Herpes B 

Updated: Dec 17, 2018
Author: Sowmya Nanjappa, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD 

Overview

Background

Herpes B virus is an alpha herpesvirus that is particularly enzootic (endemic in animals) in the rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) members of the macaque genus, Macaca (as seen in the image below). Among the nonhuman-primate herpesviruses, only herpes B virus 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.

This is a photo of long-tailed macaques socializin 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)

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. Herpes B virus demonstrates a broad host range in tissue culture, producing a lytic infection in cells of humans, nonhuman primates, small mammals, and many birds.[1, 2]

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 very similar to those caused by HSV. The most obvious manifestation of herpes B virus infection 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 common 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 herpes B virus, and almost all of these hosts naturally exist in Asia. Both wild and captive macaque populations generally exhibit high rates of herpes B virus infection, but most individuals exhibit few or no symptoms of infection. 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 exceed 70%.

Reports show that no herpes 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% in 1-year-old monkeys and 60% in adults. Other macaque species readily acquire and transmit the virus, but whether these species serve as natural hosts is unclear.

Cercopithecine herpesvirus 1 (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 herpes B virus in humans, dissemination to the central nervous system appears to occur neurally; however, herpes B virus 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.

Introduction of the virus causes necrosis in the spinal cord with ascent to the brain. At least one case in which disease occurred years after exposure has been reported, 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.

Epidemiology

Frequency

United States

No evidence shows that the prevalence of herpes B virus in macaques varies by country; however, the pattern of human infection is remarkable. Of the roughly 45 well-documented cases of herpes B virus infection in humans, two thirds occurred in the United States and the others were reported in Canada and Great Britain. Interestingly, most 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 herpes B virus, and several other cases have since been documented. This increased frequency coincides with an increased use of macaques in retroviral research.

International

The absence of reports of human herpes B virus infection from countries where macaques are prevalent and commonly interact with humans (eg, Japan) is striking. Whether the absence of these reports is due to the limited availability of herpes 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 herpes B virus. Children are 3 times more likely to be bitten than adults. Macaques in 7 nonoccupational exposure incidents were found to be seropositive for herpes B virus in two thirds of cases.

Mortality/Morbidity

Historically, human herpes B virus infection carries a case-fatality rate of approximately 70%, a rate similar to that of untreated HSV encephalitis.

As with HSV encephalitis, many survivors of herpes B virus infection have substantial residua.

Age

The average age of persons who develop herpes B virus infection reflects the demographics of individuals involved with the care of primate hosts in research laboratories.

Prognosis

Historically, human herpes B virus infection carries a case-fatality rate of approximately 70%, a rate similar to that of untreated HSV encephalitis.

As with HSV encephalitis, many survivors of herpes B virus infection have substantial residua.

Reported cases seem to have a lower case-fatality rate, possibly because of earlier diagnosis, earlier treatment, and/or 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.

 

Presentation

History

Following potential exposure to herpes B virus 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) may include the following:

  • Pain or pruritus at exposure site

  • Vesicles or ulcers at or near exposure site

  • Local lymphadenopathy

Intermediate symptoms (variably present) may include the following:

  • Fever

  • Malaise

  • Diffuse myalgias

  • Headache

  • Numbness or paraesthesias at or near exposure site

  • Nausea and/or abdominal pain

  • Persistent hiccups

Late manifestations may include the following:

  • Persistent headache

  • Alteration of mentation

  • Focal neurological symptoms

Physical

Findings of herpes B virus infection primarily include progressive neurologic deterioration that suggests a multifocal hemorrhagic encephalitis or encephalomyelitis. This finding contrasts with the temporal lobe localization of herpes simplex encephalitis. The progression of signs and symptoms may be modified by early antiviral therapy. Asymptomatic human herpes B virus 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

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

Macaques transmit the herpes B virus to each other through oral, ocular, or genital contact of mucous membranes or lesioned skin. The herpes B virus can be shed asymptomatically, including through bodily fluids (eg, semen, mother's milk, saliva, perhaps even in aerosol form). The animal stools could also conceivably transmit the herpes B virus. In captive macaques, transmission may often occur during routine colony management protocols involving tube sharing, common instrumentation, or contaminated gloves. Animals usually 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 herpes 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 herpes B virus infection involve individuals who regularly work with monkeys, thus providing 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; mucosal splash exposure; 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. In addition, one apparent case of human-to-human herpes B virus transmission involved a woman with dermatitis on her finger; she touched her husband's herpetiform lesion (resulting from a monkey bite).[3]

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. In most animals, the human B virus is latent in the trigeminal ganglia and becomes reactivated only when the macaque experiences psychological stress, pharmacological stress, or diminished immunocompetence.[4]

The widely observed pattern of increasing frequency with age suggests that horizontal transmission is far more common than vertical transmission (ie, mother to offspring). Whether this horizontal transmission occurs most commonly via oral or genital contact, including sexual behavior, is unresolved.

Complications

Aseptic meningitis results in 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 infection 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 patients, the frequency of asymptomatic or symptomatic reactivation and/or viral shedding occur is unclear.

 

DDx

Differential Diagnoses

 

Workup

Laboratory 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 was most recently 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. Although further research is required, newer recombinant DNA techniques may allow for differentiation of herpes B virus infection from HSV infection.[5]

Some human cases of herpes B virus infection have resulted in a slow or minimal rise in virus-specific antibody, confounding serological confirmation.

Polymerase chain reaction

Polymerase chain reaction (PCR) technology may permit faster and more accurate assessment of both human and primate cases. Newer studies are aimed at developing a PCR test that is not only sensitive but also specific, allowing for differentiation from HSV.[6]

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 virus 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 in only 2-3% of cases.

 

Treatment

Medical Care

The guidelines for medical treatment of individuals exposed to herpes B virus are complex. Refer to the most recently published guidelines for a detailed discussion.[3] The substance of these guidelines is delineated below. Prompt attention to a potential exposure is vital to minimize the risk of this disease, which carries 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 herpes 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. Dakin solution should never be used to wash the eyes or mucous membranes.

Antiviral therapy

Antiviral therapy is clearly indicated for suspected clinical cases of human herpes B virus infection; use of prophylactic antiviral therapy is problematic.

The decision regarding postexposure prophylaxis should be individualized and made by a health care provider experienced with the evaluation, treatment, and prevention of herpes B virus infection. Early prophylaxis may prevent either overall or symptomatic infection; on the other hand, infection is quite rare compared with the number of exposures.

The ability of therapy to prevent herpes B virus infection is not documented, and therapy can suppress shedding and seroconversion, further complicating diagnosis. In addition, the length of therapy is undefined.[3]

Surgical Care

Incision of wounds directed at diagnosis or treatment is usually of little benefit and can increase the risk of secondary bacterial infection. Therefore, it is not generally recommended.[3]

Consultations

For prevention protocol and specimen testing, obtain appropriate consultation from occupational health personnel of primate centers. In addition, the National Institute of Health’s National Center for Research Resources funds the National B Virus Resource Center, which is an excellent resource for numerous topics related to herpes B virus, including both diagnostic testing and education. Other resources include the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health.

Prevention

Developing herpes B virus–free colonies

The endeavor to develop virus-free colonies has found some success, especially 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 herpes B virus–free colonies has proven difficult because some macaques may show no antibodies but may retain latent herpes 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 animal infected with herpes B virus may compromise the virus-free status of an entire facility.

Current research focuses on the development of techniques (eg, PCR) to reduce false-negative results 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 herpes 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 herpes B 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. The risk of infection in these animals can be easily minimized by housing macaques in separate nonadjacent cages. A failure to follow this precaution has sometimes led to cross-species infection and fatalities.

Immunoprevention

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.

 

Medication

Medication Summary

Specific antiviral agents are recommended as soon as possible to attempt prevention of herpes B virus disease progression in humans or when prophylaxis is indicated. No treatment is currently approved for herpes B virus infection by the US Food and Drug Administration. 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.

Antivirals

Class Summary

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV polymerase with 30-50 times the potency of human alpha-DNA polymerase. Herpes B virus thymidine kinase has only recently been characterized. Initial in vitro study has suggested that, under experimental conditions, B virus thymidine kinase is less susceptible to several commonly used antiherpes drugs, including acyclovir and ganciclovir. This may lead to further research aimed at developing more effective alternatives than the currently accepted drugs for this infection.[7]

Acyclovir (Zovirax)

Synthetic purine nucleoside analogue with activity against a number of herpesviruses, including herpes B. Primarily available in preparations for PO and IV use. Highly selective for virus-infected cells because of high affinity for viral thymidine-kinase enzyme. This effect serves to concentrate acyclovir monophosphate into virus-infected cells. The monophosphate is then metabolized into triphosphate active form by cellular kinases.

Valacyclovir (Valtrex)

Hydrochloride salt of the L-valyl ester of acyclovir. Rapidly converted into acyclovir after prompt absorption from the gut via first-pass intestinal or hepatic metabolism. An alternative to acyclovir for prophylaxis (or possibly treatment).

Topical antiseptics

Class Summary

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

Povidone-iodine (Betadine)

Broad-spectrum germicidal agent used topically on skin or mucous membranes. Used as a surgical scrub or topical cleanser. Elemental iodine is the active form.

Chlorhexidine oral (Hibiclens, Peridex, PerioChip)

Effective, safe, and reliable topical wash or PO mouthwash antiseptic. A polybiguanide with bactericidal activity; usually is supplied as a gluconate salt. At physiologic pH, the salt dissociates to a cation that binds to bacterial cell walls. Commercially available central venous catheters impregnated with chlorhexidine and silver sulfadiazine are available.

Dakin solution

Originally described by Dakin in 1915. Made from sodium carbonate, salt, bleaching powder, and boric acid. Today, commonly referred to 0.5% sodium hypochlorite (a 1:10 dilution of household bleach). Solution deteriorates with time and should be made fresh. Further dilutions also can be made. Some physicians use it as part of pressure ulcer management. Because of potential injury, other topical antiseptics usually are used.