3Identifying Infectious Hazards Associated with the Use of Nonhuman Primates in Research

Publication Details

Many pathogenic organisms that naturally infect nonhuman primates are communicable to humans, and several human pathogenic organisms are communicable to nonhuman primates and can be retransmitted back to humans. Because humans and nonhuman primates have a close phylogenetic relationship, the risk of transmission of pathogenic organisms with nonhuman primates is greater than with any other group of laboratory animals used in biomedical research. This potential risk increases the importance of identifying infectious hazards for persons working with nonhuman primates or their blood or tissue.

Pathogenic organisms can be acquired by exposure to blood or body fluids by any route including needle inoculation, animal bites and scratches, splashes, accidental ingestion, mucous membrane contamination, contaminated caging and equipment, or even infectious aerosols. Furthermore, some of these organisms may be significantly more pathogenic in species that are not naturally exposed (for example, B virus causes mild, self-limiting lesions in macaques, but is highly pathogenic and often fatal for humans and other nonhuman-primate species such as marmosets and capuchins). The invaluable use of these animals as models of human infectious disease compounds these concerns; their care and use after inoculation with hazardous pathogens can entail substantial hazards. The tendency for zoonotic agents to cause asymptomatic infections in their natural host species raises additional considerations, as does the sharing of nonhuman-primate blood and tissues among laboratories where the procedures and safeguards in place might not be aligned with the etiologic hazards in mind.

The diversity of nonhuman-primate species in research and the lack of comprehensive knowledge regarding the biology and epidemiology of each agent make the list of infectious hazards summarized in this chapter necessarily incomplete. However, the agents described here span the taxonomic groups of pathogens described to date, including those with the most clearly documented importance for laboratory primate research colonies. New findings should be appended to these listings, and the adequacy of safety programs should be reviewed accordingly. Criteria for inclusion in this chapter were the presence of published case reports of occupational exposures, the existence of population-based surveys in research settings or native habitats, and the biologic plausibility of accidental human exposures. The plausibility is clearly less for agents that require intermediate hosts, arthropod vectors, or environmental incubation, but accidental inoculation via a penetrating injury nonetheless warrants inclusion even for some of those agents. For ease of reference, agents are described at the host genus or species level, as appropriate. Some examples of infectious hazards introduced experimentally into nonhuman primates are considered, and assessments of their potential for human exposure should be re-examined in actual institutional contexts. However, a comprehensive review of the hazards associated with experimentally-induced infections in NHP is beyond the scope of this report.

Most agents likely to be encountered in common species in research use are listed in Table 3-1. Some significant taxonomic groups of nonhuman primates used less commonly in contemporary scientific studies (such as marmosets, owl monkeys, and mangabeys) have been largely excluded from the table because of insufficient descriptions of their potential role in infectious hazards, so this chapter should not be considered exhaustive. Furthermore, some nonspecific agents (such as dermatophytes and rabies) should be considered potential hazards from any species of nonhuman primate. Finally, the possibility of zoonotic disease transmission arising from xenotransplantation of nonhuman-primate tissues to humans raises a variety of additional concerns (Michaels 1998) that are beyond the scope of this work.

TABLE 3-1. Infectious Hazards from Nonhuman Primates.

TABLE 3-1

Infectious Hazards from Nonhuman Primates.

The information on infectious agents to which humans may be exposed through contact with nonhuman primates is organized into major sections of viral diseases, bacterial diseases, protozoan parasite diseases, metazoan parasite diseases and other agents of potential importance within the context of contemporary animal care and use programs. Information relevant to each agent is presented in four categories: disease profile in nonhuman primates, mode of transmission, incubation period and clinical signs, and diagnosis and prevention. It should be clarified that not all of the agents listed have been recognized as causes of any illness or other untoward effect in human beings to date. However, given the slow rate of disease progression for some recognized human pathogens, appreciation for the potential of genetic recombination and multiple causation of disease, and the relatively short time since their discovery, the goals of an OHSP should be to prevent exposure to these agents in the work environment regardless of their suspected importance. Those responsible for the OSHP should take into account the potential for exposure to all of these agents in occupational settings that involve nonhuman primates or their tissues. Detailed considerations for the design and implementation of an OHSP relative to infectious and non-infectious hazards are presented in Chapter 7 of this report.

VIRAL DISEASES

Several virus classes are chronic or latent infections of a given species of nonhuman primate and are discussed below or listed in Table 3-1. These are likely to be present in all species of nonhuman primate although they are not necessarily described for a given species. They include herpesviruses, foamy viruses, and papovaviruses. Some species also have their own hepatitis A and B viruses as well as chronic bloodborne flaviviruses and speculatively could participate in transmission of agents of nonhuman primate or human origin.

The lentivirus taxon is particularly important because of its phylogenetic relation to human acquired immune deficiency syndrome (AIDS). It is likely that human immunodeficiency virus 1 (HIV1) originated from a chimpanzee lentivirus (Gao and others 1999) and that HIV2 derived from a sooty mangeby lentivirus (Hirsch and others 1989). Only African nonhuman-primate species have been definitively shown to be chronically infected with their own specific lentivirus. Macaques are an important consideration because they are often used as experimental models of AIDS after inoculation of lentiviruses derived from other nonhuman primates. They may be chronically viremic and a source of blood-borne infection to humans or after immunodeficiency develops may be amplifiers of opportunistic infections.

Examples of the most significant of these types of viral infection are discussed below.

B Virus

Disease Profile in Nonhuman Primates

B virus, also known as Herpesvirus simiae and Cercopithecine herpesvirus 1, is an alphaherpesvirus that occurs naturally only in macaques (Holmes and others 1995; Weigler 1992). The pathogenesis of B virus in macaques resembles that of herpes simplex viruses 1 and 2 in humans, with primary infections followed by lifelong latency, mostly in trigeminal and lumbosacral sensory ganglia, and recrudescent episodes of virus shedding on one or more occasions from tissues around the original site of virus exposure. Despite the shedding of infectious virus at those times, most macaques with B virus infections are asymptomatic or experience only mild, self-limiting, localized lesions that are often not outwardly apparent. When present, vesicles, progressing to ulcers that heal without scarring after 10-14 days, are generally noted on oral-facial or genital mucous membranes and mucocutaneous borders, often including the conjunctivae. Disseminated disease in macaques involving widespread hemorrhagic necrosis of the liver, lung, brain, and lymphoid organs occurs rarely (McClure and others 1973). Natural transmission of the agent between macaques occurs principally via biting and scratching but also via sexual activity in postpubertal animals (Weigler and others 1993Weigler and others 1995). Prevalence can reach 90% or more in group-housed breeding colonies (Weigler and others 1990). Single- or pair-housing configurations tend to have lower prevalence (Weir and others 1993), but infection status and likelihood of virus shedding are unpredictable, so it is prudent to consider all macaques to be latently or actively infected with this agent (Ward and Hilliard 2002). B virus is also known to be highly pathogenic in other species of nonhuman primates including colobus monkeys, patas monkeys, DeBrazza's monkeys, capuchins, and marmosets in contact with infected macaques or after experimental inoculation with the agent (Loomis and others 1981; Thompson and others 2000; Weigler 1992; Wilson and others 1990).

Mode of Transmission

B virus exposures in humans have resulted from animal bites and scratches, splashes, needle stick injuries (although this virus is not considered a bloodborne pathogen), and other contact of mucous membranes or broken skin with infected body fluids from macaques or with wet, unfixed tissues or primary cell culture tissue material. Contaminated husbandry and research equipment can potentially spread B virus, although its viability is not expected to be prolonged (less than 24 hours in most cases), especially when subject to drying or sunlight. However, B virus may survive for longer periods when protected from environmental exposure in certain laboratory settings (Hilliard and Henkel 1998). Severity of injury has not correlated with likelihood of B virus infection, and several human cases have been noted without clearly recognized exposure incidents.

Incubation Period and Clinical Signs

The incubation period prior to onset of clinical signs in humans is variable; typically it is about 2-3 weeks. Some cases were apparent after a few days, and others have taken several weeks or more to manifest after the likely exposure. Postexposure wound cleansing and antiviral prophylaxis can greatly alter these patterns.

Numerous early-stage symptoms have been reported, including unexplained febrile disease (fever, chills, nausea, vomiting, and dizziness) and persistent headache. On some occasions, fluid-filled vesicles have formed near skin wounds sustained from macaque bites or scratches and have been followed by localized paresthesia. Mistaken early diagnoses have included influenza or sinusitis. Progression of disease may have other symptoms attributable to central nervous system infection, such as ascending encephalomyelitis, diplopia, seizures, and respiratory failure due to virus-associated tissue destruction generally localized to the brainstem (Whitley and Hilliard 2001).

B virus infection in humans has been documented on at least 50 occasions and has led to at least 23 deaths (Palmer 1987; Cohen and others 2002). When exposure is not evaluated promptly and there is no specific antiviral therapy, case fatality rate exceeds 80% (Hilliard, personal observations; Palmer 1987); thus B virus is the most significant infectious occupational health hazard in the conduct of nonhuman-primate research. Nonetheless, human cases of B virus are extremely rare despite its high prevalence in the host species and given the large numbers of macaques used in research for many decades.

As a cautionary note, healthcare workers should remember that all primate alphaherpesviruses studied to date are capable of establishing latency and therefore have the potential to reactivate. Given the existence of at least 6 individuals with persistent high titers of B virus antibodies and previous histories of clinically diagnosed B virus infections, the biomedical community can effectively remain vigilant to the possibility of reactivated B virus infections. Additionally, severe morbidity has been recognized clinically in at least 2 antibody positive individuals who reportedly had no contact with macaque monkeys for more than a decade prior to clinical presentation. Together, these data underscore the importance of patient follow-up to accumulate objective data in the face of existing knowledge of alphaherpesvirus latency and reactivation.

Diagnosis and Prevention

Diagnosis of B virus exposure in humans is through serology, virus isolation, and polymerase chain reaction (PCR) assays in reference laboratories that are capable of detecting low-level infections and differentiating cross-reacting antibody responses due to herpes simplex viruses (Holmes and others 1995; Katz and others 1986; Scinicariello and others 1993). Evaluation of involved macaques, tissues, or research materials may be useful in these assessments.

The use of barrier methods of protection and safe-handling procedures in work with macaques is paramount to B virus prevention. Prompt and sufficient attention to disinfecting or flushing of body sites known or thought to be contaminated, followed by proper follow-up evaluation and care, as dictated by a medical professional knowledgeable in this condition, is essential.

Several colonies of rhesus macaques that have no detectable antibody are known to exist (Ward and Hilliard 2002; Ward and others 2000), which should ultimately result in fewer cases of this disease in the coming decades, at least from this species of macaque. However, due to the inaccuracy of some B virus tests, it should be assumed that all macaques, including those from SPF colonies, are infected (Ward and Hilliard, 2002). Therefore animals from SPF colonies that are involved in an exposure should be as systematically and thoroughly evaluated as animals of unknown status.

Simian Immunodeficiency Virus

Disease Profile in Nonhuman Primates

Several closely related lentiviruses, designated simian immunodeficiency viruses (SIVs), have been found as persistent nonpathogenic infections in their natural reservoir in various species of Old World nonhuman primates from geographically disparate areas, including mangabeys, guenons, mandrills, and chimpanzees (Brown 1997; Mansfield and King 1998; Santiago and others 2002). When unknowingly or deliberately inoculated into macaques, they often cause an AIDS-like syndrome. Their close nucleic acid sequence homology with human immunodeficiency viruses (HIV-1 and HIV-2) and the pathologic and clinical patterns that follow SIV infections in macaques have given them an extremely important role as experimental models of AIDS biology (Mansfield and King 1998). In experimentally infected macaques, the incubation period can vary from weeks to months, depending on the model. SIV-inoculated macaques can succumb to a chronic wasting illness and an array of opportunistic infections, including cytomegalovirus, Pneumocystis carinii, Mycobacterium avium complex, Cryptosporidium spp., Toxoplasma gondii, and Candida albicans. Animals with naturally occurring and experimental SIV infections and the associated primate tissues (including blood and blood products) constitute potential infectious hazards to personnel. Potential zoonotic hazards include lentiviruses, and in the case of immunosuppressive infections, opportunistic pathogens.

The natural mode of SIV transmission among nonhuman primates is poorly defined, but there is evidence of sexual transmission in some circumstances. Transmission from infected dams to their offspring has been demonstrated (Phillips-Conroy and others 1994), and all infections are considered to be lifelong (Mansfield and King 1998).

Mode of Transmission

To date, three individuals have been infected with SIV, these occupational exposures occurred through splashes of infectious material onto mucous membranes, contamination of open cuts or abrasions on the skin, and needle stick injuries (Essex 1994; Khabbaz and others 1994; Sotir and others 1997).

Incubation Period and Clinical Signs

The incubation period for human cases is undefined, as no clinical signs of disease have occurred in exposed persons.

Diagnosis and Prevention

Detection of SIV infection in exposed persons can be via serology, virus isolation, and PCR. Use of barrier methods of protection and safe-handling procedures is warranted in work with nonhuman primates. Experimental studies with SIV are typically conducted under animal biosafety level (ABSL) 2 or 2/3 conditions (that is, ABSL-2 facilities with ABSL-3 practices and procedures) (see Table 5-2). Postexposure prophylaxis regimens involving the use of antiretroviral agents, as used for HIV case management, have been published (CDC 2001c).

Simian Foamy Virus

Disease Profile in Nonhuman Primates

Spumaviruses (simian foamy viruses), with close phylogenetic relationships to human foamy virus isolates, have been shown capable of transmission to humans. The involved species of nonhuman primates have included macaques, baboons, guenons, and chimpanzees (Brooks and others 2002; Heneine and others 1998; Sandstrom and others 2000). Species-specific isolates have also been recovered from New World monkeys such as squirrel monkeys and spider monkeys (Meiering and Linial 2001) and could potentially represent additional sources for human infection. There is no evidence that these agents are pathogenic in nonhuman primates or humans. These viruses are found frequently in cell cultures prepared by harvesting tissues for cell growth and propagation, complicating research by their presence.

Mode of Transmission

The mode of transmission to humans is unknown but presumed to be via contaminated saliva and possibly via bites and invasive research or veterinary procedures involving the oral cavity and respiratory tract of infected animals.

Incubation Period and Clinical Signs

No illness has been described as a result of spumavirus infections of human or nonhuman-primate origin.

Diagnosis and Prevention

Serology, PCR, and virus-isolation assays are used for diagnosis. Barrier methods of protection and safe-handling procedures in work with nonhuman primates should minimize the likelihood of occupationally acquired infections.

Ebola/Marburg/Filoviruses

Disease Profile in Nonhuman Primates

Imported macaques were implicated in outbreaks of Ebola subtype Reston (Ebola-R) among macaques in US facilities beginning in 1989 (Brown 1997; CDC 1989, 1990a, 1990b, 1991, 1996; Dalgard and others 1992; Miranda and others 1999; Rollin and others 1999; Schou and Hansen 2000), and guenons brought from Uganda were the source of Marburg virus exposure among laboratory workers in Germany and Yugoslavia in 1967 (Brack 1987). Ebola outbreaks in wild chimpanzees have also been reported (Formenty and others 1999). Nonhuman primates are unlikely to be the reservoir of Ebola virus since experimental or natural infection is quickly fatal (Georges-Courbot and others 1997).

Disease presentation after infection with these filoviruses in nonhuman primates has varied with the virus strain and species involved. Lymphoid necrosis, hepatocellular necrosis, interstitial pneumonia, and rapidly progressing (less than 24 hours) fatal hemorrhagic disease have occurred in recent outbreaks among imported macaques in the United States.

Mode of Transmission

The mode of Ebola virus transmission to humans is thought to be mainly by droplets and body fluid fomites although the filoviruses form infectious aerosols. Transmission of Marburg virus between animals and humans has usually involved contact with infected tissues (NRC 1998).

Incubation Period and Clinical Signs

The incubation period for these agents in humans is unknown. There have been no clinical signs in association with small numbers of Ebola-R infections in humans. Incubation for Marburg virus is 4-16 days. Initial clinical signs include fever, myalgia, and headache, followed by nausea, vomiting, and diarrhea along with thrombocytopenia and leukopenia (NRC 1997).

Diagnosis and Prevention

Diagnosis is based on detecting virus in acute disease samples from humans or other primates (antigen-detection ELISA, RT-PCR, or virus isolation). Ebola-R virus has not been recovered from human patients.

Prevention is through use of quarantine facilities approved by the Centers for Disease Control and Prevention (CDC) and appropriate biosafety programs for imported macaques and African green monkeys undergoing quarantine, especially after receipt from endemic areas. CDC has provided specific guidelines on the requirements for testing and health reporting for these species held in quarantine (CDC 1990a). Transmission of Marburg virus to humans in 1967 led to the institution of preventive quarantine measures that have stopped any significant spread of imported filoviruses and would be expected to be effective against many of the other viruses discussed in this report (Formenty and others 1999; Miranda and others 1999). The efficacy of these measures is based on the propositions that filoviruses result in significant overt disease in nonhuman primates held during quarantine, that the agents are not chronic or latent and recrudescent, that disease is properly evaluated when it occurs, and that there is oversight by persons whose primary concern is public health. Recent experience in this regard is illustrated in Box 3-1.

Box Icon

BOX 3-1

Some Lessons from the Ebola (Subtype Reston) Episode. The most recent outbreak of disease in nonhuman primates followed an introduction of a filovirus into a U.S. quarantine facility in 1989-1990. It led to several observations relevant to the design (more...)

Pox Viruses

Disease Profile in Nonhuman Primates

Five pox viruses have been described as affecting nonhuman primates (Brack 1987; Muchmore 1987; Whitney 1976). Most noteworthy of them is monkeypox because of its clinical and immunologic similarities to smallpox and vaccinia, the other members of the genus Orthopoxvirus that affect humans. Outbreaks of human monkeypox occur often in Central and West Africa (Hutin and others 2001) and originally led to some confusion with smallpox virus activity. Monkeypox can experimentally infect a wide variety of Old World and New World nonhuman-primate species (Downie 1974; Heberling and Kalter 1971). Although antibodies may be found in wild populations of guenons, arboreal squirrels are thought to be the natural mammalian reservoirs in endemic regions of Africa (Khodakevich and others 1986), though monkey-to-monkey transmission can occur. Clinically, monkeypox presents as a vesicular exanthema leading to classic pock-like lesions of the skin and internal organs, sometimes with respiratory involvement.

Yaba virus and tanapox virus (benign epidermal monkeypox or Or-Te-Ca virus) are both members of the Yatapoxvirus genus and can cause multiple papules or masses (pseudotumors) on the skin, which occasionally involve oral, pulmonary, and other internal tissues of nonhuman primates, depending on the virus and host species. Evidence of infection has been found in macaques, baboons, guenons, mangabeys, patas monkeys, and chimpanzees, but not in New World monkey species (Brack 1987; Downie 1974). Lesions spontaneously regress by necrosis and ulceration in 3-6 weeks.

Molluscum contagiosum, a skin infection caused by the only member of the Molluscipoxvirus genus, causes umbilicated papules on the skin (genital area, face, and upper body) that can persist for up to 2 years. It is a relatively common virus thought to be specific to humans (especially immunosuppressed humans), but cases have been documented in chimpanzees (Douglas and others 1967).

Mode of Transmission

Direct contact and indirect contact (possibly via invertebrate vectors) are suspected but conclusive data are lacking. Transmission of yaba and tanapox from monkeys to humans has been documented on several occasions (including via contaminated needles), and outbreaks among human settlements have occurred in Central Africa with lesions resembling those in animals (Jezek and others 1985). In contrast with yaba and tanapox, person-to-person spread is a feature of monkeypox, although less so than that of smallpox (Hutin and others 2001). To date, nonhuman primates have not been directly implicated in human cases of monkeypox (Hutin and others 2001). Molluscum contagiosum is spread by close direct contact between humans and potentially through close contact with an infected chimpanzee.

Incubation Period and Clinical Signs

The incubation period for monkeypox in humans is thought to be about 3 weeks. Fever precedes pock-like lesions similar to those described above for nonhuman primates. Lesions arise approximately 1 week after human exposure to the Yatapoxvirus agents, and published case reports indicate that up to 6 months may be required for molluscum contagiosum to manifest in the patient.

Diagnosis and Prevention

Serology, virus isolation, and PCR assays have been developed for some agents in this group. Monkeypox cases in endemic regions of Africa may have been prevented in previous decades when smallpox (vaccinia) immunization campaigns were active, and none of these should occur in contemporary research settings with nonhuman primates, except perhaps of recently imported ones.

Yellow Fever

Disease Profile in Nonhuman Primates

Yellow fever virus (flavivirus) occurs in sylvatic maintenance cycles involving African Old World primates (including baboons, guenons, mangabeys, chimpanzees, and patas monkeys) and New World primates (including howler monkeys, spider monkeys, capuchins, and squirrel monkeys) (Mansfield and King 1998; Solomon and Mallewa 2001). Transmission of yellow fever virus is via the bite of infective mosquitoes, especially Aedes aegypti in urban maintenance cycles and human epidemics, Ae. africanus and Ae. simpsoni in sylvatic African Old World primate maintenance cycles, and Haemagogus spp. in sylvatic New World primate maintenance cycles.

Clinical signs of infection are mild or absent in African species, but New World primates tend to show high mortality, presumably because of the virus's relatively recent introduction into Central and South America in the 16th and 17th centuries.

Mode of Transmission

Human cases acquired from nonhuman-primate research work in laboratory settings have occurred (Richardson 1987), and accidental exposures with needle sticks or other sharp instruments are a continuing possibility, especially during quarantine of animals after receipt from endemic areas.

Incubation Period and Clinical Signs

After an incubation period of 3-6 days, the human disease can present with variable severity, including mild, inapparent infections in endemic areas. However, attacks of rapid onset—including fever, chills, headache, backache, nausea, vomiting, and jaundice—are common. Symptoms can progress to epistaxis and hemoptysis, melena, liver and renal failure, and in some cases, death.

Diagnosis and Prevention

Diagnosis is through serology, virus isolation, PCR, or histopathology. Yellow fever is prevented by maintaining effective quarantine programs, especially after receipt of animals from endemic areas, eliminating or destroying potential larval habitats of Aedes mosquito vectors, and protecting against mosquito bites. A human vaccine is available for research workers and the public.

Dengue

Disease Profile in Nonhuman Primates

Dengue fever viruses (flaviviruses) circulate in tropical latitudes among different species of African and Asian Old World primates, including macaques (Mansfield and King 1998; Solomon and Mallewa 2001). The dengue virus is introduced via the bite of infective mosquitoes, especially Aedes aegypti and Ae. albopictus. Both nonhuman primates and humans are competent reservoir hosts, and urban transmission cycles occur most regularly between people without dependence on nonhuman primates.

Mode of Transmission

Human cases acquired from nonhuman-primate research work in laboratory settings are not known, but accidental exposures through needles or other medical sharps are possible, especially during periods of quarantine after receipt of animals from endemic areas.

Incubation Period and Clinical Signs

This incubation period in humans is typically 3-7 days until the onset of clinical signs, which generally include a febrile illness accompanied by various signs, such as rash. Severity varies from none to hemorrhagic episodes—and occasional death in the case of dengue hemorrhagic fever-shock syndrome.

Diagnosis and Prevention

Diagnosis is through serologic testing and virus isolation assays. Prevention is by maintaining effective quarantine programs, especially after receipt of animals from endemic areas, eliminating or destroying potential larval habitats of Aedes mosquito vectors, and protecting against mosquito bites. No effective vaccine is available.

Lymphocytic Choriomeningitis Virus

Disease Profile in Nonhuman Primates

Marmosets and tamarins in zoological settings have succumbed to epizootics of lymphocytic choriomeningitis virus (LCMV), the etiologic agent of callitrichid hepatitis, after their feeding on infected mice (Montali and others 1989; Stephensen and others 1991). Dyspnea, anorexia, lethargy, jaundice, and high mortality have been reported. Rodents are the natural reservoir species (mice) and long-term carriers (hamsters) of LCMV and are responsible for maintenance cycles of the agent with chronic viremia and viruria. Transmission of the agent between callitrichid primates has not been demonstrated.

Mode of Transmission

The mode of transmission from infected animals to humans is unknown but presumably would result from oral and respiratory exposure to the virus through urine, saliva, or feces of infected animals, as in cases of human exposure to infected rodents. Seroconversion to LCMV has occurred in two zoo veterinarians after bite wounds from and necropsy examinations of infected animals during outbreaks (Montali and others 1989)

Incubation Period and Clinical Signs

The incubation period of LCMV in humans is around 8-13 days. A biphasic febrile illness has most often been reported in association with LCMV infection from rodents. Initial symptoms most often include fever, malaise, anorexia, muscle aches, headache, nausea, and vomiting. The second phase of LCMV includes symptoms of meningitis or encephalitis such as fever, headache, stiff neck, confusion, or motor abnormalities. LCMV is only rarely fatal, though temporary or permanent neurological damage is possible. Recent reports regarding the role of LCMV as a fetal teratogen raise concerns about exposure of women of childbearing age to this agent (Barton and Mets 2001).

Diagnosis and Prevention

Serology, virus isolation assays, and PCR are used for diagnosis. Screening of rodent colonies that are used as food for callitrichids and prevention of access by wild rodents should be sufficient to prevent transmission. Research or veterinary biologics for callitrichid species should be verified as free of LCMV before use. Barrier methods of protection and safe-handling procedures in work with all nonhuman primates should also minimize the likelihood of occupationally acquired infections.

Hepatitis A

Disease Profile in Nonhuman Primates

Three genotypes of simian hepatitis A virus have been found naturally in Old World primate species, including macaques and guenons (Robertson 2001). Serologic evidence of infection with simian hepatitis A has been seen in macaques, baboons, guenons, cebid and callitrichid monkeys, and other species (Lankas and Jensen 1987; Mansfield and King 1998). Molecular characterization of simian isolates shows limited nucleotide-sequence identity with human or other known isolates (Oberste and others 2002; Poyry and others 1999), and there is no evidence of human disease in association with these simian agents.

Many species of nonhuman primates are susceptible to hepatitis A viruses of human origin, and tamarins, owl monkeys, and chimpanzees have been valuable animal models of the disease (Purcell and Emerson 2001). Outbreaks of human hepatitis A in captive colonies of nonhuman primates have been attributed to exposure to human strains after capture, but only chimpanzees have been implicated in retransmission of the human hepatitis A virus to humans (Dienstag and others 1976; Robertson 2001). Overt clinical disease in nonhuman primates after infection has been rare and nonspecific; reported signs include anorexia and diarrhea in chimpanzees, although increases in liver enzyme levels to 2-10 times above normal have been noted. Hepatitis A virus may persist in chimpanzee serum for up to 91 days—much longer than previously suspected (Bower and others 2000; Cohen and others 1989).

Mode of Transmission

Transmission of hepatitis A to human beings is usually by a fecal-oral route, although transmission via parenteral inoculation is possible.

Incubation Period and Clinical Signs

The incubation period of human hepatitis A (potentially retransmitted through nonhuman primates) averages about 1 month. Illness is generally self-limiting. Signs include fever, malaise, anorexia, nausea, abdominal discomfort, and jaundice. Many cases are asymptomatic. There is no evidence of human disease associated with simian hepatitis A.

Diagnosis and Prevention

Serology is routinely used for diagnosis. Virus isolation with genomic analysis would be required for species-associated genotype investigations. Good hygiene, barrier methods of protection, and safe-handling procedures help to prevent transmission from animals infected experimentally or inadvertently with human-origin isolates. A vaccine is available, and it may be advisable to vaccinate persons who work with hepatitis A in nonhuman-primate research settings and persons who are occupationally exposed to chimpanzees. However, since hepatitis A strains from humans and nonhuman primates differ genetically and there is no evidence one way or the other that the current human vaccine would protect humans from simian strains of this virus, it is unclear as to whether vaccinations would be advantageous.

Hepatitis B

Disease Profile in Nonhuman Primates

Hepatitis B virus (HBV) infection can occur in the great apes (chimpanzees, gorillas, orangutans, and gibbons) with moderate frequency; this is due in some cases to previous exposure of the animals to human serum and in others to naturally occurring genotypes. Species-specific strains of HBV virus have been found in chimpanzees, gibbons, orangutans, and woolly monkeys; isolates from the latter species are phylogenetically most divergent from the rest. (Heckel and others 2001; Robertson 2001; Robertson and Margolis 2002; Takahashi and others 2000). Chronic-carrier status has been established for experimentally infected chimpanzees, and the clinical signs have been limited to mild anorexia, jaundice, and elevated liver enzyme levels. No transmission of these primate-origin agents to humans has been documented, but antigenic studies of the chimpanzee HBV suggest that it could infect humans (Robertson 2001). Laboratory accidents (needle sticks, mucosal exposures, possibly animal bite wounds) could pose HBV hazards for persons involved with animal models of the agent.

Mode of Transmission

No cases of transmission of HBV of nonhuman primate origin to humans has been documented, though these agents could presumably be spread by percutaneous inoculation, permucosal exposure to infective material, or vertically via mother to child in the case of human-to-human HBV.

Incubation Period and Clinical Signs

The incubation period of human HBV averages about 2-3 months. Most infections in humans go unrecognized, but various nonspecific sign —such as anorexia, abdominal discomfort, nausea, and vomiting—may be seen and often progress to jaundice. Chronic cases can persist as active hepatitis, with or without cirrhosis, and progress to hepatocellular carcinoma.

Diagnosis and Prevention

Serum antigen and antigen-assay systems are available and are directed at different markers of HBV infection that can help to indicate the type and duration of infection. Good hygiene, barrier methods of protection, and safe-handling procedures help prevent occupational exposures in laboratory settings, and the vaccines now available for the public are a requirement of the Occupational Health and Safety Administration (OSHA) for the protection of persons involved in research work on this agent and should be considered as well for all persons who work with chimpanzees or their blood, organs, or other tissues.

BACTERIAL DISEASES

Tuberculosis

Disease Profile in Nonhuman Primates

Mycobacterium tuberculosis and M. bovis can be acquired from humans and then passed between nonhuman primates. These agents can infect any species of nonhuman primate (CDC 1993; Fourie and Odendaal 1983; Kalter and others 1978; Kaufmann and others 1975; Mayhall and others 1981; Muchmore 1987; Renquist 1987; Richardson 1987; Rollin and others 1999; Sapolsky and Else 1987; Whitney 1976; Zumpe and others 1980), and secondary spread back to humans has been documented on several occasions. Old World nonhuman-primate species are more susceptible to tuberculosis infection than New World nonhuman-primate species (Aiello 1998).

There is no apparent difference between the two agents in the presentation of disease in nonhuman primates. Signs are often nonspecific and vary with the location and severity of infection, from asymptomatic cases to overwhelming infection with sudden death. They include pulmonary disease that may or may not be outwardly apparent, anorexia, and chronic weight loss. Chronic draining tracts to the skin and vertebral bone and spinal-cord involvement have been reported.

Mycobacterium avium-intracellulare and other atypical agents in this group can occur naturally in nonhuman primates, especially if they are immunocompromised; however, these are generally considered ubiquitous in nature, and nonhuman primates are not considered a reservoir source for human infections (Gibson 1998).

Mode of Transmission

Aerosols, fomites, and the fecal-oral route have all been implicated in recorded outbreaks among nonhuman primates.

Incubation Period and Clinical Signs

The incubation period for tuberculosis in humans is about 2-10 weeks from exposure to development of primary lesions or skin-test positivity. Pulmonary, meningeal, and other body systems can be involved. Signs can include chronic cough, fatigue, fever, weight loss, and hemoptysis during advanced stages of progressive pulmonary disease. Lifelong latent (nonprogressive) infections in calcified pulmonary nodules are a known feature.

Diagnosis and Prevention

Intradermal skin tests with mammalian old tuberculin, accompanied by pathologic examination as necessary, are the mainstay of tuberculosis surveillance in nonhuman-primate colonies. An enzyme immunoassay for detection of tuberculosis infection in various species of nonhuman primates via measurement of gamma interferon release from stimulated lymphocytes is also available (Desem and Jones 1998). Intradermal skin tests using PPD and pulmonary radiography, coupled with acid-fast staining and culture of sputum samples are used for humans. However, false-negative skin test results in nonhuman primates are common because of concurrent disease (such as measles virus infection), early-stage disease, or other poorly understood factors and justify the requirement for repeated testing during and after quarantine.

Test-and-removal and depopulation strategies have been used to control the disease in colonies, and must be combined with rigorous quarantine programs and continuing tuberculosis surveillance of nonhuman primates and persons who work with them to prevent colony infection. Good sanitation programs for facilities and equipment can limit spread in a colony. Some long-term multidrug protocols have been described and have been successful in individual nonhuman-primate cases. Good personal hygiene, respiratory protection for persons working with nonhuman primates not known to be free of active infection, safe-handling procedures, and rigorous quarantine and surveillance programs can minimize spread in a colony. Prevention of contact of actively infected persons with nonhuman primates through appropriate occupational health programs is also paramount.

Pseudotuberculosis

Disease Profile in Nonhuman Primates

Pseudotuberculosis, caused either by Yersinia enterocolitica or Y. pseudotuberculosis, has been reported in macaques, baboons, squirrel monkeys, guenons, and other nonhuman primates (Bielli and others 1999; Brack and Hosefelder 1992; Gibson 1998; Plesker and Claros 1992; Vore and others 2001). Birds and rodents are thought to be the primary reservoir, but nonhuman primates may be carriers and could present a risk of infection to humans.

Diarrhea, dehydration, anorexia, and weight loss are noted, sometimes hemorrhaging and occasionally splenomegaly and lymphadenopathy are seen. A peracute course ending in death has also been observed.

Mode of Transmission

Transmission is by the fecal-oral route in both humans and nonhuman primates.

Incubation Period and Clinical Signs

Incubation is about 3-7 days and is followed by acute febrile diarrhea, which may be hemorrhagic; enterocolitis; and mesenteric lymphadenitis that mimics appendicitis in infected persons may also be seen.

Diagnosis and Prevention

Diagnosis is through stool culture with biochemical evaluation of the isolates. Good hygiene, barrier methods of protection, and safe-handling procedures are preventive. Antimicrobial treatment of infected animals has been discouraging.

Shigellosis

Disease Profile in Nonhuman Primates

Shigella appears to be acquired by nonhuman primates in captivity from contact with infected humans, and various species of Shigella, most commonly S. flexneri, have been found in association with a variety of nonhuman-primate species, including macaques, baboons, squirrel monkeys, marmosets, tamarins, and apes (Gibson 1998; Juan-Salles and others 1999; Miller and others 1990; Muchmore 1987; Wolfensohn 1998). Transmission of the agent back to humans has been seen on multiple occasions. The presence of asymptomatic, chronic carriers and reinfections can maintain high rates of endemic infections in research colonies; stress promotes episodes of overt disease. Clinical signs can include diarrhea containing mucus, blood, and sometimes mucosal fragments; dehydration; and weight loss. Gingivitis, abortion, and air sacculitis are also reported.

Mode of Transmission

Transmission is by the fecal-oral route in humans and nonhuman primates.

Incubation Period and Clinical Signs

In humans, the incubation period averages 1-4 days. The disease varies from mild infections to dysentery or watery diarrhea, fever, nausea, and tenesmus. It can cause reactive arthropathy (Reiter's syndrome), especially in persons with an HLA-B27 genetic background (Hughes and Keat 1994).

Diagnosis and Prevention

Diagnosis is through stool culture and biochemical typing of isolates. Good hygiene, barrier methods of protection, and safe-handling procedures are preventive. Infected animals should be treated if possible. Culling of chronic carriers that do not respond to therapy has been used in some primate colonies.

Salmonellosis

Disease Profile in Nonhuman Primates

As in the case of Shigella, the Salmonella pathogen is probably acquired by nonhuman primates in captivity from exposure to infected humans, and transmission of the agent back to humans is not unlikely. Various species and bioserotypes of Salmonella have been isolated from nonhuman primates such as macaques, guenons, tamarins, owl monkeys, and chimpanzees (Gibson 1998; Muchmore 1987; Takasaka and others 1988). However, it is rarely reported in established colonies. Watery diarrhea, sometimes containing blood or mucus; fever; and such extraintestinal infections as neonatal septicemia, abortion, osteomyelitis, and pyelonephritis are described in association with Salmonella infections in these species.

Mode of Transmission

Transmission is by the fecal-oral route in both humans and nonhuman primates.

Incubation Period and Clinical Signs

The incubation period is 1-3 days in humans. The disease typically presents as acute enterocolitis with fever, abdominal pain, headache, nausea, and vomiting. Localization in various tissues of the body may occur and induce abscesses and septicemia.

Diagnosis and Prevention

Diagnosis is through stool culture and biochemical typing of isolates. Good hygiene, barrier methods of protection, and safe-handling procedures are preventive. Culling of infected animals has been used in some primate colonies.

Campylobacteriosis

Disease Profile in Nonhuman Primates

It is likely that many nonhuman-primate cases of Campylobacter jejuni and C. coli are acquired in captivity; Campylobacter has been commonly found in association with macaques, baboons, squirrel monkeys, cebid monkeys, chimpanzees, tamarins, and other nonhuman primates (Gibson 1998; Hubbard and others 1991; Johnson and others 2001; Renquist 1987; Taylor and others 1989; Tribe and Frank 1980). Retransmission of Campylobacter back to humans is not unlikely. Diarrheal disease of varied severity and duration may be seen, but many infections are asymptomatic.

Mode of Transmission

Transmission is by the fecal-oral route in humans and nonhuman primates.

Incubation Period and Clinical Signs

The incubation period is typically 2-5 days in humans. Diarrhea, abdominal pain, fever, nausea; and vomiting have been seen; stools sometimes contain blood or mucus.

Diagnosis and Prevention

Diagnosis is through stool culture with morphologic evaluation (the agent is spiral shaped) and biochemical evaluation of the isolates. Good hygiene, barrier methods of protection, and safe-handling procedures are preventive. Infected animals should be treated if possible, although the efficacy of antibiotic therapy is infrequently reported and some animals continue to shed the organism despite treatment (Aiello 1998).

Melioidosis

Disease Profile in Nonhuman Primates

Burkholderia (Pseudomonas) pseudomallei has been found in macaques, chimpanzees, and other nonhuman primates with nonspecific clinical signs including suppurative lesions involving pulmonary, cerebrospinal, and subcutaneous tissues (Fritz and others 1986; Gibson 1998; Trakulsomboon and others 1994;). The zoonotic potential of this agent has not been fully established. B. pseudomallei is considered a soil and water saprophyte in tropical countries and most cases have arisen among animals recently imported from endemic areas.

Mode of Transmission

Laboratory-acquired infections have occurred, and infection is thought to occur through ingestion or inhalation or via breaks in the skin.

Incubation Period and Clinical Signs

Long latent periods are characteristic. Human cases vary from asymptomatic infections to pneumonia and septicemia.

Diagnosis and Prevention

Diagnosis is by culture of the agent from affected tissues. Good hygiene, barrier methods of protection, and safe-handling procedures are warranted to minimize likelihood of exposure from infected animals. Antibiotic therapy has been discouraging in nonhuman primates because of bacterial resistance.

Leprosy

Disease Profile in Nonhuman Primates

Mycobacterium leprae has been recorded in macaques, mangabeys, and chimpanzees (Hubbard and others 1991; Meyers and others 1991; Valverde and others 1998) with single or multiple nodular lesions of the face and ears sometimes extending to other areas. Infections are believed to be acquired naturally in endemic areas. Weight loss and anemia develop late in disease.

Mode of Transmission

The exact mode of transmission is not well established, though it is suspected that most human infections are acquired via inhalation.

Incubation Period and Clinical Signs

Months to years follow exposure before onset of clinical signs in humans. Various forms of disease are reported, from tuberculoid to lepromatous with chronic infiltrative skin and nerve involvement. Zoonotic cases originating in infected nonhuman primates have not been recorded, but the potential exists.

Diagnosis and Prevention

Diagnosis is through histopathology with acid-fast staining of lesions, which is especially convincing when there is nerve involvement. Good hygiene, barrier methods of protection, and safe-handling procedures are warranted. Early recognition and isolation of cases, possibly including long-term multidrug therapy, are also beneficial.

Bite-Wound Infections

Apart from the conditions listed above, there is a potential for infectious agents to complicate bite injuries sustained from nonhuman primates, as is the case for any animal in general. The severity of B virus from macaques can overshadow these concerns during care and follow-up of bite-wound cases, but the likelihood of bacterial wound contamination after bites by nonhuman primates also warrants clinical attention with early initiation of antimicrobial therapy. The list of bacteria of interest may include Neisseria spp., Streptococcus spp., Staphylococcus spp., Haemophilus parainfluenzae, Eikenella corrodens, Moraxella spp., Bacteroides spp., Fusobacterium spp., Clostridium tetani, and Pasteurella multocida; some fungal agents can also contaminate bite wounds (Goldstein and others 1995; Janda and others 1990; Rayan and others 1987; Tribe and Noren 1983). The tetanus-immunization status of injured persons should be ascertained immediately and boosted as necessary. Reviews of animal-bite wound cleansing and medical management in general should be consulted (Smith and others 2000). Both aerobic and anaerobic cultures should be taken and empirical therapy with antimicrobial agents initiated as appropriate.

PROTOZOAN PARASITES

Amoebiasis

Disease Profile in Nonhuman Primates

Several species of Entamoeba occur in nonhuman primates, but the only known pathogenic species is Entamoeba histolytica. Entamoeba histolytica is reported in macaques, baboons, squirrel monkeys, guenons, mangabeys, and chimpanzees (Ghandour and others 1995; Hubbard and others 1991; Levine 1970; Munene and others 1998; Muriuki and others 1998; Sargeaunt and others 1982; Smith and Meerovitch 1985). The presence of diarrhea (none to severe) and weight loss (dysentery) depends on the strain of organism. Diarrhea may be hemorrhagic or catarrhal.

Mode of Transmission

Transmission is by the fecal-oral route in humans and nonhuman primates. Human cases associated with animal contact are rare.

Incubation Period and Clinical Signs

The incubation period is variable but typically ranges from 2 to 4 weeks. Many infections are asymptomatic, but acute or fulminating dysentery with fever, chills, and hemorrhagic or catarrhal diarrhea may occur.

Diagnosis and Prevention

Fecal wet-smear examination to demonstrate trophozoites and serologic tests for invasive forms of the disease are available. Antigen capture assays are also available. No successful treatment for eradication of E. histolytica in nonhuman-primate colonies has been reported, therefore colony screening for E. histolytica may be warranted (Weber and others 1999). Good hygiene, barrier methods of protection, and safe-handling procedures are indicated.

Balantidiasis

Disease Profile in Nonhuman Primates

Balantidium coli is reported in macaques, baboons, squirrel monkeys, guenons, and chimpanzees (Ghandour and others 1995; Hubbard and others 1991; Knezevich 1998; Levine 1970; Munene and others 1998; Muriuki and others 1998; Nakauchi 1999). Disease manifestations vary from none to watery diarrhea and ulcerative enterocolitis, weight loss, and rectal prolapse.

Mode of Transmission

Transmission is by the fecal-oral route in humans and nonhuman primates. Human cases associated with animal contact are rare.

Incubation Period and Clinical Signs

The incubation period is undefined but likely to be only a few days. Diarrhea, tenesmus, nausea, and vomiting are described for human infections.

Diagnosis and Prevention

Fecal examination is used to demonstrate trophozoites. Good hygiene, barrier methods of protection, and safe-handling procedures are indicated.

Cryptosporidiosis

Disease Profile in Nonhuman Primates

Cryptosporidium parvum is reported in macaques, baboons, squirrel monkeys, guenons, chimpanzees, and marmosets (Miller and others 1990; Muriuki and others 1998; Toft and Eberhard 1998). Disease manifestations vary from none to gastroenteritis and intractable diarrhea, dehydration, and weight loss. The disease is fairly common in macaques that are experimentally infected with SIV.

Mode of Transmission

Transmission is by the fecal-oral route in humans and nonhuman primates. Human cases associated with animal contact are rare.

Incubation Period and Clinical Signs

The incubation period is likely to be 1-12 days. Abdominal cramping, watery diarrhea, nausea, and vomiting are described for human infection.

Diagnosis and Prevention

Fecal examination is used to demonstrate oocysts; antigen capture assays are also available. Good hygiene, barrier methods of protection, and safe-handling procedures are indicated.

Giardiasis

Disease Profile in Nonhuman Primates

Giardia intestinalis is reported in macaques, baboons, squirrel monkeys, chimpanzees, marmosets, and other nonhuman primates (Ghandour and others 1995; Hamlen and Lawrence 1994; Levine 1970; Toft and Eberhard 1998). Disease manifestations vary from asymptomatic to diarrhea and vomiting, depending on a range of poorly understood factors.

Mode of Transmission

Transmission is by the fecal-oral route in humans and nonhuman primates. Human cases directly associated with animal contact are rarely documented.

Incubation Period and Clinical Signs

The incubation period can be prolonged to about 3 weeks but is typically 7-10 days. Many infections are asymptomatic, but chronic diarrhea, steatorrhea, abdominal cramps, bloating, and fatigue are described.

Diagnosis and Prevention

Fecal examinations are used to demonstrate cysts or trophozoites, and antibody-based antigen-detection systems for stool specimens are available. Good hygiene, barrier methods of protection, and safe-handling procedures are indicated.

Malaria

Disease Profile in Nonhuman Primates

Plasmodium cynomolgi, P. knowlesi, P. inui, P. simium, and other species have been described in macaques, baboons, squirrel monkeys, mangabeys, and other nonhuman primates (Bennett and McWilson 1965; Collins and others 1973; Most 1973; Muchmore 1987; Ollomo and others 1997; Toft and Eberhard 1998; Trakulsomboon and others 1994). Clinical signs are typically absent in the natural host species, but slight anemia in conjunction with low-grade parasitemia may occur. Stress, concurrent disease, splenectomy, or immunosuppression can precipitate episodes of overt disease in infected animals.

Mode of Transmission

Human cases acquired directly from nonhuman primates are rare; accidental exposures through penetrating injuries from needles and other medical sharps are possible as is transmission through a mosquito bite.

Incubation Period and Clinical Signs

The incubation period in humans is typically 1-4 weeks after the bite of an infective female mosquito of the genus Anopheles, which may be followed by fever, chills, sweating, headache, and nausea.

Diagnosis and Prevention

Blood-smear evaluations, PCR, and serologic tests for past infections are available. Safe blood-handling practices and effective mosquito-control programs are indicated in work with infected animals.

Trypanosomiasis

Disease Profile in Nonhuman Primates

Natural infections with Trypanosoma cruzi and related Trypanosoma organisms have been described in squirrel monkeys, marmosets, tamarins, and other New World species, in which infections are apparently lifelong. Infections have also been reported in macaques, baboons, and great apes, mostly in captive colonies in endemic areas where infection may have been acquired locally (Levine 1970; Ndao and others 2000; Toft and Eberhard 1998). Various nonspecific clinical signs are associated with infection; myocarditis is the most common.

Mode of Transmission

Human cases acquired from nonhuman-primate research work are not known, but accidental exposures through mucous membranes, non-intact skin, or penetrating injuries from needles and other medical sharps are possible. T. cruzi can be propagated among monkeys in closed-colony settings through trauma, blood-to-blood exposure, saliva, sexual activity, and transplacentally (Ndao and others 2000).

Incubation Period and Clinical Signs

The incubation period in humans is typically 1-2 weeks. Fever, malaise, lymphadenopathy, hepatosplenomegaly, myocardial damage, and a constellation of other signs are known features of this disease (Chagas disease) in humans.

Diagnosis and Prevention

Blood-smear evaluations, blood culture, serologic tests, and PCR assays are available. Safe blood-handling practices and effective control programs for involved vector species are indicated in work with infected animals.

METAZOAN PARASITES

Hymenolepiasis

Disease Profile in Nonhuman Primates

The cestode Hymenolepis nana has been reported in many species of nonhuman primates, including macaques, baboons, squirrel monkeys, and chimpanzees (Ghandour and others 1995; Muchmore 1987; Toft and Eberhard 1998). Most infections are asymptomatic, but catarrhal enteritis, diarrhea, and abdominal signs have been reported.

Mode of Transmission

Both a direct and an indirect life cycle involving insect vectors are possible. Fecal-oral exposures are plausible, in that eggs are infective when passed. Human cases acquired directly from nonhuman-primate research work have not been reported, but accidental exposures are plausible.

Incubation Period and Clinical Signs

The incubation period is variable—about 2 weeks to maturation of worms in the host. Minor infections are asymptomatic, but enteritis with or without diarrhea, abdominal pain, weight loss, and other symptoms have been reported.

Diagnosis and Prevention

Feces should be examined for eggs. Good hygiene, barrier methods of protection, and safe-handling procedures are indicated. Infected animals should be treated with anthelmintics, and intermediate vector insects should be eliminated.

Oesophagostomiasis

Disease Profile in Nonhuman Primates

The nematodes Oesophagostomum apiostomum and O. bifurcum have widespread distribution and are found occasionally in macaques, baboons, guenons, mangabeys, and chimpanzees (Abbott and Majeed 1984; Muchmore 1987; Munene and others 1998; Perolat and others 1992; Toft and Eberhard 1998;). Infected animals may be asymptomatic or can show a failure to thrive, weight loss, and diarrhea. Nodules containing viable or dead worms are seen on the serosal surface of bowel and other organs, and colonic ulcers may occur.

Mode of Transmission

Transmission is by the fecal-oral route in humans and nonhuman primates.

Incubation Period and Clinical Signs

The incubation period is poorly defined but is probably weeks to months. Abdominal pain and tenderness, appendicitis, and nodular inflammation of the intestinal wall have been described.

Diagnosis and Prevention

Fecal examination, serology, and ultrasonography for identification of nodules are warranted. Adult worms are required for definitive identification to avoid potential confusion with other nematodes. Good hygiene, barrier methods of protection, and safe-handling procedures are indicated, as is anthelmintic treatment of any infected animals.

Oxyuriasis

Disease Profile in Nonhuman Primates

Oxyuriasis is a group of threadworms that includes the pinworm nematode Enterobius vermicularis. This parasite occurs in Old World monkeys and apes, including baboons, guenons, macaques, and chimpanzees (Brack 1987; Ghandour and others 1995; Hubbard and others 1991; Muchmore 1987; Munene and other 1998; Toft and Eberhard 1998). Clinical signs in these species are generally absent. There has been some mention of anal pruritus and irritation, and severe infections have occasionally led to progressive enterocolitis, peritonitis, and death in chimpanzees. Nonhuman primates can acquire this agent from contaminated soil in endemic regions; it can then be passed between species in either direction.

Mode of Transmission

Transmission in humans and nonhuman primates is by the fecal-oral route. Eggs are deposited around the anus and become infective within a few hours, sometimes appearing in the feces. Successive reinfections can occur by transfer of eggs to the host's mouth (accidentally or via coprophagy in some species). Dustborne infections may occur in heavily contaminated environments.

Incubation Period and Clinical Signs

The life cycle of oxyuriasis is about 2-6 weeks. It takes several months for a person to develop a high parasite burden leading to symptomatic disease. People may report perianal itching, disturbed sleep, irritability, and occasional secondary skin infections of the perianal region from self-caused trauma.

Diagnosis and Prevention

A perianal tape test for eggs is standard technique. Fecal examination or sigmoidoscopy of the lower colon can also be done. Good hygiene, barrier methods of protection, and safe-handling procedures are indicated, and infected animals should be treated appropriately with anthelmintics.

Strongyloidiasis

Disease Profile in Nonhuman Primates

The nematode Strongyloides fullerborni is reported in macaques, baboons, guenons, mangabeys, chimpanzees, and other nonhuman primates (Abbott and Majeed 1984; Battles and others 1988; Hubbard and others 1991; Knezevich 1998; Muchmore 1987; Munene and others 1998; Muriuki and others 1998; Toft and Eberhard 1998; ), and Strongyloides stercorales has been documented in apes and other nonhuman primates (Penner 1981). Diarrhea (sometimes hemorrhagic or mucoid) is most commonly reported and is accompanied by weight loss, anorexia, vomiting, coughing, pulmonary hemorrhage, and other signs including death in the case of severe infections.

Mode of Transmission

Transmission in humans and nonhuman primates is by the fecal-oral route, as well as by direct skin penetration for larval stages. Free-living larval forms of this parasite are described.

Incubation Period and Clinical Signs

The incubation period is uncertain, but probably 2-4 weeks. Abdominal pain, nausea, diarrhea, and anemia are reported symptoms of Strongyloides infection in humans.

Diagnosis and Prevention

Fecal examination for eggs and larvae is standard technique. Good hygiene, barrier methods of protection, and safe-handling procedures are indicated, especially in light of the potential for free-living forms in facilities where nonhuman primates are housed. Infected animals should be treated appropriately with anthelmintics.

Trichuriasis

Disease Profile in Nonhuman Primates

The whipworm nematode Trichuris trichuria and its close relatives have a worldwide distribution in New World and Old World monkeys and the great apes (Brack 1987; Ghandour and others 1995; Hubbard and others 1991; Knezevich 1998; Toft and Eberhard 1998). Minor infections are typically asymptomatic; severe infections can cause anorexia, diarrhea, enteritis, and occasionally death.

Mode of Transmission

Transmission in humans and nonhuman primates is by the fecal-oral route but requires 10-14 days of incubation in warm, moist soil to become infective.

Incubation Period and Clinical Signs

The period to onset of clinical signs is not well established, but symptoms begin before the appearance of eggs in the feces, which takes about 3 months following ingestion.

Diagnosis and Prevention

Fecal examination for eggs and sigmoidoscopy of the lower colon are typically used. Good hygiene, barrier methods of protection, and safe-handling procedures are indicated, and infected animals should be treated appropriately with anthelmintics.

OTHER AGENTS

Because of the diversity of species involved and shared susceptibilities to common pathogens, many other infectious agents occasionally found in nonhuman primates are of potential or documented risk to persons who work with them. A few examples are given here, but other sources should be consulted for situations where comprehensive listings are needed (CDC-NIH 1999; NRC 1996).

There are a number of reports of rabies virus infections of New World monkeys, Old World monkeys, and apes; all nonhuman primates should be considered susceptible (Brown 1997; Richardson and Humphrey 1971; Whitney 1976). Both furious and paralytic forms have been seen in these species but without clinical signs specific to the condition. Human cases of rabies from nonhuman primates are generally rare, although eight deaths due to a newly described rabies virus variant have recently occurred after bite injuries from infected pet marmosets in Brazil (Favoretto and others 2001). Nonhuman primates may be exposed to rabies through bites by infected bats, dogs, or other reservoir species in endemic areas or while they are held before export. Killed vaccines have unknown efficacy when used to protect nonhuman primates, although they have been used on occasion for outdoor-housed animals in rabies-epizootic areas. Barrier methods of protection, safe-handling procedures, and prompt and appropriate follow-up are always warranted in the event of bites or scratches by these species.

Considerable controversy exists regarding the potential that exogenous simian type D retroviruses (SRVs) can be transmitted to humans. SRV occurs naturally in wild and captive macaques, where it is associated with an AIDS-like immunosuppressive disease, retroperitoneal fibromatosis, opportunistic infections, persistent refractory diarrhea, and coma. Problems in addressing this issue have been attributable to the population of persons available for testing and inconclusive seroreactivity in the results. However, one recent study provides strong evidence that SRV should be considered a zoonotic agent based on persistent seropositivity spanning 3 years in one animal handler and seroconversion possibly indicative of a transient infection in another over a 2-year period (Lerche and others 2001). Both handlers had sustained occupational exposure to different species of nonhuman primates during their careers, and both remained healthy despite infection. Use of barrier methods of protection and safe-handling procedures, including prompt disinfecting and flushing of wound sites as warranted because of B virus hazards, should help to minimize transmission in occupational settings.

Recent reports of SV40-specific antigen sequences in some types of non-Hodgkin lymphoma have renewed concerns regarding the zoonotic potential of this agent, inadvertently introduced into the human population via contaminated lots of poliovirus vaccine manufactured from 1955 to 1961 (Malkin 2002; Vilchez and others 2002). There are also epidemiologic links between SV40 infection and human malignant mesothelioma (Carbone and others 2000) and a host of other diseases (Strickler and Goedert 1998).

SV40 is a polyoma virus naturally associated with macaques that can be experimentally transmitted to African Old World species (Brack 1987). Latent infections are established, including in kidney cells used in the original production of poliovirus vaccine. Virus can spread through urinary and nasopharyngeal secretions of infected monkeys and humans (Brack 1987). The extent to which SV40 is biologically important for any human disease remains controversial (Ferber 2002), and there is a vast body of literature on experimental work with this agent in laboratory rodent models. The recommended safety precautions of good hygiene, barrier methods of protection, and safe-handling procedures should help to prevent accidental exposure in nonhuman-primate research settings.

Cases of tularemia (Francisella tularensis) have occurred in research colonies of squirrel monkeys (Doyle and others 1988) and other species, without documented sources of infection. Mammalian reservoirs for tularemia in the United States are wild rabbits and rodents, but secondary transmission to nonhuman-primate research workers in this context is conceivable.

Mycoplasma hominis, Ureaplasma urealyticum, and other unidentified mycoplasmas are commonly carried by macaques, baboons, and chimpanzees (Schoeb and others 1997), but the zoonotic significance of these agents is unknown.

Naturally acquired cases of Helicobacter pylori, H. heilmannii, and novel species in this genus have been found in macaques and baboons (Fox and others 2001; Ho and others 1991; Reindel and others 1999) with and without clinically associated disease, adding potential complications to use of infected animals as experimental models for these agents. The zoonotic potential of these agents in the context of biomedical-research use of nonhuman primates remains unresolved. Some success with elimination of H. pylori in rhesus monkeys has been documented (Dubois and others 1998). There is also evidence of infection with various serovars of Leptospira interrogans in several species of nonhuman primates, including macaques, baboons, squirrel monkeys, guenons, chimpanzees, and tamarins (Fear and others 1968; Gibson 1998; Perolat and others 1992). The agent has been associated with outbreaks of abortion and stillbirth in baboons and abortion and peracute death in squirrel monkeys, but overt disease in other cases of infection has been inapparent. Leptospira organisms can be acquired via ingestion, mucous membrane exposure, or skin abrasion; nonhuman primates carrying them could represent a hazard for humans, even if they are not the primary vertebrate reservoir.

There are occasional reports of dermatophytes and ectoparasites (lice and skin mites) with documented or suspected zoonotic significance in various species of nonhuman primates (Baker and others 1971; Gibson 1998; Goldman and Feldman 1949; Gugnani 1971; Ronald and Wagner 1973). Rapid identification and treatment in research settings and the use of barriers covering all exposed skin surfaces should help to reduce the likelihood of occupational exposures.

SUMMARY

Nonhuman primates and their tissues can become infected with micro-organisms communicable to humans in many ways. Exposure of nonhuman primates to zoonotic agents can occur in their native habitats, whether or not they function as ecologically important reservoir hosts. They may also occur through association with humans or human waste material at any stage of their handling and use; through exposure to other infected nonhuman-primate species or other infected vertebrate or invertebrate species during shipping, holding, or use; and through purposeful or inadvertent infection in the course of experimental work. Many of the infectious hazards described in this chapter are considered acutely or chronically pathogenic in nonhuman primates, and well-structured programs of veterinary care should help to identify and eliminate many of these agents from research colonies. Others typically exist for long periods as asymptomatic infections and require special efforts in disease surveillance, often with limited therapeutic options for their complete eradication. Whether these infections can be sustained in research-colony settings depends on the species of nonhuman primate, the biology of the agent, systems of husbandry and veterinary care, and the presence of competent invertebrate vectors. Likewise, the potential for occupational exposure to the agents varies with the collection of species, the type of research use, systems of husbandry and veterinary care, and contact with other vertebrate and invertebrate species at each institution. Other chapters of this book contrast the exposure rates of persons who work with nonhuman primates in a risk-based context and provide a framework for developing and monitoring programs of safety appropriate to these concerns in the modern era.