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Introduction

“The significance of zoonoses in the emergence of human infections cannot be overstated.”

—Institute of Medicine,

Emerging Infections: Microbial Threats to Health in the United States,

1992

A PERSPECTIVE ON EMERGING ZOONOSES

Frederick A. Murphy, D.V.M., Ph.D.

Professor of Virology, School of Veterinary Medicine University of California, Davis

Since the publication in 1992 of the Institute of Medicine report Emerging Infections: Microbial Threats to Health in the United States, the concept of new and emerging diseases has changed as different people have influenced priorities. The balance seen in the original report has been skewed several times, not so much in the name of research needs or prevention and control priorities but in the name of funding the “home turf” of the agencies involved. Within this changing scene, where are the zoonoses, the diseases transmitted from animals to humans? The answer differs according to whether one addresses the question from the perspective of the animal disease community or the human disease community.

For some zoonotic infectious agents, general oversight and control responsibility has largely been in the hands of people associated with animal health and agriculture. These agents include those that cause substantial morbidity or mortality (or diagnostic difficulty) in livestock or poultry; certain classic agents, such as Mycobacterium bovis and Brucella abortus; and the bacteria of concern in preharvest food safety. Although a number



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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary 1 Introduction “The significance of zoonoses in the emergence of human infections cannot be overstated.” —Institute of Medicine, Emerging Infections: Microbial Threats to Health in the United States, 1992 A PERSPECTIVE ON EMERGING ZOONOSES Frederick A. Murphy, D.V.M., Ph.D. Professor of Virology, School of Veterinary Medicine University of California, Davis Since the publication in 1992 of the Institute of Medicine report Emerging Infections: Microbial Threats to Health in the United States, the concept of new and emerging diseases has changed as different people have influenced priorities. The balance seen in the original report has been skewed several times, not so much in the name of research needs or prevention and control priorities but in the name of funding the “home turf” of the agencies involved. Within this changing scene, where are the zoonoses, the diseases transmitted from animals to humans? The answer differs according to whether one addresses the question from the perspective of the animal disease community or the human disease community. For some zoonotic infectious agents, general oversight and control responsibility has largely been in the hands of people associated with animal health and agriculture. These agents include those that cause substantial morbidity or mortality (or diagnostic difficulty) in livestock or poultry; certain classic agents, such as Mycobacterium bovis and Brucella abortus; and the bacteria of concern in preharvest food safety. Although a number

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary of these agents can be considered as emergent, many people from this community have not actively embraced the emerging disease concept. Responsibility for some other zoonotic infectious agents has largely been in the hands of people associated with public health. These agents include rabies virus; numerous arthropodborne viruses, bacteria, and protozoa; several rodentborne viruses and bacteria; and primateborne pathogens. Obviously, quite a few of these agents are emergent and, under the emerging disease concept, much progress has been made. The cap on progress lies primarily in priority and funding decisions made high in the nation’s public health bureaucracy. There also are zoonotic infectious agents that seemingly have always been “in between,” and these have often been the subject of foolish turf wars between government officials from the animal health and public health communities. These agents include new influenza viruses; Salmonella enteriditis; Listeria monocytogenes; and, most recently, the West Nile virus. Some progress is being made here, but usually only after contentious turf battles and other delays. So, the concept of new and emerging zoonotic diseases has not been fully exploited in any of the communities dealing with zoonoses. This situation seems especially appalling given the fact that nearly all emergent disease episodes of the past 10 years have involved zoonotic infectious agents. These agents have included some that maintain an ongoing reservoir life cycle in animals or arthropods, without the permanent establishment of a new life cycle in humans, as well as some “species jumpers” that derive from an ancient reservoir life cycle in animals but have subsequently established a new life cycle in humans that no longer involves an animal reservoir. Given their troubling history, merely having to ask the question “Into which camp will the next important emergent zoonotic agent fall?” suggests that something is wrong. Determinants in the Emergence of Zoonotic Disease Agents Many different determinants contribute to the emergence of new zoonotic disease agents. Rarely do such determinants act alone. Given the complexity of their interactions, there likely is no way to predict when or where the next important new zoonotic pathogen will emerge. Consider zoonotic viruses. It has become fashionable to build so-called “predictive” models—this has been done for influenza viruses, for example—but it is likely that the next virus to emerge, influenza or otherwise, will not be as predicted. A danger, of course, is that in our enthusiasm for modeling, we may not recognize the significance of an emergence that does not match up with a favorite model. There also is a danger that too many researchers will

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary be sitting in front of computer screens, modeling, and too few people will be out in the field witnessing the next emergence. Our understanding of the direction and rate of the evolution of viruses and their potential for emergence as pathogens follows upon spectacular achievements in viral genetics. We are on soundest footing when we consider the smallest variations between viruses—say, between strains. It is quite a different matter to consider variance and emergence in the context of the natural history of specific zoonotic pathogens, where key phenotypic characters, dominant selective forces, and the true essence of “fit” are much more complex and still quite mysterious. To restate this point: in the Darwinian cause–effect equation, we understand the second term (the effects of mutation and selection) rather well, but we do not understand the first term (the causative forces driving selection) very well at all. We often describe the selective forces themselves in the most theoretical fashion. For example, we tend to portray the direction of evolution as toward commensalism, that is, a relationship between two kinds of organisms in which one obtains food or other benefits from the other without damaging or benefiting it. But this picture obviously fails when we face a new emergent zoonosis that brings untoward health effects. Again, the specific forces driving selection of particular viral variants in real-world settings are quite mysterious. In considering the effects of mutation and selection on the evolution of zoonotic viral pathogens, successful variants appear to have evolved with particular characteristics. The pattern of these characteristics suggests that the variants most likely to emerge as new zoonotic threats are like their parents, but more so. They are the alpha children, but they are not, as often depicted in fiction, new “super-bugs,” such as an Ebola virus variant that is transmitted as easily as influenza viruses. From virus to virus, in keeping with diverse lifestyles in reservoir hosts and vectors, key advantageous characteristics are amazingly diverse and sometimes seemingly contradictory. We often explain the advantage to the virus in each situation in simplistic ways. For example, most virulent alphaviruses spread by mosquitoes produce very high viremia levels, or viral load levels, in their reservoir vertebrate hosts, so as to better assure transmission to the next feeding mosquito. Thus, we say that high vertebrate host viremia represents a key evolutionary advantage. But many virulent, successful flaviviruses produce low-level viremia, requiring exquisite susceptibility of those mosquitoes that serve as their vectors. So, what characteristic of a variant flavivirus might make us worry most in regard to potential for emergence? Particular viruses have evolved survival strategies to deal with the extremes in host population qualities. Of the viruses transmitted from human to human, most thrive either in the largest, densest populations or when

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary introduced into an isolated population whose members lack immunity to the particular virus. However, many of the zoonotic infectious agents survive where there are just enough susceptible reservoir hosts to sustain the transmission chain. It might seem that such transmission chains are fragile, subject to interruption by minimal human intervention, but in most cases this has not been the case. Mutation and selection work well in the circumstances of such “thready” transmission chains. Most changes in reservoir host populations that affect zoonotic infectious agents are caused either directly or indirectly by human activities. The major such changes are the ever-increasing density of human populations, the increasing density of monotypic domestic animal populations, and the crowding of wildlife in limited areas. Other changes deriving from human activities serve to amplify the risk of the emergence of new zoonotic agents, for example, the increased mobility of humans regionally and globally, changes in the natural movement patterns of birds and animals, and increased transport of a variety of products that may help to distribute viruses, vectors, and exotic hosts. The burgeoning threat of bioterrorism and biowarfare adds yet another factor to the risk equation, and some observers argue that xenotransplantation (the transfer of organs or other tissues from animals to humans) presents yet another level of risk. Given this key role of human activity in the emergence of zoonoses, the current focus of public attention on remote “econiches”—what might be called the “Ebola Mystique”—needs to be reexamined. Rather than seeing potential threats as being largely confined to exotic hosts in isolated regions, we should consider, for example, the reservoir host population represented by the cattle herd of the United Kingdom. In the 1980s, as dairy cattle were fed bovine offal in feed supplements, there followed an epidemic of bovine spongiform encephalopathy, commonly known as mad cow disease. More than 1 million cattle were infected. These cattle became the reservoir hosts for a new, emergent zoonosis: new variant Creutzfeldt-Jakob disease. In this case, no remote econiche was involved; rather, the threat emerged from less than exotic changes in common animal husbandry practices. Toward an Ideal Prevention and Control System Zoonotic diseases require rather different prevention and control strategies than diseases of etiologic agents employing only human-to-human transmission. For the latter, clinically based or laboratory-based surveillance provides the foundation for such intervention activities as vaccination. Prevention and control strategies for the zoonoses have come from amazingly diverse bases, usually stemming from individual scientists or groups of scientists who have devoted years to accumulating highly special-

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary ized knowledge and experience. In fact, the work of these scientists might best be described as basic research, that is, research that only secondarily seeks the means for disease control and prevention. Rather than dwell on what is wrong with today’s systems for studying, controlling, and preventing zoonotic diseases, it may be more beneficial to identify the elements of an ideal system. Ten such elements present themselves. In each case, the concept of new and emerging diseases can provide the impetus for moving ahead. Independent Scientific and Administrative Leadership. Responsible administrative leaders in disease prevention and control institutions need to know a great deal about the zoonotic infectious agents themselves, their reservoir hosts, their ecology and natural history, and the systems used in the past for their control. Zoonotic diseases cannot be dealt with effectively when they are last on a list of administrative responsibilities. Looking back, we see that successes in dealing with major disease episodes came from multidisciplinary, collaborative groups. Leaders of these groups were world-class scientists, who were inclusive in their style. Can such teams be rebuilt within public and academic institutions? Of course. The next step will require new thinking at higher levels. An Expanded Research Base. The research base for many recently emergent pathogens and the diseases they cause is very small and very narrow. Because of funding priorities and biosafety constraints, few grants are awarded in these subjects. The large public institutions seem to be emphasizing molecular methods for agent identification and the descriptive epidemiology needed for control actions. The middle ground is at particular risk. The next step will require developing and implementing a new model for enlisting researchers and ensuring adequate public funding. A Proper Primary and Reference Laboratory Diagnostics System. The World Health Organization’s (WHO) network of arbovirus and rabies laboratories was exemplary at one time. Building a proper network today, however, must go farther. This effort must overcome old cultural differences between laboratories operated in the animal health sector, the public health sector, and the academic sector. The current system for West Nile virus testing punctuates the problem. In some laboratories, dead birds submitted for testing are subjected to full or modified necropsy, with all the delays and expenses pertaining. In some laboratories, there is a cap on the number of birds that can be submitted, and this cap is sometimes reached early in the year, thus preventing continued testing of newly found specimens. In some laboratories, test results are reported back only to the person submitting the specimen. Since the primary purpose of nearly all testing for West Nile virus is currently focused on providing early warning of the presence of virus in an area (the sentinel concept), anything other than

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary unlimited, ultra-rapid testing and proper reporting fails to meet the needs of disease control authorities. The laboratory system must match these needs. The model for such testing is not the traditional necropsy-based diagnostic system of many veterinary laboratories, nor the “kit-based” system of many primary care laboratories. Rather, the model should be the streamlined, rapid system of rabies laboratories. The next step in developing a proper network will require a cultural paradigm shift. Adequate Laboratory Facilities. An expanded research base and a broadly based primary and reference laboratory diagnostics system must be supported by adequate laboratory facilities. This will mean expanding national Biosafety Level 3 and 4 laboratory facilities. These laboratories must operate multifaceted research programs, and they must be ready to deal with large episodes of disease. It also will mean constructing several small high-containment laboratories in academic institutions, yet plans for building such laboratories are going forward without specific federal commitment or funding. Needed, too, are facilities to meet such emergencies as bioterrorism threats. These facilities must be placed in various parts of the country, with coordination and training organized from a national center. The next step will require national leadership and new cooperation among diverse participants. Federal Interagency Communication, Cooperation, and Collaboration. In 1995, when an epidemic of Venezuelan equine encephalitis occurred in South America, reaction in the United States should have been driven by the memory of the 1970–71 epidemic. At that time, as the virus eventually found its way into Texas, agricultural disease control authorities were prepared to start shooting and burying horses in a massive “sanitary rifle” campaign, while scientists from what is now the federal Centers for Disease Control and Prevention and from other health research units provided the virologic and epidemiologic base to override the strategy of agricultural authorities, and the United States Army provided its then-new TC83 vaccine. Conflict was rampant. But when the virus threatened in 1995, it was as if nothing had been learned. Neither agricultural, public health, nor defense agencies undertook much in the way of field investigation, and there was little real effort to develop an interagency action plan. If the epidemic had progressed, jumped north, would federal agencies have worked together? What would have been done? Did the agencies have the specialists necessary to deal with a major mosquitoborne disease emergence? The evidence suggests that answers would not have proved satisfactory. These questions are being asked again in regard to the West Nile virus emergence in the United States in 1999, and answers again are very slow in coming. Although the concept of new and emerging diseases provides the impetus to fix this, the next step seems lost under the usual barrage of interagency meetings, memos, reports, and press briefings.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary Federal–State Communication, Cooperation, and Collaboration. Because state agencies that might be involved in emerging infectious disease episodes are so different from each other, there is no simple model for cooperation with federal agencies. Complicating matters, recent episodes have presented evidence of new turf tensions. The risk that this will get worse affects zoonotic disease episodes in particular, where laboratory and field activities resemble research projects and many different specialists must be involved. In several recent zoonotic episodes, however, scientists became competitive and insular, seeming to worry more about their publications than about the public’s health. The time-honored public service tradition holds the key for remedying this situation. Bureaucratic barriers, such as shipping permits and laboratory inspections, must be penetrated; agencies and individual scientists must immediately share information and materials, such as reagents. The tradition of cooperation and service in the interests of public health must be learned by every young scientist—it is the key not to personal fame but to personal and institutional integrity. The next step in resolving turf and cultural issues will require high-level leadership. Government–Academic Communication, Cooperation, and Collaboration. Interactions among federal and state government agencies and scientists and academic institutions and scientists also are marked by variations from institution to institution and person to person. Part of the complexity arises because relationships are not symmetrical: the world of the scientist in public service is a bit different from that of the academic researcher. The involvement of academic researchers with industrial partners adds to this asymmetry, as do the different traditions in the health sector versus the agricultural sector. For example, in the case of the West Nile virus, the seemingly simple matter of U.S. Department of Agriculture regulations for certifying outside laboratories to work on the virus and for shipping infectious materials seem to have caused friction and have become impediments to collaborative research. The next step in putting the public interest ahead of other motives will require bold action from institutional leaders. International Communication, Cooperation, and Collaboration. This subject is much like the previous two, with variations from country to country, institution to institution, and person to person. Despite some problems, there have been many successes in international activities, often via WHO. But when circumstances have required the involvement of institutions outside the usual public health agency loop, such as agricultural agencies, there often have been difficulties. This was true when the West Nile virus emerged in the United States, when the Nipah virus emerged in Malaysia in 1999, when the H5N1 influenza virus emerged in Hong Kong in 1997, and when the Hendra virus emerged in Australia in 1994. In each

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary case, turf issues arose, and in some instances efforts to protect agricultural markets seemed more important than efforts to protect public health. We may have been lucky that these agents did not spread farther, but who is to say what the next zoonotic agent will be like? The next step in solving such turf issues will involve recognizing the primacy of prevention and control of human disease. A System for Organizing the Involved Professional Community. Scientists interested in emerging zoonotic diseases represent diverse professional backgrounds and expertise and associate themselves with many different professional organizations. Thus, there has been no continuing venue for exchanging or integrating information and experiences. As the next step in building a better community, professional organizations should develop or help develop a unified, more comprehensive information and communications system, and they should establish a regular meeting venue, perhaps at the annual meeting of a larger organization with overlapping interests. A Strategic National Plan. To integrate all of these “next steps,” the zoonoses community, working in concert, must devise a comprehensive plan that addresses all aspects of this problem, including research needs and the needs of an effective system for disease prevention and control. As a model, the community might look to the Centers for Disease Control and Prevention’s emerging disease plan. Strategic planning must not be biased by the most recent zoonotic disease episode, the West Nile virus. Although this virus might seem an ideal model, we would be better served by using a more complex model, one that would test all facets of candidate plans. The ultimate test of candidate plans is bovine spongiform encephalopathy and the resultant new variant Creutzfeldt-Jakob disease. Today, with the wisdom of hindsight, many observers note that the ministries of agriculture and health in the United Kingdom failed to react in a timely fashion and with proper scope and scale of actions to deal with what was clearly a great risk to public health. Every aspect of the ministries’ disease prevention and control responsibilities has been called into question. This zoonosis also may be instructive in a larger sense, especially in its easy extension into the worlds of macroeconomics, international trade, national politics, and even regional governance. Data clearly show that the concerned public wants more disease control and intervention actions, more of the medical research needed to support such actions, and more participation across the country. Numerous surveys of public opinion done by Research!America and other groups also show that the concerned public is willing to pay. Such public expectations can only be met by the speedy development of a coordinated national system for studying, controlling, and preventing zoonotic diseases. In addition, the U.S. system must be fully integrated into the nascent global public

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary health network targeted at emerging diseases, as well as with networks focused on threats posed by livestock animal diseases, crop plant diseases, and bioterrorism. The public would see such an overall system as having a high cost–benefit ratio and as offering a credible approach to solving several high-priority problems most efficiently.