Alan Sipress - The Fatal Strain

“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 disease 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.”