The Fatal Strain

by Alan Sipress

  Tinh dismissed them all with a snicker. “I haven’t had any direct contact with poultry or eaten chicken or duck in a long time,” he countered. Nor had he dined at his girlfriend’s house for weeks before he fell ill, and, thank you very much, all her chickens were healthy. “But,” he added, “I was the one in the health center who had the closest contact with Mr. Tuan.”

  A rare voice of candor among Vietnamese officials was Dr. Nguyen Tran Hien, the astute and able head of the National Institute of Hygiene and Epidemiology (NIHE), the country’s CDC. He told me in April of that year that his researchers had identified a significant number of mild and even asymptomatic cases, like Tuan’s grandfather. “The symptoms are not as severe as before. Also, the transmission may be faster and easier,” he reported. “We are concerned that if the virus is changing, maybe a new virus is coming in the future.” Hien wanted more data. And he wanted outside expertise.

  Keiji Fukuda returned to Hanoi in mid-April 2005 as part of a special WHO mission. Fukuda was still with the CDC in Atlanta and would not officially transfer to WHO for several more months. But his standing and experience in Vietnam made him a natural for the assignment. Joining him was Dr. Aileen Plant, a fellow epidemiologist from Curtin University of Technology in western Australia known for her passion and wicked sense of humor. Plant had headed WHO’s highly successful response to SARS in Vietnam two years earlier. The third member was Dr. Lance Jennings, a virologist from the Canterbury Health Laboratories in New Zealand and his country’s acknowledged authority on flu.

  For about a week, they shuttled from the WHO offices on Tran Hung Dao Street in downtown Hanoi to the handsome French colonial edifice that houses NIHE about a mile away. That grand old building, with its warm, mustard-colored facade and gray shuttered windows, is located on a street named for a foreign disease detective, Alexandre Yersin, the French-Swiss bacteriologist who discovered the pathogen causing bubonic plague a century ago and later adopted Vietnam as his home. There, down the elegant, high-ceilinged corridors of NIHE, Fukuda and his team huddled with their Vietnamese counterparts, reviewing their findings.

  “We were looking at everything we could look at,” Fukuda recalled. “Was there an increase in cases? Any differences of patterns in cases? Anything different about the people who were getting infected themselves, and so on.” The evidence wasn’t conclusive. “But on the other hand, it began to appear there were some differences from earlier patterns in Vietnam.”

  During the previous year, bird flu had killed nearly three-quarters of those Vietnamese it infected. Yet over the first few months of 2005, the mortality rate had dropped by more than half, suggesting that the virus was edging closer to a pandemic strain. The shift was especially conspicuous because it took place only in the north of the country. The cases were also increasingly coming in family clusters, and often the time that elapsed between cases within the clusters was growing, making it ever more likely that relatives were passing the disease to one another rather than all catching it from the same source. Nine cases were from Thai Binh alone, including Tuan’s cluster.

  “We thought that it appeared there really could be some changes going on,” Fukuda said. “We were in that sort of gray area of understanding. Even if you have enough data to suggest, you don’t have enough data to tell you really what’s going on, and you need help interpreting.”

  Fukuda and his colleagues pressed for a wider review of the evidence, and WHO scheduled a private conference for the first week of May, just ten days after the mission left Hanoi. It was to be held in Manila, the Philippine capital and home of the agency’s regional headquarters. WHO summoned staff from Geneva and across Asia. Senior government health officials from Vietnam, Thailand, and Cambodia were pulled in, as were outside specialists from the United States, Japan, Britain, and Australia. Leading laboratories, in particular the CDC in Atlanta and the National Institute of Infectious Diseases in Tokyo, were also asked to prepare genetic analyses of H5N1 specimens so these could be compared with the pattern of cases in the field.

  “We called for the consultation knowing that it was a lot of trouble to bring a lot of people in rather quickly, but on the other hand these weren’t academic questions,” Fukuda recounted. “If there really was a change going on, we really wanted to try to come to grips with that as quickly as possible.”

  For two days, the experts cloistered in Manila and sifted the evidence. Afterward the agency issued a report that cited the shifting patterns of infection in northern Vietnam, including a wider age range of victims, more and larger clusters involving cases over a longer period of time, cases without symptoms, and a declining mortality rate. The document said this was all consistent with the possibility of human transmission and greater infectiousness.

  It also detailed genetic changes in viruses isolated in northern Vietnam. One mutation involved the place on the virus where it binds to either human or animal cells and could make it easier for the pathogen to infect people. Another change was near a site related to the lethality of the virus. The report also revealed that a sample from Nguyen Thi Ngoan, the mischievous teen from Thai Binh, showed a mutation that could cause resistance to the antiviral drug Tamiflu. If that change became widespread, it could rob doctors of a vital weapon.

  “While the implications of these epidemiological and virological findings are not fully clear,” the report concluded, “they demonstrate that the viruses are continuing to evolve and pose a continuing and potentially growing pandemic threat.”

  In the United States concern was mounting. Just three days after the Manila conference, the Central Intelligence Agency sponsored an exercise to model the global impact of a pandemic strain erupting out of an unnamed Southeast Asian country. Participants were drawn from five federal departments, including Defense and Commerce. The conclusions were sobering: economic downturns, international tension, and political instability.

  On May 26, two weeks after Nguyen Sy Tuan was finally discharged from Bach Mai Hospital, WHO’s senior communicable disease officer in East Asia, Hitoshi Oshitani, got an alarming e-mail. It was from an epidemiologist in the agency’s Hanoi office. Vietnamese researchers at NIHE had been testing specimens taken randomly at health-care facilities in Thai Binh province. The sampling had not specifically targeted suspected bird flu cases. But 10 percent of the 170 specimens had come back positive for the virus, an exceptionally high proportion.

  The results seemed to underscore the frightening scenario mooted in Manila. Even worse, the data lent credibility to separate tests conducted by Canadian scientists in Vietnam, which Oshitani had been hearing about.

  Without a word to WHO headquarters in Geneva, he flew to Hanoi to see the Canadian microbiologist responsible for the research, Dr. Yan Li. WHO’s flu hunters in Asia were trying to keep the startling information from leaking out prematurely. “We didn’t want a huge panic with unverified information,” explained Peter Horby, the agency’s lead flu investigator in Vietnam.

  Based on their briefings in Hanoi, Oshitani and Horby drafted a confidential report and on Tuesday, June 7, shared its contents with Geneva. They reported that Li, a Beijing-born scientist based at the Canadian health department’s National Microbiology Laboratory in Winnipeg, had begun a project earlier in the spring to help train Vietnamese scientists responsible for flu research in testing and laboratory techniques. As part of the work, the Canadians had sent in their own mobile lab. They began testing nearly two hundred samples previously collected by the Vietnamese. These were blood samples, or more accurately serum, the clear liquid that remains in blood once red and white cells and platelets are removed. The Canadians were using a technique called Western blot that could detect the antibodies that the human immune system produces in response to a bird flu infection. Though the Western blot technique was not entirely reliable, it did not require advanced lab safeguards like other antibody tests and could be done under local conditions in Vietnam.

  According to the confidential report, the rese
archers tested 86 specimens from people with suspected cases of bird flu. About two-thirds came back positive for the telltale antibodies, indicating the patients had caught the bug. Another 101 samples were from people who had had contact with confirmed cases or infected birds. Nearly as many of these, about three-fifths, were also positive.

  Separately, the Vietnamese had run tests using a different technique on the samples from the Thai Binh health facilities. Scientists at NIHE had established that 10 percent were positive by using a method that looked for genetic evidence of the virus itself rather than for antibodies. This technique, called polymerase chain reaction or PCR for short, uses special strands of highly sensitive genetic material called primers. Scientists would combine these with the sample and, if they matched, the primers would cause the virus’s own genetic material to rapidly reproduce until there was enough of it to identify.

  Finally, the Canadians and their Vietnamese counterparts had conducted an analysis of thirty-eight samples and found that many had specific mutations in the surface proteins of the virus, strongly suggesting it was becoming less deadly. These mutations could help explain some of the milder and asymptomatic cases in Thai Binh and elsewhere in northern Vietnam, such as those of Nguyen Sy Tuan’s sister and grandfather.

  The report concluded that the disease could be spreading among people more readily than anyone had thought. Moreover, if most cases were mild or lacked symptoms altogether, identifying those who were infected would prove nearly impossible. Even in hospitals, it would be challenging to recognize bird flu patients and segregate them from others. “Extinguishing a pandemic strain by early identification and targeted use of anti-viral [drugs] and public health measures is not going to be successful,” the document warned.

  Klaus Stohr, the influenza chief, was taken aback. But at the same time, there was something about the results that struck him as not quite right. If the virus was already racing across Vietnam, shouldn’t the hospitals be flooded with patients? They weren’t. “It should stick out like a sore thumb,” he thought.

  Calling his staff into his fourth-floor office at WHO headquarters on the morning of Thursday, June 9, Stohr said he planned to urgently convene an outside panel of experts to evaluate the information. “We’ll never have perfect data,” responded one of his lieutenants, but added, “We have data sufficient to consider raising the pandemic alert level.”

  Stohr began drafting a memo to Lee Jong Wook, the agency’s director general, outlining the arguments pro and con for sounding the global alarm. Raising the alert level would immediately activate steps to contain the outbreak. Stockpiles of antiviral drugs could be rushed to Vietnam and the surrounding region. A warning against travel to Vietnam and nearby countries might follow. Every day mattered. Any delay could hand the disease an even larger head start, potentially costing the lives of untold masses of people.

  But what if it’s a false alarm? “If you raise the level and you’re wrong,” Stohr thought, “you’ll be blamed.” The Vietnamese would be stigmatized. Their economy damaged. The move would spark waves of unnecessary panic worldwide, and WHO’s own credibility would suffer. Future warnings might be ignored.

  “You make the decision based on the data you have in a responsible way,” he later explained. “You need to get ready to defend it. You need to get ready to take the blame.”

  At that moment in mid-2005, the alert level was at level three, meaning the virus had succeeded in achieving no more than very limited human transmission. Based on the new information, WHO could hike the level to four or five, signifying greater human transmission and alerting the world that a full-blown pandemic, level six, was imminent.

  An internal document written that same day suggested the situation might be even graver: “If the results are correct . . . this could be the signal that an influenza pandemic has begun.”

  “Good morning, good afternoon, and good evening to everyone,” Stohr said as he opened the conference call at ten minutes past noon on Friday, June 10. His greeting was familiar to those who had sat in on his previous calls but the setting was not. He had summoned his staff to the WHO bunker, and they gathered around the large, circular conference table in the mezzanine overlooking the main floor of the SHOC. The command center offered a sophisticated communications network that could handle the large call while its secure doors assured that access to the session was kept strictly limited.

  On the call were WHO officers from the Hanoi office and Manila regional headquarters. Also invited to participate were Dr. Nancy Cox, chief of CDC Atlanta’s influenza division, Dr. Roy Anderson, a senior epidemiologist at London’s Imperial College and chief science advisor to the British defense ministry, Dr. John Horvath, the Australian government’s chief medical officer, Dr. Masato Tashiro, head of virology at Japan’s National Institute of Infectious Diseases, and Dr. Kiyosu Taniguchi, chief of infectious-disease intelligence at NIID. Dr. Yan Li, the Canadian scientist, was also on the line.

  They had all been supplied copies of the report detailing the test results from Vietnam. Now Stohr wanted their feedback. He said they would go in alphabetical order.

  Anderson would have started, but he was running late. So Cox, the tough-minded virologist from the CDC, was first out of the box. Wasting no time, she went on the attack, calling the tests into question.

  “The results I’m most concerned about,” Cox said, “are the antibody test.”

  She and her colleagues at the CDC had previously done extensive work developing various tests for antibodies and had discovered that some of these techniques picked up false positives for H5N1. Some even purported to show evidence of the virus in specimens from U.S. blood donors who had never been within thousands of miles of an actual H5N1 outbreak, whether in people or birds. In particular, Cox was skeptical about the reliability of Western blot testing. To avoid misleading findings, the sensitivity and precision of this kind of analysis had to be calibrated using the results of other tests.

  On the call, she grilled Li about his techniques in performing Western blot and interrogated him about whether he had used proper scientific controls to gauge the accuracy of his findings.

  “Very limited controls,” Li acknowledged. He was already on his heels. “The number of controls is very low.”

  Cox pressed on. She said the CDC had tested similar serum samples from Vietnam, and they’d all come back negative for virus antibodies. She called the rate of positives in Li’s test, or assay, “exceedingly high.”

  “I really wonder if your assay is picking up false positives,” she continued. She urged that the samples be retested using a more respected technique for detecting antibodies, called microneutralization. “The serology is very much in doubt and must be repeated with another test in another lab,” she insisted.

  “I understand the risks of Western blot,” Li responded defensively. He stressed that his findings were only preliminary. He admitted they might have overestimated the extent of infection in Vietnam.

  Cox wanted everyone on the call to take a deep breath and think hard before rushing to conclude there was evidence of an emerging pandemic. So she continued to pound away, questioning the overall reliability of Li’s approach.

  “The results are in question because they were obtained with an assay that hasn’t been validated,” she argued.

  “I agree,” Li conceded, wishing his results had never been passed to the agency. “I didn’t even want that circulated.”

  None of the other experts had yet weighed in, and already they could feel Li squirming on the other end of the line.

  For a moment, he seemed to win a respite. The call shifted to a discussion of the genetic changes Li had detected and whether these were making the virus less lethal. He said that the mutations had been found in most of the human samples that his team analyzed. He suggested that either the virus was evolving into a less deadly form, or an entirely new flu virus was now circulating in Vietnam.

  But he promptly came under fire again, t
his time from a new quarter. Anderson, the British epidemiologist, had joined the call and pushed Li on whether those mutations alone would determine the lethality of the virus. Anderson personally didn’t think so. He also noted that the analysis had examined only an “exceedingly small” number of samples.

  Cox joined back in, suggesting that a whole series of genetic changes would be needed to alter the lethality, not just one. And even if these changes did make the virus less deadly in animals, as some scientists suspected, she was unconvinced these changes would do the same in people. She wasn’t even sure the mutations had occurred at all.

  “The results need to be verified,” she said, repeating her refrain. “It’s quite possible they are true, but they need to be verified.”

  Horvath, the Australian chief medical officer, now entered the fray. He wondered whether the researchers had tried to make sense of their highly unusual lab findings by comparing them with the actual experience of patients in the hospital.

  “It’s difficult to understand, naturally,” Li offered meekly.

  Then, abruptly, the tone changed. Having roughed up Li, the expert panel shifted gears and began to ponder what it would mean if he actually proved to be correct.

  “The problem is serious, very urgent,” Anderson conceded. “We need access to information. It’s urgent that an independent lab confirms the changes.” But Vietnam might not share that sense of urgency, and Hanoi’s record of cooperation was poor. “It may be necessary to elevate the pandemic level to get the information,” Anderson suggested.

  Stohr pressed the issue of whether to in fact raise the level. “How concerned should we be?” he queried.