"The main bioterrorist is nature herself"

A Dutch expert on viruses warns that bird flu is a huge threat to humankind and urges scientists to cooperate in tracking it.

Published May 26, 2005 5:19PM (EDT)

To reach Albert Osterhaus's office on the 17th floor of the Erasmus Medical Center in Rotterdam, the Netherlands, you negotiate several biohazard laboratories, two corridors lined with deep freezers and a pair of old-fashioned egg incubators. Finally, you reach a room decorated with posters of seals and cats, and are ushered into the professor's presence by one of three secretaries he employs to manage his increasingly hectic schedule. Like the viruses he chases for a living, Osterhaus is continually on the move, and the demands on his time are constantly multiplying. Three weeks ago he was in China and Vietnam to meet officials from the World Health Organization. The week before that, it was India. This week, he is back in his office to check on the progress of research projects -- and to make time to talk to the Guardian.

A veterinarian turned virologist, Osterhaus is an authority on several viruses that have crossed the species barrier. In 1998, he showed that the canine distemper virus was responsible for the mass deaths of Siberian seals in Lake Baikal. The following year, he identified influenza B -- a strain of flu that normally infects only humans -- in seals off the coast of the Netherlands. Then, in April 2003, at the height of the panic over SARS (severe acquired respiratory syndrome) in Hong Kong, he showed that the disease was caused by a coronavirus that normally resides in civet cats and other carnivorous animals. (Osterhaus beat rival labs in the United States and Germany to the proof by fast-tracking approvals to conduct live virus trials.)

But the virus that increasingly occupies his time these days, and the one that he believes poses the greatest threat to mankind, is the avian influenza virus, H5N1.

On his trip to Vietnam, the World Health Organization presented data about how cases of H5N1 were multiplying in members of the same family group, a process known as clustering. This could indicate that the virus, which has prompted mass culling of poultry throughout Southeast Asia, is becoming infectious among people.

The following week, Nature reported that the U.N. Food and Agricultural Organization was struggling to get serum samples from people and poultry infected with the latest strains of the virus forwarded to its labs for analysis. Then, as soon as he returned to Rotterdam last weekend, the Chinese reported that 178 wild geese had been found dead at a research center in a western province, Qinghai -- also victims of H5N1.

"It's another worrying finding," he says. "Normally, these viruses don't kill wild birds. They only heat up when they pass from wild birds to poultry. It could be that we haven't looked at the mortality in wild birds closely enough. Or it could be a spill-back from domestic poultry."

The more pressing concern, however, is the threat H5N1 poses to people. Since the start of the current outbreak in Southeast Asia in 2003, there have been more than 90 human infections and 54 deaths. If H5N1 were to become a super-spreader like SARS, then infections could leap around the world in a matter of days, triggering a global pandemic.

Indeed, such is the concern among Osterhaus and his colleagues at Holland's National Influenza Center that he is now calling for the WHO and FAO to join forces with the World Organization for Animal Health and establish a global task force to combat the virus.

In the leading commentary in Thursday's edition of Nature, Osterhaus argues that while Vietnam, Hong Kong and other Southeast Asian states have taken steps to cull infected poultry and contain human outbreaks, the responses at a national level have been patchy and ad hoc. In particular, the failure to forward serum samples to WHO reporting labs quickly enough means that the true incidence of infections may be underestimated.

One of the task force's roles, says Osterhaus, would be to ensure that farmworkers with the greatest exposure to the virus are properly monitored and that adequate virological and clinical data are collected, including detailed postmortem reports. Animal health experts recruited by the task force should also survey poultry and other domestic birds for all subtypes of the virus. Osterhaus would also like to see better monitoring of wild bird populations, the natural reservoir of influenza A viruses.

"We need much more data on influenza in wild birds because that's where it comes from," he says. "But at the same time we also need better data on outbreaks in poultry and better reporting from labs so that we can get the sequences out and know if and in what direction the virus is mutating. And we need these data sets to be linked, from humans to birds, so that we can build up a repository of information. At the moment all we have is a series of snapshots."

Osterhaus argues that nothing can stop a global influenza pandemic. On average, pandemics occur every 30 years and are as inevitable as the tides. However, just as the United Nations is now establishing listening posts to provide an early warning of another tsunami, so the global flu task force could provide an equivalent early warning system.

According to Osterhaus, the task force would come under the umbrella of the WHO's flu pandemic preparedness plan and include virologists, epidemiologists and other specialists from the fields of animal and human health, as well as ecologists, agriculturists and experts in translating science into policy.

The result, write Osterhaus and his colleagues in Nature, is that when people begin to fall ill, "outbreak management teams can be formed and targeted at a specific outbreak."

To do nothing is not an option. The mortality rate from H5N1 is already high, but as the virus mutates, it could become more pathogenic. Some experts estimate conservatively that within a few months, close to 30 million people could be hospitalized and a quarter would die. "Although these estimates are speculative, they are among the more optimistic predictions of how the next flu pandemic might unfold," warns Osterhaus in Nature.

In five accompanying commentaries, other experts, including Antony Fauci of the National Institutes of Health and Michael Osterholm of the Center for Infectious Disease Research and Policy at the University of Minnesota, also argue that time is running out and that if more money is not poured into vaccine research, the world could be heading not just for a pandemic but for economic disaster too.

This is not the first time experts have issued such dire warnings. In 1957 and again in 1967, avian influenzas crossed the species barrier, triggering the Asian and Hong Kong flu pandemics. But though those pandemics, caused by H1 and H2 strains of the virus, claimed about 1 million lives worldwide, their impact was not nearly as great as the 1918 Spanish influenza, a pandemic that may have killed as many as 50 million people. And while SARS triggered scares in 2003, there were only 1,000 deaths -- a mortality rate of just 10 percent.

What makes Osterhaus think H5N1 is different? Osterhaus pauses, surveying the pictures of seals and cats pinned to his walls -- a secretary placed them there as a reminder of Osterhaus's previous life as a vet. "We know the virus kills different mammalian species, not just humans but cats and tigers, and we know that the virus spreads easily in other animals and is highly pathogenic if they are infected in the right way," he says.

"We also know that the virus has a high fatality rate. For some reason, it is not transmitting efficiently from human to human at present. However, if that were to happen, either through mutation or reassortment, it would be a big worry."

Osterhaus' is a powerful voice. "He's very dynamic. He's always on the move. We call him the 'Flying Dutchman,'" says John Oxford, professor of virology at Queen Mary Medical School in London. "As a trained vet he can deal with the interface between animal and human viruses. He's got experience on both sides of the fence, which is a tremendous advantage in this field. He's really a superstar."

In Holland, Osterhaus is known as the virus hunter because of his instinct for smelling out new viruses. After qualifying as a vet, he obtained a Ph.D, in virology from Utrech University in 1978. He then joined the Netherlands' National Institute of Public Health and Environment, where in between producing vaccines he began studying animal viruses. Besides seals, Osterhaus has found new viruses in dolphins, African wild dogs, lions, finches and cats. Then, in 2001, he isolated the human metapneumovirus. The cause of respiratory disease in young children and people with compromised immune systems, hMPV is actually an old virus; Osterhaus has found antibodies for it in serum samples from patients from the 1950s, but until 2001 no one had realized people were infected with it.

Osterhaus' discoveries enabled him to assemble his own team at Erasmus in association with the hospital's virology department, funding his research through a combination of grants, commercial trials and patent agreements with biotech companies. The result was that when in 2003 the WHO approached Osterhaus to work on SARS, he was in the perfect position.

The problem was that many of the serum samples from patients in Hong Kong contained both hMPV and the coronavirus. The only way to prove which was the primary cause of disease was to conduct live tests for each virus separately in animals. Sidestepping the hospital's animal ethics panel, Osterhaus appealed directly to a senior civil servant in the Dutch Ministry of Health and got clearance to experiment on macaque monkeys. His resulting proof that the cause was the coronavirus enabled the WHO to contain the outbreak faster.

Osterhaus' unconventional methods drew criticism from animal welfare activists and led to a reprimand from the Dutch Parliament. But he insists that he did the right thing, and points out that the Netherlands has since amended its laws governing animal experiments. Osterhaus was subsequently knighted.

The irony is that when Klaus Stohr, the head of the WHO's influenza program, first approached his lab to conduct the trials, Osterhaus nearly turned him down. In the winter of 2003, Dutch poultry farms were infected with a deadly plague. The virus responsible, H7N7, had already led to the death of a 57-year-old veterinarian, and Osterhaus' team was seeing cases of conjunctivitis in farmworkers and chicken cullers, a sure sign that they were also infected with the virus. With Holland in the grip of a winter flu epidemic, caused by the most common human strain of the virus, H3, Osterhaus feared that there was a risk of double infections.

Normally, avian influenza strains infect only bird populations or are not highly pathogenic in people and other animals. But virologists believe that pigs and sometimes people can be infected with avian and human influenza strains at the same time, providing a "mixing bowl" that allows the viruses to swap genes. Such a reassortment may have been behind the virulence of the 1918 flu, and is the reason why Osterhaus and other virologists fear that it could happen again.

Until 1997, virologists did not think avian strains could infect people directly. But when a doctor in Hong Kong sent Osterhaus serum from a 3-year-old boy who had died of a mysterious respiratory disease there, to his surprise, he found H5N1. It was another first for his lab. He immediately alerted the WHO, and the Hong Kong authorities implemented a cull, killing 1.2 million of the territory's chickens.

What worries Osterhaus is that while in 1997, only six of the 18 people hospitalized in Hong Kong with H5N1 died -- a mortality rate of 33 percent -- since then, the mortality rate has doubled, suggesting that the latest strain is more virulent. Then there are the reports of clustering, which suggest that it may also be becoming more infectious. However, Osterhaus points out that the cases may simply reflect the fact that family members are being directly exposed to the same infected poultry.

"The fact that we are seeing more clusters of human infections points in the direction of human transmission, but this should not be exaggerated. I think the bigger danger is that we will get a reassortment," says Osterhaus.

It could happen with H5N1, but it could also occur with another avian strain that scientists have yet to identify. Earlier this year, for instance, Osterhaus' colleagues discovered a new subtype of hemagglutinin -- the protein spike that protrudes from the surface of the virus and enables it to invade animal cells -- in black-headed gulls from Sweden. The discovery brings the number of hemagglutinin subtypes to 16. But had Erasmus not had an arrangement with ornithologists in Sweden to forward fecal samples from wild birds regularly, it would never have made the discovery.

A task force need not be that expensive. Osterhaus estimates the cost at less than $1.5 million a year -- a snip set against the $120 million in losses incurred by Vietnam and Thailand since the current H5N1 outbreak devastated their poultry industries. The problem is that the WHO, the FAO and the World Organization for Animal Health are already huge bureaucracies, and politicians may well decide that they already have sufficient resources to respond to the threat. That, argues Osterhaus, would be a mistake. He points out that after the 9/11 attacks, the United States poured billions into combating the threat of bioterrorism.

"That's fine, but we should not forget that the main bioterrorist is nature herself," he says. "Flu is knocking on the door. It is only a matter of time."

By Mark Honigsbaum

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