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Herpes Simplex Virus Genital Infection
Abstract
Genital herpes is a globally endemic sexually transmitted infection (STI) and the most common cause of genital ulcer disease. Classically, genital herpes manifests as a cluster of painful vesicular or ulcerative mucocutaneous lesions; however, such presentations account for a minority of cases, as the clinical manifestations vary widely. Genital herpes is caused by herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2), two closely related but genetically distinct viruses. HSV-2 causes the greater burden of genital disease worldwide, especially in resource-poor settings, and risk factors for HSV-2 acquisition are similar to those of other STIs. Both HSV-1 and HSV-2 establish latent infection in sensory nerve root ganglia and can reactivate to cause mucosal or skin recurrences throughout the life of the patient. Most infected patients have mild symptoms or are asymptomatic. Asymptomatic persons can still shed virus in the genital secretions and transmit it to their sex partners. The clinical diagnosis of genital herpes is unreliable, and laboratory testing is necessary for definitive diagnosis. Complications of genital herpes infection include aseptic meningitis and, rarely, disseminated herpes simplex infection in which multiple organ systems can be affected. Life-threatening neonatal herpes infection is the most severe consequence of genital herpes infection in women of childbearing age. Genital herpes shedding and recurrences are more frequent in human immunodeficiency virus (HIV)–infected patients and other immunocompromised individuals. There is no cure, but effective antiviral therapy is available for the treatment of active lesions and suppression of recurrences; daily use also reduces the risk of sexual transmission. Counseling patients about the disease should be a part of any management strategy. Although behavioral measures such as condom use provide partial protection against infection, no broadly effective prophylactic or therapeutic vaccine exists at this time.
Clinical Vignette
A 25-year-old woman presented to an urgent care center complaining of 1 week of burning and pain in her left labium. She stated that about 8 months earlier she had a similar presentation but at that time she had pain bilaterally and recalled feeling as if she had the flu, with fever, body aches, and headaches. During that visit, a swab of the area was taken; she was told that she had genital herpes but did not recall being told the specific type. She reported taking medication for 7 days and that her symptoms then resolved. She had not had symptoms since then. She had had one partner for the previous 3 months and they had been monogamous. He had not reported any symptoms, although the patient admitted that she had never told him that she had been diagnosed with genital herpes in the past. They had not been using condoms as she had not had any other symptoms or lesions and she did not think she could transmit HSV when she was asymptomatic.
On examination, she appeared well and her vital signs were normal. On genital exam, she had a shallow ulceration on an erythematous base on her left labium ( Fig. 55.1 ). The remainder of her exam was normal. The lesion was swabbed and sent for HSV polymerase chain reaction (PCR) examination. Blood tests were also done and sent for HIV and syphilis serology, and additional genital samples were taken for chlamydia and gonorrhea.
The patient was given valacyclovir 500 mg twice a day for 3 days, leading to the resolution of her symptoms. She was counseled on the persistence of HSV in the body and that, despite not having active lesions or symptoms, she could still be shedding the virus and transmitting it to her partner. Her risk for recurrence will depend on whether she has HSV-1 or HSV-2. Genital herpes caused by HSV-1 recurs rarely, especially after the first year. Genital herpes caused by HSV-2 recurs a median of four times in the first year. She was educated on the possibility of recurrence. Suppressive therapy was offered as an option if she was concerned about future recurrences or wanted to take antiviral therapy to reduce the risk for transmission. Disclosure to her partner was strongly recommended. She was encouraged to use a condom to reduce his risk of acquiring the infection and to avoid sex if she had active lesions. Serologic testing of the partner may be appropriate in some settings.
Epidemiology
Genital herpes infections occur throughout the world in all settings, including developed and developing nations as well as rural and urban areas. HSV-2 causes the majority of genital herpes infections, with an estimated 417 million people between 15 and 49 years of age infected worldwide. HSV-1 has been reported as an increasing cause of first episodes of genital ulcer disease in sexually active patients in developed countries, where childhood orolabial infection with HSV-1 has been decreasing. Transmission typically occurs during sexual intercourse or other intimate contact between an infected source partner who is shedding virus from a mucosal site or genital skin and an uninfected partner. Infection requires direct contact of virus-containing secretions with mucosal surfaces or breaks in the skin; a clinically visible lesion is not required for transmission. Primary infection refers to the first infection with either HSV-1 or HSV-2 in an immunologically naïve host. Subsequent infection by the other virus is often called nonprimary initial infection . For example, a person with primary infection by HSV-1 is still at risk for nonprimary initial infection caused by sexual acquisition of HSV-2.
Because HSV-infected persons are so frequently asymptomatic, most large surveys of HSV epidemiology rely on assays that detect antibodies to HSV-1 and HSV-2 in sera. In the United States, data from the National Health and Nutrition Examination Surveys (NHANES) for 2015 through 2016 suggest an HSV-2 seroprevalence of 11.9% in persons aged 14 to 49 years, with prevalence increasing with age. This represents a decrease from the HSV-2 seroprevalence of 16.2% reported in NHANES for 2005 through 2008 and 21.9% for 1988 through 1994. Consistently, only approximately 20% of persons with HSV-2 antibodies report having been diagnosed with genital herpes. In contrast, between 1999 and 2004, seroprevalence of HSV-1 was 57.7%, and 1.8% of those persons had a history of a genital herpes diagnosis. More recent surveys note a decline in HSV-1 prevalence, especially in younger age groups, reporting a prevalence of 47.8%.
HSV-2 seroprevalence varies widely across different populations. Women are more susceptible to genital HSV-2 infection and bear a greater burden of disease. In the United States, non-Hispanic black persons have the highest HSV-2 seroprevalence. Because infection persists in the host, seroprevalence also increases with age. The highest HSV-2 seroprevalences, reaching almost 100%, have been reported in persons with HIV infection and in female commercial sex workers, especially in sub-Saharan Africa.
Risk factors for genital herpes acquisition, as with other STIs, include a higher number of lifetime sex partners and a history of unprotected sex. It is interesting to note that risk factors prevalent in the community from which one chooses sex partners are more influential than individual sexual behavior in estimating the risk of HSV-2 infection. For example, African American women with few sexual partners remain at increased risk of acquiring HSV-2 because of the prevalence of the infection among African American men. Condom use reduces the risk for HSV-2 acquisition, especially among women, and prior infection with HSV-2 appears to protect against subsequent infection with HSV-1 but not vice versa.
Clinical Features
Genital infections with both types of HSV have similar presentations. A single episode of genital herpes cannot be attributed to HSV-2 or HSV-1 by history or physical examination alone. The pattern of disease recurrence provides important information, though, as HSV-2 recurs more frequently than HSV-1, especially after the first year of infection. With both viruses, true primary episodes are the most severe, followed by nonprimary initial episodes. Recurrent episodes are the least severe. However, substantial overlap exists in the severity of all types of episodes. Symptoms of the primary episode usually occur within 2 to 12 days of inoculation. Serologic studies have shown that some patients may have a delayed presentation and recognize clinical symptoms only months or years after the infection is established. Such a presentation is termed the first recognized episode , as serologic testing can document the presence of a mature antibody profile. Many patients who have clinical disease report atypical or mild manifestations that are not recognized as genital herpes by the patient or the healthcare provider.
Primary Episode
Genital herpes manifests classically as clusters of painful vesicles on an erythematous base. The primary episode can last 2 to 3 weeks. During this time the lesions progress to form pustules and then shallow ulcers. New lesions form while older ones coalesce and crust over; therefore lesions in various stages are found at the time of presentation. Mucosal lesions are typically ulcerative without a detectable vesicular stage. Lesions can occur on the external genitalia of either sex as well as on the upper thighs, buttocks, and in the perianal region ( Fig. 55.2 ). Of note, primary lesions are often bilateral, although recurrent lesions may be bilateral as well. Local tender lymphadenopathy and cervicitis may be present. Primary herpes proctitis can also occur in patients engaging in receptive anal intercourse, and ulcers may be seen with anoscopy or sigmoidoscopy.
Atypical lesions can have an appearance ranging from papules to macular lesions, fissures, or excoriations. A spectrum of symptoms—including itching, burning, dysuria, and urethral discharge—can occur, and lesions may not be obvious on visual inspection. Patients usually report headache, fevers, malaise, and myalgias accompanying the primary genital infection. Nonprimary initial infections with HSV-2 in patients already infected with HSV-1 tend to be milder.
Recurrent Episodes
Recurrences are more frequent with genital HSV-2 infection than with HSV-1, thus underscoring the need to differentiate the infecting virus. Most patients with genital HSV-2 infection and around 50% of those with genital HSV-1 infection experience a recurrence within 1 year of the first episode. Among patients who experience recurrences, those with genital HSV-1 typically have a median of one recurrence in the first year of infection and only a few afterward. In contrast, patients with genital HSV-2 have a median of four recurrences per year, and 20% have more than 10 recurrences in the first year after a primary episode.
With reactivation of either virus, patients frequently report a local prodrome that consists of itching, tingling, or pain before the development of a frank lesion. Recurrent episodes tend to be milder and shorter than the primary episode, lasting 4 to 7 days on average. Compared with the primary episode, patients have fewer lesions, usually in a unilateral distribution, and typically lack systemic symptoms (see Fig. 55.2 ). Recurrent lesions can occur on or near the genitalia, and HSV infection should always be considered during evaluation of lower abdominal, lower back, thigh, or buttock sores. In men, recurrences are typically seen on the shaft of the penis, not on the glans or in the urethra. In women, recurrences usually occur on the vulva. Recurrent lesions can also affect the perianal area, even in patients without a history of receptive anal intercourse, because of the shared nerve supply with other genital sites of primary infection. As with primary infection, atypical presentations are common. Patients and clinicians often confuse genital herpes sores with minor superficial trauma (e.g., penis caught in the zipper or trauma from intercourse), tinea cruris, vulvovaginal candidiasis, or other irritating skin abnormalities.
The triggers for recurrent episodes are incompletely understood, and there is usually no identifiable predisposing event. Psychological stress has been reported as a trigger, and animal data support the concept of physiologic stress resulting in HSV reactivation. The frequency and severity of recurrent genital herpes is significantly increased in immunocompromised persons such as HIV-infected and transplant patients, highlighting the role of cellular immunity in containing HSV infection.
Periodic asymptomatic reactivation and shedding of virus are universal features of HSV-1– and HSV-2–seropositive individuals. Asymptomatic shedding of HSV has been detected to occur as frequently as 1 day in 4 in some studies. Recent research has established that most shedding episodes are short, with about half lasting less than 12 hours. Shedding episodes of longer duration and with higher viral loads are more likely to produce clinical disease.
Differential Diagnosis
HSV-2 is by far the most common cause of genital ulcer disease, and genital herpes should always be considered in persons with a compatible presentation. The differential diagnosis of genital sores includes genital herpes, primary syphilis, chancroid, and lymphogranuloma venereum (LGV). Some genital herpes lesions are occasionally confused with herpes zoster, especially if they occur at a nongenital site. Laboratory testing is required for definitive diagnosis. It is important to note that genital herpes can manifest with only mild discomfort and dysuria, as can genital Neisseria gonorrhoeae and Chlamydia trachomatis infections. Given the high prevalence of these infections in patients seeking care for STIs, screening for them is appropriate in all patients in whom genital herpes is a consideration. Rarely, lesions caused by human papillomavirus or scabies may be confused with genital herpes infection. Primary Epstein-Barr virus (EBV) infection can also occasionally cause genital ulcerations. Finally, malignancies such as squamous cell carcinoma and inflammatory conditions—including fixed drug eruption, Behçet disease, and mucocutaneous manifestations of Crohn’s disease—should be considered in patients with persistent ulcerative lesions. If the initial evaluation of a persistent genital lesion is negative, a biopsy should be considered.
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