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The Importance of Zoonotic Diseases

PATHOGENESIS AND VIRULENCE OF ZOONOTIC INFECTIONS IN HUMANS

Robert E. Shope, M.D.

Professor of Pathology, Center for Tropical Diseases University of Texas Medical Branch

The transmission of an infectious agent from an animal to a human being initiates a series of events that constitute the pathogenesis of the infection. Pathogenesis is the entry, primary replication, spread to target organs, and establishment of infection in the target organs. The process by which a pathogen replicates itself in the human host depends on cell-specific and organ-specific receptors, cell and tissue injury, and host immunity and other defense factors. The final outcome is either termination of infection, persistence and latency of infection, transmission to another host, or some combination of these. This series of events is not specific for zoonotic infections, except possibly that zoonotic agents are rarely sexually transmitted. The zoonoses, however, illustrate some of the more interesting and complex patterns that have evolved in nature.

Virulence can be defined as “the degree of pathogenicity of an infectious agent, indicated by case fatality rates and/or its ability to invade and damage tissues of the host.” In many bacterial agents, virulence is mediated through a number of factors coded for by the genetic molecule DNA in a



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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary 2 The Importance of Zoonotic Diseases PATHOGENESIS AND VIRULENCE OF ZOONOTIC INFECTIONS IN HUMANS Robert E. Shope, M.D. Professor of Pathology, Center for Tropical Diseases University of Texas Medical Branch The transmission of an infectious agent from an animal to a human being initiates a series of events that constitute the pathogenesis of the infection. Pathogenesis is the entry, primary replication, spread to target organs, and establishment of infection in the target organs. The process by which a pathogen replicates itself in the human host depends on cell-specific and organ-specific receptors, cell and tissue injury, and host immunity and other defense factors. The final outcome is either termination of infection, persistence and latency of infection, transmission to another host, or some combination of these. This series of events is not specific for zoonotic infections, except possibly that zoonotic agents are rarely sexually transmitted. The zoonoses, however, illustrate some of the more interesting and complex patterns that have evolved in nature. Virulence can be defined as “the degree of pathogenicity of an infectious agent, indicated by case fatality rates and/or its ability to invade and damage tissues of the host.” In many bacterial agents, virulence is mediated through a number of factors coded for by the genetic molecule DNA in a

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary chromosome, a bacteriophage, a plasmid, or some other unit. These virulence factors include: Adherence. Some bacteria have specialized structures called pili that attach to the intestinal epithelium of the host and permit replication before the infecting cells are swept away. Invasion. These factors permit bacteria to gain entry into the cell, where they replicate in a protected environment. Capsules. Some bacteria, such as Pneumococcus, form an outer capsule of viscous polysaccharide gel that increases their virulence and resistance to phagocytosis and destruction. Endotoxins. Gram-negative bacteria have an outer membrane that consists of lipopolysaccharides, or fat- and sugar-based compounds, that may damage or kill the host. Exotoxins. These are proteins that are poisonous to cells and often have specific cell targets. Siderophores. Some bacteria produce these iron-binding proteins that serve to increase virulence by consuming iron needed by eukaryotic cells, which are the type of nucleus-containing cells that comprise humans. Viruses, with a rare exception, do not have bacterial-like virulence factors or toxins. Being intracellular, viruses disrupt the body’s function either by direct destructive effect on target cells and organs or by inducing pathogenic host responses. The cell can be looked on as a factory. A virus may use up the cell’s energy; shut off the synthesis of required materials; compete for the cell’s ribosomes, which are necessary for building proteins; or compete for the cell’s polymerases and inhibit its innate defense system. Some viruses have the capacity to integrate into the cell’s genome and thus cause indirect damage, leading, for instance, to malignancy. As with bacterial virulence factors, the elements responsible for viral virulence affect both zoonotic and nonzoonotic agents equally. Examples of Pathogenesis and Virulence in Zoonoses Zoonotic diseases offer some interesting insights into pathogenesis and virulence, as well as to the links between them. Consider two examples, one a bacterium and the other a virus. Anthrax Anthrax is one of the more interesting zoonoses from the point of view of a link between pathogenesis and virulence. The virulence is directly related to the site of entry of the bacterium. Bacillus anthracis is a gram-positive organism that infects cattle and

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary sheep. When dormant (not living in an animal host), the organism exists as a very hardy spore that resides in the soil. In a biological warfare experiment conducted during World War II, spores were exploded over the small Gruinard Island off the coast of Scotland. The spores remained viable in the soil for 44 years, until 1986, when formaldehyde treatment of the island finally made it habitable again. The bacillus remains in the soil until consumed by sheep, cattle, or other animals that browse on grass and leaves. Such infection is especially common during dry periods, when animals frequently ingest soil as they eat plants down to the roots and as they drink from watering holes contaminated with spores carried by soil runoff. Nearly all warm-blooded animals are susceptible. Carcasses, when opened by vultures or carnivores, are sources of infection. Sporulation occurs when an infected carcass is exposed to the open air. People who work on farms or in slaughterhouses, wool-sorting establishments, and tanneries are most apt to be exposed. Rarely, people are infected by consumption of uncooked or undercooked meat. The bacillus does not usually penetrate intact skin. Percutaneous infection occurs through open lesions or insect bites. The pathogenesis depends on the route of exposure. There are four different syndromes: Cutaneous. This is the most common form of infection in humans, representing approximately 95 percent of cases. Infection usually occurs on the arms, legs, or neck and head. Once the bacterium has entered through abraded skin, the symptoms begin after 1 to 12 days. A painless, nonpurulent lesion appears, and a zone of redness and edema forms around the lesion. Tissues in this zone begin to die, and then ulceration occurs. The lesions regress and healing occurs in most cases. About 10 percent of cases progress to involve the local lymph nodes and then dissemination with fatal septicemia. Pulmonary. This form follows inhalation of tiny spore-containing particles of less than half a centimeter in diameter. These particles enter the lung alveoli, where they are engulfed by macrophages and transported to the lymph nodes. There, the spores replicate and disseminate with virtually 100 percent fatal septicemia. Gastrointestinal. Ingestion of uncooked or undercooked meat can lead to the bacilli being passed into the digestive system, most commonly to the terminal ileum or cecum. There, lesions analogous to those in cutaneous anthrax result in fever, vomiting, abdominal pain, and bloody diarrhea; at least half of these cases are fatal. Oropharyngeal. Bacilli sometimes enter through the oral or pha-

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary ryngeal mucosae, causing fever, mucosal lesions, and edema associated with cervical lymphadenopathy. The pathogenesis of anthrax has been studied extensively in laboratory animals. In tests in mice and guinea pigs, subcutaneous inoculation of spores leads to rapid germination to form vegetative cells that replicate and elaborate toxin. Edema surrounds the primary lesion, after which the bacteria travel in lymphatics to the regional lymph nodes, then to the spleen. When the filtering capacity of the spleen is exhausted, bacteria are released into the bloodstream. The bacteria double their numbers in 50 minutes, and the animals die in 10 to 14 hours. In tests in rhesus monkeys, inhalation of anthrax results in death of the animals. Hemorrhage in certain lymph nodes, the lungs, and the small intestines is prominent. Suppurative meningitis and lesions of the spleen occur in most of the animals. There are three components of the anthrax toxin. Lethal factor is a zinc metalloprotease that is believed to stimulate activity of two proteins, interleukin-1 and tumor necrosis factor-alpha, that mediate the toxic death. Edema factor is a protein that is activated by calmodulin from the host and then produces a substance called cyclic adenosine monophosphate that stimulates edema. Protective antigen is a protein that is broken apart by cellular protease and then is capable of transporting lethal factor and edema factor to host cells. The 1979 outbreak of anthrax in Sverdlovsk, a region in the former Soviet Union, was initially attributed by Soviet sources to the consumption of contaminated meat appearing on the black market. Careful examination of the autopsy specimens, however, revealed that the cases were inhalation anthrax, not gastrointestinal anthrax. Thus, the knowledge of the pathogenesis proved highly useful in solving this mystery. Rift Valley Fever Rift Valley fever (RVF) infects sheep, cattle, and humans and is caused by a particular type of RNA virus in the genus Phlebovirus. The virus is transmitted by a wide variety of mosquitoes, and it also can be spread by airborne particles. In sheep and cattle, RVF is characterized by acute hepatitis, abortion, and death, especially in young animals. The large-scale epidemic and epizootic in 1977 in Egypt was the first time that RVF occurred outside of sub-Saharan Africa. During that event, the disease afflicted an estimated 200,000 humans, causing about 600 deaths. Some patients also demonstrated late-onset RVF encephalitis and retinitis, with associated blindness. Among sheep and cattle, observers reported widespread abor-

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary tion, but no reliable estimates of the numbers of animals involved are available. The disease does not appear to cause abortion in humans. There have been few studies in humans about the pathogenesis of RVF. Autopsies are not usually performed in sub-Saharan Africa, nor were they performed during the outbreak in Egypt. Most studies of RVF pathogenesis have involved animal experiments. Lambs, hamsters, and certain strains of rats develop high levels of the virus in their bodies and succumb in 2 to 3 days with acute hepatic necrosis. This appears to be a direct effect of the virus. Mice and other animals that are less susceptible either die later or survive acutely but develop encephalitis later, usually after 1 week. The encephalitis also appears to be a direct effect of the virus, which can be isolated from tissues of the central nervous system (CNS). It is not clear how the virus enters the CNS, but it appears that either viral entry is delayed or viral replication is delayed. Animals that were saved by treatment with drugs or other agents from acute hepatic death went on to develop encephalitis, thus confirming that the CNS was invaded. Scientists have not yet determined the pathogenesis of the lesions that form in the eyes of infected animals. A model of the disease in rats has been developed. In infected rats, RVF antigen is found in the ganglion cells of the rat retina. Uveitis, necrotizing retinitis, and hemorrhages also occur. In rhesus monkeys, RVF virus causes hepatic necrosis in a mid-zonal pattern and disseminated intravascular coagulopathy. Direct invasion of endothelial cells is believed to be involved in causing the vascular lesions. Need for Additional Research Anthrax and Rift Valley fever illustrate diseases for which there are good studies of the pathogenesis and virulence of the agents in humans or at least in animal models. Such studies may be long in coming for some of the newly emerged zoonoses, such as West Nile encephalitis and Nipah encephalitis. Part of the problem with Nipah encephalitis is the paucity of Biosafety Level 4 laboratories in which to carry out basic studies of the virus’s pathogenesis. Regarding West Nile encephalitis, a major question centers on the apparent age difference in virulence. In the 1999 outbreak in New York City, it is probable that all age groups were infected, yet why were most of the cases and all of the deaths in persons over 60 years of age? Research is urgently needed to develop animal models simulating human disease for these and other zoonotic emerging diseases.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary THE POTENTIAL “BIOWEAPONIZATION” OF ZOONOTIC DISEASES David R. Franz, D.V.M., Ph.D. Vice President, Chemical and Biological Defense Division Southern Research Institute Since World War I, a number of nations have conducted programs to develop biological agents as weapons of war. These nations have included the United States, the former Soviet Union, the United Kingdom, Canada, Japan, and others. The United States discontinued research on offensive biological weapons in 1970, and a multilateral agreement to halt offensive biological warfare programs, the Biological and Toxin Weapons Convention, was ratified in 1975. However, ratification of this agreement did not end the threat of biological weapons attacks. There is ample evidence that the former Soviet Union continued extensive research on and even production of some biological agents. In addition, U.S. forces entering Iraq during the Gulf War in 1990 found evidence of ongoing research and production of biological agents. After the demise of the Soviet offensive program, the concern about biological terrorism threats has increased, including terrorism carried out by individuals or groups, either acting alone or with sponsorship by a foreign government. Many observers now consider such terrorist attacks to be the major threat regarding biological attack against U.S. forces in peacetime deployment as well as against private citizens in major cities of the United States and the world. A majority of the biological agents that have been considered as weapons are zoonotic. The zoonoses often considered in the context of biological warfare include anthrax, brucellosis, various strains of encephalitis-causing viruses, Ebola and Marburg viruses, histoplasmosis, plague, Q fever, rabies, and tularemia, among others. A number of factors make the zoonotics especially suitable for use as weapons. Perhaps most important, most zoonotic agents are not highly contagious, which would make them relatively easy to control when incorporated into a weapons system and deployed in a tactical situation. Many of these agents also are relatively well understood scientifically, and animal species are available in which to model human disease, to test and alter the virulence of the agent, or even to serve as living bioreactors in which to grow agents. Finally, their ubiquity and public health threat justify a state-sponsored research program, which may serve as a cover for a biological warfare program. Terrorists have an even broader spectrum of zoonotic agents from which to choose than do military weaponeers. For example, the terrorist may need a less effective or lower-quality weapon, or a weapon that is

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary effective over smaller distances, than would be required for battlefield use. Such reduced requirements might make it possible to produce useful agents and delivery systems using less sophisticated equipment. In general, however, zoonotic agents that might prove useful in terrorist attacks must be produced as respirable aerosols, since nearly all of them are not highly contagious. Furthermore, unlike many chemical warfare agents, biological agents are neither volatile nor can they penetrate intact skin. There are a number of nonzoonotic human agents (e.g., smallpox virus) or animal agents (e.g., foot and mouth disease virus, Newcastle disease virus, hog cholera virus) that are highly contagious and thus might spread through a population without the necessity for weaponization and presentation as a respirable aerosol. Ironically, continued advances in biotechnology, while offering great promise for improving human health, also may make it easier for terrorists to make and deploy effective biological weapons. While some features of zoonotic agents may make them less attractive for use by terrorists—they typically are harder to produce than, say, an explosive bomb, and their effects are less immediate—other characteristics may add to their attraction. One factor is the potential scale of their threat. It might be possible, for example, to expose thousands of people to an agent. Such exposure might lead eventually to hundreds of fatalities, certainly a tragic consequence, but it also would create tremendous social disruption and public fear, both highly desirable in the terrorist’s mind. Indeed, public fear may even be created by hoaxes—claims by terrorists that they have released a biological agent into a given community. Such hoaxes have been numerous since 1997, and their numbers may well increase. The United States has mounted a broad response to the threat of biological warfare, but until recently this response has not been well coordinated or integrated with sectors of the public health community. These responses have included improving capabilities for detecting biological agents; improving physical protection for soldiers; bolstering medical defense systems; continuing intelligence operations to monitor any research and production operations, both in other nations and in the United States; and participating in treaties and other international nonproliferation efforts. A number of specific countermeasures are available or could be readily developed to protect individuals from biological agents. In addition to early detection and identification of agents and providing physical protection from exposure, these protective measures include immunization, passive forms of immunoprophylaxis, and decontamination, among others. It may be more difficult to protect citizens from unexpected terrorist attacks than to protect military troops. This dilemma heightens the importance of estab-

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary lishing and maintaining surveillance systems and diagnostic and reference laboratories to aid in rapidly identifying suspected biological agents. Indeed, protecting U.S. citizens will require an integrated approach that combines education and teamwork. Federal agencies must collaborate, and military organizations must continue to work closely with the public health community. In learning to deal with “man-made” disease, there is much to be learned from current efforts targeted at understanding and controlling emerging infectious diseases. In the future, as biological warfare proliferators introduce advanced technologies into their programs, it is unlikely that zoonotic agents will be broadly displaced; they may actually become a favored target for genetic manipulation. As we develop methods and programs to protect U.S. citizens, as well as livestock and crops, from naturally occurring diseases of animal and man, we must not forget the value of our efforts in protecting our nation from biological warfare agent attack as well. XENOTRANSPLANTATION Louisa E. Chapman, M.D., M.S.P.H. Medical Epidemiologist, Division of AIDS, STD, and TB Laboratory Research Centers for Disease Control and Prevention End-stage organ failure, an important health problem in the United States today, can be improved by transplantation of healthy donor organs. However, demand for donated human organs currently outstrips supply, and the gap between the number of people who could benefit from transplanted organs and the smaller number of organs donated annually is consistently increasing. Xenotransplantation offers a means of helping to mitigate this shortage of available organs. Moreover, the concept of xenotransplantation has been expanded in recent years to encompass a broad range of approaches to using living nonhuman animal cells or tissues in humans for therapeutic purposes in ways that go beyond simple replacement parts for failing human organs. These purposes include, for example, implantation of fetal pig neuronal cells into the central nervous system of people suffering from Parkinson’s disease, passing blood from people with liver failure through a device that contains pig liver cells, and infusing pig insulin-producing pancreatic islet cells into people with diabetes. For the purpose of Public Health Service policy discussions, xenotransplantation now refers to any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (1) live cells, tissues, or organs from a nonhuman

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary animal source, or (2) human body fluids, cells, tissues, or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs. However, while xenotransplantation offers potential benefit for both individual recipients and society, it also is a public health concern. Xenotransplantation has the potential to infect human recipients with zoonotic and other infectious agents that are not endemic in human populations, thereby potentially introducing new infections to the human community (xenogeneic infections). This potential risk is presently unquantifiable. Conceptually, xenogeneic infections should be recognized as part of a larger category of “bioproduct-acquired” infections, the most familiar of which are infections transmitted via blood transfusion. A growing number of therapeutic bioproducts provide opportunity for human exposure to infectious agents originating from nonhuman animals. Regardless of the fate of xenotransplantation technology per se, the lessons learned through attempts to develop rational public policy in this arena can serve as a model of approaches to science-based risk minimization for other bioproduct-associated biohazards. The Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation describes a system of safeguards to minimize any health risk. This guideline (available at www.fda.gov/cber/gdlns/xenophs0101.htm) is built around two key concepts: pretransplant screening to minimize the risk of xenogeneic infections with recognized pathogens, and posttransplant surveillance for previously unrecognized xenogeneic infections. Pretransplant screening is nested in animal husbandry techniques that limit and define the exposure history of the source animals. The risk that human recipients will be infected with exogenous viruses and other identifiable infectious agents can be reduced to negligible levels by limiting the geographic origin and lifelong contacts of potential source animals, combined with adequate pretransplant screening of the source animal, the colony from which it is chosen, and the xenotransplantation product itself. Posttransplantation surveillance will remain necessary to identify infectious agents that may have been transplanted with the xenograft. Such infection might occur because the agents were not known to exist (e.g., porcine hepatitis E prior to 1997), because diagnostic tools were inadequate to detect known agents (e.g., prions), or because the agents could not be removed from the xenograft (e.g., endogenous retroviruses). Endogenous retroviruses exist as an inactive form of DNA integrated into the germline of all mammals adequately studied to date, including humans. Many of these endogenous retroviruses can express infectious virus but are no longer capable of causing active infection in the host species. However, endogenous retroviruses expressed by both pig and baboon cells can infect human cell lines in vitro. Thus, all xenotransplantation

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary products from any species may contain endogenous retroviruses that, on transfer into a human host, are capable of creating active persistent infection. Recent scientific investigations have attempted to define the significance of endogenous retroviruses of pigs, the preferred source animal for xenotransplantation, in the xenotransplant setting. These tests demonstrate that porcine endogenous retrovirus (PERV) can be expressed from multiple porcine cell lines, as well as from multiple primary porcine tissues, including kidney, liver, heart, and spleen. Moreover, tests show that PERV released from both porcine cell lines and primary porcine cells can infect cell lines from humans and a variety of other mammals. Three variants of this virus have been characterized—PERV-A, PERV-B, and PERV-C—two of which can infect cells from humans. These observations support concerns that PERV expressed from porcine xenotransplantation products may be able to infect human recipients. Since October 1997, when evidence that PERV could infect human cells in vitro emerged, the Food and Drug Administration has required all sponsors of porcine xenotransplantation product trials to demonstrate plans for posttransplantation surveillance for PERV infections in recipients using testing methods adequate to detect such infections. To date, limited studies of humans exposed to pig cells and tissues have produced no evidence of PERV infection. However, some studies have found evidence that certain types of porcine cells remain present in persons who had undergone transient hemoperfusion through pig spleens up to 8 years previously. These observations suggest that transient exposure to xenotransplantation products may provide enduring exposure to infectious agents carried within them. Ironically, one of the approaches used to avoid the type of immune rejection that was the initial barrier to success with xenotransplantation has raised a potential problem regarding zoonotic infection. The endothelial cells of all lower mammals, including pigs, have a sugar-based compound called alpha-galactosyl (α-Gal) on their surface. This compound is absent from the cells of humans, who develop natural xenoreactive antibodies directed against α-Gal. To get around this hyperacute immune rejection, scientists genetically engineered a type of pig that lacks α-Gal. The problem stems from the fact that the characteristics of animal viruses are influenced by the characteristics of the cells in which they replicate. That is, if a virus replicates in a pig cell that contains α-Gal residues, then the outer envelope of the virus budded from the pig cell also will express α-Gal residues. If those pig cells were transplanted into a human, then the person’s immune system would recognize the α-Gal as foreign and inactivate the virus. However, viruses budding out of cells from genetically modified pigs that do not express α-Gal on their cell surfaces may not be recognized and inactivated.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary This finding raises suspicions that modifications intended to facilitate xenograft survival may also make it easier for PERV to survive in infectious form, thereby increasing the risk that PERV may infect human recipients. Knowledgeable observers have argued that the risk to the public from xenotransplantation may be exaggerated when compared to that from other types of ongoing exposures, such as occupational risk of accidental exposure to simian retroviruses among animal workers and researchers. This may be true. But it is important to remember that xenotransplantation is an intentional exposure, and this raises the burden of preventive responsibility on scientists and research groups that conduct such trials. In addition, xenotransplantation occurs under controlled circumstances, which means that researchers have an added responsibility to implement known measures to minimize any associated biohazards. Another issue that has been a source of public concern is whether the use of xenotransplantation products from nonhuman primates, rather than from lower mammals, poses a particular risk of introducing infections of devastating consequence to the human community. The present science is not adequate to provide a definitive answer to this question. Nor have we fully addressed the many ethical issues that would be involved in using nonhuman primates as “donors” for humans. However, from simply a practical standpoint, it is clear that we currently lack appropriate animal husbandry techniques, such as those in place for raising the pigs used in clinical trials, for maintaining a population of nonhuman primates. Taken together, these factors have led the Food and Drug Administration to ban xenotransplantation trials using nonhuman primates until adequate demonstration of safety and adequate public discussion of ethical issues have occurred. ECONOMIC AND TRADE IMPLICATIONS OF ZOONOTIC DISEASES Peter Cowen, D.V.M., Ph.D. Associate Professor, Department of Farm Animal Health and Resource Management North Carolina State University College of Veterinary Medicine and Roberta A. Morales, D.V.M., Ph.D. Senior Research Scientist, Center for Regulatory Economics and Policy Research Research Triangle Institute

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary Disease and trade have a long-standing, interwoven history. During the 14th century, Europeans began to value the exotic nature of goods and materials from Asia. In the summer of 1347, rats boarded Genoese ships at Caffa on the Black Sea, stowed away as the ships went through the Dardanelles, touched down at Messina, and later docked at Pisa, Genoa, and Marseilles. Less than a year later, plague had spread through rivers and roads deep into the interior and to ports on the Atlantic and Baltic coasts. Hungry fleas hidden in such trade goods as cloth, wool, and grain helped spread the disease between urban centers. In the five years of the Black Death, three out of every 10 Europeans, or some 24 million people, died. This pandemic, a substantial force in European history until the late 17th century, stands as a benchmark against which all other disease outbreaks have been measured. The interplay of trade, economics, and disease could be sketched out for many other zoonotic diseases, such as yellow fever in Panama (where the disease was linked to efforts to reduce shipping costs) and anthrax in North America (where the disease was distributed in alignment with settlement patterns). Despite such health risks, global trade increased substantially in the 18th, 19th, and 20th centuries, so that we enter the new millennium perched on the brink of an integrated global economic system. This system is based on transnational flows of financial capital, global market penetration of products, multinational corporate structures, real-time information systems functioning as 24-hour monitors of the global business environment, and finally, but most importantly, a globalization of technology and knowledge-based assets creating the information economy. Globalization has reached a point where technical skills and intellectual capital know no borders—but neither do pathogens. Food animal veterinarians over the past 30 or 40 years have adapted to revolutionary changes, driven by economics and technology, in the structure of animal agriculture. These changes include increasingly larger herd sizes, intensive production management systems, improvement of but simultaneous narrowing of the animal gene pool, vertical integration, and innovations of housing and physical facilities. All of these changes were predicated on the control of epidemic disease. The resulting production efficiencies have yielded an increase in global trade of animals and animal products. In 1962, the Food and Agriculture Organization and the World Health Organization created the Codex Alimentarius Commission (Codex) to encourage fair international trade in food and to protect the health and economic interests of consumers. In 1995, the World Trade Organization (WTO) was established as a successor to the General Agreement on Tariffs and Trade, providing a common framework for the conduct of trade among member countries in matters related to the Uruguay Round Trade Agree-

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary ments. Prior to this time, national governments heavily subsidized many agricultural commodities. In addition, trade was inhibited by economic policies, including nontariff barriers erected by national governments to protect the country from the introduction of exotic animal diseases. However, the changes introduced by the Uruguay Round Trade Agreements included the Agreement on Trade-Related Aspects of Intellectual Property Rights, multilateral trade agreements, and the General Agreement on Trade in Services. The common threads in these trade agreements have been harmonization, equivalence (not everybody has to ensure disease prevention in the same way, but there has to be similar risk between countries), and regionalization (whereby geographically distinct regions in a country may be designated disease-free and therefore able to export). Until recently, international standards have been the primary means of determining harmonization. The introduction of risk analysis into Codex and the WTO Agreement on the Application of Sanitary and Phytosanitary Measures (called the “SPS Agreement”) now provides other means for harmonization. Equivalence can be determined by specifying risk-based objectives. The provisions of the SPS Agreement include protective measures that must be based on scientific risk assessments. Each country has a right to set its own standards of protection, but a country cannot do so unjustifiably or arbitrarily. A significant question for developing countries is whether there is a level playing field when it comes to trade in animals and animal products. For many developing countries, agriculture is the one segment of the economy where they have the resources and infrastructure for trade. It is therefore essential that developing countries are able to institute animal health monitoring programs that document risk, thereby opening the door to trade. The development benefits of agricultural trade in terms of infrastructure can be significant in agriculturally based economies. Countries that cannot turn their natural agricultural assets into capital needed for the development of adequate public health and animal health infrastructure may have to deal with the emergence of zoonotic diseases. Furthermore, trade in agricultural products results in better global nutrition, providing a wide variety of fruits and vegetables in developed countries and more plentiful and affordable meat in developing countries. Adequate nutrition affects host resistance on a population basis by providing an important preventive measure against the emergence of zoonotic diseases. Finally, trade promotes a sense of food security over time. A nation can be sure that it can obtain all the food that is required by its people, not by producing all of the food it needs itself but by having established avenues to trade for it. Although the benefits of trade are substantial, there are legitimate concerns that efforts to keep exotic zoonotic diseases out of a country may fail.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary The cost of such an introduction can be dramatic. At present, the increasing liberalization and realignment of economic forces will force us to examine the tradeoffs from trade. Food, live animals, and other commodities (such as vaccines and biological products) with zoonotic potential have inherent efficiencies of production in certain localities. These low-cost producers now have an open market, so long as they remain free of disease, unencumbered by health-based barriers to trade. Under these circumstances, since 1980 there has been a significant increase in the volume of trade. For example, the volume of hogs and cattle entering the United States has increased 10-fold, while total global exports and imports have increased by approximately 25 percent in the same period. However, importing ham from Belgium or live cattle from Mexico also may result in importing any pathogens associated with the products. The direct and indirect costs of a zoonotic disease are hard to quantify comprehensively, since such costs involve many externalities for both the animal and human populations. Control in the animal population is crucial, as it represents primary prevention at the earliest opportunity. The most current example of costs involved with the emergence of a zoonotic disease is the outbreak in the United Kingdom of bovine spongiform encephalopathy (BSE), which eventually was identified as the causal agent of variant Creutzfeldt-Jakob disease. The outbreak was traced to the use of rendered meat and bone meal as cattle feed. One etiological hypothesis suggested use of such animal-derived feed had an economic basis—disposal of dead animals and an inexpensive source of high-quality protein. In the mid-1970s, both human safety considerations and new technology converged to suggest the elimination of a solvent extraction step in the carcass-rendering process. However, elimination of this step also meant that the product was heated one less time. While the new process promised monetary savings, the notion that it might give rise to an emerging zoonotic disease was not even on the horizon as a contingency—though it should have been. The costs for BSE eradication, which escalated dramatically after the European ban on importing British beef, have finally crested. These costs include extensive interventions to support farmers and markets because of the devastating economic conditions. Costs initially were manageable: about 237.6 million pounds sterling from 1989 to 1996. However, costs rose sharply after more extensive control measures, including the slaughter of infected and at-risk cattle, were fully instituted in 1996, totaling approximately 3 billion pounds sterling in the following 4 years. Unfortunately, the specific relationships between trade, economics, and the emergence of disease have not been adequately characterized. One question, for example, is how the West Nile virus got to the Western Hemisphere. It may have been due to human travel, mosquitoes traveling in airplanes, altered patterns for migratory birds, traffic between zoological

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary parks, or some other mechanism. We need to get very specific in terms of what disease has been caused by what specific economic activity or demographic change. It is important that we begin to unravel the causal web in detail and put some specificity on trade as a cause of disease. Molecular epidemiology tools might be very valuable in such an endeavor. Whatever the etiology, the introduction of a major zoonotic disease has the potential for resulting in significant alterations in the structure of world trade. A particularly dramatic and threatening zoonotic disease linked to a trading incident could potentially shift globalization trends to a much more protectionist stance. If trade is best viewed as a double-edged sword planted squarely between economic development and emerging diseases, how can we best mitigate its potential negative effects? One solution is to inject as much science as possible into decision making concerning the importation of animals and animal products. In order to make science-based decisions concerning trade, governments and international organizations are turning to risk analysis. For example, Codex has recently adopted principles and guidelines for the application of risk assessment as a means of enhancing food safety and reducing foodborne illness. Furthermore, risk assessment should be closely linked with steps to enhance import risk management. Import risk management can best be described as all the preventive steps and surveillance activities taken to reduce the possibility of foodborne disease related to importation of animals and animal products. Enhanced import risk management systems should include practical systems for surveillance, quarantine, regionalization of exporting countries, and testing. As the volume of animal-based trade grows, the probability of emerging zoonotic diseases likewise increases. There are several significant impediments to be overcome as we implement a global system of science-based risk analysis to control the emergence of zoonotic disease. They include: the presence of significant resource imbalances in terms of the ability of different countries to implement surveillance and accurately measure the prevalence of disease in different populations; a lack of rapid, accurate diagnostic tests that provide real-time results with acceptable levels of false positive and false negative results; our ability to become comfortable with the ambivalence engendered by our need to trade and our legitimate fear of emerging zoonotic diseases. It is correct to look at trade and other economic forces as important factors in the emergence of diseases, but we also must recognize that there is a strong logic behind trade. It is not a question of whether or not trade

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary promotes disease, but whether the benefits of trade are worth the risk of disease. We currently are in a period of global euphoria concerning the benefits of trade, but ascertaining the true risks of disease may prove to be sobering. It is for this reason that risk assessment for the occurrence of zoonotic and other animal diseases has moved front and center in the international system of trade regulation.