Health & Medicine / Infectious Diseases

In the markets of Guangdong province, which  borders on the South China Sea, thousands of chickens, ducks, quail, and geese squawk endlessly, crammed into cages next to or stacked on top of wilder creatures—civet cats, raccoon dogs, snakes, and turtles. Customers can walk into a stall, select dinner from the noisy multitude, then sit down to await the animal’s slaughter.

A crowded stall in Guangdong is where the virus that causes severe acute respiratory syndrome (SARS) jumped from an animal, probably a civet cat, into a human in 2003. From there it went on to kill at least 800 people, make 8,000 others extremely ill, and drag down the economies of several Asian countries. The markets of Guangdong are also the source of H5N1, a strain of killer avian flu that first jumped from animals to people in 1997 and then reemerged last year. H5N1 is getting far more attention than SARS from scientists who study the ecology of viruses because, of the 44 people who are known to have gotten H5N1 in 2004, 32 died. Such a high ratio of death to infection has researchers scrambling to track the virus and prevent its spread. Their worst-case scenario is that a highly virulent bird flu virus could mingle with a human flu virus to spark a pandemic like the Spanish flu of 1918, which killed at least 20 million people.

“Prior to 2004, most of us thought that a 1918 pandemic would never occur again, but now we are not so sure,” says Tim Uyeki, an epidemiologist at the Centers for Disease Control and Prevention in Atlanta. “Widespread circulation of H5N1 viruses among poultry in Asian countries is now considered a ticking time bomb for humans. The key to reducing the public-health risk of a pandemic is to control H5N1 among poultry.”

Of the 15 distinct types of flu strains known to occur in birds, H5N1 is “right at the top of the list for most-wanted strains,” says Richard Webby, a virologist at St. Jude Children’s Research Hospital in Memphis. And yet, as deadly to humans as it is, H5N1 is also very difficult to contract. It is “particularly poor at infecting humans and worse still at transmitting from human to human,” says Webby. What scientists still have not figured out about this strain is how much it must mutate before it can infect people easily. “Is it 3 amino acid changes away, or 300?” asks Webby.

Some flu experts fear that if a deadly virus like H5N1 can mutate enough to spread easily among people, no one will be prepared to deal with it. There is only a preliminary form of a vaccine against H5N1 flu strains, and even if there were a developed vaccine, the virus might spread faster than public-health officials could get people inoculated. Knowledge—understanding how flu viruses work so they can be stopped early in their journey—is likely to be the best protection we have against another epidemic.

Viruses like avian flu or the animal coronavirus that mutated into SARS must be relatively benign in their original hosts to spread from one animal in the wild to the next. Thus avian influenza in migratory birds like wild ducks has evolved to be mild, says Paul Ewald, who studies the evolution of infectious diseases at the University of Louisville in Kentucky. When flu strains become too lethal among migratory birds, the birds die out before they can spread the infection to a new area.

A mild virus becomes lethal when wild animals enter markets like Guangdong, which serve as factories for disease. The animals’ close confinement allows the virus to exploit more of its host’s tissues because it does not need to keep the host healthy to spread the infection. The next victim is right at hand, an inch or so away. Among birds in close confinement, a virus rapidly evolves the ability to transmit, not only through feces but also via the respiratory system. A single infected bird can breathe a virus into the face of many birds, with swift and disastrous results. The H5N1 strain causes tiny blood vessels throughout the body of a chicken, for example, to collapse. In some cases, the bird begins to bleed through its orifices; its comb appears to melt. Soon the entire cage is filled with bleeding, dying chickens.

The strains of H5N1 that have managed to jump species and infect people are those that are most deadly to chickens, says David Swayne, a veterinarian at the U.S. Department of Agriculture. Chicken handlers and others exposed to sick birds or their droppings are most at risk. In the case of the avian flu epidemic that broke out in December 2003 and continued into the fall of 2004, 43 of the 44 people known to have contracted the disease appeared to have done so directly from animals. A mother who held her dying child close is the only person who seems to have contracted the disease from another person.

Webby says nobody knows how many mutations it would take to permit H5N1 to pass among humans as easily as other flus do. What researchers do know is that influenza is an RNA virus, which mutates easily and rapidly. It has only eight genes, and two of the genes produce antigens, a type of protein that stands out on the surface of the virus particle. The two surface antigens are called hemagglutinin and neuraminidase, the H and N in H5N1. The human immune system is adept at recognizing antigens it has met before: Antibodies snap onto the projecting viral proteins and prevent the organism from infecting other cells. Flu viruses can evade immune-system scouts by constantly shifting surface antigens. Small changes in the H and N antigens are referred to as antigenic drift. When drift occurs each year, a new influenza vaccine must be made.

Although each new vaccine is designed to protect against the previous year’s flu, many people get partial immunity to new strains because the surface proteins often don’t look all that different to the immune system. What keeps epidemiologists up at night is antigenic shift, a radical change in surface proteins that presents the immune system with a completely different face. When this happens, no one has any immunity.

Extreme shifts in surface proteins explain why existing vaccines offer no protection against the new avian flu. More important, altered surface antigens explain how the three major flu pandemics of the last century—1918, 1957, and 1968—spread through the world like firestorms. The 1957 pandemic killed about 70,000 people in the United States. In the winter of 1968–1969, about 34,000 people in the United States died. Mystery still surrounds the greatest pandemic, in 1918, which probably killed more people than any disease outbreak since the Black Death of 1347–1351.

Molecular pathologist Jeffery Taubenberger of the Armed Forces Institute of Pathology, who has analyzed the 1918 flu strain, H1N1, says it shared characteristics with modern avian flu strains. But unlike the pandemic strains of 1957 and 1968, which appear to have resulted from the direct mixing of avian and human flu strains, the 1918 strain doesn’t seem to have jumped directly from birds to humans. “Perhaps,” he says, “it spent time in other animals” before infecting people.