TORONTO -- Three sick people.
That's all it took to make scientists who study influenza edge-of-seat nervous this week over a rapidly evolving public health situation in China.
Though the case count is now up to 14 infections and five deaths, those first three sick people and the genetic sequences of the flu viruses that infected them were enough to make the hairs on the backs of knowledgeable necks stand on end.
Four years to the month after H1N1 swine flu marched into the global consciousness, a new avian virus, an H7N9, came out of nowhere to demand attention.
While it's too soon to say if these are the first halting steps of a new pandemic virus, at this point flu experts would not bet against H7N9.
Here's what they saw in a mere three cases, and the clues they are looking for as they race to figure out if the world is on the verge of the second pandemic of the 21st century.
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Influenza scientists always pay attention when animal flu viruses start making people sick. There is a rich soup of flu viruses in nature, most of which human immune systems have never seen. Many of those viruses, at least in theory, have the potential to trigger pandemics.
So when China notified the World Health Organization over the weekend that it had found three cases of infection with H7N9 viruses, there was immediate concern.
While some H7 viruses have infected people in the past -- including two poultry workers in a big H7N3 outbreak in British Columbia in 2004 -- viruses bearing an H7 hemagglutinin and an N9 neuraminidase in combination had never been previously known to infect humans.
Adding to the alarm: The three people were not linked. That means each caught the virus from an animal, or a person. The first bet would be animals, but so far the virus hasn't been found in Chinese poultry or pigs, the likely suspects.
(On Thursday, Chinese authorities announced they had found a closely matched H7N9 virus in pigeons in a Shanghai market.
Could these birds be the sole source of the virus? The WHO's top flu expert, Dr. Keiji Fukuda, doesn't think so. "Not impossible but not the most likely scenario," Fukuda says.)
The first three cases didn't live close to one another. Two were in Shanghai, China's largest megacity. But the third was in the nearby province of Anhui. As more cases have emerged, the geographic distance among infections has become greater, making it increasingly clear that there is H7N9 virus spreading, undetected, over hundreds of kilometres in China.
Fukuda explains: "It's possible that we have infected animals. But we still haven't detected actually what is the infected animal and whether it's these animals that are spread out and individuals in a widespread area are coming into contact (with them) and becoming ill."
The other option? "At the same time you have to be thinking about is there any evidence of person-to-person transmission," Fukuda, the WHO's assistant director-general for health security and environment, told The Canadian Press in an interview.
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When people show up in hospitals sick with pneumonia, it can take a while to figure out what bacteria or virus is making them ill. It takes even longer when tests for known culprits come back negative, and laboratories have to start thinking about whether they are dealing with something new.
The first known H7N9 cases started getting sick in late February. And two died in the first part of March. But once the Chinese hospitals got the country's public health agency -- the China CDC -- involved and they found the new virus, that organization quickly mapped the genetic sequences of the first three viruses and uploaded them into a database that international flu scientists can access.
That prompt sharing allowed outside experts to start studying the viruses to look for clues to their origin.
All eight genes of each virus were avian, meaning these were bird flu viruses. But all the viruses showed several genetic changes that scientists who study influenza recognize as signals of a virus adapting to spread in mammals, not birds. Those changes mean the virus is learning to attach to the type of cells people have in their upper airways, the type of cells that human flu viruses infect.
Those signs of adaptation ratcheted up the concern.
"We would be paying very close attention to any situation in which you have a novel influenza virus which has caused some cases of infection and caused some deaths," Fukuda says.
"But I think that the molecular changes also make us pay a lot of attention."
Richard Webby, a swine flu expert who runs the WHO's influenza collaborating centre at St. Jude Children's Research Hospital in Memphis, Tenn., says those genetic changes suggest the virus may no longer be circulating in birds.
He believes it is in mammals. That could mean pigs, which are called mixing bowls of influenza, because they can be infected with both human and bird flu viruses, providing a chance for genes to swap.
Or it could mean the virus is spreading in people.
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Still another concern was the similarities among those first three viruses China CDC shared with the outside world.
Nancy Cox, a virologist who heads the influenza division of the U.S. Centers for Disease Control, says bird flu viruses swap genes all the time. It's a phenomenon called reassortment.
But when scientists see a virus that locks into a pattern, that suggests a virus has hit upon a winning combination, one with an evolutionary advantage.
"It's going to be very important to know whether there's ongoing genetic reassortment or if the virus has settled on a gene constellation that's successful, that has some kind of an evolutionary advantage and that's going to be fairly stable," Cox says.
The first three virus sequences were very closely clustered on the genetic trees flu scientists construct to study viruses. In this case, continued stability would not be a good sign, Cox says.
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Public health officials in China are monitoring contacts of known cases, looking to see if the people who have caught this flu have passed it to others.
Though all the cases that have come to light to date have involved serious illness, everyone hopes this virus will follow the typical pattern of flu viruses -- a small number of fatal cases, a few more severe cases, a bunch of sick people and a number of people whose symptoms are so mild they don't realize they have flu.
Flu infections traditionally fit into that kind of a pyramid. The base can be hard to see, because most people with flu tough it out at home in bed. If a new virus is spreading at the same time as seasonal flu, cases that are not sick enough to require medical attention would probably slip under the radar.
Everybody wants to hope that's the case. But so far there is no evidence of that pattern with this virus.
The WHO routinely pores over infectious diseases intel gathered by a Canadian-run, Internet trolling program called GPHIN, the Global Public Health Intelligence Network.
To this point, there are no reports of an unexplained increase in respiratory infections, and no signs of spread among the contacts of cases, Fukuda says.
"At the same time, we also don't have an animal reservoir right now. And so we're not quite sure how these people got infected. So they all remain open lines of investigation."
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Though the spectre of a pandemic is clearly on the minds of flu experts right now, there are a number of possibilities.
The virus could be spreading among people and eventually jump outside China's borders. Or it could be ensconced in some animal reservoir, and occasionally spill over into people, in the way the H5N1 bird flu virus has been doing for the past decade. Or it could melt back into nature.
"Right now I don't think any direction is inevitable," Fukuda says.
"I cannot predict. I really cannot predict. I know exactly the things we should be doing and we should be looking out for. But you can't second-guess what the virus is going to do.
"The whole history of influenza tells us you can't second-guess these things very well."
Given that, the WHO and others are gearing up pandemic readiness activities. Teams are working to produce a vaccine seed strain, the modified virus vaccine manufacturers would use to make H7N9 vaccine, if countries place pandemic vaccine orders.
And they are looking for answers to key questions. Where is this virus? And can it spread among people? Says Fukuda: "The answers to these questions are what will shape our thinking about the next steps that have to be taken."
