Postexposure Medical Treatment in Nonhuman-Primate Facilities
Nonhuman primates are often ideal animal models for the study of human disease processes, but their phylogenetic similarity with humans places employees at risk for transmission of a broad variety of zoonoses as described in Chapter 3. Specific occupational health services recommendations for nonhuman-primate handlers have been presented in Chapter 7. This chapter addresses the role of an institution’s occupational health care staff in prevention and treatment of staff exposure to nonhuman-primate related hazards.
Specific recommendations for occupational health services for nonhuman-primate handlers are outlined in Biosafety in Microbiological and Biomedical Laboratories (CDC-NIH 1999).
The occupational health services staff should work in concert with their facility’s occupational health and safety program to ensure that workplace health risks are minimized and that appropriate medical services for evaluation and treatment are available to workers exposed to nonhuman primates or their tissues. These important occupational health services may be provided through a variety of arrangements depending on the individual facility risk-assessment process, as described in Chapter 5. It is critical that the designated medical providers be informed and appropriately updated regarding the nature of the health risks. That might require joint participation of research personnel, animal care staff, environmental health and safety staff, and occupational health services staff in continuing education regarding use of specific agents and safety train
ing activities, as described in Chapters 7 and 8. Persons working with nonhuman primates or their tissues have the potential for exposure to infectious agents. Medical providers’ participation in infection control and biosafety review may be appropriate and help to ensure that occupational health providers are updated on these important risks of infectious disease.
Many facilities are using emergency departments in local hospitals and clinics for obtaining emergency medical care. The individual responsible for the occupational health program should develop a close working relationship with the local emergency department to ensure that (1) emergency medical staff are familiar with the specific hazards posed by nonhuman primates and (2) they can provide a timely evaluation and follow up when an employee arrives at the emergency department. This may involve periodic meetings of the occupational health program and emergency department staff, training of the emergency department staff, and developing a packet of information for the emergency-room physician. This packet should outline concerns and offer information for telephone consultation with a knowledgeable physician.
DEFINING EXPOSURE RISK
The risk of developing infection from an exposure to nonhuman primates depends on many factors, including the nature of the infectious agent, the mechanism and route of exposure, the physiologic status of the source animal and the employee, whether personal protective equipment was used, and whether appropriate postexposure first-aid procedures were followed. Data that could be used to define risk for most exposure scenarios are sparse. Therefore, assessing the risks posed by some agents is problematic, and best estimates must be based on knowledge of similar agents or exposure situations. Health-care providers will have to approach employees’ exposure concerns with a willingness to acknowledge unknowns while attempting to estimate risks and involve the employees in the clinical risk-assessment and decision tree process.
SCOPE OF POTENTIAL INFECTIOUS AGENTS IN NONHUMAN PRIMATES
The variety of potential infectious agents found in nonhuman primates is summarized in Chapter 3. Agents likely to be of concern in most facilities are reviewed here, but occupational health-care providers should become familiar with all exposures likely to be encountered in their facilities. For example, exposures to primates bred in captivity might pose different risks from exposures to wild-captured primates. Wild-captured
primates can harbor naturally occurring zoonotic agents—including helminths, bacteria, and viruses—not typically found in captive-raised populations. Furthermore, experimental treatment of nonhuman primates with agents such as immunosuppressants can increase their risk for these infections and hence transmission to handlers.
In the handling of nonhuman primates, it is reasonable to adopt universal precautions and thereby minimize exposure risk regardless of the presence or level of infection (CDC-NIH 1999). When employee injuries occur, information on the viral status of the animal and any infectious experimental agents should be communicated to the patient’s health professional. The patient should be managed on the basis of the assumption that the nonhuman primate involved was infected with the transmissible agent of concern. Defining the transmissible agent of concern is dependent on several factors: the species involved, the experimental status of the animal, the viral and microbiological status of the animal and/or colony.
Precautions must be taken in interpreting the risk posed by nonhuman primates classified as “specific pathogen free” animals because of the risk of latency of some infections and the fact that all diagnostic testing for the presence of infectious agents has technical limitations that lead to imperfect accuracy. B virus is well-known to become latent in macaques, and group-housed macaques can seroconvert and shed B virus without exhibiting clinical signs (Weigler and others 1993; Weir and others 1993). Additionally, 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). Relying on past viral testing or serologic results does not provide adequate predictive information regarding viral shedding at the time of a human exposure to bites, scratches, or splashes from the animal. Although it should be assumed that all macaques are infected with B virus (even in SPF colonies) when initiating first aid and seeking medical care, decisions on antiviral prophylaxis treatment will include considerations of the viral status of the animal/colony and are discussed under “B Virus Exposure” later in this chapter.
DEFINING ROUTES OF EXPOSURE
The most common routes of exposure among nonhuman-primate handlers are scratches, needle sticks, cuts, bites, and mucous membrane exposures (bin Zakaria and others 1996), though most published reports of injury and infection among nonhuman-primate handlers are related to bites. Animal-bite wounds are more likely to result in bacterial infection than are simple abrasions or scratches because of the inherent limitations in cleansing of puncture wounds (Trott 1997). A review of bacterial infec
tions after primate bites found that polymicrobial infections have often resulted in severe complications, including osteomyelitis caused by such bacterial flora as Eikenella corrodens, Bacteroides spp., and Fusobacterium spp. (Goldstein and others 1995).
Mucocutaneous exposures can also result in transmission of gastrointestinal pathogens, such as Shigella spp. (Kennedy and others 1993), Campylobacter spp. (Gibson 1998; Hubbard and others 1991; Johnson and others 2001; Renquist 1987; Taylor and others 1989; Tribe and Frank 1980), Giardia intestinalis (Armstrong and others 1979), Crypotosporidium parvum (Miller and others 1990; Muriuki and others 1998; Toft and Eberhard 1998), and Entamoeba histolytica (Remfry 1978).
Research involving retroviruses has demonstrated that SIV can infect humans. Occupational exposure to SIV has occurred through mucosal splashes, contamination of cuts or skin abrasions, and needle stick injuries (Essex 1994; Khabbaz and others 1994; Sotir and others 1997). The assumption that SIV infection can be transmitted by routes similar to those in occupational exposure to HIV has led the CDC to recommend that occupational exposures to SIV and hybrid strains of HIV-SIV be managed according to PHS postexposure prophylaxis guidelines for HIV (CDC 2001c).
Among the well-documented cases of human B virus infection, almost half involved exposure by monkey bite (Breen and others 1958; Bryan and others 1975; Cohen and others 2002; Davenport and others 1994; Davidson and Hummeler 1960; Holmes and others 1990; Hummeler and others 1959; Palmer 1987; Sabin and Wright 1934). Exposures also occurred by scratches (monkey or cage), mucosal exposures, exposures to blood or tissue (Cohen and others 2002) and by needle stick injury (Artenstein and others 1991). B virus can also be transmitted human-to-human by skin-to-skin contact (Holmes and others 1990).
While bites and scratches are of known importance in the transmission of B virus, systemic infection has also been reported in people not known to have been recently injured or exposed (Bryan and others 1975; Fierer and others 1973), suggesting that B virus latency in humans is a possibility. Because human herpesvirus latency in humans is known to exist, as is B virus latency in nonhuman primates, it might be presumed that B virus infection can become latent in humans (Fierer and others 1973). However, in a controlled seroprevalence study performed in 1995, there was no evidence of latent B virus infection in 321 handlers, using three high B virus antibody-titered humans who were available as references (Freifeld and others 1995). Additionally, other investigations have failed to document seroconversion among contacts of B virus-infected patients (Davenport and others 1994; Holmes and others 1990). However, several isolated cases in humans are suggestive that B virus latency in
humans may occur (personal communication; Drs. Hilliard and Davenport). Current data would suggest that if B virus latency occurs at all in humans, it is very rare. The clinical significance of B virus latency in humans is even less well defined. It is unknown whether recurrent clinical infections or a chronic neurologic illness due to B virus occurs in humans. Therefore, clinicians responsible for evaluating injured or ill nonhuman-primate handlers should be aware that absence of recent known exposure to animals might not preclude B virus infection.
DETERMINING APPROPRIATE POSTEXPOSURE MEDICAL MANAGEMENT
As outlined above, human contact with nonhuman primates—including bites, scratches, and splashes—can lead to transmission of natural zoonoses or experimentally acquired infections, although the probability of infection is low under most circumstances. Although B virus infection occurs uncommonly after nonhuman-primate exposures, the illness is often fatal when left untreated, and so substantial care must be taken in assessing and following up on such contact (Holmes and others 1995). There should be follow-up monitoring of potential B virus exposure including tracking of any unexplained influenza-like illness lasting more than 48 hours in personnel working with nonhuman primates or their tissues, to allow for appropriate treatment advice by an occupational health physician.
Determination of appropriate postexposure medical management is not well defined, because the attendant risks are difficult to measure for each pathogen. Analogous occupational-exposure data do exist for some occupationally acquired infections, including HIV infection, in healthcare workers, but there is a paucity of data to support clinical decision-making in other settings. The medical care provider should rely on consensus documents and other guidelines, develop a network of infectious-disease specialists to assist in making treatment decisions, and be aware of the potential risks of iatrogenic injury or complications when making recommendations for postexposure management. For example, aggressive medical treatment might contribute to injury and illness through medication side effects if unnecessary prophylaxis is prescribed when exposure risks are uncertain or if patients are not monitored appropriately (CDC 2001a).
When assessing risk of infection after exposure to a nonhuman primate, the medical care provider should consider the risk factors associated with the nonhuman primate and the employee. This will necessitate close communication with the facility animal-care and infection-control staff. The initial communication should be used to gather information
that will be important for decisions regarding prophylaxis and treatment and should include a discussion of the experimental, viral, and microbiological status of the animal and colony. For example, a nonhuman primate that is immunocompromised would potentially be a more likely source of B virus than otherwise (Chellman and others 1992; Holmes and others 1995). Similarly, circumstances regarding the kind of injury and the application of appropriate first aid should be taken into consideration in determining the risk of infection. In summary, defining the risk of infection after an exposure requires careful review of both the nonhuman primate and the employee in question.
FIRST AID AFTER EXPOSURES TO NONHUMAN PRIMATES
As with any human or animal exposure, postexposure first aid, including immediate cleansing of the wound or contaminated mucous membrane, is of the utmost importance in preventing infection. The importance of adequate wound cleaning must be stressed during employee training and should include a demonstration of methods and location in the workplace of cleansing materials. Nonhuman-primate facility directors and occupational health care providers should consider the use of a wallet card or other simple guide to remind employees about first aid and provide emergency contact information.
Good general guidelines for medical management of animal-bite wounds management are available (Smith and others 2000). In general, emergency first aid should be initiated before the patient travels to a health-care provider, because prompt cleaning may reduce the risk of infection with some pathogens. This is particularly important for injuries caused by macaques, because B virus becomes incorporated into host cells quickly (Ludwig and others 1983).
First aid for skin exposures should include flushing and scrubbing of the skin with a detergent and water for 15 minutes. Mechanical scrubbing of the wound margins is recommended in addition to the use of copious flowing water and detergent, povidone-iodine, or chlorhexidine (Cohen and others 2002) to further cleanse the wound of contamination. Exposed eyes or mucous membranes should be flushed for 15 minutes preferably at an eyewash station because it is difficult for employees to wash their own eyes. Detergents and antiseptics should never be used in the eyes. If an eye station is not in close proximity, workers should have ready access to a portable liter bag of sterile saline. Nonhuman-primate handling facilities must have appropriate eye-washing stations (in addition to standard sinks with running water) or appropriate eye-irrigation materials immediately available for first aid (ANSI standard Z358.1-1998). All nonhuman-primate facility employees must be taught about the location of
sink and eye-washing facilities and the importance of early initiation of standard wound cleaning and mucous membrane irrigation.
MEDICAL EVALUATION AND FOLLOWUP
It is imperative that handlers of nonhuman primates have priority access to physicians or other appropriately trained medical staff who have specific knowledge and experience regarding injuries caused by nonhuman primates. It is the employee’s responsibility to report an exposure or occurrence of symptoms. The employee’s occupational health care provider is then responsible for assessment of the exposure or symptoms. It is imperative that the chain of command for report and assessment of an exposure or symptoms be clearly defined. This is particularly important for SIV and B virus exposures, for which prophylaxis, when advised, should be initiated as soon as possible to provide the greatest benefit. In addition to developing a local network, the medical care providers should have reference material available about unique aspects of exposure to nonhuman primates. Table 9-1, for example, provides guidelines for the initial management of exposures involving macaques.
A mechanism must be in place for reaching a knowledgeable health-care provider outside ordinary working hours. For larger facilities, an on-call arrangement may be developed. For smaller facilities, the local emergency department may be utilized. Regardless of the size of the facility, the postexposure management plan must include training of employees and medical care providers. Regular follow-up must be provided after an injury; if an injured employee does not keep a recommended follow-up appointment, an effort must be made to inform the employee of the need for it.
Important factors to consider when assessing a wound caused by a nonhuman primate are outlined in Table 9-2 and should be documented in the medical record for later reference. The physical examination should include collection of vital signs and inspection of the wound or contaminated mucous membrane. This examination should be documented and should include information regarding the location, length, estimated depth, and shape of the wound, potential for nerve or tendon damage, vascular integrity, and presence of foreign body or contamination. First aid provided at the worksite should be documented. Animal bites and scratches pose a high risk of tetanus. Therefore, in addition to thorough cleaning, tetanus prophylaxis should be offered on the basis of CDC guidelines (CDC 1985).
TABLE 9-1 Initial Management of Exposures Involving Macaques
TABLE 9-2 Wound Assessment
Risk of Bacterial Infection
Clinical data on which to base a decision to provide prophylactic antibiotic treatment for a nonhuman-primate bite are sparse. However, experience with bites of other animal species and humans suggests that the most important factors in preventing wound infection are related to initial wound cleaning. Wounds on the extremities, wounds that are macerated, or punctures are more likely to become infected than superficial, proximal wounds (Aghababian and Teuscher 1992; Goldstein 1992). Goldstein and others (1995) reviewed the subject of bacterial infection following nonhuman-primate bites and has advised that the diagnosis and treatment of simian bites should be similar to those of human bites. A rational approach to preventing bacterial infection would include empiric postbite antibiotic prophylaxis for all but the most superficial wounds. This should involve an antibiotic active against streptococci, staphylococci, enterococci, Eikenella corrodens, anaerobes, and Enterobacteriaceae spp. A good choice would be amoxicillin-clavulanic acid as a single agent or penicillin plus a penicillinase-resistant penicillin or cephalosporin. If the wound is not already infected, it is reasonable to initiate a 3- to 5-day course of treatment; if no signs of infection appear, the antibiotic treatment may be discontinued at the wound-check visit. Most physicians would not recommend primary closure of a human-bite wound on an extremity, but delayed closure could be considered during a follow-up visit if there is no sign of infection (Goldstein 2000).
B VIRUS EXPOSURE
Prophylaxis after B Virus Exposure
With respect to prophylaxis after exposure to B virus, a detailed description of postexposure management was issued in 1995 (Holmes and others). More recent guidelines suggest the following (Cohen and others 2002):
Postexposure prophylaxis is recommended in the following circumstances: skin exposure with loss of skin integrity or mucosal exposure to a high-risk source (an ill macaque, an immunocompromised macaque, a macaque known to be shedding virus, or a macaque with lesions suggestive of B virus); an inadequately cleaned skin exposure with loss of skin integrity or mucosal exposure (with or without injury); head, neck, or torso laceration; deep puncture bite; needle stick associated with tissue or fluid from central nervous system; lesions suspicious for B virus on the animal’s eyelids or mucosa; puncture or laceration after exposure to an object likely to be contaminated with fluid from oral or genital lesions, central nervous system tissues, or tissue known to contain virus; post-cleaning culture positive for B virus; and immunocompromised status.
Postexposure prophylaxis for B virus is considered in the following situations: mucosal or eye splash even if adequately cleaned; laceration with loss of skin integrity; needle stick with blood from ill or immunocompromised macaque; puncture or laceration after exposure to an object contaminated with body fluid (other than from a lesion); and a potentially infected cell culture.
Postexposure prophylaxis for B virus is not recommended if the exposed skin remains intact or exposure was due to a nonhuman-primate species other than a macaque, unless such animal is highly likely to be ill from B virus due to rare cross-contamination occurrences from macaques (see Chapter 3).
Selecting Agent for Postexposure Prophylaxis
Acyclovir was suggested in the 1995 guidelines, to be given at 800 mg five times per day for 14 days (Holmes and other 1995). This regimen was based on animal studies demonstrating successful acyclovir treatment of experimental infection and case reports of successful acyclovir and gancyclovir treatment of B virus infection. Since those guidelines were published, valacyclovir has been released and has become the preferred antiviral agent because the active metabolite, acyclovir, is present at higher serum concentrations and probably leads to better compliance; it is given
at 1 g three times per day for 2 weeks (Cohen and others 2002). Cohen and others (2002) also offer a detailed discussion of postexposure prophylaxis in pregnant women and those with renal insufficiency. Physicians should check for updates on the preferred treatment regimen following B virus exposure on the CDC and B virus laboratory web sites, since this report cannot stay up-to-date.
EXPOSURE TO SIMIAN IMMUNODEFICIENCY VIRUSES
SIVs were initially identified on the basis of their cross-reactivity with HIV in serum samples from rhesus macaques with AIDS-like illnesses (Kanki and others 1985). In 1994, Khabbaz and others published a case report of a laboratory worker who was accidentally infected with an SIV strain. This case led to a seroprevalence study of HIV2-SIV antibody among nonhuman-primate handlers and laboratory workers that demonstrated that 0.4% of handlers were seropositive (Sotir and others 1997). One of those seropositive workers demonstrated waning antibody titer over time; none developed any clinical manifestations of infection.
There are no postexposure-prophylaxis guidelines available for SIV, nor is there any known effective prophylactic treatment. The only postexposure-prophylaxis guidelines available for retrovirus exposures are for occupational exposures to HIV (CDC 2001c). The HIV guidelines advise the use of nucleoside reverse transcriptase inhibitors, sometimes in combination with a protease inhibitor. Treatment recommendations depend on the results of assessment of the circumstances of the exposure and on source and exposure factors. Factors to be considered include the type of exposure (percutaneous versus mucous membrane), type and amount of fluid (blood versus other fluids), infectious state of the source (stage of disease, viral load, and antiviral-treatment status), and susceptibility of the exposed person. However, postexposure prophylaxis for SIV exposures may be different because SIV may not have the same susceptibility to prophylaxis. The most recent guidance from the CDC HIV and Retrovirology Branch for SIV exposures is to consider two-drug treatment with nucleoside reverse transcriptase inhibitors after HIV exposure (CDC 2001c). Examples would include a 4-week treatment course with zidovudine and lamivudine or lamivudine and stavudine, depending on viral susceptibility. Initial medical assessment should include baseline serology, baseline complete blood count, chemistry panel, and pregnancy testing when appropriate. Follow-up medical assessment should include repeat clinical examination every 1-2 weeks during treatment. Serology should be assessed 6 weeks, 3 months, and 6 months after exposure (CDC-NIH 1999).
Simian foamy virus, simian T-lymphotropic virus, and simian D retrovirus infections are also studied in nonhuman primates. Handlers may be exposed to these retroviruses through contact with infected materials or injuries. Simian foamy virus infections have been documented among primate handlers (CDC 1997; Heneine and others 1998; Sandstrom and others 2000). Absence of documented secondary transmissions to close contacts or through the blood supply suggests that humans may be a dead-end host for this infection (Callahan and others 1999; Winkler and others 2000). Simian D retrovirus infection was also recently documented among nonhuman-primate handlers (Lerche and others 2001). In nonhuman primates, infection with these viruses has been associated with immunodeficiency syndromes and lymphoproliferative disorders.
Recent vaccine research has used live recombinant-vaccinia virus engineered to express antigens of herpesvirus, hepatitis B, rabies, influenza, and HIV among others (CDC 2001b). Recombinant-vaccinia research has led to great advances in the development of vaccines, including the development of an oral rabies vaccine for animals. However, a recent report of a human infection caused by a recombinant-vaccinia rabies virus (Rupprecht and others 2001) has raised concerns about the adequacy of health and safety recommendations for animal handlers who may be caring for nonhuman primates infected with vaccinia virus. The issue of vaccination of laboratory animal handlers has been re-examined, and revised guidelines are now available (CDC 2001b). The guidelines recommend that laboratory animal workers be vaccinated for vaccinia if they handle cultures or animals contaminated or infected with vaccinia virus, recombinant-vaccinia virus vectored vaccines, or other orthopoxviruses that infect humans (for example, monkeypox and cowpox). The special case of variola (smallpox) virus will not be described here.