B virus (cercopithecine herpesvirus 1) therapy and prevention recommendations.
There are many herpesviruses of nonhuman primates and other animal species, but B virus stands alone as a documented zoonotic hazard. B virus, also known as Cercopithecine herpesvirus 1 (CHV-1), Herpesvirus simiae, Herpes simiae, or Simian B disease, is considered endemic among monkeys of the genus Macaca. (1) (p747) B virus is a large, double-stranded DNA a-herpesvirus that has a predilection to invade the central nervous system causing fatal encephalomyelitis in humans. (2) The historical fatality rate of untreated human infections is 70% to 80% if not treated promptly. (3) There are approximately 40 known deaths, (4) most, if not all, occurring among biomedical research personnel working with captive monkeys or their tissues. Cercopithecine herpesvirus produces a mild clinical disease in monkeys similar to human herpes simplex viruses (HSV-1 and HSV-2). Animals can shed the virus through oral, ocular, and genital secretions with or without visible lesions or open skin lesions. (3) Macaques are the most common monkey used in biomedical research and are found in more climates and habitats than any other primate except humans. (5) This disease is important to physicians and veterinarians who provide medical care during deployments as well as those who provide occupational medical oversight in biomedical research facilities. Many of the recommendations that follow in this article are from the 2002 report of the B Virus Working Group: Recommendations for Prevention of and Therapy for Exposure to B Virus (Cercopithecine Herpesvirus 1). (2) Readers are highly encouraged to read the report as it is the definitive, most current source of information on this virus.
RESERVOIR AND INCIDENCE OF DISEASE IN MONKEYS
There are 16 to 19 species of Macaca monkeys (5,6) which are part of a larger group of primates taxonomically classified as Catarrhini in reference to their elongate muzzle with a narrow, turned-down nose (similar to humans). They are indigenous to Africa, Asia, and extreme southern Europe (introduced to Gibraltar) and some possess ischial callosities for sitting. (1(p680)) Several of the more common species found in Asia are shown in Figures 1 through 5.
B virus is ubiquitous in macaques which experience an age-related increase during adolescence with the incidence of disease approaching 100% by the end of the first breeding season. Latency is established in the ganglia of the sensory nerves serving the region in which the virus was introduced. (7) Once there, the virus remains in the sensory neurons for the life of the host and results in a persistent, subclinical infection. Periodically, the virus can reactivate due to stress from social challenges, transportation, immunosuppression, breeding, illness, or new housing; travel down the neuronal axon to the mucosal epithelium; replicate; and be shed. (3) Infected monkeys often have no or very mild symptoms. (8) The frequency of active viral shedding appears to be low at 2% to 3%. (3) Virus infection in humans is rare. (2) Macaques with primary infection may develop lingual or labial vesicles or ulcers (Figure 6) which heal in 1 to 2 weeks. (7,9) Keratoconjunctivitis or corneal ulcers might also be noted. (7,9)
MODE OF TRANSMISSION
The transmission of B Virus to humans from monkeys primarily occurs by exposure to contaminated saliva through bites and scratches from animals. (9) Exposures to B Virus can also occur from contaminated tissues or fluids, needles, scalpel blades, or scratches from contaminated cages or objects in a biomedical research environment. There is one documented case of human-to-human transmission from an infected animal handler and spouse who applied hydrocortisone cream to his skin lesions and subsequently applied the cream to an area of contact dermatitis under a ring on her finger. (10) One fatal case of a female worker at a primate center occurred after an ocular exposure to biologic material (possibly fecal) from a rhesus macaque. (11)
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CLINICAL SIGNS IN HUMANS
The incubation period for B virus is reported to be from 2 days to 5 weeks after exposure. Most well-documented cases present 5 to 21 days after exposure. (2) With its varied onset of incubation and clinical signs, the description in assorted references of clinical signs of B virus is varied as well, as shown in the following examples:
* After exposure to B virus, humans might develop a herpetiform lesion at the site of inoculation. Early clinical signs and symptoms include myalgia, fever, headache, and fatigue followed by progressive neurological disease with numbness, hyperesthesia, paresthesia, diplopia, ataxia, confusion, urinary retention, convulsions, dysphagia, and an ascending flaccid paralysis. (7)
* Some patients present with a progression of symptoms that first appear near the site of exposure (vesicular rash, tingling, itching, pain, or numbness at the site). Some patients may develop lymphadenopathy proximal to the site of inoculation. However, many patients have no symptoms at the site of infection. Others present with symptoms limited to the peripheral nervous system or central nervous system. Within the first 3 weeks after exposure, paresthesia may develop and proceed proximally along the affected extremity. Associated symptoms can include fever, myalgias, weakness of the affected extremity, abdominal pain, sinusitis, and conjunctivitis. Other organs, including lung and liver, may be involved. The virus spreads along the nerves of the peripheral nervous system to the spinal cord and the brain. Symptoms can include meningismus, nausea, vomiting, persistent headache, confusion, diplopia, dysphagia, dizziness, dysarthria, cranial nerve palsies, and ataxia. Seizures, hemiplegia, hemiparesis, ascending paralysis, respiratory failure, and coma occur later in the course of infection. The presentation of late stage disease is that of brain stem encephalomyelitis evolving into a diffuse encephalomyelitis during its terminal stages. A third presentation involves flu-like illness with fever, chills, myalgias, and other nonspecific symptoms, no focal findings, later followed by an abrupt onset of central nervous system signs. (2)
* Symptoms include "vesicular skin lesions at or near the exposure site; aching; chills and other flu-like symptoms; persistent fever; nausea; lethargy; chest pain and difficult breathing; and neurological symptoms such as itching or tingling at or near the exposure site, numbness, dizziness, double vision, difficult swallowing and confusion." Other symptoms may occur as well. Treatment is critical, as coma, respiratory failure and death quickly result otherwise. (12)
The various possibilities for presentation could be problematic for medical practitioners if they are unfamiliar with recognition of the symptoms and disease in humans before the central nervous system is infected. Also, medical practitioners must recognize that deep puncture wounds which are difficult to clean; inadequately cleansed wounds; and wounds sustained on the face (especially the eye), neck, or thorax pose greater risks of infection.
Inoculation of those sites with the virus allows little time for treatment before the virus ascends to the central nervous system by the infected axon. (2) Many persons surviving B virus infection have residual neurologic sequelae, and progressive neurologic deterioration can also occur. (3)
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Research with B virus is limited, given the rarity of human infections, the lack of federal funding, and the biosafety levels 3 or 4 containment requirements (13) to work with the virus. Currently only 2 human diagnostic laboratories exist, one in the state of Georgia and the other in England. (2) No true B virus specific serologic assays are available at this time as diagnosis of human infection is difficult for a number of reasons. First, while serologic tests are the mainstay, they are unable to detect antiviral antibodies until 7 to 10 days after infection. Also, in most adults infected with HSV-1/HSV-2, anti-HSV antibodies will react with B virus antigen due to an anamnestic response of their immune system. (2) Another problem is that if a suspected exposure occurs and is treated prophylactically, the treatment with antiviral drugs could impede B Virus replication or lessen the development of an immune response in the patient. PCR (polymerase chain reaction) tests are not useful at this time due to the infrequent and intermittent viral shedding. (2) Furthermore, as there are different genotypes of B virus and the average amino acid sequence of homologous B virus and HSV proteins is 62.5% (range 26.5% to 87.5%), (14) the exquisite sensitivity of PCR testing becomes its limitation in identifying B virus.
Both adequacy and timeliness of wound or mucosa cleansing are the most important factors for reducing the risk of B Virus infection after a known or suspect exposure. First aid consists of washing the bite, scratch, or exposure to any secretion for at least 15 minutes with povidone-iodine, chlorhexidine, or detergent soap within 5 minutes of exposure. (2) Potential eye or mucous membrane exposure should be irrigated immediately with sterile saline or water for 15 minutes immediately after exposure. After that, a qualified health care provider should carefully examine the exposed area to determine the likelihood that an exposure occurred and the exposed area should be cleansed again. (2) For each primate exposure, the health care provider needs to assess 4 variables (2):
* The source of the exposure should be determined. Macaques are the only primates known to transmit B virus.
* The timeliness and adequacy of first aid for the wound should be assessed. Was the wound cleansed within 5 minutes of exposure and was the duration of cleansing a full 15 minutes?
* The type of wound or exposure, the depth of the wound, and the location of the wound should be determined. Deep punctures are likely to result in inadequately cleansed wounds and pose a higher risk of infection; superficial wounds and scratches that are easily cleansed are therefore usually considered low risk.
* Was there an exposure to materials that have come in contact with macaques, such as needles, scalpels, or cages?
Incising or biopsy of the wound is not recommended as it could lead to further infection of the site. The wound or exposure site should be cultured for B virus after cleansing. While cultures of the wound or site of exposure are usually negative, a positive wound culture does indicate an exposure occurred and that antiviral treatment is indicated. (2) Some experts debate the value of serum blood testing. If performed, enough blood must be collected to ensure that there is enough serum for serial testing. Lastly, safely examine the monkey if possible. While this is not likely outside a research environment, within a research facility it is possible for the veterinarian and staff to perform a physical examination for active herpetic ulcers and to culture mucocutaneous membranes. Also, testing for B virus is usually performed on a scheduled basis within the facility and the B virus status of the macaque might be known. If the monkey is positive and is actively shedding as evidenced by lesions or culture, antiviral treatment should be initiated.
Antiviral therapy should be started within hours of the exposure if used for prophylactic treatment. While there are pros and cons of their use as described in the 2002 Clinical Infectious Diseases report, (2) the drug of choice would be valacyclovir (1 g orally 3 times a day for 14 days). (2) An alternative drug would be acyclovir (800 mg orally 5 times a day for 14 days). (2) The most frequently reported adverse effects of oral acyclovir use are nausea, headache, diarrhea, and rash. Neurologic complications of confusion and dizziness have occasionally been reported with acyclovir use. (2) Ganciclovir is poorly absorbed orally and should not be used for prophylactic treatment. A suggested schedule for follow up appointments is 1, 2, and 4 weeks after exposure, or anytime there is a change in clinical status. (2) Further, if serologic testing is considered or performed, it is recommended 3 to 6 weeks after initial exposure and at later points (eg, 3 months) to check for rising titers. Additionally, culture of materials obtained from the conjunctivae, oropharynx, and any unhealed skin lesions might be performed 1 to 2 weeks after discontinuation of antiviral medication to detect viral shedding. (2)
TREATMENT OF VIRAL DISEASE
Treatment with intravenous (IV) antiviral therapy for B virus should be initiated with the presence of any signs or symptoms of B virus, or a positive culture other than the initial postcleansing wound culture. If central nervous system symptoms are absent, treatment with acyclovir (12.5 to 15 mg/kg IV every 8 hours) or alternatively with ganciclovir (5 mg/kg IV every 12 hours) should be used. (2) With peripheral nervous system or central nervous system involvement, ganciclovir is the recommended treatment (5 mg/kg IV every 12 hours). Proper hydration must be ensured and acyclovir must be administered slowly to avoid precipitation in renal tubules and renal insufficiency. (2) Serum levels of creatinine must also be monitored in patients receiving high doses of acyclovir and adjusted accordingly. The increased toxicity (myelosuppression) with ganciclovir must be balanced against the potential benefit of the drug. The dose of ganciclovir should be adjusted accordingly for renal insufficiency, and white blood cell and platelet counts should be monitored closely. (2) Intravenous therapy should be continued until symptoms resolve and 2 or more sets of cultures yield negative results after having been held for 10 to 14 days. (2) Some experts believe patients should then be switched to oral prophylactic treatment. Other experts believe that lifelong suppressive therapy is needed, while others recommend treatment be discontinued at some point. (2) In reality, no good data exist to aid in the determination of when or whether treatment should be discontinued, and antiviral therapy generally has not been effective in patients with advanced encephalomyelitis. Standard blood and body fluid precautions should be used in the care of patients undergoing treatment for B virus or those otherwise known or suspected to be shedding virus. (2)
B virus stands alone as a documented zoonotic hazard and all macaques should be considered positive for B virus until proven otherwise. B virus produces a mild clinical disease similar to human herpes simplex in monkeys but produces a life threatening disease in humans that has resulted in several deaths. The transmission of B virus to humans from monkeys primarily occurs by exposure to contaminated saliva through bites and scratches. Following exposure, humans may develop a herpetiform vesicle at the site of inoculation followed by a disseminated viral infection leading to ascending paralysis, encephalitis, and death in about 70% to 80% of cases. Given the prevalence of disease within the natural reservoir and the public health aspects of this disease, physicians and veterinarians should be well versed to recognize and provide initial treatment. The wound, if any, should be thoroughly cleansed as first aid is most critical for the prevention of B virus. Serum samples and cultures should be considered for serology and viral isolation. Initiation of antiviral therapy with valacyclovir, acyclovir, or ganciclovir may be warranted if the history and/or symptoms are compatible with B virus infection.
Of the 16 to 19 species of Macaca monkeys, the vast majority are found in the Asia Pacific region. This presents unique public health aspects for medical planners with the increasing deployment of military personnel into the Asia Pacific region. To protect deploying personnel, medical planners should be aware of this zoonotic disease and consider it in their force protection planning or survey estimate. Planners must understand that macaques are to be avoided as B virus is an ubiquitous disease, often with no overt clinical signs, and macaques have a wide geographical distribution. Education of deploying personnel and medical staff of signs, symptoms, and treatment of this disease should be planned and presented prior to deployment and appropriate antiviral prophylactic medications should be stocked in medical kits. The best preventive measure would be to educate all deploying members on the virus, and to leave all animals alone while deployed. Lastly, it is recommended that medical providers and veterinarians read the 2002 Clinical Infectious Diseases report, (2) and check the Centers for Disease Control and Prevention and B virus laboratory web sites for the most current information.
(1.) Bernacky BJ, Gibson SV, Keeling ME, Abee CR. Nonhuman primates. In: Fox JG, Anderson LC, Loew FM, Quimby FW, eds. Laboratory Animal Medicine. 2nd ed. San Diego, CA: Academic Press; 2002.
(2.) Cohen JI, Davenport DS, Stewart JA, Deitchman S, Hilliard JK, Chapman LE, for the B Virus Working Group. Recommendations for prevention of and therapy for exposure to B virus (Cercopithecine Herpesvirus 1). Clin Inf Dis. 2002; 35:1191-1203.
(3.) Elmore D, Eberle R. Monkey B virus (Cercopithecine herpesvirus 1). Comp Med. 2008; 58:11-22.
(4.) National Institute for Occupational Safety and Health. Cercopithecine herpesvirus 1 (B virus) infection resulting from ocular exposure. Available at: http:// www.cdc.gov/niosh/hid5.html.
(5.) Rowe N. The Pictorial Guide to the Living Primates. Charlestown, RI: Pogonias Press; 1996:120.
(6.) Ostrowski SR, Leslie MJ, Parrott T, Abelt S, Piercy PE. B-virus from pet macaque monkeys: an emerging threat in the United States?. Emerg Infect Dis. 1998; 4:117-120.
(7.) Barkley WE, Bascom R, Bush RK, et al, for the Committee on Occupational Safety and Health in Research Animal Facilities. Occupational Health and Safety in the Care and Use of Research Animals. Washington, DC: National Academy Press; 1997:6668.
(8.) National Center for Infectious Diseases, Centers for Disease Control and Prevention Website. B virus (Cercopithecine Herpesvirus 1) infection. Available at: http://www.cdc.gov/ncidod/diseases/bvirus.htm.
(9.) Fox JG, Newcomer CE, Rozmiarek H. Selected zoonoses. In: Fox JG, Anderson LC, Loew FM, Quimby FW, eds. Laboratory Animal Medicine. 2nd ed. San Diego, CA: Academic Press; 2002:1068.
(10.) Centers for Disease Control and Prevention. Epidemiologic notes and reports B-virus infection in humans--Pensacola, Florida. Morb Mortal Wkly Rep. 1987; 36(19):289-290.
(11.) Centers for Disease Control and Prevention. Fatal cercopithecine herpesvirus 1 (B virus) infection following a mucocutaneous exposure and interim recommendations for worker protection. Morb Mortal Wkly Rep. 1998; 47(49):1073-1076.
(12.) Bennett BT, Abbee CR, Henrickson R, eds. Nonhuman Primates in Biomedical Research: Biology and Management. San Diego, CA: Academic Press; 1995:395.
(13.) Chosewood LC, Wilson DE, eds. Biosafety in Microbiological and Biomedical Laboratories, 5th ed. Washington, DC: US Dept of Health and Human Services; 2007. Available at: http://www.cdc.gov/ OD/ohs/biosfty/bmbl5/BMBL_5th_Edition.pdf. Accessed December 18, 2008.
(14.) Perelygina I, Zhu I, Zurkuhlen H, Mills R, Borodovsky M, Hilliard JK. Complete sequence and comparative analysis of the genome of herpes B virus (Cercopithecine Herpesvirus 1) from a rhesus monkey. J Virol. 2003; 77:6167-6177.
LTC Christopher E. Keller, VC, USA
* Photos and geographic distribution maps courtesy of the National Primate Research Center's Primate Info Net. Available at: http://pin.primate.wisc.edu/factsheets
LTC Keller is Chief, Animal Research Section, Department of Clinical Investigation, Tripler Army Medical Center, Honolulu, Hawaii.
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|Author:||Keller, Christopher E.|
|Publication:||U.S. Army Medical Department Journal|
|Date:||Jan 1, 2009|
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