The Fatal Strain

by Alan Sipress

  “On face value, it’s a very serious report,” Horvath answered. “But it’s not sufficient to take action. I’d be concerned with raising the level of pandemic because it might shut Vietnam down.”

  “We’d have to weigh that risk,” Anderson said. The move could be highly unpopular in Southeast Asia. He said the agency would have to weigh “the urgency to understand more versus the danger of upsetting the political balance.”

  With time on the call running down, the experts turned to the third and final set of findings. These were the results of the PCR tests on the samples from the Thai Binh health-care facilities, which had revealed a 10 percent rate of infection. They were the most troubling findings. PCR was a more reliable test than Western blot.

  “Ten percent is extremely high,” Cox noted. During a seasonal flu outbreak, far fewer than 10 percent of people tested under similar circumstances would have been positive. “But if this is a pandemic beginning, it’s not impossible. It’s urgent that the results be verified.”

  Stohr concurred. “There’s an urgent need to verify the accuracies of the findings,” he concluded. WHO would rapidly assemble a new team of experienced virologists and epidemiologists, he decided, and dispatch them to Hanoi. WHO’s chief representative to Vietnam would hope to meet early the following week with senior Vietnamese officials and pressure them to let the team in. The Vietnamese government would be urged to turn over serum and other samples and related material for further testing.

  A decision on sounding the pandemic alarm, he said, would be temporarily postponed.

  At two o’clock Geneva time, Stohr adjourned the call.

  Uncertainty is what often separates public health from laboratory science. Lab researchers select questions they believe they can answer and bypass those they can’t. They design experiments to produce definitive proof. Success means generating results that can be reproduced by other scientists in other labs. Public health, by contrast, rarely gets to choose the questions it must answer. People get sick. Doctors try to diagnose. They prescribe treatment and hope it will work. Symptoms, family history, and even test results are suggestive but often not definitive. The whole purpose of getting a second opinion on medical care is not to reproduce the conclusions of the initial physician but to discover if there are different ones. If the affliction is the common cold, uncertainty can be annoying. If it’s cancer, it can be tragic. If it’s flu, it can be catastrophic.

  Medical science as a modern discipline is little more than a century old. Molecular biology goes back barely two generations. In that short period, the field has reshaped human knowledge and answered some of the basic questions about our very essence. Yet in confronting pandemic influenza, the greatest human killer in history, science still comes up short.

  The difficulties begin with diagnosing the virus. Scientists have had trouble coming up with a fast way of determining whether someone has H5N1, and this lack of an accurate rapid test has repeatedly fostered confusion and even panic, most notably when the disease came knocking on Europe’s door. In the final days of 2005, villagers in the frigid mountains of eastern Turkey began falling sick with a mysterious respiratory ailment. Flu specialists suspected the novel strain. But initial tests by Turkish health officials came up negative. Days later, they reversed themselves, announcing that further tests had confirmed bird flu in two patients. More would follow. Of eight patients ultimately confirmed with bird flu and treated at a hospital in the regional center of Van, rapid flu tests came back negative every time. So did a separate enzyme-linked immunosorbent assay, or ELISA, test. Even the initial PCR test for four of the cases failed to identify the virus, though they were already very sick. Only after additional samples were taken did they test positive.

  Then, as fear spread, Turks from around the country flooded hospitals at the first sniffle or cough. Day after day, hundreds of test samples poured in and overwhelmed the country’s national lab, which was equipped to complete at most a few dozen each day. Soon, instead of missing cases, Turkey was reporting false positives. The crest of the epidemic suddenly seemed to rise far higher than anyone had seen before. The government would eventually announce more than twenty human cases. But follow-up testing by WHO partner labs outside the country could confirm only a dozen.

  Researchers in Indonesia reported similar problems with their initial flu tests. So did doctors in Thailand, who said in 2006 that these tests were actually becoming less able to detect the virus over time. Though rapid tests for seasonal influenza are commercially available and widely used, WHO says they are not sensitive enough to be used for bird flu. False negatives are common, and even positive results cannot distinguish between H5N1 and other influenza strains. Both the U.S. government and European Union have funded efforts to come up with a fast diagnostic test for bird flu. In spring 2009, the U.S. Food and Drug Administration approved the initial marketing of a test that can take less than forty minutes to work.

  PCR tests that check for genetic evidence of the virus are more accurate but take several hours, longer than some victims can afford. And should the world face an emerging pandemic, even a short delay in detecting the virus could scuttle hopes of slowing its progress. Moreover, these are expensive tests that are frequently ill suited to much of Asia and elsewhere in the developing world. They require precise sampling, highly trained technicians, and the proper primers. As the virus strain mutates, which it does with haste, existing primers may no longer match and the tests will fail. And poorly matched primers can incorrectly detect other genetic material in the sample and yield a false result. Tests for antibodies to the virus can be even more accurate, especially established techniques like microneutralization. But these often demand labs with sophisticated safeguards. And they take much longer. Since antibodies to a virus appear only after the infection, these tests are of little use for responding to the disease in real time. A pandemic could be well on its way before antibody tests confirmed it. The “gold standard” for laboratory science is growing the live virus itself from a sample, traditionally in eggs, and using this to identify the pathogen. But this too is a long process. And for the many countries that lack high-security labs, the risk of the live virus escaping makes this technique far too risky.

  The uncertainty goes well beyond testing. Flu specialists have been asking themselves for more than a decade why they know so little about the novel strain. Not long after it first crossed to people in 1997, researchers had already ascertained that the disease could be contracted through exposure to infected birds. But as Fukuda explained, exposure could mean many things. “Do you have to touch it? Do you have to rub your face after you touch it to get the virus near your mouth or your nose? If your face is close enough to infected birds, does that mean you can really breathe it in?” Maybe you don’t have to touch it at all, he suggested. “If you mean proximity, do you mean two feet, five feet, ten feet? Bird feces the same as having contact with birds? Is touching the wall in an area where birds were in the last twenty-four hours, does that count?” These are not idle distinctions. This information would help inform a strategy for stemming the spread of the virus and in turn reduce chances of a sinister mutation.

  Research has been slow to offer answers, in large part because it is hard to conduct. Sick people don’t wander into studies. Those who are exposed and infected are often too ill to report how they got that way. Nor are time-consuming field studies involving large numbers of people a priority for countries reeling from these outbreaks. “Most of the countries where the first cases have occurred do not have traditions of analytic field investigation and the high profile of ‘bird flu’ does not encourage immediate openness,” wrote Dr. Angus Nicoll of the European Center for Disease Prevention and Control.

  Dr. Michael Perdue, an American microbiologist assigned to WHO’s influenza program for several years, said it is hard to get standardized reporting from countries because each health ministry has its own way of doing things and few are anxious to publicize their dise
ase outbreaks. “When it hits their country, they shut down,” he lamented. “WHO has to walk a fine line between demanding we have to have this information and shutting down the communications with the country, where they say, ‘Whoa, they’re coming after us. WHO is coming after us.’ You don’t get as much information as you like. There’s sort of a fine political dance that you’re doing.”

  Perhaps more surprising is the lack of autopsies. Of the first two hundred confirmed deaths from the virus, fewer than a dozen victims underwent these postmortem exams. “This has posed some major problems in understanding the biology of the disease or fully understanding the virus underlying it,” explained influenza researcher Malik Peiris from the University of Hong Kong. Autopsies could examine how the agent wages its assault on the lungs and what other organs might also come under attack. These studies could help explain why some people get infected and not others, why the disease is so severe, and how well antiviral drugs work. “These are all pretty fundamental questions,” Peiris put it to me.

  Why so few autopsies? The conventional response from leading researchers and senior officials is that local cultures bar the practice. In Chinese tradition it is said a corpse must be buried intact. Similar strictures are thought to apply in the Buddhist cultures of Thailand and Vietnam and the Muslim culture of Indonesia. “You have to get permission from the family to get that done,” explained Dr. Triono Soendoro, head of laboratory research at Indonesia’s health ministry. “People here are not used to having postmortem procedures.” Had Indonesian officials actually asked families for permission? “No, we haven’t tried,” Soendoro added.

  When I broached the subject of autopsies with victims’ relatives, I got surprising responses.

  Rini Dina Prasetyaningsih was among the first Indonesians known to succumb to the disease. Months later, I visited her small but comfortable middle-class home in South Jakarta and raised the delicate subject with her husband, Agus Mardeo. “I wouldn’t object to a postmortem as long as it was in the hospital and done by a doctor, as long they didn’t dig up the body after it was buried,” he said. Mardeo’s long, thin face turned somber. “Personally, I really wanted to know what happened to her. I would have been more than happy to have an autopsy.” But he added, “I’m just a common man. I don’t know about these medical procedures. No one suggested the idea to me.”

  In a poorer suburb just outside the capital, a woman named Ibu Samida offered the same answer. She received me in her dimly lit living room, where she sat on a tattered couch surrounded by her four children and two grandchildren. The only one missing was her middle daughter, nineteen-year-old Ina, who had died not long before of bird flu. “I would have allowed an autopsy for the benefit of my neighbors and my family and everyone else concerned about the disease,” Ibu Samida said firmly. But again the refrain: “No one asked me. If they had asked, I would have given my permission.”

  Yet even with autopsies, field studies, and fast, accurate testing, the answer to the most critical question could remain elusive: What will it take for the novel strain to become a pandemic strain? In other words, what specific genetic changes are required for the disease to become easily passed among people, and what is the sequence of biological events in animals and humans that will foster those changes? Scientists suspect these could involve mutations that make it easier for the virus to bind to human cells. But that’s likely not the whole story. Though modern science has delivered an intimate view of the pathogen’s inner machinery, the world still has little insight into how this fateful transition would work.

  David Heymann, who was WHO’s chief of communicable diseases before retiring in 2009, conceded we’re not much further along in that regard than we were in 1918. “We’re handicapped by a lack of knowledge about the risk factors that cause the virus to change,” he said. “There are a lot of things we just don’t know.”

  Scientists have little comparative data to go on because there have been only a few flu pandemics in modern times. Despite groundbreak ing work on the genetic makeup of the Spanish flu strain, Fukuda said there’s no way to be sure whether the 1918 experience is relevant to the avian flu virus. And without knowing how a pandemic strain would develop, it is nearly impossible to stop it. What steps should be taken to interrupt the evolution of a pandemic? What practices are speeding it on its way? When do changes in the pathogen represent a real and present danger? When are they a red herring? What to do about them?

  “Sometimes the decision is simply ‘Let’s wait.’ We don’t have enough to go on. Let’s see how things evolve,” Fukuda said. “Or, it’s ‘We don’t have as much information as we like but we’re worried enough that if we’re missing something, it’s worth the price of jumping now.’ ”

  For five days, WHO had been trying to get a meeting with senior Vietnamese officials. Finally, on the afternoon of Tuesday, June 14, Hans Troedsson’s delegation filed into a conference room at Vietnam’s Ministry of Agriculture and Rural Development, an unremarkable building around the corner from the monumental granite mausoleum, modeled after Lenin’s Tomb, where Ho Chi Minh, father of Communist Vietnam, still lies in repose.

  Troedsson was no influenza specialist. He was a Danish doctor who had previously been responsible for children’s health issues at WHO. But as the agency’s chief representative in Vietnam, Troedsson essentially held the rank of ambassador. Flanking him were six other foreigners, including senior figures from the United Nations, World Bank, and European Commission.

  The Vietnamese side was led by Deputy Prime Minister Nguyen Tan Dung. Considered a reformer within Communist Party ranks, Dung would be promoted a year later to become his country’s youngest prime minister since Vietnam was reunified. He was joined at the table by the agriculture minister and his deputy, the deputy health minister, and five other top officials. Such audiences with senior dignitaries would often merit a few minutes on Vietnam’s nightly news and a mention in the morning papers. But this one was to be strictly confidential.

  After opening formalities, Troedsson explained to Deputy Prime Minister Dung the significance of the recent lab findings. They indicated that bird flu infections in Vietnam were more common than previously thought.

  “Vietnam could be on the verge of experiencing a nationwide epidemic, which could spread globally and cause a pandemic,” Troedsson continued. If an epidemic broke out, it could do serious harm to Vietnam’s economy and the health of its people. If went global, it could kill as many as 40 million people. So, he warned, WHO might have to elevate the pandemic alert level to either four or five if the test results were accurate. Several UN agencies stood ready to help Vietnam fight the virus and prepare for a pandemic. But the troubling lab results had to be checked by international experts, he insisted. This was urgent.

  Troedsson closed with a veiled threat. If the results could not be checked, WHO might have to raise the alert level as a “precautionary measure.”

  Then, one by one, Troedsson’s colleagues tightened the vise. Jordan Ryan, the UN’s ranking official in the country, told the Vietnamese it was no longer question of if a pandemic was coming but when, and he urged Dung to do the right thing. Ryan’s counsel carried weight. A dozen UN agencies were active in Vietnam, engaged on multiple fronts, ranging from agriculture to childhood nutrition.

  Next came Klaus Rohland, who ran the World Bank office in Vietnam. Over the years, Vietnam had received more than $5 billion in foreign aid for development, and the World Bank was in charge of coordinating that. Rohland told Dung that his country now faced a situation that could be “disastrous.” He strongly advised him to accept WHO’s offer of assistance.

  Finally, Ambassador Markus Cornaro, head of the European Commission’s delegation in Hanoi, warned that foreign donors to Vietnam were counting on the government’s full cooperation. How the government responded to the “offer of international support” would indicate the degree of trust and cooperation between Hanoi and the donors, Cornaro told him.

  The words were
diplomatic, the threat unmistakable.

  Dung listened intently to his visitors. Then he listened to presentations from his own health officials outlining the lab findings in greater detail.

  When everyone else had finished, Dung vowed that Vietnam was concerned for the welfare of the whole world, not just itself, and wished to be proactive, neither complacent nor hasty. And so, Dung said, he would propose inviting an international team of experts to work with Vietnamese scientists in checking the recent lab findings and exploring the wider threat. The team could come immediately, but on the condition that the lab findings remained secret until the review was done.

  It seemed WHO had gotten its way. But when Troedsson reported back by telephone an hour later, Stohr and his colleagues in Geneva doubted Vietnam’s intentions. Hanoi hadn’t said anything about actually turning over the original lab samples for independent testing, and nothing less would do.

  “It’s a trap,” warned one senior official in Geneva.

  Troedsson didn’t want to dally. The deputy prime minister had offered full cooperation and Troedsson took him at his word. What Troedsson didn’t say was that some of his staff in Hanoi believed time was already up and the pandemic was under way.

  “It’s urgent here,” he pressed. “We want to have a team here next week. Klaus, don’t let us down on this one.”

  When the conference call was over, Stohr and his colleagues in Geneva were agitated. “We didn’t get the message across to Vietnam,” Stohr grumbled.

  But could they afford to continue bickering with the Vietnamese?

  “We have to get a team in there as fast as possible,” urged Tom Grein, the veteran investigator who helped coordinate the global response to Vietnam’s early outbreaks a year before. “Six hours on the ground, ask for the samples.” If Vietnam balks, Grein added, “WHO has to have the guts to pull the team out.”