Guidelines for Prevention of Herpesvirus Simiae (B Virus)
Infection in Monkey Handlers
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; 15
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.
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:
Macaque monkeys should be used for research purposes only when
clearly
indicated.
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 to assure their B virus-free status. The
possibility of acquiring and maintaining such a B virus-free
colony
should be explored by each animal facility.
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 HCl) 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.
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.
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.
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.
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 up 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 -70 C.
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).
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 (Coordinator),
CDC. RJ
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
Sabin AB, Wright AM. Acute ascending myelitis following a
monkey bite,
with the isolation of a virus capable of reproducing the
disease. J Exp
Med 1934;59:115-36.
Palmer AE. B virus, Herpesvirus simiae: historical perspective.
J Med
Primatol 1987;16:99-130.
CDC. Herpes B encephalitis--California. MMWR 1973;22:333-4.
Stones PB. Cited in: Graham-Jones O, ed. Some diseases of
animals
communicable to man in Britain. London: Pergamon Press,
1968:200-1.
CDC. B-virus infection in humans--Pensacola, Florida. MMWR
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Fox JG, Newcomer CE, Rozmiarek H. Selected zoonoses and other
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hazards. In: Fox JG, Cohen BJ, Loew FM, eds. Laboratory animal
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Whitney RA, Johnson DJ, Cole WC. The subhuman primate: a guide
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veterinarian. Edgewood Arsenal, Maryland: Department of the
Army,
Edgewood Arsenal Medical Research Laboratory, 1967; Edgewood
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Boulter EA, Thornton B, Bauer DJ, Bye A. Successful treatment
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experimental B virus (Herpesvirus simiae) infection with
acyclovir. Br
Med J 1980;280:681-3.
CDC, National Institutes of Health. Biosafety in
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Services, Public Health Service, 1984:63; DHHS publication no.
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Cabasso VJ, Chappell WA, Avampato JE, Bittle JL. Correlation of
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*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.
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