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Suggested Citation:"ZOONOSES." National Research Council. 1997. Occupational Health and Safety in the Care and Use of Research Animals. Washington, DC: The National Academies Press. doi: 10.17226/4988.
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Suggested Citation:"ZOONOSES." National Research Council. 1997. Occupational Health and Safety in the Care and Use of Research Animals. Washington, DC: The National Academies Press. doi: 10.17226/4988.
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Suggested Citation:"ZOONOSES." National Research Council. 1997. Occupational Health and Safety in the Care and Use of Research Animals. Washington, DC: The National Academies Press. doi: 10.17226/4988.
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ZOONOSES 65 5 Zoonoses The transmission of zoonotic disease in the laboratory-animal environment is uncommon, despite the number of animal pathogens that have the capacity to cause disease in humans. That is largely the result of the collaborating interac- tions and work of two groups. The laboratory-animal industry has had much success in providing high-quality laboratory animals of defined health status for use in research. And research institutions have developed comprehensive and responsive programs of veterinary care that have fostered the investigation of new disease findings and helped to ensure the continuing health of research- animal populations. Quality veterinary care itself, however, is insufficient to prevent the transmission of zoonoses in a research institution. The repeated oc- currences of laboratory-acquired Q fever and lymphocytic choriomeningitis and the emergence of newly recognized zoonoses point to a need for investigators to become more involved in their institutions’ efforts to prevent occupationally acquired zoonotic disease. The occupational-medicine services might be first to observe the symptoms of zoonotic infection, but it is also important that the institutions’ medical professionals become knowledgeable in methods for detect- ing and managing zoonoses for which workers at the institutions are at risk. All workers share the responsibility for protecting their own health. Personal hygiene affords a critical barrier to the transmission of zoonoses and should be reinforced routinely in an institution’s educational efforts and materials, in group and labo- ratory meetings of involved personnel, and in messages that emphasize appropri- ate practices for the care and use of research animals. The following discussion covers most of the zoonotic diseases important to laboratory-animal personnel. The emphasis is on likely occurrence and potential 65

66 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS for severity. Some uncommon zoonoses are covered only briefly even though they could have devastating effects if imported into the laboratory environment. In this regard, institutions should investigate situations that are peculiar to pro- posed research and instructional programs and that might pose special zoonotic hazards—e.g., the use of wild-caught birds or mammals or their fresh carcasses with their associated flora and fauna—before embarking on full-scale programs. That might occasionally necessitate the use of an integrated team from within the institution or of outside specialists or consultants to ensure that the research- animal facilities and personnel expertise are conducive to safety. The information on zoonotic diseases is organized by agent category. Major sections on viral diseases, rickettsial diseases, bacterial diseases, protozoal dis- eases, and fungal diseases are included. Material relevant to each zoonotic dis- ease is presented under four headings: reservoir and incidence; mode of transmis- sion; clinical signs, susceptibility, and resistance; and diagnosis and prevention. The discussion on reservoir and incidence addresses the natural infection in the animal host species. The three other headings deal specifically with the potential for and occurrence of occupationally acquired infection of persons involved in the care and use of animals in research. Various source materials provide detailed information on zoonoses associ- ated with laboratory animals (Fox and Lipman 1991, Fox and others 1984). Readers should find the Centers for Disease Control and Prevention (CDC) Mor- bidity and Mortality Weekly Report indispensable for reviewing contemporary issues pertaining to zoonotic outbreaks. Although the subject of xenograft transplantation is beyond the scope of this report, vigilance for zoonoses should be an important aspect of all xenograft transplantations. An important consideration should be the potential for ex- change of infectious agents between natural and foreign hosts. Xenograft trans- plantation can inadvertently introduce animal viruses into a new susceptible host. Infection in a new host might not always be apparent. Long-term management of the xenograft recipient is a necessary and prudent practice for maintaining vigi- lance because new, previously unidentified, pathogens can be anticipated to arise. VIRAL DISEASES B-Virus Infection (Cercopithecine herpesvirus 1, CHV1) Reservoir and Incidence. First described in 1933 (Gay and Holden), B virus produces a life-threatening disease of humans that has resulted in several deaths in the last decade (CDC 1987, 1989a). In macaques, B virus produces a mild clinical disease similar to human herpes simplex. During primary infection, macaques can develop lingual or labial vesicles or ulcers, which generally heal within 1-2 wk. Keratoconjunctivitis or corneal ulcer also might be noted. After acute infection, latency can be established in the ganglia of the sensory nerves

ZOONOSES 67 serving the region in which virus was introduced. Reactivation of virus from the latent state can result in recurrent viral shedding from peripheral sites and is often associated with physical or psychological stressors, such as ultraviolet irradia- tion, immunosuppression, disruption of social hierarchy, or other stressful ex- perimental situations (Zwartouw and Boulter 1984). The infection is usually transmitted between macaques via virus-laden secretions through close contact involving primarily the oral, conjunctival, and genital mucous membranes (Weigler 1995). In a domestic macaque production colony with endemic infection, an age- related increase in the incidence of B-virus infection occurred during adolescence as exposure to the agent continued; the incidence approached 100% in colony- born animals by the end of their first breeding season (Weigler and others 1993). Seroconversion to a B-virus antibody-positive status among wild-caught rhesus monkeys also indicates that eventually 100% of the newly trapped animals ac- quire the infection. Consequently, B virus should be considered endemic among Asian monkeys of the genus Macaca unless the animals have been obtained from specific breeding colonies confirmed to be free of it. Although several species of New World monkeys and Old World monkeys other than members of the genus Macaca are known to succumb to fatal B-virus infection, only macaques are known to harbor B virus naturally (Holmes and others 1995). Mode of Transmission. B virus is transmitted to humans primarily through expo- sure to contaminated saliva (in bites) and scratches. Transmission related to needlestick injury (Benson and others 1989) and exposure to infected nonhuman- primate tissues (Wells and others 1989) also has occurred. Fomite transmission through an injury obtained in handling contaminated caging was the cause of one identified infection (Palmer 1987). The transmission of B virus by the aerosol route is not thought to be important. Researchers in the field have suggested that asymptomatic human B-virus infection can occur (Benson and others 1989), but it is unknown whether viral reactivation and severe clinical disease can occur later. Human-to-human transmission was recently documented (CDC 1987). Clinical Signs, Susceptibility, and Resistance. The incubation period between initial exposure and onset of clinical signs ranges from 2 d to about 1 mo, but the time at which symptoms arise after exposure can vary widely. After exposure by bite, scratch, other local trauma, or contamination of vulnerable sites, humans might develop a herpetiform vesicle at the site of inoculation. Early clinical signs and symptoms include myalgia, fever, headache, and fatigue and are followed by progressive neurological disease with numbness, hyperesthesia, paresthesia, diplopia, ataxia, confusion, urinary retention, convulsions, dysphagia, and an ascending flaccid paralysis. Diagnosis and Prevention. After the outbreak of B-virus infection in monkey

68 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS handlers in 1987, CDC developed guidelines to prevent it in humans (CDC 1987), which were later revised by Holmes and others (1995). In brief, the recom- mendations emphasize the need for nonhuman-primate handlers to use protective clothing, including leather gloves and long-sleeved garments for hand and arm protection and face shields or masks and goggles to protect the eyes and mucous membranes from exposure to macaque secretions. Those barrier protections will minimize exposures. The use of latex gloves alone for hand protection should be reserved for the handling of monkeys that are under full chemical restraint. Chemical restraint or specialized restraining devices should be used with nonhu- man primates whenever possible to minimize direct contact of personnel with alert monkeys. Despite those handling recommendations and the heightened awareness of the B-virus hazard among personnel, exposure of personnel to monkey bites and scratches remains common, as evidenced by the numerous injuries reported to testing laboratories and CDC (Hilliard 1992). Experimental studies with B virus in animals should be conducted at Animal Biosafety Level 3 (CDC-NIH 1993). Serological methods for the detection of serum antibody are used to diagnose prior exposure to and latent infection with B virus in both humans and animals (Katz and others 1986; Munoz and others 1988). Virus isolation from either the monkey or wound site is also performed, and restriction analysis or the polymerase chain reaction is used later to confirm its presence in any sample that yields a cytopathological result. The CDC recommendations specify that institutions should be prepared to handle patients with a suspect exposure promptly. The wound, if any, should be cleansed thoroughly, and serum samples and cultures should be obtained for serological study and virus isolation from both the patient and the monkey. The initiation of antiviral therapy with acyclovir or ganciclovir might also be warranted if history and symptoms are consistent with B-virus infection. The management of antiviral therapy in B- virus-infected patients is controversial because increasing antibody titer has been demonstrated in a patient after the discontinuation of acyclovir therapy (Holmes and others 1995). Physicians should consult the Viral Exanthems and Herpesvi- rus Branch, Division of Viral Diseases, Centers for Disease Control and Preven- tion, Atlanta, GA 30333 (telephone, 404-329-1338) for assistance in case man- agement. Additional information about B-virus diagnostic resources is available through the National Institutes of Health (NIH) B Virus Resource Laboratory, Department of Virology and Immunology, Southwest Foundation for Biomedical Research, P.O. Box 28147, San Antonio, TX 78228 (telephone, 210-674-1410). Ebola-Virus Infection Reservoir and Incidence. Ebola hemorrhagic fever is a rare disease caused by a filovirus that is structurally identical with, but antigenically distinct from, Marburg-disease virus. Cases of disease related to this agent have been restricted to the continent of Africa. Sudan and Zaire strains of the virus have been shown

ZOONOSES 69 experimentally to produce lethal infection in nonhuman primates in about 8 d, but monkeys have not been shown to be the natural reservoir (Dalgard and others 1992; Johnson 1990a); the natural reservoir for Ebola virus has not yet been identified. The identification and isolation of an Ebola-like filovirus, Ebola-Reston, from macaques imported into the United States from the Philippines during 1989, the first appearance of an Ebola viral strain that did not originate in the continent of Africa, prompted the implementation of revised nonhuman-primate importa- tion and handling guidelines (CDC 1989b, 1990). Although Ebola-Reston was less virulent than Ebola-Zaire or Ebola-Sudan in nonhuman primates, it also produced a hemorrhagic disease that involved multiple organ systems and pro- duced death in 8-14 d in infected macaques. The natural reservoir of the Ebola- Reston strain has not been determined. However, a new strain of Ebola virus has been isolated from naturally infected chimpanzees from a wild troop that had experienced outbreaks of disease characterized by a hemorrhagic syndrome. Further study of this troop might begin to resolve questions about the natural reservoirs of the Ebola virus (Le Guenno and others 1995). Mode of Transmission. Transmission of Ebola-virus infection during epidemics among humans generally has involved close contact, and the low secondary- attack rate suggests that transmission is not efficient (Murphy and others 1990). Sexual contact and nosocomial transmission through exposure to contaminated syringes and needles, infected tissues, blood, and other bodily fluids are impor- tant means of viral transmission. Aerosol transmission has not been a feature of the African Ebola-virus outbreaks to date, but it cannot be discounted completely. During the outbreak of Ebola-Reston disease in the nonhuman-primate colonies in the United States, its spread within rooms between animals without direct contact supported the possibility of droplet or aerosol transmission. Clinical Signs, Susceptibility, and Resistance. In humans, the Zaire and Sudan strains produce a disease characterized by multifocal organ necrosis, coagulopathy, extensive visceral effusions, hemorrhagic shock, and death. Hu- man infections with the Reston strain during the outbreak in nonhuman primates were subclinical but resulted in seroconversion. Diagnosis and Prevention. A wide variety of techniques can be used to detect Ebola virus or the viral antigen. The infection is diagnosed serologically on the basis of antibody titer in indirect immunofluorescence assay, radioimmunoassay, and enzyme-linked immunosorbent assay. The CDC-mandated procedures for importation of nonhuman primates limit the occurrence of this disease to facilities involved in importation (CDC 1990). Personnel in those facilities should become familiar with the specialized equip- ment and procedures used to minimize Ebola-virus transmission in the event of

70 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS an outbreak. Neither vaccines nor therapeutic pharmaceuticals are available for the prevention or treatment of Ebola-virus infection. The Subcommittee on Arbovirus Laboratory Safety (SALS) of the American Committee on Arthropod- Borne Viruses recommends that work with Ebola virus be conducted at the equivalent of Biosafety Level 4 (CDC-NIH 1993). Marburg-Virus Disease Reservoir and Incidence. Marburg-virus disease has been recognized on only four occasions. The index cases involved 31 persons in three European laborato- ries who were handling tissues from African green monkeys; seven of the 31 died (Martini and Siegert 1971). There was no secondary spread of the disease among the monkeys in the facility, and no infections occurred among the animal-care staff (Martini 1973). Although African green monkeys, other nonhuman pri- mates, and other animals are susceptible and succumb to fatal infection, the natural reservoir for the virus has not been determined (Benenson 1995a; Simpson and others 1968). Mode of Transmission. The transmission of Marburg virus from animals to hu- mans has involved direct contact with infected tissues. Aerosol transmission has been suggested as a means of transmission among monkeys (Hunt and others 1978). Person-to-person transmission occurs by direct contact with contaminated blood, secretions, organs, or semen. Clinical Signs, Susceptibility, and Resistance. Marburg virus produces a serious disease, and apparently everyone is susceptible to it. After an incubation period of 4-16 d, humans develop fever, myalgia, headache, and conjunctival suffusion. Nausea, vomiting, and severe diarrhea appear within 2-3 d with thrombocytope- nia and leukopenia. Other organ involvement can include pancreatitis, orchitis, hepatocellular necrosis, and a maculopapular rash. Abnormalities in the coagula- tion pattern indicative of disseminated intravascular coagulation occur and might be the proximate cause of death in one-fourth of the cases. Diagnosis and Prevention. The diagnosis of Marburg-virus infection depends primarily on isolation of the virus from blood or tissue specimens. Immunofluo- rescent staining has demonstrated viral antigen in tissue samples with high con- centrations of infectious materials. An immunofluorescence assay also has been developed to detect serum antibodies in recovering patients (Fox and Lipman 1991; Jahrling 1989). SALS recommends that work with Marburg virus be conducted at the equiva- lent of Biosafety Level 4 (CDC-NIH 1993).

ZOONOSES 71 Hantavirus Infection (Hemorrhagic Fever with Renal Syndrome and Nephropathia Endemica) Reservoir and Incidence. Hantavirus is one of several genera in the family Bunyaviridae that can cause severe hemorrhagic disease. The hantaviruses are widely distributed in nature among wild-rodent reservoirs, and the severity of the disease produced depends on the virulence of the strain involved (Gajdusek 1982; LeDuc 1987). Strains producing hemorrhagic fever with renal syndrome are prevalent in southeastern Asia and Japan and focally throughout Eurasia. Strains producing a less-severe form of the disease known as nephropathia endemica occur throughout Scandinavia, Europe, and western portions of the former Soviet Union. Outbreaks of hantavirus infection characterized by a severe pulmonary syndrome resulting in numerous deaths were recently recognized in the south- western United States (CDC 1993a,b; CDC 1995, CDC 1996). Rodents in numerous genera (Apodemus, Clethrionomys, Mus, Rattus, Pitimys, and Microtus) have been implicated in foreign outbreaks of the disease. In the United States, serological surveys have detected evidence of hantavirus infection in urban and rural areas involving the following rodents: Rattus norvegicus, Peromyscus spp., Microtus californicus, Tamias spp., and Neotoma spp. (CDC 1993a,b; Tsai and others 1985). Numerous cases of hantavirus infec- tion have occurred in laboratory animal facility people from exposure to infected rats (Rattus), including outbreaks in Korea, Japan, Belgium, France, and England (LeDuc 1987). There is also epidemiologic evidence that cats can become in- fected through rodent contact and potentially serve as a reservoir (Xu and others 1987). Mode of Transmission. The transmission of hantavirus infection is through the inhalation of infectious aerosols, and extremely brief exposure times (5 min) have resulted in human infection. Rodents shed the virus in their respiratory secretions, saliva, urine, and feces for many months (Tsai 1987). Transmission of the infection also can occur by animal bite or when dried materials contaminated with rodent excreta are disturbed, allowing wound contamination, conjunctival exposure, or ingestion to occur (CDC 1993a,b). The recent cases that have oc- curred in the laboratory-animal environment have involved infected laboratory rats. In such an environment, the possibility of transmitting the infection from animal to animal by the transplantation of cells or tissues also should be consid- ered (Kawamata and others 1987). Person-to-person transmission apparently is not a feature of hantavirus infection. Clinical Signs, Susceptibility, and Resistance. The clinical signs are related to the strain of hantavirus involved. The form of the disease known as nephropathia endemica is characterized by fever, back pain, and a nephritis that causes only moderate renal dysfunction, from which the patient recovers; in the recent cases

72 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS in the United States, patients had fever, myalgia, headache, and cough followed by rapid respiratory failure (CDC 1993a,b). The form of the disease that has been noted after laboratory-animal exposure fits the classical pattern of hemorrhagic fever with renal syndrome; the infection is characterized by fever, headache, myalgia, and petechiae and other hemorrhagic manifestations, including anemia, gastrointestinal bleeding, oliguria, hematuria, severe electrolyte abnormalities, and shock (Lee and Johnson 1982). Diagnosis and Prevention. Human hantavirus infections associated with the care and use of laboratory animals should be prevented through the isolation or elimi- nation of infected rodents and rodent tissues before they can be introduced into resident laboratory-animal populations. Serodiagnostic tests are available for both animals and humans. Additional information about serological testing is avail- able through the Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC. Rodent tumors and cell lines can be tested for hantavirus contamination with a modified rat-antibody production test. People suspected of having the infection might benefit from intravenous ribavirin therapy initiated early in the course of the disease (Morrison and Rathbun 1995). Hemodynamic maintenance and respiratory support are criti- cal for these people after infection. Animal Biosafety Level 2 is recommended for working with experimentally infected rodent species known not to excrete the virus. All work involving inoculation of the virus into P. maniculatus or other permissive species should be conducted at Animal Biosafety Level 4 (CDC 1994b). Lymphocytic Choriomeningitis Virus Infection Reservoir and Incidence. Lymphocytic choriomeningitis (LCM) virus is a mem- ber of the family Arenaviridae, which consists of single-stranded-RNA viruses with a predilection for rodent reservoirs. Several important zoonoses are associ- ated with this family, including Lassa fever and Argentine and Bolivian hemor- rhagic fevers, but only LCM is important as a natural infection of laboratory animals. Human infection with LCM associated with laboratory-animal and pet contact has been recorded on numerous occasions (Fox and others 1984; Jahrling and Peters 1992). LCM is widely distributed among wild mice throughout most of the world and presents a zoonotic hazard. Many laboratory-animal species are infected naturally, including mice, hamsters, guinea pigs, nonhuman primates, swine, and dogs; but the mouse has remained the species of primary concern in the consideration of this disease, as it was in a recent outbreak of LCM in humans (Dykewicz and others 1992). Athymic, severe-combined-immunodeficiency (SCID), and other immunodeficient mice can pose a special risk of harboring silent, chronic infections and present a hazard to personnel (CDC-NIH 1993; Dykewicz and others 1992).

ZOONOSES 73 Mode of Transmission. The LCM virus produces a pantropic infection under some circumstances and can be present in blood, cerebrospinal fluid, urine, na- sopharyngeal secretions, feces, and tissues of infected natural hosts and possibly humans. Bedding material and other fomites contaminated by LCM-infected animals are potential sources of infection, as are infected ectoparasites. In en- demically infected mouse and hamster colonies, the virus is transmitted in utero or early in the neonatal period and produces a tolerant infection characterized by chronic viremia and viruria without marked clinical disease; spread of LCM among animals via contaminated tumors and cell lines also should be recognized (Bhatt and others 1986; Nicklas and others 1993). Infection in humans can be by parenteral inoculation, inhalation, and contamination of mucous membranes or broken skin with infectious tissues or fluids from infected animals. Aerosol trans- mission is well documented. The virus can pose a special risk during pregnancy: that of infection of the fetus. Clinical Signs, Susceptibility, and Resistance. Humans develop an influenza-like illness characterized by fever, myalgia, headache, and malaise after an incubation period of 1-3 wk. In severe cases of the disease, patients might develop a macu- lopapular rash, lymphadenopathy, meningoencephalitis, and, rarely, orchitis, ar- thritis, and epicarditis (Johnson 1990b). Central nervous system involvement has resulted in several deaths (Benenson 1995b). Diagnosis and Prevention. Virus isolation from blood or spinal fluid in conjunc- tion with immunofluorescence assay of inoculated cell cultures is the main method of diagnosing acute disease. Antibody is detectable with such an assay about 2 wk after the onset of illness. Prevention of this disease in the laboratory is achieved through the periodic serological surveillance of new animals that have inadequate disease profiles and of resident animal colonies at risk and through screening for the presence of LCM in all tumors and cell lines intended for animal passage. Intravenous ribavirin therapy substantially reduces mortality in patients infected with Lassa fever virus and also might be useful for LCM virus (Andrei and De Clercq 1993). Additional information about therapy and serological test- ing for LCM is available through the Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC. Animal Biosafety Level 2 is recommended for studies in adult mice with mouse brain-passage strains. Animal Biosafety Level 3 should be used for work with infected hamsters (CDC-NIH 1993). Poxvirus Diseases of Nonhuman Primates (Monkeypox and Benign Epidermal Monkeypox) Reservoir and Incidence. Monkeypox is an orthopoxvirus closely related to small- pox and produces a clinical disease similar to smallpox. Sporadic cases of the

74 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS human disease are noted in Africa. Recently, squirrels of the genera Funisciurus and Heliosciurus have been identified as hosts and important reservoirs of the virus (Benenson 1995b). Natural outbreaks of monkeypox also have been re- corded in nonhuman primates in the wild and laboratory settings (Fox and others 1984). Benign epidermal monkeypox, or tanapox, is a poxvirus that affects mon- keys of the genus Presbytis in Africa and captive macaques in the United States. Mode of Transmission. The transmission of monkeypox from laboratory nonhu- man-primate populations to humans has not been recorded. Human-to-human transmission of the agent has occurred, presumably through close contact with active lesions, recently contaminated fomites, or respiratory secretions. The pos- sibility of zoonotic spread should be considered. Benign epidermal monkeypox has been transmitted from monkeys to hu- mans in the laboratory-animal environment (McNulty 1968). Direct contact with infected animals or contaminated fomites is necessary for disease transmission. Clinical Signs, Susceptibility, and Resistance. Monkeypox is of interest and im- portance primarily because it produces a disease similar to smallpox character- ized by fever, malaise, headache, severe backache, prostration, and occasional abdominal pain. Lymphadenopathy and a maculopustular rash develop later. Some patients develop a severe fulminating disease and die. Benign epidermal monkeypox is characterized by the development of cir- cumscribed, oval to circular, raised red lesions usually on the eyelids, face, body, or genitalia. The lesions regress spontaneously in 4-6 wk. Diagnosis and Prevention. The diagnosis of poxvirus infections can be estab- lished on the basis of the characteristic structure of viral particles as seen with the electron microscope. Virus isolation on chick chorioallantoic membrane and char- acterization with specific biological tests are needed to differentiate among the various orthopoxviruses. Vaccinia vaccination is protective against monkeypox in humans and monkeys (Benenson 1995b). Orf Disease (Contagious Ecthyma and Contagious Pustular Dermatitis) Reservoir and Incidence. Orf disease is a poxvirus infection that is endemic in many sheep flocks and goat herds throughout the United States and worldwide. The disease affects all age groups, although young animals are most often and most severely affected. Orf produces proliferative, pustular encrustations on the lips, nostrils, mucous membranes of the oral cavity, and urogenital orifices of infected animals (Fox and others 1984). Mode of Transmission. Orf, a double-stranded-DNA virus, is transmitted to hu-

ZOONOSES 75 mans by direct contact with virus-laden lesion exudates. External lesions are not always apparent, so recognition can be difficult. Transmission of the agent by fomites or contaminated animals is possible because of its environmental persis- tence. Rare cases of person-to-person transmission have been recorded (Benenson 1995b). Clinical Signs, Susceptibility, and Resistance. The disease in humans is usually characterized by the development of a solitary lesion on the hand, arm, or face. The lesion is initially maculopapular or pustular and progresses to a weeping proliferative nodule with central umbilication. Such lesions are sometimes mis- taken for abscesses but should not be lanced. Occasionally, several nodules are present, each measuring up to 3 cm in diameter, persisting for 3-6 wk and regress- ing spontaneously. Regional adenitis is uncommon, and progression to general- ized disease is considered rare (Erickson and others 1975). Diagnosis and Prevention. The characteristic appearance of the lesion and a history of recent contact with sheep or goats are diagnostic of this condition in humans. Vaccination of susceptible sheep and goats is effective in preventing the disease. Personnel who handle sheep and goats should be cautioned to wear protective clothing and gloves and to practice good personal hygiene. Measles (Rubeola) Reservoir and Incidence. Humans are the reservoir for measles. Nonhuman pri- mates become infected through contact with human populations with endemic measles (Fox and others 1984). Both Old World and New World nonhuman primates are susceptible to infection (Fox and others 1984). The disease spreads rapidly through infected nonhuman-primate colonies; wild-caught nonhuman- primate populations often attain a 100% seroconversion rate within several weeks of capture. However, with the current emphasis on and success of domestic nonhuman-primate production, institutions could develop large populations of susceptible nonhuman primates. Mode of Transmission. Measles, a highly communicable disease, is transmitted via infectious aerosols, contact with nasal or throat secretions, or contact with fomites freshly contaminated with infectious secretions. Clinical Signs, Susceptibility, and Resistance. The clinical signs of measles are similar in nonhuman primates and humans. In humans, fever develops after an incubation period of about 10 d and is followed by conjunctivitis, coryza, cough, and Koplik’s spots inside the mouth. Later, a characteristic exanthematous rash develops, beginning on the face, becoming generalized over the body, and ending sometimes in flaky desquamation. Complications of viral replication or second-

76 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS ary bacterial infection can result in pneumonia, otitis media, diarrhea, or, rarely, encephalitis (Benenson 1995b). Diagnosis and Prevention. Characteristic clinical signs generally make diagnos- tic methods unnecessary, but serology, immunofluorescent-antibody screening for virus in clinical specimens, or viral isolation can be used. Vaccination of all nonhuman-primate handlers against measles should be ensured, and vaccination of nonhuman-primate populations also should be considered. Newcastle Disease Reservoir and Incidence. Newcastle disease is caused by a paramyxovirus. It is seen among wild, pet, and domestic birds, and wild birds transmit the infection to domestic-bird populations (Bryant 1984). The zoonotic potential of the agent in the laboratory environment has been realized on numerous occasions (Barkley and Richardson 1984). Mode of Transmission. Aerosol transmission is the important means of spread, but contaminated food, water, and equipment also transmit infection within bird populations. Clinical Signs, Susceptibility, and Resistance. The severity of the disease in birds depends on the pathogenicity of the infecting strain. Highly pathogenic strains have been largely excluded from flocks within the United States. Moderately pathogenic strains produce anorexia and respiratory disease in adult birds and neurological signs in young birds. The disease in humans is characterized by follicular conjunctivitis, mild fever, and respiratory involvement ranging from cough to bronchiolitis and pneumonia. Diagnosis and Prevention. In the laboratory environment, the disease can be prevented by immunizing susceptible birds against it or obtaining birds from flocks known to be free of the agent. Good personal-hygiene practices also should be in place. Hepatitis A Reservoir and Incidence. Humans are the primary reservoir for hepatitis A virus (HAV), and nonhuman-primate infections result from contact with infected hu- mans. However, more than 200 cases of HAV infection in humans have been associated with nonhuman primates (Barkley and Richardson 1984), and many nonhuman-primate species are susceptible, including chimpanzees and other great apes, marmosets, owl monkeys, cynomolgus monkeys, and patas monkeys (Fox and Lipman 1991; Hollinger and Glombicki 1990). A recent outbreak of HAV

ZOONOSES 77 infection in young, domestically reared rhesus monkeys has renewed the concern for potential zoonotic transmission (Lankas and Jensen 1987). Mode of Transmission. HAV is transmitted by the fecal-oral route, and some outbreaks can be related to contaminated food and water. Clinical Signs, Susceptibility, and Resistance. The disease in nonhuman primates is much less severe than the disease in humans and is often subclinical. Some species of nonhuman primates develop malaise, vomiting, jaundice, and increased serum concentrations of hepatic enzymes. The disease in humans varies from a mild illness lasting 1-2 wk to a severely debilitating illness lasting several months. After an incubation period of about a month, patients experience an abrupt onset of fever, malaise, anorexia, nausea, and abdominal discomfort, followed within a few days by jaundice. Children often have mild disease without jaundice, whereas HAV infections in older pa- tients can be fulminant and protracted with prolonged convalescence. Diagnosis and Prevention. Enzyme immunoassay and radioimmunoassay are available for the demonstration of immunoglobulin M-specific anti-HAV in the serum or plasma. Alternatively, fecal samples can be tested for virus particles or viral antigen. An approved vaccine is now available for the control of HAV infection in humans. Passive immunization with immune serum globulin has also been used at intervals of 4-6 mo for personnel in contact with recently imported chimpan- zees (Fox and Lipman 1991). The use of protective clothing, good personal hygiene, and appropriate practices of sanitation of equipment and facilities also will minimize the potential for zoonotic transmission. Hepatitis B, C, D, and E Humans are considered the natural host for hepatitis B, C, D, and E viruses (Benenson 1995b). Various nonhuman primates, particularly chimpanzees, can be infected experimentally, but only one case of natural infection has been re- ported (Kornegay and others 1985). Viral hepatitis B has been suggested in recently imported cynomolgus monkeys by the demonstration of hepatitis B sur- face antigen in hepatic cells (Kornegay and others 1985), but it was not associ- ated with zoonotic disease transmission; these animals developed mild clinical disease characterized by anorexia, increased hepatic enzyme concentrations, and hyperbilirubinemia. Although natural infections of nonhuman primates with hepa- titis B, C, D, and E viruses are extremely rare, personnel should adhere to appro- priate precautions when handling nonhuman primates. Animal Biosafety Level 2 practices, containment equipment, and facilities are recommended for activities using naturally or experimentally infected chim-

78 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS panzees or other nonhuman primates. Licensed recombinant vaccines against hepatitis B are available and highly recommended for personnel involved in studies with hepatitis B virus (CDC-NIH 1993). Simian Immunodeficiency Virus (SIV) Infection Reservoir and Incidence. Simian immunodeficiency virus (SIV) is a lentivirus that produces in rhesus monkeys and other susceptible macaque species a clinical syndrome that has many important parallels to AIDS. Although the seroprevalence of SIV in Asian macaques is low and most SIV infections in these species are related to their use as animal models of AIDS, the seroprevalence among wild-caught African green monkeys (Cercopithecus aethiops), which ap- parently does not manifest clinical signs, is about 30% or higher (Lairmore and others 1989). Mode of Transmission. Transmission of SIV between monkeys is believed to require direct inoculation of open wounds or mucous membranes with infectious secretions. Aerosol transmission between monkeys has not been demonstrated where uninfected macaques have been housed in separate cages near SIV-in- fected monkeys (Lairmore and others 1989). The blood, secretions, and tissues of SIV-infected monkeys should be presumed to be infectious for persons poten- tially exposed to these materials. Two human cases of seroconversion associated with known exposure have been recognized (CDC 1992a; Khabbaz and others 1992), and a blind serological survey of other personnel working with SIV has identified perhaps an additional three seropositive persons. The possible inclu- sion of the aforementioned cases of known SIV exposure and the cross reactivity of SIV and HIV-2 in the assay used confounded the interpretation of the results of this survey (CDC 1992b). The person involved in the first case had a skin punc- ture caused accidentally by a needle contaminated by the blood of an infected macaque. In the second case, a laboratory worker who had hand and forearm dermatitis handled SIV-infected blood specimens without wearing gloves. The pattern of seroreactivity suggested the possibility of infection in the second case, and attempts to isolate SIV from this person were successful (Khabbaz and others 1992). Clinical Signs, Susceptibility, and Resistance. Clinical signs have not been re- corded in cases of human SIV exposure. Diagnosis and Prevention. Serological techniques and virus isolation are avail- able for the diagnosis of SIV exposure and infection. Personnel should be en- rolled in a medical-surveillance program and maintain work practices consistent with the handling of bloodborne pathogens (CDC 1988). Animal Biosafety Level 2 practices, containment equipment, and facilities are recommended for

ZOONOSES 79 activities using naturally or experimentally infected nonhuman primates or other animals. Rabies Reservoir and Incidence. Rabies occurs worldwide except for a few countries that have excluded the disease through animal-importation and animal-control programs and the aid of geographic barriers (Fox and others 1984). Rabies virus infects all mammals, but the main reservoirs are wild and domestic canines, cats, skunks, raccoons, bats, and other biting animals. The disease historically has not posed a problem in the laboratory-animal setting. However, the incidence of rabies in wildlife in the United States has been rising in recent years, and the possibility of rabies transmission to dogs or cats with uncertain vaccination histo- ries and originating in an uncontrolled environment must be considered. In addi- tion, rabies-susceptible wildlife introduced into the laboratory for special re- search investigations have the potential to harbor infection. Mode of Transmission. Rabies virus is most commonly transmitted by the bite of a rabid animal or the introduction of virus-laden saliva into a fresh skin wound or an intact mucous membrane. Airborne transmission probably can occur in caves where rabid bats roost, but this mode of transmission is extremely unlikely in the laboratory (Benenson 1995b). The virus also has been transmitted through cor- neal transplants from persons with undiagnosed central nervous system disease. Personnel who handle tissue specimens or other materials potentially laden with rabies virus during necropsy or other procedures should be regarded as at risk for infection. Clinical Signs, Susceptibility, and Resistance. Rabies produces an almost invari- ably fatal acute viral encephalomyelitis. Patients experience a period of appre- hension and develop headache, malaise, fever, and indefinite sensory changes referred to the site of a prior animal-bite wound. Further progression of the disease is marked by paresis or paralysis, inability to swallow and the related hydrophobia, delirium, convulsions, and coma. Death is often due to respiratory paralysis. Diagnosis and Prevention. Rabies usually is diagnosed with specific immuno- fluorescent antibody staining of brain tissue, corneal smears, mucosal scrapings, or frozen skin-biopsy specimens. Virus isolation also can be used to confirm the diagnosis. The most important factor in preventing human rabies, apart from the immediate and thorough cleaning of bite and scratch wounds, is control of the disease in the domestic-animal population. Stringent vaccination measures and enforced animal-control measures help to reduce the population at risk. When- ever possible, animals brought into the laboratory should have histories that

80 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS preclude their exposure to rabies or ensure their having been vaccinated for this disease. Pre-exposure immunization should be available to personnel in high-risk categories, such as veterinarians, people who are working with or involved in the care of infected or inadequately characterized animals, and wildlife-conservation personnel who work in rabies-endemic areas. Animal Biosafety Level 2 prac- tices, containment equipment, and facilities are recommended for activities using naturally or experimentally infected animals (CDC-NIH 1993). Influenza Reservoir and Incidence. Humans are considered the reservoir for human-influ- enza viruses. Influenza-virus infections with different antigenic strains occur naturally in many animals, including avian species, swine, horses, mink, and seals (Benenson 1995b). Animal reservoirs are thought to contribute to the emer- gence of new human strains of influenza viruses, perhaps by reassortment of animal strains with human strains. In the laboratory, ferrets are highly susceptible to human influenza and often are used as experimental models of influenza (Fox and Lipman 1991). Mode of Transmission. Transmission is by the airborne route and by direct con- tact. The transmission of animal-influenza strains from animals to humans is rare (CDC-NIH 1993). However, ferrets housed in the laboratory will develop epi- zootic infection concomitant with human outbreaks of the disease. Ferret-to- human transmission of the virus also has been documented (Marini and others 1989). Clinical Signs, Susceptibility, and Resistance. Influenza is an acute disease of the respiratory tract characterized by fever, headache, myalgia, prostration, coryza, sore throat, and cough. Viral pneumonia and gastrointestinal involvement mani- fested by nausea, vomiting, and diarrhea also can develop. Diagnosis and Prevention. Personnel should wear appropriate protective clothing and practice good personal hygiene if contact with ferrets suspected of having influenza is unavoidable. Arboviral Infection Reservoir and Incidence. The arboviruses (arthropod-borne viruses) are taxo- nomically diverse, each involving its own web of mammalian or avian hosts (or both) and specific arthropod vectors (Benenson 1995b; Tsai 1991). The presence of arboviral infection among laboratory animals generally would be restricted to situations where these agents are the focus of experimental study, wild-caught animals are brought into the laboratory for study, or nontraditional laboratory

ZOONOSES 81 animals are housed outdoors, permitting the perpetuation of the natural cycle of arboviral infection. Mode of Transmission. Natural cycles of infection involve transmission from mosquitoes, ticks, midges, or sandflies (Benenson 1995b; Tsai 1991). In the laboratory setting, transmission can occur via parenteral inoculation, aerosol ex- posure, contamination of unprotected broken skin, and possibly animal bites (CDC-NIH 1993). Clinical Signs, Susceptibility, and Resistance. The clinical manifestations of arboviral infections are diverse, including fever, hemorrhagic fever, rash, arthral- gia, arthritis, meningitis, and encephalitis (Benenson 1995b). Diagnosis and Prevention. Personnel involved in research-animal studies of arboviral infections should observe strictly the biosafety-level practices deemed appropriate for the particular arboviral agent (CDC-NIH 1993, SALS 1980). Institutions sponsoring research programs involving wild-caught animals should ensure that veterinary and occupational-health personnel have performed an ad- equate review of the scientific literature to establish a potential-disease profile for the animal species under study and have implemented corresponding measures for personnel protection. RICKETTSIAL DISEASES Q Fever Reservoir and Incidence. Q fever is caused by the rickettsial agent Coxiella burnetii. C. burnetii has a worldwide distribution perpetuated in two intersecting cycles of infection—in domestic animals and in wildlife animals and their associ- ated ticks. Infection is widespread within the domestic-animal cycle, which in- cludes sheep, goats, and cattle. Cats, dogs, and domestic fowl also can be infected (Fox and others 1984). The prevalence of the infection among sheep is high throughout the United States, and sheep have been the primary species associated with outbreaks of the disease in laboratory-animal facilities (Bernard and others 1982). However, an outbreak of Q fever with one death in a human cohort exposed to a parturient cat and her litter and cases of the disease associated with exposure to rabbits indicate that other species should not be overlooked as pos- sible sources of the infection in the laboratory environment (Langley and others 1988; Marrie and others 1990). Mode of Transmission. Humans usually acquire this infection via inhalation of infectious aerosols, although transmission by ingestion has been recorded (Benenson 1995b). The organism is shed in urine, feces, milk, and especially

82 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS birth products of domestic ungulates, which generally are asymptomatic. The placenta of an infected ewe can contain up to 109 organisms per gram of tissue, and milk can contain 105 organisms per gram (CDC-NIH 1993). The organism is resistant to desiccation and persists in the environment for long periods, contrib- uting to the widespread dissemination of infectious aerosols. The risk of infection is high because the infectious dose by inhalation is less than 10 microorganisms (CDC-NIH 1993, Wedum and others 1972). The importance of those factors was evident in outbreaks of the disease associated with the use of pregnant sheep in research facilities in the United States when personnel became infected along the routes of sheep transport and in the vicinity of sheep surgery from contact with soiled linens (Bernard and others 1982). Clinical Signs, Susceptibility, and Resistance. The disease in humans varies widely in duration and severity, and asymptomatic infection is possible. The disease often has a sudden onset with fever, chills, retrobulbar headache, weak- ness, malaise, and profuse sweating. In some cases, pneumonitis occurs with a nonproductive cough, chest pain, and few other signs. Acute pericarditis and acute or chronic granulomatous hepatitis also have been reported. Endocarditis can occur on native or prosthetic cardiac valves and often extends over a period of months or years and results in relapsing systemic infection. Most cases of Q fever resolve within 2 wk (Benenson 1995b). Persons with valvular heart disease should not work with C. burnetii (CDC-NIH 1993). Diagnosis and Prevention. Serological methods available for the detection of a rise in specific antibody between acute and convalescent samples include microagglutination, immunofluorescent, complement fixation (CF), and ELISA tests. The organism can be isolated from blood or other tissues, but doing so poses a hazard for laboratory personnel. Recommendations for the control of Q fever in a research facility are avail- able and should be applied rigorously in surgical, laboratory, and housing areas used for sheep (Bernard and others 1982). In brief, the recommendations empha- size the need for the separation of sheep-research activities from other areas. Physical barriers or air-handling systems, the appropriate use and disposal of protective clothing, and the use of disinfectants in the sanitation and waste- management programs minimize the risk of exposure. Whenever possible, male or nonpregnant female sheep should be used in research programs. However, many research studies require the use of pregnant sheep. Neither antimicrobial therapy nor serological testing in combination with the culling of infected ani- mals has led to the reliable development of disease-free flocks for use in biomedi- cal-research programs (Fox and Lipman 1991). Serological monitoring of sheep for evidence of C. burnetii infection also is unrewarding because serological status is not a useful indicator of organism shedding. Since infected guinea pigs and other rodents may shed the organism in urine and feces, the CDC and NIH

ZOONOSES 83 recommend maintaining experimentally infected rodents under Animal Biosafety Level 3 (CDC-NIH 1993). An investigational new Phase 1 Q-fever vaccine is available from the Special Immunizations Program, US Army Medical Research Institute for Infectious Disease (USAMRIID), Fort Detrick, Maryland 21701. The use of this vaccine should be limited to personnel at high risk of exposure who have no demonstrated sensitivity to Q-fever antigen. Cat-Scratch Fever Reservoir and Incidence. Bartonella henselae, a newly described rickettsial or- ganism, has been directly associated with cat-scratch fever and bacillary angi- omatosis, an unrelated condition that develops usually in people infected with the human immunodeficiency virus (Koehler and others 1994). This gram-negative, pleomorphic organism has a predilection for intracellular growth and has been demonstrated to produce chronic, asymptomatic bacteremia, especially in younger cats, for at least 2.5 mo and possibly as many as 17 mo. The organism has been isolated on fleas that fed on infected cats, and fleas have been shown to be capable of transmitting the organism between cats. This finding suggests that fleas could serve as a vector in zoonotic transmission (Chomel and others 1996). Results of a recent prevalence survey indicated that about 40% of pet and pound cats examined had blood cultures positive for the organism and six of 13 house- holds with cats had at least one positive cat (Koehler and others 1994). Although cat-scratch fever usually has been associated with the scratch or bite of a young cat, other animals have been implicated, including dogs, monkeys, and porcu- pines (Goldstein 1990b). The incidence of the disease in humans is unknown; an estimate of 2.5 cases per 100,000 population per year has been proposed (Groves and others 1993). Mode of Transmission. Of patients with the disease, 75% report having been bitten or scratched by a cat, and over 90% report a history of exposure to a cat. Most cases of the disease appear between September and February, and the incidence peaks in December (Fox and others 1984). Clinical Signs, Susceptibility, and Resistance. The disease begins with inocula- tion of the organism into the skin of an extremity, usually a hand or forearm. A small erythematous papule appears at the site of inoculation several days later and is followed by vesicle and scab formation. The lesion resolves within a few days to a week. Several weeks later, regional lymphadenopathy appears, often in a solitary lymph node, and it can persist for months. Suppuration of the lymph node sometimes occurs. Fever, malaise, anorexia, headache, and splenomegaly can also be present. Other, less-frequent complications of the disease include periocular lymphadenopathy with palpebral conjunctivitis, central nervous sys-

84 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS tem involvement, osteolytic lesions, granulomatous hepatitis, and pneumonia. Cat-scratch fever can progress to a severe systemic or recurrent infection that is life-threatening in immunocompromised hosts. Such severe cases are reminiscent of bacillary angiomatosis, a condition of HIV-infected patients. Diagnosis and Prevention. Isolation of the causative organism from the blood, a cutaneous lesion, or biopsy material is required for a definitive diagnosis of cat- scratch fever. Clinical signs, a history of cat contact, failure to isolate other bacteria from affected tissues, and histopathological examination of lymph-node biopsies are used for diagnosis by most physicians (Groves and others 1993). Many patients can be found to be serologically positive for R. henselae with the indirect fluorescent-antibody test. The use of proper cat-handling techniques and protective clothing should minimize the likelihood of personnel exposure to the organism of cat-scratch fever. Clinical trials have indicated that antibiotic treatment can be used to elimi- nate the carrier state in cats (Koehler and others 1994), but this approach to disease prevention might be impeded by the current difficulty in detecting the carrier state. Flea-control measures should also be implemented. Other Rickettsial Diseases Reservoir and Incidence. Dogs, rodents, and their ticks and fleas are the reser- voirs for Rickettsia rickettsia. R. akari, R. prowazekii, and R. typhi are found in wild rodents and their associated fleas and mites (Fox and others 1984). Ehrlichia canis produces natural infection only in dogs; human infections result from the bites of infected ticks. These rickettsial infections are considered rare in the United States. Mode of Transmission. Zoonotic transmission of these diseases in the laboratory has involved aerosols, accidental parenteral inoculation, and bites by natural ectoparasitic vectors (CDC-NIH 1993). Clinical Signs, Susceptibility, and Resistance. These rickettsial diseases are char- acterized by fever, headache with encephalitis, myalgia, and a rash of varied distribution according to the species involved (Saah 1990). A rash does not develop in E. canis infections. Eschar development at the site of a vector bite is seen in R. rickettsia and R. akari infections. Diagnosis and Prevention. The rickettsial diseases generally are diagnosed sero- logically with complement-fixation and direct immunofluorescence tests. Concern for the zoonotic potential of these diseases in the laboratory should focus on situations where wild-caught rodents or other small mammals are brought into the laboratory for study or where feral-rodent infestation has oc-

ZOONOSES 85 curred. Ectoparasite control in such populations is essential, particularly the elimi- nation of Ornithonyssus bacoti, a free-living mite capable of transmitting some of the rickettsial agents (Fox and others 1984). Personnel who are conducting stud- ies with wild-caught animals also should be instructed to practice good laboratory safety and personal hygiene. BACTERIAL DISEASES Tuberculosis Reservoir and Incidence. Tuberculosis of animals and humans is caused by acid- fast bacilli of the genus Mycobacterium. Laboratory animals are potential reser- voirs of several mycobacterial species, including M. tuberculosis, M. avium- intracellulare, M. bovis, M. kansasii, M. simiae, M. marinum, and M. chelonae (Des Prez and Heim 1990; Saunders and Horowitz 1990). In addition to cattle, birds, and humans that serve as the main reservoirs for these mycobacteria, many laboratory animals—including nonhuman primates, swine, sheep, goats, rabbits, cats, dogs, and ferrets—are susceptible to infection and contribute to spread of the diseases (Fox and Lipman 1991). However, nonhuman primates are of pri- mary importance in the consideration of these diseases in the laboratory-animal environment. Contact with nonhuman primates infected with Mycobacterium spp. is a recognized risk factor in the development of a positive tuberculin skin reaction (Kaufman and others 1972). Nonhuman primates generally develop tuberculosis from humans during capture and exportation from parts of the world where the prevalence of the disease in humans and animals is high. However, the resur- gence of human tuberculosis in the United States and the recognition of nosoco- mial outbreaks of multiple-drug-resistant tuberculosis (CDC 1994a) should serve as reminders that nonhuman primates can continue to be at risk for contracting tuberculosis from humans after introduction into established research colonies. The close confinement of these animals in holding facilities and in shipment crates creates an environment conducive to the spread of infection. The incidence of infection in a population varies with the species and the source of the primates. A recent survey of tuberculosis in 22,913 imported nonhuman primates in the United States yielded an incidence of 0.4% (CDC 1993c). Although macaques are considered to be particularly sensitive to infection with M. tuberculosis, surveillance programs for tuberculosis should be extended to all species of non- human primates (Bennett and others 1995; CDC 1993c; NRC 1980). Mode of Transmission. M. tuberculosis is transmitted via aerosols from infected animals or tissues, and this mode of transmission also applies to most of the other mycobacterial species that might be encountered in laboratory-animal contact. Laboratory personnel involved in the care, use, or necropsy of infected animals

86 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS are especially at risk for tuberculosis. Humans can contract the disease in the laboratory through exposure to infectious aerosols generated by the handling of dirty bedding, the use of high-pressure water sanitizers, or the coughing of ani- mals with respiratory involvement. Other potential sources of exposure include fecal shedding by animals with enteric infection and skin exudates resulting from scrofuloderma or suppurative fistulated lymph nodes. Mycobacterial disease also can be spread by entry of the bacilli into the body by ingestion or wound contami- nation. Clinical Signs, Susceptibility, and Resistance. The most common form of tuber- culosis reflects the involvement of the pulmonary system and is characterized by cough, sputum production, and eventually hemoptysis. The incubation period for the development of a demonstrable primary lesion or a substantial secondary skin reaction is 4-12 wk. After that, the risk of progressive pulmonary or extrapul- monary disease remains highest during the next 1-2 yr, but recrudescence of a latent infection persists for the rest of a person’s life. Extrapulmonary forms of the disease can involve any tissue or organ system and include disseminated (miliary) infections of multiple organs due to the hematogenous spread of the organism, regional lymphadenitis, tuberculous meningitis, and disease of the pericardium, pleura, skeleton, intestines, peritoneum, kidneys, and skin. General symptoms as the disease progresses include weight loss, fatigue, lassitude, fever, chills, and cachexia. Diagnosis and Prevention. The diagnosis of tuberculosis in humans and nonhu- man primates relies primarily on the use of the intradermal tuberculin test, chest radiography, and the demonstration of acid-fast bacilli in sputum smears. Defini- tive diagnosis can be obtained by isolating organisms in body fluids or biopsy specimens and identifying them with biochemical techniques or DNA probes. Additional information can be found in guidelines established for the diagnosis and control of tuberculosis in humans (American Thoracic Society 1992; CDC 1994a); revisions have been proposed recently. The prevention and control of tuberculosis in a biomedical-research facility require personnel education, periodic surveillance for infection in nonhuman primates and their handlers, isolation and quarantine of any suspect animals and prompt euthanasia, necropsy, and microbiological and histopathological analysis of animals confirmed as positive. For extremely valuable animals, chemoprophy- laxis with effective antituberculosis agents may be elected (Wolf and others 1988). The CDC and NIH recommend Animal Biosafety Level 3 for animal studies using nonhuman primates experimentally or naturally infected with M. tubercu- losis or M. bovis. Experimentally infected guinea pigs and mice pose a lesser risk to personnel because droplet nuclei are not produced by coughing in these spe- cies; however it is prudent to use Animal Biosafety Level 3 for these infected

ZOONOSES 87 laboratory animals because contaminated litter can be a source of infectious aerosols (CDC-NIH 1993). The vaccination of nonhuman primates with the bacillus Calmette Guérin (BCG) strain of M. bovis also can be considered. However, the use of BCG does not prevent infection but only suppresses proliferation of the organism to prevent the development of clinical disease (Sutherland and Lindgren 1979). Further- more, this vaccination complicates the use of the tuberculin test for surveillance because those vaccinated become skin-test-positive. Institutions should consider the implications of BCG vaccination as related to disease monitoring and man- agement in nonhuman primates and the assignment of personnel to the care of these species. Personnel who convert to a positive tuberculin skin reaction should be evaluated further. Institutions should recognize the risk that such personnel pose for nonhuman-primate populations; it might warrant their reassignment to work with other animals. Consistent institutional policies should be developed to address this issue. Psittacosis (Ornithosis, Parrot Fever, Chlamydiosis) Reservoir and Incidence. The genus Chlamydia contains three species: C. psittaci, C. trachomatis, and C. pneumoniae. Only C. psittaci is widely distributed among animals and is recognized as a zoonotic pathogen. C. psittaci is distributed widely among birds and mammals worldwide and occurs naturally among many labora- tory species, including birds, mice, guinea pigs, rabbits, ruminants, swine, cats, ferrets, muskrats, and frogs (Fox and others 1984; Storz 1971). Mode of Transmission. C. psittaci produces a diverse spectrum of conditions in animals, including conjunctivitis, pneumonitis, air sacculitis, pericarditis, hepati- tis, enteritis, arthritis, meningoencephalitis, urethritis, endometritis, and abortion. Latency is a common characteristic of the infections and is especially important in the epizootology of the disease in birds; stress can reactivate enteric shedding of the organism and clinical signs. The organism is spread to humans from infectious material in exudates, secretions, or desiccated fecal material via direct contact or the aerosol route. Clinical Signs, Susceptibility, and Resistance. In general, the C. psittaci strains associated with mammalian infections are less pathogenic for humans than the avian strains of the organism (Schachter and Dawson 1978). Human conjunctivi- tis has been observed in people involved in the care of cats with chlamydial conjunctivitis and pneumonitis (Schachter and others 1969). Human abortion resulting from infection with a C. psittaci strain that is associated with abortions in sheep also has been recorded (Hadley and others 1992). The progression of disease in humans related to infection with avian strains of C. psittaci includes fever, headache, myalgia, chills, and upper or lower respi-

88 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS ratory tract disease. More serious manifestations of disease also can occur, such as extensive pneumonia, hepatitis, myocarditis, thrombophlebitis, and encephali- tis. Relapses occur in untreated infections (Benenson 1995b). Diagnosis and Prevention. Psittacosis can be diagnosed with serological tests for specific antibody or isolation of the organism. Psittacosis can be prevented by permitting birds only from disease-free flocks to be introduced into an animal facility. If wild-caught birds or birds of unknown disease status are brought into a facility, chlortetracycline chemoprophylaxis should be instituted in these birds. Cases of chlamydiosis in other animals should be treated promptly to prevent the spread of infection to personnel who work with them. Animal Biosafety Level 2 practices, containment equipment and facilities, and respiratory protection are recommended for personnel working with natu- rally or experimentally infected caged birds (CDC-NIH 1993). Rat-Bite Fever Reservoir and Incidence. Rat-bite fever is caused by either Streptobacillus moniliformis or Spirillum minor, two microorganisms that are present in the upper respiratory tracts and oral cavities of asymptomatic rodents, especially rats (Anderson and others 1983). These organisms are present worldwide in rodent populations,. although efforts by commercial suppliers of laboratory rodents to eliminate Strep. moniliformis from their rodent colonies now appear to have been largely successful. The form of the disease caused by Spir. minor can be differen- tiated clinically from the form due to Strep. moniliformis and is generally more common in Asia. Several cases of the disease in laboratory-animal handlers have been reported in recent years (Anderson and others 1983; Taylor and others 1984). Mode of Transmission. Most human cases result from a bite wound inoculated with nasopharyngeal secretions, but sporadic cases have occurred without a his- tory of rat bite. Infection also has been transmitted via blood of an experimental animal. Persons working or living in rat-infested areas have become infected even without direct contact with rats (Benenson 1995b). Clinical Signs, Susceptibility, and Resistance. In Strep. moniliformis infections, patients develop chills, fever, malaise, headache, and muscle pain and then a maculopapular or petechial rash most evident on the extremities. Arthritis occurs in 50% of Strep. moniliformis cases but is considered rare in Spir. minor infec- tions. One or more large joints usually become painful and enlarged and contain a serous to purulent effusion. Complications of untreated cases of the disease

ZOONOSES 89 include focal abscesses, endocarditis, and, less frequently, pneumonia, hepatitis, pyelonephritis, and enteritis. Diagnosis and Prevention. The disease is diagnosed by isolating the causative organisms, both of which have unusual growth requirements (Fox and others 1984). Strep. moniliformis can be isolated in vitro from joint fluid, but Spir. minor requires animal inoculation and identification of the organism with dark- field microscopy. Proper animal-handling techniques are critical to the prevention of rat-bite fever. Plague Reservoir and Incidence. Plague, caused by Yersinia pestis, has never been rec- ognized as an important disease entity in the laboratory-animal setting. However, focal outbreaks of this once-devastating disease continue to be recognized world- wide, including in the United States, where the disease exists in wild rodents in the western one-third of the country. In the United States, most human cases are related to wild rodents, but cats, dogs, coyotes, rabbits, and goats have also been associated with human infection (Rollag and others 1981; Rosner 1987). Mode of Transmission. Most human cases are the result of bites by infected fleas or contact with infected rodents. In human plague associated with nonrodent species, infection has resulted from bites or scratches, handling of infected ani- mals (especially cats with pneumonic disease), ingestion of infected tissues, and contact with infected tissues. Nonrodent species can serve as transporters of fleas from infected rodents into the laboratory (Fox and others 1984). Clinical Signs, Susceptibility, and Resistance. Human plague has a localized (bubonic) form and a septicemic form. In bubonic plague, patients have fever and large, swollen, inflamed, and tender lymph nodes, which can suppurate. The bubonic form can progress to septicemic plague with dissemination of the organ- ism to diverse parts of the body, including the lungs and meninges. The develop- ment of secondary pneumonic plague is of special importance because aerosol droplets can serve as a source of primary pneumonic or pharyngeal plague, creat- ing a potential for epidemic disease. Diagnosis and Prevention. Many tests are used for early rapid diagnosis of plague, including direct microscopic examination of clinical specimens, a fluorescent- antibody (FA) test of tissue specimens, and an antigen-capture ELISA test. Diag- nosis is confirmed by culture and identification of the organism or demonstration of a change in antibody titer by a factor of 4 or more (Benenson 1995b). Preventive measures in a laboratory-animal facility should encompass the

90 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS control of wild rodents and the quarantine, examination, and ectoparasite treat- ment of incoming animals with potential infection. Those measures need to be applied continuously for animals that are housed outdoors and therefore have an opportunity for contact with plague-infected animals or their fleas. Vaccines are available for personnel in high-risk categories but confer only brief immunity (Benenson 1995b). Animal Biosafety Level 2 practices, containment equipment and facilities are recommended for personnel working with naturally or experimentally in- fected animals (CDC-NIH 1993). Brucellosis Reservoir and Incidence. The incidence of brucellosis, which is caused by Bru- cella spp., in agricultural species in the United States is low because eradication of the disease is emphasized. Foci of infection persist in cattle, swine, and rumi- nant populations. Although zoonotic transmission of the disease from those spe- cies is not considered important in the laboratory, B. suis of swine might achieve importance as the use of swine in the laboratory increases. B. canis in dogs remains a zoonotic hazard in the laboratory-animal facility; canine brucellosis has been identified in dog-production colonies and in 1-6% of dog populations, depending on the geographic area sampled (Fox and others 1984). Mode of Transmission. Most of the reported human cases of B. canis infection have resulted from contact with aborting bitches, and placental tissues are typi- cally rich in organisms in infected animals. B. canis also produces prolonged bacteremia and can be present in the urine of infected animals (Mumford and others 1975). Direct contact with the skin or mucous membranes during speci- men handling or preparation in the laboratory has resulted in transmission; aero- sol transmission also has resulted in large outbreaks of the disease in the labora- tory setting. The portal of entry is less well defined in animal-associated transmission of the disease, and a low incidence of seroconversion after exposure might indicate a low likelihood of transmission of the disease. Clinical Signs, Susceptibility, and Resistance. Human infection with B. canis is characterized by fever, headache, chills, myalgia, nausea, and weight loss. Bacte- remia can occur, and other systemic involvement is manifested by generalized lymphadenopathy and splenomegaly. Subclinical and inapparent infections also can occur (Benenson 1995b), as evidenced by the seroconversion of 0.5% of asymptomatic military personnel who had contact with infected dogs (Mumford and others 1975). Diagnosis and Prevention. Organism isolation and serological tests that show a rise in antibody titer are the principal means of diagnosis. Preventive measures

ZOONOSES 91 should be aimed at excluding infected animals from the facility. Animal handlers should wear appropriate protective clothing and practice good personal hygiene to prevent transmission. Animal Biosafety Level 3 practices, containment equipment and facilities are recommended for animal studies involving B. canis, B. abortus, B. melitensis, or B. suis (CDC-NIH 1993). Leptospirosis Reservoir and Incidence. Leptospirosis has a worldwide distribution in domestic and wild animals. Rats, mice, field moles, hedgehogs, squirrels, gerbils, ham- sters, rabbits, dogs, domestic livestock, other mammals, amphibians, and reptiles are among the animals that are considered reservoir hosts (Benenson 1995b; Hanson 1982). Pathogenic leptospires belong to the species Leptospirosis interrogans and are divided into serovars according to serological reactivity. In the United States, the predominant serovars are L. icterohaemorrhagia (in rats and dogs), L. pomona (in swine), L. hardjo (in cattle), L. canicola (in dogs), L. autumnalis (in raccoons), and L. bratislava (in swine). Rats and mice are com- mon hosts of L. ballum, which also has been found in other wildlife, including skunks, rabbits, opossums, and wild cats (Fox and others 1984). The possibility of zoonotic transmission of leptospirosis from most animal species maintained in the laboratory would have to be considered. Several recent outbreaks of the disease in laboratory animals emphasize the continued importance of this zoono- sis in the laboratory-animal facility (Alexander 1984; Barkin and others 1974; Geller 1979). Mode of Transmission. Leptospires are shed in the urine of reservoir animals, which often remain asymptomatic and carry the organism in their renal tubules for years. Mice infected with L. ballum are believed to harbor the organism for life (Fox and others 1984). Transmission occurs through skin abrasions and mu- cous membranes and is often related to direct contact with urine or tissues of infected animals. Inhalation of infectious droplet aerosols and ingestion also are effective modes of transmission. Clinical Signs, Susceptibility, and Resistance. The manifestations of this disease are diverse, ranging from inapparent infection to severe systemic illness (Benenson 1995b). Common features are fever with sudden onset, headache, chills, myalgia, and conjunctival suffusion. Other manifestations of the disease are orchitis, rash, hemorrhage into the skin and mucous membranes, hemolytic anemia, hepatorenal failure and jaundice, mental confusion with encephalitis, and pulmonary involvement. Diagnosis and Prevention. Leptospirosis is diagnosed by showing rising anti-

92 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS body titers in serological tests, such as the microscopic agglutination test, or by isolating the organism. Efforts to prevent this zoonotic disease in a laboratory- animal facility should focus on effective control of the infection in laboratory- animal populations and use of protective clothing and gloves by personnel. Campylobacteriosis Reservoir and Incidence. Organisms of the genus Campylobacter have been recognized as a leading cause of diarrhea in humans and animals in recent years, and numerous cases involving the zoonotic transmission of the organisms in pet and laboratory animals have been described (Blaser and others 1980; Deming and others 1987; Fox 1982; Fox and others 1989a,b; Russell and others 1990). Re- sults of prevalence studies on dogs, cats, nonhuman primates, and group-housed animals suggest that young animals readily acquire the infection and shed the organism; young animals often are implicated as the source of infection in zoonotic transmission. Mode of Transmission. The organism is transmitted by the fecal-oral route via contaminated food or water or direct contact with infected animals. Clinical Signs, Susceptibility, and Resistance. Campylobacters produce an acute gastrointestinal illness, which in most cases is brief and self-limiting. The clinical signs of campylobacter enteritis include watery diarrhea, sometimes with mucus, blood, and leukocytes; abdominal pain; fever; and nausea and vomiting. The infection generally resolves with specific antimicrobial therapy. Unusual compli- cations of the disease include a typhoid-like syndrome, reactive arthritis, hepati- tis, interstitial nephritis, hemolytic-uremic syndrome, febrile convulsions, menin- gitis, and Guillain-Barré syndrome (Benenson 1995b, Blaser 1990). Diagnosis and Prevention. Organism isolation is used to diagnose campylobacter infection. Although the treatment of animals with campylobacter enteritis is use- ful in the control of the infection, the attempt to eliminate the carrier state in asymptomatic animals might be less rewarding. Personnel should rely on the use of protective clothing, personal hygiene, and sanitation measures to prevent the transmission of the disease. Animal Biosafety Level 2 is recommended for activities using naturally or experimentally infected animals (CDC-NIH 1993). Salmonellosis Reservoir and Incidence. Enteric infection with Salmonella spp. has a worldwide distribution among humans and animals. Among the laboratory-animal species, rodents from many sources are now free from salmonella infection because of

ZOONOSES 93 successful programs of cesarean rederivation accompanied by rigorous manage- ment practices to exclude the recontamination of animal colonies. The pasteur- ization of feeds also has contributed to the control of salmonellae in laboratory- animal populations. However, despite those efforts to eliminate the organisms in laboratory-animal populations, salmonella carriers continue to occur as a result of infection by contaminated food or other environmental sources of contamination and represent a source of infection for other animals and personnel who work with the animals (Nicklas 1987). Results of recent surveys in dogs and cats have indicated that the prevalence of infection remains about 10% among random-source animals (Fox and Lipman 1991). Salmonellae continue to be recorded frequently among recently imported nonhuman primates (Tribe and Fleming 1983). Infection with salmonellae is nearly ubiquitous among reptiles; during the 1970s, salmonellosis in turtles was a major public-health concern, which was eventually controlled by restricting the sale of viable turtle eggs or live turtles with a carapace length of at least 10.2 cm to institutions with a scientific or educational mission. Avian sources are often implicated in foodborne cases of human salmonellosis, and birds should be con- sidered likely sources of zoonotic transmission in a laboratory-animal facility. Mode of Transmission. Salmonellae are transmitted by the fecal-oral route via food derived from infected animals or contaminated during preparation, contami- nated water, or direct contact with infected animals. Clinical Signs, Susceptibility, and Resistance. Salmonella infection produces an acute febrile enterocolitis; septicemia and focal infections occur as secondary complications (Benenson 1995b; Hook 1990). Focal infections can be localized in any tissue of the body, so the disease has diverse manifestations. Many host factors have been associated with increased severity of the disease, including infancy, old age, AIDS, neoplasia, immunosuppressive therapy or other debilitat- ing condition, achlorhydria, gastrointestinal surgery, or prior or current broad- spectrum antibiotic therapy. Diagnosis and Prevention. Organism isolation with standard microbiological techniques is used to diagnose this infection. Concomitant isolation of the same organism as determined with appropriate molecular biology and molecular epide- miology can be used to implicate a suspect animal as a source of zoonotic trans- mission. Whenever possible, animals known not to harbor salmonellae should be used in laboratory-animal facilities, and the combination of microbiological screening of individual animals or a representative sample of the animal population for the presence of salmonellae and isolation or elimination of carriers can aid in exclud- ing the pathogen from an animal facility. The use of antibiotic treatment of salmonella-infected animals as a means of controlling the organism in a labora-

94 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS tory-animal facility might not be rewarding, because antibiotic treatment can prolong the period of communicability (Benenson 1995b). Personnel should rely on the use of protective clothing, personal hygiene, and sanitation measures to prevent the transmission of the disease. Animal Biosafety Level 2 is recommended for activities using naturally or experimentally infected animals (CDC-NIH 1993). Shigellosis Reservoir and Incidence. Nonhuman primates are the only important reservoir for shigella infection in animal facilities (Fox and others 1984; Richter and others 1984), although zoonotic transmission of the organism from guinea pigs, other rodents, and dogs has been recorded under unique circumstances (Benenson 1995b; CDC-NIH 1993). Nonhuman primates can harbor several Shigella spp. that are pathogenic for humans, including S. flexneri, S. sonnei, and S. dysenteriae. The organisms produce in nonhuman primates a diarrheal disease similar to that seen in humans. Nonhuman-primate infections occur as a result of contact with other infected primates, including humans, or contaminated food, water, or fo- mites. Mode of Transmission. Shigellosis is transmitted by a direct or indirect fecal-oral route. Shigella spp. are extremely infectious, requiring only 10-100 organisms to produce infection. Clinical Signs, Susceptibility, and Resistance. Shigellosis is characterized by an acute onset of diarrhea accompanied by fever, nausea and sometimes vomiting, tenesmus, cramps, and toxemia (Benenson 1995b). In contrast with findings in salmonellosis, bacteremia is very uncommon. The diarrhea is often watery, con- taining blood, mucus, and pus; and it can be life-threatening in the elderly, debili- tated, and malnourished. All age groups are susceptible to infection, but healthy adults infected with a small number of organisms can develop asymptomatic infection. Diagnosis and Prevention. Routine microbiological methods are used to isolate and identify shigellae. The prevention of shigellosis in a laboratory-animal facil- ity should be based on identification and treatment of the carrier state or disease in a nonhuman-primate reservoir (Fox and Lipman 1991). Personnel also should rely on the use of protective clothing, personal hygiene, and sanitation measures to prevent the transmission of the disease. Animal Biosafety Level 2 is recommended for activities using naturally or experimentally infected animals (CDC-NIH 1993).

ZOONOSES 95 Enteric Yersiniosis Reservoir and Incidence. Yersinia enterocolitica and Y. pseudotuberculosis are present in a wide variety of wild and domestic animals, which are considered the natural reservoirs for the organisms. The host species for Y. enterocolitica in- clude rodents, rabbits, pigs, sheep, cattle, horses, dogs, and cats; Y. pseudotuber- culosis has a similar host spectrum and also includes various avian species (But- ler 1990). Human infections often have been associated with household pets, particularly sick puppies and kittens (Benenson 1995b). Occasional reports of yersinia infections in animals housed in the laboratory—such as guinea pigs, rabbits, and nonhuman primates—suggest that zoonotic yersinia infection should not be overlooked in this environment (Fox and others 1984). Mode of Transmission. Yersinia spp. are transmitted by direct contact with in- fected animals through the fecal-oral route. Clinical Signs, Susceptibility, and Resistance. Y. enterocolitica produces a gastroenterocolitis syndrome characterized by fever, diarrhea, and abdominal pain. In some cases, ulcerative mucosal lesions occur in the terminal ileum; they are often accompanied by mesenteric lymphadenitis mimicking the clinical pre- sentation of acute appendicitis (Butler 1990). Other serious sequelae of infection include postinfectious arthritis, iritis, skin ulceration, hepatosplenic abscesses, osteomyelitis, and septicemia. Diagnosis and Prevention. Most clinically important infections can be detected with routine enteric culturing methods, although cold enrichment, alkali treat- ment, or selective CIN agar can be used to enhance growth of the organisms. Laboratory animals with yersiniosis should be isolated and treated or culled from the colony. Personnel should rely on the use of protective clothing, personal hygiene, and sanitation measures to prevent the transmission of the disease. PROTOZOAL DISEASES Vector-borne protozoal diseases generally are not considered a direct threat to personnel in laboratories, because the importation of vectors with hosts is highly improbable. However, accidental inoculation and wound contamination with infected tissue derivatives are conceivable means of transmitting plasmodal, trypanosomal, and leishmanial infections, and appropriate precautions should be taken by personnel who work with these agents in animals. Toxoplasmosis Reservoir and Incidence. Toxoplasma gondii is a coccidian parasite with a world-

96 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS wide distribution among warm-blooded animals. Wild and domestic felines are the only definitive hosts of this organism; they are infected by one another or through predation of an intermediate host, and they support all phases of the T. gondii life cycle in their intestinal tract, although numerous other tissues are also involved in feline toxoplasmosis (Dubey and Carpenter 1993). Results of sero- logical surveys have indicated that 30-80% of cats have evidence of T. gondii infection (Ladiges and others 1982). Intermediate hosts, including humans, can contract the infection from oocysts, which are present only in materials contami- nated by cat feces, or by ingesting infectious bradyzoites or cystozoites encysted in the tissues of another infected animal. In a laboratory-animal facility, the control of this zoonosis is centered principally around the management of cats (Fox and others 1984). Although many other laboratory animals could serve as intermediate hosts and harbor T. gondii in extraintestinal sites, they have not proved to be important sources of zoonotic transmission in the laboratory envi- ronment. Mode of Transmission. Infection results from the ingestion of infectious oocysts in food, water, or other sources contaminated by feline feces. The ingestion of uncooked or undercooked meat, especially pork and beef, is an important source of human infection. Consequently, human infection from improper handling of tissue of an infected intermediate host in the laboratory should be considered a remote possibility. Clinical Signs, Susceptibility, and Resistance. Toxoplasmosis generally produces an asymptomatic or mild infection with fever, myalgia, arthralgia, lymphaden- opathy, and hepatitis (Benenson 1995b). Toxoplasma infection can have severe consequences in pregnant women and immunologically impaired people. In a pregnant woman with a primary infection, rapidly dividing tachyzoites can circu- late in the bloodstream and produce a transplacental infection of the fetus. In early pregnancy, the fetal infection can result in death of the fetus or chorioretini- tis, brain damage, fever, jaundice, rash, hepatosplenomegaly, and convulsions at birth or shortly thereafter. Fetal infection during late gestation can result in mild or subclinical disease with delayed manifestations, such as recurrent or chronic chorioretinitis. Primary infection in immunosuppressed people can be character- ized by maculopapular rash, pneumonia, skeletal myopathy, myocarditis, brain involvement, and death. Diagnosis and Prevention. Toxoplasmosis can be diagnosed by finding the or- ganism in clinical specimens, isolating it in an animal or cell culture, or demon- strating rising antibody titers. Personnel should practice appropriate personal-hygiene practices and main- tain rigorous sanitation of an animal facility to prevent exposure to toxoplasma. Unless they are known to have antibodies to toxoplasma, pregnant women should

ZOONOSES 97 be advised of the risk associated with fetal infection. Cat feces and litter should be disposed of promptly before sporocysts become infectious, and gloves should be worn in the handling of potentially infective material. Giardiasis Reservoir and Incidence. Many wild and laboratory animals serve as a reservoir for Giardia spp., although cysts from human sources are regarded as more infec- tious for humans than are those from animal sources (Benenson 1995c). Dogs, cats, and nonhuman primates are the laboratory animals most likely to be in- volved in zoonotic transmission. According to recent surveys of endoparasites in dogs, the prevalence of giardia generally ranges from 4 to 10% and approaches 100% in some breeding kennels (Jordan and others 1993; Kirkpatrick 1990). Mode of Transmission. Giardiasis is transmitted by the fecal-oral route chiefly via cysts from an infected person or animal. The organism resides in the upper gastrointestinal tract where trophozoites feed and develop into infective cysts. Clinical Signs, Susceptibility, and Resistance. Humans and animals have similar patterns of infection. Infection can be asymptomatic, but anorexia, nausea, ab- dominal cramps, bloating, and chronic, intermittent diarrhea are often seen. Al- though the organism is rarely invasive, severe infections can produce inflamma- tion in the bile and pancreatic ducts and damage the duodenal and jejunal mucosa, resulting in the malabsorption of fat and fat-soluble vitamins. Diagnosis and Prevention. Giardiasis is diagnosed by finding cysts or trophozoi- tes in stool specimens or in duodenal aspirates of humans or animals. Identifica- tion and treatment of giardiasis in a laboratory-animal host in combination with effective personal-hygiene measures should reduce the potential for zoonotic transmission in a laboratory-animal facility. Cryptosporidiosis Reservoir and Incidence. Cryptosporidium spp. have a cosmopolitan distribution and have been found in many animal species, including mammals, birds, reptiles, and fishes (Fayer and Ungar 1986). Cross-infectivity studies have shown a lack of host specificity for many of the organisms (Tzipori 1988). Among the labora- tory animals, lambs, calves, pigs, rabbits, guinea pigs, mice, dogs, cats, and nonhuman primates can be infected with the organisms. Cryptosporidiosis is common in young animals, particularly ruminants and piglets. Mode of Transmission. Cryptosporidiosis is transmitted by the fecal-oral route and can involve contaminated water, food, and possibly air (Soave and Weikel

98 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS 1990). Many human cases involve human-to-human transmission or possibly the reactivation of subclinical infections. Several outbreaks of the disease have been associated with surface-water contamination; a recent waterborne epidemic in Milwaukee, Wisconsin, was believed to involve more than 370,000 people (Dresezen 1993). Zoonotic transmission of the disease to animal handlers has been recorded, including a recent report of cryptosporidiosis among handlers of infected infant nonhuman primates; this emphasizes the importance of this zoono- sis in the laboratory-animal environment (Anderson 1982; Miller and others 1990; Reese and others 1982). Clinical Signs, Susceptibility, and Resistance. Although cryptosporidiosis has become identified widely with immunosuppressed people, particularly AIDS pa- tients, the ability of the organism to infect immunocompetent people also has been recognized. In humans, the disease is characterized by cramping, abdominal pain, profuse watery diarrhea, anorexia, weight loss, and malaise (Soave and Weikel 1990). Symptoms can wax and wane for up to 30 d, eventually resolving in immunocompetence. However, in AIDS patients, who might have an impaired ability to clear the parasite, the disease can have a prolonged course that contrib- utes to death. Diagnosis and Prevention. Cryptosporidiosis is diagnosed by finding the organ- ism in stool specimens with immunofluorescent or other special staining tech- niques (Soave and Weikel 1990). Several samples might be necessary because of intermittent shedding of the organism. Appropriate personal-hygiene practices should be effective in preventing the spread of infection. No pharmacological treatment is effective for this infection. Amebiasis Reservoir and Incidence. Humans serve as the reservoir for Entamoeba his- tolytica, the causative agent of amebiasis, although nonhuman-primate infections have been recorded (Fox and others 1984). The importance of nonhuman pri- mates as a reservoir host appears to have diminished in recent years. Mode of Transmission. The disease is transmitted by ingestion of amebic cysts that are present in the feces of infected animals. Clinical Signs, Susceptibility, and Resistance. Clinical signs of amebiasis can range from mild abdominal discomfort with intermittent diarrhea containing blood and mucus to acute fulminating dysentery with fever, chills, and bloody or mu- coid diarrhea. In severe cases, the organism can penetrate the colonic mucosa, become disseminated in the bloodstream, and produce liver, lung, or brain ab- scesses.

ZOONOSES 99 Diagnosis and Prevention. The disease is diagnosed by finding cysts or tropho- zoites in fresh fecal specimens or other clinical specimens. Nonhuman-primate carriers of the infection should be identified and treated. Appropriate facility sanitation and personal-hygiene practices should prevent the zoonotic transmis- sion of the agent. Balantidiasis Reservoir and Incidence. Balantidium coli has a worldwide distribution and is common in domestic swine, which generally are regarded as the main reservoir for human infection. Nonhuman primates also can harbor the organism enterically (Fox and others 1984). Mode of Transmission. The agent is transmitted by the fecal-oral route. Clinical Signs, Susceptibility, and Resistance. Most humans appear to have a high natural resistance to this infection. However, ulcerative colitis characterized by diarrhea, abdominal pain, tenesmus, nausea, and vomiting can occur in severe cases of the disease. Diagnosis and Prevention. The treatment of clinically apparent infections in a laboratory-animal host should be coupled with good sanitation and personal- hygiene practices to eliminate the zoonotic transmission of this organism in an animal facility. FUNGAL DISEASES Dermatomycosis Reservoir and Incidence. The dermatophytes have a cosmopolitan distribution; some dermatophytes have a regional geographic concentration (Benenson 1995b). These organisms cause ringworm in humans and animals, which continues to be common among dogs, cats, and livestock (Fox and others 1984). In the United States, several dermatophytes of animal origin are involved in the superficial mycoses of humans, including Microsporum canis, Trichophyton mentagro- phytes, and T. verrucosum. M. canis is most prevalent in dogs, cats, and nonhu- man primates and in human infections associated with these species, but it can also occur in rodents. T. mentagrophytes has been associated more commonly with ringworm in rodents and rabbits and occurs among laboratory personnel who work with these species and agricultural personnel who work around grana- ries, barns, and other rodent habitats. T. verrucosum is restricted generally to cases of ringworm in livestock and their agricultural attendants.

100 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS Mode of Transmission. The transmission of dermatophyte infection from humans to animals is by direct skin-to-skin contact with infected animals or indirect contact with contaminated equipment or materials. Infected animals can have no, few, or difficult-to-detect skin lesions that result in transmission to unsuspecting persons. Dermatophyte spores can become widely disseminated and persistent in the environment, contaminating bedding, equipment, dust, surfaces, and air and resulting in the infection of personnel who do not have direct animal contact. Clinical Signs, Susceptibility, and Resistance. The clinical expression of der- matomycosis depends on various host factors and the predilection of the organ- ism. Dermatophytes generally grow in keratinized epithelium, hair, nails, horn, and feathers and are classified according to their optimal substrate as geophilic (soil), zoophilic (animals), or anthropophilic (human). Many of the zoophilic fungi are species-adapted and cause infection without inciting serious inflamma- tory lesions in their host species; however, in an aberrant host, such as a human, a vesicular or pustular eczematous lesion with intense inflammation and rapid regression can occur. Dermatophytes that are better adapted to humans produce focal, flat, spreading annular lesions that are clear in the center and crusted, scaly, and erythematous in the periphery. Lesions often are on the hands, arms, or other exposed areas, but invasive and systemic infections have been reported in immunocompromised people. Diagnosis and Prevention. The definitive diagnosis of dermatomycosis is achieved by fungal culture and identification, but lesion appearance and scrapings of active lesions cleared in 10% potassium hydroxide and examined microscopi- cally for fungal filaments can be used for a tentative diagnosis. In addition, about half of M. canis isolates and lesions are fluorescent in Wood’s lamp examination. Animals with suggestive lesions should be screened for dermatomycosis and isolated and treated if positive. The use of protective clothing, disposable gloves, and other appropriate personal-hygiene measures is essential to the reduction of this zoonosis in a laboratory-animal facility. Animal Biosafety Level 2 practices and facilities are recommended for ex- perimental animal activities with dermatophytes (CDC-NIH 1993). Sporotrichosis Reservoir and Incidence. Sporothrix schenckii is a fungal agent reported in all parts of the world and generally associated with agricultural occupations. How- ever, sporotrichosis has been reported in numerous laboratory-animal species, including dogs, cats, swine, cows, goats, rats, and armadillos (Werner and Werner 1993). Mode of Transmission. Most cases of zoonotic transmission have implicated the

ZOONOSES 101 direct inoculation of the fungus into bites or skin wounds inflicted by animals, but several people who have developed infections could not recall pre-existing skin lesions or skin injury in conjunction with exposure. Thus, this organism might be capable of penetrating intact skin. Clinical Signs, Susceptibility, and Resistance. Humans usually develop a solitary nodule on the hand or extremity and nodular extension along the path of the lymphatic vessels. Ulceration and drainage of the lesions can occur. Arthritis, pneumonia, and other deep visceral infections occur as rare complications (Benenson 1995b). Diagnosis and Prevention. Sporotrichosis is diagnosed by culture and identifica- tion of the organism with Sabouraud dextrose agar. Animals with known or suspected sporothrix infections should be isolated and treated, and personnel should practice appropriate personal-hygiene measures when handling these ani- mals. Animal Biosafety Level 2 practices and facilities are recommended for ac- tivities using naturally or experimentally infected animals (CDC-NIH 1993). HELMINTH INFECTIONS Despite the large number of helminth-parasite infections that either are di- rectly zoonotic or have cycles of infection that encompass animals and humans (see Table 5-1), the transmission of helminthic zoonoses in the laboratory-animal environment should be regarded as unlikely (Fox and others 1984). Many of the organisms have indirect life cycles that are interrupted in the laboratory environ- ment or have ova embryonation periods that are long enough to permit removal of ova during routine sanitation before they become infective for humans (Flynn 1973). In addition to contemporary laboratory-animal management practices that impede zoonotic transmission of helminth parasites, animal-health conditioning practices should be in place to eliminate infections. The use of appropriate per- sonal-hygiene practices also must be emphasized to eliminate any possibility of zoonotic infection. ARTHROPOD INFESTATIONS Very few ectoparasite infestations of humans are associated with the han- dling of conventional laboratory animals, but several have been reported (Fox and others 1984). Appropriate attention needs to be given to the control of this risk; animals are introduced from the wild, animals are used in studies under natural field conditions, or conventional laboratory animals are used in facilities whose vermin-control measures are inadequate to preclude the introduction of these agents on endemically infected wild-animal reservoirs.

102 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS TABLE 5-1 Zoonotic Helminth Parasites of Laboratory Animals Zoonosis Parasite Host Comments Ascariasis Ascaris Old World Infection occurs by ingestion lumbricoides primates of embryonated eggs only; embryonation, requiring 2 weeks or more, ordinarily would not occur in laboratory; heavy infections can produce severe respiratory and gastrointestinal tract disease. Cestodiasis Hymenolepis Rat, mouse, Intermediate host is not nana hamster, essential to life cycle; direct nonhuman infection and internal primates autoinfection can occur also; heavy infections result in abdominal distress, enteritis, anal pruritus, anorexia, and headache. Larval migrans Ancylostoma Dog Transcutaneous infection causes (cutaneous) caninum parasitic dermatitis called Ancylostoma Dog, cat “creeping eruption.” braziliense Ancylostoma Dog, cat duodenale Uncinaria Dog, cat stenocephala Necator Dog, cat americanus Generally, human ectoparasite infestations are manifested as mild allergic dermatitis (see Table 5-2). The more-important, albeit rarer, risk associated with these infestations is transmission of zoonotic agents that can produce systemic disease with arthropods as a vector. Every major group of pathogenic organ- isms—including bacteria, rickettsiae, chlamydia, viruses, protozoa, spirochetes, and helminths—is represented among the agents transmitted by arthropod vec- tors, and personnel who work with research animals that potentially harbor these agents or the ectoparasite vectors should be informed of the hazard. Rigorous ectoparasite-control programs should be instituted as part of the veterinary-care program, especially for wild-caught species that are brought into a laboratory, animals housed previously under field conditions, and animals with inadequate disease profiles from any source. The control of vermin in an animal facility also is essential; consideration should be given to the ectoparasite and disease evaluation of wild or feral rodents caught in an animal facility.

ZOONOSES 103 TABLE 5-1 Continued Zoonosis Parasite Host Comments Larval migrans Toxocara canis Dog Chronic eosinophilic (visceral) Toxocara cati Cat granulomatous lesions Toxocara leonina Dog, cat distributed throughout various organs; should not be encountered in laboratory. Strongyloidiasis Strongyloides Old World Oral and transcutaneous stercoralis, primates, infections can occur in animals Strongyloides dog, cat and humans; heavy infections fulleborni can produce dermatitis, verminous pneumonitis, and enteritis; internal autoinfection can occur. Oesophagostomiasis Oesophagostomum Old World Heavy infections result in spp. primates anemia; encapsulated parasitic granulomas are usually innocuous sequelae of infection. Ternidens infection Ternidens Old World Rare and asymptomatic. deminutus primates Trichostrongylosis Trichostrongylus Ruminants, Heavy infections produce colubriformis, pig, dog, diarrhea. Trichostrongylus rabbit, Old axei World primates Source: Adapted from: Fox and others 1984.

104 OCCUPATIONAL HEALTH AND SAFETY OF RESEARCH-ANIMAL WORKERS TABLE 5-2 Zoonotic Ectoparasites of Laboratory Animals Disease in Species Humans Host Comments Fleas Ctenocephalides felis, Dermatitis Dog, cat Vector of Hymenolepis C. canis diminuta, Dipylidium caninum Xenopsylla cheopsis Dermatitis Mouse, rat, Vector of H. nana, H. wild rodents diminuta Nasopsyllus fasciatus Dermatitis Mouse, rat, Vector of H. nana, H. wild rodents diminuta, R. mooseri Leptopsylla segnis Dermatitis Rat Vector of H. diminuta, H. nana, R. mooseri Pulex irritans Irritation Domestic animals (especially pig) Mites Obligate skin mites Sarcoptes scabiei subspp. Scabies Mammals Notoedres cati Mange Cat, dog, rabbit Nest-inhabiting parasites Ornithonyssus bacoti Dermatitis Rodents and other Vector of western equine vertebrates, encephalitis and St. Louis including birds encephalitis viruses, Rickettsia mooseri Allodermanyssus Dermatitis Rodents, Vector of Rickettsia akari sanguineus particularly Mus musculus Trixacarus cavae Dermatitis Guinea pig Facultative mites Cheyletiella spp. Dermatitis Cat, dog, rabbit (bedding)

ZOONOSES 105 TABLE 5-2 Continued Disease in Species Humans Host Comments Ticks Rhipicephalus sanguineus Irritation Dog Vector of Rickettsia rickettsia, Francisella tularensis, Ehrlichia canis Dermacentor variabilis Irritation Wild rodents, Vector of Rickettsia cottontail rabbit, rickettsia, Francisella dogs from tularensis, Ehrlichia endemic areas canis Dermacentor andersoni Irritation Small mammals, Vector of Rickettsia uncommon on dog rickettsia, Francisella tularensis, Ehrlichia canis Dermacentor occidentalis Irritation Small mammals, Vector of Rickettsia uncommon on dog rickettsia, Francisella tularensis, Ehrlichia canis Amblyomma americanum Irritation Wild rodents, dog Ixodes scapularis Irritation Ixodes dammini Irritation Dog, wild rodents Vector of Borrelia burgdorferi, Babesia microtis Adapted from: Fox and others 1984.

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Much has been written about the care of research animals. Yet little guidance has appeared on protecting the health and safety of the people who care for or use these animals.

This book, an implementation handbook and companion to Guide For the Care and Use of Laboratory Animals, identifies principles for building a program and discusses the accountability of institutional leaders, managers, and employees for a program's success. It provides a detailed description of risks-- physical and chemical hazards, allergens and zoonoses, and hazards from experiments--which will serve as a continuing reference for the laboratory.

The book offers specific recommendations for controlling risk through administrative procedures, facility design, engineering controls, and periodic evaluations. The volume focuses on the worker, with detailed discussions of work practices, the use of personal protective gear, and the development of an emergency response plan.

This handbook will be invaluable to administrators, researchers, and employees in any animal research facility. It will also be of interest to personnel in zoos, animal shelters, and veterinary facilities.

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