Mira J. Leslie & Jennifer H. McQuistoncourses.washington.edu/zepi526/Papers08/Rabies chapter.pdf · in animal feces and fecal-oral transmission (inges-tion) plays an important role

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8 Surveillance for zoonotic diseasesMira J. Leslie & Jennifer H. McQuiston

Introduction

Zoonotic infections (zoonoses) involve pathogensthat are sustained in animal populations but canbe transmitted to and cause disease in humans.Zoonoses encompass some of the most ancientcommunicable diseases, such as rabies and plague,as well as newly recognized emerging infections,such as hantavirus pulmonary syndrome (HPS)and severe acute respiratory syndrome (SARS).A recent review of agents known to infect hu-mans identified 61% (868/1415) as zoonotic in ori-gin; furthermore, 75% (132/175) of human dis-eases classified as emerging were zoonotic [1].The global distribution, diversity, clinical sever-ity, and potential use as bioweapons all con-tribute to the importance of zoonotic pathogensin public health. In this chapter, we describe keyhost and transmission attributes of zoonotic infec-tions and discuss some strategies for surveillanceof zoonotic pathogens. We also discuss ongoingsurveillance for rabies in the United States (US)and enhanced surveillance during a monkeypoxoutbreak.

Overview of zoonotic diseases

Zoonoses constitute a diverse group of viral, bac-terial, rickettsial, fungal, parasitic, and prion dis-eases with a variety of animal reservoirs, includ-ing wildlife, livestock, domestic pets, and birds(Table 8.1). Some zoonotic pathogens, such as ra-

bies virus and Coxiella burnetii (Q fever), can in-fect a broad spectrum of animal hosts that mayeach serve as a source of infection to humans.Other zoonotic pathogens, such as rodent-bornehantaviruses and arenaviruses, are found in a nar-rower range of reservoir hosts.

Transmission

Many common zoonotic pathogens are excretedin animal feces and fecal-oral transmission (inges-tion) plays an important role in foodborne and wa-terborne infections due to enteric pathogens (e.g.,Escherichia coli, Salmonella; see also Chapter 5).Other diseases caused by zoonotic pathogens aretransmitted by inoculation of infected animal tissueor contaminated products (e.g., cutaneous anthrax,rabies); inhalation of small droplets or aerosols(e.g., HPS, Q fever, psittacosis); or by an arthro-pod vector (e.g., Lyme disease, Rocky Mountainspotted fever; see also Chapter 9). Anthrax, plague,and many other zoonoses have multiple routes oftransmission.

For most zoonoses, the pathogen is maintainedin one or more animal reservoirs with occasionaltransmission to humans but without subsequenthuman-to-human spread (e.g., anthrax, HPS, tu-laremia, Q fever). However, in some cases, initialzoonotic transmissions are responsible for signifi-cant disease epidemics that are sustained by sub-sequent person-to-person transmission (e.g., pan-demic influenza, SARS).

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Table 8.1 Selected important zoonotic diseases.

Organism Disease Primary reservoir or host Transmission to human

BacterialBacillus anthracis Anthrax Livestock Cutaneous inoculation;

ingestion; inhalationBartonella

henselae/quintanaCat scratch disease Cats Inoculation

Brucella abortus, B.melitensis, B. canis, B.suis

Brucellosis Cattle, sheep, goats, dogs,swine

Ingestion; inoculation;inhalation

Burkholderia mallei Glanders Equine InoculationChlamydophila psittaci Psittacosis Birds InhalationCoxiella burnettii Q fever Livestock Inhalation; ingestionEscherichia coli

O157:H7Hemolytic uremic

syndrome/E. coli infectionLivestock, wild ruminants Ingestion

Francisella tularensis (vartularensis andpalaeartica)

Tularemia Rabbits, hares, voles,muskrat, beaver, rodents

Inoculation; inhalation;vector-borne;ingestion

Leptospira interrogans(multiple serovars)

Leptospirosis Wild and domestic animals Inoculation; ingestion

Salmonella spp. (multipleserovars)

Salmonellosis Birds, mammals, reptiles,amphibians

Ingestion

Yersinia pestis Plague Rodents Inoculation; inhalation;vector-borne

ViralArenaviruses Lymphocytic choriomenin-

gitis virus, Bolivian(Machupo), Brazilian(Sabia), Argentine (Junin),African (Lassa)hemorrhagic fevers

Rodents Inhalation

Filoviruses Ebola, Marburg Unknown (possibly bats) InoculationHantaviruses

(Bunyavirus)Hantavirus pulmonary

syndrome, hemorrhagicfever with renal syndrome,hantaviral illness

Rodents Inhalation

Influenza A Avian influenza, swineinfluenza

Wild birds, swine Inhalation

Lyssaviruses Rabies Dogs, wild carnivores, bats InoculationOrthopoxviruses Monkeypox, cowpox Rodents, cattle Direct contact

PrionPrion New variant

Creutzfeldt–Jakob diseasein humans; BovineSpongioformEncephalopathy (BSE, madcow disease) in cattle

Cattle Ingestion

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Table 8.1 (Continued)

Organism Disease Primary reservoir or host Transmission to human

ProtozoalCryptosporidium parvum Cryptosporidiosis Wild and domestic animals IngestionGiardia lambia Giardiasis Wild and domestic animals IngestionToxoplasma gondii Toxoplasmosis Felids Ingestion

Parasitic NematodesToxocara canis, T. cati,

Baylisascaris procyonisLarval migrans Dogs, cats, raccoons Ingestion

Ancylostoma spp.,Strongyloides spp.

Cutaneous larval migrans Inoculation; directcontact

Trichinella spp. Trichinosis Swine, rodents, wildcarnivores

Ingestion

FungalMicrosporum canis,

TrichophytonDermatophytosis (ringworm) Mammals, some birds Direct contact

Host factors

In humans, host factors such as occupation, age,immune status, and recreational activities mayfacilitate exposure or susceptibility to zoonoticpathogens. For example, occupations that involvehandling of animals or animal carcasses such asveterinary work, farming, aviary work, zookeep-ing, and slaughterhouse work may expose work-ers to zoonotic pathogens. Persons with immunecompromising conditions such as HIV/AIDS maybe more susceptible to some zoonotic pathogens[2]. Recreational and peridomestic activities that in-volve animals or animal product handling such ashunting, cleaning rodent infested buildings, owningexotic pets, visiting petting zoos, and ecotourism,also put people at risk for exposure to zoonoticpathogens.

Environmental factors

Zoonoses are sustained in epizootic and enzooticcycles in reservoir animals. These cycles are in-fluenced by environmental factors such as biome,climate, land use, and the presence and behaviorsof appropriate hosts. Interactions between humanpopulations, domestic animals, and wildlife facili-tate transmission of infections among these groupsin what has been described as a host–pathogen

continuum (Figure 8.1) [3]. In North America,zoonoses such as rabies, plague, hantavirus, andtularemia are widespread in wildlife, posing an on-going risk to human health. The emergence of azoonotic disease often results from encroachmentof human and domestic animal populations intowildlife habitat [3,4]. For example, recent serosur-veys show evidence of novel viral infections withas yet unknown consequences in humans that huntand trap native populations of nonhuman primates[5,6]. The global trade in wildlife shows how en-vironmental and social factors combine to createa high risk for zoonotic disease emergence in sus-ceptible human populations [7]. In this example,animals of unknown health status are trapped inthe wild to be sold for human consumption, tradi-tional medicine, or the commercial pet trade. Dis-ease transmission may occur when humans havecontact with infected animals. Activities involvingthe sale and consumption of infected wildlife inChina likely resulted in the initial transmission ofSARS-coronavirus to humans [8].

Prevention and control

In the US, successful surveillance and control pro-grams have been developed for some zoonoses asso-ciated with domesticated animals. For example, a

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Fig 8.1 The host–pathogen ecological continuum for emerging infectious diseases (EIDs) of zoonotic origin. (Reprinted withpermission from [3]. Copyright 2000 AAAS.)

national brucellosis-eradication campaign in live-stock conducted by state and federal agriculturedepartments has included comprehensive animaltesting, vaccination of breeding animals, and de-population of affected herds. The program reducedinfected herds from 124,000 in 1956 to only 5 herdsnationally in 2000 [9]. Concurrently, reported bru-cellosis in humans plummeted from a high of ap-proximately 6300 reported cases in 1947 to 114cases in 2004 [10]. In the early 1900s, approxi-mately 10,000 rabid dogs were reported annuallyin the US. Widespread canine rabies vaccinationprograms and stray animal control in the 1940sand 1950s allowed elimination of circulating ca-nine variant of rabies virus, and in 2005 only 76cases of rabies were reported in dogs following con-tact with rabid wildlife [11]. Successful programssuch as these require enormous resources. As a re-sult, there are no eradication programs for the ma-

jority of zoonotic pathogens, especially those withwildlife reservoirs.

Surveillance for zoonoses

The interconnected roles of wildlife, domestic ani-mals, the environment, and human populations inzoonotic disease pathogenesis pose distinct chal-lenges for surveillance. In contrast to those diseasesthat only affect humans, zoonotic diseases cannotbe adequately studied or controlled without an un-derstanding of the influences and dynamics of in-fection in animal hosts. Therefore, the approach tozoonotic disease surveillance involves flexibility, in-novation, and interdisciplinary strategies. Four es-sential objectives of zoonotic disease surveillanceinclude (1) designing systems for early identificationof a human and animal health threat; (2) describing

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the epidemiological and ecological factors influenc-ing zoonoses; (3) guiding and evaluating preven-tion, education, and control measures; and (4) de-scribing the public health burden.

Surveillance and reporting of human infections

With the exception of rabies, zoonotic diseasesare usually first recognized when human illness isreported. Surveillance depends on timely report-ing of suspected and confirmed zoonotic infectionsby healthcare providers and laboratories to pub-lic health authorities. Depending on the pathogenand available resources, the animal source may beidentified as part of the public health investigation.Linking human infection to the animal source is of-ten more feasible with pets or livestock than withwildlife, as they may be more accessible to investi-gators for testing. For example, several outbreaksof human salmonellosis have been linked to contactwith infected domestic and exotic pets, includingcats, pet rodents, baby chicks, and reptiles [12,13].In 2004 and 2005, three separate outbreaks identi-fied over 170 people infected with E. coli O157:H7who had visited livestock pens in petting zoos [14].In 2005, lymphocytic choriomeningitis virus infec-tion in four organ transplant recipients was tracedto a donor who acquired infection from a pet ham-ster [15]. Determining whether there is ongoing riskto the public from a suspected animal source influ-ences how much investigation is warranted.

Surveillance and reporting of animal diseases

In the US, veterinarians are required to report cer-tain animal diseases to animal health and agricul-ture officials. Diseases under surveillance includediseases of livestock and poultry with serious eco-nomic implications and suspected foreign animaldiseases [16]. Though many of these diseases donot infect humans, anthrax, rabies, and brucellosisare among the reportable animal diseases that alsocause disease in humans (Table 8.2). Recent recog-nition of emerging zoonotic diseases and bioter-rorism preparedness initiatives has bolstered publichealth’s outreach to veterinarians. Some state andlocal public health agencies, such as those in NewYork City and Washington State, have developed

Table 8.2 Selected reportable zoonotic diseases in humansand animals, United States, 2006.

Reportable ReportableDisease in humans in animals

Anthrax Yes YesBrucellosis Yes Yes (cattle)Cryptosporidiosis Yes NoEscherichia coli

O157:H7; HUSYes No

Hantaviruspulmonarysyndrome

Yes No

Leptospirosis In some states YesLyme disease Yes NoPlague Yes In some western

statesPrion diseases In some states Yes (BSE)Psittacosis Yes YesQ fever Yes YesRabies Yes YesSalmonellosis Yes In some statesTularemia Yes YesTrichinosis Yes Yes

additional reporting regulations for zoonoses in an-imals that more commonly infect humans [17,18].

To more effectively monitor zoonotic diseases,animal and human disease data from public healthand animal health agencies and laboratories shouldbe integrated. Currently, the sharing of diseasesurveillance information in most states dependslargely on interpersonal relationships, legal agree-ments such as memoranda of understanding, andagency priorities. As electronic databases becomemore widely utilized in public health and animalhealth agencies, coordination of disparate systemsshould be a primary goal.

Strategies for surveillance of zoonoses

Several strategies may be useful for surveillance ofzoonotic pathogens in animals, including veteri-nary surveillance, sentinel surveillance, longitudinalsurveillance, and laboratory-based surveillance.

Veterinary surveillanceAs frontline healthcare providers, veterinarians as-sist with the recognition, diagnosis, reporting, and

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control of zoonotic disease in animals. When anunusual zoonotic disease trend or outbreak is rec-ognized, veterinarians can assist the investigationthrough enhanced surveillance for animal disease.Many states, through cooperation of state veteri-nary medical associations, agricultural and publichealth agencies, have developed veterinary alert sys-tems for rapid notification of zoonotic or animaldisease outbreaks. Health alerts typically include in-formation on veterinary occupational risks as wellas symptoms, diagnosis, and reporting protocols forthe disease in animals.

Sentinel surveillanceMonitoring animals for zoonotic pathogens canprovide early recognition of human health risks andmay allow for control efforts prior to the trans-mission of disease to humans. Mortality events areparticularly important and some data on wildlifemortality is monitored and compiled nationally bythe National Wildlife Health Center [19]. As oneexample, prairie dog colonies in northern Arizonaexperience periodic die-offs caused by enzootic cy-cles of plague (Yersinia pestis). Sentinel surveillanceinvolves routine visual observation of prairie dogcolonies to detect any increases in mortality. Whenplague is confirmed as the cause of a die-off, humandisease prevention measures are initiated, includingpublic education campaigns, posting of signs in theaffected area, pesticide dusting of burrows to kill in-fected fleas, and warnings to pet owners to confinepets and use flea control.

Longitudinal surveillanceWhere resources are available, meaningful surveil-lance to elucidate disease patterns in animal reser-voirs includes ongoing systematic data collection.For example, prospective longitudinal studies atsites in Arizona, Montana, and Colorado involveserial monthly trapping of Peromyscus spp. of miceand serological testing for antibody to Sin Nombrevirus [20,21]. Data from these studies show thatthe prevalence of infection in mice is influenced bylocal seasonal and climatic events that affect foodsupply and mouse population density. Trends ob-served assist in predicting human disease risk.

Laboratory-based surveillanceEffective surveillance for zoonotic pathogens re-quires diagnostic laboratory capacity for both hu-

man and animal specimens. In some states, com-mercial clinical laboratories are required to reportpositive findings for zoonotic pathogens to pub-lic health authorities. Diagnosis often requires spe-cialized confirmatory testing that is available onlyin state or federal veterinary, agriculture, or pub-lic health laboratories. Advanced laboratory tech-niques are increasingly able to confirm genetic re-lationships among pathogens infecting humans andanimals. This information, combined with epidemi-ological data, is useful for establishing zoonotictransmission events. For example, PulseNet, a na-tional network of public health and food regula-tory agency laboratories coordinated by the Centerfor Disease Control and Prevention (CDC), main-tains a national database of molecular fingerprintsof foodborne pathogens submitted from laborato-ries throughout the US. This system has provenvery successful in detecting disease outbreaks asso-ciated with zoonotic pathogens such as E. coli andSalmonella [22]. PulseNet was used to determinethat infected rodents distributed in commercial petstores were the cause of a multistate outbreak ofsalmonellosis in humans [13].

Examples of zoonotic diseasesurveillance

The following two descriptions of zoonotic diseasesurveillance systems in the US illustrate some ofthe key ideas explained in this chapter, includingthe interconnected roles of human and animal dis-ease surveillance and partnerships between humanand animal health agencies. The first example de-scribes routine disease surveillance for rabies andthe second describes surveillance instituted duringan outbreak of monkeypox.

Surveillance for rabies in the US

BackgroundRabies is a viral disease of the central nervous sys-tem that, after the onset of clinical symptoms, isalmost universally fatal—thus, rabies is a seriouspublic health threat. Although all mammals are sus-ceptible to rabies, the disease is efficiently main-tained in enzootic cycles by specific animal reser-voirs including raccoons, skunks, foxes, and several

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species of insectivorous bats in North America.These wildlife reservoirs account for over 90% ofconfirmed rabid animals and sporadic domestic ani-mal and human rabies cases in the US result primar-ily from interactions with these wildlife reservoirs[11].

Despite its high mortality rate, rabies infectioncan be prevented in most domestic pets and live-stock with appropriate vaccination before and afterexposure. Furthermore, infection in humans can beprevented after exposure through the timely admin-istration of rabies postexposure prophylaxis (PEP)that usually consists of a series of vaccinations andadministration of rabies immune globulin. Severalmillion animal bites occur annually in the US andit is estimated that more than 35,000 people bittenby animals receive PEP every year [23]. Examplesof potential human rabies exposures include batsfound in houses, stray dog and feral cat bites, andwild animal bites. National guidance for human ra-bies exposure management is found in the AdvisoryCommittee on Immunization Practices (ACIP) Ra-bies Prevention document [24].

Overview of rabies surveillanceRabies surveillance in the US integrates human andanimal zoonotic disease detection and prevention.Surveillance provides epidemiologic information toassist human PEP decisions and focus preventionand control programs. Animal bites to humansmust be reported to public health authorities andeach reported event is investigated. In addition,laboratory-confirmed rabies infection in both hu-mans and animals is reportable. Because rabiesposes a significant human health threat, in most ar-eas animal rabies surveillance is primarily under thejurisdiction of local and state (human) public healthagencies rather than animal health agencies. An ex-ample of a model rabies surveillance and controlprogram is shown in Figure 8.2.

Goals and objectives of surveillanceA primary goal of rabies surveillance is to quicklyevaluate and mitigate any risk of rabies; in the eventof possible human exposure, this includes properand timely administration of PEP. State and localhealth departments support 24/7 availability forconsultation with healthcare providers and their

patients to assist in animal bite assessment, describelocal and regional rabies epidemiology and risk, andfacilitate correct administration of rabies PEP toprevent human rabies infection. When the bitinganimal is available, testing or observation periodsfor rabies may be initiated; however, in situationswhere the biting animal is not available, it is impor-tant to have robust epidemiological animal surveil-lance data to guide medical decisions.

Other goals of rabies surveillance include defin-ing enzootic and epizootic status of rabies in a re-gion, directing prevention efforts such as publiceducation campaigns and animal control policies,detecting changes in disease patterns, and identi-fying unusual or novel disease events such as newmodes of transmission or the evolutionary emer-gence of rabies virus variants. Notable recent ex-amples in the US include the discovery of rabiestransmission via organ transplantation [25] andthe emergence of bat-associated rabies transmittedamong skunks in an area previously free of terres-trial rabies [26].

Finally, rabies surveillance is used to evaluate theefficacy of animal vaccination in rabies control. Forexample, a thorough investigation of rare cases ofrabies occurring in vaccinated dogs helps assess theefficacy of rabies vaccines [27]. Programs distribut-ing oral rabies vaccine baits to control rabies in rac-coons also benefit from post baiting surveillance toassess program efficacy [28].

Surveillance in animal populationsIn the US, wild carnivores and bats are the mostimportant potential source of rabies infection forhumans and domestic animals. All states exceptHawaii report annual cases of rabies in animals[11]. Rabies surveillance in animals includes iden-tifying the disease in both domestic animals andwildlife. Rabies surveillance is enhanced signifi-cantly when public awareness is raised by mediareports of unusual animal rabies cases, a humanrabies case, or local epizootic rabies activity. Thenumber of animals tested and those found rabiddepends on the rabies reservoirs in the area, the hu-man population base, and whether animal control,diagnostic laboratory infrastructure, and resourcesare available. During 2005, five states reported lessthan 11 rabid animals each (Alaska, Louisiana,Mississippi, New Mexico, and Oregon), and five

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Fig 8.2 Example of a rabies surveillance and control system.Refer to national guidance for management of situationsinvolving animal bites to human [24,30]. Designated agency

responsibilities, authorities, and systems, vary locally; StateDepartments of Agriculture manage rabies inlivestock.

states reported over 400 animal rabies cases each(New York, North Carolina, Pennsylvania, Texas,and Virginia) [11].

Case definition of rabies in animalsDefinitive diagnosis of rabies infection in animalsrequires laboratory testing performed on freshbrain tissue using the direct fluorescent antibody(DFA) test. Standardized protocols for perform-ing the DFA test reduce laboratory errors and

consequently improve the accuracy of confirmedcase surveillance [29]. Additional testing involv-ing monoclonal antibody panels and nucleotide se-quence analysis of rabid animal tissues can iden-tify the specific rabies virus variant, its associatedanimal reservoir, and often its geographic associa-tion. Rabies virus variant typing provides importantepidemiological information about rabid domesticanimals and wild animals that are submitted fromoutside of enzootic areas.

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Rabies surveillance in domestic pets and livestockVeterinarians, animal control officials, and publichealth agencies conduct rabies surveillance in do-mestic pets and livestock. Veterinarians caring foranimals with severe progressive neurological signsmay suspect rabies and request public health con-sultation and laboratory testing. Local health oranimal control officials evaluate reports of animalbites and manage the biting animal to determine ifthere was a potential risk of rabies transmission.Public health laboratories perform the majority ofanimal rabies testing. National guidance for rabiesvaccination, prevention, and control in animals isfound in the National Association of State Pub-lic Health Veterinarian’s Compendium of AnimalsRabies Prevention and Control, which is updatedannually [30].

Rabies surveillance in wildlifeConducting surveillance for rabies in wildlife ischallenging because of the difficulty in effectivelyobserving and monitoring illness and death in wildanimals. Successful wildlife rabies surveillance pro-grams promote and encourage citizen reporting andlaboratory testing of all sick and dead wild carni-vores that do not have obvious evidence of trauma,even in situations without human or pet exposure.In situations requiring enhanced surveillance, pro-grams may include collection and testing of road-killed animals. In some states, limited resources pre-clude this type of surveillance and rabies testing ofwildlife is consequently performed only after bitesare inflicted on people or pets. To facilitate wildlifesurveillance, a direct rapid immunohistochemicaltest that can be performed by trained wildlife bi-ologists on animals in the field has recently beendeveloped. Field testing reduces the need for refrig-eration of the brain and transport to public healthlaboratories [31].

Rabies surveillance in humansHealth departments receive and investigate reportsof human illnesses and death due to unexplainedviral encephalitis with characteristics resemblingrabies. However, the disease is so uncommon inNorth America (less than 10 cases annually) thatit is often clinically unrecognized by physicians un-familiar with its presentation. A history of an an-

imal bite may be absent in some patients, particu-larly because of the long incubation period (usually3–16 wk; range 2 wk to several years), the inabil-ity of encephalitic patients to recall exposures, andthe minor injury related to exposures from bats.Bat-associated rabies viruses cause the majority ofNorth American human rabies cases; 85% of the 24indigenously acquired human rabies cases reportedin the US between 1997 and 2004 were caused bybat-associated rabies virus variants [11,32]. In rareevents, donors infected with rabies have been thesource of human to human transmitted infectionvia corneal and organ transplantation [25].

Case definition of rabies in humans Diagnosis ofhuman rabies is based on laboratory testing. Clin-ical rabies rapidly progresses to death and mostcases of human rabies in the US are diagnosed post-mortem during laboratory examination of braintissue collected at autopsy. Antemortem tests forhuman rabies, performed primarily at CDC, mayprovide a diagnosis of rabies before death; however,negative antemortem test results are not definitiveand must be confirmed by brain tissue examinationpostmortem [33].

Molecular laboratory tests are used to identifythe rabies virus variant causing infection in hu-man patients. This information has established thatmost human rabies cases acquired in the US are at-tributable to variants of rabies virus found in in-sectivorous bats [11,30]. Knowledge that contactwith bats poses an important public health risk tohumans has improved PEP recommendations andeducational and prevention efforts.

Data collection, analysis, feedbackConfirmed animal rabies cases are reported regu-larly from state public health laboratories to theirepidemiology programs, local health agencies, thesubmitter (animal control, veterinarians, wildlifebiologists, etc.), and to national databases. Na-tional rabies data are summarized and publishedannually, including changes in trends and distribu-tion of reported animal cases [11]. State and lo-cal health departments compile and disseminatecurrent local epidemiological rabies informationon Web sites, in health alerts, and in media re-leases. A geographic information system (GIS) with

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an Internet-accessible centralized database calledRabID is being developed to map, compile, and dis-seminate rabies data in real time [34]. Surveillanceusing GIS is described in Chapter 31.

PartnersSurveillance for rabies relies on an extensivenetwork of partnerships, including healthcareproviders, veterinarians, animal control officers,public health officials (local, state, and federal),agriculture and wildlife officials, laboratories,wildlife rehabilitators, humane organizations, phar-maceutical companies, and the general public. Thisframework can also be adapted and used to ad-dress other zoonoses. In many areas, interagencyadvisory committees and task force groups are or-ganized to coordinate rabies issues. Risk commu-nication skills and public information officers areessential to public health messaging about rabies.Rapid surveillance efforts are often assisted by themedia especially during attempts to identify peoplewho may not be aware that they were potentiallyexposed to rabies, for example, by contact with arabid animal in a petting zoo, campground, or petstore.

Strengths and weaknessesSeveral limitations affect the efficacy of rabiessurveillance. Clinical rabies infection in both hu-mans and domestic animals may be underrecog-nized since it resembles several other encephaliticdiseases. Many fatal cases of unexplained viral en-cephalitis in humans do not undergo postmortemautopsy. Antemortem rabies tests for animals arenot available and definitive diagnosis requires pub-lic health resources for specialized laboratory test-ing of fresh brain tissues. Where resources are lim-ited, rabies testing is often offered only for animalsthat have potentially exposed pets or people. Thus,the data generated are incomplete and biased bythe degree of human and pet interaction with a par-ticular species. The number of confirmed cases ofanimal rabies does not approximate the true inci-dence of disease, since many infected wild, stray,and feral animals are not observed or submitted fortesting.

A primary strength of the system is that the re-sults of surveillance (animal test results) are usedto guide human treatment options and prevent hu-

man infection and death. As a result, very few hu-man cases are reported each year in the US withmany potential cases avoided through appropriateand timely administration of PEP.

Surveillance for monkeypox during an outbreak

BackgroundIn 2003, an outbreak of monkeypox occurred inthe US, representing the first time this disease hadbeen recognized in humans outside of Africa wherethe disease is endemic [35]. Monkeypox is in the or-thopoxvirus group of viruses (as is smallpox) andis capable of causing severe or fatal illness in hu-mans. Some strains of monkeypox may be transmis-sible between humans and associated with highermortality. Fortunately, the virus associated with the2003 outbreak in the US was a less virulent WestAfrican strain of virus.

During the US outbreak, disease transmissionwas linked to contact with infected prairie dogs dis-tributed in the commercial pet trade through an Illi-nois animal dealer. Over 70 persons in several Mid-western states were infected [36]. Extensive investi-gations of the implicated prairie dogs revealed thatthe Illinois dealer also bought and sold African ro-dents and epidemiologic evidence suggested that theprairie dogs were infected at this location. Trace-back investigations of the African rodents linkedthem to a shipment from Ghana that containedover 800 small mammals [36]. Laboratory testingshowed that several of the imported African rodentspecies were infected with monkeypox virus. Theinvestigation was complicated by inadequate recordkeeping and widespread dissemination of the im-ported animals.

In the following section we will describe the en-hanced surveillance for monkeypox virus infectionin humans and animals that enabled characteriza-tion of the outbreak and guided containment of dis-ease. Early identification of cases offered the possi-bility of reducing the clinical impact. Additionally,rapid control of the outbreak was needed to preventthe establishment of an enzootic cycle of monkey-pox in native US wildlife. Federal emergency ordersrestricting the movement, trade, and importation ofimplicated species of animals contributed to controlof the outbreak [37].

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Goals of surveillanceA primary goal of surveillance was to define theextent and magnitude of the outbreak in humansand animals. The number of infected animals andtheir distribution was unknown initially, as was theclinical spectrum of illness in prairie dogs. There-fore, surveillance to detect human infection was themost effective way to define the extent and magni-tude of the outbreak initially. Effective control ofthe outbreak required identification of close con-tacts to infected humans to monitor for and pre-vent human-to-human transmission of virus. Animportant objective of surveillance in animals wasto identify infected and exposed animals so theycould be removed from situations where they couldtransmit the infection to humans or other ani-mals. Surveillance in animals also facilitated trace-back investigations to identify the source of in-fection and to determine how many animals werepotentially involved. Surveillance in native and cap-tive wild rodents and other mammals was initiatedto determine whether monkeypox had been intro-duced to, and spread among, native US wildlifespecies.

Surveillance in humansBecause human monkeypox had never been previ-ously reported outside of continental Africa and itwas considered implausible that the virus could af-fect the US, it was not a reportable disease at thetime of the outbreak. However, its public healthsignificance, clinical resemblance to smallpox, andthe fact that it was not an endemic disease, al-lowed surveillance and reporting to be implementedunder state regulations that address public healthemergencies due to bioterrorism or novel agents.Retrospective surveillance included contacting andinterviewing people who had handled potentiallyinfected animals and reviewing patients with recentclinically compatible illnesses in outbreak-affectedareas. Prospective surveillance involved identify-ing suspected cases meeting the clinical and epi-demiologic case definition through reports fromhealthcare providers. Surveillance was facilitatedby dissemination of outbreak updates and re-porting guidelines through Internet-based systems(e.g., Health Alert Network, Epidemic Informa-tion Exchange (Epi-X) and Morbidity and Mortal-ity Weekly Report (MMWR) [36,38–40].

Human cases identified during the investigationwere classified as either suspect, probable, or con-firmed monkeypox infections depending on theclinical presentation (presence of rash, fever, andlymphadenopathy) and epidemiological informa-tion available [37]. Confirmed cases required lab-oratory demonstration of the presence of virusthrough culture, electron microscopy, or nucleicacid detection techniques in the absence of anotherpotential poxvirus [37]. Because laboratory testingfor monkeypox is highly specialized, it was initiallyprimarily conducted at CDC. However, through thehealthcare worker smallpox vaccination programpreparations, the Laboratory Response Network(LRN) laboratories had the capacity to screen clini-cal rash-derived samples for orthopoxvirus nucleicacid signatures; these facilities were used to aid inthe triage and initial testing of samples, largely de-rived from the Midwestern states.

The investigations and case follow-up requiredextensive local, state, and federal resources and per-sonnel and in many cases these resources were di-verted from other important public health issuesto accommodate outbreak needs. Coordinationamong affected states, confirmatory testing, andcommunication was facilitated by the CDC withdaily national conference calls. This ensured consis-tency of case investigations and reporting, appro-priate laboratory submissions, and rapid dissemi-nation of current information and case numbers.

Surveillance in animalsIn 2003, although many studies of experimentalinfection of animals existed, scientific informationabout the natural history of monkeypox in ani-mals was sparse. Unknown factors included therange of susceptible animal species, the spectrumof clinical syndromes, and the possibility of viralshedding from asymptomatic animals. Therefore,surveillance focused on identifying animals with po-tential exposure to infected or exposed animals. Thehistories of infected animals were meticulously in-vestigated, including their points of sale and ship-ments to identify additional exposed animals, andto reveal the source of infection for the animals.Clinical presentations were compiled to generatean animal case definition [37]. The investigation in-volved site visits to animal dealers and traders, petshops, pet owners’ homes, and the examination of

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written records or verbal interviews. Known clini-cal symptoms such as lethargy, cough, conjunctivi-tis, and skin lesions were useful in identifying po-tentially infected animals [37]. Because CDC andLRN laboratory testing was prioritized for humanillness, there were inadequate laboratory resourcesfor processing and testing animal specimens. Addi-tionally, tests had not been fully evaluated with anyof the animal specimen types submitted for analysis.Viral and serologic testing at CDC was conductedto confirm the initial infections in prairie dogs, toinvestigate possible infections in African rodentsfrom the implicated shipment, and to investigatereports of diseased/suspect case animals in newlocations.

A coalition of federal and state agricultureofficials, state and local public health officials,and practicing veterinarians conducted the animalsurveillance and investigations. Involved federalagencies included CDC, the Food and Drug Admin-istration (FDA), and the United States Departmentof Agriculture (USDA)/Animal and Plant Health In-spection Service (APHIS). Animal breeders licensedby the USDA were visited and provided informationabout the outbreak. Educational materials were de-veloped and disseminated to pet stores and veteri-narians. National conference calls were held severaltimes a week between federal and state agency per-sonnel to coordinate activities.

Surveillance to determine whether monkeypoxhad exposed native wild rodents was coordinatedby USDA-APHIS Wildlife Services. Traps were seton and near premises holding infected prairie dogsor African rodents. Blood collected on trappedwildlife was tested for antibodies to assess whetherinfection had been transmitted to native species.This surveillance found no evidence of infection innative rodents.

Strengths and weaknessesA weakness of human and animal surveillance as-sociated with this outbreak is that the systems werenecessarily largely reactive and were implementedduring the height of the outbreak. Because the ini-tial infections in prairie dogs were not recognizedas significant and reported to authorities, recog-nition of the outbreak was delayed until the firsthuman cases were diagnosed. Thus, health authori-ties missed an early opportunity to control the out-

break. Educating animal dealers and veterinariansto quickly report unusual or suspicious illnesses inanimals to authorities, and ensuring that state agri-culture, wildlife, and human heath agencies havethe capacity to respond could facilitate a more rapidresponse in the future.

A primary strength of the surveillance system isthe collaborative efforts that evolved between stateand federal partners for human health and ani-mal health. Although this emerged out of neces-sity during the emergency response, the relation-ships that were forged proved to be effective andhave continued during subsequent zoonotic diseaseoutbreaks and preparedness activities. Bioterrorismpreparedness initiatives related to the detection anddiagnosis of orthopoxviruses (due to smallpox con-cerns) greatly assisted in the response to this out-break at both CDC and affiliated LRN laboratories.Additional benefits of the investigation include anenhanced understanding of the natural history ofmonkeypox virus and the development of testingstrategies that may be used to identify monkeypoxin various animal species.

Discussion

Surveillance for zoonotic diseases involves manychallenges and offers opportunities for early de-tection of disease threats, improved assessment ofrisks posed by enzootic pathogens, and target-ing effective prevention and control measures (seeChapter 10). In addition to providing direction forimmediate public health actions, surveillance sys-tems for zoonoses can provide vital insight into thefactors influencing disease emergence, persistence,and spread. The importance of good communica-tion and multidisciplinary participation in monitor-ing zoonoses is highlighted by the examples of ra-bies and monkeypox surveillance, and also throughprograms such as ProMED-mail, an Internet-basedreporting system dedicated to rapid global dissem-ination of information on outbreaks of infectiousdiseases in humans, animals, and plants (availableat: www.promedmail.org). ProMED-mail, a pro-gram of the International Society of Infectious Dis-eases, is widely used by public health agencies, an-imal health agencies, scientists, and medical andveterinary providers to provide early warnings of

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zoonotic disease issues that might benefit from en-hanced surveillance efforts [41].

The close association of humans and animalsin modern society, including the globalization ofagriculture, the pet trade, tourism and recreation,combined with ecologic pressures such as habitattransformation, climate change, and human over-population, will continue to facilitate unpredictablezoonotic disease threats [42]. Whether dealing withthe persistence of ancient zoonoses, or the myster-ies of newly recognized diseases, astute, innovative,and vigilant disease surveillance is imperative to re-duce morbidity and mortality among humans andanimals.

Acknowledgments

The authors thank Charles Rupprecht, IngerDamon, and Russ Regnery from the Centers forDisease Control and Prevention (CDC) for assis-tance in developing the content matter of this chap-ter. The authors also thank Doug Beckner for tech-nical assistance.

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