pandemic not if, but when it breaks. Thankfully, there's quite an effort going into pandemic preparedness through the development of tools to help contain an outbreak and influenza virus surveillance and risk assessment.

"There will be another pandemic of influenza, that is for sure," Dye says. "It's just a matter of when it happens, how it happens, and how deadly that pandemic is going to be."

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