The Pandemic Century

by The Pandemic Century- One Hundred Years of Panic, Hysteria

  To cater to Guangdong’s newly affluent entrepreneurial classes, in the early 2000s chefs also began offering ever more exotic fare on restaurant menus, including game animals that had previously been considered rare seasonal delicacies. Animal traders responded to this increased demand by sourcing exotic game from countries such as Laos and Vietnam, or breeding game animals on small, unregulated farms, from where they were transferred to animal markets in Guangzhou and Shenzhen when they were ready to be eaten. The result was a mixing of multiple species in animal markets that would rarely, if ever, encounter one another in nature, and certainly not in such crowded conditions.

  Fortunately, Hong Kong, unlike Guangzhou and other provincial towns and cities in Guangdong, benefits from world-class medical facilities and teaching hospitals equipped with the latest diagnostic technologies. Because of the greater political freedoms enjoyed in Hong Kong, Kowloon, and the New Territories under China’s “one country, two systems” policy, Hong Kong is also not subject to the cloying regulations and fear of authority that make potentially embarrassing disclosures anathema to the communist authorities on the Chinese mainland. Rather, Hong Kong health officials, many of whom were trained overseas in American and European universities, seek to apply the same clinical and public health standards as they would anywhere else in the world. This reputation for medical rigor, combined with Hong Kong’s unique political and geographical position, make it something of a “sentinel” for the health of the rest of the world. In short, when a new epidemic or pandemic virus emerges somewhere in China, it is in Hong Kong that the alarm is likely to sound first.

  FROM HIS SIXTH FLOOR office at Hong Kong University’s School of Public Health, Malik Peiris has a perfect view of Pok Fu Lam country park and Queen Mary Hospital. For the soft-spoken microbiologist with a passion for epidemiology and viruses that cross the species barrier, it is the perfect situation. In the winter, geese, teal, and other wild migratory birds swoop past his window en route to the Mai Po Nature Reserve, a protected wetland on the edge of the Inner Deep Bay that is an important waystation for birds migrating south from Siberia to New Zealand during the northern winter. And when an unusual respiratory case presents itself in the emergency room of Queen Mary Hospital, Peiris’s laboratory is well placed to perform a viral assay. So when in November 2002 public health officials began hearing rumors of an unusual respiratory outbreak in Guangzhou, it was only natural that Peiris’s lab should be placed on alert in the expectation that similar cases would soon be presenting themselves at Queen Mary and other public hospitals in Hong Kong.

  Peiris’s interest in viral ecology dates from 1987 when, shortly after obtaining his PhD in microbiology at Oxford University, he was asked to investigate an outbreak of Japanese encephalitis in his native Sri Lanka. A viral disease spread by mosquitoes that breed in rice paddies, Japanese encephalitis had broken out in Anuradhapura, a historic city in northern Sri Lanka famous for its architectural ruins. Some 360 people fell ill, the majority of them rice farmers. This was puzzling; although the virus can be transmitted to humans, it usually cycles between birds, mosquitoes, and pigs. Moreover, although outbreaks of Japanese encephalitis in humans had previously been documented in Japan and other parts of Asia, large human outbreaks had not occurred in Sri Lanka before. Clearly something had changed; the question was what?

  At first, Peiris and his colleagues thought that the outbreak might be due to a sudden change in the virulence of the virus, but when they looked at the virus in the lab they could see it had not mutated. Next, they trapped mosquitoes in and around farmers’ fields to see if there had been a change in the transmission dynamics of the disease. Perhaps a species other than Culex, the usual vector, was now transmitting the virus, or there had been a sudden increase in mosquito numbers. But, once again, in both cases the answer was negative. Then they looked at pigs. To diversify the agricultural base and supplement farmers’ incomes, the Sri Lankan provincial authorities had handed each farmer twenty pigs free of charge. These pigs now grazed freely in the farmers’ backyards beside the rice paddies. In so doing, Peiris discovered, the pigs not only provided mosquitoes with a ready blood meal, but greatly increased the chances of transmission of Japanese encephalitis to humans. “It was like putting a match to dynamite,” he said. “Pigs turned out to be perfect amplifiers. With the best intentions, somebody puts this in and, boom, you have this huge explosion.” The investigation peaked Peiris’s interest in veterinary epidemiology and the interface of animal and human diseases, and set him wondering about other human interventions that might alter the balance of microbial ecologies.

  Peiris’s next big opportunity came in 1997 soon after he joined Hong Kong University’s medical faculty as a senior lecturer in microbiology. His appointment coincided with the first documented transmission of avian influenza from birds to humans. An influenza virus, known as H5N1, had been isolated from the throat washings of a three-year-old boy. He had been admitted to Queen Elizabeth Hospital in Kowloon in early May with what appeared to be a run-of-the-mill upper respiratory tract infection. Initially, the boy was given aspirin to relieve his fever and sore throat, but within days his condition had deteriorated and he was transferred to intensive care. Soon, his tiny body was being racked by an unusual cluster of conditions, including viral pneumonia, Acute Respiratory Distress Syndrome (ARDS), and Reye’s syndrome. He died on May 21, the cause being recorded as multi-organ failure.

  H5 influenza viruses were not entirely unknown to flu researchers in 1997—the virus had first been isolated nearly four decades earlier in Scotland. However, since then, veterinary virologists had seen it on only two other occasions: during a devastating outbreak of “fowl plague” in Pennsylvania in 1984 that had forced the authorities to cull 20 million chickens, and on an English turkey farm in 1991. The point is that until 1997 no one had imagined that H5N1, or any other bird flu virus, might be capable of jumping the species barrier and sickening humans, much less killing them.

  Working backward, a team from the CDC, headed by Keiji Fukuda, a Japanese-American clinical epidemiologist and the future coordinator of the WHO’s Global Influenza Program, learned that a few months earlier chickens on farms near Yuen Long, in rural northwest Hong Kong, and the Mai Po Marshes close to Kowloon, had been struck by a mysterious plague. The culprit also seemed to be H5N1. Alarmingly, one of the farms was only fifteen miles from the boy’s home. Not only that but several weeks before he had fallen ill, teachers at his nursery school had brought in three baby chicks and two ducklings for the children to play with. By the time Fukuda arrived at the school in August both ducklings had died, as had two of the chicks.

  To flu ecologists the latter findings were especially worrying. Ducks are considered “silent reservoirs” of bird flu viruses—silent, because they harbor and excrete the virus without exhibiting symptoms of illness or other obvious signs of infection. Not so chickens, which are highly susceptible. When they come into contact with diseased ducks and are exposed to the virus for the first time—typically through excreted fecal matter—they fall violently ill. One moment they are clucking contentedly, the next they are staggering from side to side as their brains, stomachs, lungs, and eyes leak bloody hemorrhagic fluids. It is for this reason that poultry farmers describe such infections as a “plague” and that Robert Webster, the world’s preeminent avian influenza expert, has dubbed mallards and teals “Trojan ducks.”

  Both chickens and ducks can also transmit bird flu to pigs, and because swine can simultaneously be infected with human strains of influenza this makes them the perfect vessel for the reassortment of avian and human flu viruses. Indeed, scientists hypothesize that it is when these avian and human strains exchange genes, reconfiguring their surface proteins and generating a new, hybrid virus, that you get pandemics. This is what appears to have caused both the 1957 “Asian flu” pandemic and the 1968 “Hong Kong” flu pandemic, triggered respectively by H2N2 and H3N2 hybrid viruses containing both bird and mammalian influen
za genes.

  In addition, scientists suspect that pandemics may also be triggered by spontaneous mutations of avian viruses. Viruses are continuously making copying errors, and avian viruses are no exception. The theory is that some of these mutations could result in subtle changes to the molecules on the surface of the virus, enabling it to bind deeper into the human respiratory tract. As people are not ordinarily infected with bird flus, once such a virus found a way of transmitting efficiently to humans, runs the theory, there would be little to stop it because our immune systems would be powerless to mount an antibody response. Instead, the infection might trigger a catastrophic cascade similar to the syndrome that killed the three-year-old Hong Kong boy. Indeed, when scientists looked more closely at the genome of H5N1 they discovered that its surface proteins had the ability to bind to both avian receptor sites and human cells deep in the lungs. That discovery sparked renewed interest in the natural history of influenza and the ecological conditions driving adaptations of wild viruses circulating in aquatic bird populations. It also led to speculation that similar processes may have triggered the emergence in 1918 of the Spanish flu—a virus that a leading flu expert has described as “the most bird-like of all mammalian flu viruses”—which was associated with a similarly unusual pathology in young adults.

  As spring turned to summer then fall, Hong Kong held its breath. By now teals and other migratory waterfowl had begun to gather in the city’s Deep Bay and Mai Po Marshes en route from their Siberian breeding grounds, adding to anxieties that the birds might communicate H5N1 to local ducks and chickens. Then in November there were two further human cases, followed in December by several more. Panicked, the Hong Kong authorities closed the city’s wet markets and ordered the culling of 1.5 million of the territory’s chickens. That seemed to do the trick. Although the virus continued to turn up every now and again in samples collected from wild birds, no more cases were reported in domestic chickens. Nevertheless, by the time the outbreak ended in 1998, eighteen people had been infected and six had died, five of them adults.

  For Peiris, the outbreak was a wake-up call. Together with his Hong Kong University colleagues Yi Guan and Ken Shortridge, he warned that the H5N1 virus had been “possibly one or two mutational events from achieving pandemicity.” The good news was that because of Hong Kong’s geographical position and the territory’s concentration of microbiological expertise, it was well positioned to act as an “influenza sentinel”—an early warning post for avian flu viruses that might suddenly emerge from their aquatic reservoirs. By 2002 these included not only H5N1, but another bird virus, H9N2, that was widely seeded in pigeons, pheasants, quail, and guinea fowl in southern China. More alarming still was the fact that the H9N2 virus had also infected two children in Hong Kong, though without sickening them, and shared several of the same internal proteins as H5N1. Indeed, the more Peiris, Guan, and Shortridge looked at the range of viruses circulating in live poultry markets, the more they realized that genetic reassortment was a common occurrence in nature, and that, far from being in evolutionary stasis in aquatic birds, avian flu viruses were constantly transiting between ducks and poultry and back again, generating “multiple reassortants.”

  The result was that when in December 2002, ducks, geese, flamingos, swans, egrets, and herons suddenly started dying in two popular Hong Kong parks, and soon after Peiris began hearing rumors of an unusual respiratory outbreak in Guangzhou, he naturally assumed that bird flu had returned in a more virulent form. Two months later, at the beginning of February 2003, using web-crawling software to scan the internet for reports of unusual respiratory outbreaks, the WHO picked up an item about an outbreak of “atypical pneumonia” in three hospitals in Guangzhou. Soon after, the WHO intercepted text messages saying there had also been a major outbreak at a fourth Guangzhou hospital and that there was panic-buying of gauze masks, antibiotics, and white vinegar, a traditional Chinese remedy for warding off respiratory infections. This was followed by an advertisement by the Chinese subsidiary of the Swiss drug company Roche that its antiviral medication Tamiflu was effective against bird flu. According to Klaus Stohr, the head of WHO’s influenza vaccination program, “that put in the minds of people that a bird flu epidemic had started.” However, the clincher came when a seven-year-old girl from Hong Kong suddenly died of respiratory disease while visiting her family in Fujian. Although she was buried before the cause of death could be ascertained, nine days later her father was stricken with what appeared to be the same disease, dying in mid-February in Hong Kong. His son also developed symptoms of respiratory distress but recovered. Laboratory tests subsequently showed that both had been infected with the same strain of H5N1 that had been killing ducks and other birds in Hong Kong’s parks. By now Peiris was convinced he was seeing the start of a new bird flu outbreak, possibly far bigger than the one that had visited Hong Kong in 1997. He was skeptical of the official line being peddled by the communist authorities in Guangdong that the respiratory outbreaks were due to a form of chlamydia, so he asked two Chinese colleagues who had previously worked at the Institute of Respiratory Diseases in Guangzhou to make discreet inquiries. Ignoring the usual diplomatic channels, the medics traveled to Guangzhou independently and returned with throat washings from twenty Chinese respiratory patients. Peiris and Yi had expected the washings to light up when they added the samples to sera infected with H5N1, but to their surprise nothing happened. Next, they looked for reactions for other common respiratory viruses, but once again the serological tests were negative so they began testing for more exotic viruses, such as Hanta. Finally, Peiris and Yi added the washings to various off-the-shelf cell cultures to see if they could persuade anything to grow in them. But whatever was lurking in the throat washings did not replicate in the usual laboratory growth media. All they could be sure of was that it was not bird flu or other commonly known causes of respiratory illness.

  LIKE OTHER HONG KONG streets commemorating important events in British history, Waterloo Road seems to belong to a bygone era. Named after the Belgium battleground at which the Duke of Wellington bested Napoleon Bonaparte, the road is one of Kowloon’s principal thoroughfares, running east past Ferry and Nathan Roads, before turning sharply in the direction of Logan’s Rock to the north. It is not a pretty road. Clogged with traffic and hemmed in by ugly highrises, it is for passing through rather than lingering in. Indeed, were it not for Kwong Wah Hospital at one end and the 487-room Metropark Kowloon—a midpriced hotel formerly known as the Metropole—at the other, there would be little reason for stopping here.

  On February 21, Liu Jianlun, a sixty-four-year-old professor of nephrology, checked into room 911 on the ninth floor of the Metropole. A doctor at the Second Affiliated Hospital of Zhongshan Medical University in Guangzhou, Liu was feeling a little under the weather. A few weeks earlier, a Guangdong seafood trader had presented at his hospital with peculiar respiratory symptoms. Although the trader spent only eighteen hours in the emergency room, in that time he infected twenty-eight hospital staff. He was then transferred to the Third Affiliated Hospital, where he set off further respiratory clusters among health care workers, earning himself the nickname “poison king.” On February 15, Liu had developed similar respiratory symptoms. But after dosing himself with antibiotics he felt well enough to travel and boarded a bus in Guangzhou for the three-hour ride south to Kowloon. After checking in to the Metropole, Liu had mustered the energy to go shopping, but the following morning he woke with a high fever. Instead of attending his nephew’s wedding he turned right outside the hotel and walked to Kwong Wah Hospital. Once there Liu asked to be admitted, informing medical staff that Guangzhou had many patients with atypical pneumonia and that it was “a very virulent disease.” He also said that he had treated some of the patients in the hospital’s outpatient clinic, but as he had been wearing a mask and gloves he was confident he had not contracted anything. He was wrong.

  On March 4 Liu died of what would later be called SARS—short for Sev
ere Acute Respiratory Syndrome. Not only that, but during his stay at the Metropole, via a mechanism that was never identified, he managed to transmit the disease to sixteen other guests on the same floor and a visitor to the hotel, though not, miraculously, to the hotel’s staff. Within seventy-two hours, sixteen of those guests, who included airline crew members, had introduced the disease to seven other countries, including Vietnam, Singapore, and Canada, sparking similar respiratory outbreaks in hospitals in Hanoi and Toronto. At this juncture, no one connected those outbreaks to Liu or to room 911 of the Metropole—that would come later. Instead, convinced that this was the start of the long-feared bird flu pandemic, on March 12 the WHO issued a global travel alert. As images of nervous Hong Kong commuters in face masks flashed around the globe, air travel to Southeast Asia ground to a halt and financial markets went into a tailspin. On a China Airlines flight from Hong Kong to Beijing, a seventy-two-year-old man who, unknown to him or anyone else on board, had been infected with SARS while visiting Hong Kong, communicated the disease to twenty-two passengers on the same flight, as well as two crew members. Meanwhile, in Thailand, at the end of March the mysterious pathogen claimed the life of one of Asia’s most respected doctors, Carlo Urbani. The head of WHO’s infectious disease division in Vietnam, the Italian parasitologist and clinician had contracted the infection while tending to a young Chinese American businessman who had presented with severe respiratory symptoms at the French Hospital in Hanoi on February 26. A few nights before, the businessman, Johnny Chen, had been staying on the ninth floor of the Metropole, though it was only later that the significance of that fact would be appreciated.

  Urbani’s death at the age of forty-six, heavily sedated on morphine and hooked up to a ventilator in a makeshift isolation room in a Bangkok hospital (after treating Chen, Urbani had flown to the Thai capital, not realizing he was incubating the infection), sent shock waves through Southeast Asia’s expatriate medical community. How was it possible that at the dawn of the twenty-first century a physician familiar with the measures for treating highly infectious patients had contracted such a severe respiratory disease? And why had the pneumonic ailment resisted treatment with antibiotics and antiviral drugs? Once again the question was asked: was it H5N1 or some other strain of avian influenza?