The Plague In Wating...
By Pete Davies
The Mail And Guardian

Two years ago, a vicious form of chicken flu swept Hong Kong. Then, to the astounded horror of scientists, it spread to humans. If the virus had mutated further, 1998 could have seen a pandemic on the scale of the 1918 flu. But a future global outbreak is not a possibility, it's a certainty.
HONG KONG'S Central Market is on Queen's Road, a few minutes' walk from the hub of the Territory's capital around Statue Square. On three floors of a nondescript grey building you'll find clothing, fruit and vegetables, meat, fish and chickens. These last two are sold on the ground floor, from separate aisles of concrete stalls under a tangle of strip-lights and ventilation ducts.
For all the Territory's hectic modernity, most Chinese still view fresh food as one of life's essentials, and many shop for it daily before they go to work. As a result, when I got to the market at 9.30 one morning in June 1998, much of the day's business was already done. Seafood -- live crabs, tuna steaks, king prawns and slinky eels -- still lay on beds of ice; on the other aisle, however, the chicken merchants were packing up.
Birds jostled and squawked, crammed tight in cages made of metal or plastic. Others floated in wooden tubs, plucked and gutted for restaurants, tied in bunches at the neck or feet with lengths of reed. Even packing up, the place was vivid to the senses -- but you'll not find any poultry market in Hong Kong as vibrant today as they were until the last days of 1997.
Before then, you'd have found chickens, ducks, geese, quail, pigeons and pheasants squeezed, higgledy-piggledy, together in wooden cages in a honking mayhem of beak and feather. Among those birds in 1997, however, a virus load was building up that led to one of the most frightening outbreaks of disease this century, carrying within it the potential to kill millions upon millions of people.
The first sign of trouble came in March 1997, when chickens started dying on a farm near Yuen Long, in Hong Kong's rural New Territories. On a second farm, and then a third, they started dying in droves -- in all, nearly 7 000 birds succumbed -- and the disease that was killing them was flu. When a pathogenic strain of influenza takes hold in chickens, 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 haemorrhage until, from the tips of their combs to the claws on their feet, the birds literally melt.
Apart from being thoroughly unpleasant, for the farmers involved it's economically disastrous. In the spring of 1997, therefore, the agricultural authorities in Hong Kong took the only possible course of action; on the farms affected, every bird not already dead was destroyed. On two of the three farms, the disease had killed virtually every bird already.
The virus responsible was isolated by Hong Kong's Department of Agriculture and Fisheries, and passed for identification to Kennedy Shortridge, an Australian professor of microbiology at the Territory's university, who'd been studying multifarious strains of flu in birds and animals for the best part of 25 years.
There are countless types of flu virus; some are harmless, others are lethal, but either way they're characterised according to the nature of two proteins on their outer skin. One, called haemagglutinin, is shaped like a spike; the other, neuraminidase, looks like a long-stemmed mushroom. To date, flu strains with 15 different forms of haemagglutinin have been found, and with nine different variants of neuraminidase -- so viruses are labelled H1N1, H2N2, and so forth.
The new Hong Kong virus was an H5N1 --and virologists know that when an H5 turns nasty in chickens, it can turn very nasty indeed. Shortridge readily accepted that his lab at the pathology building in the Queen Mary hospital compound wasn't sufficiently secure. "The last thing I wanted," he says, "was for this virus to escape." He called Rob Webster in Memphis, Tennessee, a New Zealander who's worked in the United States for nearly 30 years and runs the World Health Organisation's (WHO) Collaborating Centre for Influenza Viruses of Lower Animals and Birds.
On and off, he and Shortridge had worked together for many years; when Shortridge called him now, says Webster, "I said we should get right on it. Whenever there's an H5 outbreak anywhere in the world, you want to characterise the damn thing." The natural reservoir for influenza viruses is aquatic wildfowl; the viruses live in the birds' intestinal tracts, happily co-existing in a state of evolutionary stability, and the infections are asymptomatic -- the birds don't get sick. This means that whenever a new flu virus turns up in domestic animals (be it chickens, pigs or horses), what you've got is a mutation, or more likely a series of mutations, that's jumped at least one species barrier. In short, it's a freak -- so you need to figure out fast what it's up to.
Shortridge and Webster arranged to have the virus shipped to Ames, Iowa, where the US Department of Agriculture has a high-security lab. There a virologist tested Hong Kong's H5 on chickens, and watched it killing every one of them. At the time, however, they could at least feel sure that it didn't threaten human beings. All the received wisdom, all the evidence said that people didn't get sick with an H5.
In 1918, in the worst medical catastrophe in history, influenza killed probably the best part of 40-million people; the virus that did that was an H1N1. In 1957, the Asian flu that raced around the world -- killing perhaps a million people -- was an H2N2. The viral offspring of this century's second pandemic strain held sway for 11 years; then, in 1968, Hong Kong flu appeared and took over, and it's been with us ever since. It's an H3N2 -- and variants of those three Hs, from one to three, were the three types scientists thought we needed to watch out for.
H5 was a different issue. Periodically it flared up around the world in highly virulent forms -- but wherever it turned up, humans didn't catch it. Or at least there was no record anywhere of people dying with an H5.
On May 9 1997, a three-year-old boy fell sick in Hong Kong. At first, it seemed he had an ordinary upper respiratory illness -- a sore throat and a fever. His regular physician said it looked like a bread-and-butter case. After five days, however, this particular cough and temperature weren't going away, and his parents took the boy to a community hospital.
The staff couldn't identify what was wrong with him and the admitting physician felt sufficiently uncomfortable about the case to transfer him to the Queen Elizabeth hospital in Kowloon. Again nothing specific was found --just that the boy was having increasing difficulty breathing and becoming progressively more ill.
He was put into intensive care; his illness worsened. Oxygen wasn't getting round his body. The respiratory failure was consistent with viral pneumonia; consistent with another condition called Reye's Syndrome, he became unresponsive, mentally lifeless. Despite mechanical ventilation and a wide spread of antibiotics, the boy died 12 days after he'd fallen ill. The cause of death was noted as acute respiratory failure, liver and kidney failure, and "disseminated intravascular coagulopathy". In effect, his blood had curdled.
On May 20, the day before he died, Wilina Lim, an Indonesian, chief virologist at the Department of Health, received a specimen of fluid from the boy's windpipe. In her lab, on a normal day, Lim might receive 80 different samples of blood and tissue for analysis. Her staff went to work on this particular specimen, and confirmed three days later that the infectious agent was an influenza virus. The next thing to be done, as standard, was to discover what kind of influenza -- in the jargon of the trade, to type it.
Lim had reagents for H1 and H3; her lab tried them out, and came up blank. Over the following days, they double-checked. They did serology, fluorescence tests, electromicroscopy -- and still they got nothing. All the same, Lim wasn't unduly concerned; like flu in general, H3 is busy mutating all the while, so she figured the reagents she had didn't fit this particular strain. The next move was to send it to people who had a lot more reagents than she did.
Like terrorism -- and more than a few scientists have described influenza as a terrorist, single-minded, travelling light, always switching disguises -- this protean virus is under constant, worldwide surveillance. At the apex of the network stand four WHO collaborating centres, in London, Tokyo, Melbourne and Atlanta. In mid-June, stumped, Lim freeze-dried samples of her virus and sent them to London and Atlanta. She also sent a sample to Holland, to Jan de Jong at the Dutch National Institute of Public Health in Bilthoven. Although he and Lim had never met, he'd first been in touch with her 10 years before, asking her to send him anything out of the ordinary.
At this stage, she had no cause to be worried; interesting viruses crop up all the time, and besides, no one had told her that the boy had died. So she continued about her work, the weeks went by, and she heard nothing. Then, on August 8, she got a phone call from De Jong. He'd booked a flight, he told her, and was arriving in Hong Kong on Sunday. He didn't say why he was coming.
On the Monday morning, she picked him up and they set off towards her lab in Pok Fu Lam. In the car De Jong said, "Do you have any idea what virus you sent me?" Lim told him she assumed it was an H3, a strain that had evolved and changed to the extent that her reagents couldn't spot it. De Jong said, "It was an H5."
Lim was astounded. De Jong had received Lim's virus in late June; he spent 10 days propagating and, like Lim before him, he came up blank. He tried testing it with antisera to any number of old variants of H1 and H3, with human flu strains, and with flu strains from pigs. By the end of July, he still had no reaction at all. "In my whole life I never saw any virus that didn't react at all with any antisera. So then I knew we had to hurry very much."
De Jong sent the virus from Bilthoven to the National Influenza Centre in Rotterdam. Among the staff there was a virologist called Eric Claas, who had twice been to Memphis to work for Rob Webster and had brought back with him a panel of reagents to every type of flu strain yet known. So far there'd never been any cause to use them. Now he fished them out of the freezer, ran tests you couldn't argue with -- and within a week, he knew he was looking at an H5N1.
He couldn't believe it. He says now, "I thought, that's impossible. So you repeat the tests, you confirm the findings, you know it's H5 -- and it amazed me a lot." Could there have been some kind of laboratory contamination in Hong Kong? There was only one way to know for sure. De Jong had to get on a plane.
The news was a bombshell in Atlanta -- and there was egg on a few faces as well. With the quality of its people and the weight of its resources, CDC -- the Centres for Disease Control and Prevention -- doesn't often get caught out.
Kanta Subbarao, a quietly spoken woman from Kanpur on the Ganges, works at CDC's influenza branch in a cubbyhole of an office whose most prominent feature is two colour images on the wall of the molecular evolution of the current human flu strain. One of them looks disconcertingly like a nuclear mushroom cloud.
Confronted with the news from Rotterdam, she had to get some H5 reagents fast -- they had none to hand -- and got in touch with her avian virology colleagues at the agriculture department. There was, she says, "a certain amount of panic. We were very fortunate that we had their expertise nearby, and a willingness on their part to share it with us. It was pretty exciting, but it was scary. There was a certain amount of dread."
CDC confirmed the Dutch findings in three days. This was a new flu virus that had infected a human being -- a flu virus all eight of whose gene segments were avian, not human. One of Subbarao's colleagues, an epidemiologist called Keiji Fukuda, was called in San Francisco. He remembers it all too clearly. "All of us were immediately aware of the potential implications. It made all of our guts tighten considerably. I've been involved in a number of investigations, but in terms of infectious diseases there are very few comparable events to an influenza pandemic.
Most infectious diseases have regional or local implications; even a really devastating disease like malaria is confined to warmer areas. There's probably no other disease like influenza that has the potential to infect a huge percentage of the world's population inside the space of a year."
With three others from CDC, Fukuda arrived in Hong Kong a couple of days later, and went to work with the Department of Health. Amid a flurry of investigative activity, one of the things they looked at hardest was whether the dead child had had any contact with chickens.
Fukuda was in Hong Kong for three weeks; during that time his team, together with the local authorities, took 2 000 throat swabs and blood samples. They wanted specimens from the boy's close contacts; for control purposes, they also took specimens from other people wholly unconnected to the child. Their objective was to discover if anybody else had been ill; to find out if the H5 was spreading.
From 2 000 samples, they found antibodies in only nine people suggesting exposure to H5N1. No member of the boy's family had been infected; out of 261 playschool staff, pupils and their parents, one child was found with H5 antibodies. Among 54 health care workers who'd been involved in the case, one doctor showed positive; she recalled that when she'd examined the boy, she'd come into contact with the tears in his eyes. Otherwise, one out of 63 neighbours was found positive, and one out of 73 lab staff.
More disturbingly, five out of 29 poultry workers proved to have been exposed to H5. None of these nine positive cases, however, had been ill -- and nine out of 2 000 people picking up an asymptomatic infection was no kind of pandemic.
The second case was a two-year-old boy. He fell ill on November 6 with a fever, a sore throat, a cough and a runny nose, and although he wasn't too poorly, he was admitted to Queen Mary the next day as a precaution, because it was known that he had a weak heart. He recovered in two days and was discharged -- but not before a specimen from his nose and throat had gone to Lim's lab. They tested as usual for H1 and H3, got no reaction, pulled out the H5 primers and got a positive.
It was early December when Fukuda returned to Hong Kong. The Department of Health officials who met him at the airport had more news for him: there was a third case now. A 37-year-old man from Kowloon had gone down on November 17 with chills, muscle pains and a general malaise, and had been admitted to Queen Elizabeth a week later; he was still in hospital when Fukuda arrived.
Nor was he the only one. On November 20, a girl of 13 fell sick with headaches, a cough and a fever. She went into hospital six days later, and was there for nearly a month. Four days before Christmas, she would die of pneumonia and multiple organ failure. In Kowloon, meanwhile, on November 24, a man of 54 fell ill. He died of pneumonia in the Queen Elizabeth 12 days later. By December the outbreak was well under way.
"That month was terrible," says Wilina Lim. "Suddenly everyone was panicking. Everyone with the most minor illness was going to the doctor wanting tests, scared they had bird flu; specimens were just pouring into the laboratory."
By now, the Department of Health had the media to contend with -- Hong Kong has two English newspapers and more than 30 Chinese ones, and competition is intense. Every morning, staff were facing 20 or more camera crews and 70 or 80 reporters. They were working until midnight and beyond, seven days a week, Christmas was just a day at work like any other -- and all the while, news of more real or potential cases kept coming in.
Towards the end of the month, Dr Paul Saw, the department's deputy director, began to fear that the world was standing on the brink of another 1918. The cases were building up -- in the main they were desperately serious, there was no way to know when it would peak -- and, most chillingly, unlike ordinary flu, the disease wasn't only taking the very old and the very young. As had happened in 1918, it was cutting down people in the prime of their lives.
The H5 outbreak was unprecedented because the receptor cells in the human respiratory tract -- the cells which the flu virus can attack -- are very different from the receptor cells in birds. Prior to Hong Kong, therefore, it had been widely held that for a bird virus to get into people, it needed first to acquire some human characteristics. It needed to mutate, and to do that it had to pass through a mammalian mixing vessel.
The prime candidate for this role of viral blender was the pig. Pigs have receptor cells that can be infected by both human and avian strains of flu. What had been thought to happen in both 1957 and 1968, therefore, was that a human flu virus and an avian flu virus had met up in a pig, swapped their genes about, and produced a hybrid that was part-bird, part-human and wholly deadly. That mix, which gave the potential for a pandemic, hadn't happened in Hong Kong -- but what if it did?
If that came to pass, you could catch the hybrid virus just by breathing -- and you could start counting the cases in millions.
As public health officials contemplated that doom-laden prospect, scientists were puzzling over another enigma. A few months earlier, this flu strain had killed thousands of chickens. But if people were catching it from chickens now, why weren't any of the birds getting sick?
The acknowledged expert in the ramifications of avian flu was Rob Webster. As he says himself, "All my life, I've believed that human flu comes from avian flu -- maybe through the pig, maybe direct." Everyone was agreed: Webster was needed in Hong Kong. He arrived in early December and, together with Shortridge and his Australian assistant, worked out a plan of action. First and foremost, they had to find out where the virus was coming from; that meant intensive sampling in the Territory's live bird markets. To do that, they'd have to upgrade Shortridge's lab, and they'd have to put together an international team to work in it. And to do all that, they'd need money.
Funds were rapidly made available -- from the Hong Kong authorities and from the US. Like the scientists, the funding agencies wanted to find the source of the virus -- and to develop a non-pathogenic version of it, so they could make a vaccine.
Next, the people. In Hong Kong, Webster called colleagues all around Asia and the US to tell them, "I need your best young virologists in Hong Kong. Now." By December 22, the team had assembled and were ready to start sampling in the markets. "It was frightening," says Shortridge. "We were in this phase of what could have been the start of a pandemic, and we were handling the virus at source, the virus from the animal." They wore masks, gowns and gloves.
In 1918, however, the populations of entire cities had worn masks for weeks, and it hadn't done them any good.
From early December, says Shortridge, "It was fairly obvious the chickens had to go. But at that stage, the psyche of Hong Kong society wouldn't have accepted it. We had to reach a certain point, almost of no return, when it was obvious to everybody."
Then, on a farm in the New Territories and in the Cheung Sha Wan wholesale market in Kowloon, more birds started dying.
Amid mounting panic, the decision to slaughter Hong Kong's poultry was taken at the highest levels of the Territory's government on December 27. The Hong Kong public, and the market system in particular, went berserk. On Monday, December 29, the day the cull was due to start, Webster, Shortridge and their team went to the wholesale market in Kowloon. The virologists fanned out to take their samples -- and to this day, Shortridge finds it hard to believe what they saw there. Chickens were standing up, apparently normal, pecking at their food -- then slowly they'd keel over and die, with blood trickling out of their cloacae.
Hundreds of people were instructed by officials from the agriculture department in the business of gassing chickens. All manner of government workers, right through to men who'd normally be tending flowers in the public gardens, gathered for a few short hours' training in mass slaughter.
On that day and the two days following, they killed around 1,2-million chickens and 400 000 other birds. They cleaned out every bird from every market; they slaughtered every chicken on every farm, and every other bird that had had any sort of contact with them. They buried them in mass graves, and they shut the border to stop any more birds coming over from China.
Eight months later, in August 1998, I was sitting with Webster on a bleak Arctic mountainside 960km from the North Pole, and I asked him if they'd done the right thing when they killed all those chickens in Hong Kong. If they hadn't been killed, he said, "I would predict that you and I would not be sitting here talking now. Because one of us would be dead."
By that time, he'd been studying the H5N1 intensively for months, and the rate of evolution in that virus was as high as he'd ever seen. He said, "It would probably have taken weeks, maybe months, to acquire whatever mutations are needed for transmitting between people -- but it would have done it. And if it had got away, my God -- I am convinced that this virus was probably like 1918. It was wholly avian, yes -- but it had human aspects that we've never seen before."
By August 1998, no new H5N1 had shown up. The 18th and last human victim of the outbreak had fallen ill on December 28, the same day the slaughter was announced. That there'd been no more cases since then couldn't be a coincidence -- and on the face of it, the international flu surveillance system had worked. Those involved had stood on the cusp of a pandemic, and it looked like they'd stopped it.
Under the auspices of the WHO, the CDC is making a major push to improve flu surveillance in the People's Republic. Monitoring well over a billion people and all their poultry in China, however, is a very different task from monitoring 6,5-million people in a contained and efficient place like Hong Kong. We simply don't know whether the virus is still out there, what it's doing if it is, and exactly how much danger that might represent.
We do know what a major flu pandemic would be like. In the minds of all those who lived and worked through the incident in Hong Kong lay the shadow of 1918. Spanish flu -- as the 1918 pandemic became known -- happened at the climax of the most appalling war yet seen in history. At any other time, it would have been everywhere acknowledged, instantly and in horror, as a global disaster. At that time, however, it was just another layer atop the deepest pile of nightmares.
At the peak of the pandemic in the US, conditions in the immigrant-packed slums of the country's burgeoning cities came to resemble the worst images of the Black Death of the Middle Ages. In Philadelphia, 7 500 people died in two weeks. The supply of coffins ran out; tramcars were used as hearses; there were too many bodies, and not enough men fit to bury them. Thousands of children were orphaned; thousands of young people lost the partner they'd just married.
One is obliged to conclude that fatalities worldwide must have been nearer 40-million than 20-million. That would be four times as many people dying as were killed in the Great War -- and most of them died in less than a year.
Just as we do not know the exact numbers of fatalities, so too we don't know where the 1918 pandemic came from. Scientists want to know why the 1918 virus was so deadly. They can guess from antibodies what that killer strain might have been like, but they'd dearly like to know what gave it its particularly virulent properties.
The hunt for the Spanish flu began in the Armed Forces Institute of Pathology (AFIP) in Washington in 1995. It was undertaken by Jeffery Taubenberger, a researcher at the institute who had never previously had anything to do with flu.
Clearly not a man low on ambition, he wanted to show what his division could do, because over the previous few years they'd developed techniques for getting nucleic acids out of antique or degraded material to a high and rare pitch of precision.
The AFIP has an archive containing millions of tissue samples from surgical and autopsy pathology going back 100 years. It covers all aspects of human disease, and it covers animal disease, too. It also contains slides of tissue taken from soldiers who died in the 1918 pandemic.
Taubenberger's team, with the necessary combination of luck, brilliance and plain hard work, are the people who'll sequence the genome of the 1918 flu virus. We don't know the statistical likelihood of another virus appearing like 1918; we only know that it could happen.
"The problem is," says Taubenberger, "it happened once. So whatever conditions allowed it to be as nasty as it was can obviously happen again. And a lot of people ask me, what's the chance of another pandemic like 1918? The answer is, I've no idea. But if you ask me what the chance of another flu pandemic of some kind is, I'll tell you. It's 100%. And I'd like to be ready, wouldn't you?"
-- The Mail & Guardian, August 18, 1999.
This is an edited extract from Catching Cold: 1918's Forgotten Tragedy and the Scientific Hunt for the Virus That Caused It by Pete Davies, published by Michael Joseph. It will be available in South Africa within the next few months and can be placed on order at a bookshop