B-virus was first isolated by Sabin and Wright in 1932 from the brain and spinal cord of a researcher who died of meningoencephalitis following a bite from a macaque monkey. The virus has since been recognized to be endemic among Old World Macaca genus monkeys and to cause minimal morbidity in its natural host. The prevalence of persistent latent B-virus infection is low among immature animals but has been found to be greater than 70% in adult populations. Chronically infected monkeys actively shed virus intermittently and it was found in one study that 2-3% of the monkeys shed detectable virus at any given time. During intermittent reactivation, the macaque may shed B-virus from the buccal mucosa, urogential tract, and in conjunctival fluid. Monkeys are more likely to shed B-virus when they are ill, under stress, immunocompromised, and during the breeding season.

Risk to Humans

The risk of humans acquiring B-virus infection from macaques appears to be very low. Thousands of people have handled macaques and fewer than 40 human B-virus cases were reported through January 1998. Reported human infections have been attributed to macaque bites or scratches, injuries from needles used near a macaques’s mucous membranes or central nervous system, mucocutaneous exposure (exposure to eye) without injury, and contact with infective biologic materials from macaques. One human-to-human transmission has been identified. The incubation period in humans has been reported to be as short as 2 days but more frequently is 2-5 weeks.

B-virus infection in humans is associated with an extreme degree of morbidity and mortality. B-virus infection in humans is recognized as a rapidly ascending encephalomyelitis with a fatality rate of approximately 70%. B-virus infection is characterized by symptoms including vesicular skin lesions at or near the site of inoculation, localized neurologic symptoms, and ultimately, encephalitis. Patients infected with B-virus who were treated aggressively with either intravenous acyclovir or ganciclovir after onset of symptoms, but before respiratory arrest or coma have survived. The consequences of symptomatic infection with B-virus are such that strict adherence to these guidelines is warranted. Furthermore, the macaque model should be selected for research only when clearly indicated.

Prevention of B-Virus Exposures and Safe Handling of Macaques

B-Virus Status of Macaques

1. At the time of acquisition, all macaque monkeys should be free of B-virus infection, if possible, and maintained under conditions to assure their B-virus free status. Therefore, only B-virus-free animals should be purchased if they are available.
2. All macaque monkeys and their products should be regarded as infected with B-virus even if determined to be free of B-virus.
3. Routine screening of macaques for evidence of B-virus infection is not recommended. Even animals previously found to be negative for the virus or antibody might be positive at the time of human exposure. Also, the screening process may increase the risk of infection of workers. However, the investigator may elect to determine the infection status of the animals to be used in situations in which laboratory studies may cause immunosuppression of the animals, since virus shedding might be enhanced under such circumstances.
4. Quarantine macaques with oral lesions suggestive of active B-virus infection until the lesions have healed to reduce the risk of viral transmission to workers and other macaques.

Handling Macaques

5. Direct handling of macaques should be minimized and should be done only by trained personnel. Capturing, restraining, or otherwise handling fully awake macaques by hand is not recommended.
6. Use chemical restraint by injection before removing the animal from the cage, particularly for larger animals or for animals that are otherwise difficult to handle.
7. Handle physically active animals only with arm-length reinforced leather gloves. In addition, wear a water-resistant long-sleeved gown, goggles, and a surgical mask to prevent exposure to macaque secretions and scratches. Chemically restrained animals can be handled with latex or vinyl gloves to prevent direct contact with macaque secretions.
8. Macaques that need to be handled regularly should be housed in squeeze-back cages that permit physical restraint of the animal before handling. When a number of animals are caged together, provide tunnels or chutes so individual monkeys can be separated and restrained before handling.
9. Use behavioral conditioning or training of macaques whenever possible for cooperation with dosing, sampling, restraining or other procedures.

Preventive Measures

10. Limit the access of areas where macaques are kept to workers who are properly trained in risk prevention procedures, or to those accompanied by such workers.
11. Wear protective goggles designed for splash protection in combination with a mask designed to protect other mucous membranes. Face-shields can be worn in combination with goggles and masks, but not in substitution of them unless such face-shields are designed to prevent droplet splashes to the head from running down into the eyes and prevent mucous membrane exposure around the edges. In addition, wear a water-resistant long-sleeved gown, hair bonnet and shoe covers when entering areas containing macaques, conducting captures, transporting caged macaques, and during other procedures where there is a risk of exposure to macaque secretions, tissues, or fluids.
12. Eliminate sharp edges and corners from cages and other equipment that may cause scratches or wounds to workers. Arrange cages in animal housing areas so that the risk of workers being accidentally grabbed or scratched by animals is minimized.
13. Use soap and water to thoroughly clean cages and experimental equipment immediately after being contaminated with macaque secretions.

Personnel Training

14. Training is required for persons who handle macaques or fresh/fresh-frozen macaque tissues, including primate veterinarians, animal technicians and scientific investigators. Training in the following areas is required:

    • Standard operating procedures in restraint, transport, and handling of macaques;
    • The risk of B-virus infection and possible routes of exposure;
    • The methods of preventing B-virus infections;
    • The need to clean wounds immediately;
    • The early symptoms of B-virus infection;
    • The need to report injuries and/or symptoms suggestive of B-virus infection to supervisors immediately;
    • The procedure to receive medical attention when an exposure occurs;
    • Sharps precautions and disposal.

15. Training should be followed up with continual observation for lapses in these procedures as they occur.
16. Periodically (and following exposures) assess the hazards of exposure and effectiveness of safety practices in place for prevention of B-virus exposures with regard to each procedure conducted. Determine whether the safety practices in place can be improved.
17. Responsibility for ensuring that personnel undergo refresher training resides with the Principal Investigator.

First Aid Procedures

Risk of infection by B-virus can be reduced by immediate and very thorough cleansing of the exposure site. B-virus infection can be fatal if not treated immediately. Herpes simplex virus (HSV) may infect human cells in 5 minutes of exposure and it is likely that B-virus may as well.

1. Open the monkey bite kit and follow the directions provided inside the kit. All bites, scratches, abraded skin or mucosal membranes exposed to macaque secretions or biological materials should be cleansed/scrubbed/irrigated immediately (i.e., within 5 minutes of the exposure/injury) and thoroughly with the povidone iodine surgical scrub brush/sponge and water for at least 15 minutes. Gentle massage of deep wounds can increase contact with the cleansing solution. If eyes, mouth, or nose have been exposed, irrigate the exposure site for at least 15 minutes with sterile saline or rapidly flowing water. Use the emergency eyewash and/or shower.

   Examples of injuries that are exposures:

   • A bite or scratch that causes bleeding;
   • A cage scratch that causes bleeding;
   • A puncture by a needle that has previously been in a macaque;
   • A splash of feces, urine, saliva, blood or unknown fluid into your eye, mouth, nose or on your skin.

2. After cleansing the injury, cover the injury with sterile dressing and proceed to either Occupational Health Facility or the UCLA Medical Center Emergency Room. Bring the bite kit and instructions. Occupational Health Facility is located in CHS room 67-120 and is open Monday through Friday 7:30 a.m. to 4:30 p.m. except holidays. The UCLA Medical Center Emergency Room is located in CHS room BE-144 and can be entered via the underground parking lot located at Tiverton Avenue and Le Conte Avenue.
3. Report the exposure to your supervisor or Principal Investigator as soon as practical. Report the identification of the animal involved to the veterinarian staff or DLAM staff.
4. Report any symptoms suggestive of B-virus infection immediately to your supervisor and/or the Occupational Health Facility physicians.

Symptoms of B-virus Infection¹

• Early manifestations (inconsistently present)

• Vesicular eruptions or ulcerations at or near the exposure site
• Severe pain or itching at the exposure site
• Regional lymphadenopathy

• Intermediate manifestations (inconsistently present)

• Fever
• Numbness, paresthesia or other hyperesthesias at or near the exposure site, with or without progression
• Muscle weakness or paralysis in the exposed extremity
• Conjunctivitis
• Persistent hiccups

• Late manifestations (avoidable with early therapy)

• Sinusitis
• Neck stiffness
• Headache lasting longer than 24 hours
• Nausea and vomiting
• Brain-stem findings: diplopia, dysarthria, dysphagia, dizziness, cross-hemiparesis, cerebellar signs with ataxia, crossed sensory loss, cranial nerve palsies, or drop attacks
• Altered mentation
• Other signs compatible with CNS impairment or viral encephalitis, including urinary retention, respiratory failure, convulsions, twitching, hemiparesis, hemiplegia, other localized neurological signs, progressive ascending paralysis, or coma

¹ Table taken from Holmes et. al. 1995.

Glossary

Ataxia: An inability to coordinate muscle activity during voluntary movement.

Conjunctivitis: Inflammation of the mucous membrane investing the anterior surface of the eyeball and the posterior surface of the lids.

Diplopia: Double-vision.

Dysarthria: A disturbance of speech and language due to emotional stress, to brain injury, or to paralysis, incoordination, or spasticity of the muscles used for speaking.

Dysphagia: Difficulty in swallowing.

Encephalitis: Inflammation of the brain.

Hemiparesis: Weakness affecting one side of the body.

Hemiplegia: Paralysis of one side of the body.

Hyperesthesia: Abnormal acuteness of sensitivity to touch, pain, or other sensory stimuli.

Lymphadenopathy: Any disease process affecting a lymph node or lymph nodes.

Palsy: Paralysis, or partial or incomplete paralysis.

Paresthesia: An abnormal sensation, such as of burning, pricking, tickling, or tingling.

Sinusitis: Inflammation of the lining membrane of any sinus.

Ulceration: The formation of a lesion on the surface of the skin or on a mucous surface, caused by superficial loss of tissue, usually with inflammation.

References

Center for Disease Control. 1998. Fatal Cercopithecine herpesvirus 1 (B virus) infection following a mucocutaneous exposure and interim recommendations for worker protection. Morbidity and Mortality Weekly Report 47:1073-6, 1083.

Holmes, GP; Chapman, LE; Stewart, JA; Straus, SE; Hillard, JK; and Davenport, DS.  1995. Guidelines for the prevention and treatment of B-virus infections in exposed persons. Clin. Infect. Dis. 20:421-39.

Centers for Disease Control. 1987. Guidelines for prevention of Herpesvirus simiae (B virus) infection in monkey handlers. Morbidity and Mortality Weekly Report 36:680-2, 687-9.

Stedman’s Medical Dictionary, 26^th edition, 1995, Williams & Wilkins, Baltimore, MD.

Approved 4/98
Revised 3/99, 6/99, 2/23/04