3
Assessment of Current Framework: Case Studies

INTRODUCTION

In this chapter, a series of case studies are examined to assess the capabilities and limitations of the framework in preventing, detecting, and diagnosing animal diseases. The analysis of disease events that have occurred nationally and abroad provides useful information on the responsiveness of the framework as a whole and lays the groundwork for Chapter 4, which identifies gaps and opportunities to strengthen the framework. This chapter does not attempt to provide a comprehensive analysis of all animal diseases, but examines a “cafeteria-style” sample of diseases that could have potentially large economic, human, and/or animal health impact. Box 3-1 lists the animal diseases and disease categories selected for analysis. The list is not based on diseases that are the most problematic or prevalent in the United States. (For example, food-borne diseases caused by Salmonella enteriditis and Escherichia coli O157:H7 are not on the list; they pose greater concerns for the health of humans than for animals.) Instead, the animal diseases or disease scenarios described here, from acute to chronic, endemic to exotic, naturally occurring to intentionally introduced, were selected to consider the breadth of issues that must be addressed by an inclusive infrastructure capable of detecting, diagnosing, and preventing a wide variety of events affecting animal and human health. The diseases selected involve each of the major animal types, namely food-animals, wildlife, and companion animals.



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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases 3 Assessment of Current Framework: Case Studies INTRODUCTION In this chapter, a series of case studies are examined to assess the capabilities and limitations of the framework in preventing, detecting, and diagnosing animal diseases. The analysis of disease events that have occurred nationally and abroad provides useful information on the responsiveness of the framework as a whole and lays the groundwork for Chapter 4, which identifies gaps and opportunities to strengthen the framework. This chapter does not attempt to provide a comprehensive analysis of all animal diseases, but examines a “cafeteria-style” sample of diseases that could have potentially large economic, human, and/or animal health impact. Box 3-1 lists the animal diseases and disease categories selected for analysis. The list is not based on diseases that are the most problematic or prevalent in the United States. (For example, food-borne diseases caused by Salmonella enteriditis and Escherichia coli O157:H7 are not on the list; they pose greater concerns for the health of humans than for animals.) Instead, the animal diseases or disease scenarios described here, from acute to chronic, endemic to exotic, naturally occurring to intentionally introduced, were selected to consider the breadth of issues that must be addressed by an inclusive infrastructure capable of detecting, diagnosing, and preventing a wide variety of events affecting animal and human health. The diseases selected involve each of the major animal types, namely food-animals, wildlife, and companion animals.

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases FOREIGN ANIMAL DISEASES: EXOTIC NEWCASTLE DISEASE AND FOOT-AND-MOUTH DISEASE Exotic Newcastle Disease Exotic Newcastle disease (END) is a contagious and fatal disease affecting all species of birds. Previously known as velogenic viscerotropic Newcastle disease (VVND), END is one of the most infectious diseases of poultry worldwide. A death rate of nearly 100 percent can occur in unvaccinated poultry flocks. The virus is so virulent that many birds die prior to showing clinical signs, and END infection can have high mortality even in vaccinated birds (University of Georgia, 2003). END is classified as a foreign animal disease in the United States, historically causing severe economic losses when commercial poultry industries become infected, as occurred in a major outbreak of END in southern California in 1971. The disease threatened not only California poultry production, but it also had a significant economic impact on the entire U.S. poultry and egg industry. In all, 1,341 infected flocks were identified and 11.9 million birds were destroyed over a multiyear disease control effort. Disease eradication cost taxpayers $56 million (over $250 million in 2003 dollars), severely disrupted the operations of many producers, and increased the price of poultry and poultry products to U.S. consumers (Utterback, 1973; Davidson-York et al., 1998). It took 3 years to fully eradicate the disease, and nearly two decades before another outbreak of END occurred in U.S. commercial poultry. In the early 1990s, over 26,000 commercial turkeys were destroyed in North Dakota following detection of END. The virus is believed to have been transmitted to the turkeys from cormorants or other free-ranging birds. Hundreds of cormorants had previously died at a lake not far from the turkeys, in an outbreak that is believed to be the first documented Newcastle-related die-off of wild birds in the United States (Meteyer et al., 1997). Though END virus has not been detected in commercial birds in the United States since then, it is now known to exist in free-ranging wild birds, as well as in psitticine species. A variety of psitticine species enter the United States through the pet bird trade, generally traveling through USDA quarantine stations; however, illegal movements across U.S. borders also occur. END is detected nearly every year in California, primarily in psitticine and free-flying wild-bird species; however, in 1998, END was detected in urban gaming chickens in the state (Crespo et al., 1999). Subsequent to the 1971 outbreak, the presence of END has been detected numerous times through case submissions to the state’s diagnostic laboratory (passive surveillance), confirmed as END by the federal laboratory system, and rapidly

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases BOX 3-1 Animal Diseases Addressed in This Chapter Foreign Animal Diseases. Important transmissible livestock or poultry diseases that are largely absent from the United States and its territories and that have the potential to cause significant health or economic impact should the causative agent be introduced. Foreign animal diseases discussed in this chapter include: Exotic Newcastle disease (END) Foot-and-mouth disease (FMD) Recently Emergent Diseases. Infectious diseases for which the risk in animals has increased in the past two decades or threatens to increase in the near future. These diseases include: New infections resulting from changes or evolution of existing organisms or newly infectious particles (such as prions) Known infections spreading to new geographic areas or populations Previously unrecognized infections emerging in new geographic areas and human populations due to changing technologies and behaviors Old infections reemerging as a result of antimicrobial resistance in known agents or breakdowns in animal disease control measures. The recently emergent diseases addressed in this chapter are: Monkeypox Bovine spongiform encephalopathy (BSE) Previously Unknown Agents. Pathogens previously unrecognized that have recently (within the past decade) been transmitted from animals to humans. Included for discussion in this chapter: Severe acute respiratory syndrome (SARS) coronavirus eliminated by state regulatory authorities prior to spread of the disease (Molenda, 2003). Detection and Diagnostic Methods Despite the recognized and significant economic impacts of END introduction into the U.S. commercial poultry industry and the repeatedly observed risk of reintroduction in California, surveillance, detection, and diagnostic approaches were little changed in 2002 from those used in 1971. The accepted diagnostic standard was virus isolation in embryonated

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases Endemic Diseases. Animal-borne diseases that are native to or commonly found in the United States. Examples addressed here include: Avian influenza Chronic wasting disease West Nile virus While the committee recognizes that at one time these agents may have been considered as newly emergent, each of them has now become firmly established in North America and is considered endemic for the purposes of this report. Novel Naturally Occurring Pathogens. Organisms previously unreported or infrequently associated with being a primary pathogen in a given host species. Novel naturally occurring pathogens may contain new genomic elements acquired through natural processes and not as the result of in vitro insertion. Bioengineered Animal Pathogens. Organisms containing genomic elements that were acquired in vitro. Diseases of Toxicological Origin. Diseases caused by exposure to toxic substance(s), including drug residues, in a concentration that alone or in combination meets either of the following criteria: (1) the animal(s) affected is/are a potential source of toxicological contamination to humans or other animals and/or (2) the source of the toxicological agent or exposure is potentially hazardous to humans or other animals. eggs, a process requiring 2 to 7 days, followed by pathogenicity testing of the isolated virus by inoculation into chickens or direct nucleic acid sequence analysis of the virus’ pathogenicity marker. Isolation and characterization of the virus requires several days to several weeks, depending on the availability of eggs and experimental birds, access to containment and/or sequencing facilities, and technical resources at the federal laboratory. Though state and university veterinary diagnostic laboratories typically have virus isolation facilities with trained technical staff, consideration had not been given to using these resources; instead, the existing paradigm was for the federal laboratory to perform foreign animal dis-

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases ease testing. National technical training and proficiency evaluation for the isolation and characterization of foreign animal diseases, including END virus, did not exist, which limited possibilities for providing surge capacity needed in the face of an END outbreak. Proven technology that would allow surge capacity in the form of rapid and sensitive diagnostic assays had not yet been directed toward END detection, primarily because the U.S. Department of Agriculture (USDA) Cooperative State Research, Education, and Extension Service (CSREES), the major funding agency for animal health, discouraged allocation of competitive research dollars for projects solely targeting the development and validation of veterinary diagnostic assays. However, in response to heightened biothreat awareness in early 2002, the USDA, in cooperation with the Department of Homeland Security, created a list of eight high-risk agriculture pathogens (USAHA, 2003a). Included in the $14 million funding allocated to the USDA Agricultural Research Service (ARS) for developing rapid diagnostics for the high-risk agricultural pathogens was $2.8 million for two poultry pathogens included in the list: highly pathogenic avian influenza (AI) virus and END virus (USDA, 2002f; USDA ARS, 2002). Months later, prior to the development or availability of rapid detection assays in the United States (though rapid END diagnostic approaches were documented in the international literature), END was again found in game fowls in southern California (Nolen, 2002). The END outbreak illustrates the following findings: The animal health infrastructure lacked an analysis system for anticipating challenges to animal agriculture and a system for providing appropriate intervention or rapid detection strategies despite acknowledged risks of introduction of a high consequence pathogen into the United States. The existing infrastructure did not support timely development, validation, and implementation of state-of-the-art technologies for prevention, detection, and diagnosis of recognized and economically threatening pathogens. The 2002 END Outbreak The timing and movement of the END outbreak in 2002–2003 followed a pattern eerily similar to the 1971 outbreak (see Table 3-1). In late September 2002, a game chicken was presented to the state’s animal health laboratory by a private veterinary practitioner on behalf of a southern California game fowl owner that had lost 200 birds (90 percent mortality) over a 5-day period. Two days later a veterinarian in a neighboring county contacted the state laboratory to report high mortality in a small backyard

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases flock of laying hens. Within the previous 6 months, two unrelated companion animal bird submissions with confirmed END infections had been traced to origins in southern California. In all cases the laboratory suspected END virus, and samples were transported to the federal laboratory in Ames, Iowa, as required for confirmation of END (Humanitarian Resource Institute, 2004). The END viruses isolated in the spring and fall of 2002 had identical genomic sequences, suggesting the virus may have entered bird populations in southern California at least 6 months before the declared outbreak. By the time the initial game fowl cases were detected by passive surveillance in late September, the disease had spread throughout the urban population of game and noncommercial poultry in southern California. The size and significance of the urban poultry population had clearly gone unrecognized, and the social and cultural barriers to effective surveillance within that population had not been addressed. Within the first week of the outbreak response alone, more than 5,000 noncommercial birds were depopulated and 30 backyard flocks placed under quarantine in a three-county area. Ultimately, nearly 300,000 premises were visited during the outbreak, and 90,000 of them had avian species, primarily poultry. Though trade partners had been notified by USDA of the END detected in game chickens on October 1, 2002, a federal emergency was not declared until January 6, 2003, by which time virus had been detected in 5 of the ultimate 22 infected commercial poultry flocks (USDA APHIS, 2003b). Requests to the European Union for regionalization to protect U.S. trade and questions of federal and state authorities had, however, been initiated by USDA in late October and November (Rob Werge, personal communication, 2004). Heightened awareness of the disease resulted in the detection of END in neighboring Nevada game chickens in mid-January 2003, Arizona game chickens in early February, and an isolated incident of an unrelated END virus in Texas game chickens in early April. By the time the final END positive bird was detected 9 months later, 22 commercial premises and a total of 3.21 million birds had been depopulated at a cost of more than $160 million in federal control efforts. Up to 71 percent of USDA veterinary services staff—and a total of 7,690 state and federal employees—were recruited into the eradication effort (USDA APHIS, 2004a). Based on this review, the committee found: The existing animal health infrastructure was designed to detect and respond to disease in commercial agriculture production systems, and was not appropriate for nontraditional species, management, or environments, effectively delaying both detection and response activities. The lack of adequate surveillance for END, a foreign animal disease already known to enter the country periodically, allowed the virus to

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases TABLE 3-1 Timeline of 2002-2003 Exotic Newcastle Disease (END) Outbreak in Southern California 2002 March • Two unrelated companion animal birds diagnosed with END. Federal efforts trace origin of birds to Southern California.   September 25 • Index case END outbreak game fowl submitted to state diagnostic laboratory by private practitioner.   September 27 • Second case in backyard chickens submitted to state laboratory.     • Task force formed. Urban door-to-door disease eradication efforts begin.   October 1 • National Veterinary Services Laboratories (NVSL) confirms END virus. U.S. Department of Agriculture (USDA) notifies state veterinarians and trade partners. EU bans import of U.S. poultry.     • USDA transfers $7.4 million in funds from Virginia LPAI to END ($5 million for state, $2.4 million for USDA VS).     • Initial development of rapid diagnostic assay begins.   November • Prototype Real-time Reverse Transcriptase (RRT) Polymerase Chain Reaction (PCR) used in conjunction with virus isolation by state laboratory to detect END.   December 23 • First detection of END in a commercial flock, presumptive diagnosis by state laboratory using virus isolation and RRT PCR, officially confirmed December 21 by USDA testing.     • Secretary of Agriculture approves $121.8M fund request for END control. 2003 January • USDA declares extraordinary emergency.     • Prototype RRT PCR used in federal laboratory.     • END detected in Nevada game fowls (January 16, 2003). Nevada Task Force established. USDA declares extraordinary emergency for Nevada (January 17, 2003).     • E.U. and Mexico agree to regionalize United States, restricting trade only with California, Nevada, and Arizona.     • Arizona Task Force established due to proximity to California quarantine zones.   February 4 • Arizona game fowl confirmed positive for END.   February 7 • USDA declares extraordinary emergency for Arizona.     • Virus isolation (egg inoculation) reaches peak laboratory capacity at ~4,000 samples per month.   March • Last detection of END in a commercial poultry flock.

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases   April 9 • END detected in Texan game fowl.   April 10 • USDA declares extraordinary emergency for Texas and border state New Mexico.     • USDA reports genomic sequence of Texas isolate differs from outbreak virus indicating introduction not due to spread from California, Nevada, and Arizona.     • USDA officially validates USDA single-tube END RRT PCR. Test turn-around is 4–24 hours, laboratory capacity ~184 tests per day based on 3 cyclers and 3 technicians.   May • Final positive noncommercial bird detected.     • State laboratory initiates use of modified high-throughput RRT PCR. Test turn-around is 4–24 hours, laboratory capacity ~1900 samples per day.     • USDA lifts quarantines from all but original infection sites in Nevada and Arizona.   June • USDA lifts quarantine in Texas and New Mexico except for area around original positive premise.   July • Quarantines lifted from Arizona, Nevada, Texas, reduced areas in California.   August • E.U. lifts trade restrictions except for Southern Califonia, and original infection sites in Arizona, Nevada, and Texas.     • California and Mexico sign agreement for regional plan for prevention and mitigation of future END outbreaks.   September • USDA approves $9.476 million for END surveillance.     • USDA lifts California quarantine. Surveillance efforts directed toward avian health and mitigation continue.     • Mexico and Canada lift END-related trade restrictions. Final totals • 19,146 premises quarantined • 932 confirmed infected premises identified • 3.21 million birds depopulated in four states • $160 million in control costs • 7670 state and federal employees on the END task force spread and become established in a relatively large animal population before detection. In the absence of available rapid detection and diagnostic assays for END, the USDA and the state diagnostic laboratory, in a largely uncoordinated effort, initiated development of a molecular-based diagnostic ap-

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases proach to reduce from days to hours the time needed to obtain an END diagnosis. The federal approach was based on past experiences and successes with flock-based detection, while the state responded to the character of the current outbreak by focusing on high-throughput capacity and reliable detection in individual birds. Both groups used the established technology of real-time polymerase chain reaction (PCR). The state laboratory lacked significant fiscal resources specifically allocated for assay development and so relied on partnerships and collaborations with other federal agencies (such as the Department of Energy) and with commercial biotechnology equipment and reagent suppliers. The use of the extensive network of expertise located outside of the federal (and state) system allowed for timely development of a more cost-effective and rapid approach to detection and diagnosis of END, which was ultimately used on more than 81,000 samples during detection and control efforts by the state laboratory. The combination of real-time PCR with the high-throughput approach allowed a 10-fold increase in workload to more than 1,500 samples tested daily with results available within 4 to 24 hours, and is credited with supporting rapid and effective testing for disease eradication. The final END quarantines were lifted within 11 months of initial END detection in game fowls, despite earlier USDA Animal and Plant Health Inspection Service (APHIS) projections of a 3-year disease control effort (USDA APHIS, 2003c). The committee found the following: Private industry, local and regional resources, and the willingness to capitalize on expertise located outside the centralized federal animal health system allowed a more timely, cost-effective, and reliable assay to be developed, validated, and implemented for disease detection and control. Foot-and-Mouth Disease Foot-and-mouth disease (FMD) is a highly contagious viral disease of cattle, swine, and other cloven-hoofed species including sheep, goats, and deer. The disease is characterized by fever and blister-like lesions followed by erosions on the tongue and the lips, in the mouth, on the teats, and between the hooves. For some strains of the virus and host species, clinical signs of infection can be minimal or go clinically unrecognized. Most affected animals recover, but the disease can leave them debilitated and livestock herds can experience severe losses in production of meat and milk, providing the economic justification for including FMD virus among the OIE List A diseases (OIE, 2003). Pigs amplify most strains of FMD virus to high concentrations, so they transmit the disease readily, while cattle are generally considered the species most susceptible to infection. The virus can be transmitted readily to susceptible animals either by in-

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases gestion or inhalation of the virus from contagious animals or innate objects, such as contaminated vehicles, clothing, or feed or water. The virus is well known for its potential to spread widely and rapidly in the absence of obvious clinical signs that would trigger early detection and appropriate control measures. FMDV in the United Kingdom The United States has not had an incursion of FMD virus (FMDV) since 1929, but the devastating outbreak of FMD in the United Kingdom in 2001 (Box 3-2) has provided lessons about prevention, detection, and control of the disease in the United States. As in the United Kingdom, the United States does not permit the use of FMDV vaccine, creating a national population of FMDV-susceptible animals. Moreover, the United States has a large wildlife population—including feral swine, deer, and other susceptible cloven-hoofed animals—for which timely detection and prevention would be difficult, if not impossible. Establishment of infection in susceptible wildlife, such as feral swine, could result in widespread dissemination of the disease throughout the country. Prevention in both countries was and continues to be heavily reliant on federal policies restricting trade in animals and animal products from FMDV-endemic countries. Despite such policies, in early 2001 the FMDV entered the United Kingdom, most probably through an illegally imported meat product. By the time the disease was detected several weeks later, it had spread throughout the country and to as many as 79 premises primarily through animal movement (Mansley et al., 2003). Disease entry through import, either intentional or unintentional, is a similar risk for the United States, where a very small percentage of cargo and baggage is inspected. The USDA Safeguarding Review cites that 489 million passengers and pedestrians and 140 million conveyances crossed U.S. borders in 2000, and the review predicted this number to double in 2009 (NASDARF, 2001). In addition, approximately 38,000 animals were imported daily into the United States in 2000. The committee found that: FMD prevention, and disease prevention in general, through exclusion of infected animals and animal products cannot be relied on as infallible and would require a significantly more effective infrastructure than currently exists at U.S. borders and ports of entry. The lack of early detection following FMD virus introduction in the United Kingdom was responsible for the widespread dissemination of disease throughout the country and into neighboring countries (Haydon et al., 2004). Standard methods for testing clinical material (lesion swabs,

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases BOX 3-2 Foot-and-Mouth Disease Epidemic in Great Britain in 2001 On February 19, 2001, a routine inspection at an abattoir near London revealed “highly suspicious” signs of foot-and-mouth disease in 27 pigs. The Ministry of Agriculture confirmed the outbreak and the next day set up a 5-mile exclusion zone around the abattoir. With increasing numbers of FMD cases reported on cattle and sheep farms 5 days after the initial case, the government announced plans to slaughter pigs, sheep, and cattle in affected areas in an attempt to eliminate the disease. As the outbreak continued through the end of the month, the ban on movement of livestock was extended. By early March, neighboring countries had begun investigating their own suspected cases of FMD and enhanced precautionary measures were initiated to prevent FMD from entering their countries. The epidemic, however, extended beyond England to other European countries, with Scotland, Northern Ireland, France, Belgium, Denmark, Germany, and the Netherlands responding with programs to destroy animals in affected areas. At a meeting of European ministers on March 6, a proposal was made to extend the ban on British livestock exports until March 27. Veterinary experts recommended against mass vaccination, and the E.U. agriculture ministers concurred with their advice. Despite extensive efforts, the number of new unconfirmed cases reached 1,000 by the beginning of April. On April 26, the government announced a change in policy, ending the practice of slaughtering healthy, unaffected livestock on farms neighboring farms with animals showing suspicious signs. By May 8, restrictions on livestock movement were eased across the European Union. The British government killed 6.5 million animals during the epidemic: about 4 million for disease control and an additional 2.5 million for reasons of animal welfare. The epidemic lasted 214 days and involved over 10,000 herds and flocks. Annual festivals and international sporting events were cancelled due to the epidemic and tourism declined substantially. The epidemic incurred losses to agriculture and tourism estimated to be at least £6.3 billion. SOURCES: Thompson et al., 2002; Haydon et al., 2004. fluids, blood) from suspect animals, including virus isolation in cell culture and antibody detection by serum testing, were available in the United Kingdom and used with reportedly high accuracy. Had the government invested years earlier in the development of accurate and rapid real-time virus detection assays, it would have been very difficult for the govern-

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases cation programs were initially hindered by lack of defined USDA regulatory authority for endemic diseases and absence of an established indemnity program for the depopulated birds. In February 2004, prompted by the H5 avian influenza outbreaks in Southeast Asia, HHS and USDA officials cooperatively announced a ban on importation of birds from eight Asian countries. Globally, public health as well as animal health agencies have closely followed the appearance and movement in 2004 of H5 avian influenza viruses in poultry and are particularly concerned about its rapid spread through Asia, where acceptance or compliance with slaughter-based control efforts is considered not economically feasible or socially acceptable. The millions of affected birds, commingling of different avian and mammalian species, difficulty in protecting poultry workers from respiratory exposure, and the recognition of bird-to-human transmission have placed the global community on high alert for the potential evolution of a pandemic influenza virus. The committee drew the following conclusions regarding AI: Gaps in scientific knowledge, focused and applied research, understanding of disease risks, and lack of access to validated rapid detection methodologies have complicated and jeopardized effective and timely responses to AI. Lack of a standardized reporting mechanism among animal health agencies has delayed laboratory findings and epidemiological investigations. Though clearly defined for highly pathogenic avian influenza, the regulatory lines of authority are not defined for endemic (low pathogenecity) avian influenza, hindering the nation’s ability to prevent a potentially devastating disease situation. Chronic Wasting Disease As a prion-associated transmissible spongiform encephalopathy (TSE), CWD belongs to a group of diseases that merit careful study and monitoring (NRC, 2004a). Over a relatively short time span, CWD has become a major problem in some U.S. western and midwestern states, affecting both farmed and wild cervids, thus impacting the markets for farmed cervids and cervid products and for wildlife-related recreation and aesthetics. While there is no conclusive evidence to date that a CWD prion has caused naturally occurring disease in domestic animals or people, research needs to continue to determine whether this disease is a threat to other than cervid species (Belay et al., 2004).

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases Occurrence and Transmission CWD was first identified as a disease syndrome in 1967 in a mule deer in a research facility in Colorado that had been populated by wild deer captured in that state (Williams and Young, 1980). It is likely the disease existed in nature but went unrecognized. About 10 years later CWD was determined to be a TSE (Williams and Young, 1980; Williams et al., 2002; Belay et al., 2004). CWD occurs in free-ranging native elk, mule deer, and white-tailed deer and was first reported in northeast Colorado and southeast Wyoming in the 1980s. Its prevalence in this area over the period 1996–1999 was found to be about 5 percent in mule deer, 2 percent in white-tailed deer, and less than 1 percent in elk (Miller et al., 2000). Since 2002, the wider application of testing of hunter-killed or other animals has uncovered endemic loci of infected animals in western Colorado, Nebraska, New Mexico, South Dakota, Utah, Wyoming, Wisconsin, Illinois, and New York, and in Saskatchewan, Canada. The prevalence of CWD in endemic areas has been estimated to be less than 1 percent for elk and to vary from less than 1 percent to 15 percent for mule deer (Williams et al., 2002). CWD has been a major problem for the cervid farming industry. The first diagnosis on an elk farm occurred in South Dakota in 1997 and marked the beginning of more widespread testing (USDA APHIS-VS, 2005). Subsequently the disease has been found on a substantial number of game farms in other parts of the United States (Colorado, Kansas, Minnesota, Montana, Nebraska, New York, Oklahoma, and Wisconsin) and Canada (Alberta and Saskatchewan) (AVMA, 2005; Belay et al., 2004). It is reasonable to assume that CWD has been spread in large part through trade associated with the growth and development of the game farming industry. Spread from game farms to free-living cervids appears to have occurred in at least some but not all situations where game farms have been established. The widespread dissemination of CWD among game farms in Canada resulting from importation of infected elk is beyond dispute (Bollinger et al., 2004). However it occurred, CWD has emerged as an immediate and serious threat to wildlife resources that generally are highly prized by society and serve as the basis for substantial economic activity. Pathogenesis CWD is associated with the accumulation of abnormal prions in brain and lymphatic tissue. While not yet universally accepted, the “infectious” agent is believed to be an abnormal prion (Belay et al., 2004). The disease has a long incubation period, probably 15 months or more before the ap-

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases pearance of clinical signs (Belay et al., 2004). Affected animals lose weight and may show neurological signs. Definitive diagnosis is based on direct laboratory examination of brain or lymphatic tissue by immunodiagnostic techniques that can determine the presence of the agent in clinically normal animals as well as those showing signs. These tests are the basis of epidemiological surveys for prevalence of the disease in culled and hunter-killed animals. It is likely that CWD is transmitted among cervids by urine, feces, and saliva (Miller et al., 2004). The CWD agent remains infective in contaminated premises for at least 2 years and presumably this would also be true in the natural environment (Miller et al., 2004). No evidence suggests that other species can acquire CWD under natural circumstances or when housed in direct contact with affected deer or on contaminated premises. There is no known risk to humans from consuming meat from deer or elk, but prudence makes consumption of meat or nervous tissue from animals known to be infected unwise until more is known about this disease (Belay et al., 2004). APHIS has developed procedures to validate and approve testing procedures for diagnosing CWD. There is a danger of moving animals to new habitats in the absence of the means to certify their health with a high level of assurance or guarantee of their quarantine in the new location. The history of CWD illustrates that controlling the translocation of captive wildlife is of paramount importance in preventing the spread of wildlife disease. The national response to CWD has been guided since 2002 by a Plan for Assisting State and Federal Agencies and Tribes in Managing CWD in Wild and Captive Cervids (USDA APHIS, 2002), developed by a task force of federal and state wildlife management agencies. Subsequently a group representing a broad constituency of universities, professional organizations, and interest groups developed action items. The task force has directed attention to six broad areas of activity: communications, dissemination of technical information (including education), diagnostic methodology, disease management, research, and surveillance. Both USDA and DOI have provided funding for CWD programs (FYs 2003–2005). Implementation of the plan has been coordinated through the Multi-States CWD Working Group, U.S. Animal Health Association, and the International Association of Fish and Wildlife Agencies. The DOI (NPS, USGS, FWS) and USDA (APHIS, CSREES) have established interagency work groups to deal with specific issues. Interested nongovernment organizations have banded together to form the CWD Alliance to keep stakeholders appraised of developments. The formation of the CWD Alliance by conservation organizations and the development of its web site (www.cwd-info.org) have been particularly effective in pro-

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases viding a source for accurate information among nonexperts. Also, a substantial number of continuing education programs for biologists and others working on CWD have been developed or are in preparation by agencies involved in the Plan. Diagnosis Immunohistochemistry (IHC) tests of tissue samples remain the approved means for definitive diagnosis of CWD. ELISA based methods have been developed for screening samples more rapidly, but positives must be verified by IHC. Research continues on developing methods that could be used to diagnose infection in live animals or be more cost-effective. By April 2003, the NVSL had approved 26 university or state diagnostic laboratories to provide CWD testing, a number that accommodated demand prior to the onset of BSE surveillance. Currently the system is stretched to or somewhat beyond capacity, and additional laboratories may be approved. Prevention Steps are being taken to prevent or limit the spread of CWD. All 50 states and several federal and tribal agencies have conducted monitoring and management activities partially funded by APHIS through cooperative agreements. As of June 2004, 24 state wildlife management agencies adopted a policy set out in Multi-state Guidelines for Chronic Wasting Disease Management in Free-ranging White-tailed Deer, Mule Deer and Elk. The APHIS-proposed rule, Chronic Wasting Disease (CWD) Herd Certification Program and Interstate Movement of Captive Deer and Elk, is pending. Some states have put restrictions on baiting and feeding of free-ranging cervids. Experience in both the United States and Canada indicates that eradication of CWD in farmed cervids should be possible (Bollinger et al., 2004). On the other hand, containing CWD in free-living cervids and preventing its spread to contiguous regions free of the disease will be extraordinarily difficult (Gross and Miller, 2001). Of paramount importance is controlling the translocation of animals or infected material. It has been recognized this will require not only appropriate regulations, but also an educated public that will not be tempted to ignore restrictions on the movement of cervids. Containing CWD will require a well-coordinated management program supported by an aggressive research program that defines the population density, buffer zone size, and time required to render contaminated environments free of infectivity to arrest spread to contiguous areas. It

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases has been suggested that deer densities of less than 1 square kilometer of critical habitat will likely have to be maintained for prolonged periods of up to 10 years or more to create such buffer zones and prevent spread from endemic areas (Bollinger et al., 2004). Through an examination of CWD, the committee learned that: The infrastructure to detect, diagnose, and prevent wildlife diseases is an essential element in the nation’s framework for dealing with animal diseases and its consequences. In the past, it has been flawed by inadequate (1) coordination of relevant agencies, (2) diagnostic expertise, (3) research support, and (4) education and training of professionals. Experience with CWD, and other diseases of wildlife such as WNV or the pathogens they may harbor, such as avian influenza, has highlighted these deficiencies and provided the motivation to correct these inadequacies. In purely biomedical terms, the discovery of CWD has provided a research opportunity in comparative medicine for gaining greater insight into the pathogenesis of TSEs. The recent creation by the White House of an interagency working group on disease-causing prions to identify gaps in knowledge is timely. The spread of CWD, taken together with the history of the spread of raccoon rabies and of monkeypox, provides compelling contemporary evidence of the need for much more effective control of translocation of wild animals in preventing the spread of animal disease. It reaffirms an essential strategy for disease control that has been recognized since the establishment of the first U.S. national animal health agency, the Bureau of Animal Industry, in 1884. The translocation of wildlife, both indigenous and exotic, is fraught with every bit as much risk as translocation of domestic animals, especially since organisms that are symbiotic in wildlife may be pathogenic in people and/or domestic animals. West Nile Virus The introduction and rapid spread of WNV (caused by a single stranded RNA flavivirus) across the North American continent is a simple and powerful illustration of the growing importance of a zoonotic disease that is harbored and spread in wildlife in an increasingly interconnected world. The disease was first described in Uganda in 1937. Since that time it has become endemic in other parts of Africa, Southwest Asia, and Europe, where it appears to cause relatively few cases of disease in people, domestic animals (horses and geese), or wildlife. WNV appeared in New York in 1999 from an unknown source. By 2003 it had spread across the continent in a naive bird population that sustained the infection and allowed it to be spread by mosquitoes that

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases feed largely on birds. While WNV primarily infects birds, and while most species are apparently resistant, corvids are particularly susceptible and many died from the infection. Surveillance for the virus in dead crows proved to be a better indicator of looming human and animal infection than isolation of the virus from trapped mosquitoes or sentinel flocks of chickens. Humans and horses become infected when species of mosquitoes that feed on both mammals and birds (e.g., some Culex spp) are favored by climatic circumstances. About 80 percent of the people who become infected with WNV will have no symptoms and the vast majority of the remaining 20 percent will have mild disease symptoms (CDC, 2004e). Unfortunately, a few acquire encephalitis that can be fatal. In 2002 and 2003, WNV infected 15,300 and 5,200 horses in North America, respectively (USDA APHIS, 2004b). It can be expected that the disease will become entrenched permanently in some North American ecosystems. The industrial and research establishment in the United States responded to this outbreak by developing an effective vaccine to protect horses and a rapid screening test that provided for efficient and cost-effective presumptive diagnosis. The committee found that globalization brings increasing risk from diseases such as WNV that have hitherto not been present in the United States but are transmissible to people and domestic animals by wildlife. It is unlikely that all such diseases can be prevented from entering and staying in the country. North America has large, pristine, nonimmune populations of animal hosts, humans, multiple efficient and competent vectors, and a favorable environment for disease transmission and spread. The introduction of WNV became the key catalyst and final element needed to produce one of this country’s most significant epidemics. Every year since 1999 has led to new information about this epidemic. West Nile virus has an extremely broad host range replicating in birds, reptiles, amphibians, mammals, and numerous mosquito vectors. While WNV is primarily a vector-borne zoonotic disease that is maintained through a bird-to-bird transmission cycle via mosquito vectors, new information has also revealed that this flavivirus can be transmitted by other means: for example, contaminated blood products, organ transplantation, maternal transmission via breast milk and intrauterine, percutaneous exposure in a lab setting, and, at least experimentally, direct horizontal transmission between and among birds due to exposures via fecal shedding. The WNV epidemic is still evolving and not well understood. The recent recognition of a very large host range, numerous potential vectors, nonvector modes of transmission, and the potential movement into Central and South America via bird migrations has revealed that WNV is a much greater threat and more difficult to control than initially realized. There is every indication that WNV is becoming established as an en-

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases demic zoonosis and will be a permanent part of the animal and human medical landscapes in the United States and beyond for many years to come. The scope, scale, intensity, and consequences of this ongoing disease problem are unprecedented for an arbovirus (an arthropod-spread virus). WNV is a remarkable example of an emerging zoonosis that involves the dynamic and complex interface among domestic animals, humans, and wildlife species. The United States was an ideal setting for this epidemic, and the virus continues to adapt and move into new ecological settings that produce new selective pressures and exposures to new hosts and vectors that constantly change the nature of this disease. The final chapter on this disease has not been written because the story continues to unfold and will continue to do so in unprecedented ways. Important lessons to be learned from the WNV epidemic include the following: With the propitious epidemiological conditions for arboviruses in the United States, epidemic events can result in long-term endemic disease problems in multiple sites and species. The ease of spread of WNV also provides a living model and example of what a purposeful introduction of a vector-borne zoonotic disease might do. Rift Valley fever, for example, has epidemiological similarities to WNV that should be of serious concern. There is a need for a better understanding of most aspects of WNV, including its adaptations, environmental survival, host and vector range, and nonvector transmission modes. Ecology, wildlife dynamics, and epidemiology are among the scientific disciplines that need to be addressed by the animal health framework in the future. WNV offers further evidence that the veterinary profession and animal health organizations must develop the expertise, knowledge, and skills needed to address the implications of zoonotic diseases. The epidemic illustrates the need for strategic and collaborative partnerships between government agencies, and especially among animal and human health officials and communities. Those partnerships also need to extend globally. The confluences of human and animal health, along with wildlife, create new opportunities for pathogens to emerge and reemerge. Microbes will adapt, gain competitive ecological advantages, and threaten populations in novel and dangerous ways. WNV is a wakeup call to both human and animal health officials and organizations—it is a clarion suggesting that the past systems and operations in both of these communities will need to reconsider how and with whom they work.

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases NOVEL AND BIOENGINEERED PATHOGENS The past two decades have witnessed the evolution and emergence of new strains or entirely new groups of animal or human pathogens. Many of these are thought to have emerged from interspecies transmission or as variants of established strains with new tissue tropisms. In this respect, emergent RNA viruses are notorious because of the presence of quasispecies or “swarms of virus within a viral population,” high mutation rates due to lack of proofreading mechanisms for RNA polymerases, and the ability to generate genetic recombinant or reassortant viruses. Recent examples include the emergence of several RNA viruses in swine such as: The porcine respiratory and reproductive syndrome virus (PRRSV), an economically important arterivirus first isolated in 1991 in Europe and in 1992 in the United States, but with no known previous host and no prior serological evidence of previous infection detected in swine (Benfield et al., 1999). The porcine respiratory coronavirus (isolated in Europe in 1984 and the United States in 1989), an emergent virus that acquired a new tissue tropism (respiratory) and is a naturally occurring deletion mutant of TGEV, common, widespread swine intestinal coronavirus (Saif and Wesley, 1999). The porcine epidemic diarrhea virus (PEDV), a new group I coronavirus, which was reported initially in Europe in 1978 and in Asia in the 1990s as a major cause of diarrheal deaths in piglets, but still has not been detected in the United States (Pensaert, 1999). These new viruses appear to have emerged independently in swine in Europe and the United States, suggesting that they have separate evolutionary origins. Equally troubling was the recent emergence in Malaysia of the new swine RNA virus, the Nipah virus, a zoonotic paramyxovirus that was transmitted to humans, necessitating the precautionary slaughter of large numbers of pigs (Chua, 2003). This latter virus was acquired by swine through interspecies infections, presumably from fruit bats. The identification of these novel porcine viruses required the use of classical (EM, cell culture) virological techniques, as well as molecular approaches, such as reverse transcriptase-polymerase chain reaction (RT-PCR). If the challenge of diagnosing new, naturally occurring diseases were not already difficult enough, the prospect of identifying an intentionally-introduced recombinant (bioengineered) pathogen presents an even greater challenge. A bioengineered disease agent might, for example, be a chimera formed from unrelated pathogens that would confuse diagnostic

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases tests by causing multiple reactivities. Specific antigen sites or genetic regions of a pathogen could be masked or deleted so that serological or genetic tests would result in false negatives. Therefore, a broad array of diagnostic tests with a wide spectrum of agent detection capabilities may be required to identify both novel pathogens, whether naturally occurring or intentionally engineered. Identification of Novel Pathogens Classical virological techniques and the fulfillment of Koch’s postulates (for example, verifying a causative agent by using it to reproduce a similar disease syndrome in susceptible animal models) will remain important tools in disease diagnosis. However, rapid and unambiguous diagnostic tools are needed for early intervention in the event of a bioterrorism-related national crisis or for identifying novel pathogens. New molecular assays are evolving to meet those needs. For example, the SARS coronavirus was identified using microarray technology that targeted consensus regions of gene expression within distinct virus families (Ksiazek et al., 2003). Pathogen specific detection methods using gene probes derived by genome mining, in conjunction with target or signal amplification, can yield methods sensitive enough to detect just a few organisms in suspect materials. The same technologies in combination with sequencing or microarrays can aid in genotyping pathogens, specifically in the diagnosis of antimicrobial agent resistance (Hamels et al., 2001). Of particular interest are microarrays designed to enable detection of major classes and families of organisms based on intergenic and polymorphic loci. Once such classification has been worked out, family-specific arrays may be used to scan for homologies and major differences to identify new pathogens. Another example is the use of mass spectroscopy and high-performance liquid chromatography methods on whole microorganism (bacteria, viruses, and protozoa) extracts to define protein profiles that can be matched to an existing database of fingerprints. This may enable classification of organisms into major families that can be used to further design molecular probes for a finer degree of discrimination (Bernardo et al., 2002; Huang et al., 2002; Frazier et al., 2003). Rapid Monitoring of the Host Response to Pathogens Serology (monitoring serum antibody responses to pathogens) is important in assessing seroresponders and the seroprevalence of infections to determine levels of exposure of the populations. However, it is inadequate for rapid disease diagnosis because antibody development usually takes 2–3 weeks.

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases Recognition of the rapid response (hours or days) in immunomodulatory factors such as cytokines in the blood to various pathogens suggests that microorganism-specific cytokine tests may permit more rapid monitoring of host-specific responses. An example is the adoption of assays to monitor for mycobacteria-specific antigen-induced secretion of the cytokine interferon-gamma in blood mononuclear cells as a more rapid diagnostic assay than slower cultivation protocols (weeks) required for isolation of Mycobacterium bovis from cattle (Stabel, 1996). Such tests could also provide rapid data on new immunosuppressive pathogens, naturally occurring or bioengineered, by revealing significant decreases in certain cytokine levels. Another example is the recognition that some immunomodulatory factors (the cytokine IL-4) coexpressed with a virus may increase the virulence of certain viruses (mousepox) in the host (Jackson et al., 2001). Monitoring of a dramatically up-regulated single cytokine level could signal the presence of such a bioengineered pathogen-cytokine recombinant or guide treatment with antibodies to the relevant cytokine or counter-regulatory cytokines. Besides of diagnostic value, innate immune factors (such as cytokines and interferons) occurring early (hours or first days) after infection, and preceding the acquired immune responses, might be manipulated as treatment modalities to reduce or prevent infection of contact or susceptible animals. Early innate immunomodulator intervention strategies might block or reduce pathogen infection and shedding, decreasing transmission to other animals or making contact animals more resistant to infection. INTENTIONALLY INTRODUCED PATHOGENS AND DISEASES OF TOXICOLOGICAL ORIGIN Of course, an act of bioterrorism need not involve a bioengineered pathogen. The intentional spread of known microorganisms or microbial toxins can be accomplished using the same routes as accidental introductions, which occur when disease agents are brought to new areas via the movement of air and water, fomites, vectors, infected animals, or animal products. Currently, if naturally occurring, endemic agents were intentionally introduced into a new locale, investigatory agencies would be reliant solely on the pattern of outbreak to distinguish an attack, since there is currently no methodology to distinguish between intentionally versus accidentally introduced. The purposeful introduction of an exotic disease through channels of international commerce could also be disguised, since such an occurrence could as easily be the result of an accident as not. In the 2003 National Research Council report Countering Agricultural Bioterrorism, the Committee on Biological Threats to Agricultural Plants

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Animal Health at the Crossroads: Preventing, Detecting, and Diagnosing Animal Diseases and Animals offered advice about animal diseases and animal disease vectors that could be used as agents of agricultural bioterrorism. Because the report discusses themes that are relevant to both intentionally introduced and naturally occurring disease and the potentially devastating consequences of a failure of the animal health network, we have included the conclusions of the report as Appendix D. In addition to pathogens, toxins, chemicals, and radiological weapons might also be used to purposefully threaten animal health. These topics are outside the focus of this report. However, the committee acknowledges that toxic diseases (such as botulism and domoic acid) are an important concern for animal and human health. Diseases of toxicological origin present challenges different from those of other types of animal diseases. Domestic and wild animals are subject to toxins that occur naturally, for example in plants, or that are the result of human activity. Paralytic shellfish poisoning, domoic acid, Pfeisteria outbreaks, and related phenomena appear tied to coastal pollution and have the potential to make poisonous and inedible a growing proportion of the country’s protein food supply. Therefore toxicology is an essential element in any program addressing animal disease. SUMMARY The lessons of past disease outbreaks and the prospects of future epidemics suggest that the animal health framework faces a formidable challenge in preventing, detecting, and diagnosing the spectrum of animal diseases, some of which have direct consequences for humans as well as animals. The challenge is multifaceted and includes planning for outbreaks; conducting multidisciplinary research across species; developing new vaccines and rapid diagnostic tools; effectively using the broad capabilities of university, industry, state veterinary diagnostic laboratories; and ensuring that an appropriate and state-of-the-art infrastructure exists to accomplish diagnosis. More than ever, there is a need to develop strong connections between public health and animal health officials, both domestically and internationally, and to expand the scope of animal disease concern to include wild and exotic animals.