Key Point:

• New naturally occurring infectious diseases are spreading worldwide at a rate of about one per year; this, combined with the threat of bioterrorism, suggests that all physicians must remain alert for symptoms and signs of novel contagious conditions.

SAN FRANCISCO—Naturally emerging infections, such as the severe acute respiratory syndrome, HIV, West Nile virus, Nipah virus, and others, have been appearing with remarkable frequency in the past few decades. When coupled with the potential for bioterrorism, the odds of a new microbial disease spreading and leading to an epidemic are as great as they have ever been, according to Richard T. Johnson, MD.

“The amount of movement of people, of all classes and groups, is really quite extraordinary in terms of allowing any known agent worldwide to be in your community within one asymptomatic incubation period,” said Dr. Johnson. “Now that’s disturbing enough, but if you add the additional factor that’s become of interest—bioterrorism—the question is, ‘How much more should one worry?’” Dr. Johnson is a Professor of Neurology at Johns Hopkins University in Baltimore. He made his presentation at the 128th Annual Meeting of the American Neurological Association.[1]

In the mid-20th century, the discovery of antibiotics and the development of vaccines for polio, measles, and other contagious conditions led many people to believe that infectious disease would no longer be a serious public health problem, said Dr. Johnson. This belief was strengthened by the eradication of smallpox.

What was unforeseen at the time was the emergence of new disorders, including legionnaires’ disease, toxic shock syndrome, Lyme disease, and many others. However, the “pressing realization that emerging infections represented a global threat didn’t come until the 1980s with the emergence of HIV infections and the presence of AIDS,” said Dr. Johnson. “If one looks then from that period to the present, … you can see that there has been an evolution of a huge number of new agents, at a rate of about one a year, of real significance.”

Added to the threat of what nature creates on its own is the threat of what humans do to each other. In the past 20 years, there have been at least four incidents in which infectious agents were intentionally released in the United States—the contamination of salad bars in Oregon by a religious group wanting to change an election, the contamination of donuts and muffins in a Texas hospital by a disgruntled worker, the anthrax attacks by an unknown assailant that killed five people in 2001, and the more recent anthrax episodes.

“However, there is fear of much greater devastation of bioterrorism, and I think that fear is real,” said Dr. Johnson. “It’s very likely to happen. On the other hand, spontaneous emergence of new lethal agents is an absolute certainty.”

EVOLUTION OF DISEASE

New agents have emerged through different patterns of evolution, including enhanced virulence, geographic relocation, and contact with animals and crossing of species barriers. Dr. Johnson offered details of three such examples—Enterovirus 71, West Nile virus, and the Hendra-Nipah group of paramyxoviruses.

Enterovirus 71 was originally recovered in California in 1969 from children with hand-foot-and-mouth disease. A few years later, cases were observed in Eastern Europe of a paralytic polio-like virus. In 1997, there were reports of cardiopulmonary collapse and death in children younger than 5 in Taiwan, Malaysia, Singapore, and Japan. “Over a period of time, this appears to be a virus that has changed in virulence,” said Dr. Johnson.

West Nile virus, on the other hand, has not only changed its virulence but also its habitat. West Nile virus was originally isolated in a febrile woman in the province of West Nile in Uganda in 1937. Cases of meningitis were later observed in the 1950s, particularly in Israel. In the 1990s, cases of encephalitis were reported in the Mediterranean and India, followed by an epidemic in Bucharest in 1996.

In 1999, two patients in Queens, New York, initially appeared to have encephalitis accompanied by paralysis and weakness. However, it was soon discovered that birds, crows, and other animals in the area had died from encephalitis. “The CDC then realized that it was West Nile and went back and found that it was a cross-reaction serologically, and all these other cases had been West Nile virus,” said Dr. Johnson. The epicenter has continued to move farther west, with more than 5,600 cases (2,000 in Colorado alone) in 2003. “It has not disappeared in the areas where it was originally,” Dr. Johnson pointed out. “So, it does not appear and then go away. It does appear to be moving west, and most people assume that it will be in California [in 2004].”

Nipah virus was first observed on a pig farm in Malaysia on September 29, 1998. Initially, it was believed to be an outbreak of Japanese encephalitis. However, it was found mainly in adults among Chinese households, and a high percentage of those infected had direct contact with pigs.

Eventually, a paramyxovirus was isolated. Investigators believe the disease was initially spread by fruit bats, which ate fruit from trees and dropped pieces into pigpens. The virus has been recovered from the saliva of bats and from fruit lying on the floor of the pigpens. Pigs in turn developed a nonfatal respiratory disease, which then spread to humans, causing a new form of fatal encephalitis.

“The clinical disease is unique,” said Dr. Johnson. “This is a new kind of encephalitis that is really of great interest. It has an incubation period of about two weeks, and then there is a very abrupt encephalitis with multifocal signs,” he noted. In a follow-up study conducted in Malaysia about two years after the first epidemic, investigators found that 7.5% of patients had relapsed.

A number of factors contribute to the evolution, maintenance, and spread of new agents, including cutting down rain forests, new methods of animal husbandry, and preschooling, which leads to greater exposure for children, according to Dr. Johnson. “But probably the two most important things are the human population size and the fact that they are moving fast and a lot,” he said. More than 500 million people cross international borders on commercial airliners every year, 70 million people work in countries other than their own, and there are 50 million refugees worldwide.

THE A TEAM

The CDC has listed six groups of potential bioterrorism agents as category A agents, or those with the highest priority—anthrax, smallpox, plague, tularemia, botulism, and viral hemorrhagic fevers. However, noted Dr. Johnson, it is thought that the former Soviet Union may have weaponized as many as 40 to 50 different agents.

Bioterroism agents may be disseminated in a variety of ways. Anthrax, for example, can be spread by aerosol but normally is not transmitted between humans. In contrast, for smallpox, the great concern is human-to-human spread. Although it may develop slowly, a worldwide smallpox epidemic could be set off by a single case, noted Dr. Johnson.

Plague normally is transmitted by fleas from infected rodents, but antimicrobial-resistant bacteria have been engineered for aerosolization in the Soviet Union. An outbreak of pneumonic plague (caused by Yersinia pestis), spreading from person to person, would result in a death rate of nearly 100%, said Dr. Johnson.

Tularemia has also been weaponized with vaccine-resistant strains, but it is not spread from person to person. An aerial release of 50 kg of Y pestis over a city of five million people could lead to about 500,000 cases with 100,000 deaths, said Dr. Johnson. A similar release of the same quantity of tularemia would cause about 250,000 illnesses with 19,000 deaths.

Botulinum toxin is highly lethal through both oral transmission and aerosolization. It is estimated that 100 g, if equally distributed in food or beverage, would kill about one million people, but only 1 g, if adequately aerosolized, would be needed to kill the same number of people, according to Dr. Johnson. Viral hemorrhagic fevers are a somewhat diverse group, generally involve a severe multisystem syndrome, and can also be spread by aerosolization.

It is important to distinguish bioterrorism from biowarfare, Dr. Johnson noted. “Biowarfare is weapons,” he said. “They are designed to kill or immobilize an enemy. Bioterrorism is really not for that purpose. It is to evoke fear, disrupt social order, and make political statements. Bioterrorism is not aimed at strategic sites, and part of the fear is enhanced by the ability [of bioterrorism] to occur at any time, at any place, and at any magnitude. Bioterrorism also may target farm animals and crops, and there’s been considerable concern about agroterrorism.”

STRATEGIES TO COMBAT DISEASE

Efforts to control both natural and terrorist agents require similar approaches, stressed Dr. Johnson. “Both require a global surveillance, rapid positive identification of the agent, its characterization, and then the development and employment of a vaccine and drugs, if such are available,” he explained. New methods are also continually needed to detect as early as possible when a new agent has been introduced.

“If there is any geographic or seasonal change, it would be a warning that something strange and different is happening,” said Dr. Johnson. “There are several problems, however, with this sort of an approach, which is the traditional approach used for warnings, and that is we don’t know what to anticipate. We know there are 50 or so agents out there ready for deployment or potentially ready for deployment. So what has been worked on is [organizing] emergency rooms by syndromes.”

Tracking billing codes is one of the most rapid ways of spotting a possible outbreak, because most primary care physicians bill within 12 hours of seeing a patient. There is also the ability to track drug prescriptions, as well as the bar codes of over-the-counter drugs. “So, if there’s a new respiratory disease appearing, look for cough syrups or respiratory drugs to have a bounce in sales in a particular location,” said Dr. Johnson. “This all may sound futuristic, but there is a program in effect right now called ESSENCE II—Electronic Surveillance System for the Early Notification of Community-Based Epidemics.” ESSENCE II is a tracking system that pools both military and civilian information in the Washington, DC, area in an effort to detect abnormal health conditions.

“There are some decisions we all need to be involved in,” stated Dr. Johnson. “The first is the fact that the infrastructure of public health worldwide has been a catastrophe and needs to be strengthened. I think some of the concerns about bioterrorism may have a secondary positive effect of strengthening some of the infrastructure. Second, I think it’s important to use evidence-based decision making and not political decision making. The surveillance and detection needs to be for new agents. The same methods are needed for both the new agents that we know are coming as well as for bioterrorism agents, which may come. Finally, there is a tremendous need for this to be done globally, and for it to be an international campaign. We need to invest in new methodologies such as the science of ESSENCE II, in rapid diagnosis, and in vaccines that can be rapidly produced.” Another problem, said Dr. Johnson, is the fact that no pharmaceutical company wants to develop a vaccine that may never be used. “There’s just no economic sense to that,” he said. “The other problem for pharmaceutical companies is that there are no new classes of antibiotics at this time.”

Dr. Johnson believes that new infectious agents will continue to emerge each year. “In a world of growing anger, the international release of agents will also occur,” he said. “So we need to have global international cooperation, and it just makes good sense to realize that it’s better to improve infection control in a hospital in the Congo than to head ebola virus off at Kennedy Airport.”

—Colby Stong