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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
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66 OCCUPATIONALHEALTH AND SAFETY OFRESEARCH-ANIMALWORKERS
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, protozoa! 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 corneas ulcer also might be noted. After
acute infection, latency can be established in the ganglia of the sensory nerves
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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
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68 OCCUPATIONALHEALTH AND SAFETY OFRESEARCH-ANIMALWORKERS
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
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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
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70 OCCUPATIONALHEALTH AND SAFETY OFRESEARCH-ANIMALWORKERS
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~.
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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 excrete 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
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72 OCCUPATIONALHEALTH AND SAFETY OFRESEARCH-ANIMALWORKERS
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~.
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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 l990b). 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 (Andre)
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
(Monkeypex and Benign Epidermal Monkeypex)
Reservoir and Incidence. Monkeypox is an orthopoxvirus closely related to small
pox and produces a clinical disease similar to smallpox. Sporadic cases of the
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74 OCCUPATIONALHEALTH AND SAFETY OFRESEARCH-ANIMALWORKERS
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 monkeypod also have been re-
corded in nonhuman primates in the wild and laboratory settings (Fox and others
1984).
Benign epidermal monkeypod, 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 monkeypod 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 monkeypod 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 monkeypod 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 monkeypod
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
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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
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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 protozoa! 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
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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
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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. A1-
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
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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.
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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 cold 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 cants, Trichophyton mentagro-
phytes, and T. verrucosum. M. cants 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.
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100 OCCUPATIONALHEALTH AND SAFETY OFRESEARCH-ANIMALWORKERS
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. cants 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
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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.
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102 OCCUPATIONALHEALTH AND SAFETY OFRESEARCH-ANIMALWORKERS
TABLE 5-1 Zoonotic Helminth Parasites of Laboratory Animals
Zoonosis Parasite Host
Comments
Ascariasis Ascaris Old World
lumbricoides primates
Cestodiasis Hymenolepis Rat, mouse,
nana hamster,
nonhuman
primates
Larval migrans
(cutaneous)
Ancylostoma
caninum
Ancylostoma
braziliense
Ancylostoma
duodenale
Uncinaria
stenocephala
Necator Dog, cat
americanus
Dog
Dog, cat
Dog, cat
Dog, cat
Infection occurs by ingestion
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.
Intermediate host is not
essential to life cycle; direct
infection and internal
autoinflection can occur also;
heavy infections result in
abdominal distress, enteritis,
anal pruritus, anorexia, and
headache.
Transcutaneous infection causes
parasitic dermatitis called
"creeping eruption."
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.
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TABLE 5-1 Continued
103
Zoonosis Parasite Host Comments
Larval migrans Toxocara cants Dog Chronic eosinophilic
(visceral) Toxocara call 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 autoinflection
can occur.
Oesophagostomiasis Oesophagostomum Old World
spp. primates
Ternidens infection Ternidens Old World
deminutus primates
Heavy infections result in
anemia; encapsulated parasitic
granulomas are usually
innocuous sequelae of
infection.
Rare and asymptomatic.
Trichostrongylosis Trichostrongylus Ruminants, Heavy infections produce
colubriformis, pig, dog, diarrhea.
Trichostrongylus rabbit, Old
axed World primates
Source: Adapted from: Fox and others 1984.
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104 OCCUPATIONALHEALTH AND SAFETY OFRESEARCH-ANIMALWORKERS
TABLE 5-2 Zoonotic Ectoparasites of Laboratory Animals
Species
Disease in
Humans
Host Comments
Fleas
Ctenocephalides fells,
C. cants
Xenopsylla cheopsis
Nasopsyllus fasciatus
Leptopsylla segnis
Pulex irritans
Dermatitis
Dermatitis
Dermatitis
Dermatitis
Irritation
Mites
Obligate skin mites
Sarcoptes scabiei subspp. Scabies
Notoedres call Mange
Nest-inhabiting parasites
Ornithonyssus bacoti Dermatitis
Allodermanyssus Dermatitis
sanguineus
Trixacarus cavae
Facultative mites
Cheyletiella spp.
Dermatitis
Dermatitis
Mouse, rat,
wild rodents
Mouse, rat,
wild rodents
Rat
Dog, cat Vector of Hymenolepis
diminuta, Dipylidium
caninum
Vector of H. nana, H.
diminuta
Vector of H. nana, H.
diminuta, R. mooseri
Vector of H. diminuta, H.
nana, R. mooseri
Domestic animals
(especially pig)
Mammals
Cat, dog, rabbit
Rodents and other Vector of western equine
vertebrates, encephalitis and St. Louis
including birds encephalitis viruses,
Rickettsia mooseri
Rodents, Vector of Rickettsia akari
particularly
Mus musculus
Guinea pig
Cat, dog, rabbit
(bedding)
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TABLE 5-2 Continued
105
Species
Disease in
Humans Host Comments
Ticks
Rhipicephalus sanguineus Irritation Dog Vector of Rickettsia
rickettsia, Francisella
tularensis, Ehrlichia
cants
Dermacentor variabilis Irritation
Dermacentor andersoni Irritation
Dermacentor occidentalis Irritation
Wild rodents, Vector of Rickettsia
cottontail rabbit, rickettsia, Francisella
dogs from tularensis, Ehrlichia
endemic areas
Small mammals,
cams
Vector of Rickettsia
uncommon on dog rickettsia, Francisella
tularensis, Ehrlichia
cants
Small mammals, Vector of Rickettsia
uncommon on dog rickettsia, Francisella
tularensis, Ehrlichia
cants
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.
Representative terms from entire chapter:
infected animals
