The Pandemic Century

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

  In March 2003 no one knew the answers to those questions and, except for Peiris and other specialists in viral ecology, few people appreciated the threat posed by SARS. This was understandable given that, at the time, the world’s attention was focused on the Middle East, where British and American troops were massing on the Iraqi border in preparation for a ground war prompted by “intelligence” that the Iraqi dictator Saddam Hussein was harboring weapons of mass destruction in breach of United Nations Security Council resolutions. It had been less than two years since Islamist terrorists had seized the controls of four commercial airliners and piloted three of them into the World Trade Center and the Pentagon in a shocking act of international terrorism. The Bush administration was eager for revenge, and it had decided Iraq was the place to exact it. In fact, there was no evidence of Saddam’s involvement in 9/11 and, it subsequently emerged, the Iraqi dictator had destroyed his deadly weapons arsenal several years earlier. Instead, the real weapon of mass destruction had been incubating in Guangdong and was now, seemingly, in the process of spreading worldwide through the simple expedient of hitching rides on buses, trains, and airplanes.

  Solving the mystery of SARS involved the mobilization of hundreds of scientists and laboratories all over the world. It would also require microbiologists to challenge their assumptions about a pathogen that had long been considered uninteresting and a “Cinderella” of the microbial world. As with the Legionnaires’ disease outbreak nearly thirty years earlier, unraveling the mystery hinged on epidemiologists and microbiologists working hand-in-hand. And their efforts would lead to a deeper appreciation of the importance of urban ecologies, medical technologies, and human-made surroundings—particularly hotels, hospitals, and apartment blocks—in the spread of respiratory infections. But on March 12, when WHO issued its alert, and as Peiris experimented with yet another cell culture in an effort to grow the virus—or whatever organism was lurking in the throat washings—all this lay in the future. By now, with the help of Dr. Wilimina Lim, chief virologist at Hong Kong’s Department of Health and the head of Queen Mary’s public health laboratory, Peiris had set up a surveillance system for people presenting with atypical pneumonias at Hong Kong outpatient departments. Specimens were pouring into his laboratory (Peiris had wanted to include recent travel to Guangdong in the case definition, but his request was overruled out of concern that it might offend the Chinese authorities).

  The urgent need for a reliable diagnostic test, so as to distinguish true cases of SARS from run-of-the-mill pneumonias and respiratory infections, was underlined by the horror stories reaching Peiris from clinicians and health workers on the front line. At the Prince of Wales Hospital in Sha Tin, in the New Territories, some fifty doctors, nurses, and medical orderlies appeared to have contracted the infection, prompting the hospital’s management to quarantine them in a special isolation room with its own air conditioning system. However, the measures were ineffective. Over the following days and weeks nearly one hundred more health workers and patients succumbed, followed by friends and relatives who had visited them in the hospital. As at the Second Affiliated Hospital in Guangzhou, the outbreak appeared to have begun with a single case—what would later be dubbed a “super spreader” event.

  ON MARCH 4, a twenty-six-year-old airport worker, identified only as “Mr. CT,” presented at Hong Kong’s Prince of Wales Hospital complaining of fever, body aches, and breathlessness—typical symptoms of community-acquired pneumonia. Accordingly he was admitted to the hospital’s eighth-floor medical ward and given a course of antibiotics. The drugs appeared to do the trick, and over the next few days his fever abated and the patches on his lungs began to fade. However, the scratch in his throat would not go away and he coughed incessantly. Finding his airways choked with phlegm, doctors decided he needed a nebulizer—a device that delivers drugs to the lungs in the form of a fine mist. It was a big mistake. A nebulizer is an excellent way to deliver drugs to the lungs. Unfortunately, it is also a highly efficient way for viruses and bacteria lingering in the respiratory tract to be diffused more widely as after each inhalation comes an exhalation. In the case of Mr. CT, it is thought the nebulizer aerosolized the virus-laden droplets in his breath, turning them into a mist that scattered the particles throughout the Prince of Wales’s medical ward. Four times a day, for seven days in a row, Mr. CT sucked on the nebulizer, then exhaled, releasing a fine mist of viral particles that drifted over the beds of other patients and infected passing health care workers. Although Mr. CT was eventually isolated in a private room with negative-pressure ventilation and medical staff were instructed to wear disposable gloves and N95 masks, the measures came too late. The result was a mini-epidemic that very nearly closed the hospital.

  By the second week of March there were also several reports of cases occurring outside of hospitals, fueling rumors that the pathogen was spreading freely in the community and that no one was safe. At first, Dr. Yeoh Eng-kiong, Hong Kong’s secretary for Health, Welfare, and Food, tried to make light of the rumors, but on March 18 he was forced to acknowledge the reports were true and convened a “war council” at health department headquarters in Queen’s Road East. There, using a computer program loaned from the police, Yeoh and his director of health, Dr. Margaret Chan, the future director-general of the WHO, pored over the latest reports as they tried to predict the pathogen’s next move. “Every day we asked, ‘What are we dealing with? What do we know?’ ” Chan recalled.

  In an office on the eighteenth floor of the same building, Thomas Tsang Ho-fai, a consultant in the communicable disease unit, was asking similar questions. A slightly built man, Tsang was a graduate of the CDC’s elite Epidemic Investigation Service. Tipped for higher things (he would eventually be appointed controller of Hong Kong’s Centre for Health Protection), Tsang had first come to prominence during the 1997 bird flu outbreak, but it was during SARS that he got a chance to demonstrate his sleuthing skills and was dubbed “detective Fai” by Hong Kong’s media. Since the first week of March, Tsang had been working around the clock, tracking SARS patients and their contacts. On March 26 he noticed that one hospital had reported fifteen SARS cases in a single day and that all the patients had given their address as Amoy Gardens, a nearby housing complex overlooking Kowloon Bay. That was unusual, so Tsang decided to take a closer look.

  When he arrived at the complex he found that cases were increasing at an alarming rate: thirty-four people hospitalized on March 28, thirty-six more the following day, and sixty-four more on March 31. With the outbreak threatening to overwhelm the public hospital system, and his bosses considering quarantines, Tsang was under pressure to locate the source of the outbreak as quickly as possible. The problem was how. Without knowing whether SARS was a virus or a bacterium, and whether it was an aerosol or droplet infection, it was difficult to determine how it was transmitted and how best to halt its progression. However, Tsang reasoned that since most of the SARS cases had come from block E, that was the logical place to start.

  Built in 1981, Amoy Gardens is typical of many of the middle-income housing projects that blight Hong Kong. The complex consists of fourteen hideous beige tower blocks laid out in a cruciform shape. Each block has thirty-three floors and each floor has eight units arranged in pairs. In all, the blocks are home to some 19,000 residents. As a solution to Hong Kong’s housing shortage, Amoy Gardens must at one time have seemed elegant. Unfortunately, the complex also presented the ideal environment for the spread of SARS.

  Tsang noted that most of those who had fallen ill lived in the corner units, numbered seven and eight on each floor, suggesting that the disease had spread vertically between each floor. Tsang also noted that while there had been cases in other blocks, those who lived in Block E had fallen ill about three days earlier, indicating that this was probably the seat of the outbreak. But what was the mechanism? Was it contamination from the water tanks, as had occurred during the Legionnaires’ disease outbreak? Or could it have something to do with the
high-powered exhaust fans that many of the residents had installed in their bathrooms? Tsang set up a classic epidemiological study, comparing rates of infection among residents who owned exhaust fans with those who did not. The results showed that those who used exhaust fans while taking showers had a five times greater chance of contracting SARS, suggesting that the pathogen may have been sucked into their bathrooms via sewerage leaking into the drains fitted to the floors of showers. However, when Tsang took samples from the sewer pipes and the building’s water tanks, the tests were negative. Next, he examined the garbage for signs of cockroaches and rodents. Also negative. Finally, he considered the possibility that, like the anthrax letter mailings that had followed the 9/11 terrorist attacks in the United States, the residents of Amoy Gardens had been deliberately targeted by a foreign power or a terrorist organization. “We thought it might be a biological attack because of the vertical arrangement of cases,” Tsang explained. However, this theory was also soon ruled out.

  Amoy Gardens was not the only building to attract Tsang’s attention. By now epidemiologists from the Department of Health were also scouring the Metropole Hotel. The first indication that the hotel might be implicated in the outbreak came on March 12 when the Singaporean authorities notified Hong Kong’s health department that three young women who had recently been hospitalized with SARS in Singapore had stayed at the Metropole. It subsequently transpired that one of the women, Esther Mok, a twenty-three-year-old former airline stewardess who had been in Hong Kong on a shopping expedition, had stayed in a room on the same floor as Liu. On February 28 she had been admitted to Singapore’s Tan Tock Seng Hospital, sparking an outbreak that infected twenty-one of the hospital’s medical staff. One of the people she infected was a prominent infectious disease physician, Leong Hoe Nam, who subsequently had to be hauled off a flight that was returning to Singapore from New York, where he had been attending a conference. Deplaned at Frankfurt airport, Leong, who was traveling with his pregnant wife and mother-in-law, became Europe’s first official SARS patient.

  By March 18, Tsang had learned of two further cases who had stayed at the Metropole: a seventy-two-year-old Canadian man who had been hospitalized in Vancouver, and a seventy-eight-year-old Chinese-Canadian woman, Kwan Sui Chu. Mrs. Kwan and her husband had been visiting their sons in Hong Kong over the new year and had taken a room at the Metropole as part of an airline package deal, their stay overlapping with Liu’s. Two days after returning to Toronto, Mrs. Kwan fell ill and by March 5 she was dead. In the interim, she transmitted SARS to four family members, including her forty-four-year-old son, who in turn introduced SARS to Scarborough Grace Hospital, in Toronto, sparking the worst disease outbreak in the hospital’s history.

  The information prompted the Hong Kong health department to review all its files on severe community-acquired pneumonia, and by March 19 Tsang knew of seven SARS cases linked to the ninth floor of the Metropole, including Johnny Chen, the Chinese American businessman who had introduced SARS to Hanoi, infecting Carlo Urbani. Tsang and his colleagues spent days combing the Metropole for clues, taking samples from the carpets, furniture, elevators, air vents, and toilets. Perhaps Liu had sneezed on Chen when he walked by him in the corridor of the ninth floor, or perhaps he had been infected when they shared an elevator. Or perhaps, the bug had been communicated to Chen and other guests via the hotel’s air conditioning system, as had occurred with Legionnaires’ disease at the Bellevue-Stratford in Philadelphia. These were all plausible hypotheses, but without knowing what they were looking for and being able to test for it, Tsang and his team could make little progress.

  THE DISCOVERY THAT the Metropole was the common denominator in the spread of SARS to other countries shook senior WHO officials. Unlike on 9/11 when the Pentagon’s inability to imagine that terrorists might weaponize commercial airliners had caught America’s security apparatus by surprise, in 2002 the WHO felt sure it had a system in place for detecting novel biological threats before they could cause widespread epidemics or pandemics. The name of that system was GOARN, short for Global Outbreak Alert and Response Network. The brainchild of David Heymann, the head of WHO’s Communicable Diseases Division and a former CDC epidemiologist who was a veteran of the Legionnaires’ and Ebola outbreaks, GOARN routinely trawled the internet for electronic “chatter” about outbreaks occurring in remote regions of the world. It used systems developed by Canada’s Global Public Health Intelligence Network (GPHIN) and the Program for Monitoring Emerging Diseases (ProMED). The idea was that once alerted to a suspicious event, WHO officials could make discreet inquiries with the relevant health authorities and dispatch a team to investigate. Essentially, the electronic eavesdropping network was WHO’s version of 911 and GOARN its fire and ambulance service. Indeed, it was the WHO’s interception in November 2002 of the report about an unusual respiratory outbreak in Guangdong that had first prompted officials to make inquiries. But of course, in 2002 the pathogen that WHO officials had in mind was bird flu. The result was that when officials persuaded the Chinese to forward samples from Guangdong to a WHO laboratory for testing and it was found that those samples contained only routine strains of flu, no one thought to check for other pathogens and the samples were discarded.

  Initially, Peiris had also assumed that the respiratory outbreaks in Guangdong and Hong Kong were due to a mutant strain of bird flu. “It was not at all clear at that stage that we were looking at something unknown,” he said. “The only unusual thing about the disease was that health care workers seemed to get affected disproportionately, but a particularly severe influenza could conceivably have produced the same effect.” What changed Peiris’s view and swept away the assumptions clouding experts’ view of the SARS outbreak were two samples that arrived at Peiris’s laboratory in the second week of March. As it happened, one of those samples came from Liu’s brother-in-law, Chan Ying-pui, who had also been hospitalized in Hong Kong and who had died shortly after the 64-year-old professor of nephrology. Unlike other samples arriving at Peiris’s laboratory, many of which only broadly fitted the WHO’s case definition and may not have been true cases of SARS, Chan’s clearly was. Moreover, as the biopsy had been taken while he had been alive, there was a good chance that live virus might still be present in the tissue.

  Once again, Peiris instructed technicians at his laboratory and at Queen Mary’s to run tests using the usual cell cultures for growing respiratory viruses. It was only when these failed, as they had before, that Peiris suggested using other cell lines, including fetal kidney cells from rhesus monkeys that had proved useful for growing hepatitis and the human metapneumovirus, a common cause of severe bronchitis in children. Thus it was that on March 13, Dr. Chan Kwok Hung, a senior scientist in the microbiology laboratory at Queen Mary’s, introduced Chan’s lung biopsy into a monkey cell culture. Two days later, examining the culture through a microscope, he spotted a sheet of cells that appeared shinier and rounder than the others. However, the change in the culture was extremely subtle so he asked Peiris for a second opinion. Peiris agreed the culture looked “a bit unusual,” but two days later there had been no further change, as one would expect if a virus were growing, so Peiris suggested scraping a bit off and transferring the material to a fresh cell line. This time, they could see more of the rounded bodies, suggesting that something was definitely growing in the monkey cells. However, the same effect might be produced by a contaminant, such as a mycoplasma, or a drug that had been administered to the patient in the hospital. To be certain Peiris asked a pathologist colleague, John Nicholls, to examine the cells through a high-powered electron microscope. Gathering in a room in the hospital’s pathology department, Nicholls and Peiris could clearly see the particles. Peiris now had no doubt that a virus was growing in the cell culture, but what kind of virus was it and how could he be certain it was the cause of SARS?

  Microbiologists tend to be a cautious lot and Peiris is no exception. To be sure he had isolated the agent of SARS he needed to confirm t
hat the virus was also present in other SARS cases. The simplest way to do that was to use a serology test—the same test McDade had used to demonstrate that Legionella was the cause of Legionnaires’ disease in 1977. If the virus they had isolated was SARS, then serum from SARS patients would contain antibodies that would react with it. The strongest evidence of all would be if the virus reacted with serum taken from patients at an advanced stage of infection. Accordingly, to make the test as rigorous as possible, Peiris asked Lim at the public health laboratory to send him “paired” serum samples from patients with suspected SARS, i.e., samples collected from patients in the early and late stages of infection. In addition, he asked for serum from patients who did not have SARS and instructed Dr. Lim not to tell him which was which. As they added the serum samples to the virus, they noted a marked antibody reaction. Importantly, the sera from the patients who did not have SARS gave no reaction. Moreover, using an indirect immunofluorescence assay to demonstrate seroconversion, they could see the reaction was stronger in the later serum samples—a strong indication of rising antibody levels in the SARS patients.

  Peiris was now confident he had found the virus of SARS, and on March 21 he emailed Klaus Stohr at the WHO to tell him the news. However, as Peiris still did not know the classification of the virus, he asked Stohr to keep the finding confidential to give him time to complete the identification. Unfortunately, at this point scores of suspect cases were being reported in Canada, Hong Kong, Vietnam, and Singapore, many of them among health workers, and the WHO was desperate for positive news. Somehow or other the news leaked out, forcing Peiris to go public on March 22nd.