OVERVIEW: What every practitioner needs to know

Are you sure your patient herpes B virus infection? What should you expect to find?

  • Incubation period is usually 1-3 weeks, although a case occurred more than 10 years after macaque exposure.

  • Early Manifestations (may or may not be seen):

    vesicular rash or ulcers at or near the site of the exposure

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    pain or pruritis at the site of the exposure

    influenza-like illness

    regional lymph node enlargement

  • Intermediate Manifestations (may or may not be seen):

    fever

    numbness or other dysesthesias at or near the exposure site, which may spread proximally

    conjunctivitis

  • Late Manifestations (which might be avoided with early intervention):

    meningismus manifested by nausea and vomiting

    persistent headache or stiff neck

    headache for more than 1 day

    altered mental state or coma

    evidence of brain stem involvement, including diplopia, dysphagia, cerebellar signs with ataxia, and cranial nerve palsies

    retinitis

    signs of encephalitis, including progressive ascending paralysis, hemiplegia, seizures, urinary retention, respiratory failure, or other focal neurological signs

How did the patient herpes B virus infection? What was the primary source from which the infection spread?

  • Contact with the primate reservoir of herpes B virus, also referred to as B virus, or their products, including monkey kidney cells, through bite, scratch, exposure of primate saliva on mucosal surfacesparticularly the conjunctiva, or contaminated needlestick can transmit the virus.

  • B virus, Herpesvirus simiae, Cercopithecine herpesvirus and McHV1, is enzootic in Old World macaques, especially rhesus (Macaca mulatta) and cynomolgus (M. fascicularis) monkeys but also bonnet macques (M. radiata), Japanese macaques (M. fuscata), Taiwan macaques (M. cyclopis), stump-tail macaques (M. artoides) and Southern pig-tailed macaques (M. nemestrina).

  • No other Old World monkey and no New World monkey naturally harbors the virus.

  • The prevalence of seropositivity to the virus is reported to be low in immature animals and increases quickly as they reach sexual maturity, reaching close to 100% among adults. This prevalence is similar in free-living and captive animals including pets.

  • At any given time in a high seroprevalent groups of macaques, only 2-4% may shed the virus from tears, salvia, or genital fluids.

  • The frequency if active shedding is increased during breeding season, times of stress, and with immunosuppression.

Which individuals are of greater risk of developing herpes B virus infection?

  • Those exposed to potentially infected macaques or monkey fluids or tissue culture are at greater risk of infection. Individuals at risk are those physicians, veterinarians, or medical or veterinary technicians who are potentially exposed.

  • Several cases have been reported in which no monkey exposure had occurred in a number of years, which brings up the possibility of latency and reactivation.

  • Postmortem examination of fatal human cases of infection also poses a risk.

  • Individuals with pet macaques or people bitten or otherwise exposed to wild macaques can also be considered at risk.

  • The disease, however, must be considered an uncommon result of human-macaque interactions even in the era without post-exposure treatments.

  • Non-adherence with standard procedures in dealing with macaques, including appropriate mechanical restraints, heavy protective gloves and clothing, and lack of preventative measures if a relevant exposure, including ones with a non-decontaminated cage, has occurred.

Beware: there are other diseases that can mimic herpes B virus infection:

  • Herpes simplex encephalitis

  • Herpes zoster encephalitis

  • Arbovirus encephalitis, such as St. Louis, West Nile, and Easten or Western Equine diseases

  • Rabies

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Active shedding in the index macaque strongly suspected by herpes-like lesions in the animal or one that is ill or immunocompromised but totally asymptomatic shedding clearly occurs. These exposures represent those of highest risk. Exposure-directed specimens should be obtained from the involved macaque’s buccal mucosa (for saliva exposure), conjunctivae, or urogenital area (for urine exposure) and will be reflective of the risk of human wound contamination without having to delay local wound cleansing.

  • If the direct exposure is to a non-decontaminated cage, specimens from the macaque most recently housed in that cage should be likewise obtained. These specimens can be cultured for the B virus and examined by polymerase chain reaction (PCR) for presence of specific viral DNA. Additionally, seroconversion or a rise in specific antibody titer between initial and delayed sera from the macaque suggests primary infection and probable shedding at the time of exposure, so an initial negative antibody test should not be interpreted as this animal being non-infected.

  • Diagnosis of infection in the human is generally made empirically in an individual with an appropriate history of exposure and clinical findings. Routine chemical and hematologic tests should be done. Neurologic testing should include lumbar puncture to obtain cerebrospinal fluid, brain imaging with MRI technology and, if not available, CT scanning, and an EEG.

Results that confirm the diagnosis

  • Cerebrospinal fluid (CSF) culture positive for herpes B virus or PCR positive for viral DNA

  • CSF positive for B virus antibody using a specific test

  • EEG showing brain stem disease

  • Brain stem auditory evoked potentials in an unconscious patient to help show brain stem or upper spinal cord involvement

  • Seroconversion using a specific B virus antibody able to differentiate B virus from Herpes simplex 1 and 2; these tests are performed through a State Health Department, the US Centers for Disease Control and Prevention (CDC) or specific herpes B reference laboratory; discriminatory assays include Western blot and radio-immunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA).

What imaging studies will be helpful in making or excluding the diagnosis of herpes B virus infection?

  • MRI or CT showing brainstem involvement in the appropriate epidemiologic setting, as opposed to the temporal lobe involvement in herpes simplex virus encephalitis, is helpful. CT is more likely to be negative.

  • Head CT scan ($$$) – Range: $750-2000, average $1150

  • Head MRI scan ($$$$) – Range: $1000-$3500, average $2000

What consult service or services would be helpful for making the diagnosis and assisting with treatment? Infectious Diseases consultant

Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Treatment of active herpes B infection should begin with the clinical suspicion of active herpes B viral infection and should be given until symptoms resolve and the results of two cultures for the virus are negative. After intravenous therapy, most experts suggest implementing oral therapy at postexposure prophylaxis (PEP) dosing for 6-12 months, and some suggest lifetime therapy (Table I).

Table I.
Organism Antibiotic Dose Alternative
Herpes B virus Ganciclovir (IC50 = 9 microg/mL) 5 mg/kg iv every 12 hours Acyclovir
Herpes B virus Acyclovir (IC50 = 18 microg/mL) 12.5-15 mg/kg iv every 8 hours Ganciclovir

Ganciclovir is generally recommended, especially if definitive signs of symptoms of nervous system infection due to this virus are manifested, and is recommended by some even if no central nervous system (CNS) disease is manifested.

Human Herpes B Virus Infection (IC50 = 50% of the maximal inhibitory level of the drug)

2. Next list other key therapeutic modalities.

Despite cross-neutralizing antibodies between herpes B and herpes simplex virus (HSV) 1/2, there is neither evidence to support that individuals with substantial titers of antibodies against H. simplex prior to exposure to herpes B are less susceptible to infection nor data supporting the post-exposure or therapeutic use of high-titer HSV plasma. In a rabbit model, however, the concurrent administration of B virus and antiserum to the virus protected against overt infection.

What complications could arise as a consequence of herpes B virus infection?

What should you tell the family about the patient's prognosis?

Human herpes B virus encephalitis is a severe CNS infection that, even with rapid and appropriate anti-viral therapy, carries a case fatality rate of about 70-80%, and many, but not all, survivors have residual neurologic defects.

Family members should be counseled quickly about the dire nature of this disease.

The clinical infection is primarily manifested with neurologic symptoms, including:

  • diminution in mental status progressing to stupor and coma

  • hemiparesis

  • myelitis

  • cranial nerve paresis

  • retinitis

  • neurogenic urinary bladder with urine retention

  • neurogenic respiratory failure

The latter two complications requiring cauterization of the urinary bladder and tracheal intubation with ventilatory support puts these already debilitated individuals at risk for nosocomial infections.

Add what-if scenarios here:

  • What if a traveler walking on a deserted Indonesian beach is bitten on the neck by a wild cynomolgus monkey foraging for crabs on the beach?

  • What if a hiker on Florida’s Key Lois sustains a deep scratch while trying to keep a feral rhesus monkey away from his campsite?

  • What if a 5-year-old is bitten on the hand by a schoolmate’s pet stump-tailed macaques?

Feral macaque colonies do exist in Florida and Texas, originating as escapees from either homes or laboratories. Wild macaques all over the Eastern Hemisphere are mostly seropositive for the B virus, as well as are most pet macaques. All three scenarios are probably not uncommon, and there is little, if any, evidence that human infection with the B virus has occurred with these scenarios. Despite this, the recommendations for post-exposure prophylaxis for B virus do not exclude this group. In the third scenario, it is hoped that the brave owner of this primate should have been smart enough to have the animal tested for B virus antibodies prior to any biting incident.

As an example of B virus risk outside the research lab setting, a Balinese Hindu temple that is both a refuge for free-range macaques and a tourist attraction has been reported to have numerous potential human-primate exposures. A serosurvey of the macaques found that more than 80% are seropositive, yet no clear cases of B virus human infection are known to have occurred. Regarding pet macaques, potential exposures included the usual bites and scratches, as well as food sharing, close physical contact, and even sharing chewing gum. Again, no cases of human B virus infection were apparent.

This is a 2008 report from the Democratic Republic of the Congo related to a “suspected clinical case” of herpes B involving a woman sustaining a bite from a vervet monkey in a national park. It is not clear how well documented the diagnosis was.

How do you contract herpes B virus infection and how frequent is this disease?

Essentially, all the cases of human herpes B infection have occurred in the United States and Europe among individuals who work with the natural reservoir or tissues derived from the natural reservoir in a husbandry or research milieu, despite people in Africa and Asia living and working with wild macaques and suffering bites and scratches. The wild monkeys are just as likely to be seropositive. It is possible that the stress of captivity, especially in a research facility, could increase the likelihood of, and raise the amount of virus, herpes B virus excretion in saliva and elsewhere.

Herpes B virus in man was first described in 1933 in a physician dying of encephalomyelitis following a macaque exposure. His last name began with B, hence, the herpes B designation. Since then, the total number of human cases has remained small with no more than 50 cases having been reported.

Two clusters of infection have been described, one reported in 1990 from a military medical research facility in Florida and a second in 1994 from a large animal research facility in Michigan. The first outbreak involved four cases, three involving individuals who worked with macaques and the fourth being a spouse of one of the three who probably acquired a local skin infection from autoinoculation through an over-the-counter skin cream shared with the affected spouse. The Michigan cluster involved three men who had contact with macaques. A noteworthy finding of this cluster was that two of the three individuals were treated quite early and survived without sequelae. This clearly suggests that very early treatment (aseptic meningitis in one, subtle brainstem signs in the other) may be quite useful.

In 26 well-documented cases of human infection with the B virus, the exposure was known in 25 cases (Table II):

Table II.
Exposure Number of Cases
Monkey bite 10
Monkey scratch 2
Monkey saliva wound contamination 1
Tissue culture bottle cuts 1
Needle stick injury 2
Possible aerosol 2
Cleaned monkey skull 1
Needle scratch and monkey bite 1
Cage scratch 2
Possible reactivation 1
Human-to-human contact 1
Mucosal splash (animal feces) 1

Of the nonprimate herpes viruses, only the B virus has been shown to definitively produce human infection. Other simian herpes virus include simian varicella virus, rhesus cytomegalovirus, lymphocryptovirus, Herpes saimiri, and rhesus macaque rhadinovirus, as well as SA-8 (simian agent 8) and herpes virus papio 2 (HVP2). The neuropathogenesis of HVP2 seems to parallel human infection with the B virus.

B virus rarely causes systemic infection in its natural reservoirs, the various species macaque monkey, but in the presence of immunosuppression can cause, as with Herpes simplex, disseminated disease. Like in man, the B virus causes severe, fatal infection in several New World monkeys, including cebus (capuchin) monkeys and common marmosets (Callithrix jacchus).

What pathogen is responsible for this disease?

Genus Simplexvirus, subfamily Alphaherpesvirinae, family Herpesviridiae.

This virus is clearly a simian mimic of the human herpes simplex viruses 1 and 2, including viral morphology, pathogenesis of infection, and genetic and antigenic similarities with overlap of a number of antigenic epitopes.

It is an enveloped virus of 160-180 nm size with a double-stranded, linear DNA genome of about 100-115 million molecular weight corresponding to about 150-170 kilbase pairs.

The surface glycoproteins of the virus cross-react with those of the herpes simplex viruses, especially HSV 2, and can cross-neutralize in vitro, but there is no clear evidence for a protective role of HSV antibodies or for the use of high-titer anti-HSV plasma therapeutically.

Cell-free virus is not likely to persist for any length of time in the environment because of the virus’ sensitivity to heat, ultraviolet light, and lipid solvents.

Unlike HSV 1, the B virus does not have much host restriction for growth in tissue culture.

The virus can clearly contaminate macaque kidney cell lines and did so in the cell lines used for the production of inactivated poliovirus vaccines. Fortunately, the virus was inactivated with the formalin and heat processes used in vaccine production.

Latency in sensory nerve ganglia clearly occurs in macaques and has been shown to occur in rabbits as well. Latency in humans with this virus has been proposed in an individual who presented with trigeminal (opthalmic division) zoster-like disease with no exposure to monkeys for more than 10 years.

How does herpes B virus cause encephalitis?

After inoculation, the virus replicates in the local skin and may cause a local herpes-like vesicular rash from which the virus can be isolated. Isolation of the virus from the epidermis can occur even without overt lesions. Drainage to regional lymph nodes may occur, causing lymph node enlargement. The lymphadeopathy may show hemorrhage and focal necrosis, histopathologically.

After entrance into peripheral sensory and autonomic nerves, the B virus ascends in axons into the CNS. Replication in the nerve cells results in inflammation primarily composed of microglial cells in areas of the cervical spinal cord, brain stem, and cerebrum. The inflammation tends to be most obvious in the brain stem areas of the medulla and pons. Hemorrhagic infarcts can be seen, but, in some cases, histopathologic damage seems to be minimal despite overt neurologic disease.

Unlike HSV 1 encephalitis, the B virus disease does not often cause the typical intranuclear inclusion bodies in the CNS but does when replicating in tissue culture.

Also unlike HSV 1 encephalitis that causes an encephalitis centered in the temporal lobe, the encephalitis is much more generalized.

What other clinical manifestations may help me to diagnose and manage herpes B infection?

Multiorgan involvement in herpes B encephalitis clearly occurs, although may not be clinically overt. This can occur in disseminated HSV 1 infection but not in the HSV 1 encephalitis. Organs possibly involved include liver, spleen, and adrenal gland, and the virus can be cultured from such organs. In the liver, congestion is accompanied by periportal infiltration of neutrophils and mononuclear cells and scattered necrotic foci may be found. Viral inclusion bodies can be seen in the areas of inflammation. Focal necrosis may be seen in other organs as well.

Asymptomaticinfection with herpes B virus probably does not occur at least based ona serosurvey of individuals who have worked directly with macaques.

Oculardisease has been described in herpes B encephalitis. Descriptions ofthe process include multifocal necrotizing retinitis, which can beassociated with vitritis, optic neuritis, and panuveitis. The virus canbe isolated from the retina and vitreous.

How can herpes B virus infection be prevented?

Initial intervention post-exposure:

  • This maneuver is felt to be the most important modality in the prevention of human herpes B infection.

  • Immediate cleansing of the skin or mucosa, depending on the exposure, is essential.

  • Ocular or buccal mucosa needs to be irrigated with a sterile normal saline solution or sterile water for a minimum of 15 minutes.

  • If an eye-washing station is more than a few minutes separated from the individual exposed, an exposure kit containing functional irrigation should be available directly at the work station.

  • Skin that has been potentially exposed requires washing with a liquid, such as chlorhexidine, detergent soap, and povidone-iodine, that can destroy the viral lipid envelope but are overly harsh to use after ocular exposures. Expert committees have also recommended that any wound be gently massaged to be able to facilitate exposure to the cleansing liquid.

  • Incision of the wound to facilitate irrigation and biopsy or swab culture of the wound to facilitate finding virus are not suggested and could allow the virus to go further into the wound.

  • Dakin’s solution (0.25% hypochlorite solution) rapidly inactivates herpes viruses, but concern exists that any tissue damage could facilitate infection and should never be used on mucosal surfaces. If to be used on a wound, it should be prepared when needed, as the hypochlorite solution is not very stable. After using this diluted bleach solution, a wound wash as described above should be used.

Postexposure prophylaxis (PEP) should be utilized, especially in what are likely high-risk exposures, including:

  • exposure to an ill or immunocompromised macaque or one with vesicular or ulcerative lesions compatible with virus infection

  • exposures not given wound cleansing within 5 minutes of exposure or less than 15 minutes in duration

  • deep wounds or punctures or wounds of the head, neck, or torso, as opposed to the extremities

  • appropriate exposure to specimens from the CNS or known to contain the B virus

Antiviral oral medications available for PEP, none of which are formally approved by the US Food and Drug Administration (FDA) for prophylaxis or treatment of the virus include:

  • acyclovir 800 mg five times per day

  • valacyclovir 1000 mg three times per day (a prodrug of acyclovir that will produce four-fold higher levels)

Oral ganciclovir should not be used related to its toxicity profile as compared to the other drugs.

As compared to herpes simplex, these agents are about ten times less sensitive to the agents.

PEP treatment is recommended to be started within the first few hours after exposure and is recommended to be given for 2 weeks with careful clinical and serological follow-up during and after PEP. If evidence of active B virus infection develops, PEP should be abandoned and treatment of active infection begun.

The development of herpes B-free colonies of macaques, although not easy to maintain, can be a giant step in the prevention of the infection in humans. Vaccination for the B virus is a possibility; however, research on herpes virus vaccines in humans have not produced much overall optimism.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Fujima, A, Ochiai, Y, Saito, A. “Discrimination of antibody to herpes B virus from antibody to herpes simplex virus types 1 and 2 in human and macaque sera”. J Clin Microbiol. vol. 46. 2008. pp. 56-61.

Boulter, EA, Zwartouw, HT, Thornton, B. “Postexposure immunoprophylaxis against B virus infection”. Br Med J (Clin Res Ed). 1982. pp. 284-746.

Huff, JH, Barry, P. “B-virus (Cercopithecine herpesvirus 1) infection in humans and macaques: potential for zoonotic disease”. Emerg Infect Dis. vol. 9. 2003. pp. 246-50.

Ostrowski, SR, Leslie, MJ, Parrott, T. “B-virus from pet macaque monkeys: an emerging threat in the United States”. Emerg Infect Dis. vol. 4. 1998. pp. 117-21.

Nsabimana, JM, Moutschen, M, Thiry, E, Meurens, F. “Human infection with simian herpes B virus in Africa”. vol. 18. 2008. pp. 3-8.

Holmes, GP, Hillard, JK, Klontz, KC. “B virus (Herpesvirus simiae) infection in humans: epidemiologic investigation of a cluster”. Ann Intern Med. vol. 112. 1990. pp. 833-9.

Estep, RD, Messaudi, I, Wong, SW. “Simian herpesviruses and their risk to humans”. Vaccine. vol. 28. 2010. pp. B78-84.

Rogers, KM, Ritchey, JW, Payton, M. “Neuropathogenesis of herpesvirus papio 2 in mice parallels infection with Cercopithecine herpesvirus 1 (B virus) in humans”. J Gen Virol. vol. 87. 2006. pp. 267-76.

Freifeld, AG, Hillard, J, Southers, J. “A controlled seroprevalence survey of primate handlers for evidence of asymptomatic herpes B virus infection”. J Infect Dis. vol. 171. 1995. pp. 1031-4.

Nanda, M, Curtin, VT, Hillard, JK. “Ocular histopathologic findings in a case of human herpes B virus infection”. Arch Ophthalmol. vol. 108. 1990. pp. 713-6.

Cohen, JI, Davenport, DS, Stewart , JA. “Recommendations for prevention of and therapy for exposure to B virus (cercopithecine herpesvirus 1)”. Clin Infect Dis. vol. 35. 2002. pp. 1191-203.

DRG CODES and expected length of stay

DRG code – Non-bacterial infections of the nervous system excluding viral meningitis with MCC: 097

Expected length of stay is 28 or more days for the few survivors.

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