B virus infection

INTRODUCTION — B virus (Macacine [formerly Cercopithecine] herpesvirus 1) causes a herpes simplex virus (HSV)-like infection in macaque monkeys but can also cause a fatal encephalomyelitis in humans. Fatal cases of B virus infection have been reported after exposures to monkey bites, monkey scratches, cage scratches, a mucosal splash from monkey material, and from infected cell cultures. Postexposure prophylaxis has been demonstrated to be effective in an animal model and is likely effective in humans exposed to the virus. Prompt therapy for B virus infection of humans is critical to prevent severe morbidity and mortality.

The pathogenesis, epidemiology, clinical manifestations, prognosis, prevention, postexposure prophylaxis, and treatment of B virus infection will be reviewed here. Infections caused by other zoonoses are discussed separately. (See "Zoonoses: Animals other than dogs and cats" and "Zoonoses: Cats" and "Zoonoses: Dogs".)

PATHOGENESIS AND EPIDEMIOLOGY

Natural infection in macaques — B virus is a herpesvirus in the same subfamily as herpes simplex virus (HSV) that naturally infects macaque monkeys (eg, rhesus macaques, cynomolgus monkeys, pig-tailed macaques, bonnet macaques, Japanese macaques, and stump-tail macaques) and usually results in either no symptoms in these animals or oral or genital lesions similar to HSV in humans [1-3]. B virus has not been detected in other Old World monkeys or in New World monkeys.

Macaques become latently infected, and virus is shed lifelong in oral and genital secretions and from the conjunctivae, including when animals are asymptomatic [4].

The complete sequence of the virus has been determined [5].

Infection of humans — The majority of B virus infections in humans has occurred in individuals who work with nonhuman primates. Humans become infected after exposure to oral, genital, or ocular secretions or central nervous system tissue from macaque monkeys. Of 26 well-documented cases of B virus infection in humans, 10 cases were due to monkey bites [6,7] and two each were due to monkey scratches, monkey cage scratches, needlestick injuries, or possible aerosols [8]. One of the needlestick injuries was from a needle used to inject tissues around the eye of an animal and may have been contaminated with infected ocular secretions. Exposure to monkey blood has not been reported to cause B virus disease in humans. One of the possible aerosol exposures was thought to occur during autopsy of a monkey.

Case reports include a mucosal splash in which a woman died after material from a monkey splashed into her eye [9], person-to-person transmission in which a woman became infected after applying glucocorticoid cream to her husband's vesicular B virus lesion and then to her contact dermatitis lesion [10], a laceration from a tissue culture bottle used to grow monkey cells [11], contamination of a wound with monkey saliva [12], and cleaning a monkey skull [13]. One case was thought to be due to reactivation of B virus; however, it is uncertain if this really was due to reactivation or an unappreciated recent exposure to the virus [14]. Another case report describes reactivation of the virus in the eye of a person previously exposed to B virus [15].

Travelers have the potential to be exposed to free-ranging monkeys that are seropositive for B virus, which are native in India, Indonesia, and Nepal [16-19]. In Malaysia, about 39 percent of free-ranging long-tailed macaques were reported to shed B virus [20]. In addition, monkeys that are seropositive for B virus have escaped from research institutes and are now free-ranging in certain locations such as Puerto Rico and other sites in the Caribbean [21]. About 25 percent of free-ranging rhesus macaques at a public state park in central Florida were found to be seropositive for B virus and 4 to 14 percent of animals shed the virus from their oral mucosa [22]. Macaques, including cynomolgus monkeys, have been kept as pets, some of which are seropositive for B virus, and this has the potential to be a source of transmission of virus [23].

Risk factors — Both the age and the health status of macaques contribute to the risk of transmitting B virus. Most animals more than 2.5 years old have been infected with B virus [24]. Animals that are immunocompromised, ill, stressed, or have visible genital or oral lesions are more likely to shed B virus [4,6,25-28]. Virus is shed from oral and genital secretions as well as from the conjunctivae [4,25,27,28].

Since 20 to 100 percent of captive macaques are seropositive for B virus [4] and approximately 2 percent of seropositive macaques shed B virus on a given day [25], it is estimated that 0.4 to 2 percent of contacts with macaques have the potential to transmit B virus to humans [8]. With the large number of exposures to macaques that occur each year, the observation that only about 50 cases of B virus have been reported in the literature indicates that the vast majority of B virus exposures in humans do not result in disease [8].

Certain types of exposures to macaques carry a higher risk of transmitting virus than others. Wounds involving the head or neck (in which the virus can be transmitted more rapidly to the central nervous system before the development of local symptoms), deep puncture wounds, and wounds that are not adequately cleaned are thought to pose the highest risk of infection [29]. In contrast, exposures that involve intact skin are not thought to pose a risk of infection.

CLINICAL MANIFESTATIONS — Approximately five days to three weeks after an exposure (range two days to five weeks), patients present with one of three patterns of disease [8]:

●Vesicular or ulcerative lesions, tingling, pain, or itching at the site of exposure, and local lymphadenopathy [29].

●Influenza-like illness with fever and myalgias. Later symptoms may include numbness or paresthesias near the site of exposure, fever, conjunctivitis, abdominal pain, hepatitis, or pneumonitis followed by central nervous system (CNS) symptoms.

●Nausea and vomiting and CNS symptoms including headache that may progress to meningismus, cranial nerve deficits, dysarthria, dysphagia, seizures, paralysis, respiratory failure, and coma.

Whether asymptomatic infection of humans with B virus occurs is uncertain; if it occurs, it is likely very rare. In a study of 321 primate workers, none of 166 persons with documented exposures to primates and none of the other 155 individuals were seropositive for B virus [30]. In a second study, none of 116 asymptomatic primate workers tested during a cluster of B virus cases were seropositive for B virus [7]. A third study found that none of 130 persons who either had contact with B virus-infected individuals or who were primate workers were seropositive for B virus [10]. However, a personal communication within a United States Centers for Disease Control and Prevention report states that seroconversion has occurred in some persons suggesting that asymptomatic infection is possible [31].

PROGNOSIS — Prior to the availability of antiviral therapy, the mortality rate of B virus infection in humans was 80 percent [1]. It is estimated that 80 percent of individuals infected with B virus since the early 1980s have survived due to the availability of antiviral therapy [1]. To date, no cases have occurred in individuals who have received postexposure prophylaxis with antiviral medication within three days of B virus exposure.

PREVENTION — Primate workers need to be appropriately educated about the risk of exposure to B virus, be knowledgeable about the importance of wound cleansing and first aid, have access to an eyewash, and have access to an occupational health care system that is knowledgeable about the virus [8]. Persons working with macaques should protect their eyes from mucosal splashes with either goggles or glasses that have side shields and either a chin-length face shield or mask to protect their mouths from splashes. Body fluids from patients suspected of having B virus infection should be considered potentially infectious.

Family members and health care workers should use blood and body fluid precautions to avoid exposure to B virus from infected individuals. B virus has been cultured from the oral mucosa and from skin lesions in a patient during intravenous acyclovir therapy [8,10].

POSTEXPOSURE EVALUATION — After injury to the skin and exposure to macaque fluids or tissues, the skin should be thoroughly washed as soon as possible with soap containing detergent such as chlorhexidine or briefly with a fresh 1:20 dilution of bleach (0.25% hypochlorite) followed by detergent [8]. Exposed mucous membranes or eyes should be flushed with water or sterile saline. Washing of skin or mucous membranes should continue for 15 minutes.

Evaluation by health care providers should include the following [8]:

●Whether the individual was exposed to macaques or macaque body fluids or tissues

●Determining the extent of the risk – Health of the primate, infection history of the primate (including retroviruses), type of exposure, site of exposure, time since exposure occurred

●Assessment of the adequacy of cleansing and, if inadequate, initiate cleansing of the site of exposure

●Assessment of the need for postexposure prophylaxis for B virus, rabies vaccination and immunoglobulin, tetanus vaccination, or antibiotic prophylaxis [32]

●Examination of the exposure site

●Consideration of diagnostic testing – Baseline serum from the exposed individual, viral culture at site of exposure after cleansing (see 'Postexposure cultures and serology' below)

●Education of the exposed individual regarding B virus and symptoms to watch for (eg, fever, myalgia, peripheral and central nervous system signs or symptoms)

●Ensure that the individual's supervisor and occupational health care provider are aware of the exposure

●Ensure that the individual has a health care provider who can be seen for follow-up

Postexposure cultures and serology — While some authorities believe that postcleansing cultures and serologies for B virus should be performed, others do not feel that these are necessary [8]. Although positive cultures at the site of the exposure indicate that a true exposure to B virus occurred, cultures may be negative due to sampling error or removal of virus during cleansing. Obtaining cultures prior to cleansing is not recommended due to the risk of infection from delay of cleansing or from inoculation of virus deeper into the wound.

There is even more uncertainty regarding the value of polymerase chain reaction (PCR) for B virus, since a positive result does not necessarily indicate infectious virus.

Serology for B virus can be helpful in persons who have symptoms that are suggestive of B virus. Comparison of B virus serology three to six weeks after the exposure (or at the time of symptoms) with serology before or at the time of the exposure is especially helpful. For this reason, some occupational health centers obtain serologies on nonhuman primate workers before employment. A rise of ≥4-fold in titer of paired sera tested concurrently is considered diagnostic of infection.

For individuals who receive postexposure prophylaxis, seroconversion might be delayed and repeat testing should be considered approximately three months after exposure. (See 'Postexposure prophylaxis' below.)

Cultures and serology in nonhuman primates — The usefulness of B virus culture or serology in primates is even more uncertain than for exposed humans. A negative serology for B virus might occur in an animal early after primary infection, and a positive serology does not prove that the animal is shedding virus [8]. A negative culture may occur due to sampling error, and a positive culture from the animal does not prove that an exposed human was infected. Given the risk to primate workers of obtaining these samples and their limited usefulness, many authorities do not recommend obtaining these samples except in special circumstances.

Diagnostic laboratories — Culture, PCR, and serology for B virus in humans and nonhuman primates are performed in the United States by the National B Virus Resource Center at Georgia State University in Atlanta, Georgia (phone 404-413-6550). Culture, PCR, and serology of nonhuman primates can also be performed in the United States by VRL Laboratories in San Antonio, Texas (phone 877-615-7275).

Culture, PCR, and serology for B virus in humans and nonhuman primates are performed in the United Kingdom by the Virus Reference Department in London, United Kingdom (phone 020-8327-6017).

POSTEXPOSURE PROPHYLAXIS — A B Virus Working Group convened by the United States Centers for Disease Control and Prevention has published guidelines for the prevention and therapy of B virus infection for individuals who have had potential exposures to B virus [8]. Our recommendations for postexposure prophylaxis are consistent with these guidelines.

Animal studies — No studies of postexposure prophylaxis have been performed in humans; however, studies have been done using experimentally infected rabbits. Postexposure prophylaxis of rabbits using intravenous acyclovir three times daily for two weeks beginning one day after exposure was 100 percent effective in preventing B virus disease [33]. Postexposure prophylaxis of rabbits with intravenous acyclovir for two weeks beginning five days after exposure was partially effective for preventing disease.

In another study in rabbits, postexposure prophylaxis with oral ganciclovir was more effective than oral acyclovir at preventing development of B virus disease [34]. In a dose-escalation experiment, prophylaxis with oral ganciclovir dosed at 86 to 175 mg/kg per day for two weeks beginning one day after exposure was effective in preventing disease. In addition, prophylaxis with 170 mg/kg per day of oral ganciclovir for two weeks beginning five days after exposure resulted in survival of all animals. Postexposure prophylaxis with oral acyclovir given at 700 mg/kg per day for three weeks beginning one day after exposure was 100 percent effective in preventing disease. However, disease developed when given at 500 mg/kg per day, although all the rabbits survived. The concentration of drug needed to inhibit B virus replication in vitro is lower for ganciclovir than for acyclovir [35].

Postexposure prophylaxis is recommended for high-risk exposures to macaques if the exposure occurred within the prior five days (table 1). These recommendations are based on the types of exposures that resulted in B virus disease in humans and the timing of postexposure prophylaxis found to be effective in the animal studies discussed above. Antiviral medication should be started as soon as possible after exposure.

Indications for prophylaxis — Postexposure prophylaxis is recommended for individuals with the following types of exposures to macaque monkeys [8]:

●Skin or mucosal exposures to animals that are at high risk of shedding B virus (ill or immunocompromised macaques, animals with oral or genital lesions, or animals known to be shedding virus)

●Inadequately cleaned skin or mucosal exposures

●Lacerations of the head, neck, or torso

●Deep puncture bites

●Needlestick injuries in which the needle was exposed to macaque tissue or fluid from the central nervous system (CNS), mucosa, or eyes

●Lacerations or puncture wounds with objects contaminated with macaque fluid from oral or genital lesions, CNS tissues, or known to contain B virus

●Exposures in which postcleansing cultures are positive for B virus

Prophylaxis should be considered for some types of lower-risk exposures (table 1). Prophylaxis is not necessary for exposures of intact skin or exposures associated with non-macaque species of nonhuman primates.

With regard to needlestick injuries involving blood from macaques, blood from healthy animals is extremely unlikely to contain B virus [26], whereas blood from ill animals has been found on some occasions to contain the virus [36].

A decision tool with a point-scoring system has been developed to use for deciding whether to give antiviral prophylaxis for researchers after macaque-related injuries [37].

Antiviral medications — Valacyclovir, which is converted to acyclovir in the gastrointestinal tract, is considered the drug of choice for postexposure prophylaxis of B virus since it results in higher acyclovir levels than oral acyclovir, and B virus has about a 10-fold higher half maximal inhibitory concentration (IC₅₀) for acyclovir than herpes simplex virus [8,33,38]. Acyclovir is considered the drug of choice for pregnant women due to its experience during pregnancy and is also considered an alternative to valacyclovir for nonpregnant individuals.

The dosing of valacyclovir is 1 g orally every eight hours. The dosing of acyclovir is 800 mg orally five times per day. Based on the animal data discussed above, postexposure prophylaxis is given for 14 days. Neither acyclovir nor valacyclovir has been approved by the US Food and Drug Administration for prophylaxis of B virus infection.

We do not recommend famciclovir for postexposure prophylaxis of B virus infection given the lack of animal data on its use for this indication.

B VIRUS DISEASE — Our recommendations for treatment of B virus disease are consistent with the B Virus Working Group guidelines [8]. None of the antiviral agents recommended in the following section has been approved by the US Food and Drug Administration (FDA) for the treatment of B virus infection.

Evaluation — Individuals with symptoms of B virus disease or with a positive culture for B virus other than a postcleansing culture should be thoroughly evaluated, and treatment should be initiated promptly. In addition to a thorough physical examination including a full neurologic examination, laboratory testing should include the following [8]:

●B virus serology (which should be tested concurrently with serum obtained before or at the time of the exposure if possible)

●B virus cultures of lesions, conjunctivae, and the oropharynx

●Pregnancy testing if a woman is of childbearing age

●Brain magnetic resonance imaging (MRI; or computed tomography [CT] if MRI is not available) to assess for brain stem encephalomyelitis [7,13,39]

●Lumbar puncture with cerebrospinal fluid (CSF) sent for routine chemistry and cell counts, B virus culture, polymerase chain reaction (PCR) [40,41], and serology

●Electroencephalogram should be considered if needed to help to differentiate B virus encephalitis (a brainstem encephalitis that becomes diffuse over time) from herpes simplex encephalitis (usually a unilateral temporal lobe encephalitis)

Treatment — Intravenous (IV) acyclovir (12.5 to 15 mg/kg every eight hours) is the drug of choice for treatment of B virus disease in patients without peripheral or central nervous system findings [8]. This high dose of acyclovir is recommended because of the higher half maximal inhibitory concentration (IC₅₀) for B virus than for herpes simplex virus. IV ganciclovir (5 mg/kg every 12 hours) is the alternative medication. In addition, patients should be switched from acyclovir to ganciclovir if symptoms progress during therapy with acyclovir.

IV ganciclovir is considered the drug of choice for treatment of B virus disease in persons with peripheral or central nervous system symptoms or signs [8]. The rationale for using IV ganciclovir in patients with nervous system disease is based on its superior efficacy compared with acyclovir in the rabbit model, its lower IC₅₀ for B virus, and the successful outcome in a patient with B virus encephalitis treated with ganciclovir [7,35]. (See 'Animal studies' above.)

High-dose IV antiviral therapy for B virus disease is given for at least two to three weeks and until symptoms resolve, whichever is longer. We recommend that two consecutive oropharyngeal and conjunctival cultures for B virus be obtained after symptoms have resolved and IV therapy is about to be changed to oral therapy as discussed below. In general, cultures for B virus should be obtained and remain negative for 10 to 14 days each time there is a change in therapy or if therapy is discontinued [8].

Most experts recommend that oral antiviral therapy at postexposure prophylaxis doses be given for up to one year after high-dose IV treatment is discontinued, since B virus might establish latency in humans and intermittent shedding could occur, although this has not been proven. (See 'Antiviral medications' above.)

Following the completion of antiviral therapy at postexposure prophylaxis doses, many experts suggest lifelong suppression with one of the following regimens, which are based on the regimens for suppression of genital herpes (see "Treatment of genital herpes simplex virus infection", section on 'Suppressive therapy'):

●Valacyclovir 500 mg orally once or twice daily or

●Acyclovir 400 mg orally twice daily

Some experts feel that antiviral therapy can eventually be discontinued since recurrences of genital herpes simplex virus (a human counterpart to B virus) tend to diminish over time; however, many others feel that antiviral prophylaxis should continue for life [8,29], since there are two reports that B virus may reactivate months or years after primary infection [14,15]. Long-term suppressive therapy with acyclovir for up to 10 years or with valacyclovir for up to 1 year has been well tolerated [42]. In view of the potential for reactivation of B virus, any decision to stop antiviral prophylaxis should be discussed in detail with the patient, and it is essential to educate the patient regarding signs and symptoms of B virus disease.

If antiviral therapy is stopped, sequential oropharyngeal and conjunctival cultures should be performed at least weekly for several weeks to ensure that patients are not shedding virus [8]. If cultures are negative for at least two weeks after treatment has been discontinued, the frequency of cultures can be reduced and eventually performed once or twice a year.

SUMMARY AND RECOMMENDATIONS

●Life-threatening infection in humans − B virus (Macacine [formerly Cercopithecine] herpesvirus 1) causes a herpes simplex virus (HSV)-like infection in macaque monkeys but can also cause a fatal encephalomyelitis in humans. Fatal cases of B virus infection have been reported after exposures to monkey bites, monkey scratches, cage scratches, a mucosal splash from monkey material, and from infected cell cultures. (See 'Introduction' above and 'Infection of humans' above.)

●Natural infection in macaques − Macaques become latently infected, and virus is shed lifelong in oral and genital secretions and from the conjunctivae, including when animals are asymptomatic. (See 'Natural infection in macaques' above.)

●Clinical course − Approximately five days to three weeks after an exposure (range two days to five weeks), patients present with one of three patterns of disease (see 'Clinical manifestations' above):

•Vesicular or ulcerative lesions, tingling, pain, or itching at the site of exposure, and local lymphadenopathy.

•Influenza-like illness with fever and myalgias. Later symptoms may include numbness or paresthesias near the site of exposure, fever, conjunctivitis, abdominal pain, hepatitis, or pneumonitis followed by central nervous system (CNS) symptoms.

•Nausea and vomiting and CNS symptoms including headache that may progress to meningismus, cranial nerve deficits, dysarthria, dysphagia, seizures, paralysis, respiratory failure, and coma.

●Postexposure management − Following a potential exposure to B virus, thorough and prompt cleaning of exposed areas should occur, followed by evaluation for the need for postexposure prophylaxis. Cultures and serologies of the exposed individual are often recommended but remain controversial. (See 'Postexposure evaluation' above.)

●Postexposure antiviral prophylaxis − For individuals who are seen within five days of a high-risk macaque exposure, we recommend postexposure antiviral prophylaxis (Grade 1C). We suggest prophylaxis with oral valacyclovir (1 g orally every eight hours) (table 1) (Grade 2C). Oral acyclovir (800 mg five times daily) is an alternative, and we suggest this antiviral agent in pregnant women (Grade 2C). Prophylaxis should be continued for 14 days. (See 'Indications for prophylaxis' above and 'Antiviral medications' above.)

●Treatment for patients without nervous system involvement − For treatment of B virus disease without peripheral or central nervous system signs or symptoms, we suggest intravenous acyclovir (12.5 to 15 mg/kg every eight hours) rather than ganciclovir (Grade 2C). (See 'Treatment' above.)

●Treatment for patients with nervous system involvement − For treatment of B virus disease with peripheral or central nervous system signs or symptoms, we suggest intravenous ganciclovir (5 mg/kg every 12 hours) rather than acyclovir (Grade 2C). (See 'Treatment' above.)

•Most clinicians give oral antiviral therapy at postexposure prophylaxis doses for up to one year after high-dose intravenous treatment is discontinued. (See 'Treatment' above.)

•Following sequential high-dose intravenous treatment and oral antiviral therapy at postexposure prophylaxis dosing, many experts use chronic suppression with valacyclovir 500 mg orally once or twice daily or acyclovir 400 mg orally twice daily. This regimen should be continued indefinitely. (See 'Treatment' above.)