AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

The herpes B virus is an alpha herpesvirus that is particularly enzootic (endemic for animals) in the rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) members of the macaque genus, Macaca (see Image 1). Among the nonhuman primate herpesviruses, only herpes B is clearly able to cause disease in humans. The disease, usually a devastating infection of the central nervous system, occurs in humans and some primates that are not common hosts for this virus.

The pathogen is an enveloped herpesvirus, approximately 160-180 nm in size, that is quite similar to the human herpes simplex virus (HSV). Herpes B contains double-stranded linear DNA and has a molecular weight of approximately 110 megadaltons (approximately 162 kilobase pairs). Analysis of the envelope glycoproteins suggests cross-reactivity of glycoproteins B and D between herpes B and HSV types 1 and 2. The virus demonstrates a broad host range in tissue culture, producing a lytic infection in cells of humans, nonhuman primates, small mammals, and many birds.

In 1934, the term herpes B was derived from the initials of the first human case, which was described in detail by Sabin and Wright. The case was that of a 29-year-old laboratory worker ("W.B.") who developed fatal meningoencephalitis and transverse myelitis following a bite on the hand from a seemingly healthy rhesus monkey.

Herpes B virus infects a broad range of mammalian and avian species, including New World monkeys, Old World monkeys, and humans. Most infected macaques are asymptomatic. When symptoms do occur, they are highly similar to those symptoms caused by HSV. The most obvious manifestation is fluid-filled vesicles on the back of the tongue, lips, and elsewhere in the mouth; occasionally, the vesicles appear on the skin. When the vesicles rupture, they often give rise to ulcers and fibronecrotic scabs, which may lead to secondary bacterial and fungal infections. Scabs typically heal within 7-14 days. Conjunctivitis of varying severity is another frequent symptom. In rare instances, systemic illness is associated with herpes B virus in macaques, including the occurrence of ulcerative lesions in the mouth, esophagus, and stomach and necrosis of the liver, spleen, and adrenal glands.

Members of the genus Macaca (>16 species) are natural hosts of the virus, and almost all of these hosts naturally exist in Asia. Both wild and captive macaque populations generally exhibit high rates of infection, but most individuals usually express few or no symptoms. The strongest evidence for this pattern of high prevalence and mild infection comes from the rhesus, Japanese, and long-tailed (or cynomolgus) macaques, all of which are very closely related phylogenetically.

In captive populations of Japanese long-tailed and rhesus macaques, the prevalence of herpes B virus–induced antibodies is quite variable but may reach 100%. In wild and semi–free-ranging populations of long-tailed and rhesus macaques, seroprevalence rates (or prevalence of serum-detected herpes B virus–induced antibodies) typically are higher than 70%.

Reports show that no B virus exists in a population of long-tailed macaques introduced 400 years ago on the island of Mauritius. In all populations studied, the likelihood of infection increases dramatically with age. For example, in a study of semi–free-ranging macaques on the island of Cayo Santiago, Puerto Rico, 50% of 1-year-old macaques were infected, compared to 100% of adults; in a study of captive rhesus and Japanese macaques in Japan, the prevalence rates were 20% for 1-year-old monkeys and 60% for adults. Other macaque species readily acquire and transmit the virus, but whether these species serve as natural hosts is unclear.

Cercopithecine herpes virus (CHV-1), interestingly, is the formal name of the virus, which implies that all members of the primate family Cercopithecidae serve as natural hosts. Nevertheless, little evidence supports this theory for nonmacaque species of this taxon (eg, baboons, mangabeys, guenons, vervet monkeys); thus, CHV-1 may be a misnomer. Part of the difficulty in identifying taxonomic patterns is that many of the nonmacaque cercopithecine species are natural carriers of closely related viruses (including the baboon herpesvirus SA8), which are serologically difficult to distinguish from herpes B.

Pathophysiology

After inoculation of the virus in humans, dissemination to the central nervous system appears to occur via the neural route; however, herpes B can produce local infection in the skin at the inoculation site, with concomitant local and regional inflammatory changes. Indeed, lymph nodes draining the entry point can be histopathologically hemorrhagic and focally necrotic.

Arrival of the virus causes necrosis in the spinal cord with ascent to the brain. At least one case has been reported in which disease occurred years after exposure, suggesting that herpes B virus might be able to become latent in humans. Self-limited aseptic meningitis has been reported, but almost all cases produce substantial morbidity and mortality.

Frequency

United States

No indication exists that the prevalence of herpes B varies by country for macaques; however, the pattern of human infection is remarkable. Of the roughly 45 well-documented cases of human infection, two thirds occurred in the United States and the others were reported in Canada and Great Britain. Interestingly, a majority of the well-documented human cases of herpes B virus infection occurred in the 1950s and 1960s, when large numbers of rhesus macaques were used in the production and testing of poliomyelitis vaccines. In the late 1980s, several cases in Pensacola, Florida and Kalamazoo, Michigan refocused attention on the virus, and several other cases have been documented since. This increased frequency coincides with an increased use of macaques in retroviral research.

International

The absence of reports from countries where macaques are prevalent and commonly interact with humans (eg, Japan) is striking. Whether the absence of these reports is because of the limited availability of B virus diagnostic facilities (ie, actual cases not identified) or if some other factors are responsible (eg, different animal-handling procedures) is unclear. Concern exists that pet macaques (in addition to laboratory macaques) can spread the B virus. Children are 3 times more likely to be bitten than adults. Macaques in 7 nonoccupational exposure incidents were found to be seropositrive for this virus in two thirds of cases.

Mortality/Morbidity

• Historically, the case fatality rate in human herpes B infection has been approximately 70%, a rate similar to untreated HSV encephalitis.
• Like HSV encephalitis, many survivors have substantial residua.

Age

Age in human cases reflects the demographics of individuals involved with the care of primate hosts in research laboratories.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Following potential exposure in humans, the wound and the at-risk individual should be monitored because of the potential for severe infection, a protocol involving the exposing primate (see Lab Studies). An incubation period of 2-30 days has been described, with progression of symptoms over 7-10 days.

• Early symptoms (variably present)
• • Pain or pruritus at exposure site
  • Vesicles or ulcers at or near exposure site
  • Local lymphadenopathy
• Intermediate symptoms (variably present)
• • Fever
  • Malaise
  • Diffuse myalgias
  • Headache
  • Numbness or paraesthesias at or near exposure site
  • Nausea and/or abdominal pain
  • Persistent hiccups
• Late manifestations
• • Persistent headache
  • Alteration of mentation
  • Focal neurological complaints

Physical

Findings primarily are progressive neurologic deterioration, which suggests a multifocal hemorrhagic encephalitis or encephalomyelitis. This finding contrasts the temporal lobe localization of herpes simplex encephalitis. The progression of signs and symptoms may be modified by early antiviral therapy. Asymptomatic human infection is rare, if not nonexistent. Typical physical signs include the following:

• Meningismus
• Confusion progressing to coma
• Brain stem findings, which may include the following:
• • Diplopia
  • Dysarthria
  • Dysphagia
  • Cerebellar signs, including ataxia
  • Cranial nerve palsies
• Signs of meningoencephalomyelitis, which may include the following:
• • Seizures
  • Hemiparesis or hemiplegia
  • Progressive ascending paralysis
  • Transverse myelitis
• Non–central nervous system signs, which may include the following:
• • Conjunctivitis or chorioretinitis
  • Sinusitis

Causes

In order to understand how to prevent this high-mortality infection, information regarding the epidemiology and transmission of herpes B virus in primates is vital.

• Macaques transmit the herpes B virus to each other through oral, ocular, or genital contact of mucous membranes or lesioned skin. The B virus can be shed asymptomatically, including through bodily fluids (eg, semen, mother's milk, saliva, perhaps even in aerosol form). The animal stools also could conceivably transmit the B virus. For captive macaques, transmission often may occur during routine colony management protocols involving tube sharing, common instrumentation, or contaminated gloves. Animals most frequently become infected as juveniles, at the onset of sexual activity; however, younger animals can become infected through contact with another virus-shedding animal. For example, a nursing mother has repeated opportunities to transmit B virus in buccal or conjunctival fluids to a nursing infant during grooming.
• Conclusively determining transmission pathways may not be possible because most human cases of B virus infection involve individuals who work with monkeys on a regular basis and, thus, have many potential means of exposure. Suspected transmission modes include monkey bites, monkey scratches, or cage scratches; direct contamination of a preexisting wound with macaque saliva; respiratory exposure to aerosol macaque saliva; cuts sustained from culture bottles containing macaque kidney cells; needle-stick injuries following needle use in macaques; and cleaning a rhesus macaque skull without gloves. Also, one apparent case of human-to-human transmission involved a woman with dermatitis on her finger; she touched her husband's herpetiform lesion (resulting from a monkey bite).
• Given the myriad potential transmission pathways and abundance of macaques in contact with people, the fact that relatively few documented cases of B virus infection occur in humans may seem surprising. Nevertheless, although most macaques test positive for herpes B virus antibodies, only a small percentage (ie, 0-2%) shed the virus at any given time. For most animals, the B virus is latent in the trigeminal ganglia and becomes reactivated only when the macaque experiences psychological stress, pharmacological stress, or diminished immunocompetence.
• The widely observed pattern of increasing frequency with age indicates that horizontal transmission is far more common than vertical transmission (ie, mother to offspring). Whether this horizontal transmission most frequently occurs via oral or genital contact, including sexual behavior, is unresolved.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Herpes simplex encephalitis
Arthropod-associated meningoencephalitis

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Evaluation of the potential primate vector
• • To avoid delaying wound cleansing and forcing the virus deeper into the wound (even after wound cleansing), obtain the exposure-directed primate virus cultures from buccal mucosa (for saliva exposure), conjunctivae, and the urogenital area (for urine exposure). If a cage was involved, acquire swab cultures from the monkey that most recently was housed there.
  • Because herpes B is a class 4 pathogen, cultures should be performed only at a designated reference laboratory.
• Serologic evaluation of the exposed patient
• • If frozen serum from the last 6 months is not available, acquire, freeze, and store a serum sample.
  • Obtain a follow-up serum sample approximately 3 weeks after exposure or after the onset of illness (as close to 3 wk as possible) to test with the initial specimen for herpes B virus seroconversion.
  • Perform serologies in a reference laboratory to minimize cross-reacting HSV antibodies.
  • Some human cases have had a slow or minimal rise in virus-specific antibody, confounding serological confirmation.
• Polymerase chain reaction technology may permit faster and more accurate assessment of both human and primate cases.

Other Tests

• Veterinary evaluation of monkeys
• • The importance of evaluating the primate should be weighed against the potential of further injuries if the monkey must be recaptured without anesthesia.
  • After anesthesia, the monkey should be examined for oral lesions, genital lesions, or conjunctivitis.
  • High-risk exposure includes any injury associated with an ill, immunocompromised, or lesioned animal.
  • Remember that asymptomatic shedding of herpes B may occur and is more likely during breeding season or times of stress.
  • Serial serologies can be obtained from the primate because a rise suggests primary infection and a higher risk of viral shedding. Stable serologies do not predict shedding, which occurs only 2-3% of the time.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Guidelines for medical treatment of exposed individuals are complex. Refer to Holmes (1995) for detailed discussions. The substance of these guidelines is delineated below. Prompt attention to a potential exposure is vital to minimize the risk of this disease, which has high morbidity and mortality rates.

• Wound decontamination
• • Cleansing of the exposed area within minutes of the episode is the only means of preventing a contaminated wound from progressing to actual infection. The B virus is likely to enter host cells within 5 minutes.
  • At least 15 minutes of scrubbing and/or irrigating the exposed area is recommended. Sterile saline or rapidly flowing water is used for the eye, and decontaminants (eg, soap solution, povidone-iodine, chlorhexidine) can be used at other sites.
  • Dakin solution (0.25% hypochlorite) has been suggested for high-risk deep lacerations or needle sticks. The solution must be fresh, and standard decontaminants should be used after a 5-minute treatment.
• Antiviral therapy
• • This therapy is clearly indicated for suspected clinical cases of human herpes B infection; use of prophylactic antiviral therapy is problematic.
  • Early prophylaxis may prevent either overall or symptomatic infection; on the other hand, infection is quite rare when compared to exposures.
  • The ability of therapy to prevent infection is not documented, and therapy can suppress shedding and seroconversion, making diagnosis more difficult. Also, the length of therapy is undefined.

Surgical Care

Some experts suggest surgical excision of needle-track sites under local anesthesia to reduce exposure and increase contact with detergent.

• Surgery usually is not justified, unless it can be done within minutes.
• The procedure may further traumatize the site and increase the risk of secondary infection and/or poor wound healing.

Consultations

For prevention protocol and specimen testing, obtain appropriate consultation from occupational health personnel of primate centers.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Specific antiviral agents are recommended as soon as possible to attempt prevention of disease progression in humans or in situations in which prophylaxis is suggested. No treatment currently is approved by the US Food and Drug Administration for herpes B. Early treatment has been successful in modifying infection in some animal models, but human data, albeit anecdotal, have been mixed. The progression of complications seems to be limited in some human reports. The dosing, especially for prophylaxis, is not clearly delineated. Because of its bioavailability profile, valacyclovir seems preferable to acyclovir for oral use in either treatment or prophylaxis.

Topical antiseptic compounds or preparations are used topically on potentially contaminated or infected body surfaces or on inanimate objects. In these cases, the topical antiseptics are used to inactivate any herpes B virus remaining in the wound after irrigation.

Drug Category: Antivirals

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV polymerase with 30- to 50-times the potency of human alpha-DNA polymerase.

Drug Category: Topical antiseptics

These agents are to be used for decontamination of affected areas. Scrubbing should persist for at least 15 min.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention

• Developing virus-free colonies
• • Some success has occurred in the endeavor to develop virus-free colonies, and this is especially apparent in the United States, where the National Center for Research Resources took a leading role in the 1990s by promoting experimental strategies in husbandry and management.
  • Achieving completely virus-free colonies has proven difficult because some macaques may show no antibodies but may retain latent B virus particles. Furthermore, the B virus may become reactivated and shed without any visible symptoms.
  • Because of the relative ease of monkey-to-monkey transmission, even a single infected animal may compromise the virus-free status of an entire facility.
  • Current research focuses on the development of techniques (eg, polymerase chain reaction) to reduce false-negative results (ie, not detecting virus when actually present) and the implementation of regular screening protocols that quickly identify infected monkeys.
• Accepting moderate to high infection rates in macaques but minimizing human exposure to B virus
• • Minimizing social, nutritional, pharmacological, and psychological stress (especially overcrowding and shipping) can reduce viral shedding by monkeys. Promoting good veterinary care and immunocompetence also can reduce shedding.
  • Eliminating transmission pathways can prevent human exposure. Some means of prevention include the use of protective suits, gloves, eye shields, and similar devices. Given the difficulties and costs of achieving virus-free colonies, these methods may remain the reality at most facilities, at least for the near future.
  • Nonmacaque species are highly susceptible to herpes B virus infection. Risk for these animals can be minimized easily if macaques are not housed in the same or adjacent cages. A failure to follow this precaution has sometimes led to cross-species infection and fatalities.
• Immunoprevention has been attempted in animal studies using several different vaccines. Most recently, a recombinant vaccinia virus that expresses herpes B glycoprotein D appears promising in preventing infection and/or latency.

Complications

• Aseptic meningitis occurs with a moderate lymphocyte pleocytosis and erythrocytes, moderately elevated cerebrospinal fluid (CSF) protein level, and normal CSF glucose. In humans, herpes B virus can be grown from CSF, skin lesions, and urine.
• Nonfatal cases of human herpes B virus may result in complete recovery, but residua are common and include the following:
• • Extremity paresis or plegia
  • Aphasia
  • Dysarthria
  • Residual chorioretinitis
• Because of prolonged or long-term use of antiviral therapy in surviving cases, how often asymptomatic or symptomatic reactivation and/or viral shedding occur is not clear.

Prognosis

• Historically, the case fatality rate in human herpes B infection has been approximately 70%, a rate similar to untreated herpes simplex encephalitis.
• Like HSV encephalitis, many survivors have substantial residua.
• More recently reported cases seem to have a lower case fatality rate, which could be due to the following:
• • Earlier diagnosis
  • Earlier treatment
  • Better supportive care

Patient Education

• Until a vaccination is available or certified, herpes B virus-free colonies are the rule; educating primate workers on the avoidance of high-risk exposures is mandatory.
• All workers should be aware of prevention and treatment protocols.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure of any facility maintaining macaques to have an aggressive educational campaign to maximize protection for its workers

Special Concerns

• Long-term therapy with antiviral drugs has been used in the few individuals who had clinical recoveries from overt herpes B encephalitis.
• Asymptomatic shedding of HSV can occur despite drug treatment, but whether this occurs with herpes B is unclear.
• The advisability of discontinuing antiviral therapy is unclear with regard to clinical reactivation or possible human-to-human spread (one case documented).
• Likewise, if clinical decisions to use antiviral prophylaxis with established protocols are made, the length of treatment is poorly defined.
• • Immediate antiviral treatment usually is instituted for deep wounds or wounds inflicted by symptomatic monkeys.
  • Many experts suggest prophylaxis only if surveillance cultures are positive.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  This is a photo of long-tailed macaques socializing in the wild. The long-tailed macaque, Macaca fascicularis, is a major reservoir for the herpes B virus. (Photo courtesy of Carel van Schaik)
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Bennett AM, Slomka MJ, Brown DW, et al. Protection against herpes B virus infection in rabbits with a recombinant vaccinia virus expressing glycoprotein D. J Med Virol. Jan 1999;57(1):47-56. [Medline].
• Bryan BL, Espana CD, Emmons RW, et al. Recovery from encephalomyelitis caused by Herpesvirus simiae. Report of a case. Arch Intern Med. Jun 1975;135(6):868-70. [Medline].
• Chellman GJ, Lukas VS, Eugui EM, et al. Activation of B virus (Herpesvirus simiae) in chronically immunosuppressed cynomolgus monkeys. Lab Anim Sci. Apr 1992;42(2):146-51. [Medline].
• Davenport DS, Johnson DR, Holmes GP, et al. Diagnosis and management of human B virus (Herpesvirus simiae) infections in Michigan. Clin Infect Dis. Jul 1994;19(1):33-41. [Medline].
• Fierer J, Bazely P, Braude AI. Herpes B virus encephalomyelitis presenting as ophthalmic zoster. A possible latent infection reactivated. Ann Intern Med. Aug 1973;79(2):225-8. [Medline].
• Freifeld AG, Hilliard J, Southers J, et al. A controlled seroprevalence survey of primate handlers for evidence of asymptomatic herpes B virus infection. J Infect Dis. Apr 1995;171(4):1031-4. [Medline].
• Hilliard JK, Weigler BJ. The existence of differing monkey B virus genotypes with possible implications for degree of virulence in humans. Lab Anim Sci. Feb 1999;49(1):10-1. [Medline].
• Holmes GP, Chapman LE, Stewart JA, et al. Guidelines for the prevention and treatment of B-virus infections in exposed persons. The B virus Working Group. Clin Infect Dis. Feb 1995;20(2):421-39. [Medline].
• Holmes GP, Hilliard JK, Klontz KC, et al. B virus (Herpesvirus simiae) infection in humans: epidemiologic investigation of a cluster. Ann Intern Med. Jun 1 1990;112(11):833-9. [Medline].
• Jainkittivong A, Langlais RP. Herpes B virus infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Apr 1998;85(4):399-403. [Medline].
• Kessler MJ, Hilliard JK. Seroprevalence of B virus (Herpesvirus simiae) antibodies in a naturally formed group of rhesus macaques. J Med Primatol. 1990;19(2):155-60. [Medline].
• Ostrowski SR, Leslie MJ, Parrott T. B- virus from pet macaque monkeys: an emerging threat in the United States?. Emerg Infect Dis. 1998;4:117-21.
• Oya C, Ochiai Y, Taniuchi Y. Specific detection and identification of herpes B virus by a PCR-microplate hybridization assay. J Clin Microbiol. 2004;42:1869-74.
• Palmer AE. B virus, Herpesvirus simiae: historical perspective. J Med Primatol. 1987;16(2):99-130. [Medline].
• Perelygina L, Patrusheva I, Hombaiah S. Production of herpes B virus recombinant glycoproteins and evaluation of their potential. J Clin Microbiol. 2005;43:620-8.
• Scinicariello F, Eberle R, Hilliard JK. Rapid detection of B virus (herpesvirus simiae) DNA by polymerase chain reaction. J Infect Dis. Sep 1993;168(3):747-50. [Medline].
• Weigler BJ, Scinicariello F, Hilliard JK. Risk of venereal B virus (cercopithecine herpesvirus 1) transmission in rhesus monkeys using molecular epidemiology. J Infect Dis. May 1995;171(5):1139-43. [Medline].
• Weigler BJ. Biology of B virus in macaque and human hosts: a review. Clin Infect Dis. Feb 1992;14(2):555-67. [Medline].

Article Last Updated: May 26, 2006