Management of Cutaneous and Genital Herpes Simplex

Herpes simplex virus is a ubiquitous virus that clinically affects humans. Herpes simplex virus type 1 (HSV-1) is the prototypical infectious agent in cutaneous disease of the upper body; herpes simplex virus type 2 (HSV-2) generally infects the genitals and the lower body, but the two types share 50% of their genetic material and may be interchangeable clinically. In recent years, they differ slightly in their sensitivity to antiviral drugs and in their proclivity to cause specific disease in other organs. Serologic studies indicate a 22% prevalence for HSV-2 infection among adults in the United States. The prevalence of HSV-2 is declining, but that of genital HSV-1 is increasing and now accounts for the majority of new cases of genital herpes infection.

Many patients seek confirmation of a suspected herpes infection or treatment of frequent and recurrent rashes and symptoms. The primary care physician must know how to obtain a prompt diagnosis, use the current approaches to prevention and treatment, and address the patient’s concerns and negative social stigmata that often accompany genital infection.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7 and 8)

The severity and duration of symptoms are a function of the patient’s state of immunity to HSV. In primary infection, preexisting antibody protection is lacking, and symptoms tend to be more severe and longer lasting than at other stages of the illness. With time, the frequency and severity of recurrences tend to decline, especially with HSV-1 infection. The majority of HSV-2 infections are asymptomatic; less than 25% of persons with HSV-2 antibodies have recurrent symptomatic genital infection. Some cross-type antibody protection is also afforded, so that when a person with a prior history of HSV infection of one type contracts HSV infection of another type (i.e., first episode of nonprimary herpes), the resulting clinical presentation may be less severe than that of primary disease; similarly, vaccines made against the HSV-2 glycoprotein D have been found to confer some protection against both HSV-1 and HSV-2 in previously unexposed persons. In many instances, seroconversion after infection precedes symptomatic disease by many months. Because of their inability to mount effective antibody responses, immunocompromised patients are at great risk for severe, sustained outbreaks (see Chapter 13). As noted, the prevalence of HSV-2 infection is declining as the prevalence of genital HSV-1 infection is increasing, probably due to changes in sexual behavior, such as more careful partner selection, more condom use, and/or choosing oral sex over vaginal sex.

Initial Presentation: Primary Infection

Primary infection is usually the most dramatic form of HSV disease, but the spectrum of presentations is wide, ranging from asymptomatic disease to a florid outbreak with systemic symptoms. In almost half of cases, seroconversion occurs silently, with initial symptoms not developing for many months. The characteristic lesions are erythematous papules, which evolve during 2 to 3 days to vesicles with clear fluid and then progress to pustules, which erode and leave superficial, tender ulcerations, especially in moist areas. Healing occurs within 2 to 6 weeks. Systemic symptoms develop in one third of men and two thirds of women; fever, malaise, nausea, headache, and myalgias are all reported. Meningeal irritation, manifested by headache, stiff neck, and photophobia, can occur. Regional lymphadenopathy is characteristic of primary infection; the nodes are enlarged, firm, and tender.

Primary HSV-1 Infection

Primary HSV-1 infection usually goes unnoticed but may present as severe exudative pharyngitis or gingivostomatitis, with high fevers and tender lymphadenopathy. The illness often is mistaken for streptococcal disease, other bacterial infections of the oropharynx, or mononucleosis. Systemic manifestations of the illness may be more prominent than local symptoms. HSV-1 infection may also present as painful genital lesions, a consequence of oral-genital sexual activity and an unappreciated risk factor for neonatal herpes. The old clinical dictum that HSV-1 infection does not cause genital disease is belied by the finding of equal numbers of oropharyngeal and genital presentations for persons with initial symptomatic HSV-1 infection.

Primary HSV-2 Infection

Primary HSV-2 infection also may be missed or misdiagnosed. In its most overt form, an exudative, painful, bilateral vulvovaginitis is seen in female patients and painful penile ulceration with tender inguinal nodes in male patients. The genital lesions are painful in 95% of men and 99% of women. Cervicitis develops in nearly three fourths of women with primary infection, manifested by vaginal discharge and intermenstrual spotting. Local symptoms increase during the first 6 to 7 days of illness and peak between days 8 and 10, gradually decreasing during the next week. Lymph nodes are enlarged, firm, and tender. Although suppurative lymphadenopathy
does not occur, superimposed bacterial infections can produce this finding. Atypical presentations occur in about 15% of symptomatic persons and include urethritis, cystitis, and meningitis.

Primary genital infection usually takes place in adolescence, but it may be contracted at the time of birth. Fever and malaise occur in 67% of patients, dysuria (resulting from urethral involvement or urinary irritation of ulcers) in 63%, and tender adenopathy in 80%. In 20%, extragenital lesions appear on the hands or in the oropharynx. Complications include secondary yeast infection in 11%, aseptic meningitis in 8%, and sacral autonomic neuropathy leading to bladder or bowel dysfunction in 2%. The association of HSV infection with cervical cancer may be epidemiologic rather than etiologic. Infection with HSV-2 may increase the risk of HIV infection and its transmission. Increased genital shedding and transmission of HIV-1 have been documented in persons with HSV-2 infection.

Uncommon Presentations

An unusual form of primary infection results from the implantation of virus into broken skin; this produces a herpetic whitlow characterized by pain, swelling, and erythema of the fingers, with pronounced adenopathy. In wrestlers, herpes gladiatorum, a primary herpes infection, may develop on exposed parts of the body that are inoculated during the rough activity of wrestling.

First Episode of Nonprimary Disease

In most cases, a first episode of nonprimary disease represents new infection with HSV-2 in persons with clinical and serologic evidence of HSV-1 exposure earlier in life. Patients with a past history of fever blisters or cold sores note a new onset of painful lesions of the genital skin or mucous membranes. Women are more likely to be symptomatic than man. The severity and duration of symptoms are characteristically intermediate between those of primary infection and recurrent disease—lesions are fewer in number, and healing takes place within 1 to 3 weeks. Cervicitis, urethritis, adenopathy, and systemic symptoms are minimal, if present at all.

Clinical Course and Complications

Latent Disease

After primary infection, latent disease develops in all patients, with the virus residing in the associated dorsal root ganglion and circulating along the endoneurial sheath to the skin if host defenses break down. Emotional or physical stress, ultraviolet (sun) exposure, and skin trauma are among the reported precipitants of recurrences. The result is a localized, self-limited form of illness with fewer lesions, which resolve more quickly than in primary infection.

Recurrent Disease

Recurrences may be symptomatic or asymptomatic.

Symptomatic.

Symptomatic recurrences begin with a prodrome of tingling or discomfort in the skin, and sometimes, mild systemic symptoms are present, although they are not as severe as in primary disease. Infections can recur in different distributions along the same ganglia, and heterogeneity characterizes the illness. Genital disease may recur in a nongenital area (e.g., legs or buttocks) in about 10% of cases. If both genital and nongenital lesions are present at the time of primary infection, the chance of a nongenital recurrence is close to 50%.

Although pain without rash develops in some symptomatic patients, most patients experience the characteristic maculopapular-vesicular eruption. The lesions become turbid as interferon is produced in the vesicles and as lymphocytes stimulated by interleukin-2, interleukin-6, and other cytokines begin controlling the infection.

Asymptomatic.

Most recurrences of genital herpes are overlooked by both patient and physician because symptoms are inapparent, atypical, or truly absent. It is in this stage that viral shedding is most likely to result in transmission to sexual partners.

Viral Shedding

Viral shedding occurs during both active disease and latency. The rate of viral shedding and risk for transmission is greatest in the first 96 hours after the appearance of the rash. Silent viral shedding occurs on 8% to 13% of days, with rates highest for persons with a history of symptomatic disease. During the initial 3 to 4 days of recurrent infection, patients can inoculate themselves in other areas (hands, eyes, periorbital areas), but secondary infections are usually brief, mild, and self-limited, and disease is not established in new regions. Eventually, reepithelialization of the skin occurs, usually without scarring. Recurrent erythema multiforme is the result of HSV in the majority of cases. Disease may occur without evidence of vesicles.

Complications

Complications of local recurrent infections are few but can be clinically important. Secondary bacterial infections (caused by streptococci or staphylococci) can lead to cellulitis and lymphangitis and must be anticipated. Sacral disease is associated with a risk for hemorrhagic cystitis, dyspareunia, and sacral radiculopathy (which leads to difficulty in voiding, fecal soilage, or both). It may also cause recurrent aseptic meningitis. Perirectal disease can cause proctitis. Disseminated disease is rare, even in immunocompromised patients, but lesions of autoinoculation may occur on the fingers or about the eyes. In atopic persons, HSV can produce a devastating generalized eczema herpeticum. Chronic pain syndromes associated with infection but without lesions are being identified more frequently. Postherpetic neuralgia caused by HSV-1 is described as a recurrent syndrome without clinical evidence of skin lesions. Vulvar burning alone may be an expression of HSV-2 infection. Elsberg syndrome with radiculomyelopathy and acute urinary retention may also be secondary to clinically inapparent disease. HSV has been associated with an acute retinal necrosis syndrome presenting as eye pain and visual loss.

Neonatal Herpes

Neonatal HSV is most often the consequence of direct contact between the infant and HSV (both type 1 and type 2) during passage through the birth canal of an asymptomatic mother with active genital infection. The risk is estimated at 10% in women with recurrent or primary infection at 32 weeks and is several times higher if infection is present at term in the absence of antibody production. Congenital HSV infection frequently leads to death or severe neurodevelopmental problems. Acquisition of HSV infection early in pregnancy followed by a normal antibody response does not appear to compromise the outcome of pregnancy, but infection in the last trimester may not leave enough time for type-specific antibodies to form, so that the infant is at risk.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of genital ulceration in conjunction with inguinal lymphadenopathy includes syphilis and chancroid (see Chapter 141). Ulcerations may also be associated with noninfectious conditions, such as Behçet syndrome and inflammatory
bowel disease, or they may simply represent excoriation and secondary bacterial infection caused by vigorous sexual activity. Syphilis serology should always be obtained in the setting of a genital ulcer, even one that is painful. Approximately 50% of ulcerative lesions in the genital area prove to be herpetic.

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