B virus infection is caused by Macacine herpesvirus 1 (formerly Cercopithecine herpesvirus 1 [CHV-1]), an alphaherpesvirus closely related to herpes simplex virus. B virus is also commonly referred to as herpes B, monkey B virus, herpesvirus simiae, and herpesvirus B.
The virus is commonly found among macaque monkeys, including rhesus macaques, pig-tailed macaques, and cynomolgus monkeys (also called crab-eating or long-tailed macaques), any of which can harbor latent B virus infection and appear to be natural hosts for the virus. Monkeys infected with B virus usually have no or only mild symptoms. In addition, rabbits, guinea pigs, and mice can be experimentally infected with B virus.
Infection with B virus is extremely rare in humans; however, when it does occur, the infection can result in severe neurologic impairment or fatal encephalomyelitis if the patient was not treated soon after exposure (see Risks for Infection and Treatment sections).
B virus is classified as a select agent, with the potential to pose a threat to public health and safety, by the U.S. Public Health Service, Department of Health and Human Services
Cause and Incidence
B virus infection is caused by the zoonotic agent Macacine herpesvirus (formerly Cercopithecine herpesvirus 1 [CHV-1], an alphaherpesvirus commonly found among macaques—a genus of Old World monkeys that serve as the natural host. B virus infection in macaques results in a disease similar to herpes simplex virus infection in humans.
B virus infection in macaques is usually symptom-free or causes only mild disease, but in humans the infection can be fatal.
Reported cases of infection in humans are very rare; since the identification of the virus in 1932, there have only been 31 documented human infections by B virus, 21 of which were fatal. Most of these infections have resulted from animal bites or scratches or from percutaneous inoculation with infectious materials. However, in 1997 a researcher died from B virus infection following a mucosal splash exposure.
Risks for Infection
Persons at greatest risk for B virus infection are veterinarians, laboratory workers, and others who have close contact with Old World macaques or monkey cell cultures. Infection is typically caused by animal bites or scratches, by exposure to the tissues or secretions of macaques, or by mucosal contact with body fluid or tissue. Human infection can also result from indirect contact via, for example, a needlestick injury from a contaminated needle.
Macaques housed in primate facilities usually become B virus positive by the time they reach adulthood. B virus establishes latent infection in macaques and can only be transmitted during active viral shedding into mucosal surfaces. This happens only on reactivation from the latent state, which occurs rarely—most commonly in animals that have been stressed or immunosuppressed.
In late 1997, a worker at a primate center died from B virus infection that developed after biologic material from a monkey was splashed into the worker's eye. In response to this case, CDC formed a working group to reassess the existing recommendations for the prevention, evaluation, and treatment of B virus infection in humans.
Signs and Symptoms
Monkeys infected with B virus usually have no or only mild symptoms. In humans, however, B virus infection can result in acute ascending encephalomyelitis, resulting in death or severe neurologic impairment.
Disease onset in B virus–infected humans typically occurs within 1 month of exposure, although the actual incubation period can be a little as 3 to 7 days. Symptoms associated with B virus infection include
- Vesicular (small blister) skin lesions at or near the site of exposure
- Localized neurologic symptoms (pain, numbness, itching) near the wound site
- Flu-like aches and pains
- Fever and chills
- Headaches lasting more than 24 hours
- Fatigue
- Muscular incoordination
- Shortness of breath
Initial symptoms include fever, headache, and vesicular skin lesions at the site of exposure. Neurologic symptoms vary. Respiratory involvement and death can occur 1 day to 3 weeks after symptom onset.
Disease progression depends on the location of the exposure (usually a bite or scratch) and on the number of infectious virus particles that get delivered by the exposure. Although vesicular lesions have sometimes been observed at the exposure site, they are not invariably observed. The first signs of disease typically include the onset of flu-like symptoms (e.g., fever, muscle ache, fatigue, and headache). Lymphadenitis, lymphangities, nausea and vomiting, abdominal pain, and hiccups have also been observed in patients. Once the virus spreads to the central nervous system (CNS), a variety of neurologic signs develop, including hyperesthesias, ataxia, diplopia, agitation, and ascending flaccid paralysis. CNS involvement generally heralds grave consequences. Most patients with CNS complications will die despite antiviral therapy and supportive care, and those who survive usually suffer serious neurologic sequelae. Respiratory failure associated with ascending paralysis is the most common cause of death.
Given the number of potential exposures for animal care workers, asymptomatic or mild human B virus infection has been postulated to occur, but no evidence for asymptomatic B virus infection or for latent infection has been observed in humans at elevated risk of infection. Antibodies produced in response to the human herpesviruses HSV-1 and HSV-2 (present in >80% of adults) are capable of neutralizing B virus in vitro but are not protective against B virus infection. Moreover, such antibodies complicate diagnostic testing for B virus due to their high level of cross-reactivity (i.e., they increase the potential for both false-positive and false-negative results).
Transmission
B virus infection in humans usually occurs as a result of bites or scratches from macaques—a genus of Old World monkeys that serve as the natural host—or from direct or indirect contact of broken skin or mucous membranes with infected monkey tissues or fluids. The virus can be present in the saliva, feces, urine, or nervous tissue of infected monkeys and may be harbored in cell cultures derived from infected monkeys.
Possible routes of transmission to humans include
- Bite or scratch from an infected animal
- Needlestick from contaminated syringe
- Scratch or cut from contaminated cage or other sharp-edged surface
- Exposure to nervous tissue or skull of infected animal (especially brain)
B virus may survive for hours on the surface of objects, particularly on surfaces that are moist. The injury need not be severe for infection to occur, although non-penetrating wounds are thought to carry a lower risk of transmission.
Transmission risks of B virus to humans should be considered in the context of the rarity of observed transmission, even among broadly infected populations of animals. Hundreds of macaque bites and scratches occur annually in primate facilities in the United States, but B virus infection in humans occurs only rarely. In a study of more than 300 animal care workers, among whom, 166 reported possible transmission risk exposures to macaques, none of the workers was considered to be B virus positive.
Only one case of human-to-human transmission has been documented; the case, which was reported in a study of a B virus outbreak involving 4 persons in Florida, resulted from direct physical contact with lesions. Among the 4 case patients, 3 were animal handlers (2 suffered bite wounds and 1 had close contact with the sick macaque but was not injured or exposed to other bodily fluids and did not develop symptoms). The fourth patient was the wife of 1 of the animal handlers. She used an ointment to treat her husband's lesions and subsequently used it on herself to treat contact dermatitis. She seroconverted to B virus but never developed symptoms. The study found no evidence of B virus infection among 130 close contacts of the 4 patients, healthcare workers, or primate workers. Moreover, even though B virus seroprevalence among adult macaques is >70%, only a few people in the study developed laboratory evidence of B virus exposure. Thus, transmission of this virus, both human-to-human and primate-to-human, is quite rare.
First Aid and Treatment
On this Page
Although B virus infection in humans is extremely rare, when it does occur, it is often fatal unless treated right away—about 70% of untreated patients die of complications associated with the infection.
Diligence in the recognition of possible exposures, followed by recommended first aid and rapid diagnosis of B virus infection, are the keys to controlling human B virus infection.
First Aid
First aid should begin immediately:
- Cleanse the exposed area by thoroughly washing and scrubbing the area or wound with soap, concentrated solution of detergent, povidone-iodine, or chlorhexidine and water, and then
- Irrigate the washed area with running water for 15-20 minutes.
WARNING: a specimen for PCR testing should not be obtained from the wound area prior to washing the site because it could force virus more deeply into the wound, reducing the effectiveness of the cleansing protocol.
After the site is cleansed, a serum specimen should be obtained from the patient to provide a baseline antibody level.
Treatment Criteria
- Type and physical condition of the implicated animal. Only monkeys of the macaque family serve as the natural reservoir for B virus infection. No other primates carry any risk of B virus transmission unless they have had the opportunity to become infected by a macaque. Infected macaques will not ordinarily be shedding B virus. Animals with lesions consistent with B virus infection (fluid-filled blisters on the skin) and animals that are immunocompromised or stressed are far likelier to be excreting virus.
- Thoroughness and timeliness of wound cleansing procedure. Wounds that have been cleansed within 5 minutes of exposure and that have been cleansed for at least 15 full minutes are less likely to lead to B virus infection. Delay in cleansing or inadequate cleansing of the wound increases the risk of infection.
- Nature of the wound. Bites or scratches that penetrate the skin, and particularly deep puncture wounds, are considered higher risk than wounds that are superficial and thus more easily cleansed. Wounds to the head, neck, or torso provide potentially rapid access to the CNS and thus should be considered higher risk. Prophylaxis is recommended for this type of wound regardless of its severity. Superficial wounds to the extremities are less likely to lead to fatal disease, and antiviral treatment is considered less urgent in such exposures.
- Exposure to materials that have come into contact with macaques. Accidental needlesticks with syringes that have come into contact with the CNS, eyelids, or mucosa of macaques are considered to carry a high risk of infection. Punctures from needles exposed to the peripheral blood of macaques are considered relatively low risk. Scratches resulting from contact with possibly contaminated objects, such as animal cages, are considered to carry a lower risk for infection.
It should be stressed, however, that in none of these potential exposures, can the risk of infection be considered zero. As such, the decision to treat with antivirals should be made at the physician’s discretion, with liberal consideration of the patient’s wishes and concerns.
People with a known risk of exposure should be monitored for symptoms regardless of whether a treatment regimen has or has not been implemented. The animal responsible for the putative exposure should be examined for evidence of disease, and serologic and PCR testing should be done to look for evidence of B virus infection and shedding.
Exposure Scenarios and Treatment Options
Treatment is recommended
- Skin exposure (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, known to be shedding virus, or has lesions compatible with B virus infection).
- Inadequately cleansed skin exposure (with loss of skin integrity) or mucosal exposure with or without injury
- Laceration of the head, neck, or torso.
- Deep puncture bite.
- Needlestick associated with tissue or fluid from the nervous system, lesions suspicious for B virus, eyelids, or mucosa.
- 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 contain B virus.
- Post-cleansing culture is positive for B virus.
Treatment should be considered
- Mucosal splash that has been inadequately cleaned.
- Laceration (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) a possibly infected cell culture.
Treatment is not recommended
- Skin exposure in which the skin remains intact.
- Exposure associated with non-macaque species of non-human primates, unless they were in a situation where they could have been infected by a macaque.
Antiviral Therapy
Recommended dosages for specific antivirals are as follows.
Prophylaxis for exposure to B virus
- Valacylovir—1g by mouth every 8 hours for 14 days, or
- Acyclovir—800 mg by mouth 5 times daily for 14 days
Treatment of B virus infection
- With no CNS symptoms
- Acyclovir—12.5–15 mg/kg intravenously every 8 hours, or
- Ganciclovir—5 mg/kg intravenously every 12 hours
- With CNS symptoms
- Ganciclovir—5 mg/kg intravenously every 12 hours
It should be noted that while herpesvirus antivirals have been shown to effectively protect rabbits from lethal infectious doses of B virus, no comparable studies of efficacy in humans have been possible.
On external surfaces, B virus is susceptible to 1% sodium hypochlorite, 70% ethanol, 2% glutaraldehyde, and formaldehyde. The virus can also be inactivated by heat treatment at 50°–60°C for at least 30 minutes, by lipid solvents, by exposure to acidic pH, and by detergents.
B virus can remain viable in monkey CNS tissue and saliva and in monkey kidney cell cultures. The virus can also survive up to 7 days at 37°C or for weeks at 4°C, and it is stable at −70°C. Although survival studies under conditions of virus desiccation (i.e., dry surfaces) have not been performed, it is presumed that survival times will be comparable to those of other mammalian herpesviruses (with typical survival times of 3–6 hours).
There are no vaccines available for B virus. Experimental vaccines have been evaluated in animal models, but none are being considered for human trial.
Prevention
There are no vaccines available for B virus. Experimental vaccines have been evaluated in animal models, but none are being considered for human trial.
With the substantial increase in the use of macaque models for research (e.g., HIV), the number of potential human exposures to B virus has increased concomitantly. This has led to the publication of guidelines, which have been updated several times, by expert panels of virologists, veterinarians, and physicians.
Principal Recommendations for Prevention
While exposures that involve unpredictable, potentially aggressive animals are not completely preventable, adherence to appropriate laboratory and animal facility protocols will greatly reduce the risk of B virus transmission.
- Work with B virus–susceptible monkeys should be done using humane restraint methods that reduce the potential for bites and scratches.
- Proper personal protective equipment, including a lab coat, gloves, and a face shield, must be used when working with macaque monkeys.
- Any bites, scratches, or exposure to the tissues or secretions of macaques must be cleansed immediately, as detailed in the Recommendations mentioned above.
- Following B virus exposure, samples from both the exposed human and the implicated macaque should be sent for B virus diagnostic testing
