Herpes Simplex

INTRODUCTION

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Background: Herpes simplex viruses (HSVs) are ubiquitous, extremely host-adapted pathogens that can cause a wide variety of illnesses. Two types exist: type 1 (HSV-1) and type 2 (HSV-2). Both are closely related but differ in epidemiology. 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.

Herpes simplex infections are asymptomatic in as many as 80% of patients, but symptomatic infections may be characterized by significant morbidity and recurrence. Moreover, infections can cause life-threatening complications, particularly in immunocompromised hosts.

HSV infection appears to have increased in prevalence worldwide in the last 2 decades, making it a major public health concern. The availability of effective chemotherapy underscores that the prompt recognition of the infection and early initiation of therapy are of utmost importance in the management of the disease.

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Pathophysiology: HSV, belonging to the family Herpesviridae and to the subfamily Alphaherpesvirinae, is a double-stranded DNA virus characterized by the following unique biological properties:

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• Neurovirulence (the capacity to invade and replicate in the nervous system)

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• Latency (the establishment and maintenance of latent infection in nerve cell ganglia): In HSV-1 infection, the trigeminal ganglia are involved most commonly, while in HSV-2 the sacral nerve root ganglia (S2-S5) are involved.

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• Reactivation: The reactivation and replication of latent HSV can be induced by a variety of stimuli (eg, fever, trauma, emotional stress, sunlight, menstruation), resulting in overt or covert recurrent infection and peripheral shedding of HSV. In immunocompetent patients with equal chances of acquiring HSV-1 and HSV-2 both orally and genitally, HSV-1 reactivates more frequently in the oral rather than the genital region. Similarly, HSV-2 reactivates 8-10 times more frequently in the genital region when compared to orolabial HSV-2. Reactivation is more frequent and severe in immunocompromised patients.

Dissemination of infection occurs in people with impaired T-cell immunity such as organ transplant recipients and individuals with HIV-related disease.

Distribution of HSV is worldwide. Humans are the only natural reservoirs, and no vectors are involved in transmission. Because of latent infection, periodic reactivation, and virus shedding, endemicity is easily maintained in most human communities.

The mode of transmission is 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 occur rarely.

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Frequency:
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• In the US: HSV is ubiquitous. Most individuals show evidence of infection due to HSV. HSV-1 usually is acquired in childhood by contact with oral secretions containing the virus. HSV-2 becomes an issue when the individual becomes sexually mature. (The presence of HSV-2 is an indirect measure of sexual activity.) Seroprevalence rates do not reflect how many of these individuals have or will have symptomatic episodes of HSV recurrence.

  Seroprevalence: Antibodies to HSV-1 increase with age starting in childhood and correlate with socioeconomic status. By age 30 years, 50% of individuals in a high socioeconomic status and 80% in a lower socioeconomic status are seropositive. Antibodies to HSV-2 begin to emerge at puberty, correlating with the degree of sexual activity. The lifetime seroprevalence can be 20-80%.

• Internationally: HSV is well distributed worldwide.

CLINICAL

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History: The clinical course of the disease depends upon the age and immune status of the host, the anatomic site of involvement, and the antigenic type of the virus. While the primary infections caused by HSV-1 and HSV-2 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).

• Acute herpetic gingivostomatitis

• This manifestation of primary HSV-1 infection occurs in children aged 6 months to 5 years.

• Infected saliva from an adult or another child is the mode of infection. The incubation period is 3-6 days.

• Clinical features

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  • Abrupt onset

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  • High fever (102-104°F)

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  • Anorexia and listlessness

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  • Gingivitis is the most striking feature, with markedly swollen, erythematous, friable gums.

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  • Vesicular lesions develop on the oral mucosa, tongue, and lips and later rupture and coalesce, leaving ulcerated plaques.

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  • Tender regional lymphadenopathy

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  • Perioral skin also may be involved because of contamination with infected saliva.

• Course: Acute disease lasts 5-7 days, and the symptoms subside in 2 weeks. Viral shedding from the saliva may continue for 3 weeks or more. Adults also may develop acute gingivostomatitis, but it is less severe and is associated more often with a posterior pharyngitis.

• Acute herpetic pharyngotonsillitis

• In adults, oropharyngeal HSV-1 causes pharyngitis and tonsillitis more often than gingivostomatitis.

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• Fever, malaise, headache, and sore throat are presenting features.

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• The vesicles rupture to form ulcerative lesions with grayish exudates on the tonsils and the posterior pharynx.

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• Associated oral and labial lesions occur in fewer than 10% of patients.

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• HSV-2 can cause similar symptoms and is associated with orogenital contact or can occur concurrently with genital herpes.

• Herpes labialis

• This is the most common manifestation of recurrent HSV-1. A prodrome of pain, burning, and tingling often occur at the site, followed by the development of erythematous papules that rapidly develop into tiny, thin-walled, intraepidermal vesicles that become pustular and ulcerate. In most patients, fewer than 2 recurrences manifest each year, but some individuals have monthly recurrences.

• Maximum viral shedding is in the first 24 hours of the acute illness but may last 5 days.

• Genital herpes: The severity and frequency of the disease and the recurrence rate depend on a number of factors that include viral type, prior immunity to autologous or heterologous virus, gender, and immune status of the host.

• Primary genital herpes

• Primary genital herpes can be caused by both HSV-1 and HSV-2 and is asymptomatic in most patients. 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.

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• Primary genital herpes is characterized by severe and prolonged systemic and local symptoms. The symptoms of persons with a first episode of nonprimary HSV-2 infection are less severe and of shorter duration.

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• Preexisting antibodies to HSV-1 have an ameliorating effect on disease severity caused by HSV-2.

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• Prior orolabial HSV-1 protects against genital HSV-1 but not HSV-2.

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• Women’s symptoms are more severe, and women have a higher rate of complications than men.

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• Clinical features: The incubation 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 may be involved in 70-90% of patients and is characterized by ulcerative or necrotic cervical mucosa. Cervicitis may be 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 causes urethritis more often than HSV-2.

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• 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 crust. Herpetic urethritis occurs in 30-40% of patients and is characterized by severe dysuria and mucoid discharge. The perianal area and rectum can be involved in persons who engage in anal intercourse, resulting in herpetic proctitis.

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• In men and women, the ulcerative lesions persist from 4-15 days until crusting and reepithelialization occur. New lesions can 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.

• Recurrent genital herpes

• 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. For HSV-2 infection 38% had 6 recurrences in 1 year, and 20% had more than 10 recurrences in the first year.

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• Both subclinical and symptomatic reactivation are more common with HSV-2 compared to HSV-1. Sixty percent of patients with primary genital HSV-2 experience recurrences in the first year.

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• Patients who had severe primary genital herpes tend to have more frequent recurrences of longer duration.

• 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 may occur.

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• 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.

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• In men, recurrent genital herpes presents as 1 or more patches of grouped vesicles on the shaft of the penis, prepuce, or glans. Urethritis is uncommon. Pain is mild, and lesions heal in 7-10 days. The frequency and severity of recurrences decrease with time.

• Subclinical genital herpes

• The majority of primary genital HSV infections are asymptomatic, and 70%-80% of seropositive individuals have no history of symptomatic genital herpes. Nevertheless, they experience periodic subclinical reactivation with virus shedding, thus making them a source of infection.

• The rate of viral shedding may be 1-2% in immunocompetent persons and may be as high as 6% in the first few months after acquiring the infection. This fact is important in neonatal herpes because most mothers have no signs and symptoms of genital herpes during pregnancy.

Physical: This section addresses the physical examination of the herpetic lesion as it relates to primary and recurrent lesions of cutaneous or mucosal HSV infection. This can be related to either oral or genital infection.

• Primary mucocutaneous HSV infections

• Primary (first episode) infections present within several days of exposure to secretions containing viable virus.

• Often painful, the lesions develop into vesicles quickly and can continue to erupt over 1-2 weeks.

• The lesions are prominent and often are present internally on the mucosal surface of the oral or genital area as well as on the surrounding skin.

• Constitutional symptoms often are prominent with fever, malaise, myalgias, and anorexia. Weight loss is not uncommon, either related to illness or dysphagia (in primary gingivostomatitis).

• 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 candidosis. Those on cutaneous surfaces remain as vesicles longer, only to develop into crusted ulcers that heal in 5-7 days.

• Recurrent mucocutaneous HSV infections

• Following the establishment of latency in the corresponding sensory nerve ganglion cells, HSV can cause recurrent infection that can be subclinical (manifest by viral excretion without lesions) or overt (manifest by mucosal or cutaneous lesions with viral excretion).

• Oral recurrences often are 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 and not pyrexia. Females may relate a relationship to the menstrual cycle.

• Burning or paraesthesias at the point where the lesions are to occur may herald recurrences. Unlike primary infection, constitutional symptoms are minimal in most cases.

• Recurrences last 3-7 days and can occur numerous times per year or once or twice in a lifetime. Overall, the number of yearly recurrences tends to decrease over time.

• Although recurrent HSV 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 without overt lesions being present. In genital disease, this means barrier protection should be used whether lesions are present or not, even if no history of genital HSV is present.

• 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.

• Sacral HSV recurrences also may present with signs and symptoms of meningeal inflammation; and, in fact, an aseptic meningitis picture can be found upon examination of the cerebrospinal fluid.

Causes:

• The mode of transmission is by close personal contact.

• Infection occurs via inoculation of virus into susceptible mucosal surfaces (eg, oropharynx, cervix, conjunctiva) or through small cracks in the skin.

• The virus is inactivated readily at room temperature and by drying; hence, aerosol and fomitic spread occur rarely.

• 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.

WORKUP

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Lab Studies:
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• HSV infection is best confirmed by isolation of virus in tissue culture (the criterion standard for diagnosis).

• Rapid diagnosis is possible by the histological appearance of the lesion.

• Multinucleated giant cells and epithelial cells containing eosinophilic intranuclear inclusion bodies distinguish the lesions of herpesviruses.

• 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.

• Aspiration should facilitate complete collapse of the vesicle because it is not multiloculated as cutaneous poxvirus infections can be.

• After aspiration, the vesicle should be unroofed aseptically.

• 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.

• Staining can be performed with a Papanicolaou smear stain. (In actuality, whatever is available as Gram, Giemsa, or Wright stain will suffice.)

• A positive result is the finding of multinucleate giant cells.

• Using appropriate immunofluorescent antibody reagents, the smear can distinguish different herpesviruses and nonherpesviruses that may be present (eg, vaccinia, smallpox).

TREATMENT

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Medical Care:

• Overall, medical treatment of HSV revolves around specific antiviral treatment.

• In situations in which constitutional effects such as fever occur, symptomatic treatment can be used.

• Appropriate wound care is needed, and treatment for secondary bacterial skin infections may be required.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
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Drug Category: Antivirals -- Nucleoside analogs are phosphorylated initially by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV polymerase with 30-50 times the potency of human alpha-DNA polymerase.

FOLLOW-UP

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Deterrence/Prevention:
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• Because of the ubiquitous and cosmopolitan nature of HSV, avoiding contact with individuals who (often asymptomatically) are excreting the virus in saliva or sexual secretions is difficult.

• Although not easily applicable to oral-oral contact, barrier protection using latex condoms is recommended to minimize exposure to genital HSV infections.

• Because genital ulcers due to HSV may occur outside of areas covered by the condom, transmission can occur in those areas.

• Herpetic whitlow can be avoided by the use of latex gloves when health care workers insert their hands into the oral cavity of patients. Transmission of genital virus to the hand, however, can occur during unprotected finger-genital contact related to sexual exposures.

• Suppressive antiviral therapy is used for individuals with frequent and/or particularly symptomatic relapses.

Complications:
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• Balanitis can occur in an uncircumcised male as a result of bacterial infection of the herpetic ulcers.

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• Candidal vaginitis has been described in as many as 10% of women with primary genital herpes, particularly if they have diabetes. Care should be taken to confirm the diagnosis of candidosis because ulcerative herpetic disease can have whitish mucosal lesions that can be confused with yeast infection.

• Ocular infections

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  • This complication is not uncommon in children as a result of autoinoculation during acute herpetic gingivostomatosis or asymptomatic oropharyngeal HSV infection.

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  • Ocular infection is caused primarily by HSV-1, except in neonates in whom it may be caused by HSV-2, and manifests as unilateral follicular conjunctivitis or as acute herpetic keratoconjuctivitis with dendritic corneal ulcers.

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  • Recurrences can 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 US.

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• Skin infections: Various cutaneous complications related to HSV can occur.

• Eczema herpeticum: This occurs in individuals with underlying dermatitis and may be localized (which can be confused with herpes zoster) or disseminated. The process also can occur in patients with extensive skin breakdown as with burns, pemphigus, or Sézary syndrome.

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• Herpetic whitlow: HSV of the fingers of the hand occurs 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.

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• Herpes gladiatorum: Scattered cutaneous HSV-1 lesions have been observed in wrestlers who have had viral contact through exposure to infectious saliva during a match.

• Visceral infections: 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 immunologically normal hosts.

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  • 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.

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  • It is associated with leukopenia, thrombocytopenia, and disseminated intravascular coagulation.

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  • Disseminated HSV-1 and HSV-2 infections also can result in herpetic esophagitis, adrenal necrosis, interstitial HSV pneumonitis, HSV cystitis, HSV arthritis, HSV meningitis, and HSV encephalitis.

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• Central nervous system complications

• Aseptic meningitis: This condition is an acute, generally benign lymphocytic meningitis. In 1 series, 36% of women and 13% of men with primary genital HSV-2 had meningeal symptoms on 2 consecutive examinations. It is more common with HSV-2 infection. Meningeal symptoms usually start 3-12 days after the onset of genital lesions; they reach a maximum 2-4 days into the illness and recede over 2-4 days. Signs and symptoms of encephalitis are unusual and neurological sequelae are rare. HSV-1 also has been identified by PCR in the CSF of patients with benign lymphocytic recurrent meningitis (Mollaret meningitis), suggesting that HSV may be the cause of this so-called idiopathic syndrome.

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• Ganglionitis and myelitis: 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 rarely is reported.

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• Herpes simplex encephalitis: 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. Clinical features include the following:

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  • Nonspecific findings common to all forms of encephalitis, which include headache, signs of meningeal irritation, altered mental status, and generalized seizures

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  • Changes referable to focal necrosis of the orbitofrontal and temporal cortex and the limbic system, including anosmia, memory loss, olfactory and gustatory hallucinations, and focal seizures

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  • Rapid development of hemiparesis and coma may occur. In some patients, the clinical picture may be protracted, mimicking acute psychosis or delirium tremens.

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  • The CSF has moderate pleocytosis with mixed mononuclear cells and polymorphonuclear cells, moderate RBCs, and mildly elevated protein with normal glucose.

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  • MRI is the most sensitive imaging procedure.

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  • The most sensitive noninvasive method of diagnosis is the demonstration of HSV DNA by PCR.

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  • The mortality rate is high (70%) in untreated patients. Even with treatment, a high incidence of neurological sequelae remains.

• Genital herpes and pregnancy

• Recurrent genital herpes is similar in pregnant and nonpregnant women, although an increase in the number of recurrences in the course of pregnancy may occur.

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• Recurrent genital herpes accounts for 1-2% of all cases of neonatal herpes. Considering the fact that a high serological evidence of herpes and low incidence of neonatal herpes exists, recurrent herpes is not an important risk factor. Hence, cesarean delivery is recommended only in mothers who have active genital lesions during labor.

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• First-episode infections have more severe consequences to the mother and infant. Thus, identification of women at risk for primary infection (seronegative for HSV-2) is of paramount importance.

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• Serological discordance between partners may be 15-20%, so that the risk of a seronegative mother becoming infected from the father during pregnancy is 10-15%.

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• Pregnant women may have widely disseminated infection with a high mortality rate of 50%.

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• Infection in the third trimester of pregnancy is associated with neonatal HSV infections, intrauterine growth retardation, and prematurity.

• Neonatal HSV disease

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  • Ninety percent of infections are acquired perinatally, 5-8% are acquired congenitally, and a few are acquired postnatally.

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  • Neonatal infection is caused by contact with infected genital secretions.

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  • In 70% of mothers, the infection is asymptomatic. The risk of transmission from a mother with primary infection is about 50%.

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  • 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.

• The disease may be confined to the skin, eyes, or mouth, or it may manifest as encephalitis or disseminated visceral disease involving the lungs, liver, heart, adrenals, and skin.

MISCELLANEOUS

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Medical/Legal Pitfalls:
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• Suits over sexual transmission

• Legal actions have been taken over transmission of HSV through unprotected sexual activity.

• Demonstration that both partners are infected with the same type of HSV is not adequate to prove that one partner infected the other.

• The use of restriction endonucleases, which lyse DNA at very specific base sequences, can strongly suggest an epidemiologic link between 2 isolates but does not indicate the direction of the transmission.

• The presence of genital HSV-2 infection in young children can be an indicator of sexual abuse in parallel to gonococcal infections but is not necessarily the case.

• Recognition of HSV encephalitis

• Because prompt treatment of HSV encephalitis appears to minimize residual neurologic damage and death, considering this diagnosis early is important in appropriate cases. Perform necessary diagnostic tests, and institute early, usually empirical, antiviral therapy.

• Unsatisfactory outcomes can occur, however, even with the early use of antiviral treatment.

Special Concerns:
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• Development of antiviral drug resistance

• Antiviral resistance of HSV can be selected for both in vitro and in vivo.

• Once these isolates are present, commonly representing thymidine kinase¡Vnegative mutants, the usual treatments are not likely to be effective, and alternate modalities of therapy must be sought.

• The use of prolonged suppressive therapy for HSV no doubt contributes substantially to the risk of developing resistance.

• Because of the possibility of developing resistance, the decision to use chronic suppression (or patient-driven relapse treatment) must be made while carefully balancing the positive effect of suppression or any likely minimal effect of therapy on an already overt mucocutaneous relapse against the potential for resistance.