Herpes simplex virus (HSV) hepatitis is a rare complication of HSV infection with a high reported mortality rate in untreated patients. The diagnosis was made by needle biopsy of the liver, and the patient was intravenously treated with acyclovir for 15 consecutive days (total dose, 21 g). In both cases, liver biopsy was instrumental in arriving at the diagnosis. Initial investigations including CSF analysis were negative and the patient was given ampicillin plus netilmicin. The prevalence of HSV infection worldwide has increased over the last several decades, making it a major public health concern. Prompt recognition of herpes simplex infection and early initiation of therapy are of utmost importance in the management of the disease. Therapy with acyclovir was immediately initiated and the patient recovered.
HSV is transmitted by close personal contact, and infection occurs via inoculation of virus into susceptible mucosal surfaces (eg, oropharynx, cervix, conjunctiva) or through small cracks in the skin. The virus is readily inactivated at room temperature and by drying; hence, aerosol and fomitic spread are rare. HSV is ubiquitous, and most individuals show some evidence of HSV infection. HSV-1 is usually acquired in childhood by contact with oral secretions that contain the virus. The presence of HSV-2 can be used as an indirect measure of sexual activity in some cases. The dose of acyclovir was increased to 60 mg/kg/day, 9 days after admission. Morbidity and mortality rates associated with HSV infections are discussed in Complications.
Overall, the mortality rate associated with herpes simplex infections is related to 3 situations: perinatal infection, encephalitis, and infection in the immunocompromised host. The clinical course of herpes simplex infection depends on the age and immune status of the host, the anatomic site of involvement, and the antigenic virus type. Primary herpes simplex virus (HSV)–1 and HSV-2 infections are accompanied by systemic signs, longer duration of symptoms, and higher rate of complications. Recurrent episodes are milder and shorter. Both HSV-1 and HSV-2 can cause similar genital and orofacial primary infections after contact with infectious secretions containing either HSV-1 (usually oral secretions) or HSV-2 (usually genital secretions). Primary genital herpes can be caused by both HSV-1 and HSV-2 and can be asymptomatic. The clinical features and course of primary genital herpes caused by both HSV-1 and HSV-2 are indistinguishable, but recurrences are more common with HSV-2.
Primary genital herpes is characterized by severe and prolonged systemic and local symptoms. The symptoms of persons with a first episode of secondary HSV-2 infection are less severe and of shorter duration. Clinical features: The incubation of primary genital herpes period is 3-7 days (range, 1 d to 3 wk). Constitutional symptoms include fever, headache, malaise, and myalgia (prominent in the first 3-4 d). Local symptoms include pain, itching, dysuria, vaginal and urethral discharge, and tender lymphadenopathy. Clinical features in women: Herpetic vesicles appear on the external genitalia, labia majora, labia minora, vaginal vestibule, and introitus. In moist areas, the vesicles rupture, leaving exquisitely tender ulcers.
The vaginal mucosa is inflamed and edematous. The cervix is involved in 70%-90% of cases and is characterized by ulcerative or necrotic cervical mucosa. Cervicitis is the sole manifestation in some patients. Dysuria may be very severe and may cause urinary retention. Dysuria is associated with urethritis, and HSV can be isolated in the urine. HSV-1 infection causes urethritis more often than does HSV-2 infection. Clinical features in men: Herpetic vesicles appear in the glans penis, the prepuce, the shaft of the penis, and sometimes on the scrotum, thighs, and buttocks.
In dry areas, the lesions progress to pustules and then encrust. Herpetic urethritis occurs in 30%-40% of affected men and is characterized by severe dysuria and mucoid discharge. The perianal area and rectum may be involved in persons who engage in anal intercourse, resulting in herpetic proctitis. In men and women, the ulcerative lesions persist from 4-15 days until encrusting and reepithelialization occur. New lesions occur during the course of the illness in 75% of patients, usually forming in 4-10 days. The median duration of viral shedding is about 12 days. The major morbidity of genital herpes is due to its frequent reactivation rate.
In one study, 90% of patients reactivated within the first 12 months. In patients with HSV-2 infection, 38% had 6 recurrences in 1 year, and 20% had more than 10 recurrences in the first year. Both subclinical and symptomatic reactivation is more common in HSV-2 infection than in HSV-1 infection. Sixty percent of patients with primary genital HSV-2 infection experience recurrences in the first year. Recurrent genital herpes is preceded by a prodrome of tenderness, pain, and burning at the site of eruption that may last from 2 hours to 2 days. In some patients, severe ipsilateral sacral neuralgia occurs. In women, the vesicles are found on the labia majora, labia minora, or perineum.
The lesions are often very painful. Fever and constitutional symptoms are uncommon. The lesions heal in 8-10 days, and viral shedding lasts an average 5 days. The symptoms are more severe in women than men. Most primary genital HSV infections are asymptomatic, with 70%-80% of seropositive individuals having no history of known genital herpes. However, upon education regarding the varied clinical manifestations, many patients recognize the symptoms of genital herpes. Truly asymptomatic viral shedding may occur in 1%-2% of infected immunocompetent persons and may be as high as 6% in the first few months after acquisition of the infection.[3, 8] This property is important when attempting to prevent transmission sexually or perinatally.
Individual vesicles on mucosal surfaces break down rapidly, forming shallow painful ulcers (usually < 8-10 mm in diameter). They may be covered with a white exudate that can be confused with mucosal candidiasis. Those on cutaneous surfaces remain as vesicles longer, only to evolve into crusted ulcers that heal within 5-7 days. Following the establishment of latency in the corresponding sensory nerve ganglion cells, HSV can cause recurrent infection that can be subclinical (manifesting as viral excretion without lesions) or overt (manifesting as mucosal or cutaneous lesions with viral excretion). Oral recurrences are often triggered by recognizable stimuli such as pyrexia (fever blisters and cold sores), stress, or sunburn. Genital recurrences are more likely to be linked to stress rather than to pyrexia. Females may relate a relationship to the menstrual cycle.
Although recurrent HSV infections may last much longer (>30 d) in immunocompromised hosts, such as individuals with AIDS, frequent recurrences are not necessarily a sign of an altered immune system. Because recurrences can be clinically unrecognizable, transmission to susceptible individuals can occur in the absence of overt lesions. In genital HSV infections, barrier protection should be used regardless of existing lesions, even in the absence of a history of genital HSV infection. Vesicles occurring in a sacral dermatomal distribution (zosteriform) can occur in recurrent genital HSV disease and be confused with herpes zoster. A history of similar recurrences should alert the clinician to this possibility. HSV-1 is transmitted chiefly by contact with infected saliva, whereas HSV-2 is transmitted sexually or from a mother’s genital tract infection to her newborn. However, lesion location does not always indicate viral type.
Herpes simplex virus (HSV) infection is best confirmed by isolation of the virus in tissue culture (the criterion standard for diagnosis). Tissue culture success is operator-dependent, but this modality can yield positive results within 48 hours of inoculation. Typically, an intact vesicle is used from which the vesicular fluid is aspirated by puncture with a sterile tuberculin syringe. This fluid can be used for viral culture or PCR. Using a sterile instrument, the floor of the newly produced ulcer can then be scraped. The obtained material can be spread on a glass microscope slide and then dried and fixed for staining. In immunocompromised patients with invasive HSV infection, consultation of specialty associated with the organ system affected should be sought early (eg, pulmonologist for possible HSV pneumonitis) in order to aid in diagnosis.
Clinical Context: Synthetic purine nucleoside analogue with activity against a number of herpesviruses, including herpes simplex and varicella-zoster. Highly selective for virus-infected cells because of its high affinity for viral thymidine kinase enzyme. This effect serves to concentrate acyclovir monophosphate into virus-infected cells. The monophosphate then is metabolized into the triphosphate active form by cellular kinases. Nucleoside analogs are phosphorylated initially by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase. Because of the ubiquitous and cosmopolitan nature of herpes simplex virus (HSV), avoiding contact with individuals who (often asymptomatically) are excreting the virus in saliva or genital secretions is difficult.
Daily antiviral therapy can be given to reduce episodes of asymptomatic genital shedding and to further reduce the risk of transmission; however, it is unclear how long this should be administered. Herpetic whitlow can be avoided with latex gloves when health care workers insert their hands into the oral cavity of patients. Transmission of genital virus to the hand can occur during unprotected finger-genital contact during sexual activities. Candidal vaginitis has been described in as many as 10% of women with primary genital herpes, particularly in women with diabetes. Care should be taken to confirm the diagnosis of candidiasis, as ulcerative herpetic disease can have whitish mucosal lesions that can be confused with yeast infection. Recurrences occur in as many as 25% of patients and can be associated with progressive scarring of the cornea. HSV has been the leading infectious cause of blindness in the United States.
Eczema herpeticum: This occurs in individuals with underlying dermatitis and may be localized (which can be confused with herpes zoster) or disseminated. The process can also occur in patients with extensive skin breakdown as with burns, pemphigus, or Sézary syndrome. Herpetic whitlow: HSV infections of the fingers occur at or near the cuticle or at other sites associated with trauma. When involving the nail area, it has been confused with a bacterial felon and been subjected, inappropriately, to incision and drainage. Herpetic whitlow is associated with HSV-1 in health care workers and children related to saliva exposure and with HSV-2 related to digital-genital exposure. HSV infection of the visceral organs usually results from viremia, and multiple organ involvement is common. This may occur during otherwise asymptomatic primary infections and sometimes in seemingly immunocompetent hosts.
In most cases of disseminated herpes, the lesions are confined to the skin; however, fatal visceral dissemination can occur with or without vesicular skin lesions. Multiple organs are involved, but fulminant HSV hepatitis is usually clinically prominent. Genital and anorectal HSV infections may be complicated by urinary retention, sacral neuralgia, and sacral anesthesia. This is due to associated ganglionitis and radiculitis. The symptoms usually resolve in 1-2 weeks. Transverse myelitis is rarely reported. This is an acute necrotizing viral encephalitis that, beyond the neonatal period, is nearly always caused by HSV-1.
It accounts for 10%-20% of all cases of encephalitis and is the most common cause of sporadic acute necrotizing encephalitis in the United States. Herpes simplex encephalitis occurs as a primary infection in about 50% of cases and may be due to recurrent infection or to reinfection with a different strain of HSV-1 in the remainder. Neonates and infants (aged < 6 wk) have a very high frequency of visceral and CNS infections. Without therapy, the mortality rate is 65%, and a high degree of neurological sequelae exists. Multiple studies have shown that the presence of antibodies to HSV-2 increases the risk of becoming infected with HIV, independent of the presence of genital ulcers. While early studies in Africa have demonstrated a reduction of HIV viral load in patients with HIV infection receiving therapy directed toward HSV infection, the mechanism is unclear.[24, 25] The association between HIV and HSV may change the epidemiologic approach to sexually transmitted diseases worldwide. For patient education resources, see the Sexual Health Center and the Oral Health Center. Also, see the patient education articles Genital Herpes, Oral Herpes, Birth Control Overview, and Birth Control Methods.
Herpes simplex virus type 1. Recurrent herpes is most often noted clinically as herpes labialis, with clustered vesicles (often coalescing) on the lip vermilion and often on the perioral skin. Recurrences generally occur in the same area each time, although their severity may vary. Courtesy of Sara Gordon, DDS. Herpes simplex virus type 1. Recurrent herpes is occasionally observed intraorally. Inside the oral cavity, recurrent herpes typically affects only keratinized tissues, such as the gingiva or the hard palate.
Vesicles often break quickly, so the clinician may observe small clustered ulcers. Courtesy of Sheldon Mintz, DDS. Herpes simplex virus type 1. Recurrent herpes is most often noted clinically as herpes labialis, with clustered vesicles (often coalescing) on the lip vermilion and often on the perioral skin. Recurrences generally occur in the same area each time, although their severity may vary. Courtesy of Sara Gordon, DDS. Herpes simplex virus type 1.
Recurrent herpes is occasionally observed intraorally. Inside the oral cavity, recurrent herpes typically affects only keratinized tissues, such as the gingiva or the hard palate. Vesicles often break quickly, so the clinician may observe small clustered ulcers. Courtesy of Sheldon Mintz, DDS.