First symptoms of herpes B usually develop within four weeks of exposure, but may appear within a few days [1]. At the site of injury, patients may develop severe vesicular exanthema and regional lymphadenopathy, but these symptoms may be missing [2]. If present, herpes B blisters cause pruritus and patients may describe dysesthesias and paresthesias in surrounding tissues. Pain, tingling, and numbness are most common. Over the course of the disease, affected individuals develop flu-like symptoms including fatigue, fever and chills, headache, abdominal and limb pain [2] [3]. While pneumonia is a dreaded complication of herpes B, central nervous system involvement does usually determine the outcome for the individual patient: In contrast to herpes simplex encephalitis, which is associated with focal neurological disease, herpes B causes symptoms of diffuse encephalomyelitis [1]. The initially flu-like disorder rapidly progresses to encephalomyelitis, which may follow a self-limiting course or lead to death [4]. Herpes B-related encephalomyelitis may cause the abrupt onset of distinct neurological symptoms, e.g., agitation, diplopia, dysarthria, movement disorders, ascending flaccid paralysis. Ascending paralysis eventually involves the respiratory muscles and patients die of respiratory failure within one to three weeks after the onset of symptoms.

• Fever

  Virus 579 Akabane Virus 589 Bluetongue Virus 599 Bovine Spongiform Encephalopathy Agent 611 Camelpox Virus 625 Capripoxviruses 639 Classical Swine Fever Virus 647 FootandMouth Disease Virus 655 Lumpy Skin Disease Virus 665 Malignant Catarrhal Fever Virus [books.google.com]

  They include the "haemorrhagic fever viruses" e.g. [pathology.royalberkshire.nhs.uk]

  The first indications of B virus infection are typically flu-like symptoms: fever and chills muscle ache fatigue headache Then, you may develop small blisters in the wound or area on your body that had contact with the monkey. [cdc.gov]

  […] infected animals or tissue, those who work with the primates in laboratories, animal houses, zoos, and animal hospitals, are more at risk for developing Simian B Virus Infection Some common signs and symptoms of Simian B Virus Infection may include fever [dovemed.com]

• Chills

  The first indications of B virus infection are typically flu-like symptoms: fever and chills muscle ache fatigue headache Then, you may develop small blisters in the wound or area on your body that had contact with the monkey. [cdc.gov]

  Chills and other flu-like symptoms, persistent fever, nausea, lethargy, chest pain, and difficulty breathing. Furthermore, encephalitic symptoms (numbness, dizziness, double vision, difficulty swallowing, and confusion). [altmeyers.org]

  Over the course of the disease, affected individuals develop flu-like symptoms including fatigue, fever and chills, headache, abdominal and limb pain. [symptoma.com]

• Fatigue

  The first indications of B virus infection are typically flu-like symptoms: fever and chills muscle ache fatigue headache Then, you may develop small blisters in the wound or area on your body that had contact with the monkey. [cdc.gov]

  Over the course of the disease, affected individuals develop flu-like symptoms including fatigue, fever and chills, headache, abdominal and limb pain. [symptoma.com]

  The second case occurred in an 86-year-old man who presented with a 2-year history of chronic productive cough, progressive dyspnea, and fatigue (patient 17, table 1). [vdocuments.net]

• Malaise

  […] infected animals or tissue, those who work with the primates in laboratories, animal houses, zoos, and animal hospitals, are more at risk for developing Simian B Virus Infection Some common signs and symptoms of Simian B Virus Infection may include fever, malaise [dovemed.com]

  > Synonyms Herpesvirus Simiae, B Virus H Simiae Encephalomyelitis Monkey B Virus < Previous section Next section > < Previous section Next section > Signs & Symptoms Simian B Virus Infection is characterized by fever, headache, vomiting, discomfort (malaise [rarediseases.org]

  After an incubation period of 2 to 7 days, fever, malaise, and inguinal adenopathy develop; these symptoms are associated with the appearance of vesicular lesions. [what-when-how.com]

• Sepsis

  Newborns often present with vesicles or conjunctivitis, or a syndrome resembling neonatal sepsis may be evident. [what-when-how.com]

  Recurrent Infections Due to Aeromonas Species [pp. 651-658]Perspectives on Switching Oral Acyclovir from Prescription to Over-the-Counter Status: Report of a Consensus Panel [pp. 659-663]Reliability of Procalcitonin Concentrations for the Diagnosis of Sepsis [vdocuments.net]

• Nausea

  Other symptoms may include: Shortness of breath Nausea and vomiting Abdominal pain Hiccups As the disease progresses, the virus spreads to and causes inflammation (swelling) of the brain and spinal cord. [cdc.gov]

  […] animals or tissue, those who work with the primates in laboratories, animal houses, zoos, and animal hospitals, are more at risk for developing Simian B Virus Infection Some common signs and symptoms of Simian B Virus Infection may include fever, malaise, nausea [dovemed.com]

  Chills and other flu-like symptoms, persistent fever, nausea, lethargy, chest pain, and difficulty breathing. Furthermore, encephalitic symptoms (numbness, dizziness, double vision, difficulty swallowing, and confusion). [altmeyers.org]

  Editor, We present the case report of a fifty-eight-year-old female hypertensive and obese, with no history of previous abdominal surgery was admitted in the emergency department of our hospital with abdominal pain in right flank and lower quadrant with nausea [scielo.isciii.es]

• Diarrhea

  At the time of the first isolation, the patient complained of low- grade fevers, diarrhea, and intermittent abdominal pain. He was receiving stavudine monotherapy and had a CD4 lymphocyte count of 12/.L. [vdocuments.net]

• Diplopia

  Herpes B-related encephalomyelitis may cause the abrupt onset of distinct neurological symptoms, e.g., agitation, diplopia, dysarthria, movement disorders, ascending flaccid paralysis. [symptoma.com]

• Suggestibility

  These similarities suggest that a sample from a patient with herpes B virus infection also contains HSV and that misidentification occurs in a diagnosis of the infection. [jcm.asm.org]

  One exposed family had flu-like symptoms and another individual developed symptoms at the wound site suggesting infection. [rarediseases.org]

  Therefore, the positive correlation between viral persistence and expression of immune regulatory factors (FoxP3, PD-1, and CTLA-4) has been suggested. [dbpia.co.kr]

  The former designations already suggest that certain Old World monkeys are the natural reservoir of herpesvirus simiae. [symptoma.com]

  There is data to suggest that it is able to cause roseala infantum. 2. [virology-online.com]

• Headache

  The first indications of B virus infection are typically flu-like symptoms: fever and chills muscle ache fatigue headache Then, you may develop small blisters in the wound or area on your body that had contact with the monkey. [cdc.gov]

  Symptoms of severe cases include Severe headache Sudden fever Drowsiness Vomiting Confusion Seizures In babies, additional symptoms may include constant crying, poor feeding, body stiffness, and bulging in the soft spots of the skull. [icdlist.com]

  Patient 3 had a headache without meningismus and was also treated with acyclovir. Both patients 2 and 3 survived and did not have objective sequelae. [pubmed.ncbi.nlm.nih.gov]

• Rabies

  When To Refer to Emergency Department Need for Rabies PEP (for any mammal bite occurring in a rabies-endemic country, ie most countries in Asia, Africa, S.America) Persons who never had rabies vaccine before the bite usually require rabies vaccines AND [ttsh.com.sg]

  Hepatitis B (and Deltavirus Hepatitis) + Hepatitis C Virus Herpes simiae infection Histoplasmosis HIV and HTLV infection Hydatid Disease Leishmaniasis Leprosy Lymphocytic choriomeningitis (LCM) Meliodosis Naegleria Infection Plague Psittacosis Q Fever Rabies [pathology.royalberkshire.nhs.uk]

  The pathogen then ascends sensory nerves in a manner similar to other herpesviruses and rabies virus. [symptoma.com]

• Paresthesia

  If present, herpes B blisters cause pruritus and patients may describe dysesthesias and paresthesias in surrounding tissues. Pain, tingling, and numbness are most common. [symptoma.com]

  Pain, itching, tenesmus, discharge, fever, chills, sacral paresthesias, headache, and difficulty in urinating may all occur. Vesicles and ulcerations may lead to an ery-thematous cryptitis with inguinal adenopathy. [what-when-how.com]

• Tingling

  Recurrent herpes labialis is a shorter and milder affliction, often heralded by local pain or tingling for a few hours. [what-when-how.com]

  Pain, tingling, and numbness are most common. Over the course of the disease, affected individuals develop flu-like symptoms including fatigue, fever and chills, headache, abdominal and limb pain. [symptoma.com]

• Dysarthria

  Herpes B-related encephalomyelitis may cause the abrupt onset of distinct neurological symptoms, e.g., agitation, diplopia, dysarthria, movement disorders, ascending flaccid paralysis. [symptoma.com]

Herpesvirus simiae may be transmitted by bite, scratch, needlestick or mucous membrane exposure to body fluids from infected macaques [5]. Thus, patients who present symptoms that suggest herpes B should be asked whether they have been exposed in this way. In patients working with laboratory animals, zoonotic diseases should always be considered as differential diagnoses.

Serum samples should be obtained from the patient and the animal, if possible. Serological tests are likely to yield positive results about a month after exposure, so their sensitivity is limited: Monkeys may shed virus before seroconversion and humans may have been exposed to the pathogen despite negative results. Serological tests may thus have to be repeated three and six weeks after possible exposure [3]. Furthermore, antigenic cross reactivity between herpesvirus simiae and herpes simplex virus should be considered when interpreting serological results [2].

The detection of viral DNA by means of molecular biological assays may confirm the presence of herpesvirus simiae before seroconversion [6]. These assays may be carried out on fluid from herpes B blisters, on cerebrospinal fluid, or ganglia, where the virus persists post mortem. Viremia during herpes simiae infection is short and viral DNA can't usually be detected in serum samples [3]. Similar to what has been indicated above, the close genetic relationship between herpesvirus simiae and herpes simplex virus may lead to false-positive results and often requires the post-PCR verification of findings [2].

Detection of the virus by conventional culture is the most sensitive approach to diagnosis. However, this time-consuming method can only be performed in special laboratories meeting highest safety standards.

Of note, herpes B-associated encephalomyelitis may possibly be distinguished from herpes simplex encephalitis when analyzing an electroencephalogram. Herpes simplex encephalitis usually presents as focal encephalitis involving the temporal lobes, but patients with herpes B suffer from diffuse encephalomyelitis [1].

Wounds inflicted by macaques and possibly contaminated mucous membranes should be rinsed under running water for several minutes and be desinfected afterwards [1]. Even in the absence of serological or virological evidence, patients suspected to suffer from herpes simiae infection should receive adequate treatment as early as possible. Chemotherapy with antiviral compounds acyclovir, famcyclovir, gancyclovir, or valacyclovir is the mainstay of post-exposure prophylaxis and therapy in confirmed cases. Valacyclovir is the drug of choice for post-exposure prophylaxis and should be administered three times a day at a dose of 1 g for two weeks [3]. In confirmed cases, antiviral agents should be administered intravenously. Acyclovir (up to 15 mg/kg three times a day) is recommended if symptoms of central nervous system involvement are not present, and ganciclovir (5 mg/kg twice a day) is preferred if such neurological deficits are observed [1]. The recommendation of ganciclovir is based on the fact that the only patient ever reported to recover completely from herpes B with central nervous system involvement has been treated with ganciclovir [4]. Resistance of herpesvirus simiae to antiviral compounds has not been reported, but hasn't been extensively studied either [1]. Antiviral chemotherapy is generally well tolerated by the patient.

Patients with clinical herpes B have an unfavorable prognosis, especially if the virus has spread to the central nervous system and neurological deficits are observed. Mortality rates have been estimated to >70%. And although the availability of effective antiviral agents may improve this detrimental outcome, most survivors still suffer from severe neurological sequelae [2].

The causative agent of herpes B is herpesvirus simiae, an alphaherpesvirus of the genus simplexvirus [2]. In literature, the pathogen is also referred to as Macacine herpesvirus 1, Cercopithecine herpesvirus 1, monkey B virus or herpesvirus B. The former designations already suggest that certain Old World monkeys are the natural reservoir of herpesvirus simiae. In detail, the virus persists in distinct species belonging to the genus Macaca in the family Cercopithecidae and can be shed by infected animals [6].

Serological studies have shown that 70-90% of adult macaques are infected with herpesvirus simiae [6]. Even though macaques infected with herpesvirus simiae tend to remain asymptomatic, they periodically shed the virus in body fluids. Other primate species, including humans, but also non-macaque species such as capuchin monkeys, baboons, gibbons, and chimpanzees, may then become infected [5] [6]. Human-to-human transmission has been described in one case only [7] and case reports on patients who acquired the disease from non-macaque species have not yet been published.

According to current knowledge, people exposed to primates shedding herpesvirus simiae, to contaminated tissues or body fluids are the only ones at risk to contract herpes B. There are some case reports on laboratory personnel who became infected while working with macaques maintained in primate facilities [4] [8]. Furthermore, people who share their living or working environment with these monkeys may be at risk of infection [8] [9]. This has been shown for Indonesians working at a temple that has become a tourist attraction because of its monkeys, where the animals are fed and may bite or scratch people. However, clinical disease has not been reported although antibodies against herpesvirus simiae have been detected in serum samples of the majority of workers [8]. This is in agreement with observations made in research facilities in Japan: Despite a relatively high prevalence of antibodies against herpesvirus simiae, few people ever develop herpes B [5]. By contrast, other authors have found no evidence of asymptomatic human infection or a carrier state [2].

In sum, human herpes B is a very rare disease. The risk of infection is low even in people who work with Asian macaques, the main reservoir of the causative pathogen [3]. Less than 50 cases have been reported since 1930 [8].

The pathogen is generally transmitted percutaneously or transcutaneously by infected tissue or body fluids, mainly saliva and blood, of macaques. Wound or mucous membrane contact, stab wounds and cuts may also lead to an infection. Macaques are known to intermittently excrete the virus, which persists in their nervous system. Periodic recrudescence from latency delivers the virus to mucosal epithelial cells, where it replicates and may be released [2]. No symptoms occur during reactivation. Therefore, mucous membrane fluid and tissues of seropositive animals should always be considered a possible source of infection [3].

After crossing the physical barrier of the skin, herpesvirus simiae is assumed to infect epithelial cells, to complete several rounds of transcription, and to subsequently induce cell lysis. As is characteristic of herpesviruses, herpesvirus simiae may then enter into neurons forming sensory nerve endings. Of note, transcription in epithelial cells may be skipped and pathogens may directly enter into neurons. Thus, immediate cleansing and desinfection of the possible site of entry is the most important measure to prevent an infection after exposure [2].

The pathogen then ascends sensory nerves in a manner similar to other herpesviruses and rabies virus. In this context, it has been speculated that the likelihood of fatal encephalomyelitis increases with the proximity of the site of entry to the brain. This would mean that bites and scratches in the head-and-neck region were of greater risks than similar injuries of the hands or fingers [3].

Prevention of herpes simiae infection comprises both measures to avoid getting bitten or scratched by possibly infected monkeys and to avoid the infection of laboratory animals in the first place [3]:

• With regard to the former, facility management and handling techniques should be adapted to minimize the exposure of personnel. Experiments requiring the participation of primates should be replaced whenever possible, for ethical and sanitary reasons. In a similar way, this also applies to the handling of monkeys in their natural habitat.
• Considerable knowledge gaps regarding the epidemiology of herpes simiae infection in macaque populations make it difficult to eradicate the pathogen from research facilities. Nevertheless, attempts are made to establish specific pathogen-free macaque colonies. In any case, care should be taken when purchasing animals and serological tests should be carried out to identify those that have been in contact with the pathogen.

Finally, post-exposure rinsing and desinfection of the wound as well as chemoprophylaxis may help to prevent the onset of symptoms. Ideally, wounds are cleaned immediately and antiviral treatment is started within 24 hours after exposure [2] [3].

Asian macaques are the natural host of herpesvirus simiae, but the virus may be transmitted to other primate species, including humans. Thus, herpes simiae infection is a zoonotic disease. People who are directly or indirectly exposed to infected primates are at risk to contract the disease, which is commonly referred to as herpes B. While infected macaques are unlikely to develop any symptoms other than herpetic gingivostomatitis, the disease is often fatal in men [1]. Up to one month after exposure, patients present with flu-like symptoms and localized neurological deficits. Upon involvement of the central nervous system, herpes B commonly progresses to fatal encephalomyelitis.

Antiviral chemotherapy seems to be effective in patients who don't yet present symptoms of central nervous system infection, but disease progression may hardly be halted afterwards. In fact, mortality rates exceed 70% [2]. Thus, every possible effort should be made to prevent an infection with herpesvirus simiae: The contact between monkeys and men should be kept to a minimum and if animals have to be handled, appropriate safety measures should be established and implemented. They should be based on the knowledge that the virus is transmitted via bites, scratches, and mucous membrane exposure to contaminated tissues and body fluids.

Diagnosis of herpes simiae infection rests on anamnestic data, results of serological and molecular biological studies, and virus culture. Due to the high mortality associated with herpes B, people who have been exposed to the virus should receive antiviral treatment even before an infection can be confirmed [3].

Herpesvirus simiae is widely distributed among Asian macaques, similar to herpes simplex virus among men. Infected monkeys periodically excrete the virus, which persists in their nervous system without triggering any symptoms. Mucous membrane fluids and tissues of animals carrying the virus are most infectious. Men may contract the infection via bites, scratches, and mucous membrane exposure to contaminated tissues and body fluids. People who share their living or working environment with these monkeys are at risk of infection, e.g., laboratory personnel, employees in zoos, pet owners, and inhabitants of the natural habitat of macaques. Although herpes simiae infection of men is rare, it often leads to fatal encephalomyelitis. Mortality rates exceed 70%. Thus, every possible effort should be made to prevent an infection in the first place. In order to do so, it is important to establish and implement safety measures according to the required type of animal handling.

1. Cohen JI, Davenport DS, Stewart JA, Deitchman S, Hilliard JK, Chapman LE. Recommendations for prevention of and therapy for exposure to B virus (cercopithecine herpesvirus 1). Clin Infect Dis. 2002; 35(10):1191-1203.
2. Huff JL, Barry PA. B-virus (Cercopithecine herpesvirus 1) infection in humans and macaques: potential for zoonotic disease. Emerg Infect Dis. 2003; 9(2):246-250.
3. Remé T, Jentsch KD, Steinmann J, et al. Recommendation for post-exposure prophylaxis after potential exposure to herpes b virus in Germany. J Occup Med Toxicol. 2009; 4:29.
4. Davenport DS, Johnson DR, Holmes GP, Jewett DA, Ross SC, Hilliard JK. Diagnosis and management of human B virus (Herpesvirus simiae) infections in Michigan. Clin Infect Dis. 1994; 19(1):33-41.
5. Sato H, Arikawa J, Furuya M, et al. Prevalence of herpes B virus antibody in nonhuman primates reared at the National University of Japan. Exp Anim. 1998; 47(3):199-202.
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7. Centers for Disease Control. B-virus infection in humans--Pensacola, Florida. MMWR Morb Mortal Wkly Rep. 1987; 36(19):289-290, 295-286.
8. Engel GA, Jones-Engel L, Schillaci MA, et al. Human exposure to herpesvirus B-seropositive macaques, Bali, Indonesia. Emerg Infect Dis. 2002; 8(8):789-795.
9. 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(1):117-121.