by Alan Sipress
First thing Monday morning, she picked him up. They set off for Queen Mary Hospital. De Jong wanted to see her lab. Lim was behind the wheel of her Nissan, seated on the right like all drivers in Hong Kong, de Jong to her left.
After five minutes, as they approached the harbor tunnel, de Jong looked over and asked, “Do you have any idea what virus you sent me?”
“No, I don’t know,” she responded. She was betting it was some idiosyncratic version of the common H3 strain.
“It’s an H5.”
“What?” she asked. “H5?”
Lim was bewildered. She had never come across an H5 strain. She wondered to herself, “Where did this H5 come from?”
De Jong didn’t say much more about the test results during the ride, but privately he had a suspicion. It could be contamination or some confusion in classifying samples. That was why he wanted to inspect her lab, why he had come all the way to Hong Kong. But once they arrived at the hospital, he quickly saw her operation was well run.
A few hours later, Lim called Margaret Chan, the health department director. The scientists at the CDC in Atlanta, which had independently reached the same results, had yet to inform Hong Kong of their findings. So Lim’s news came as a shock.
“Are you sure?” Chan pressed. “H5N1? I have never heard of H5N1 infecting people.”
“That’s why I’m calling you,” Lim explained.
“Please educate me,” Chan told her.
Chan’s expertise was not infectious diseases. Her early medical interest had been pediatrics, followed later by women’s and family health issues. In reality, she had never intended to be a doctor at all. Growing up in Hong Kong, Chan had trained to be a teacher and for a year taught English, math, and home economics to elementary school students. But when her sweetheart, David, left for Canada to attend college in 1969, she followed him to the far side of the world and enrolled in a Catholic women’s college in Ontario. Before long, they were married. When David then decided to brave the rigors of medical school, she concluded the only way to assure his continuing attention was to become a doctor, too. Chan had little background in college science. But she did have the late-night tutoring of her new husband. After receiving their medical degrees from the University of Western Ontario, she and David returned to Hong Kong. Chan joined the government in 1978, rising quickly through the ranks of the health department. Sixteen years later, she was running it.
Chan has a charm that makes her seem taller than her modest height. Her manner is eminently self-assured yet empathetic. Her black hair is coiffed and her preferred lipstick bright red. Her brown eyes radiate warmth from behind large, round lenses. She speaks with authority, whether lecturing on health-care politics or the therapeutic qualities of her mother’s recipe for pork tenderloin soup. (Chan swears it’s good for stamina. Years later, after leaving Hong Kong and rising to the top post at WHO, she would get the Chinese herbal ingredients shipped to her in Geneva.) But in a realm of outsize egos, she is quick to admit what she doesn’t know.
When Chan heard about the test results, she asked Lim to bring de Jong over to see her at the health department. The next day, Chan took the visiting researcher out for lunch at the Hopewell Centre, a circular, sixty-story skyscraper that for a time had been Hong Kong’s tallest building. Over a lunch of dim sum, she continued to press him for an explanation.
“What is the implication of this?” Chan asked.
“Dr. Chan,” de Jong answered, “if this is true, we are heading for something really serious.”
By the time the CDC team arrived in Hong Kong, Chan’s health officers were already hunting for clues, trying to pinpoint the source of the boy’s infection. But even a seasoned sleuth like Fukuda would find them elusive. Hoi-ka had died three months earlier, and the trail was getting cold.
The investigators got their first break when they learned the virus had already been implicated in a previous outbreak. Earlier that year, a baffling plague had raced through three farms in the rural north- west of Hong Kong. Every single bird at one farm had fallen over dead. So did most of those at the other two. About five thousand chickens had crashed out. Researchers from Hong Kong University, who studied influenza at a veterinary lab in Queen Mary Hospital, were stumped. They forwarded samples to a high-security lab run by the U.S. Department of Agriculture in Ames, Iowa. “It was one of the most highly virulent influenza viruses we’d ever worked with,” recalled Dennis Senne, a USDA microbiologist. “We’d never seen anything like it before. We’d never seen anything that killed so quickly.”
Senne inoculated ten chickens with the virus to test its pathogenicity. Some died within a day, the rest a day later. At first Senne couldn’t believe the virus was responsible. “We thought they’d somehow suffocated in the cages,” he said. But when researchers examined the dead birds, they found the lungs had been devastated. Genetic analysis revealed the culprit was an H5N1 flu virus. The discovery surprised the researchers back in Hong Kong, since this stripe of flu had never before troubled the city’s poultry. Yet they didn’t bother to stroll over to the adjacent building where Lim had her public-health lab and share the chilling news. Why should they? This virus had never been known to infect people. It was considered strictly avian.
When Fukuda learned in August there’d been an outbreak among birds, he was convinced it was somehow related to his case. Yet he wasn’t sure how. The infected farms were clear across Hong Kong in Yuen Long, more than fifteen miles from the boy’s home, and Hoi-ka had been nowhere near them. The investigators searched his apartment and found bird droppings in the air-conditioning ducts. Was this the missing link? Or was it the live poultry market they discovered close by? The evidence was at best circumstantial.
The trail soon led to the boy’s nursery school. Several weeks before he fell sick, the staff had brought in three baby chicks and two ducklings to help the children get closer to nature. The cages were placed on the ground and the youngsters encouraged to peer inside, even to touch the birds. That was in the spring. By the time the investigators arrived in August, both ducklings had died, as had two of the chicks. The final chick had been removed, and no one knew where it was. There were no samples to take, no evidence that the birds were the source of infection. But suspicions ran strong.
On the remote chance they’d detect some vestige of virus, health officers scraped up dirt and dust from the school grounds for testing. The lab analysis found no trace. The investigators asked after the health of other children at the school and the staff. But there had been no unexplained absences. Nor had there been any other unusual illnesses.
In fact, there seemed to be practically none anywhere in Hong Kong. Fukuda and his colleagues examined medical records from hospitals and clinics from around the city, searching for atypical respiratory cases that might signal a swelling wave of infections. They visited intensive-care doctors and medical directors, urging them to report patients who were ending up on respirators with undiagnosed ailments. The phones started ringing, but they were all false alerts. “We didn’t see a big upsurge in respiratory illnesses going through the city,” he recalled. “We weren’t hearing about kids dying of mysterious illnesses.”
The team had even gathered two thousand blood samples, including several dozen from Hoi-ka’s schoolmates and teachers, to check for antibodies indicating exposure to the virus. These would ultimately all test negative except for a few from otherwise healthy poultry workers. The virus had gone silent. Fukuda’s anxiety about a nascent pandemic began to ebb. “This is perhaps an odd infection that we don’t quite understand where this one child became infected,” Fukuda thought. “Perhaps it’s a one-off, a freak event.”
Yet even as he prepared to wrap up the probe and head home, he couldn’t put his mind to rest. Was this the end or the beginning? Could this virus still spark a global epidemic? He didn’t know how to answer the question.
Before Fukuda left Hong Kong, he met health department officials one last time. “We don�
��t fully understand what happened,” he admitted to them. “Look, we don’t know how this virus works. We don’t know what’s going to happen.” He urged them to step up surveillance for additional cases in city hospitals. He privately wondered whether he’d be back.
There was no doubt the threat would ultimately return. Flu pandemics are inevitable. Divining precisely when one will strike may be no easier than predicting the timing of earthquakes and hurricanes, but global epidemics are just as certain.
Three times in the twentieth century, novel flu strains crossed the species barrier from animals to humans, then circled the globe. The Spanish flu in 1918 claimed about 50 million lives, according to official estimates. But because many deaths occurred in far-flung corners of the world, beyond the range of medical chroniclers based in the United States and Europe, scientists and historians now believe the true toll could have reached 100 million. This plague killed about 675,000 Americans, more than the American death toll in all the wars of the twentieth century. Until recently, Spanish flu was considered the worst-case scenario. Bird flu has made the experts reconsider.
A better-case scenario is illustrated by the two subsequent pandemics, the Asian flu in 1957 and Hong Kong flu in 1968. Together, they claimed an estimated 3 million people worldwide. What distinguished the Spanish flu from its successors was how sick it made people, not whether it made them sick in the first place. In rough terms, all three pandemics were equally contagious, infecting a quarter to a third of the world’s population. The coming pandemic will likely do the same. Even in the mildest scenario, hospitals and other medical care will buckle.
It is not just precedent that makes a flu pandemic inevitable. There is a dynamic to the virus that accounts for the historical pattern of recurring pandemics, and that dynamic continues to hold today. Influenza is among the most capricious and mutable of viruses, and it is this very unpredictability that makes a pandemic a sure thing.
All viruses, influenza and otherwise, can be grouped by the nature of the genetic material at their core. Some are built around DNA, or deoxyribonucleic acid. These viruses contain an inherent self-correcting mechanism that discourages the microbe from mutating. When the virus reproduces, this genetic spell-check detects inadvertent changes in the code and fixes them. But other viruses, including all influenza, are built around a second form of genetic material, RNA, or ribonucleic acid, and lack this proofreading mechanism. As a result, many of the copies contain subtle and not-so-subtle errors.
Among viruses, flu is exceedingly sloppy, constantly spinning off mutant progeny. Most of these copies are defective, with mutations that impede their ability to spread and reproduce. But a different kind of accidental change, instead of undermining survival, can take the virus in a new, more perilous direction.
The flu virus reproduces so vigorously that there are enough viable copies to propel it forward. The other copies, those with damaging mutations, are cast aside, as the virus is swept along a path of ever-shifting forms and threats. Ultimately, the virus hits upon precisely the set of mutations needed to infect people and spread like a common cold, the recipe for pandemic. It’s just a matter of chance. Each time the virus replicates, it’s a roll of the dice. Each new bird that’s infected, each person who’s exposed, each one who’s sickened is another toss. Throw the dice enough times and they’re sure to come up snake eyes.
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 m
any 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.
