West Nile here to stay; treatments sought

Washington -- West Nile virus has assumed its place as an infectious disease with which the nation must reckon -- only five years after its arrival was first noted in New York City.

Transmitted primarily by mosquitoes and carried by wild birds, the virus has swept across the country, causing the deaths of more than 600 people and triggering serious neurological conditions in many others. The virus has most recently been linked to cases of acute flaccid paralysis due to the development of West Nile poliomyelitis.

Closely observed during its relentless march west to California, much has been learned about the virus, but there is still much to discover.

The virus was quickly identified as a member of the flavivirus family, which includes viruses that cause yellow fever, dengue fever and St. Louis encephalitis. Most people infected by West Nile experience no symptoms, and many others experience fairly mild symptoms of fever, headache and sometimes swollen glands and a mild rash.

However, among the 10,000 cases of the illness reported last year, there were 761 cases of such neuroinvasive diseases as meningitis and encephalitis and 503 cases with additional serious clinical outcomes, such as acute flaccid paralysis.

"It's still unknown what the natural history of this virus will be," said Steven Opal, MD, professor of medicine at Brown University School of Medicine's infectious disease division. So far the virus has a very different epidemiology from that in Africa, where it has been recognized for decades.

"In Egypt, it is found mostly in children where they develop antibodies and are fine for the rest of their lives," Dr. Opal said. The scenario differs when "you take this virus and dump it here in America where we have a huge susceptible population of older people who have never seen [it]."

"When this virus first showed up, no one knew what the future would hold, and that is still true," said Dr. Opal. The biggest surprise was probably the discovery that the virus could be transmitted via blood transfusions and organ transplants, he said.

The good news this year is that there seems to be a decline in the number of cases reported to the Centers for Disease Control and Prevention. With mosquito season just drawing to a close in most parts of the nation, 2,151 cases had been reported by mid-October, compared with the nearly 10,000 cases for all of 2003. However, environmental factors such as a scarcity of rain could have played a role, Dr. Opal said.

Kurt Reed, MD, director of clinical research at Marshfield Clinic in Wisconsin, is paying close attention to the conditions and habitats in which the virus flourishes. "We are all trying to make predictive models about where the outbreaks will occur and where the main risks are for humans."

One of the first unknowns about the virus, which was first identified in Uganda in 1937, was whether it could survive a harsh New York winter, said Dr. Reed. It obviously did so. Dr. Reed was surprised at how quickly the virus crossed the nation, even though it was aided in its journey by the migration of wild birds. Weather patterns may also play a role, he said. "It's a complicated virus."

Gearing up for prevention, treatment

Unraveling the complexities of the virus was made a bit easier by an already available basic research program on flaviruses that has served as a foundation for research on West Nile virus, according to Anthony Fauci, MD, director of the National Institute on Allergy and Infectious Diseases, who spoke to a congressional panel last month.

An existing research program accompanied by an influx of funding has fostered swift scientific progress over the past five years, Dr. Fauci told the House Committee on Government Reform's Subcommittee on Energy Policy, Natural Resources and Regulatory Affairs.

As a result, a vaccine is now being tested in humans. A chimeric vaccine is showing promising results in a phase 1 safety trial. If development proceeds as expected, a vaccine could be on the market within two to three years, he predicted.

A second vaccine, this one using the virus's DNA, is also being developed. The vaccine candidate contains no protein or whole virus, only certain genes that are encoded in short sequences of DNA. When these DNA sequences are injected, host cells take up the genes, translate them into proteins and display them on their outer surfaces. The immune cells are then primed to mount a fast protective response should the live virus be encountered, Dr. Fauci explained. Human trials are planned for early 2005, pending approval by the Food and Drug Administration.

Since physicians can now offer only supportive care for patients with West Nile virus, work is also under way to develop effective treatment options, Dr. Fauci said.

Passive immunization is one such strategy now being tested in a randomized, double-blind clinical trial. It involves the injection of human antibodies derived from blood plasma donated by people living in regions where West Nile has been endemic for decades.

In this study, patients who have already been diagnosed with West Nile neurological illness, or who are infected and at high risk for developing neurologic illness, are being given either the preparation, a different immunoglobulin preparation without antibodies, or a placebo. The trial began last year in 35 sites and was recently expanded to more than 60 sites with an enrollment of 100 patients.

Treatment options are also being sought among antiviral drugs, said Dr. Fauci. So far, 1,000 compounds have been screened, and 12 identified as showing effectiveness against West Nile virus. The 12 are now being evaluated in animal models.