The report of a case of encephalitis caused by B virus in a monkey
handler in 1932 indicated that B virus can be highly pathogenic for
humans (1 ). Seventeen additional cases of B virus infection in humans
were described through 1973 (2)* and four cases, including the first
known case of person-to-person transmission of the virus, occurred in
Pensacola, Florida, in 1987 (5 ). Twenty of the 22 cases resulted in
encephalitis; 1 5 of these patients died. This extreme degree of
morbidity and mortality has given the impression that B virus infection
in humans nearly always results in severe or fatal disease. The
frequency of mild or asymptomatic B virus infection, however, has
never been adequately assessed.
In his review, Palmer (2 ) reports a total of 24 cases from 1932 to
1973, citing a reference from CDC (3 ). Documentation of B virus
infection, however, was established in only 17 of these cases; an 18th
case, which occurred in 1958 (4 ), was omitted in Palmer's review.
The occurrence of the four 1987 cases of B virus infection prompted CDC
to convene a working group to discuss guidelines for preventing B virus
infection in monkey handlers. In formulating these guidelines, the
working group recognizes that other methods of caring for nonhuman
primates and preventing transmission of pathogenic agents from animal
to human and from human to animal have been described (6,7). The
purpose of the working group was to supplement existing methods with
specific guidelines intended to minimize transmission of B virus
infection from macaque monkeys to humans.
Herpesvirus simiae (B virus) is a member of the herpes group of viruses
that is enzootic in rhesus (Macaca mulatta ), cynomolgus (M.
fascicularis ) and other Asiatic monkeys of the genus Macaca. As with
herpes simplex virus I infection in humans, primary infection with B
virus in macaques may result in gingivostomatitis with characteristic
buccal mucosal lesions, but it probably occurs frequently without such
signs. Subsequently, the virus remains latent in the host and may
reactivate spontaneously or in times of stress, resulting in shedding
of virus in saliva and/or genital secretions. In captivity, as well as
in the wild, sexually mature macaques are more likely to have been
exposed to the virus and more likely than immature animals to be
shedding virus at any given time.
Although it is commonly believed that transmission to humans occurs by
exposure to contaminated monkey saliva through bites or scratches, such
exposure has not been consistently documented. Except for one instance
of person-to-person transmission, however, all cases of B virus
infection in humans have occurred in persons exposed to monkeys or
monkey tissues.
B virus-related disease is characterized by a variety of symptoms,
which generally occur within 1 month of exposure. These symptoms
include vesicular skin lesions at or near the site of inoculation,
localized neurologic symptoms, and ultimately, encephalitis.
A unique feature of the 1987 Pensacola cases was the occurrence of mild
disease in two of the four patients (5). Both of these persons received
acyclovir (9-[2-hydroxyethoxymethyl]-guanine) in the early stages of
disease. They became culture-negative, and their lesions healed during
therapy. Whether their infections would have become more severe without
therapy is not known. Both in vivo (8 ) and in vitro efficacy of
acyclovir (Southwest Foundation for Biomedical Research, unpublished
data) against B virus has been demonstrated.
The working group recognizes that B virus infection may occur in
persons not handling live macaques. One case of B virus infection
occurred following the person's exposure to contaminated cell cultures
of simian origin, and one case occurred after the patient had cleaned
a monkey skull (2 ). Although transmission of infection has not been
documented for persons working~with B virus in the laboratory, such
work is potentially hazardous. Guidelines concerning appropriate
biocontainment measures for working with B virus are published
elsewhere (9 ). The guidelines described herein pertain only to the
risk associated with the care and maintenance of living macaques.
The working group also recognizes that the paucity of information
regarding the transmissibility of B virus, the efficacy of measures to
prevent transmission, and the chemotherapy of B virus infection have
rendered these guidelines difficult to formulate. These guidelines are
therefore based on the available information, much of which is
anecdotal and much of which is based on theoretical considerations from
knowledge of other herpes viruses.
The risk of acquiring B virus infection from macaques appears to be
very low. Persons who have handled macaques since B virus infection
was first reported in humans number in the thousands, yet only 22
well-documented cases of infection have been described. The reasons for
such an apparently low rate of transmission may include infrequent B
virus shedding by macaques, cross-reactive immunity against B virus
stimulated by herpes simplex virus infection (10,11 ), and undetected
asymptomatic infection. Nevertheless, the consequences of symptomatic
infection are such that these guidelines are warranted, especially
since such infections appear preventable.
Guidelines for prevention of B virus infection in monkey handlers:
1. Macaque monkeys should be used for research purposes only when
clearly indicated.
2. When feasible, monkeys that are required for research purposes
should be free of B virus infection and should be maintained under
conditions that are appropriate
3. All macaque monkeys not known to be free of B virus infection should
be regarded as infected because viral shedding is intermittent and can
occur in the absence of visible lesions. Direct handling of macaques
should be minimized as much as possible. Capturing, restraining, or
otherwise handling fully awake macaques by hand is not recommended.
Rather, such procedures should be accomplished using acceptable
physical and chemical restraint methods. Macaques that are 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, tunnels or chutes should be provided whenever feasible
so that individual monkeys can be separated and restrained before
handling. When feasible, chemical restraint by injection (e.g.,
ketamine HCI) may be used before removing the animal from the cage,
particularly for larger animals or for animals that are otherwise
difficult to handle. Behavioral conditioning of macaques is a practical
and useful adjunct to the application of these restraint procedures and
is particularly recommended where several animals are caged together.
4. Macaque handlers should remove physically active animals from cages
only with arm-length reinforced leather gloves. Handlers should be
additionally protected with a long-sleeved garment to prevent scratches
and a face shield (or surgical mask and goggles or glasses) to prevent
exposure of eyes and mucous membranes to macaque secretions. In warm
climates, where use of long-sleeved garments and leather gloves may be
uncomfortable, supervisors may wish to rotate work schedules or have
workers handle animals at cooler times of the day to minimize such
discomfort in the daily work routine. If macaque handlers choose
not to handle chemically restrained animals with arm-length leather
gloves, latex or vinyl gloves should be worn to prevent direct contact
with macaque secretions.
5. Cages and other equipment that may be contaminated with virus should
be free of sharp edges and corners that may cause scratches or wounds
to workers. Cages should be designed and arranged in animal housing
areas so that the risk of workers being accidentally grabbed or
scratched is minimized. Access to areas where macaques are maintained
and used should be limited either to workers who are properly trained
in procedures to avoid risk of infection or to those accompanied by
such workers.
6. The routine screening of macaques for evidence of B virus infection
is not recommended. Even animals previously found to be negative for
virus or antibody might be positive at the time of a human exposure.
Also, screening may increase the risk of infection to workers. In
situations in which laboratory studies may cause immunosuppression of
the animals, the investigator may elect to determine the infection
status of the animals to be used, since virus shedding might be
enhanced under such circumstances. Macaques with oral lesions
suggestive of active B virus infection should be quarantined until the
lesions have healed to reduce the risk of virus transmission to workers
and other macaques.
7. Persons who handle macaques, including primate veterinarians and
scientific investigators, should be trained in proper methods of
restraint and in the use of protective clothing to help prevent bites
and scratches. Such persons should be acquainted with standard
operating procedures and other available training materials before
handling animals. Training should be followed UD with continual
observation for lapses in these procedures as they occur. Macaque
handlers should also be educated concerning the nature of B virus
infection; the need to prevent bites, scratches, and other exposure to
macaque secretions; and the need to clean wounds immediately. They
should be educated concerning the early symptoms of B virus infection
and the need to report injuries and/or symptoms suggestive of B virus
infection to supervisors immediately. Animal handlers should be advised
that persons who are immunosuppressed because of medication or
underlying medical conditions may be at higher risk for B virus
infection. A pre-employment serum sample should be obtained from all
persons who work with macaques, and additional samples should be
obtained annually to serve as a baseline for retrospective studies in
the event of a suspected B virus infection. Such specimens should be
aliquoted and frozen, preferably at-70xC.
8. All bite or scratch wounds incurred from macaques or from cages that
might be contaminated with macaque secretions and that result in
bleeding should be immediately and thoroughly scrubbed and cleansed
with soap and water. Such incidents should be reported to the
animal-care supervisor and recorded in a bite/scratch log. Superficial
wounds that can be adequately cleansed probably require no further
treatment. More extensive wounds should be referred to a medical
consultant. Each animal-care facility should identify a medical
consultant who will be on call to assist in such situations. Such
consultants, in addition to having general knowledge concerning animal
bites, should be knowledgeable concerning the hazard of B virus
infection, its symptoms, and treatment. Following a bite or scratch,
the animal handler should be instructed to report immediately
any skin lesions or neurologic symptoms (such as itching, pain, or
numbness) near the site of the wound or any other unusual illness. It
is the responsibility of the supervisor, when no illness is reported,
to determine the clinical status of the handler at weekly intervals for
1 month after the exposure. Symptoms suggestive of B virus infection
should be reported immediately to the medical consultant. When the
possibility of B virus illness is seriously entertained, appropriate
diagnostic studies should be performed and specific antiviral therapy
should be instituted. (At the time of this writing, experimental and
limited clinical data indicate acyclovir to be the drug of choice.) The
physician may wish to consult the Viral Exanthems and Herpesvirus
Branch, Division of Viral Diseases, CDC (Dr. Gary Holmes, [404]
329-1338) and, for laboratory assistance, the Southwest Foundation
for Biomedical Research (Dr. Julia Hilliard, [512] 674-1410).
9. In some situations, prophylactic treatment with an antiviral agent
may be considered in the absence of signs or symptoms suggestive of
B virus infection. Such a situation might arise when an animal handler
sustains a deep, penetrating wound that cannot be adequately cleansed.
In such situations, studies to determine the B virus status of the
animal should be considered, especially if the animal has clinical
findings suggestive of B virus infection. These situations should be
managed by the medical consultant, who may wish to consult the resource
persons mentioned above. There is no evidence that pooled immune
globulin is effective in preventing or ameliorating B virus infection.
Neither hyperimmune human B virus globulin nor vaccine against B virus
is currently available.
Reported by The B Virus Working Group: JE Kaplan, MD (CoordinatorJ,
CDC. BJ Whitley, MD, University of Alabama--Birmingham, Birmingham,
Alabama. B Swenson, DVM. Southeast Regional Primate Center, Atlanta,
Georgia. Col WC Cole, US Army Medical Research Institute of
Infectious Diseases, Ft. Detrick, Maryland. DO Johnsen, DVM, RW
McKinney, PhD, RA Whitney Jr, DVM, National Institutes of Health,
Bethesda, Maryland. JH Vickers, DVM, MS, Food and Drug
Administration, Bethesda, Maryland. M Balk, DVM, MS, Charles River
Laboratories, Wilmington, Massachusetts. MD Daniel, DVM, PhD, New
England Regional Primate Center, Southboro Massachusetts. B Brock, VMD,
Lederle Laboratories, Pearl River, New York. T Butler, DVM, MS,
J Hilliard, PhD, Southwest Foundation for Biomedical Research, San
Antonio, Texas. JW Glosser, DVM, US Dept of Agriculture, Washington,
DC. JR Broderson, DVM, PhD, GP Holmes, MD, JW McVicar, DVM, CDC.
References
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