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Public Veterinary Medicine: Public Health Review of the highly pathogenic avian influenza outbreak in Texas, 2004 Angela M. Pelzel, DVM; Brian J. McCluskey, DVM, PhD, DACVPM; Aaron E. Scott, DVM, PhD, DACVPM

I

n February 2004, an HPAI virus was confirmed to have infected a flock of broiler chickens in Gonzales County, Texas. Subsequent epidemiologic investigation identified infected birds in 2 live-bird markets in the area of Houston, Tex; these markets had received birds from the index flock or birds that had been transported by the index flock manager. All infected premises were depopulated, cleaned, and disinfected. Disease surveillance standards were established to assess the potential for spread of this virus from the index flock. Surveillance testing in commercial and noncommercial poultry operations revealed no area spread of virus from the index flock. We believe that the effective control of this outbreak that limited the disease to the index premises and 2 live-bird markets was attributable to the preexisting plan for surveillance and control developed for use by the TPF in the event of identification of a notifiable AI virus outbreak; the rapid response of the TAHC to implement control procedures following identification of the index flock; the establishment and subsequent efforts of a joint USDA-TAHC task force in Gonzales, Tex; the ability of the TVMDL to rapidly and accurately test samples collected as part of the ongoing surveillance program; and the cooperation of commercial and noncommercial poultry operation managers and owners in surveillance testing of flocks. All quarantines and hold orders established during this outbreak were released by March 31, 2004. The purpose of this report is to provide an overview of the AI outbreak in Texas in 2004. The Disease Avian influenza affects most species of birds with a host range that may include other species such as pigs, humans, ferrets, tigers, leopards, and domestic cats.1-3 The most virulent AI strains frequently result in large numbers of deaths and severe illness in naïve poultry flocks with considerable economic consequences.4,5

From the USDA, Animal and Plant Health Inspection Service, Veterinary Services, 903 San Jacinto Blvd, Room 220, Austin, TX 78701 (Pelzel); and Centers for Epidemiology and Animal Health, National Surveillance Unit, 2150 Centre Ave, Building B, Fort Collins, CO 80526 (McCluskey, Scott). Address correspondence to Dr. Pelzel. JAVMA, Vol 228, No. 12, June 15, 2006

AI HPAI TPF TAHC TVMDL LPAI AGID rRT-PCR NVSL

ABBREVIATIONS Avian influenza High pathogenicity AI Texas Poultry Federation Texas Animal Health Commission Texas Veterinary Medical Diagnostic Laboratories Low pathogenicity AI Agar gel immunodiffusion Real-time reverse transcriptase PCR National Veterinary Services Diagnostic Laboratory

The disease is caused by an enveloped type A influenza virus of the family Orthomyxoviridae. Its genome includes 8 single-stranded linear segments of RNA. Further classification involves unique combinations of surface glycoproteins and categorizes the virus into 16 hemagglutinin subtypes (H1 through H16) and 9 neuraminidase subtypes (N1 through N9). The viruses are also distinguished by pathogenicity and classified as LPAI or HPAI viruses on the basis of the amino acid sequence at the cleavage site of the receptor binding protein or on the basis of their ability to cause disease in young chicks. The LPAI viruses may be any of the 16 H subtypes, whereas HPAI viruses are predominately of the H5 or H7 subtypes. The LPAI H5 and H7 viruses are of particular concern because of their potential for mutation into HPAI viruses.5,6 Recent changes to the Terrestrial Animal Health Code of the Office International des Épizooties (World Organization for Animal Health) combine all H5 and H7 AI viruses into a reportable category of notifiable AI. Because reporting of notifiable AI is an international issue, trading partners are rapidly informed of a disease outbreak and may stop all importation of poultry and poultry products from the country or region in which the outbreak occurs.7 Economic consequences of a prolonged or uncontrolled outbreak may be substantial. Many AI viruses are zoonotic and may cause disease in humans. The first reported direct transmission of an AI virus from birds to humans occurred in 1997 in Hong Kong, where 18 people were infected with an HPAI H5N1 virus; 6 of those patients died.8 Although Vet Med Today: Public Veterinary Medicine

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an AI virus does not spread efficiently from humans to humans, it has the potential to recombine with human transmission genes while maintaining its virulence. Thus, outbreaks of AI (particularly involving HPAI viruses) present a potential risk of human epidemic or pandemic disease.9 In birds, the virus is primarily spread via feces and respiratory discharges and may remain viable for long periods in tissues, manure, mucus, or water. Once infected, viral incubation is generally short and death may occur within 3 to 5 days of exposure. Clinical signs include signs of severe depression, inappetence, drastic decline in egg production, and facial edema with swollen and cyanotic combs and wattles. Sudden deaths (mortality rate can reach 100%) may be the only evident clinical sign. For a definitive diagnosis, virus isolation is required to rule out similar avian diseases such as exotic Newcastle disease.10 Outbreaks of AI occur sporadically in the United States in commercial poultry flocks and are managed on an individual basis. Control measures include depopulation or controlled marketing of infected flocks; biosecurity enhancements; public outreach campaigns; and, in some instances, the use of inactivated vaccines. An H7N3 killed-virus vaccine was successfully used to control and eradicate an LPAI H7N2 outbreak in a layer flock in Connecticut in 2003 and 2004.a History Focal outbreaks of AI are not uncommon in the United States. In regions located in the northeastern United States, many of the outbreaks involving LPAI viruses have been linked to an H7N2 subtype that has been circulating within the northeastern US livebird market system (Table 1).11-13,b In addition to the outbreaks linked to the northeastern live-bird market system, several other recent outbreaks involving LPAI viruses have occurred in Minnesota in 2000 and 2002 (associated with H1N1),c California in 2000 to 2002 (associated with H6N2),14 and Pennsylvania in 2004 (associated with H2N2).b Prior to the identification of HPAI H5N2 virus in Gonzales, Tex, the most recent outbreaks of AI in Texas had been 2 separate LPAI H5N3 outbreaks in 2002 that occurred in Weimar and Carmine. It is the HPAI H5N2 outbreak in Gonzales in 2004 that will be described in this report in detail.

The AI Outbreak in Texas in 2004 Because of increased death loss (approx 3% death loss) and signs of respiratory disease among a flock of approximately 6,600 broilers in a commercial facility, chickens were submitted by the owner to the TVMDL for diagnostic evaluation. The operation was located in Gonzales County, Texas, and the owner supplied birds to live-bird market retail premises in Houston, Tex (Figure 1). On February 16, 2004, the initial diagnosis of AI virus infection was made on the basis of results of a chromatographic immunoassayd and AGID and rRTPCR procedures. On February 23, 2004, the USDANVSL reported that an AI virus, subtype H5N2, was isolated from specimens collected from the index infected premises in Gonzales; the same H5N2 virus was subsequently isolated from 1 of the 2 infected livebird markets in Houston. The amino acid profile at the hemagglutinin cleavage site in this virus was compatible with that of HPAI viruses. On March 1, 2004, the results of a chicken inoculation test to assess the pathogenicity of the isolated virus were reported; because there had been no illness or deaths among the chickens during the 10-day challenge, the pathogenicity index was zero. However, on the basis of the amino acid sequencing result, the virus was still considered highly pathogenic. The deaths that occurred in the index flock were likely a result of concurrent infection of birds with both AI virus and Mycoplasma gallisepticum (a bacterial pathogen of the respiratory tract), which was confirmed by laboratory results at the TVMDL. The index flock consisted only of chickens (colored straight-run broiler stock) that were raised for retail in live-bird markets in Texas. The birds originated from a Texas hatchery and were placed on the farm as 1-day-old chicks in multiple batches between November 11 and December 12, 2003. Vaccinations against Newcastle disease, bronchitis, and fowl pox were given at 6 weeks of age. The index farm had 4

Table 1—Outbreaks of H7N2 AI virus infection associated with live-bird markets in the northeastern United States in 1996 through 2004. Year or period 1996–1998 2001 2001–2002 2002 2003 2004

States involved Pennsylvania Connecticut Pennsylvania Virginia, West Virginia, and North Carolina Connecticut Delaware and Maryland

No. of flocks* No. of birds† 21 1 7

2.7 million 16,000 80,000

197 4 3

4.7 million 3.9 million 410,000

*Includes infected and contact flocks. †Total number of birds depopulated in infected and contact flocks.

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Figure 1—Map of Texas illustrating the location of Gonzales County, where the index farm of 6,600 broiler chickens in which infection with HPAI H5N2 virus was identified in February 2004 was located. (Map produced by USDA Centers for Epidemiology and Animal Health, Center for Emerging Issues, Fort Collins, Colo.) JAVMA, Vol 228, No. 12, June 15, 2005

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poultry houses on the property that had contained turkeys approximately 1.5 years previously. The chickens were placed in 2 houses (designated 2 and 4), whereas the other 2 houses (designated 1 and 3) remained empty. The owner detected increased death loss and signs of respiratory tract disease in the birds located in house 4 on February 16, 2004; some of these birds were submitted to the TVMDL in Gonzales for diagnostic evaluation. Although M gallisepticum infection was present in birds from both houses, AI virus infection was detected only in birds from house 4. The sharp increase in deaths between February 16 and 18, 2004, suggested that the AI virus had been recently introduced into house 4. Records of flock deaths from house 4 and an assumption that the viral incubation period was 3 to 5 days were used to estimate the onset of the infection. Given that approximately 2 to 3 incubation cycles were needed to amplify the virus to the level that was in effect between February 16 and 18, it was estimated that introduction of virus into the flock had occurred between February 2 and 11, and the most likely exposure date (median of the range) was February 5 through 8, 2004. Although all 4 houses once housed turkeys and none of the houses appeared to have been cleaned and disinfected prior to placement of the chickens, it was ultimately only the chickens in house 4 that became infected with H5N2 virus. The turkeys were unlikely to have been the source of the infection because of the period of time (approx 1.5 years) that the houses remained empty prior to placement of the chickens, the sudden increase in flock mortality rate, and the lack of AI virus infection in house 2. Our epidemiologic investigation suggested that the infection was likely introduced directly into house 4 through an unusual situation in which birds from the index farm were briefly exposed to circulating virus at one of the infected Houston live-bird markets and then returned to house 4 on February 5, 2004. This unusual exposure as the potential virus source is discussed in further detail in a later section of this report. State and USDA Responses Prior to February 23, 2004, there was no indication that the AI virus associated with this outbreak was highly pathogenic. Therefore, the immediate response was guided by the existing response plans of the TAHC and TPF. The TPF has been overseeing an ongoing active serologic surveillance program in participating commercial poultry operations since March 1995. Within the plan for the ongoing surveillance program, there are guidelines provided for response by the TAHC including surveillance of noncommercial poultry operations following the identification of an H5 or H7 type AI virus in Texas. Although participation in the TPF’s ongoing surveillance program is voluntary, response by the TAHC to a confirmed notifiable AI virus outbreak is mandatory. The response plan guidelines include depopulation of the infected flock, movement restrictions on all flocks located ≤ 8 km (< 5 miles) from the infected flock, surveillance testing of all flocks located ≤ 16 km (< 10 miles) from the infected flock, movement restrictions on and surveillance JAVMA, Vol 228, No. 12, June 15, 2006

testing of all flocks linked epidemiologically to the infected flock, and cleaning and disinfection of the infected premises. In commercial flocks participating in the TPF’s voluntary program, ongoing routine surveillance includes performance of approximately 175,000 AGID tests/y for both routine slaughter surveillance and egg yolk serologic surveillance. Sampling is designed to represent all geographic areas, and all surveillance samples are analyzed at the TVMDL. Broilers and turkeys are examined as they are removed from production. At least 25% of all flocks (minimum of 15 birds/flock) are tested on the broiler and turkey farms prior to their movement to slaughter. Commercial layer flocks are monitored every 30 days via analysis of ≥ 15 eggs/house from ≥ 50% of all poultry houses. Every 60 days, a minimum of 20 birds in all commercial immature and mature flocks of layer, broiler, and turkey breeders are tested. The costs of this monitoring program are paid by participating companies, and all sample collection and submission is performed by designated poultry servicemen employed by the commercial poultry company. The index flock in this outbreak was not a participant in the active serologic surveillance program. On disclosure of H5 AI virus infection, the index flock was depopulated by TAHC personnel and the carcasses were buried on-site. The premises were then thoroughly cleaned and disinfected. On February 23, 2004, NVSL reported that the H5N2 virus isolated from the index farm had an amino acid sequence at the hemagglutinin cleavage site that was compatible with HPAI virus. At this time, a joint USDA-TAHC task force in Gonzales, Tex, was established, which was responsible for the epidemiologic investigation and the surveillance plan that was implemented. Blood samples were immediately collected from birds on all premises that contained domestic avian species and were located ≤ 16 km from the index flock, and sera were tested for AI via AGID; all results were negative. Through epidemiologic investigation, 2 live-bird market retail premises in Houston, Tex, that had received birds from the index flock were identified. Avian influenza virus infection was detected in birds at both retail premises via AGID and rRT-PCR procedures; these sites subsequently underwent depopulation, cleaning, and disinfection. Virus isolation was successful in samples from only 1 of the 2 infected markets; the virus isolated from that market had the same genotype as the virus isolated from the index farm. At the time of the outbreak, there were 5 live-bird markets in the Houston area of Texas. Live-bird market retail operators in Houston sell only birds that are slaughtered on-site, and none are sold live from the premises to consumers. The 2 infected live-bird markets were located in an industrial area of Houston that had no farms nearby. Area surveillance within 2 miles surrounding the infected markets was conducted, and only 2 premises were identified as having resident domestic poultry. All samples from poultry on those premises yielded negative results for AI virus via AGID and rRT-PCR procedures. Although there was no evidence of exposure or infection in the remaining 3 Vet Med Today: Public Veterinary Medicine

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Houston live-bird markets, those markets were voluntarily depopulated, cleaned, and disinfected as a precautionary measure and as a show of good faith by the market owners to prevent the noninfected markets from profiting from the temporary closure of the infected markets. All known suppliers of birds to the Houston retailers were identified and issued hold orders; samples were collected from their premises, and all yielded negative results for AI virus via AGID and rRT-PCR assays. All other premises with epidemiologic links to the index premises were issued hold orders; samples were also collected from those premises, and all yielded negative results for AI virus via AGID and rRT-PCR assays. A surveillance plan was implemented by the joint USDA-TAHC task force during the week after identification of the index case, which established the following 3 distinct zones with varying intensities of surveillance: an affected zone that included the area within a radius of 8 km from the index flock; a surveillance zone that included the area that was located 8 to 16 km from the index flock; and a buffer zone that included the area that was located 16 to 50 km (31 miles) from the index flock (Figure 2). The plan included baseline serologic evaluation (via AGID) of all flocks of gallinaceous birds and analysis (via rRT-PCR assay) of cloacal swabs collected from all domestic waterfowl residing within a 16-km radius of the index premises (in the affected and surveillance zones). After the initial baseline testing, a 4-week schedule of weekly surveillance testing in the

affected and surveillance zones was established; this involved evaluation (via AGID) of sera and analysis (via rRT-PCR assays) of tracheal and cloacal swabs collected from birds. In week 1 (March 1 through 7), sera and swabs collected from birds in the affected and surveillance zones were analyzed. In weeks 2 (March 8 through 14) and 3 (March 15 through 21), swabs collected from birds in the affected zone were analyzed, whereas in week 4 (March 22 through 28), swabs collected from birds in the affected and surveillance zones were analyzed. Tracheal and cloacal swab samples were each pooled (as many as 5 birds/sample). A sample size for each of the premises or poultry houses was calculated to provide 95% confidence of detecting the disease if it were in the flock at a prevalence of 25%. Because of the highly contagious nature of most HPAI viruses, this was considered adequate for flocks; however, the population-sampling plan was designed to identify and test a census of flocks. In addition to the testing of samples collected from birds in the affected and surveillance zones, the surveillance plan outlined evaluation of all commercial flocks and all backyard flocks located ≤ 1.5 km (< 0.9 miles) from the commercial flocks in the buffer zone. Tracheal and cloacal swabs were collected from birds in the buffer zone for analysis via rRT-PCR assay during weeks 3 and 4. Overall, 39 premises in the affected zone, 167 premises in the surveillance zone, and 162 premises in the buffer zone were evaluated. Samples were collected from 368 premises within the 3 zones

Figure 2—Map of area surveillance zones initiated around the index farm in Gonzales County, Texas, in response to diagnosis of HPAI H5N2 virus infection in the index flock. All flocks in the affected zone were placed under movement restrictions. Surveillance was conducted in all flocks located in the affected and surveillance zones. In the buffer zone, surveillance was conducted on commercial flocks and any flocks that were located within a 1.5-km radius of a commercial flock. To convert kilometers to miles, multiply by 0.62. (Map reproduced with permission. Copyright: 2005 DeLorme [www.delorme.com]) Street Atlas USA.) 1872


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and 8 suppliers that were epidemiologically linked to the live-bird markets; 3,608 individual AGID tests and 3,685 rRT-PCR assays on pooled swab samples were performed. All samples yielded negative results for AI virus regardless of diagnostic procedure used. Increased serologic surveillance was continued in all commercial flocks in Texas for 3 months following the resolution of the outbreak. A comprehensive public information campaign that involved a variety of distribution methods to alert and inform livestock industry personnel and the public about the outbreak, the disease, and biosecurity protocols was launched. Feed stores located within a 50-km radius of the index premises were visited and provided display materials and fact sheets (in both Spanish and English) pertaining to AI virus infection. Informational updates along with AI and biosecurity fact sheets were distributed via a TAHC e-mail database (> 20,000 recipients) that included media outlets, government agencies, private and public stakeholders, school professionals, and veterinarians. Regular mail was also used to provide information to livestock trade associations and private veterinary practitioners. Movement Restrictions Movement controls were initiated on all flocks within the affected zone. These flocks were visited initially for surveillance testing (as described previously) and were visited weekly for sample collection and to review numbers of birds for the hold orders. Four additional flocks that were epidemiologically linked to the index premises by bird movements and the 8 suppliers of birds to the infected live-bird markets were similarly placed under hold order and monitored weekly. All 5 live-bird markets in the Houston area of Texas, including the 2 infected markets, were placed under hold order, depopulated, cleaned, and disinfected. The infected markets were additionally placed under quarantine, as was the index site. After allowing controlled repopulation under approved protocols, inspectors visited the markets a minimum of once per week to review records, permits, and compliance. Premises that were located outside the affected zone were allowed to move birds but were inspected and monitored according to the surveillance plan. Laboratory Diagnosis For baseline serologic evaluation of gallinaceous birds, an AGID test for AI virus that adhered to the Office International des Épizooties recommended protocol was used.15 The AGID targets viral matrix protein and is a sensitive detector of previous exposure of a bird to the AI virus. Because it is a serologic test, it would not be expected to identify recent infections of birds that had not resulted in development of an adequate antibody response to the virus. Repeated surveillance testing and analysis of tracheal and cloacal swab samples via rRT-PCR assay removed this concern. Agar gel immunodiffusion does not differentiate between different subtypes of AI virus and is therefore not a specific test; samples that yielded positive results via AGID were further examined by hemaglutination inhibition techniques to characterize virus subtypes. JAVMA, Vol 228, No. 12, June 15, 2006

An rRT-PCR procedure involving primers that target the viral matrix protein was used according to the NVSL protocol for analysis of tracheal swab samples collected from gallinaceous birds and cloacal swabs collected from waterfowl during the continued 4-week surveillance period.16 An rRT-PCR assay involving primers specific for the hemagglutinin antigen was used in some instances to identify the AI virus subtype. Virus isolation was performed on samples from the index farm and the 2 infected live-bird markets that yielded positive results via rRT-PCR assay. Virus isolation and amino acid sequencing of the virus were used to confirm the diagnosis of HPAI virus infection. Additionally, isolates were inoculated into 4- to 8week-old chicks to determine the pathogenicity index of the virus. Although the virus was identified as highly pathogenic on the basis of results of amino acid sequencing, findings of chick inoculation suggested that the isolates were nonpathogenic. International Impacts On disclosure of HPAI virus infection in Texas, at least 44 countriese imposed import restrictions on either Texas or US-origin poultry or poultry products. As of August 2005, there were still 15 countries imposing import restrictions on poultry or poultry products as a result of AI in Texas. The USDA Economic Research Service estimated that the value of all poultry and poultry products that were produced and exported from Texas was $123 million in 2002, which represented 5.4% of the total value of US exports of poultry and poultry products in that year. Although no economic impact analysis on the effect of the 2004 outbreak has been done, it can be extrapolated that the US poultry industry may have lost hundreds of millions of dollars or more because of the closure of export markets following the HPAI outbreak in 2004. Hypothesis Regarding Virus Source Despite a thorough epidemiologic investigation, the source of the virus was not definitively identified. However, all evidence points to sustained virus circulation within 1 specific live-bird market in the Houston area of Texas and a unique situation in which the virus was transferred back to the facility of one of the livebird market suppliers, which was labeled during the outbreak as the index farm. Although results of diagnostic evaluations indicated that birds from all other known suppliers of the infected live-bird markets were negative for AI virus, there were several 1-time suppliers who delivered birds in the months prior to the outbreak and for which the market was unable to provide names or contact information; therefore, those source flocks could not be tested. One of these unknown suppliers likely supplied infected birds to the market sometime in the past, which resulted in sustained circulation of the virus among the dynamic bird population housed at the market. This viral circulation would have gone unnoticed at the market because the H5N2 virus isolated from the infected premises caused no deaths among healthy birds, as determined at the NVSL. Vet Med Today: Public Veterinary Medicine

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During the investigation, it was identified that an unusual contact occurred between the infected livebird market and birds from the index farm, which could have resulted in disease transmission. Within 1 week prior to the occurrence of high numbers of deaths in the index flock, the index farm manager transported 600 birds to the infected live-bird market. The manager of the market indicated that the birds were smaller than the optimal size, but because the market was understocked, any available birds were potentially acceptable. The market manager had been handling birds in the market all day and, without adequate biosecurity precautions, chose to personally remove each bird from the transport load by hand and determine which birds were large enough to be kept and which would be rejected from the order. There were approximately 300 birds selected from the load to remain at the market, and the remaining 300 birds were individually reloaded onto the trailer, transported back to the index farm, and replaced into the only poultry house on the farm that was later found to be infected (house 4). This action of returning birds from the market to the farm of origin is not a normal occurrence and may have resulted in transmission of disease back to the farm. The second Houston live-bird market that was later found to be infected had received a shipment of birds from the index farm several days after the exposed birds had been returned to the farm during the aforementioned unusual movement. Although the birds at the first market were infected with AI virus (determined on the basis of AGID and rRT-PCR assay findings) but were without clinical signs of disease, there was a high mortality rate among birds on the index farm in house 4. The high number of deaths was attributable to concurrent infection of birds in house 4 with both AI virus (determined on the basis of findings of AGID, rRT-PCR assay, and virus isolation) and M gallisepticum (determined on the basis of results of M gallisepticum plate tests performed at the TVMDL). Overview In this outbreak, AI H5N2 virus transmission appears to have been limited to the index farm and 2 live-bird markets in the area of Houston, Tex. The livebird market system in Texas is limited in size and complexity, compared with similar systems in other areas of the United States. Presently, there are 5 retailers in the Houston area and 1 in the Fort Worth area that deal with 8 routine suppliers and additional occasional suppliers. All birds entering the live-bird market system originate in the immediate geographic area of the retailers, and there are no known sources from out-ofstate operations. The 3 infected premises (the index farm and 2 markets) were identified and depopulated within 6 days of the first laboratory report of confirmed AI virus infection and before the AI virus was classified as highly pathogenic. Samples were collected from premises that participated in the live-bird market system during the response phase of the outbreak and weekly during the 4-week surveillance period; all samples yielded negative results for AI virus via diagnostic procedures. 1874


Intensive sample collection from premises housing birds in the 50-km surveillance area surrounding the index premises was performed, and subsequent analyses revealed that there was no area spread of AI virus. During the response phase of the incident and weekly during the 4-week surveillance period, samples were collected from all premises housing birds that were located ≤ 8 km from the index premises; AI virus was not identified in these samples. During the immediate response phase of the incident and during weeks 1 and 4 of the surveillance period, samples were collected from all premises housing birds that were located 8 to 16 km from the index premises; similarly, AI virus was not identified in these samples via diagnostic procedures. All noncommercial premises housing birds that were located 16 to 50 km from the index premises and ≤ 1.5 km from commercial premises were evaluated once during the last 2 weeks of the surveillance period, and AI virus was not identified at any site. We believe the effective control of this outbreak that limited the disease to the index premises and 2 live-bird markets can be attributed to the following factors: ' Availability of a preexisting plan for surveillance and control that had been developed for use by the TPF in the event of identification of a notifiable AI virus outbreak. ' Rapid response of the TAHC to implement control procedures following identification of the index flock. ' Establishment of a joint USDA-TAHC task force in Gonzales, Tex. ' Ability of the TVMDL in Gonzales and College Station, Tex, to rapidly and accurately analyze surveillance samples. ' The cooperation of commercial and noncommercial poultry operation managers and owners in surveillance testing. Overall, early detection of infection in a flock and rapid response to that infection are the key elements that lead to the successful control of an HPAI outbreak. a. Smith W, USDA, APHIS, Veterinary Services, Riverdale, Md: Personal communication, 2004. b. Senne D, USDA, National Veterinary Services Laboratory, Ames, Iowa: Personal communication, 2004. c. Halvorson DA, University of Minnesota, Saint Paul, Minn: Personal communication, 2004. d. Directigen EZ Flu A+B lateral flow test kit, Becton-Dickinson, Franklin Lakes, NJ. e. Argentina, Azerbaijan, Brazil, Chile, China, Colombia, Costa Rica, Cuba, Czech Republic, Egypt, Estonia, European Union, French Polynesia, Guatemala, Hong Kong, Hungary, Iceland, India, Indonesia, Japan, Jordan, Kazakhstan, Latvia, Lithuania, Malaysia, Mexico, New Caledonia, Nicaragua, Peru, Philippines, Poland, Qatar, Romania, Russia, Saudi Arabia, South Africa, South Korea, Sri Lanka, Taiwan, Thailand, Turkey, Ukraine, United Arab Emirates, and Uzbekistan.

References 1. Capua I, Alexander DJ. Avian influenza and human health. Acta Trop 2002;83:1–6. 2. Keawcharoen J, Oraveerakul K, Kuiken T, et al. Avian influenza H5N1 in tigers and leopards. Emerg Infect Dis 2004;10: 2189–2191. JAVMA, Vol 228, No. 12, June 15, 2006

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3. Kuiken T, Rimmelzwaan G, van Riel D, et al. Avian H5N1 influenza in cats. Science 2004;306:241. 4. Alexander DJ. A review of avian influenza in different bird species. Vet Microbiol 2000;74:3–13. 5. Easterday BC, Hinshaw VS, Halvorson DA. Avian influenza. In: Calnek BW, ed. Diseases of poultry. 10th ed. Ames, Iowa: Iowa State University Press, 1997;583–605. 6. OIE (World Organization for Animal Health) Web site. Manual of diagnostic tests and vaccines for terrestrial animals. Available at: www.oie.int/eng/normes/mmanual/A_00037.htm. Accessed Jul 29, 2005. 7. OIE (World Organization for Animal Health) Web site. Terrestrial Animal Health Code 2005, Avian Influenza. Available at: www.oie.int/eng/normes/mcode/en_chapitre_2.7.12.htm. Accessed Jul 29, 2005. 8. CDC Web site. Instances of avian influenza infection in humans. Available at: www.cdc.gov/flu/avian/gen-info/avian-fluhumans.htm. Accessed Feb 28, 2006. 9. Kaye D, Pringle CR. Avian influenza viruses and their implication for human health. Clin Infect Dis 2005;40:108–112. 10. OIE (World Organization for Animal Health) Web site. Technical disease cards: highly pathogenic avian influenza. Available

at: www.oie.int/eng/maladies/fiches/a_A150.htm. Accessed Jul 29, 2005. 11. Davidson S, Eckroade RJ, Ziegler AF. A review of the 1996–1998 nonpathogenic H7N2 avian influenza outbreak in Pennsylvania. Avian Dis 2003;47(suppl 3):823–827. 12. Lu H, Dunn PA, Wallner-Pendleton EA, et al. Investigation of H7N2 avian influenza outbreaks in two broiler breeder flocks in Pennsylvania, 2001–2. Avian Dis 2004;48:26–33. 13. Akey BL. Low-pathogenicity H7N2 avian influenza outbreak in Virginia during 2002. Avian Dis 2003;47(suppl 3): 1099–1103. 14. Castellan DM. Low pathogenic H6N2 avian influenza in California, in Proceedings. 106th Annu Meet U S Anim Health Assoc 2002;532–534. 15. OIE (World Organization for Animal Health) Web site. Manual of diagnostics tests and vaccines for terrestrial animals, 2004: avian influenza. Available at: www.oie.int/eng/normes/mmanual/A_00037.htm. Accessed Oct 21, 2005. 16. Spackman E, Senne DA, Myers TJ, et al. Development of a real-time reverse transcriptase PCR assay for type A influenza virus and the avian H5 and H7 hemagglutinin subtypes. J Clin Microbiol 2002;40:3256–3260.

Palatability: Palatability trials conducted in 244 dogs from 10 different U.S. veterinary practices demonstrated that INTERCEPTOR Flavor Tabs were willingly accepted from the owner by over 95% of dogs. Efficacy: INTERCEPTOR Flavor Tabs eliminate the tissue stage of heartworm larvae and the adult stage of hookworm (Ancylostoma caninum), roundworms (Toxocara canis, Toxascaris leonina) and whipworm (Trichuris vulpis) infestations when administered orally according to the recommended dosage schedule. Precautions: Do not use in puppies less than four weeks of age and less than two pounds of body weight. Prior to initiation of the INTERCEPTOR Flavor Tabs treatment program, dogs should be tested for existing heartworm infections. Mild, transient hypersensitivity reactions manifested as labored respiration, vomiting, salivation and lethargy may occur after treatment of dogs carrying a high number of circulating microfilariae. Brief Summary: Please consult full package insert for more information. Caution: U.S. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Indications: INTERCEPTOR® (milbemycin oxime) Flavor Tabs® are indicated for use in the prevention of heartworm disease caused by Dirofilaria immitis, the control of adult Ancylostoma caninum (hookworm), and the removal and control of adult Toxocara canis, Toxascaris leonina (roundworms) and Trichuris vulpis (whipworm) infections in dogs and in puppies four weeks of age or greater and two pounds body weight or greater. Dosage: INTERCEPTOR Flavor Tabs are given orally, once a month, at the recommended minimum dosage rate of 0.23 mg milbemycin oxime per pound of body weight (0.5mg/kg). Recommended Dosage Schedule for Dogs Body Weight

INTERCEPTOR

2-10 lbs.

One tablet (2.3 mg)

11-25 lbs.

One tablet (5.75 mg)

26-50 lbs.


51-100 lbs.


Dogs over 100 lbs. are provided the appropriate combination of tablets. Administration: INTERCEPTOR Flavor Tabs are palatable and most dogs will consume the tablet willingly when offered by the owner. As an alternative, the dual-purpose tablet may be offered in food or administered as other tablet medications. Watch the dog closely following dosing to be sure the entire dose has been consumed. If it is not entirely consumed, redose once with the full recommended dose as soon as possible. INTERCEPTOR Flavor Tabs must be administered monthly, preferably on the same date each month. The first dose should be administered within one month of the dog’s first exposure to mosquitoes and monthly thereafter until the end of the mosquito season. If a dose is missed and a 30-day interval between dosing is exceeded, administer INTERCEPTOR Flavor Tabs immediately and resume the monthly dosing schedule.

Adverse Reactions: The following adverse reactions have been reported following the use of INTERCEPTOR: depression/lethargy, vomiting, ataxia, anorexia, diarrhea, convulsions, weakness and hypersalivation. Safety: In well-controlled clinical field studies 786 dogs completed treatment with milbemycin oxime. Milbemycin oxime was used safely in animals receiving frequently used veterinary products such as vaccines, anthelmintics, antibiotics, steroids, flea collars, shampoos and dips. Studies in heartworm-infected dogs demonstrated mild, transient hypersensitivity reactions in dogs with high microfilaremia counts. Safety studies in pregnant dogs given an exaggerated dosing regimen, resulted in measurable concentrations of the drug in milk. Puppies nursing these females which received exaggerated dosing regimens demonstrated milbemycin-related effects. Subsequent studies included using 3X daily from mating to one week before weaning and demonstrated no effects on the pregnant females or their litters. A second study where pregnant females were dosed once at 3X the monthly use rate either before, on the day of or shortly after whelping resulted in no effects on the puppies. Some nursing puppies, at 2, 4, and 6 weeks of age, given greatly exaggerated oral INTERCEPTOR doses (9.6 mg/kg = 19X) exhibited signs typified by tremors, vocalization and ataxia. These effects were all transient and puppies returned to normal within 24 to 48 hours. No effects were observed in puppies given the recommended dose of INTERCEPTOR (0.5 mg/kg). This product has not been tested in dogs less than 1 kg (2.2 lbs) weight. A rising-dose safety study conducted in roughcoated collies, manifested a clinical reaction consisting of ataxia, pyrexia and periodic recumbency, in one of fourteen dogs treated with milbemycin oxime at 12.5 mg/kg (25X monthly use rate). No adverse reactions were observed in any of the collies treated with a rising-dose regimen up through the 10.0 mg/kg (20X monthly use rate) dose. How Supplied: INTERCEPTOR Flavor Tabs are formulated according to the weight of the dog. Each tablet size is available in color-coded packages of six or twelve tablets each. ©2004 Novartis Animal Health US, Inc. INTERCEPTOR and Flavor Tabs are registered trademarks of Novartis AG NAH/INT-FT/BS/5 10/04

If INTERCEPTOR Flavor Tabs replaces diethylcarbamazine (DEC) for heartworm prevention, the first dose must be given within 30 days after the last dose of DEC.

JAVMA, Vol 228, No. 12, June 15, 2006


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