5
Surveillance and Management of Zoonotic Disease Outbreaks

PUBLIC HEALTH LABORATORY SURVEILLANCE

Mary J. R. Gilchrist, Ph.D.

Director, University Hygienic Laboratory, University of Iowa

Public health laboratories traditionally have conducted surveillance for critical infectious diseases, such as influenza, rabies in animals, and arboviruses. As new infectious diseases emerge and older ones alter their patterns of distribution, these laboratories may have to employ new strategies and tactics for disease surveillance.

One lesson is clear: surveillance strategies must be sufficiently flexible to adapt to the circumstances that we recognize as a disease emerges. With zoonoses, the emergence may be complete before detectable disease occurs in humans. This provides an opportunity to anticipate disease in a population and prevent its appearance by implementing appropriate control measures. The ecosystems are complex, however, and we must adapt our surveillance strategies as we learn more about the pathogens, their vectors, and the reservoirs. Temporal and spatial relationships should cause us to change our strategies as the disease advances. Different strategies should apply in areas where emergence is complete than in areas where disease is emerging or yet unknown.

It also will be imperative to devise adequate financial means to support surveillance programs. Unfortunately, waning public interest in a disease



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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary 5 Surveillance and Management of Zoonotic Disease Outbreaks PUBLIC HEALTH LABORATORY SURVEILLANCE Mary J. R. Gilchrist, Ph.D. Director, University Hygienic Laboratory, University of Iowa Public health laboratories traditionally have conducted surveillance for critical infectious diseases, such as influenza, rabies in animals, and arboviruses. As new infectious diseases emerge and older ones alter their patterns of distribution, these laboratories may have to employ new strategies and tactics for disease surveillance. One lesson is clear: surveillance strategies must be sufficiently flexible to adapt to the circumstances that we recognize as a disease emerges. With zoonoses, the emergence may be complete before detectable disease occurs in humans. This provides an opportunity to anticipate disease in a population and prevent its appearance by implementing appropriate control measures. The ecosystems are complex, however, and we must adapt our surveillance strategies as we learn more about the pathogens, their vectors, and the reservoirs. Temporal and spatial relationships should cause us to change our strategies as the disease advances. Different strategies should apply in areas where emergence is complete than in areas where disease is emerging or yet unknown. It also will be imperative to devise adequate financial means to support surveillance programs. Unfortunately, waning public interest in a disease

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary during a quiescent period often leads to reduction in political, and hence financial, support for surveillance activities. Ironically, it is during these quiescent periods that surveillance would best be conducted, to detect the appearance of an infectious agent in environmental reservoirs and eradicate the agent before it infects humans. When surveillance is abandoned, an outbreak of human disease may be well under way before it is detected. Of course, surveillance is of little use if not shared with other groups or individuals who can act on the information to prevent or diagnose disease. In Iowa, for example, the University Hygienic Laboratory has posted influenza surveillance data on its web site (www.uhl.uiowa.edu/HealthIssues/index.html) for the past several flu seasons. Data are updated automatically each night. Anyone wanting to know which viruses are circulating in their area can easily view a table that shows numbers of Influenza A and B detected during the current week, the past week, or all year. This information may influence a decision to administer prophylactic or therapeutic drugs or to control exposures. The web site also provides the latest data on a variety of other diseases, including some zoonoses. Sharing data with those who participate in its reporting and accumulation will encourage timely reporting and dialogue between the private and public health care communities. In our efforts to improve surveillance for zoonotic agents, we can learn much by analyzing current programs, such as the Centers for Disease Control and Prevention (CDC)’s Emerging Infections Program and its Epidemiology and Laboratory Capacity Program. In addition, examining some of the diseases that public health laboratories now face may help to illustrate some possible new approaches to designing surveillance strategies, as well as possible means to sustain them. Arbovirus Encephalitis Surveillance for arboviruses in the United States has focused primarily on three types of encephalitis viruses: St. Louis, Western equine, and Eastern equine viruses. One method of surveillance involves trapping mosquitoes, pooling and enumerating individual species, and checking extracts of the pools for the presence of these viruses. This activity is labor intensive and limited in sensitivity by the selection of the location and number of sites for mosquito collection. Another method of surveillance is to use birds, often chickens, as sentinels for the appearance of virus in a region, since the mosquitoes that transmit these viruses preferentially feed on birds. Surveillance can be accomplished by sampling wild birds or by housing chickens outdoors and bleeding them periodically during the summer to monitor for the appearance of antibodies to an encephalitis virus. Seroconversion requires time, however, and may not occur sufficiently early to signal the

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary introduction of virus in advance of human infections. In some circumstances, tandem sequential surveillance is employed: chicken sentinels, when positive, elicit the institution of mosquito surveillance. In other settings, both arms of surveillance are carried out simultaneously throughout the season. The Association of Public Health Laboratories conducted a survey to determine which states had been engaged in arbovirus surveillance prior to the summer of 2000, when funding for West Nile virus surveillance reinvigorated many state programs. Surveillance was by no means universal. Roughly 32 percent of states had ongoing programs of both mosquito and chicken surveillance, while an additional 24 percent performed either mosquito or chicken surveillance but not both. (Information was not collected regarding the extent of the programs, so it is not known whether all of these states had sustained fully competent surveillance programs.) Although New York had sustained a modest surveillance program, New York City, where the West Nile virus was first detected in the United States, had no surveillance program. Approximately 40 percent of states had completely abandoned surveillance for arboviruses, presumably because of the reduction in funding during a period of inactivity of arboviruses. The challenge to public health remains the identification of a means to sustain surveillance programs for arboviruses in periods of relative quiescence. Our experience in Iowa suggests a possible alternative to the on-again, off-again cycle of surveillance, which almost inevitably leads to periodic outbreaks of human disease. Since the major outbreak of arbovirus encephalitis in the Midwest in the 1970s, Iowa has retained a very modest surveillance program. Participants are committed to its operation. An entomologist at Iowa State University trains students in medical entomology to collect and pool mosquitoes by species. Local health departments identify outdoor sites to house flocks of chickens and periodically bleed the chickens. The University Hygienic Laboratory performs the laboratory tests, seeking evidence of arboviruses in mosquitoes and of arboviral antibodies in the chickens. The program costs approximately $50,000 per year, but even at this modest cost it has come under consideration for abandonment. When stakeholders were assembled to address the issue, local health department officials asserted that the program should be retained. They also maintained that they were able to decrease pesticide spraying in areas where negative surveillance results suggested the absence of encephalitis viruses. This reduced spraying may help offset the cost of the surveillance program. Presumably, if the medical consequences of pesticide exposure in humans were also considered as costs of abandoning surveillance, then an intensified surveillance program would be economically justifiable. A medical economist’s assessment of these speculations is recommended. Ideally, such an assessment also would model the economic value in saving human lives

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary and in preventing incapacitating sequelae that often follow nonfatal cases of arbovirus encephalitis and may require the individual to receive institutional care for life. In some locations, however, outbreaks of human arbovirus disease have precipitated the introduction of massive surveillance programs that could not be sustained in the subsequent quiescent period and were thus abandoned completely. Such a cycle might best be blunted by programmed contraction from a control mode to a sentinel mode when the outbreak has subsided. Modeling of ideal programs might specify such blunted cycles and suggest means to tailor them to conditions in different parts of the country. Our knowledge of the complex arbovirus ecosystem has grown greatly in recent decades, but our approach to surveillance has not been concomitantly adjusted. The West Nile virus outbreak has reunited the public health community with partners in the wildlife, veterinary, and entomology communities. It is time to devise a surveillance strategy involving a cycle of expansion and contraction instead of our historical cycles of engorgement and extinction. Tickborne Diseases Several tickborne diseases have emerged over the past several decades, including two Ehrlichia diseases known as human monocytic ehrlichiosis (HME) and human granulocytic ehrlichiosis (HGE). HME occurs most often in Missouri, Arkansas, and Oklahoma, but cases have been reported in at least 30 states. HGE is common in Wisconsin and Minnesota, and it occurs sporadically in other regions of the country. Iowa is located next to the two states where HGE is common, yet few cases of the disease are reported in the state. Some observers have suggested that since Iowa is intensely agricultural, with few public lands that might provide habitat for the mammals that serve as reservoirs of disease and as hosts for the ticks, Ehrlichia might not have penetrated into the state. However, Iowans converge each summer on public lands in Minnesota, Wisconsin, and Missouri. Thus, the infrequent, or absent, reports of human disease in Iowa cannot account for all the disease that must occur in its citizens who regularly travel to these states for recreation. One explanation for this suspected underreporting is that clinicians and citizens may not be alert to the possibility of encountering human ehrlichiosis, even among travelers to recognized endemic areas. To help determine whether HGE may be more prevalent than reported, the University Hygienic Laboratory and the Iowa Department of Public Health performed surveillance of human serum samples that were collected and submitted during tick season to be analyzed for some other disease. These tests found numerous instances in which serum was positive for HGE, with

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary other samples proving positive for HME or Lyme disease. When the results were reported to the patients’ clinicians, a common response was, “What is ehrlichiosis?” It is apparent that these diseases are underrecognized in Iowa. How should surveillance for tickborne diseases be conducted? For Iowa, some insight can be gained by looking at the results of how disease-carrying ticks are moving through the state. The University Hygienic Laboratory has examined blood taken from some 2,000 deer killed by hunters, testing the samples for antibodies to HME. Counties where positive samples occurred proved to be contiguous with the Missouri and Mississippi rivers, as well as with many of their tributaries. It appears that the hosts and reservoirs for the disease have moved northward into Iowa from Missouri along the riverbanks, where there is more cover than in farm fields. In general, tickborne diseases most often spread at a leading edge (in contrast with arboviruses, which often are spread to remote areas by birds). By using ground warfare and air warfare, respectively, as analogous phenomena, it is easy to understand why different surveillance strategies are necessary for these different modes of spread. Birds that fly into an area unexpectedly bring arboviruses in a manner not unlike bombers in air warfare. With ticks, the surveillance strategy must be tailored to the mode of contiguous spread in a manner that is not unlike the front lines in ground warfare. In areas where there is widespread recognition of emergence of a tickborne disease, activities might focus more on control of the vector and education of the citizens. In adjacent areas where disease is not yet recognized, surveillance might be focused on detecting initial appearance and tracking ultimate distribution of vectors and agents. In areas remote from the emerging margins of infection, human surveillance would be the focus, to identify disease in those individuals who had traveled to endemic areas or who were victims of unexpected introductions, as, for example, from ticks on hunting dogs brought into the area. As with arboviruses, the proposed surveillance strategy for tickborne diseases should be tailored to the cycle of emergence and the region of the country, and the strategy should be altered if there is a change in circumstances. Maintaining a system that does not change with changing conditions likely will be futile. Rabies in Animals Rabies virus in animals has long been the subject of surveillance. In cases where humans have been exposed to a suspect animal, detection of the virus also is used to guide decisions about prophylaxis with immune globulin and vaccine. Surveillance of rabies enables officials to track and attempt to prevent the dispersal of infected animals, as is happening with the current spread of rabies among raccoons. Surveillance focused on silver-haired bats also has intensified in recent years, since it became known that

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary these bats might be responsible for transmitting rabies in cases where there was no other known bite exposure. Laboratories doing such surveillance should be encouraged to record the species of bat as well as its rabies virus status; laboratory personnel can receive training in speciation of bats from a local wildlife expert. Of concern to the medical community is the accurate determination of the rabies status of each animal for which a human exposure has been documented. Unfortunately, the federal Clinical Laboratory Improvement Act (CLIA) provides rules for testing human clinical specimens but not rules for animal specimens, even when such test results may affect human therapy and outcome. The government should expand CLIA coverage to include testing of animal specimens when it impacts on treatment of humans. The government also should require laboratories performing rabies tests on animals involved in human exposures to enroll in proficiency testing and quality assurance programs equivalent to those used to license laboratories that test human clinical specimens. The adverse consequences of poor testing are grave: false negative tests may produce fatal human disease because prophylaxis would not be administered, while false positive tests may lead to excessive use of expensive interventions and to a general loss of confidence in the tests. Hantavirus Pulmonary Syndrome First detected in the U.S. Southwest in the early 1990s, hanta-virus pulmonary syndrome, which is transmitted to humans by rodents, has since been found throughout the Americas. In the United States, most states in the West, Midwest, and mid-Atlantic regions have recognized one or several cases, while most states in the Southeast and New England remain untouched. Until the past 3 years, most midwestern states had few or no reported cases. In Iowa, following the first reported case, extensive surveillance of rodents in the implicated exposure area did not yield evidence of a reservoir of disease. It remains to be proven whether surveillance can anticipate and prevent disease, and under what circumstances surveillance might be efficacious. Meaningful surveillance protocols should be developed in a research mode and evaluated for their ability to anticipate and prevent human disease. Unless proven to be efficacious, surveillance of animals should not be instituted on a routine prospective basis. Instead, good surveillance of human populations, augmented with excellent prevention education programs, would be the primary undertaking.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary Traditional Zoonoses Traditional zoonoses include such diseases as anthrax, plague, tularemia, and brucellosis. The agents that cause these diseases are currently considered prime candidates for deployment in bioterrorism and biowarfare. Recent attention to the potential for such activities in the United States has led the government to institute the Laboratory Response Network, sponsored by the CDC and managed by the Association of Public Health Laboratories, to enhance the detection of these agents in humans. As part of this nationwide program, personnel in laboratories that test clinical specimens from humans will receive training in the means to rule out these agents, as well as in how to forward the isolates to public health laboratories for specific identification and subsequent molecular fingerprinting. By providing a link between public and private laboratories, this network will increase the nation’s capacity to detect and prevent the spread of zoonoses, whether they are transmitted naturally or intentionally. New Zoonotic Challenges A variety of agents of zoonoses have emerged or reemerged during the past several years, including Campylobacter, E. coli O157:H7, Cryptosporidium, and antibiotic-resistant bacteria from animal origin. The current practices used to detect and control these agents are suboptimal, for a variety of reasons. Some laboratories have been slow to adopt routine methods for detecting these agents. Moreover, in some managed care settings, tests are done that may detect evidence of a toxin but not yield an isolate of the organism that produces the toxin. Unfortunately, the origin of the organism cannot be tracked without the isolate. As a result, the foodstuff that is the source of the infections cannot be identified, which means that other individuals may continue to ingest the foodborne organisms and succumb to the disease. One way to help rectify these circumstances would be for the government to specify expectations of clinicians and laboratories in the private health care setting. For example, it would be useful to clarify what circumstances dictate the performance of a culture and submission of the isolate to a public health laboratory. To help increase participation by private managed care organizations, the government, perhaps through the Health Care Financing Administration (HCFA), may at first need to offer some type of incentive. Adjustments in both reimbursement policies and quality indicator requirements are candidate incentives that HCFA might entertain.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary CHALLENGES OF VECTORBORNE DISEASE SURVEILLANCE FROM THE LOCAL PERSPECTIVE: WEST NILE VIRUS EXPERIENCE Marcelle C. Layton, M.D. Assistant Commissioner, Bureau of Communicable Diseases New York City Department of Health New York City’s Communicable Disease Program investigates 52 different human infectious diseases and conditions that are mandated to be reported by physicians, hospitals, and laboratories. We handle between 70,000 and 90,000 case reports annually. However, since our General Communicable Disease Unit has only four field staff members, we are not able to investigate each of these cases fully with a medical record review and/or patient interview. This means we have to prioritize our investigations to focus on the diseases of current public health concern. For all diseases, our standard practice is to examine routine demographic data, geographic location, and the time of infection, in order to determine whether there is an increase or clustering of disease that requires further investigation. We process our data weekly to ensure rapid recognition of outbreaks. For certain diseases, we assign all case reports for further investigation; this will include reviewing a patient’s medical charts and conducting in-person interviews to look at risk factors for infection and the clinical spectrum of illness. Prior to the recognition of the West Nile outbreak in New York City in 1999, viral encephalitis cases were not prioritized for more detailed case investigations, so there was no active follow-up to ensure that full viral laboratory testing was completed, and thus the specific viral etiology for most cases remained unknown. In recent years the city has faced several outbreaks of zoonotic and vectorborne diseases. In addition to the outbreak of West Nile encephalitis, these outbreaks have included a cluster of locally acquired malaria cases in Queens in 1993, the reintroduction of raccoon rabies in 1992, a foci of Rocky Mountain spotted fever in the South Bronx, and the spread of Lyme disease into areas at the city’s borders from adjacent jurisdictions where Lyme disease has been endemic for years (e.g., Westchester County). Prior to the West Nile outbreak, the bureau’s surveillance system for vectorborne and zoonotic diseases was primarily passive (with the exception of our active laboratory-based surveillance program for malaria that was instituted in response to the 1993 outbreak). Thus, cases come to our attention only when reported by a laboratory or clinician, generally by telephone, telefax, or regular mail. Like most other cities, New York City did not have a formal infrastructure for monitoring diseases in the animal

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary kingdom. The only animal disease that veterinarians are required to report is rabies. At one time, we did have a mosquito surveillance and control program, but its funding was discontinued in 1988. We do conduct limited tick surveillance, focused primarily on areas of the city that are at high risk for Rocky Mountain spotted fever and Lyme disease. The bureau’s laboratory capacity to investigate arboviral and other vectorborne diseases also was quite limited, and in most cases we sent specimens that needed analysis to another reference laboratory, either at the state level or to the federal CDC. Because the bureau must rely on passive surveillance, the role of physicians is especially important, especially for diseases, such as encephalitis, where the diagnosis is usually based on a constellation of clinical findings, as opposed to a positive laboratory test. An astute clinician who reports something unusual may be our first indication of a citywide trend. Indeed, this is what happened on August 23, 1999, when a physician called to report two cases of an unusual neurologic disease. Her initial concern was that at least one of the patients might have botulism, as suggested by the presence of severe muscle weakness. Based on the clinical and laboratory evidence, however, we determined that botulism was unlikely. Rather, some of the symptoms (e.g., fever, altered mental status, and an inflamed spinal fluid) suggested that a viral encephalitis infection might be the cause of illness. Thus, we recommended that the physician send appropriate clinical specimens to the state laboratory for additional tests. We also stayed in touch with the physician, and we sent staff out to further investigate these cases. Four days later, on a Friday, the physician called to report that another patient with similar symptoms had been admitted to her hospital, and that by now all three cases had developed muscle paralysis—and in the middle of this call, a neurologist colleague entered her office and reported to us that he was treating a similar case at another hospital nearby. So, by the end of this telephone call we were aware of four cases of viral encephalitis—all associated with severe muscle weakness, all clustered in one small area of the city, and all occurring during a 1-week period. In a typical year, we usually receive reports on only nine encephalitis cases citywide. Faced with what appeared to be an unusual outbreak, our staff spent the weekend at the two hospitals, investigating these cases. We also began some active case-finding efforts at other nearby hospitals. By Sunday morning, we had identified a total of eight suspected cases. Of particular concern, the cases were nearly identical—all in healthy older adults who lived at home; all with similar symptoms, including fever, confusion, and severe diffuse muscle weakness; and all living in close proximity to each other. Our investigation focused on the possibility of two types of viral encephalitis that can occur in clusters in the summertime: one caused by an

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary enterovirus (which is transmitted from person to person and is known to be common in New York City during the late summer months, although primarily among children), and the other by an arbovirus (which is transmitted to humans by arthropods, although there had been no reports of arboviral disease in the city in more than 100 years and there had been no recognized arboviral activity in the Northeast that summer). Based on extensive interviews with the patients’ families, we determined that the only thing that linked the patients in time and place was that they all spent time outdoors in their backyards or neighborhoods, especially in the evening hours. That same weekend we consulted with enteroviral and arboviral experts at CDC, and everyone agreed that the general facts of these cases—the predominant finding of severe muscle weakness, the older age range, and the absence of prior or nearby arboviral activity in the New York City area—were not typical for either family of viruses. So, we continued to prioritize getting clinical specimens to the state laboratory to help determine the specific diagnosis. On Monday morning, we began extensive case-finding citywide. We broadcast a fax alert to several departments in all 70 city hospitals, asking the staff to report any similar cases, and we began calling physicians citywide who specialized in infectious diseases and neurology to determine if they were aware of additional cases. As the week unfolded, we learned of nearly 40 suspected cases throughout the city. Because arboviruses were a possibility, we sent a communicable disease team that included an entomologist to do an assessment of where these patients lived. (Since the bureau did not have an entomologist on staff, we borrowed one from the American Museum of Natural History.) Based on the findings of significant larval and adult mosquito activity in the neighborhood of these patients, the team became more convinced that the suspect virus was being transmitted to humans by mosquitoes. Soon, the state laboratory issued the results of its analysis, preliminarily identifying the disease as St. Louis encephalitis (SLE). CDC then reported that its results using a nonspecific immunoassay test were also most consistent with SLE, based on the clinical and epidemiologic findings. This was on the Friday afternoon before Labor Day weekend. The city’s health department immediately launched a mosquito control program, at first in the neighborhoods in northern Queens where the initial cases were concentrated. This was no small task, since the city lacked an existing infrastructure for such programs. We also continued active surveillance, and as we identified more cases in other parts of the city, we expanded mosquito control citywide. We sprayed pesticide by air and on the ground; we applied larvicide extensively in locations that had standing water where mosquitoes could breed; and we implemented an extensive multimedia educational campaign to inform the public about the outbreak and the need for

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary mosquito control precautions, as well as to address concerns about exposure to the pesticides being used. This effort required extensive communication and coordination among a number of agencies at the local level, as well as with state and federal agencies. Indeed, as the outbreak unfolded and was recognized to involve jurisdictions throughout the greater New York City metropolitan area, the number of agencies involved grew considerably. As it turned out, the cause of this outbreak was West Nile virus, a flavivirus closely related to SLE, but one that had never before been identified in the Western Hemisphere. By the time West Nile virus was recognized, more than a month after the initial outbreak, all necessary mosquito control measures had been implemented and the outbreak was essentially over. It is important to note that the identification of West Nile virus was due, in part, to observations during this period by veterinarians that a large bird die-off was occurring, especially among crows. Two independent investigations, by the veterinary pathologist at the Bronx Zoo and by the wildlife biologist at the New York State Department of Environmental Conservation, found pathologic evidence of widespread viral inflammation, including encephalitis, among dead birds found in the greater New York City area. Avian tissues were submitted for viral testing, and a flavivirus was isolated that was subsequently determined by CDC to be West Nile virus. In all, there were 62 persons diagnosed with West Nile virus in the greater New York City metropolitan area, including 59 patients who required hospitalization and seven who died. West Nile viral activity in birds involved a much larger geographic area, with infected dead birds found in areas where no human cases were detected, including eastern Long Island; the lower Hudson Valley; eastern New Jersey; southern Connecticut; and Baltimore, Maryland. Although thousands of birds were estimated to have died from West Nile virus in 1999, with over 23 species affected, the highest percentage of avian fatalities (88 percent) occurred among crows. Concerned that the West Nile virus might return the following year, we conducted surveillance during the winter, looking for evidence of West Nile viral infection among overwintering mosquitoes hibernating underground. We did find evidence of infected overwintering mosquitoes in northern Queens, the epicenter of the 1999 outbreak. In addition, in February a dead bird (thought to be nonmigratory) discovered in Westchester County tested positive for the virus. Based on such evidence, local, state, and federal agencies mounted an aggressive surveillance and control plan throughout the northeastern United States for the 2000 summer mosquito season. In New York City we implemented a program to eliminate mosquito breeding sites on city property; this effort included putting larvicide in every one of the city’s 150,000 storm sewer drains and all sewage treatment sites. We also encouraged private citizens to eliminate breeding sites near their

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary fit for its new circumstances. (Of course, some emergences, such as with influenza or canine parvovirus, have been driven by mutation, but most viral mutations occur randomly and are then selected by the immune pressures of the host or other external factors.) Travel of humans and transport of vectors and reservoir host animals then stirs the mixing pot, moving a particular pathogen into an ecological milieu where it can test itself, perhaps with its appropriate helper vector or host reservoir. Social and environmental changes are occurring at an increasing rate, in both the developed and developing worlds. The developed world has the greatest travel and transport, providing particular risks. However, ecological change is greatest in the developing world and biodiversity is greatest in the tropics, which makes these regions the best “hunting ground” for new pathogens. In the final analysis, we really do not know which zoonotic pathogen will emerge next or cause the biggest problem. Given the obvious link between human health and viruses that circulate in domestic animals and wildlife, we cannot ignore pathogen flow in any of these areas. One issue that is particularly important but also contentious is the ability of some pathogens to establish themselves as disease agents in humans without need for their previous host reservoirs. Measles and other viruses appear to have made this transition in the past, and it is now established that influenza A makes the leap with some regularity (although flu prognosticators cannot determine how regular such leaps may be). This cross-species traffic could form the basis for “new” human diseases that might be particularly difficult to control because they have cut the zoonotic link; in such cases, we will have to deal with a human-adapted virus. HIV is such an example, but HIV has the same survival strategy in humans as it did in chimpanzees or sooty mangabeys. Can other viruses switch their basic transmission cycles? One concrete example would be filoviruses, which have a proven capability to pass through several generations of interhuman transmissions. Thus, we should remain alert to end the chains of spread to prevent any opportunities to adapt to continuous interhuman spread. In any case, there is a candidate for the breeding ground of these possible human pathogens: the megacity, with its crowded conditions, poor sanitation, and weak surveillance. This situation, of course, has counterparts in agriculture and crop production today. What sort of response is needed to these threats? The usual answer, “increased surveillance,” is correct but insufficient. We also need “trip wires” that will launch active investigations. These investigations need to be multidisciplinary, involving physicians, veterinarians, entomologists, mammalogists, ecologists, molecular biologists, vaccinologists, epidemiologists, and a large number of other specialties (including pathogenesis and immunology). Formal designation of the specialties is unimportant, but having the right expertise present on the team is crucial. It also will be

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary important that the leader of the team have the ability to communicate effectively with the representatives from all the disciplines, as well as with other people who will play key roles in control efforts. In addition, with the increasing numbers of alarms being raised as communications and awareness increase, there has to be a reasonable way to sort through the possibilities to arrive at priorities for investigation. Such prioritization might best derive from collaboration between multidisciplinary teams of researchers and a central specialty group, such as the CDC’s Special Pathogens Branch or the National Institute of Virology in South Africa, both of which have particular expertise in certain areas, as well as access to special expertise in infectious disease pathology, and therefore are well prepared for conducting pathogen-specific analyses. In determining what pathogens to study, we can identify a rogues’ gallery of agents to receive special attention. We know that some viruses already have proved themselves to be bad actors with major human disease potential, and we also know that at some point they are likely to return to center stage. This list includes Venezuelan equine encephalitis virus, West Nile virus, yellow fever virus, Rift Valley fever virus, and Nipah virus, among many others. Is it too much to ask to understand more about the transmission of these agents and to have useful antiviral drugs and prototype vaccines available for such established threats? Of course, we also are certain to face the emergence of previously unknown pathogens. Thus, we would be well advised to do basic groundwork now, and not when we are faced with a “mystery disease” or a new, challenging pathogen. One approach would involve studying certain classes of viruses, such as filoviruses and parvoviruses, so we will not be caught without at least the basic tools to respond to new threats. Of course, most plans will not work unless they are developed with an eye to their functioning in addition to their goals. Experience points to a number of potential problems and needs: There needs to be a specific organization that can take the first call in cases of new disease emergences. Maintaining such a group, from providing adequate funding to ensuring employee morale, has often proved difficult. This will be especially challenging in the international arena. Most laboratories, including those at CDC, do not have adequate reagents for all viruses to share with all researchers who want to study them. This function should be covered with generic reagent production, either explicitly funded through CDC or through a program similar to the one once used by the National Institutes of Health for producing arbovirus reagents. Better mechanisms are needed for distributing supplementary funding for handling emergencies. This problem was particularly evident with

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary funding for studies of the West Nile virus and hantavirus. Such funding now must be disbursed according to federal acquisitions regulations, and this process too often leads to delays in the distribution of funds and to inflexibility in selecting funding recipients. Cooperation among U.S. agencies and among U.S. and international agencies often proves difficult. The National Science and Technology Council’s Committee on International Science, Engineering, and Technology—whose main mission is to develop, on an interagency basis, policies for furthering international science and technology cooperation in the national interest—has markedly improved the interactions of federal agencies. Nevertheless, during some recent disease outbreaks, the interactions of federal agencies within such varied departments as Health and Human Services, Defense, and Agriculture were not coordinated and efficient in important aspects of containing the diseases. In the international arena, there is no strong and efficient leadership in responses to emerging disease epidemics, and the organization of such responses often is complicated by the need to coordinate the actions of multiple international and national agencies as well as the increasingly assertive initiatives by some nongovernmental organizations. There needs to be up-front recognition of some of the things that now can be done scientifically but, for a variety of practical considerations, cannot or will not be done in everyday practice. In diagnostics and vaccine development, for example, scientists can make prototypes, but the complexities of manufacture, distribution, and quality control are beyond the scope of universities or government laboratories, and usually below the interests of industry. This inability to produce new human vaccines and diagnostics on a practical level may become a serious deficiency in our ability to respond to emerging infectious diseases. There also are problems in supporting expensive longitudinal studies and innovative high-risk research. Public education programs are needed both to increase awareness of the problems and to minimize undue fears. A joint approach should involve developing a better curriculum for use in schools and devising information programs to reach influential organizations and the media. In an era of deregulation, the biomedical community is being choked with regulations that often do not address real risks or abuses but rather reflect political perceptions. Such regulations affect animal experimentation, shipping of various disease-related agents, research on certain agents, and the use of certain vaccines for occupational safety, among many other areas. Not only do unwarranted restrictions fail to improve public or occupational safety appreciably, they also limit research that may indeed reduce the risk from threat diseases.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary Many people in the United States, within government and among the public, have only minimal understanding of conditions in other countries. This is especially true regarding the developing world, where new zoonotic diseases are most likely to originate. It is critical to improve our general understanding of the various cultural, infrastructure, and other issues that will affect how the United States can best work with the world community to improve the surveillance, control, and management of disease. FOODBORNE ZOONOTIC AGENTS: SALMONELLA ENTERITIDIS IN EGGS Kaye Wachsmuth, Ph.D. Deputy Administrator, Office of Public Health and Science Food Safety and Inspection Service, U.S. Department of Agriculture In the United States the most common foodborne bacterial pathogen is Campylobacter, which causes almost 2 million cases of infection per year, according to a 1999 report from the CDC. Second is Salmonella, with more than 1.3 million cases. However, Escherichia coli O157:H7 and Listeria monocytogenes appear to cause the most severe illnesses, as judged by their rates of reported hospitalizations and deaths. All of these pathogens, with the possible exception of Listeria, are zoonotic; they are silent infections in the animal host, causing no overt symptoms or problems at that point in the food supply. Salmonella, which hospitalizes and kills the most people each year, serves as an example of this class of pathogens. In recent years, Salmonella enteritidis (SE) has become a leading cause of Salmonella infection, increasing from about 5 percent of all such infections in 1976 to about 26 percent by the mid-1990s. SE infections primarily are associated with the consumption of eggs. Of particular note, this problem exemplifies a new scenario of foodborne infection that moves beyond the traditional church supper or potato salad outbreaks. As described by CDC’s Robert V. Tauxe, this new scenario involves low-level contamination of a widely distributed commercial food product. Such outbreaks typically are detected only because of a fortuitous concentration of cases in one location. A diffuse increase in sporadic cases can occur well before a local or large outbreak focuses attention on the emergence of a pathogen. With SE, for example, the egg connection was not really appreciated until 1986, when a large multistate outbreak of infections was traced to stuffed pasta made with raw eggs rather than fully cooked eggs. Since then, SE has been found on farms of egg-laying chickens, and the pathogen has been demonstrated to be the cause of outbreaks and

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary sporadic cases of infections. Part of the difficulty of preventing SE from reaching humans is that infected hens exhibit no outward signs of carrying the pathogen. The hens’ reproductive tracts become colonized with SE, and there now is convincing evidence that SE can be passed to the inside of eggs during egg formation. With the emergence of health problems posed by SE and egg consumption, the USDA and several other government agencies collaborated to bring everything known about the pathogen into the organized framework of risk assessment. The goal was to determine exactly where information gaps occurred and how to best address this issue. The risk assessment was conducted by a multidisciplinary team that included veterinarians, physicians, epidemiologists, microbiologists, and risk analysts, and the team consulted extensively with industry officials to determine current industry practices. The risk assessment model built from this framework is based on the flow of eggs from production through, in some cases, processing, preparation, and consumption. The model consists of four basic modules concerning eggs consumed as “shell eggs.” Each of these modules has unique inputs and outputs. Ultimately, the model predicts the probability of human illness of varying severity (that is, risk) associated with consumption of egg-containing servings. The first module focuses on egg production at the farm. Its first input is the approximate number of infected flocks in the country. However, these data are not readily available and in many cases are difficult to interpret. For example, evidence collected from different regions of the country often cannot be extrapolated to every state, for a number of reasons. Consequently, the model incorporates uncertainty regarding the estimated fraction of all flocks that are infected. The module also seeks to determine how many eggs produced are likely to carry the pathogen, as well as the final destinations of SE-contaminated eggs. Under current conditions, the module predicts that the most likely frequency of contaminated eggs in the United States is one in every 20,000 eggs produced. Since the industry produces about 65 billion eggs a year, this means that several million contaminated eggs reach the marketplace, with many of them being consumed as shell eggs by individuals. Information from the production module then flows into the various other modules. One module, for example, mathematically models the potential for SE growth and death within an individual egg as it moves from the farm to the consumer. A major rate-limiting determinant of SE growth involves changes in the permeability of the yolk membrane, with increased permeability associated with elevated temperatures and/or times of storage. When the yolk membrane is totally compromised, it releases nutrients into the albumen (or white) of the egg, creating an egg in which the pathogen

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary may multiply to large numbers—and thus the egg poses a very high risk of causing human illness. Another module deals with how eggs are prepared. More often than not, they are going to be cooked, which should eliminate SE and thus any risk of infection. Nevertheless, the number of different cooked food dishes that have been implicated in SE outbreaks suggests that many individuals, as well as many companies that make or sell food items, may not be fully cooking the eggs they use. The list includes eggnog, Caesar’s salad, omelets, French toast, lasagna, and meringue pies. One SE outbreak several years ago, which caused approximately 250,000 cases, was traced to ice cream that had been contaminated postprocessing by exposure to raw eggs during transport. The final module, which incorporates information from all of the others, deals with the public health consequence of exposure to contaminated egg meals. Outputs include projected numbers of illness, postillness sequelae, recovery without a physician visit, recovery with and without hospitalization, and death. Among the efforts to validate both the individual modules and their combined performance, we compared their projections with various field observations. For example, we compared outputs from the public health module with the number of illnesses estimated from national disease surveillance systems. Although the results were not a perfect match, they did suggest that the model’s output was approximately consistent with independently derived data. Moreover, any discrepancies noted occurred in favor of public health, with the model projecting more illnesses than were reported. Whether this is the model’s fault, or whether surveillance systems are failing to detect all cases of illness, remains to be determined. Thus, experience suggests that the model can provide a scientific basis for policy decisions related to consumption of eggs. Among its uses, the model can examine which types of changes, especially in production and distribution, would be most effective in terms of human health outcome, and this insight will help in selecting the most efficient and cost-effective intervention or management strategies. For example, the model predicts that immediately transferring a freshly laid egg, which has a temperature of over 99 degrees Fahrenheit, into an environment with an ambient temperature of 45 degrees can reduce human illness by 8 percent. In current practice, however, freshly laid eggs are first washed in warm water and then packaged in cartons. These cartons are put on a large pallet with many other cartons, stacked up to 10 feet high, and wrapped in plastic. Even in a refrigerated environment, eggs toward the middle of the stack will stay at about 80 degrees for up to a couple of weeks. Obviously, changing that industry practice can reduce the level of SE in the eggs and thus reduce the risk of disease among people who consume those eggs.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary In developing the model, several lessons emerged that may help in developing risk assessment tools targeted at other foodborne health threats. Stakeholder input is imperative; without early and continued participation by all parties involved, including the general public and industry, development efforts may be slowed and acceptance of the results endangered. A multidisciplinary approach is essential. Given the scope of the food chain, a modular approach that breaks problems into integrated parts can facilitate modeling. Finally, the modeling process must be iterative, with newly gathered data being used to revise the model and its outputs. With the SE model, for example, we now are examining new FoodNet data, and we will be revising some of the modules based on recent industry changes in egg production and distribution, as well as on new data on the occurrence and distribution of SE in the egg industry. In 1999 the President’s Food Safety Council convened a multiagency group to examine egg safety. After gathering input from a variety of stakeholders, the group proposed an action plan that calls for eliminating SE illness associated with egg consumption, with an interim goal of reducing the risk by 50 percent by the year 2005. The plan, which draws heavily on USDA’s modeling efforts, has eight objectives, built on a modular construct from farm to table. (Details of the plan are available on the World Wide Web at www.foodsafety.gov/~fsg/ceggs.html.) The plan lays out a time line for reaching each objective, and in many cases it specifies which agencies should be responsible. Such guidelines will prove valuable, given the complexity of the “egg continuum.” The Food and Drug Administration has jurisdiction at the farm level, but the agency does not really have a presence on farms. FDA sets standards for producers, and the states are responsible for inspecting eggs and for enforcing regulations on producers. USDA’s FSIS is responsible for establishing and enforcing standards for egg packers and processors. CDC is responsible for surveillance programs to monitor human health and will ultimately document whether the new egg-safety program is meeting its goals. The government is beginning to use this risk assessment approach for other foodborne pathogens. FDA is leading a study of Listeria monocytogenes in ready-to-eat foods. One of the objectives of this study is to rank various foods on the basis of their risk to human health, so that regulatory agencies can better focus their scarce resources. The FSIS has used its modular approach to study Escherichia coli O157:H7 in ground beef, and these results will become the basis for new USDA policy and regulatory considerations. Of course, this pathogen is found in many other foodstuffs as well, such as lettuce, apple juice, and even water. The FSIS model may help in the modeling of these routes of infection, because it

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary incorporates on-farm inputs that can be used as a starting point in these other risk assessments. Campylobacter is another major concern for FSIS. This pathogen, which is the most frequent cause of sporadic bacterial foodborne disease, is readily found on poultry farms, in chickens, and in chicken carcasses at slaughter. Canada has mounted a relatively large risk assessment study of this problem, and U.S. efforts will build on that work. In addition, FSIS is supporting a project, in collaboration with the APHIS, on BSE, or mad cow disease. We have contracted with the Harvard Risk Analysis Center to evaluate current U.S. risk management actions to prevent BSE from occurring in this country. Many other countries that the United States trades with face similar, and often worse, safety problems related to foodborne pathogens. As the global marketplace increasingly becomes reality, U.S. consumers are becoming more concerned about the origins of their food and the public health situation in the countries of origin. Concerns may be particularly acute regarding developing countries, some of which lack any surveillance systems for monitoring foodborne diseases. The federal government is trying to address these issues through the Codex Alimentarius Commission (Codex), which sets international food safety standards. Risk assessment will play a role in mitigating this enormous potential problem. Within Codex, the Committee on Food Hygiene has developed a priority list for risk assessment activities. The pathogens singled out for immediate attention include those described above. The hope is that this approach will provide officials in different countries with a sound scientific basis for discussing food safety, particularly in cases where countries now disagree. LEGISLATIVE AND POLICY CONCERNS IN PROTECTING THE NATION’S HEALTH David C. Bowen, Ph.D. Congressional Fellow Office of U.S. Senator Edward M. Kennedy (D-MA) Senators Edward M. Kennedy and Bill Frist (R-TN) have grown increasingly concerned that the United States is inadequately prepared for dangerous outbreaks of infectious disease. Through hearings and conferences with experts in the field, the senators set out to discover where the nation’s needs for increased preparedness were greatest. As chairman and ranking member of the Senate Subcommittee on Public Health, the two senators maintain close ties with the medical and scientific communities. Through this contact with medical experts, the senators realized that infec-

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary tious disease outbreaks were a growing threat to the nation’s health. When the senators began this investigation, the dangers of infectious disease outbreaks were not widely discussed in the media or other public forums. Now, because of widespread awareness of disease outbreaks, such as the emergence of West Nile virus in New York and the “mad cow” epidemic in Britain, the American public has become increasingly attuned to the need to improve our nation’s defenses against disease outbreaks. Extensive consultation with the medical community revealed that the nation’s local, state, and national public health agencies are poorly equipped to detect, monitor, and respond to outbreaks of infectious disease. This deficiency impairs the nation’s ability to respond to infectious disease outbreaks of all types but is particularly troubling in light of two disease threats that pose particular danger to the public health: the rise of microbes resistant to antibiotics, and the threat that a terrorist may deliberately release a dangerous infectious agent. To address both the general threat of infectious disease outbreaks and the specific threats of resistant bacteria and bioterrorism, Senators Frist and Kennedy introduced the Public Health Threats and Emergencies Act of 2000. The bill lays out a blueprint for strengthening the nation’s capacity to detect and respond to the threat that disease emergencies pose to the public’s health. The legislation authorizes major initiatives to improve public health capacity, to address the threat of antimicrobial resistance, and to improve preparedness for acts of bioterrorism. (Since this IOM Forum, many of the provisions contained in the Frist–Kennedy bill have been enacted into law as part of the Public Health Improvement Act of 2000 [Public Law 106-505]). To improve the nation’s ability to respond effectively to infectious disease threats, the bill will strengthen the capacity of public health agencies to detect, diagnose, and contain infectious disease outbreaks. Many public health agencies lack the basic computer equipment to communicate data on disease outbreaks electronically or cannot perform simple laboratory tests to diagnose infections. Most agencies do not even have an up-to-date assessment of their current capacities and needs. To address these weaknesses, the Frist–Kennedy bill establishes grant programs to enable state and local public health agencies to: Assess their current capacities and identify their areas of greatest need. Upgrade the ability of public health laboratories to identify disease-causing microbes. Improve and expand electronic communication networks. Develop plans to respond to public health emergencies. Train public health personnel.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary The widespread use of antibiotics beginning in the 1940s provided, for the first time in history, effective treatments for infectious diseases. Antibiotics that once had the power to cure dangerous infections are now often useless, however, because microbes have become resistant to all but the newest and most expensive drugs. Disturbingly, some patients have contracted infections resistant even to these drugs of last resort. The World Health Organization (WHO) estimates that 14,000 Americans die every year from drug-resistant infections and that the United States spends $10 billion a year treating antibiotic-resistant infections—and this burden will grow heavier as more and more microbes become resistant. To meet the grave and growing problem of antimicrobial resistance, the Frist–Kennedy bill: Directs the Department of Health and Human Services (HHS) to conduct a nationwide campaign to educate patients and doctors about the appropriate use of antibiotics. Authorizes HHS initiatives to monitor and contain the spread of resistant microbes. Authorizes grants for public health agencies to combat antimicrobial resistance. Establishes demonstration grants for hospitals and clinics to promote more responsible use of antibiotics and to control the spread of resistant infections. The HHS Office of Emergency Preparedness estimates that 40 million Americans could die if a terrorist released smallpox into the population. Anthrax could kill 10 million. Although experts may dispute the probability of a bioterrorist attack, few would disagree that the consequences of such an attack could be devastating. To enhance the ability of the nation’s public health agencies to respond to acts of bioterrorism against the civilian population, the Frist–Kennedy bill: Establishes grants to train health care professionals in recognizing and treating illnesses caused by such attacks. Improves coordination among federal agencies to develop public health countermeasures against bioterrorism, such as stockpiles of necessary drugs. Authorizes expenditures to revitalize and improve the security of laboratory facilities at the CDC. Reauthorizes an existing provision of law that allows the Secretary of HHS to protect the public health in the event of a bioterrorist attack or other disease emergency.

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The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health - Workshop Summary Through these measures the Public Health Threats and Emergencies Act can lay the foundation for a strong public health response to the danger of infectious disease outbreaks. With the passage of this legislation, the sustained involvement of the medical and scientific communities will now be essential in ensuring that the programs authorized by the act are properly funded and implemented.