Aaalac.org

Recommendations for Preventionof and Therapy for Exposure to B Virus(Cercopithecine Herpesvirus 1) Jeffrey I. Cohen,1 David S. Davenport,2 John A. Stewart,3 Scott Deitchman,3 Julia K. Hilliard,4 Louisa E. Chapman,3
and the B Virus Working Groupa
1Medical Virology Section, Laboratory of Clinical Investigation, National Institutes of Health, Bethesda, Maryland; 2Division of Infectious Diseases,Michigan State University Kalamazoo Center for Medical Studies, Kalamazoo; and 3Centers for Disease Control and Prevention and 4ViralImmunology Center, Georgia State University, Atlanta B virus (Cercopithecine herpesvirus 1) is a zoonotic agent that can cause fatal encephalomyelitis in humans. The
virus naturally infects macaque monkeys, resulting in disease that is similar to herpes simplex virus infection
in humans. Although B virus infection generally is asymptomatic or mild in macaques, it can be fatal in humans.
Previously reported cases of B virus disease in humans usually have been attributed to animal bites, scratches,
or percutaneous inoculation with infected materials; however, the first fatal case of B virus infection due to
mucosal splash exposure was reported in 1998. This case prompted the Centers for Disease Control and Prevention
(Atlanta, Georgia) to convene a working group in 1999 to reconsider the prior recommendations for prevention
and treatment of B virus exposure. The present report updates previous recommendations for the prevention,
evaluation, and treatment of B virus infection in humans and considers the role of newer antiviral agents in
postexposure prophylaxis.
B virus (Cercopithecine herpesvirus 1) is a naturally oc- infectious virus from the oral, conjunctival, or genital curring infectious agent that is endemic among ma- mucosa of animals with or without visible lesions.
caque monkeys (including rhesus macaques, pig-tailed Infections due to B virus in humans are rare and macaques, cynomolgus monkeys, and other macaques) occur as a result of exposure to either macaques or [1–3]. Animals become infected with the virus pri- their secretions or tissues. The incubation period for marily through exposure of the mucosa or skin to oral infection in humans after an identified exposure is re- or genital secretions from other monkeys. Vertical ported to range from 2 days to 5 weeks; most well- transmission of the virus to neonates is rare. Infected documented cases present 5–21 days after exposure.
monkeys often have no or very mild symptoms, al- Some patients present with a progression of symptoms though oral and genital lesions may develop. The virus that first appear near the site of exposure; others present persists in the sensory ganglia for the lifetime of the with symptoms limited to the peripheral nervous sys- animal and can reactivate, resulting in the shedding of tem or CNS. A third presentation involves flulike illnesswith fever, chills, myalgias, and other nonspecific symp-toms, with no focal findings, and it may later be fol-lowed by the abrupt onset of CNS symptoms.
Received 19 June 2002; accepted 24 July 2002; electronically published 17 After infecting humans, B virus replicates at the site Financial support: The Elizabeth R. Griffin Research Foundation, Kingsport, of exposure and may result in the development of a vesicular rash at this site. Additional symptoms can a Members of the study group are listed after the text.
include tingling, itching, pain, or numbness at the site; Reprints or correpondence: Dr. Jeffrey I. Cohen, Medical Virology Section, Laboratory of Clinical Investigation, Bldg. 10; Rm. 11N228, National Institutes of Health, 10 Center however, many patients have no symptoms at the site Dr., MSC 1888, Bethesda, Maryland 20892 (jcohen@niaid.nih.gov).
of infection. Some patients develop lymphadenopathy Clinical Infectious Diseases
2002; 35:1191–203
proximal to the site of inoculation. Within the first 3 This article is in the public domain, and no copyright is claimed.
1058-4838/2002/3510-0008 weeks after exposure, paresthesias may develop and Prevention of and Therapy for B Virus Exposure • CID 2002:35 (15 November) • 1191
Well-documented cases of B virus infection in humans.
proceed proximally along the affected extremity. Associatedsymptoms can include fever, myalgias, weakness of the affected extremity, abdominal pain, sinusitis, and conjunctivitis. Other organs, including the lung and liver, may be involved.
The virus spreads along the nerves of the peripheral nervous system to the spinal cord and then to the brain. Symptoms of infection can include meningismus, nausea, vomiting, persis- tent headache, confusion, diplopia, dysphagia, dizziness, dys- arthria, cranial nerve palsies, and ataxia. Seizures, hemiplegia, hemiparesis, ascending paralysis, respiratory failure, and coma more commonly occur later in the course of infection. Some patients have presented with symptoms within 48 h after ex- posure to the virus [4]. The overall presentation of late-stage disease is that of brain stem encephalomyelitis that may evolve into diffuse encephalomyelitis during its terminal stages. This presentation is in contrast to the more focal neurologic disease observed in association with herpes simplex encephalitis.
Among untreated humans, the mortality rate associated with a Cultures involved monkey kidney cells.
B virus infection is estimated to be 80% [3]. The mortality rate b In one case, a needle had been used to inject the tissues around the eye, has declined since the advent of antiviral therapy.
and, in the other case, a needle “may have been used previously to injectmonkeys” [4, p. 974].
c In one case, aerosol may have been generated during autopsies performed on macaques, and, in the other case, the patient presented with respiratory TYPES OF EXPOSURE
d The patient applied cream to her husband’s herpes vesicles and to areas of her own skin that were affected by contact dermatitis.
Humans have become infected after exposure to the infectious e The patient was splashed in the eye with material, possibly feces, from tissues or fluids of monkeys. The ocular, oral, or genital se- cretions of monkeys, as well as the CNS tissues and CSF ofmonkeys, are potentially infectious. Primary cell cultures de- primates (“primate workers”) [19], the risk of B virus infection rived from macaque kidneys are a potential source of virus.
due to percutaneous exposure to infectious body fluids (pri- Exposure to peripheral blood from monkeys has not been re- marily saliva) appears to be greater than that of B virus infection ported to cause infection in humans. Although ∼50 cases of B virus infection in humans have been identified to date, only 26 Of importance, many cases of B virus infection in humans cases have been well documented (table 1). Documented routes have been associated with exposures that were considered triv- of B virus infection include animal bites and scratches, exposure ial. In other cases, multiple exposures had occurred over a to tissue culture material, exposure to tissue obtained during period of years, although patients could not recall having had autopsies of monkeys, needlestick injuries, cage scratches, mu- a recent exposure at the time of infection [8, 12, 20]. One case cosal splash, and human-to-human transmission. The only case of B virus disease was reported to have occurred in a worker of person-to-person transmission occurred in a woman who whose last documented exposure to primates occurred 110 applied medication (hydrocortisone cream) both to areas of years before infection developed [18]. The patient was reported her skin that were affected by contact dermatitis and to her to have had reactivation of latent B virus infection; however, husband’s vesicular lesions (which contained B virus) [10]. B it is possible that infection resulted from a more recent exposure virus was subsequently cultured from samples of her skin le- that had seemed trivial at the time and that had not been sions and conjunctiva. The only documented case of B virus infection resulting from mucosal exposure without percuta-neous injury occurred in a person who worked with primates RISK FOR TRANSMISSION OF B VIRUS
and who was splashed in the eye with material from a rhesus TO PRIMATE WORKERS
monkey [19]. She washed her eye briefly 45 min after theexposure occurred, but she developed conjunctivitis 10 days The prevalence of shedding of B virus is increased among pri- later and died of B virus encephalomyelitis 6 weeks later. Be- mates that are stressed, breeding, immunosuppressed, or ill. In cause it appears that mucocutaneous contact with the body one survey, nearly 100% of captive macaques у2.5 years of age fluids of nonhuman primates (hereafter known as “primates”) were seropositive for the virus, whereas ∼20% of animals !2.5 is common among persons who work with or near nonhuman years of age were seropositive [21]. On a given day, ∼2% of 1192 • CID 2002:35 (15 November) • Cohen et al.
one group of seropositive rhesus monkeys shed B virus [22].
monly recommended antiviral agents, acyclovir, has a shorter plasma half-life in rabbits than in humans. For all these reasons, that from 1 in 50 to 1 in 250 contacts with macaques have the postexposure prophylaxis might be more effective in humans potential to result in exposure to material contaminated with than in experimental studies of rabbits; however, it is not known How frequently disease occurs after exposure to B virus– Boulter et al. [24] evaluated the efficacy of intravenous acy- contaminated material is unknown. However, although hun- clovir given for 5–14 days to rabbits inoculated with lethal doses dreds of monkey bites and scratches occur among primate of B virus. Treatment that began within 24 h after exposure to workers in the United States each year, B virus infection in B virus and that lasted for 2 weeks resulted in complete pro- humans is rare. Asymptomatic infection of humans has not tection from death, whereas treatment initiated up to 5 days been documented [23]. In a study of 321 primate workers, after exposure yielded a significant decrease in mortality. To be potential exposures to B virus, including those resulting from effective, treatment was required every 8 h for 14 days. A shorter bites and scratches, were reported by 166 workers; however, duration of treatment resulted in delayed onset of ultimately none of the workers were considered to be B virus seropositive, as defined by positive results of both ELISA and Western blot Zwartouw et al. [25] compared oral acyclovir and oral gan- analysis [23]. In a study of household contacts of patients with ciclovir for the treatment of rabbits for a period of 3 weeks B virus infections, hospital workers, and primate workers that that began the day after the rabbits were inoculated with B was performed when a cluster of cases of B virus infection virus. Although animals that received acyclovir at a dosage of occurred in Florida, 0 of 130 asymptomatic persons tested were 500 mg/kg/day for 3 weeks survived, a dosage of 700 mg/kg/ found to be seropositive for B virus [10]. Similarly, in a study day was required to prevent animals from developing disease.
of animal workers that was performed when a group of cases In contrast, ganciclovir was more effective than acyclovir for of B virus infection occurred in Michigan, 0 of 116 asymp- the prevention of disease; animals required only 2 weeks of tomatic employees were found to be seropositive [11].
treatment with ganciclovir given at a dosage of 100 mg/kg/day Analysis of cases of B virus infection among primate workers beginning 1 day after inoculation for the prevention of disease.
suggests that certain types of exposures may pose greater risks.
Furthermore, all animals that received ganciclovir at a dosage These exposures include deep puncture wounds that are dif- of 170 mg/kg/day within 5 days after inoculation with B virus ficult to clean, inadequately cleansed wounds, and wounds sus- tained on the face (especially wounds to the eye), neck, or Few data exist to assess the effectiveness of postexposure thorax. Because the virus replicates at the site of infection and prophylaxis for B virus infection in humans. To our knowledge, then ascends to the CNS along the axon, inoculation of the there have been no cases in which humans who received pos- head or thorax with the virus allows little time for the devel- texposure prophylaxis within 72 h of exposure developed dis- opment of symptoms that do not involve the CNS, and it may ease; however, as previously noted, the number of persons be difficult to recognize and treat the disease before the CNS with potential exposure to B virus is large, and the number of cases of documented infection is small, even without the useof prophylaxis.
RATIONALE FOR POSTEXPOSURE
PROPHYLAXIS
RECOMMENDATIONS
FOR THE MANAGEMENT OF PERSONS
Postexposure prophylaxis is defined as administration of an- EXPOSED TO B VIRUS
tiviral medication to a person potentially exposed to B virusbut not known to be infected. The use of postexposure pro- Planning before Exposure
phylaxis to prevent B virus infection in humans has not been Previous recommendations for the prevention of B virus in- proven to be effective. However, postexposure prophylaxis pre- fection in humans [1, 26] were published before the fatal case vents disease in rabbits experimentally inoculated with B virus.
transmitted by an ocular splash was reported [19]. In view of There are several reasons why these experiments are not a per- this case, the use of either protective eyewear (e.g., goggles or fect model for infections in humans. First, the amount of in- glasses with solid side shields) and a mask or a chin-length oculum used in experiments in animals may be greater than wraparound face shield and a mask is recommended to protect the inoculum during human exposure to a primate. Second, the mucous membranes of workers in areas where captive ma- in rabbits, the animal most commonly used in studies, B virus caques are located. Furthermore, face shields or glasses with infection results in more rapid progression of virus to the CNS side shields must be able to prevent splashes to the head from than has been noted in humans. Third, one of the most com- Prevention of and Therapy for B Virus Exposure • CID 2002:35 (15 November) • 1193
Laboratories that perform tests for B virus.
Physician, laboratory, and contact information PO Box 4118Atlanta, GA 30302-4118Phone: 404-651-0808E-mail: biojkh@panther.gsu.eduInternet address: http://www.gsu.edu/∼wwwvir/ Enteric, Respiratory, and Neurological Virus Laboratory 61 Colindale Ave.
London NW9 5HT, EnglandPhone: 44-208-200-4400E-mail: dbrown@phls.org.uk San Antonio, Texas 78229Phone: 210-614-7350E-mail: sy.kalter@esoterix.com An occupational health care system should be made available to take in the event of exposure should be posted in areas in to primate workers for documentation of potential exposures, which exposures to macaques may occur.
for counseling, and, in some cases, for treatment of workers Because confirmed cases of B virus infection have occurred who have been exposed; follow-up should also be provided for in animal caretakers who work with macaques but who do not such workers. Animal workers who care for macaques should recall obvious exposures, workers need to be aware that any be informed of the biohazards associated with these monkeys episode of prolonged fever (for 148 h), flulike symptoms, or and the importance of notifying their supervisors and occu- symptoms compatible with B virus infection, even in the ab- pational health care personnel if bites, scratches, or mucocu- sence of a known exposure, needs to be reported to their su- taneous exposures occur. All macaques should be treated as if pervisor and to occupational health care personnel. Primate they are seropositive for B virus, regardless of their origin.
workers should be given a card to carry in their wallet that Workers must receive training about B virus and other bio- indicates the symptoms of B virus infection, contact infor- hazards before working with primates, and additional education mation for a local health care provider who is knowledgeable should be provided on an annual basis, whenever there is a about B virus, contact information for expert clinical and lab- change in job responsibilities, and whenever an exposure has oratory consultation regarding B virus (e.g., the state health occurred. Training should include practice in or demonstra- department, the Centers for Disease Control and Prevention tions of eye washing and wound cleansing, in addition to di- [Atlanta, GA], or a B virus diagnostic laboratory) (table 2), dactic training. So that baseline serum levels are available for and a reference for prophylaxis and therapy guidelines. In ad- comparison in the event of an exposure, the occupational health dition, both the worker and the primate facility should have care provider should consider collecting and then storing access to a physician who has specific knowledge about B virus, serum samples obtained from primate workers at the time of so that delays do not occur during evaluation of the worker.
Materials including supplies used for first aid and specimen Intervention after an Exposure
collection, copies of written instructional materials, and treat- First aid.
The most critical period for the prevention of B ment protocols for exposures should be available in areas where virus infection and other infections is during the first few exposure can occur. The primate facility is responsible for mak- minutes after an exposure occurs. Both the adequacy and the ing these materials available and for educating employees re- timeliness of wound or mucosa cleansing are the most im- garding their use. In a field station, where access to emergency portant factors for reducing the risk of infection. Primate work- evaluation and care will be delayed, an exposure kit (reviewed ers should be instructed to immediately cleanse the skin or in [1]) should be in place. Signs that indicate the proper actions mucosa affected by bites, scratches, or exposure to any poten- 1194 • CID 2002:35 (15 November) • Cohen et al.
Initial management of B virus exposure.
Mucous membrane exposure: flush eye or mucous membranes with sterile saline solution or water Wash skin thoroughly with a solution containing detergent soap (e.g., chlorhexidine or povidone- Consider washing skin with 0.25% hypochlorite solution, followed by detergent solution, for 10–15 min (see the “First aid” subsection of the Recommendations for the Management of PersonsExposed to B Virus section of the text for precautions) Assess the adequacy of cleansing; the health care provider should repeat cleansing Determine the date, time, location, and description of the injury, and the type of fluid or tissue Evaluate general health (including medications) and determine when the last tetanus booster was Determine the need for postexposure prophylaxis with antibiotics or rabies vaccine and Identify the monkey associated with the exposure, the species of that monkey, and the Assess general health (including medications and involvement in past and present research studies) Evaluate prior serologic history (including infection with B virus or simian immunodeficiency virus) Physical examination, especially evaluation of the site of the exposure and neurologic examination Consider obtaining serum samples at baseline for serologic analysis Consider culturing specimens from the site of the wound or the exposed mucosa Examine the animal for mucosal lesions (e.g., vesicles, ulcers), conjunctivitis, etc.
Consider culturing specimens from the lesions, conjunctiva, and buccal mucosa Consider serologic testing for B virus (if the animal is not known to be seropositive) Counsel the patient regarding the significance of the injury Provide the patient with information on the signs and symptoms of B virus infection Ensure that the patient has a card (to carry in his or her wallet) that includes information on B virus and a phone number to call for advice in an emergency Ensure that the patient’s occupational health care provider and supervisor are notified of injury Review with the patient and his or her work supervisor the safety precautions in place at the time Consider postexposure prophylaxis (see table 5) tially infected material from macaques (table 3). Washing of she should transport a 1-L bag of saline to that site, so there the involved site should last for at least 15 min.
will not be a delay in cleansing the wound or mucosa.
Eyes or mucous membranes potentially exposed to B virus Potentially exposed skin should be washed with povidone- should be irrigated immediately with sterile saline solution or iodine, chlorhexidine, or detergent soap. These solutions can water for 15 min. If reaching the nearest eye-washing station destroy the virus lipid envelope and inactivate virus on the requires a delay of more than a few minutes, then a kit that skin; however, they are too harsh to use when washing the eye contains a 1-L bag of sterile saline should be available at the or mucous membranes. In addition to being washed, wounds work site. If the worker is based at a remote location, he or may be gently massaged to increase their contact with the Prevention of and Therapy for B Virus Exposure • CID 2002:35 (15 November) • 1195
cleansing solutions. Incision of wounds or biopsy of wound health status to the physician. The monkey should be examined for active lesions that are compatible with B virus infection, if Use of a 0.25% hypochlorite solution (Dakin’s solution) can this can be done safely. Both the circumstances of the human cause rapid inactivation of herpesviruses. However, this solu- exposure and information on the health status of the monkey tion is more toxic than are the previously mentioned detergents, should be considered when decisions are made regarding eval- and the risk of harming tissues needs to be balanced against uation and treatment. These decisions include whether to per- the benefit of increased antiviral activity. Hypochlorite solution form cultures for the detection of B virus; whether to collect (0.25%) is not stable for long periods; it should be prepared, blood samples for serologic analysis; whether to administer when needed, by diluting standard household bleach 1:20 in postexposure prophylaxis, a tetanus booster, rabies immuno- water. If hypochlorite solution is used, the exposed area should globulin and vaccine, or antibiotic prophylaxis for bacterial subsequently be washed with detergent as previously described.
infections [27]; and whether other potential exposures (e.g., to Hypochlorite solution should never be used to wash mucous membranes or the eye, and, therefore, caution should be ex- Although only 1 case of person-to-person transmission of B ercised when hypochlorite solution is used to wash areas near virus has occurred, positive results of cultures from the con- junctiva and buccal mucosa of an infected patient receiving Initial evaluation by the health care provider.
intravenous acyclovir therapy demonstrated shedding of infec- with potential exposure to B virus should report to their oc- tious B virus for 11 week after the onset of therapy ([10]; L.E.C.
cupational health care provider for counseling and education and J.K.H., unpublished data). Thus, potentially infected per- and to receive written materials about the signs and symptoms sons should be counseled to avoid exposing others to body of B virus infection. In addition to providing counseling, the fluids or skin lesions during the incubation period.
occupational health care provider should facilitate rapid access to a local medical consultant who is knowledgeable about B LABORATORY TESTING
virus and other hazards associated with primates. The person OF THE EXPOSED WORKER
who has been exposed to B virus should have the informationneeded to gain direct access to the occupational health care provider as well as to a local medical consultant for follow-up.
B virus is classified as a Biosafety Level–4 biologic agent (be- A procedure should be in place to handle exposures to B longing to the same group as Ebola virus and Marburg virus).
virus that occur after regular working hours. If the person who Work involving concentrated stocks of B virus should be per- has been exposed prefers to be evaluated by his or her personal formed at Biosafety Level–4 facilities, whereas testing of ma- physician, the occupational health care provider should be terial known or suspected to contain B virus should done at a available for consultation. The person who has been exposed facility designated as having a Biosafety Level of 3 or higher should be aware that his or her personal physician is unlikely [28]. Cultures must not be sent to routine diagnostic labora- to have any knowledge of or experience in treating or pre- tories but, rather, to a facility that has expertise in testing for venting B virus infection, and the occupational health care B virus. There are 3 laboratories that perform diagnostic testing provider should make written information about B virus avail- for the agent (table 2). The B Virus Research and Resource Laboratory at Georgia State University (Atlanta) is the major The health care provider should obtain a detailed history, reference laboratory in the United States for diagnostic testing which should note the time, source, and type of exposure; the for B virus in humans. Materials sent for B virus culture and safety procedures that were in place at the time of exposure; PCR analysis, which may contain infectious material, must be and the time and adequacy of cleansing after the exposure. To ensure that cleansing is done properly, the exposed area should It is important to determine how the information obtained be cleaned again (as described in the “First aid” subsection from culture or other diagnostic tests (e.g., PCR analysis for above), regardless of a history of having been cleaned. The area viral DNA) will be used and interpreted before it is obtained.
that may have been exposed should be carefully examined, Decisions regarding postexposure prophylaxis need to be made and the likelihood that an exposure has occurred should be before the results of cultures are available, because several days may be required for cultures to yield positive results if virus is The monkey’s medical record should be reviewed to deter- mine the following information: the monkey’s current state of Culture of material from the wound or the site of exposure health, history of exposure to infectious agents, and the type before cleansing is not recommended because it delays cleans- of research in which the monkey has been involved. The re- ing, may force virus on the surface of the wound further into ferring facility should provide information about the monkey’s the wound, and may further contaminate the wound with in- 1196 • CID 2002:35 (15 November) • Cohen et al.
fected material located nearby. Cultures of specimens from the a significant (у4-fold) increase in titer is highly suggestive of wound or the site of exposure that are performed after cleansing acute infection. In some cases, a third serum sample, obtained (even cultures of material from wounds that have resulted in 3 months after exposure, may be useful, particularly if postex- known infections) are usually negative for B virus, and some posure prophylaxis is given (see the Follow-up after Exposure authorities do not believe that performance of such cultures is section below). If a baseline serum antibody level has not been worthwhile, except in unusual circumstances. Conversely, pos- obtained, serial testing of serum samples can be performed to itive results of cultures of wounds or other exposure sites do detect a change in titer and, thus, the likelihood of the presence not confirm infection with B virus. Positive wound culture of a new infection. Serologic analysis should involve the testing results do confirm that a high-risk exposure has occurred and of paired samples. Testing of single specimens might be con- that postexposure prophylaxis is indicated. The use of PCR for sidered if clinical signs or symptoms of B virus infection are the detection of B virus might provide more-rapid results than present. Even if signs and symptoms are present, it is important does culture; however, there is less experience in how to in- to obtain a second specimen at a later date to allow for testing terpret a positive PCR result, because it is not clear that rep- of paired (acute- and convalescent-phase) serum samples. Be- lication-competent virus is present if a wound is found to be cause of the cross-reactivity of B virus with herpes simplex positive for viral DNA by PCR analysis. B virus was not detected virus, a serologic test that is positive for B virus should be by PCR in a published study of wound swab samples [29].
confirmed with a Western blot (immunoblot) or competition Identification of virus at the site of exposure or in a wound does not prove infection with the virus. However, a positiveculture or PCR result indicating the presence of viral DNAeither at a site not directly associated with the exposure (e.g., LABORATORY TESTING OF THE PRIMATE
the conjunctiva, in the case of a bite), or in a wound or at a site of exposure concurrent with symptoms compatible with B virus disease should be considered indicative of infection.
The possible benefits of obtaining specimens from the primatemust be balanced against the risks incurred by other workers Serologic Analysis
in obtaining these specimens. In less-controlled settings and in The employer and the occupational health care provider should the absence of expertise in capturing animals, it may be more have a policy in place for determination of when serologic advisable to observe the primate and look for obvious lesions, testing should be performed. In some cases, it may be appro- rather than to trap the animal to obtain for blood for testing.
priate to collect and store serum samples at the time of the However, it is important to note that oral or genital lesions are exposure and again 3–6 weeks after exposure occurred, and to rarely visible when an animal is shedding B virus, and that not send them for testing if warranted. In the United States, human serum samples obtained for B virus testing should be sent to The sites from which specimens can be obtained from pri- the B Virus Research and Reference Laboratory at Georgia State mates for B virus culture include the buccal mucosa (for ex- posures that involve oral secretions), the conjunctiva, or the Asymptomatic seroconversion has not been reported in the urogenital area (if contaminated urine or feces are implicated literature. Although some authorities recommend performing in the exposure). Cultures are subject to sampling error, and serologic testing only for symptomatic persons, others rec- shedding of virus can be intermittent.
ommend testing serum samples obtained from asymptomaticbut potentially exposed persons if the health care provider and/or the primate worker believe that the results would be helpfulin making additional management decisions or providing peace Serologic Analysis
Assessment of serum antibody levels is most useful if sero- Currently, all macaque monkeys should be considered sero- logic analysis has been performed at the time of exposure and positive for B virus. Interpretation of negative serologic test its results can be compared with those of serologic analysis results may be misleading. Monkeys found to be seronegative performed at a later date. The initial serum sample obtained when tested weeks before an exposure occurred could be se- should be frozen at a temperature of –20ЊC or lower, preferably ropositive at the time of the exposure. Animals that are sero- in a freezer that does not go through freeze-thaw cycles. A negative at the time of exposure could be undergoing primary second serum sample should be obtained 3–6 weeks later or infection and may not yet have seroconverted; thus, retesting at the onset of clinical symptoms. If sent for testing, these serum of the animals several weeks after the exposure may be required samples should be analyzed simultaneously. Seroconversion or to rule out acute infection at the time of the exposure.
Prevention of and Therapy for B Virus Exposure • CID 2002:35 (15 November) • 1197
POSTEXPOSURE PROPHYLAXIS
from a peripheral site to the CNS, have shown that animalbites to the head and neck are more likely to result in fatal Although fatal cases of B virus disease in humans have occurred disease (percent mortality, 30%–100%) than are bites to the in primate workers who do not recall an obvious exposure or fingers or hands (percent mortality, 15%–20%) [31]. Because who have had what would be considered a low-risk exposure, B virus also travels to the CNS by these pathways, we rec- it is not reasonable to provide prophylaxis for every potential ommend postexposure prophylaxis for potential exposures to exposure (table 4). We are currently unable to accurately quan- B virus when the head, neck, or torso is involved. Superficial tify the risk associated with all exposures. Thus, these recom- wounds and scratches are easily cleansed and, therefore, usually mendations can only be considered as guidelines. For certain are considered low risk. Deep punctures—in particular, those “low-risk” exposures, postexposure prophylaxis may be appro- caused by bites—are likely to result in inadequately cleansed priate when the primate worker and/or the occupational wounds and pose a higher risk. Studies of rabies virus indicate health provider would be more comfortable with the use of that superficial wounds and scratches to the extremities are less likely to result in fatal disease (percent mortality, 0.5%–5%) For each primate exposure, 4 major variables need to be than are deeper bites (percent mortality, 15%–20%) [31]. Thus, assessed. First, the source of the exposure should be determined.
we recommend postexposure prophylaxis for persons with po- Macaques are the only primates known to transmit B virus.
tential B virus exposures involving deep wounds or punctures.
Other primates pose no known risk unless they have had the opportunity to acquire infection directly from a macaque. Ma- Fourth, exposure to materials that have come in contact with caques that have lesions compatible with B virus or that are macaques, in addition to direct exposure to the animals, must known to be culture positive for the virus are more likely to be evaluated. B virus is latent in the CNS of macaques and be shedding virus. Immunocompromised or otherwise ill an- is shed intermittently from the mucosa of infected animals.
imals, stressed animals, breeding animals, and recently acquired Therefore, punctures with needles that contain material from primates that are still in quarantine are all more likely to shed the CNS, eyelids, or mucosa of macaques are considered high- risk exposures. Although a case of viremia in an ill monkey Second, the timeliness and adequacy of first aid for the has been reported [32], viremia rarely occurs in healthy animals wound should be assessed. Was the wound cleansed within 5 [33]. Therefore, punctures with needles contaminated with pe- min of exposure, and was the duration of cleansing a full 15 ripheral blood from monkeys are considered exposures of much min? Mucosal splashes or wounds that are inadequately lower associated risk. Needlestick injuries were associated with cleansed are more likely to become infected, because there is 2 of the cases of B virus presented in table 1. One of the injuries an increased duration of exposure to infectious material.
involved a needle that had been exposed to the ocular tissues Third, the type of wound or exposure, the depth of the of a monkey [14], whereas the other injury involved a needle wound, and the location of the wound should all be deter- that “may have been used previously to inject monkeys” [4, p.
mined. Infections that occur as a result of exposure of the head, torso, or neck may result in no signs or symptoms before the Using the aforementioned principles, we have identified 7 CNS is involved and should be classified as high risk (see the different exposures for which postexposure prophylaxis is rec- Risk for Transmission of B Virus to Primate Workers section).
ommended (table 5). If postexposure prophylaxis is adminis- Studies of rabies virus, which progresses along neural pathways tered, it should be started soon (within hours) after the ex- Pros and cons of postexposure prophylaxis for persons exposed to
Initiation of acyclovir therapy within 24 h after exposure to B virus prevents Initiation of acyclovir therapy within hours of exposure may prevent or modify Infection with B virus is very rare relative to the number of possible exposures There are no controlled studies that document the ability of immediate empiri- cal therapy to prevent infection or symptomatic B virus infection in humans Acyclovir therapy can suppress virus shedding and seroconversion, which may 1198 • CID 2002:35 (15 November) • Cohen et al.
Recommendations for postexposure prophylaxis for persons exposed to B virus.
Skin exposurea (with loss of skin integrity) or mucosal exposure (with or without injury) to a high-risk source (e.g., a macaque that is ill, immunocompromised, or knownto be shedding virus or that has lesions compatible with B virus disease) Inadequately cleaned skin exposure (with loss of skin integrity) or mucosal exposure (with Needlestick associated with tissue or fluid from the nervous system, lesions suspicious Puncture or laceration after exposure to objects (a) contaminated either with fluid from monkey oral or genital lesions or with nervous system tissues, or (b) known to containB virus A postcleansing culture is positive for B virus Mucosal splash that has been adequately cleaned Laceration (with loss of skin integrity) that has been adequately cleaned Needlestick involving blood from an ill or immunocompromised macaque Puncture or laceration occurring after exposure to (a) objects contaminated with body fluid (other than that from a lesion), or (b) potentially infected cell culture Skin exposure in which the skin remains intact Exposure associated with nonmacaque species of nonhuman primates a Exposures include macaque bites; macaque scratches; or contact with ocular, oral, or genital secretions, nervous system tissue, or material contaminated by macaques (e.g., cages or equipment) (see the Postex-posure Prophylaxis section of the text for details).
posure. Prophylaxis should be initiated by the occupational by the US Food and Drug Administration for treatment of B health care provider, who should determine whether first aid virus infection. The IC of acyclovir for B virus is 18 mg/mL, and cleansing has been appropriate, properly document the and that of ganciclovir is 9 mg/mL [25]. Famciclovir is the injury, provide counseling and education about B virus, and ensure appropriate testing of the worker and the primate. In ∼15 mg/mL (J.K.H., unpublished data). These values are ap- addition, the risks of the medication should be discussed, and proximately 8–14-fold higher than the corresponding IC val- the medication given to and used by the patient should be ues for herpes simplex virus. Oral ganciclovir is poorly absorbed documented. Careful evaluation of the history of a presumed and should not be used for prophylaxis. Oral valganciclovir is exposure has, on occasion, indicated that an exposure has not well absorbed; however, we do not recommend this agent for occurred (e.g., the wrong species of primate was involved or prophylaxis because of its potential for toxicity, compared with the instruments were not actually used on primates) and that postexposure prophylaxis was not indicated.
Although acyclovir has been the mainstay for postexposure Postexposure prophylaxis is administered if the exposure oc- prophylaxis of B virus [1], 2 newer drugs have been approved curred within the previous 5 days, because animals have bene- for the oral treatment of herpesvirus infections. Valacyclovir is fited from prophylaxis given as late as 5 days after infection the 6-valine ester of acyclovir and is metabolized to acyclovir occurs. We also recommend postexposure prophylaxis if wound in the liver and intestine. Serum levels of acyclovir are ∼4-fold cultures done after cleansing are positive for B virus. Although greater when oral valacyclovir, 1 g q8h, is given than when oral this may result in administration of prophylaxis beyond 5 days acyclovir, 800 mg 5 times daily, is given. Famciclovir is an after the exposure occurred, a positive wound culture result esterified form of penciclovir and is converted to penciclovir indicates that a high-risk exposure to B virus has occurred.
in the intestine and the liver. Inside cells, both acyclovir andpenciclovir are phosphorylated to the monophosphate form by Antiviral Agents for Postexposure Prophylaxis
the viral thymidine kinase and, then, to the active triphosphate Three orally administered agents—acyclovir, valacyclovir, and form by cellular kinases. Famciclovir is administered orally be- famciclovir—are currently available for postexposure prophy- cause it is better absorbed than is penciclovir. Compared with laxis of B virus infection. These drugs have not been approved acyclovir triphosphate, penciclovir triphosphate is less active in Prevention of and Therapy for B Virus Exposure • CID 2002:35 (15 November) • 1199
inhibiting the herpesvirus polymerase; however, penciclovir tri- Antiviral Agents for Pregnant Women
phosphate is present in higher concentrations and has a longer Of the available orally administered antiherpesvirus agents, acy- intracellular half-life than does acyclovir triphosphate. Fam- clovir is the agent for which clinical experience is most exten- ciclovir and valacyclovir have similar efficacy in the treatment sive, especially when it is used during pregnancy. Although the of herpes zoster and therefore might be expected to have similar use of acyclovir should be limited during pregnancy, findings effectiveness when used for prophylaxis of B virus infection.
from a registry of women receiving the drug have not shownan increase in the incidence of congenital abnormalities. How-ever, the number of pregnant women who have received acy-clovir is not large enough to detect a small increase in congenital Antiviral Agents Recommended for Postexposure Prophylaxis
problems. Few data are available on the use of valacyclovir or We recommend oral valacyclovir, 1 g given 3 times daily, as famciclovir during pregnancy; thus, acyclovir would be the pre- the preferred drug for postexposure prophylaxis of B virus in ferred agent if postexposure prophylaxis is recommended for adults and nonpregnant women (table 6), because valacyclovir a pregnant woman. If a woman is of childbearing age, a urine results in much higher serum levels of acyclovir than does oral or serum pregnancy test should be considered to help direct acyclovir, the previously recommended drug [1]. The choice the choice of the antiviral medication.
of valacyclovir is supported by animal studies that show that acyclovir (the active metabolite of valacyclovir) is effective in Side Effects of Antiviral Agents
postexposure prophylaxis. In addition, valacyclovir is given 3 Oral acyclovir usually is very well tolerated. The most frequently times daily, whereas acyclovir is required 5 times daily; there- reported adverse effects are nausea, headache, diarrhea, and fore, compliance may be better with valacyclovir. Dosages may rash. Renal insufficiency has not been associated with use of need to be adjusted for renal insufficiency. The first alternate oral acyclovir. Neurologic side effects, including confusion and choice is oral acyclovir given at a dosage of 800 mg given 5 dizziness, occasionally have been reported in association with times daily. Although 500 mg of oral famciclovir given 3 times oral acyclovir use, but such side effects are less common than daily might be equally as efficacious as valacyclovir, the lack of those associated with use of intravenous acyclovir.
animal studies evaluating famciclovir (or its active metabolite Valacyclovir is generally well tolerated. High-dose (8 g/day), penciclovir) provides some concern regarding the effectiveness prolonged therapy (median duration, 54 weeks) with oral va- of the drug for postexposure prophylaxis.
lacyclovir has been associated with thrombotic microangio- Antiviral medication should be given soon after potential pathy that presented as thrombocytopenic purpura or hemo- exposure to virus (preferably within the first few hours after lytic uremia syndrome in patients with AIDS [34]. These exposure) but only after first aid has been provided and cleans- patients, however, were receiving numerous other drugs, and ing has been done. Postexposure prophylaxis should be given it is unclear whether valacyclovir or another drug or associated for 2 weeks, on the basis of the previously cited animal studies.
condition was responsible for the microangiopathy [35]. High- If the patient remains asymptomatic, antiviral medication dose, prolonged therapy with valacyclovir has also been asso- should be discontinued at 2 weeks, and careful follow-up (see ciated with CNS disturbances in renal transplant recipients [36].
the Follow-up after Exposure section below) should be per- Such side effects are unlikely to occur in otherwise healthy formed. In the event that the patient develops symptoms com- persons who are receiving much lower doses of valacyclovir (3 patible with B virus infection, postexposure prophylaxis should g/day) for 2 weeks as postexposure prophylaxis. Resistance of be discontinued and treatment of B virus disease should be B virus to antiviral agents has not been reported or extensively Summary of recommendations for prophylaxis and treatment of B virus infection.
a To be given until symptoms resolve and the results of 2 cultures are negative for B virus; see the Discontinuation of Treatment of B Virus Infection section of the text for additional therapy used after intravenously administered therapy hasbeen completed.
1200 • CID 2002:35 (15 November) • Cohen et al.
FOLLOW-UP AFTER EXPOSURE
conjunctiva, and oropharynx for B virus, serologic testing ofserum for B virus (preferably along with analysis of serum After counseling has been completed, questions have been an- samples obtained either at the time of or before the presumed swered, and, in some cases, postexposure prophylaxis has been exposure), routine chemical and hematologic studies, and a initiated, follow-up appointments should be scheduled for a urine or serum pregnancy test, when appropriate. Neurologic primate worker who has been exposed to B virus. A suggested tests should include lumbar puncture and MRI of the brain; schedule for follow-up appointments might include visits oc- electroencephalography (EEG) should also be considered. CSF curring at 1, 2, and 4 weeks after the exposure and at any time samples should be sent for culture, PCR detection of viral DNA, there is a change in the clinical status of the exposed primate and serologic testing. PCR has been used to detect B virus in worker. If the worker does not report for a follow-up appoint- the CSF of a patient with meningitis caused by B virus [37], ment, attempts should be made to contact him or her to verify as well as in human necropsy specimens [29]. CT of the brain that the worker has remained healthy and to emphasize the should be performed if an MRI is not immediately available.
potential seriousness of the exposure. In addition, the worker’s However, CT findings have been negative in recent cases of B supervisor or occupational health care provider should ask the virus meningoencephalitis. The primary usefulness of EEG is worker about his or her clinical status at least weekly during to help differentiate herpes simplex virus encephalitis (which the first month after the exposure occurs. Similar procedures most often presents as focal encephalitis involving the temporal should be in place in the event that a supervisor is exposed to lobes) from B virus disease (which usually presents as brain stem encephalitis). Brain stem auditory evoked responses in a At follow-up visits, the wound and the signs and symptoms conscious patient or somatosensory evoked potentials in an of B virus infection should be evaluated, compliance with med- unconscious patient may provide useful information about ication should be determined, questions that the patient may brain stem or upper spinal cord function in patients with sus- have should be answered, and the worker’s supervisor should be asked whether corrective measures have been taken to pre- vent future exposures. Blood samples should be obtained from Some experts recommend intravenous acyclovir for the in- selected patients for serologic testing.
itial treatment of B virus infection in patients without CNS Postexposure prophylaxis may delay the development of the disease [1]. Other authorities recommend ganciclovir for all antibody response to B virus or suppress viral shedding. Thus, symptomatic B virus infections because of the unpredictability follow-up of patients receiving postexposure prophylaxis of rapid and life-threatening brain stem involvement. When should be extended. Serologic testing should be performed 3–6 acyclovir is used, a higher intravenously administered dosage weeks after the initial exposure occurs, and, in addition, serum (12.5–15 mg/kg q8h) is recommended because B virus is less specimens from patients receiving postexposure prophylaxis susceptible to acyclovir than is herpes simplex virus. It is critical should be tested at later points in time (e.g., 3 months after to ensure proper hydration and to administer the drug slowly exposure). Furthermore, for patients who had an initial wound to avoid precipitation of the drug in the renal tubules and renal culture that was positive for B virus, cultures of material ob- insufficiency. In addition, it is important to monitor the serum tained from the conjunctivae, oropharynx, and any unhealed levels of creatinine in patients receiving high-dose acyclovir skin lesions might be performed 1–2 weeks after the discon- therapy and to adjust doses accordingly. If patients develop tinuation of antiviral medication, to detect virus shedding.
further symptoms while receiving acyclovir, intravenous gan-ciclovir should be used.
For patients with definitive signs and symptoms of peripheral TREATMENT OF B VIRUS DISEASE
nervous system or CNS involvement, intravenous ganciclovir, The presence of any signs or symptoms of B virus disease (see 5 mg/kg q12h, is recommended. As previously noted, B virus the first 4 paragraphs of the present report) or laboratory con- is more susceptible to ganciclovir than to acyclovir both in firmation of a positive culture result (not a positive result of vitro and in an animal model. In addition, the only case of the postcleansing wound culture referred to in the Laboratory documented brain stem encephalitis for which the outcome Testing of the Exposed Worker section) necessitates treatment was complete recovery occurred in a patient treated with gan- with intravenous antiviral therapy, not with orally administered ciclovir [11]. The increased toxicity (especially myelosuppres- medication used for postexposure prophylaxis. For any patient sion) associated with ganciclovir must be balanced against the with symptomatic B virus infection, a thorough evaluation (in- potential benefit of the drug. The dose of ganciclovir needs to cluding a detailed history and physical examination) should be be adjusted for renal insufficiency, and WBC and platelet counts done, with particular attention given to the presence of any skin lesions and to the neurologic status of the patient. Lab- In recent years, the use of acyclovir and ganciclovir therapy oratory tests should include cultures of specimens of lesions, for patients with the early stages of B virus disease, including Prevention of and Therapy for B Virus Exposure • CID 2002:35 (15 November) • 1201
patients with early signs of CNS disease, has probably been in which B virus was interpreted by some, but not all, experts responsible for an increased survival for some patients [10, 11].
to have reactivated months to years after primary infection.
However, antiviral therapy generally has not been effective in Most experts recommend that cultures of the conjunctivae patients with advanced encephalomyelitis.
and oral mucosa be performed at least weekly during the first Standard blood and body fluid precautions should be used few weeks after discontinuation of therapy, to check for shed- in the care of patients undergoing treatment for B virus infec- ding of B virus. If shedding is not present for у2 weeks after tion or those otherwise known or suspected to be shedding therapy has been discontinued, shedding can be assessed at virus, so that health care personnel and family members are less-frequent intervals, with an ultimate goal of assessment be- not exposed to potentially infectious blood, body fluids, or skin ing done only once or twice yearly. If neurologic symptoms or mucosal lesions. B virus has been cultured from the buccal develop at any time, cultures for B virus should be obtained.
mucosa and skin lesions of infected patients receiving intra-venous acyclovir ([10], L.E.C. and J.K.H., unpublished data); THE B VIRUS WORKING GROUP
thus, precautions must be continued during therapy.
Members of the B Virus Working Group met at the Centersfor Disease Control and Prevention in January 1999. The mem- DISCONTINUATION OF TREATMENT
bers of the group were James Blanchard, John Burnham, Paul OF B VIRUS INFECTION
Bystrom, Louisa Chapman, Jeffrey Cohen, David Davenport,Scott Deitchman, Ralph Dell, Tom Demarcus, Lisa Flynn, Gale Intravenous therapy for B virus infection should be continued Galland, Peter Gerone, Donna Goldsteen, Bryan Hardin, Julia until symptoms resolve and у2 sets of cultures yield negative Hilliard, Susan Iliff, Thomas Insel, Gregg Kasting, Stephen Kel- results after having been held for 10–14 days. Most experts ley, Max Kiefer, Richard Knudsen, Nicholas Lerche, Robert believe that therapy should not be discontinued but, rather, Letscher, David Lumby, Bertha Madras, Keith Mansfield, Bill should be switched to oral valacyclovir, famciclovir, or acyclovir Morton, Chris O’Rourke, Stephen Pearson, Jeffrey Roberts, administered at the dosages used for postexposure prophylaxis.
Jerry Robinson, John Stewart, David Taylor, Maureen Thomp- No good data exist to aid in the determination of when or son, Paul Vinson, Benjamin Weigler, and Deborah Wilson.
whether treatment should be discontinued. Some experts sug-gest that after oral therapy has been administered using the Acknowledgments
doses recommended for postexposure prophylaxis for 6 months to 1 year, the dose can be further reduced to a “suppressive” We thank Richard Whitley, Stephen Straus, Cyndi Jones, level to reduce the risk of reactivation of B virus. Although oral James Schmitt, John O’Connor, and Jonathan Kaplan for their acyclovir has been given in suppressive doses for many years to prevent reactivation of genital herpes, less is known aboutthe long-term toxicities of valacyclovir and famciclovir. Nev- References
ertheless, any risks associated with prolonged administration 1. Holmes GP, Chapman LE, Stewart JA, Straus SE, Hilliard JK, Davenport of antiviral medication must be balanced against the possible DS. Guidelines for the prevention and treatment of B-virus infections devastating effects of B virus reactivation.
in exposed persons. The B Virus Working Group. Clin Infect Dis Some experts believe that lifelong suppressive therapy is 1995; 20:421–39.
2. Weigler BJ. Biology of B virus in macaque and human hosts: a review.
needed, while others recommend that it be discontinued at Clin Infect Dis 1992; 14:555–67.
some point. The latter opinion is based on the observation 3. Whitley RJ, Hilliard JK. Cercopithecine herpesvirus 1 (B virus). In: that, over time, patients with frequently recurring genital her- Knipe DM, Howley PM, eds. Fields virology, 4th ed. Philadelphia:
Lippincott Williams & Wilkins, 2001:2835–48.
pes have a diminishing rate of recurrences and, therefore, less 4. Davidson WL, Hummeler K. B virus infection in man. Ann NY Acad need for long-term suppressive therapy [38]; however, it is Sci 1960; 85:970–9.
not known whether this finding applies to B virus infection 5. Sabin AB, Wright AM. Acute ascending myelitis following a monkey bite, with the isolation of a virus capable of reproducing the disease.
in humans. The decision to discontinue therapy is often dif- J Exp Med 1934; 59:115–36.
ficult and requires careful deliberation and discussion with 6. Breen GE, Lamb SG, Otaki AT. Monkey-bite encephalomyelitis: report the patient. If therapy is discontinued, the patient should give of a case with recovery. Brit Med J 1958; 2:22–3.
7. Hummeler K, Davidson WL, Henle W, LaBoccetta AC, Ruch HG.
his or her informed consent and should be followed closely.
Encephalomyelitis due to infection with Herpesvirus simiae (herpes B Because B virus remains latent in the sensory ganglia of mon- virus): a report of two fatal, laboratory-acquired cases. N Engl J Med keys and can reactivate, discontinuation of therapy has the 1959; 261:64–8.
8. Bryan BL, Espana CD, Emmons RW, Vijayan N, Hoeprich PD. Re- potential for leaving the patient “unprotected” in the event covery from encephalomyelitis caused by Herpesvirus simiae: report of that the virus reactivates. There has been at least 1 case [18] a case. Arch Intern Med 1975; 135:868–70.
1202 • CID 2002:35 (15 November) • Cohen et al.
9. Palmer AE. B virus, Herpesvirus simiae: historical perspective. J Med 25. Zwartouw HT, Humphreys CR, Collins P. Oral chemotherapy of fatal Primatol 1987; 16:99–130.
B virus (Herpesvirus simiae) infection. Antiviral Res 1989; 11:275–83.
10. Holmes GP, Hilliard JK, Klontz KC, et al. B virus (Herpesvirus simiae) 26. Guidelines for prevention of Herpesvirus simiae (B virus) infection in infection in humans: epidemiologic investigation of a cluster. Ann monkey handlers. MMWR Morb Mortal Wkly Rep 1987; 36:680–2,
Intern Med 1990; 112:833–9.
11. Davenport DS, Johnson DR, Holmes GP, Jewett DA, Ross SC, Hilliard 27. Goldstein EJ, Pryor EP III, Citron DM. Simian bites and bacterial JK. Diagnosis and management of human B virus (Herpesvirus simiae) infection. Clin Infect Dis 1995; 20:1551–2.
infections. Clin Infect Dis 1994; 19:33–41.
28. United States Department of Health and Human Services (DHHS).
12. Love FM, Jungherr E. Occupational infection with virus B of monkeys.
Herpesvirus simiae. In: Biosafety in Microbiological and Biomedical JAMA 1962; 179:804–6.
Laboratories, 4th ed. Washington, DC: DHHS, 1999:158–61.
13. Sabin AB. Fatal B virus encephalomyelitis in a physician working with 29. Scinicariello F, Eberle R, Hilliard JK. Rapid detection of B virus monkeys. J Clin Invest 1949; 28:808.
(Herpesvirus simiae) DNA by polymerase chain reaction. J Infect 14. Artenstein AW, Hicks CB, Goodwin BS Jr, Hilliard JK. Human infection Dis 1993; 168:747–50.
with B virus following a needlestick injury. Rev Infect Dis 1991; 13:
30. Weigler BJ, Hird DW, Hilliard JK, Lerche NW, Roberts JA, Scott LM.
Epidemiology of cercopithecine herpesvirus 1 (B virus) infection and 15. Nagler FP, Klotz M. A fatal B virus infection in a person subject to shedding in a large breeding cohort of rhesus monkeys. J Infect Dis recurrent herpes labialis. Can Med Assoc J 1958; 79:743–5.
16. Hull RN. The simian herpesviruses. In: Kaplan AS, ed. The herpes- 1993; 167:257–63.
viruses. New York: Academic Press, 1973:389–425.
31. Baer GM, Bellini WJ, Fishbein DB. Rhabdoviruses. In: Fields B, Knipe 17. Stones PB. Some diseases of animals communicable to man in Britain.
DM, eds. Virology. New York: Raven Press, 1990:883–942.
In: Graham-Jones O, ed. Proceedings of a symposium organized by 32. Simon MA, Daniel MD, Lee-Parritz D, King NW, Ringler DJ. Dissem- the British Veterinary Association and the British Small Animal Vet- inated B virus infection in a cynomolgus monkey. Lab Anim Sci erinary Association (London). New York: Pergamon Press, 1968:200–1.
1993; 43:545–50.
18. Fierer J, Bazeley P, Braude AI. Herpes B virus encephalomyelitis pre- 33. Keeble SA. B virus infection in monkeys. Ann NY Acad Sci 1960; 85:
senting as ophthalmic zoster: a possible latent infection reactivated.
Ann Intern Med 1973; 79:225–8.
34. Feinberg JE, Hurwitz S, Cooper D, et al. A randomized, double-blind 19. Centers for Disease Control and Prevention. Fatal Cercopithecine her- trial of valaciclovir prophylaxis for cytomegalovirus disease in patients pesvirus 1 (B virus) infection following a mucocutaneous exposure and with advanced human immunodeficiency infection. AIDS Clinical Trial interim recommendations for worker protection. MMWR Morb Mor- Group Protocol 204/Glaxo Wellcome 123-014 International CMV Pro- tal Wkly Rep 1998; 47:1073–6, 1083.
phylaxis Study Group. J Infect Dis 1998; 177:48–56.
20. Pierce EC, Pierce JD, Hull RN. B virus: its current significance, de- 35. Bell W, Chulay JD, Feinberg JE. Manifestations resembling thrombotic scription and diagnosis of a fatal human infection. Am J Hyg 1958;
microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204).
21. Weigler BJ, Roberts JA, Hird DW, Lerche NW, Hilliard JK. A cross Medicine (Baltimore) 1997; 76:369–80.
sectional survey for B virus antibody in a colony of group housed 36. Lowance D, Neumayer HH, Legendre CM, et al. Valacyclovir for the rhesus macaques. Lab Anim Sci 1990; 40:257–61.
prevention of cytomegalovirus disease after renal transplantation. In- 22. Keeble SA, Christofinis GJ, Wood W. Natural virus B infection in rhesus ternational Valacyclovir Cytomegalovirus Prophylaxis Transplantation monkeys. J Pathol Bacteriol 1958; 76:189–99.
23. Freifeld AG, Hilliard J, Southers J, et al. A controlled seroprevalence Study Group. N Engl J Med 1999; 340:1462–70.
survey of primate handlers for evidence of asymptomatic herpes B 37. Scinicariello F, English WJ, Hilliard JK. Identification by PCR of men- virus infection. J Infect Dis 1995; 171:1031–4.
ingitis caused by herpes B virus. Lancet 1993; 341:1660–1.
24. Boulter EA, Thornton D, Bauer DJ, Bye A. Successful treatment of 38. Straus SE, Croen KD, Sawyer MH, et al. Acyclovir suppression of experimental B virus (Herpesvirus simiae) infection with acyclovir. Br frequently recurring genital herpes: efficacy and diminishing need dur- Med J 1980; 280:681–3.
ing successive years of treatment. JAMA 1988; 260:2227–30.
Prevention of and Therapy for B Virus Exposure • CID 2002:35 (15 November) • 1203

Source: http://www.aaalac.org/accreditation/RefResources/OHS_Bvirus.pdf