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 (see Epidemiologic Notes and Reports B-virus Infection in Humans -- Pensacola, Florida. Morbidity and Mortality Weekly Report 1987). 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.

Treatment Criteria

The decision about whether to implement antiviral therapy or not should take into account the following criteria [adapted from the Recommendations for Prevention of and Therapy for Exposure to B virus (Cercopithecine Herpesvirus 1) , published in Clinical Infectious Diseases in 2002]:

 1.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.

2.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.

3.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.

4.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

Specific exposure scenarios and the corresponding urgency for post-exposure antiviral treatment, as proposed in the Recommendations for Prevention of and Therapy for Exposure to B virus (Cercopithecine Herpesvirus 1), are as follows:

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

Administration of B virus–specific immunoglobulin, if available, may be effective, and ganciclovir or acyclovir may be effective. The proposed use of specific immunoglobulin is based solely on the effectiveness of i.v. immunoglobulin as a safe prophylactic against other alphaherpesvirus infections, notably varicella-zoster virus. 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.

 

Specimen Collection and B virus Detection

Specimen Collection

In cases of B virus exposure and infection, specimens for virus culture and serologic testing should be obtained from the exposed person and, when feasible, from the source animal. Recommendations for sample collection, storage, and shipment are available from the National B virus Resource Center at Georgia State University’s Viral Immunology Center.

This Center provides diagnostic testing, educational resources, and emergency information 24 hours a day, year round. Its diagnostic laboratories are adjacent to the research laboratories, a proximity that facilitates exchange of the most up-to-date strategies for identification of B virus infections in the natural host and in zoonotically infected humans. Antiviral research provides current drug sensitivities and treatment monitoring for zoonotic infections.

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.

Virus Detection

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.

Diagnosis of B virus infections has been hampered by the fact that herpes simplex virus (HSV) and B virus are closely related (both members of the Alphaherpesviridae) and, as such, antibodies produced in response to either virus have substantial levels of cross-reactivity. The development of diagnostic methods that can reliably differentiate between HSV and B virus infection was an essential first step in advancing B virus detection for the National B virus Resource Center. Direct culture of B virus has been the standard for diagnosis of infection, although this testing requires a biosafety level 4 (BSL-4) containment facility to reduce the risk of exposure for laboratory workers. The specificity of B virus serologic methods has improved substantially; however, the assays rely on specimens obtained weeks after the possible exposure event and, thus, cannot be of help in making therapy decisions, which must be made soon after exposure.

The availability of PCR protocols that reliably discriminate B virus from HSV should permit the direct detection of B virus infection without needing to resort to the more hazardous procedure of culturing virus. PCR has the additional advantage of being more rapid, potentially providing results in a matter of hours rather than days. A quantitative real-time PCR method has been developed by the National B virus Resource Center and is being evaluated for use as a clinical diagnostic. While a PCR diagnostic would substantially reduce the risk to laboratory workers, the samples tested could contain viable B virus and need to be handled with appropriate caution.