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

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.



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

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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. 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

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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

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TABLE 3-1 Infectious Hazards from Nonhuman Primates   Macaques Baboons Guenons Squirrel Monkeys Chimpanzees Viruses B virus Foamy virus Simian retrovirus (Type D) SV40 SIV Pox viruses Yellow fever Dengue Ebola Foamy virus Pox viruses Yellow fever Dengue Foamy virus SIV Pox viruses Yellow fever Dengue Dengue Yellow fever Foamy virus SIV Hepatitis B Molluscum contagiosum Hepatitis A Pox viruses Yellow fever Dengue Ebola Bacteria Burkholdria pseudomallei Campylobacter spp. Mycobacterium tuberculosis Mycobacterium bovis Mycobacterium leprae (also known in mangabeys) Leptospira spp. Salmonella spp. Shigella spp. Yersinia pseudotuberculosis Yersinia enterocolitica Campylobacter spp. Leptospira spp. Mycobacterium tuberculosis Mycobacterium bovis Salmonella spp. Shigella spp. Yersinia pseudotuberculosis Yersinia enterocolitica Campylobacter spp. Leptospira spp. Mycobacterium tuberculosis Mycobacterium bovis Salmonella spp. Shigella spp. Yersinia pseudotuberculosis Yersinia enterocolitica Campylobacter spp. Leptospira spp. Mycobacterium tuberculosis Mycobacterium bovis Salmonella spp. Shigella spp. Yersinia pseudotuberculosis Yersinia enterocolitica Burkholdria pseudomallei Campylobacter spp. Mycobacterium tuberculosis Mycobacterium bovis Mycobacterium leprae Leptospira spp. Salmonella spp. Shigella spp. Yersinia pseudotuberculosis Yersinia enterocolitica

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Metazoan Parasites Hymenolepis nana Oesophagostomum spp. Strongyloides spp. Trichuris spp. Enterobius vermicularis Hymenolepis nana Oesophagostomum spp. Strongyloides spp. Trichuris spp. Oesophagostomum spp. Strongyloides spp. Trichuris spp. Hymenolepis nana Trichuris trichuria Hymenolepis nana Oesophagostomum spp. Strongyloides spp. Trichuris spp. Enterobius vermicularis Protozoan Parasites Balantidium coli Cryptosporidium spp. Entamoeba histolytica Giardia intestinalis Plasmodium spp. Balantidium coli Cryptosporidium spp. Entamoeba histolytica Giardia intestinalis Plasmodium spp. Balantidium coli Cryptosporidium spp. Entamoeba histolytica Giardia intestinalis Plasmodium spp. Balantidium coli Cryptosporidium spp. Entamoeba histolytica Giardia intestinalis Plasmodium spp. Trypanosoma cruzi Balantidium coli Cryptosporidium spp. Entamoeba histolytica Giardia intestinalis Plasmodium spp.

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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 1993, 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.

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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 labora

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tories 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 prod

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ucts) 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 mon

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keys 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 rap

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idly 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.

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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.

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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.

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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.

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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.

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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 hy

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giene, 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.

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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

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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

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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

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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

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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.