A new phase seems to have begun in the evolution of avian flu viruses. They have found their way directly to man.72
In April 1997 Hong Kong issued a set of postage stamps celebrating the migratory birds that flock each winter to the city’s Deep Bay and the Mai Po marshes. Deep Bay’s mangrove swamps are a freshwater/saltwater interface “rich with pickings for birds,” while Mai Po, although now surrounded by the skyscraper New Towns of Yuen Long and Tin Shui Wai, is such a luxuriant bird habitat that it has been designated “a wetland of international importance.”73 Hong Kong is proud of preserving so much avian diversity next door to extraordinary urban density. Indeed it is a bird-crazy city: thousands of residents are avid birdwatchers, and Kowloon’s famed Bird Garden is one of the world’s largest marketplaces for exotic birds of all kinds. In 1997, moreover, the poultry industry was still thriving in the New Territories, supplying ducks, geese, and chickens for sale in the live-poultry markets (also called “wet markets”) that are such colorful parts of the urban mosaic. Birds of one kind or another seem to be everywhere.
One of the birds depicted on a new stamp is a handsome, medium-sized duck called falcated teal. The drakes—somewhat larger than their North American cousins—have dark bills, white throats, and glossy green heads and crests. The teals breed in eastern Siberia before their annual fall migration to the Pearl River Delta and the Mai Po marshes. They like to forage in rice fields or float in freshwater ponds, where they often come into contact with the domestic ducks that are such an integral part of south Chinese agriculture. The teals are treasured for their beautiful plumage and are frequently kept in captivity (again, often alongside domesticated ducks and other birds). Like other wild ducks, they are also safe havens for influenza. Amongst the flu subtypes identified in a Hong Kong teal is H5N1. That might well make the falcated teal the duck of the apocalypse.
In March 1997, a month before the bird stamps were issued, chickens started dying on a farm near Yuen Long and the Mai Po marshes; they displayed the unmistakable violent symptoms of Highly Pathogenic Avian Influenza (HPAI). As Pete Davies explains in his account of the outbreak: “It’s an ugly business. The virus spreads through the bloodstream to infect every tissue and organ; the brain, stomach, lungs, and eyes all leak blood in a body-wide hemorrhage until, from the tips of their combs to the claws on their feet, the birds literally melt.”74 The disease spread to two nearby poultry farms, and as is so often the case with HPAI outbreaks, almost all the birds died. The virus was identified by Hong Kong University researchers as H5N1, a subtype first isolated in 1959. Veterinary virologists had seen it on only two other occasions: during a devastating outbreak in Pennsylvania in 1983 that forced authorities to cull 20 million chickens, and, more recently, among English turkeys in 1991.
The gruesome pathology of so-called “fowl plague” was first described in 1878, but the pathogen was not confirmed as influenza A until 1955. Episodic outbreaks in poultry farms along major migratory flyways in California and Minnesota suggested to scientists that it originated in ducks and other waterfowl. Like all influenza, HPAI is essentially mysterious: it flares up unexpectedly among chickens and turkeys in different countries, continents, and hemispheres. Until recently, it has been relatively rare, with fifteen localized outbreaks between 1959 and its sudden appearance in Hong Kong in 1997. HPAI in all of these instances was caused by influenza subtypes containing either H5 or H7; researchers believe that these hemagglutinins contain extra basic amino acids at their cleavage sites that amplify virulence by allowing viruses to invade a broader variety of tissues and, possibly, species.75 But there was no evidence at all to suggest that these avian superviruses posed any threat to humans, not even to the poultry workers who tended the ill birds and cleaned up in the aftermath of HPAI’s carnage. “In fact,” Hong Kong researchers emphasized, “attempts to transmit experimentally a number of avian virus subtypes directly to humans were not successful.” The species barrier was believed to be insurmountable.76
After agricultural authorities killed off the remaining sick chickens in April, HPAI seemingly disappeared, with extensive testing failing to reveal any further traces of H5N1 in New Territory chicken farms or Hong Kong’s live-poultry markets. Veterinary scientists relaxed. Then in mid-May a three-year-old boy—previously in perfect health—was admitted to Queen Elizabeth Hospital in Kowloon with a sore throat, fever, and abdominal pain. Despite top-flight intensive care, his condition deteriorated catastrophically, and he died on 21 May. Physicians and nurses were appalled by the relentless cascade of disasters that wracked his tiny body: viral pneumonia, acute respiratory distress syndrome (ARDS), Reye’s syndrome, and finally, kidney and liver failure. The local department of health ran tests on secretions from the dead child’s throat and found an unusual influenza subtype that it could not identify; frozen samples were sent off in June to two of WHO’s four collaborating centers (CDC in Atlanta and NIMR in London), as well as to the National Influenza Center in Rotterdam.
In retrospect, influenza experts would applaud the vigilance of Hong Kong health officials. The city, with its world-class medical community, is the sentinel for influenza surveillance in the south China region, where interspecies transmission of viral strains is believed to be most frequent and intense. If the three-year-old had died in neighboring Guangdong, or for that matter, in any of the poorer countries of southeast Asia, it is unlikely that the identification of his pathogen would have been pursued with such vigor.77 The team in Rotterdam was the first to uncover the lethal strain’s identity. As Davies recounts, the Dutch worked throughout July in an unsuccessful attempt to match the Hong Kong virus against their reference archive of human and swine influenzas. Baffled by the failure of the virus to react with any of their antisera, in early August they tested it against a long-shot H5N1 reagent that been brought back from the Memphis laboratory of the famous influenza authority Robert Webster. To the consternation of the Rotterdam team, it was a positive match.78
The Dutch result was soon confirmed by Atlanta and London, but no one was yet ready to accept that H5N1 had actually vaulted the species barrier and killed the child in Hong Kong. It seemed more plausible that Hong Kong public-health scientists had unwittingly submitted a contaminated sample. Leaving nothing to conjecture, the Dutch, followed by the CDC and WHO, sent experts, including Webster, to double-check conditions in the Hong Kong lab. They soon discovered that the Chinese had been scrupulous in their procedures—there was no contamination. H5N1 was indeed the killer, and as Webster later discovered, it was almost identical to the strain that had killed the chickens in March. A slight hemagglutinin mutation—a difference of only three amino acids—had apparently allowed the bird virus to open the lock on human cells and infect the child.79
It was a staggering, paradigm-shifting discovery. This H5N1 was not a reassortant, as textbooks predicted, but an avian virus that had come to roost in the human body with a little help from genetic drift. Having made such a seemingly impossible species leap, moreover, there was no theoretical reason why H5N1 could not subsequently reassort with human flu genes in the lungs of a co-infected human; pigs might not be the virus’s indispensable intermediaries after all. A pandemic of frightening lethality therefore might be imminent, and it was desperately important for the team of international flu experts in Hong Kong to uncover the exact circumstances of the child’s infection.
The most obvious hypothesis—that he had encountered sick chickens at one of the New Territory farms or in a local live-poultry market—turned out to be unlikely. Indeed, the only plausible avian contact that researchers could establish were some chicks and ducklings that had been pets at his preschool; the baby birds had died mysteriously, but when researchers painstakingly tested dust in the playroom they could find no sign of the virus. On the other hand, extensive blood testing revealed that a handful of the child’s contacts, including a playmate, a nurse, and a few others (but not his immediate family), had antibodies to H5N1. Five poultry workers also displayed immunological evidence of contact with the virus, but none had become sick. Meanwhile, the trail grew cold, and no more cases appeared: perhaps the child’s death had been a fluke. The international experts returned home.
Virologists remained unsettled by the fierce behavior of H5N1/97 in the laboratory. “It reproduced much faster than ordinary flu strains, and in cells that ordinary flu strains couldn’t live in, and if you grew it in eggs, it killed them. This virus, said Lim [a Hong Kong scientist], was like an alien.” Indeed, when veterinary researchers in Athens, Georgia, infected a poultry flock with the recently isolated human strain, the entire flock died within a day. Horrified scientists, who had never seen such a rapid killer, immediately donned biohazard containment suits and dosed themselves with antivirals; this ignited a controversy about the safety protocols necessary for work with the Hong Kong virus. Influenza diagnostic labs, at least in the United States, were not equipped with the elaborate containment systems required for working with such a potent virus: federal biosafety guidelines had not anticipated an influenza that acted like the nightmare protagonist of a sci-fi thriller. (Nor did they foresee the possibility that by 2004 scientists would use reverse genetic engineering to re-create the 1918 monster in their labs.) A majority of the research community now decided that H5N1 research should be confined to a small number of Biosafety Level 3-plus or Level 4 labs, but a few scientists chafed under the restrictions (and were later accused of cutting corners on safety). Lurking in the background was the memory of the unexpected resurrection of the H1N1 virus in 1977, an outbreak that almost certainly resulted from the inadvertent escape of the strain from a Russian, or possibly Chinese, laboratory. H5N1, however, might be incomparably more dangerous.80
None of the journalistic accounts of the 1997 outbreak mention the extreme weather, but it was the wettest year in Hong Kong’s meteorological record—a massive Pacific El Niño event brought typhoons and torrential rain to southern China throughout the summer. (Did the deluges wash away the poultry excrement that spread the infection?) The city was still soaked when the pandemic threat suddenly returned at the beginning of winter. A six-year-old with heart problems was hospitalized on 6 November with ordinary flu symptoms; he recovered quickly, but the lab assay confirmed he had H5N1. Two weeks later, a teenager and two adults—all unrelated—were hospitalized with the virus. State-of-the-art intensive care failed to prevent the onset of viral pneumonia or other macabre complications like those that had killed the toddler in May; two of the patients died in December. Meanwhile, flu experts from Atlanta, Memphis, and Tokyo were flying back to Hong Kong. The WHO set up a special Pandemic Task Force and expected the worse.
The city was on the edge of panic. Although Hong Kong had just been returned to Chinese sovereignty, the local press was unfettered in its coverage of the new outbreak. Opposition politicians hammered the administration of Tung Chee-hwa for any perceived hesitancy in its response to the threat.81 Throughout December public anxiety was reinforced by the seemingly random fashion in which new human cases were appearing across the territory. In addition, the regular flu season had started early, thus increasing the chance of co-infection and reassortment between H5N1 and the prevailing H3N2 human virus. CDC’s top scientist on the scene, Dr. Keiji Fukuda, later reminisced to the New York Times: “None of us was sleeping much. The adrenaline was really flowing at this point. A pandemic was suddenly not a misty historical possibility. It seemed very current.”82
Parallels with 1918 were becoming obvious. Like its ancestor, H5N1 was now focusing its virulence on healthy adults. Of the seventeen new cases diagnosed between early November and the end of December, eight children, happily, all recovered, with few complications; five of the nine teenage and adult victims, however, were destroyed by viral pneumonia and ARDS. The silver lining (and scientific paradox) was that the virus’s success in replicating so efficiently inside humans was not yet matched by equivalent transmissibility. The pandemic spark existed, but there was not yet any conflagration. Nonetheless, frantic Hong Kong authorities bought up a large share of the available world supply of the antiviral medication rimantadine as a precaution.
Then in mid-December the “missing link in the epidemiology of avian influenza” suddenly revealed itself: chickens started dropping dead on poultry farms and in the city’s markets. The poultry epidemic that had vanished in the spring was now everywhere: H5N1 infected at least 20 percent of the city’s chickens, as well as a few domestic ducks and geese. (Not surprisingly, other influenza A subtypes with H9, H6, and H11 hemagglutinins were also identified in birds, although none was yet a homicide suspect.) The virus load in the city’s birds seemed to be approaching some kind of ominous critical mass, but there was no precedent for understanding the consequences of such a large-scale animal epidemic in the heart of a great city. Public-health workers, however, did establish that most of the sick humans had had direct contact with poultry, which made it less likely that H5N1 had succeeded in passing from person to person.83 On the other hand, some of the infected poultry had come from Guangdong and scientists worried that a stealth epidemic—either undiagnosed or concealed for political reasons—already existed in other parts of the Pearl River Delta. (Evidence later would emerge of an epidemic among geese in Guangdong the previous year.)
Hong Kong’s local government could not make public-health decisions for the rest of China, but it acted decisively to protect its own citizens. Warned by scientists that there was not a second to lose, on 27 December authorities ordered the destruction of all 1.6 million live poultry within the city and its environs; they also embargoed the import of live birds from Guangdong and disinfected the city’s markets. The bird cull, as agriculture official Clive Lau explained to reporters from Asia-Week, was a dismal business:
One evening, Lau was at the command center and phoned a four-person team on a farm with 20,000 chickens. In four hours they had killed 35. The unpenned birds were proving remarkably elusive. “You start killing and killing and killing,” says Lau. “And there are still thousands of birds.” Often the reluctant butchers had to break necks and slit throats. The birds struggled and scratched. Some people threw up from the smell. Others broke down and cried.
Lau is father to a one-year-old boy and five-year-old girl. All the while, he fretted that he could catch the virus and pass it to them. Back home, the first thing he did was shout, “Get away from me!” He threw his bloody shoes outside, stripped to his underwear and ran to the bathroom, yelling at his family not to come near. After cleaning up, throwing away his clothes and scrubbing his shoes, Lau at last said hello to his children. He wanted to kiss them, but didn’t dare.84
Other Hong Kong residents were no less apprehensive. The day before the slaughter, a Filipina domestic worker was diagnosed with bird flu, and the whole city worried whom would be next—every sneeze, cough, and fever that winter was a source of anxiety. Day after day, week after week, health workers nervously tested and retested every case of serious influenza or respiratory distress. Apart from the domestic worker who died in mid-January, they found no further trace of H5N1, and so the economic crisis in Southeast Asia began to displace flu from the headlines again. Authorities very cautiously allowed the sale of live chickens and other terrestrial poultry to resume, although live ducks and geese were banned; in addition, all poultry imported from Guangdong was now screened for influenza.
City authorities celebrated a victory although researchers knew that “an H5N1 pandemic had been averted rather than prevented.” A trio of Hong Kong microbiologists who had been at the eye of the storm—Yi Guan, Malik Peiris, and Ken Shortridge—wrote that “the H5N1/97 virus was possibly one or two mutational events from achieving pandemicity.” These researchers also began to unravel the virus’s genealogy. They found evidence that aquatic bird influenzas had reassorted themselves within the mixing vessel of a quail before jumping to chickens. The two water birds were likely a goose, and yes, possibly a teal.85