4th National Symposium on Biosafety

Zoonoses in Animal Care Facilities

Christian E. Newcomer, VMD
Director and Research Associate Professor
The University of North Carolina at Chapel Hill
CB #7115; B-12 Berryhill Hall
Chapel Hill, NC 27599-7115
919-966-3113

Zoonotic diseases are a small but important part of the hazards that are associated with the care and use of laboratory animals. The large number of potential zoonoses in the laboratory animal facility includes organisms from every category of causative agents and really spans the spectrum of the types of animals that are used in biomedical research. However, what would seem to be a continuous opportunity for zoonotic infections to occur in the laboratory, the number of cases reported in the literature suggests that these are, in fact, very infrequent. Most laboratory animal facilities, and many laboratory animal veterinarians, have never had any experience with zoonotic infections among their personnel.

The explanation for why there are so few actual reported zoonotic infections really relates to four items. Most institutions already have a program of integrated management for the oversight of zoonotic infections in animal facilities. This reflects, first and foremost, the terrific progress that has been made in the laboratory animal industry in the past 20 years to improve the health of laboratory animals. This involves the veterinarians and other laboratory animal specialists who are providing a very high quality laboratory animal for most applications in biomedical research. Once the animals arrive at the animal facility, if in fact they are not from sources which are of excellent health, the veterinary programs are generally quite mature, and have an interest in zoonotic infections. They pursue hem in a timely fashion, they are aware of appropriate diagnostic techniques and methods, and they define these new problems promptly to try to control them in the animal populations. Where that is not possible, of course, infections may be present in the facility. Then the health and safety professionals have to play an important role in informing personnel and devising preventive programs which include immunizations appropriate for the agents present in the facilities. The importance of proper training and education of personnel must be emphasized for the control of zoonoses. The recent passage of OSHA's Personal Protective Devices regulation has further bolstered the need to have written plans for the kinds of protective equipment to reduce hazards in the workplace. Under that broad umbrella, the consideration of zoonotic hazards and the barriers to the prevention of those hazards has made it even more unlikely that an actual zoonotic infection would occur even when the agent is present. Finally, there has been an evolution in the field to move towards progressively more exclusionary caging systems and other engineering controls to prevent the spread of infection from the animal housing environment to the individuals working in that environment.

There are several ways of defining these hazards, several factors that one should consider when weighing a program and trying to set priorities for the control of zoonoses in the laboratory. The first thing to consider is animal species. Generally, the small laboratory rodent is not of concern with zoonoses. However, it has recently been shown that lymphocytic choriomeningitis virus in rodents is a potential zoonotic infection in laboratory animal facilities. But once that particular organism is discounted with regard to rodents, there is relatively little opportunity for personnel involved with the care of rodents to contract zoonotic infections. As one moves to other species, the likelihood of encountering potentially zoonotic agents increases. One such extremely important agent is, Herpes B virus.

The source of animals also needs to be considered. Laboratory rodents have undergone their growth and development in a highly defined environment and therefore they have little opportunity to contract unwanted infections. Other animals coming from sources that are less regulated and less stable have more opportunity to have acquired an infection which can subsequently be introduced it into the workplace.

The physical environment for the animals also has a direct bearing on the potential for acquiring an unwanted infection. Once animals are in the highly defined laboratory environment, there is not much opportunity for them to then acquire infections from other animals in the facility. If animals are kept in a more naturalistic setting, and there is somewhat more emphasis on doing that nowadays (particularly if they're housed outdoors as agricultural animals), the risk increases. You may have looked at that animal at one point in time and determined that it had no zoonotic risk, but that animal has had a continual exposure to other animals which might introduce new infections. Then you need to look at the animal on a recurring basis to determine that it's safe to be used within the facility.

Finally, it is important to consider the intrinsic difficulties in the characterization or identification of the hazard. For example, some hazards are technically difficult to isolate. Agents which cause latent infections require specialized diagnostic techniques, and this may put their detections out of the reah of most animal facilities. You have to use specialized resources or call upon specialized expertise to determine whether those agents are present or not. That interacts with the last factor, namely that there are very serious expense constraints in the detection of some of these agents. I think there is an unstated hierarchy in the likelihood of detecting zoonoses according to the source of the animals in your facilities. Many animals go through a cesarean re-derivation process, and as part of the process, all the endemic infections may have been eliminated. These populations are generally maintained under a very high veterinary diagnostic surveillance, so that if there are problems in the facilities, they are promptly detected and reported to the user of the animals. Purpose-bred animals are perhaps one notch down on the scale. These are animals which have not been through cesarean re-derivation so they do have their native infections. Because they have been purpose-bred and under professional care for long time, the diseases of these populations are generally highly characterized. There has been focused efforts to eliminate any organisms which might be problematic within the animal facility. There has been reports in recent years of some purpose-bred populations having serious zoonotic infection.

Further down on the list are random-source populations containing animals from multiple points with unknown personal disease and exposure histories. Frequently these animals are mixed in larger pools where disease is exchanged, and a real opportunity exits to encounter zoonotic infections in these animals. One problem that you encounter with the characterization of these populations is expense. Imagine a program which uses hundreds of dogs a year to look for an enteric pathogen. That would entail sampling those animals to determine in each animal whether they harbored something which might be a zoonotic concern for personnel. This gets to be prohibitively expensive and requires a lot of thinking about how the institution will expend its resources.

At the absolute bottom of the hierarchy are wild-caught animals, leaving us open to not just infections from every source, but also a number of arcane and unusual infections that are not usually thought of in the laboratory animal environment. Among the zoonoses, all the major disease categories are represented, and there generally is a hierarchy of agents by importance as well. The top four groups, viruses, bacteria, fungi and protozoa are the ones of most concern, and in each of those categories, there is an agent or agents which are serious in nature and have a potential to be in the laboratory environment. The helminth parasites are generally less problematic because the routine sanitation that's performed on laboratory animal facilities removes most of these organisms before they've gone through embryonation or other important developmental steps which makes them infectious for personnel. Other parasites are also present on occasion, and they can be vectors for other diseases. They're important to consider, but don't rank up there with some of the other agents. In addition to B virus, note there are other herpes viruses carried by macaques. At least one herpes virus infecting squirrel monkeys has been noted historically to cause a disease similar to Herpes B, although not as severe. Individuals who are bitten develop a vesicular rash on the wound area where the bite occurred, then a general flu-like syndrome and a non-fatal encephalitis. This is a weaker variant, perhaps of the Herpes B. It points out the importance of regarding any bite from a non-human primate as a very serious incident, and clearly bites of macaques are very important. Other important viral infections of non-human primates are hepatitis viruses A and E, agents which are passed by the fecal oral route. There have been cases reported where Hepatitis A has been passed from infected chimps to humans. That has been a recognized zoonoses. Hepatitis E has not been recognized as a zoonoses at this point, but many of the non-human primates species are susceptible to Hepatitis E. It is also fecal-orally spread. In the recen literature there have also been outbreaks of Hepatitis A among a colony of young macaques. This is an agent which is still present in some of the colonies here in the United States.

The other group under non-human primates which bear some discussion are the pox viruses; these would mostly be seen in quarantine stations from imported animals. Facilities which conduct that kind of activity need to look for monkey pox. Another one that's noteworthy is simian immunodeficiency virus. There have been several needle exposures to SIV of personnel who work with non-human primates. One of these individuals has been shown to have sero-converted and actually became viremic with the agent. So it's something that warrants watching.

Among the other animal species there is a similar list of viruses. I glossed over the arbo viruses because they require an insect vector for passage from the animal host into the human. In the laboratory setting there are a number of cases where humans have been infected with arbo viruses from generated aerosols and while working with copious amounts of materials. Personnel have been experimentlly infected with arbo viruses from infected rodents. With wild-caught animals, each animal becomes its own experimental situation. As shown by the recent outbreak of Hanta virus in the southwest a couple of summers ago, we must always be on the look-out for emerging infectious diseases. Although not present in our commercial laboratory animal stocks, Hanta virus is one, which like lymphocytic Choriomeningitis virus or other viruses that are tumor-associated, may be brought into a colony by tumor passage. It might be within certain wild-caught rodents which is not uncommon in biomedical research. Just a five minute exposure by people casually walking through rooms that house mice infected with Hanta virus has been known to transmit the disease. So it is a very transmissible agent. One agent with which I had a personal and intimate relationship with is orf virus. I had this as a veterinary student as a result of doing an oral exam on a sheep that had a sore mouth. I was bitten on my fingers and developed these very large and painful nodules on my hand for about the next six weeks. In some individuals that's known to be a generalized infection with lymphadenectomy. In many of these species, we need to consider rabies as a possibility.

Bacterial zoonoses can be split basically into the major systems that they affect.The respiratory group is most important. Microbacteriosis is a very important disease. The veterinary and occupational health programs work "glove and hand" to control this agent in the animal facility. Q-fever is another very important agent for people who work with sheep, particularly pregnant sheep. The problem with this agent is that it is very difficult to detect because the organism is generally latent; it is only shed in copious amounts around the time of parturition. In other words, the serological tests for the organism are not reliable in that there are a large number of false negatives. So it's problematic that it will be routinely detected. In a similar vein, chlamydiosis falls into a similar pattern, but is much less common in the laboratory animal environment.It might be associated with laboratory housed birds.If you're bringing in wild-caught birds for any purpose, you need to be aware of this. There are reported cases of agricultural workers dealing with turkeys who are infected, and this organism is very transmissible.

The enteric bacteria zoonoses are also important to consider; for the most part these are related to non-human primates, ogs, cats, and some of the larger animals. One does not frequently think of the rodents as a cause of human infection. Rodents can get contaminated either through feed or through other means and harbor agents like salmonella. For the most part, these relate to the larger animals and frequently the younger animals within the species. They can cause a serious problem in personnel who contract them. One of the problems in the detection of these relates just to the money issue. It is one thing to detect a disease which is showing clinical signs because the organism is presumably in high number, making it fairly easy to culture, but the difficulty is that many of these organisms can exist in a carrier state with intermittent shedding of the organism. This requires that you do multiple cultures on a given animal to determine whether it is there. The problem is that with cultures costing anywhere from twenty-five to forty dollars each, it is a very expensive proposition for the animal facility environment. The systemic bacterial zoonoses (some are actually more regional infections with the potential to become systemic) can be quite serious. Brucellosis is one which has been reported in some dog breeding colonies. The organism is available in copious amounts at the time of parturition in dogs and in other species which harbor brucella, but it is also shed in urine so urinary contact can cause the spread of that disease. Cat-scratch disease is better defined now that that organism has been isolated and characterized. This is something that is fairly common among cats, especially young cats. They have a low grade bacteremia with continual infection; the agent is transmitted with bites and scratches. Leptospirosis is pretty much unheard of in the laboratory animal facility. With the great number of pigs and other animals coming directly off farms into animal facilities for acute surgical procedures, one has to wonder when we will see this organism again. Anecdotally, I have heard of several technicians who contracted leptosirosis just through that means. Plague is mostly associated with wild animals, and rat bite fever is something you would have to consider with any rodent bite.

There are a number of different fungi that can be harbored both clinically and subclinically. They cause a ringworm like condition. In certain rare circumstances, individuals that are immunosuppressed have been known to develop systemic infections. The protozoal diseases are important, mostly in that they can infect the gastrointestinal tract and the larger animal species which have these include the primates, dogs, cats, etc. Amebiasis has not been reported in some time in non-human primates, but the oral reports indicate that entameba histolytica is not uncommon in primates. It caused a disease similar to enteritis with perforating ulcers in humans, and so primates would need to be considered a possible point of origin. Cryptosporidium occurs in many of the laboratory animal species; it was the celebrated cause of diarrhea for the City of Milwaukee a couple of summers ago. You would be more inclined to look for it in large animals coming directly off farms where you don't know too much about the husbandry and conditions of those farms. Giardia is the most important agent, at least from my perspective, and from the health reports and clinical cases that I see. Its very common for non-human primates and cats and dogs from random sources to harbor giardia lamblia, a zoonotic organism which is spread by the fecal oral route. We need to make people aware of it when it's in the environment and treat those animals in a timely fashion. Toxoplasmosis is mostly related to cats. They are the definitive hosts in which the organisms replicating in the gut are shed in high amounts in the environment. There are many other laboratory animals which can be infected with toxoplasmosis. If you are working inappropriately with tissues from those animals, there would be some chance that you could get the infection through contamination of the hands, ingesting the organism, or inoculation of small lesions on your hands.

Zoonoses in Animal Care Facilities Breakout Session
Rapporteur: David Dreesen, MPVM Medical Microbiology Rm 346, College of Veterinary Medicine University of Georgia Athens, GA 30602-1386 706-542-4979

Dr. Chris Newcomer continued his presentation from the earlier session on the zoonoses. He first emphasized occupational safety and health concerns about animal bites and scratches, calling attention to training of personnel in proper restraint; whether such restraint is physical or chemical. The environment in the facility must be evaluated to eliminate physical impediments that may lead to injuries to both handlers and animals during restraint. It is essential that the availability of medical care is known to personnel; that is, where the first aid kit is kept and who calls who if extended emergency medical care is required.

Dr. Newcomer pointed out that the animal mouth is a veritable "garden of infectious diseases" and referred to a relatively long list of pathogens that can cause human infections following animal bites. I'd like to emphasize three of these: First, the most common of the pathogens in that "garden" that Chris referred to is Pasteurella multocida, causing 50-90% of all human infections following bites. The risk of such infections are 10 times greater from cat bites, often resulting in cellulitis, erythema, pain, and swelling at the site of the bite and a gray, malodorous exudate. Second, a relatively new pathogen, originally called Dysgonic fermenter 2 (DF-2), now termed Captocytophagia caninmorsis is of increasing concern as this opportunistic bacterial pathogen can cause multi-organ disease in humans. The organisms can be isolated from the oropharyngeal cavity of 8-10% of normal dogs. People who have undergone splenectomy, suffer from alcoholism, have chronic pulmonary disease, or are on corticosteroids are at the highest risk CFR. Various studies indicate that approximately 43% of persons with this condition have a history of an animal bite. Of concern is that the case fatality rate is about 28%. Such disease agents indicate the need for periodic health reviews of personnel. Just hiring a person and never re-evaluating their health condition on a periodic basis is not a satisfactory procedure. The third pathogen is Bartonella henselae, formerly known as Rochalimae henselae, the etiologic agent of cat scratch disease. This organism is carried in the oral cavity of normal cats, especially kittens and young adults. Following a bite and infection with B. henselae, healthy persons often show pain and swelling at the site of the bite, some with regional lymphadenopathy, though it is usually self-limiting. However, in those with AIDS, on immuno suppressive therapy, or the elderly, it can result in a condition known as Bacillary Angiomatosis, a progressive systemic disease often resulting in life-threatening endocarditis. Again - do you know the urrent health status of your personnel?.

At this point, I'd like to make two recommendations in reference to Animal Bites.

First - in the breakout session, I recommended that a 35-50 ml syringe with an 18 gauge blunted needle be part of your first-aid kit along with 100-200 mls of sterile saline or water for injection. When a bite occurs thoroughly irrigate the wound to flush out any potential pathogens prior to using an antimicrobial or antiseptic.

My second recommendation: The 3rd edition of the CDC/NIH manual on Biosafety in Microbiological and Biomedical Laboratories does not address potential infections following animal bites. Yet bites are not uncommon when handling various animal species. I would like to recommend, respectfully, that the pathogens associated with animal bites be included in the next edition of this excellent publication.

Dr. Newcomer also mentioned the need for comprehensive training and a high level of security in facilities where poisonous snakes and venomous animals are maintained. Dr. Newcomer continued his presentation by again addressing several of the viral zoonoses, most particularly rabies, hepatitis and herpes associated with primates, Hanta virus, and Orf.

Regarding rabies, I'd like to bring to your attention results of our studies we are conducting in cooperation with CDC and Kansas State University on the pathogenesis of rabies in ferrets. Of 50 ferrets inoculated, with 5 serial dilutions of the North Central Skunk variant of the rabies virus, in each of 10 ferrets. No animal with virus in the CNS showed any evidence of viral shedding in the saliva and only one had virus in the salivary gland. These studies are continuing but the results were rather unusual and somewhat unexpected.

Monkey-pox virus was discussed by Dr. Newcomer. Of particular interest was the notation that monkey-pox virus transmission to humans may occur in nature, but no reports of lab associated cases have occurred. Monkey-pox resembles small pox, so human cases must be clearly evaluated to rule out the chance - however remote - of small pox.

Zoonotic respiratory diseases were also touched upon in the breakout session. It was noted that 9% of imported primates are infected with Mycobacterium, the agent of tuberculosis. Even with all our efforts, TB still occurs in primate colonies and must be reckoned with.

Cats and rabbits as well as sheep and goats have been incriminated in the transmission of Coxiella burnetii, the etiologic agent of Q-fever. It was noted that serology is not reliable and there is no reliable method to assure that sheep flocks are free of disease. It was pointed out that C. burnetii is extremely hardy and can permeate the environment for long periods of time. It was recommended that the placenta and other fluids be examined at parturition for evidence of the pathogen. Many persons with a farm-based background are seemingly immune due to previous exposures to the agent. However, serologically naive researchers in closely confined facilities involved in parturition of infected animals are at high risk of infection.

Various enteric pathogens were also discussed. Virtually any animal with diarrhea, or recent enteric disease, may be harboring Salmonella or Camphylobactor or even the less common Yersinia organism. Care must be exercised in hanling such animals to prevent human infections.

Another enteric pathogen is Toxoplasma. The definitive hosts are felines. This coccidian parasite can be easily aerosolized in laboratories. Infected cats can elaborate the organisms in their feces; however, this occurs only once following infection for a period of 10-25 days. After the oocyst is passed in the feces, it requires 2-3 days, or longer, for sporulation to occur, allowing the organism to become infectious. Thus, by daily cleaning of the litter box, chance of possible human infections from contact with cat feces is virtually eliminated.

Dr. Newcomer briefly discussed the problems associated with ringworm infections in personnel due to Trichophyton. This dermatophyte can survive in facilities long after animals have been removed. Various ectoparasites, especially mites, can also cause problems, both by causing dermatitis in animal handlers, and by carrying certain pathogens, most notably rickettsiae.

The session ended with a note that though not discussed, rickettsial agents and the emerging zoonotic pathogen, Ehrlichia chaffeensis and other Ehrlichia require our attention. I encourage you to read Emergence of the Ehrlichioses as Human Health Problems. D.H. Walker and J.S. Dumber. Emerging Inf. Dis. 2(1), Jan-Mar, 1996.

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Zoonoses in Animal Care Facilities