Most of the sero-surveys have been small; few have contained more than 500 people. Whereas one study—among poultry market workers in Hong Kong in 1997—found around 10 per cent had H5N1 antibodies, most reported either no positives or low rates of people with antibodies. Some were under 1 percent, two were in the 3 to 4 percent range.
The study Racaniello drew on to argue H5N1 infection was more prevalent (and thus less lethal) than official numbers suggest looked for evidence of antibodies in 800 Thai adults living in villages where outbreaks of H5N1 had occurred in birds and where at least one human infection had been reported. The researchers found 5.6 percent had elevated antibodies to one H5N1 virus and 3.5 percent to another.
Not everyone agrees, however, that this particular study can be used to support Racaniello's argument. The threshold used in the Thai research as evidence of antibodies is substantially lower than most studies use. With a cutoff that low, says Malik Peiris, chair of the Department of Microbiology at the University of Hong Kong, one cannot be sure whether what is being detected is antibody-specific to H5N1, or antibodies to other flu viruses that happen to cross-react with the H5N1 test. Having low levels of antibodies that react to—and might even protect against—H5N1 does not prove that the person was infected with H5N1, Peiris says.
The senior author of the Thai study, Gregory Gray, chair of the Department of Environmental and Global Health at the University of Florida, says his group used the low threshold because they know antibody levels wane over time. They were looking for "subtle evidence" of infections that might have occurred years previous. But Gray says the results should not be overinterpreted. "It is a stretch to say this is population-based and also a stretch to say these all represented H5N1 infections," he says.
Although Krug, Treanor, Uyeki and Peiris all agree the official 59 percent H5N1 case fatality rate is not the true number, none takes much comfort from the fact. Krug is agitated that the controversy over the studies is drawing attention away from their key message—this virus can adapt to spread in mammals, which may include humans. And Treanor scoffs at the idea that concern over H5N1 is overblown. "If H5 is not dangerous, why are we even bothering to study it at all?" he asks. "I think it is without a doubt the case that it is not as dangerous as it looks from the cases that we have. But it is still without a doubt an extremely dangerous virus—particularly if it gained the ability to spread from person to person."
As for how far off the case/fatality rate is, there is no way of knowing. Uyeki, who has studied the issue at length, gives his estimate: "Are we missing some [cases]? Yeah, probably we're missing some. But are we missing hundreds of thousands? No, I don't think so. Are we missing tens of thousands? Probably not. Are we missing hundreds? Possibly. It's really hard to know."