It is widely accepted that the cases that come to light and get tallied by WHO are only an unknown portion of the total human infections that have occurred. Official case counts are certainly missing some infections—but not enough to morph H5N1 into a benign virus, a number of flu scientists agree in interviews for Scientific American.
"I think all these numbers are flexible, and Peter is undoubtedly right it's not 60 percent. But I don't know what it is. And I don't think he does either," says Robert Krug, chairman of Genetics and Microbiology at the University of Texas at Austin, where his work focuses on the molecular mechanisms at play during influenza infection.
"It's dangerous. How dangerous? I have no idea…. I'm sure it's less than 60 percent but it's still too high for the world to tolerate a (human-to-human) transmissible H5N1 virus," says Krug, who believes both papers should be published in full.
The problem with the case/fatality rate, as Palese pointed out in PNAS, is that human infections with what is still a bird virus generally only come to the attention of medical authorities when someone gets really sick. In fact, in order to count as a case by WHO's definition, a person must have a high fever, known exposure to the virus, and needs to test positive for H5N1. A specimen for a test would generally only be taken at a hospital and that facility would have to have access to a laboratory. If H5N1 is causing mild cases, they are unlikely to come to light under that definition. Is a person living in a remote Cambodian village who feels lousy for a couple of days going to seek that kind of medical care? If there are H5N1 cases like that, the fact they are being missed artificially lowers the denominator.
"If the only cases you know about are the ones who are going to die, then you might believe that the case/fatality rate is very high because you lack surveillance of less symptomatic cases," says John J. Treanor, chief of the Infectious Diseases Division at the University of Rochester Medical Center in New York State.
But what of the numerator, or the number of deaths? For the case/fatality rate to plummet, the numerator must be a smaller fraction of the total cases. But it is clear the numerator is off as well, notes Tim Uyeki, an influenza epidemiologist at the U.S. Centers for Disease Control who has spent a lot of time in the field studying human H5N1 cases and outbreaks.
Uyeki points as an example to the first report in the scientific literature of presumed person-to-person spread of H5N1. It was a cluster of three infections that started with an 11-year-old girl who fell ill in September 2004. She lived with an aunt while her mother worked in a distant city. Both the aunt and the mother, who came home to care for the girl, got sick; the mother and daughter died.
All three clearly had H5N1—a throat swab confirmed it in the aunt and virus was found in tissue from the mother. But the hospital had thought the girl had dengue fever. By the time they realized these were H5N1 cases, the girl had died and her body was cremated. Officially that cluster went down on the books as two cases, not three. There are other cases that were designated as probable infections but which never made the official count, Uyeki says.
Given the limitations of the system for finding human cases, researchers have been conducting what are known as sero-surveys—drawing blood samples from groups of people who were likely exposed to the virus to see if they have antibodies specific to it. That would be a sign that they had been infected and survived. More than 20 such studies have been completed since 1997, when the first known cases of H5N1 infection in humans cropped up. Groups that have been tested included workers who culled infected chickens, health care workers who cared for H5N1 patients, people who worked in live animal markets and people who lived in villages where cases have occurred. The studies have been done in China, Indonesia, Nigeria, Cambodia, Thailand and elsewhere, important because different subfamilies of H5N1 viruses circulate in different parts of the world and some—hypothetically—may cause more severe disease than others.