As if the threat of mutation wasn’t enough, the virus can also take a shortcut through what’s called genetic reassortment. Flu viruses are notoriously promiscuous because of a rare gift for swapping genes with other flu viruses. Though most other viruses can’t do this, flu can go out and acquire entirely new attributes. This is because the genetic
material in a flu virus—unlike nearly all other RNA viruses—is composed of separate segments that can each be individually replaced. If two different flu strains infect a person or even a pig at the same time, a new hybrid strain could emerge that is both lethal and has the tools to spread with ease. The poster child for gene swapping is swine flu. It was produced by the recent, seemingly improbable encounter of two different flu viruses: one known to circulate among pigs in the eastern hemisphere and another among pigs in the western hemisphere. The latter strain was a so-called triple reassortant, born from even earlier flu strains originating in humans, birds, and swine.
With the wholesale genetic changes that reassortment allows, it doesn’t require too many rolls of the dice to splice together a pandemic this way. “You can move a whole lot of characteristics in one go,” explained Robert Webster, a veteran virologist at St. Jude Children’s Research Hospital in Memphis, Tennessee, and the dean of avian flu researchers. “Flu is an RNA virus and it’s also a segmented RNA virus. That gives it a double whammy.”
Among flu strains, none unnerves disease specialists as much as H5N1 bird flu. In the decade after it surfaced, the virus spread over a swath of Earth unprecedented for a highly lethal avian virus. It extended its reach among animals, even infecting mammals like tigers and leopards. It grew more tenacious. The disease persisted longer in birds and spread more easily among them than only a few years earlier. The dice were being rolled faster and faster.
Researchers have concluded that the continuing outbreaks “appear out of control and represent a serious risk for animal and public health worldwide.” No matter how many times governments claim they’ve expunged the virus, it returns. In some countries, like Indonesia and China, the disease has become deeply entrenched in poultry, posing a permanent threat of contagion to their neighbors. Global eradication, according to senior animal-health experts at the UN Food and Agriculture Organization, “remains a distant and unlikely prospect.”
Yet this strain is not the only avian virus menacing humanity. A little-noticed but equally novel avian strain called H9N2 has also
proven it can infect people, including several in Hong Kong and mainland China since 1999. This pathogen, like its better-known cousin, has quietly spread across the birds of Asia and the Middle East and on to Europe and Africa. Studies have suggested that human cases of H9N2 are more common than generally acknowledged, and human transmission may have already occurred. Most worrisome, scientists say the H9N2 virus is actually a better fit for receptors in the human airway, giving it perhaps an edge in the pandemic sweepstakes. “The establishment and prevalence of H9N2 viruses in poultry pose a significant threat for humans,” an international team of researchers reported.
A separate family of novel strains, the H7s, has meantime been circulating in both North America and Europe. Several of these pathogens have also shown an increased affinity for receptors in the human airway. Researchers have urged “continued surveillance and study of these viruses as they continue to resemble viruses with pandemic potential.”
But the H7s, like H9N2, so far remain fairly benign, far less lethal than H5N1. The latter, with a recorded human mortality rate of about 60 percent, is so savage that most flu specialists agree it is the one to be most feared.
Some medical scholars dissent. Although another flu pandemic is inescapable, they doubt that H5N1 will be the source. They note that years have passed, tens of millions of birds have been infected, and countless people exposed without the virus crossing the pandemic threshold. “If it was going to happen, it would have happened already,” said Dr. Peter Palese, chairman of microbiology at the Mount Sinai School of Medicine in New York. Moreover, he suggested that H5N1 wasn’t nearly as virulent as many of his colleagues claim. “I feel the virus is awful for chickens. But this is not a virus that has been shown to really cause disease in humans except in unusual circumstances when the dosage has been extraordinarily high,” he told me, adding that a person has had to practically sleep with a sick chicken to catch a bad case. Perhaps there is some hidden, immutable attribute of the virus that precludes it from ever spreading easily among people. Maybe the dice are loaded, never to come up snake eyes no matter how many times they’re tossed.
This line of reasoning is comforting but, unfortunately, unconvincing to many other virologists. “Such complacency is akin to living on a geological fault line and failing to take precautions against earthquakes and tsunamis,” wrote a leading team of flu specialists. How much time does a virus need to become a pandemic strain? Scientists don’t know. There’s scant information about the virological events that preceded previous pandemics. Had the 1918 strain been smoldering in animals for many years before it crossed to people? Had the 1957 and 1968 strains been circulating for a long time, bouncing between birds and people, but gone unnoticed because these pathogens did not cause mass poultry die-offs like H5N1? Is a decade a long time for a virus to evolve into an epidemic strain? With severe acute respiratory syndrome (SARS), for example, it wasn’t too long. Malik Peiris, the Hong Kong microbiologist who identified the virus behind the 2003 outbreak of SARS, cites evidence that people were exposed to that microbe for quite a number of years before it finally acquired the ability to be transmitted among humans. Once it did, it spread like fire. Flu could do the same.
“The virus has evolved in alarming ways in domestic poultry, migratory birds, and humans in just the last four years,” Margaret Chan told a conference of American business leaders in early 2007. “Global spread is inevitable.”
Chan’s remarks came a month after she’d become director general of WHO. She herself had traveled far since the scare of 1997. In 2003, after staring down outbreaks of both bird flu and SARS, she had left Hong Kong for Geneva. Before long, she was the agency’s assistant director for communicable diseases and its special envoy for pandemic influenza, which she identified as the most serious health threat facing humanity. By the time she ascended to the world’s top health post in January 2007, she was well schooled in flu and convinced that a pandemic was coming.
“If you put a burglar in front of a locked door with a sack of keys and give him enough time, he will get in,” she later warned at a summit of international health policy makers in Seattle. “Influenza viruses have a sack of keys and a bag full of tricks. They are constantly mutating, constantly delivering surprises.” She cautioned that a pandemic
strain would be unstoppable once it became fully transmissible. No corner of the world would be spared. So no country could count on outside relief as with earthquakes or tsunamis. “This will almost certainly be the greatest health crisis experienced for almost a century,” she said.
But back in the fall of 1997, as the mystery of Hoi-ka’s death had faded with Hong Kong’s steamy summer, flu had all but vanished from Margaret Chan’s mind. She was facing a new crisis. A public health clinic in Hong Kong had been mistakenly dispensing toxic mouthwash to sick babies instead of syrup for their fever. Many of the children had developed diarrhea and vomiting. The public was clamoring for an explanation. The scandal captured the city’s grim mood as an historic year approached its end. Months earlier, with the world watching on television, Britain had ended more than 150 years of colonial rule by relinquishing sovereignty over Hong Kong to China. But the sheen quickly came off the handover. The Asian financial crisis that autumn rocked Hong Kong. The stock market crashed. The property market tanked. Tourism dried up. Even the weather was rainier than usual.
In late November, Wilina Lim’s lab received a sample from a two-year-old boy who had been briefly hospitalized in another building at Queen Mary with a fever, cough, and sore throat. The lab staff tested the specimen for seasonal flu. They drew a blank. But now they had the chemical reagents required to check for H5N1. When they ran this test, it came back positive.
Lim called over to the health department headquarters. Dr. Thomas Tsang, a senior medical officer responsible for infectious diseases, got the news. “Not again,” he said to himself, thinking of all the work this would mean.
Tsang led a team of Hong Kong investigators to the boy’s home. It was located in Kennedy Town, an older urban quarter of aging apartment buildings and street-level shops at the westernmost end of Hong Kong island, far from the site of the original case. The neighborhood is tucked between the island’s steep green slopes and the sea, the cranes of Kowloon’s port just visible across the channel. The boy was
Vietnamese, the son of a migrant construction worker. Though the youngster suffered from a congenital heart condition, he had succeeded in recovering from the attack of flu and was back in the family’s cramped apartment when Tsang came calling.
The interview was difficult because the parents spoke little other than Vietnamese. It took a lot of patience, and the investigators often resorted to hand gestures to convey the intent of their questions. Tsang asked about the boy’s recent history, in particular whether he’d had contact with ducks, chickens, or other birds. The parents insisted he hadn’t. But when the health officers produced a calendar and went over it day by day with the couple, they noted a Vietnamese festival about a week before the boy got sick. “What did you do for the holiday?” Tsang asked. The mother remembered she had bought a live duck or goose at the market. She had slaughtered it at home, littering the apartment with feathers and feces. To Tsang, the source of infection seemed clear.
Lim had also e-mailed the CDC in Atlanta with the results of this most recent test. When Keiji Fukuda was notified of this second case, he had no doubts this time that the results were correct. “OK, are we off to the races?” he thought darkly. The initial case was no longer a freak occurrence. His mind sped through possibilities. “Is this the first of many cases? Are there more cases going on? Is this the tip of the iceberg?” Fukuda packed his bags again and on Friday, December 5, headed with a fellow CDC investigator for the airport. The probe would be under the auspices of WHO, but CDC staff would carry it out.
The flight from Atlanta to Hong Kong takes about twenty-four hours. As Fukuda sat in his economy-class seat, he had a long time to reflect. He reviewed everything he would need to know. He thought about what his years on the trail of influenza had taught him and about the findings of the earlier investigation in Hong Kong. His mind groped for what was crucial, sorting and filtering the information. He sketched out the scientific surveys he’d want to conduct this time. He plotted out what he’d do as soon as he arrived. He didn’t want to waste a second. “Question one, two, and three,” he said to himself. “Are there other people infected? Are they passing it to each other? Is there an animal source?” So far, thankfully, the answer to the first question seemed to be no.
When the plane landed, Tsang met him at the airport. While officers were clearing Fukuda’s passport through immigration and customs, Tsang whisked him into a side room to begin briefing him on the outbreak.
“I’ve got good news and bad news,” Tsang quipped.
Fukuda waited for the rest.
The good news, Tsang said, is that he’d be taking Fukuda to a nice dinner. The bad news was that while Fukuda had been in the air, Hong Kong had confirmed two more cases.
Tsang brought Fukuda to his hotel in the downtown Wan Chai neighborhood, the former red-light district of
The World of Suzie Wong,
which in recent years had gone through a commercial renaissance. Then they went to work. They reviewed the lab data and the findings from the preliminary investigation, mapping out the next steps. It would be the first of many late nights spent together.
Fukuda and a growing CDC team was set up with an office in Wu Chung House, the imposing thirty-eight-story tower on Queen’s Road East that was home to the health department and assorted other government agencies and private enterprises. From the windows of their corner room on the seventeenth floor, the Americans looked out at one of Asia’s great skylines and each night watched the lights in the opposing buildings go dark. The team consistently worked past midnight, recapping the progress of their probe and debating its mystifying results. Cases continued to surface all over the city with no apparent geographic pattern. The ultimate source of infection remained elusive. “I’ve never been in an investigation where the stakes were both so high and information was so little about what was going on,” Fukuda said. “I don’t think I have ever slept less over a sustained period of time.”
Early each morning, the questions would rouse him, at five o’clock, four o’clock, even three thirty, and he would resume his self-interrogation. “What are we missing?” he pondered. “What are we not asking? Is there anything obvious going on?”
He and his growing team of CDC investigators would meet for breakfast and compare notes on the day. By eight o’clock, they were
back at the health department. They had dragged the desks to the center of the room to form a single large rectangular table and covered it with computer printers and laptops they had brought from home. At the far end of this command center was a whiteboard, where they recorded each suspected case, jotting down the age, gender, location, and crucial dates of the illness. The ultimate outcome was marked at the end of each listing. A downward arrow meant death.
The scrutiny from politicians, foreign officials, and particularly the press grew intense. The earlier investigation in August had received little media attention. But when Fukuda returned to the health department in December, the hallways were already crammed with reporters. Walking to the bathroom, he recounted, was an “exercise in photography.” Press conferences became high-pressure events where the subtleties of epidemiology were often lost in the journalistic scrum, buried beneath shouted questions and the forest of microphones. One day after he arrived, Fukuda faced the media. “There’s a possibility these cases are the only cases that appear and the virus completely vanishes. Another possibility,” he added with foreboding, “is that these viruses may increase.” By the middle of December, the number of cases had in fact reached double digits.