A 32-year-old man presents with complaints of a 1-week history of multiple painful vesicles on the shaft of his penis associated with tender groin adenopathy (Figure 135-1). The vesicles broke 2 days ago and the pain has increased. He had similar lesions 1 year ago but never went for a healthcare examination at that time. He has had 3 different female sexual partners in the past 2 years but has no knowledge of them having any sores or diseases. He was given the presumptive diagnosis of genital herpes and a course of acyclovir. His herpes polymerase chain reaction (PCR) came back positive, and his rapid plasma reagin (RPR) and HIV tests were negative.
Recurrent genital herpes simplex virus on the penis showing grouped ulcers (deroofed vesicles). (Reproduced with permission from Richard P. Usatine, MD.)
Herpes simplex virus (HSV) infection can involve the skin, mucosa, eyes, and central nervous system. HSV establishes a latent state followed by viral reactivation and recurrent local disease. Perinatal transmission of HSV can lead to significant fetal morbidity and mortality.
HSV affects more than one-third of the world's population, with the 2 most common cutaneous manifestations being genital (Figures 135-1, 135-2, 135-3, 135-4) and orolabial herpes (Figures 135-5, 135-6, 135-7).1
Herpes simplex on the penis with intact vesicles and visible crusts. (Reproduced with permission from Eric Kraus, MD.)
Vulvar primary herpes simplex virus at the introitus showing vesicles, pustules, and ulcers in this pregnant woman. (Reproduced with permission from Richard P. Usatine, MD.)
Recurrent herpes simplex virus on the buttocks of a woman with clusters of vesicles. Women are prone to getting buttocks involvement owing to sleeping with partners who have genital involvement. (Reproduced with permission from Flowers H, Brodell RT. Recurrent vesicular rash over the sacrum. J Fam Pract. 2015 Sep;64(9):577-579.)
Primary herpes gingivostomatitis presenting with multiple ulcers on the tongue and lower lip. (Reproduced with permission from Richard P. Usatine, MD.)
Close-up of recurrent herpes simplex virus-1 showing vesicles at the vermilion border. (Reproduced with permission from Richard P. Usatine, MD.)
Orolabial herpes simplex virus in an adult woman showing deroofed blisters (ulcer). (Reproduced with permission from Richard P. Usatine, MD.)
The Centers for Disease Control and Prevention (CDC) reports that at least 50 million persons in the United States have genital HSV-2 infection. Over the past decade, the percentage of Americans with genital herpes infection in the United States has remained stable. Most persons infected with HSV-2 have not been diagnosed with genital herpes.2
Genital HSV-2 infection is more common in women (approximately 1 of 5 women 14 to 49 years of age) than in men (approximately 1 of 9 men 14 to 49 years of age). Transmission from an infected male to his female partner is believed to be more likely than from an infected female to her male partner.
Orolabial herpes is the most prevalent form of herpes infection and often affects children younger than 5 years of age (Figure 135-7), although all age groups are affected. The duration of the illness is 2 to 3 weeks, and oral shedding of virus may continue for as long as 23 days.1
Herpetic whitlow is an intense painful infection of the hand involving the terminal phalanx of one or more digits. In the United States, the estimated annual incidence is 2.4 cases per 100,000 persons.3
ETIOLOGY AND PATHOPHYSIOLOGY
HSV belongs to the family Herpesviridae and is a double-stranded DNA virus.
HSV exists as 2 separate types (types 1 and 2), which have affinities for different epithelia.3 Ninety percent of HSV-2 infections are genital, whereas 90% of those caused by HSV-1 are oral–labial.
HSV enters through abraded skin or intact mucous membranes. Once infected, the epithelial cells die, forming vesicles and creating multinucleated giant cells.
Retrograde transport into sensory ganglia leads to lifelong latent infection.1 Reactivation of the virus may be triggered by immunodeficiency, trauma, fever, and UV light.
Genital HSV infection is usually transmitted through sexual contact. When it occurs in a preadolescent, the possibility of abuse must be considered.
Evidence indicates that 21.9% of all persons in the United States 12 years or older have serologic evidence of HSV-2 infection, which is more commonly associated with genital infections.4
As many as 90% of those infected are unaware that they have herpes infection and may unknowingly shed virus and transmit infection.5
Primary genital herpes has an average incubation period of 4 days, followed by a prodrome of itching, burning, or erythema (Figure 135-8).
With both types, systemic symptoms are common in primary disease and include fever, headache, malaise, abdominal pain, and myalgia.6 Recurrences are usually less severe and shorter in duration than the initial outbreak.1,6
Maternal–fetal transmission of HSV is associated with significant morbidity and mortality. Manifestations of neonatal HSV include localized infection of the skin, eyes, and mouth, central nervous system (CNS) disease, or disseminated multiple organ disease. The CDC and the American College of Obstetricians and Gynecologists recommend that cesarean delivery should be offered as soon as possible to women who have active HSV lesions or, in those with a history of genital herpes, symptoms of vulvar pain or burning at the time of delivery.
Herpetic whitlow occurs as a complication of oral or genital HSV infection and in medical personnel who have contact with oral secretions (Figures 135-9 and 135-10).
Toddlers and preschool children are susceptible to herpetic whitlow if they have herpes labialis and engage in thumb-sucking or finger-sucking behavior.
Like all HSV infections, herpetic whitlow usually has a primary infection, which may be followed by subsequent recurrences. The virus migrates to the peripheral ganglia and Schwann cells where it lies dormant. Recurrences observed in 20% to 50% of cases are usually milder and shorter in duration.
Primary genital herpes in a 51-year-old woman with prominent erythema and very small vesicles. The woman was in a great deal of pain. (Reproduced with permission from Richard P. Usatine, MD.)
Herpetic whitlow lesion on distal index finger. (Reproduced with permission from Richard P. Usatine, MD.)
Severely painful herpetic whitlow on the thumb. (Reproduced with permission from Eric Kraus, MD.)
The diagnosis of HSV infection may be made by clinical appearance. Many patients have systemic symptoms, including fever, headache, malaise, and myalgias. Nontypical cases should be confirmed with laboratory testing.2
Orolabial herpes typically takes the form of painful vesicles and ulcerative erosions on the tongue, palate, gingiva, buccal mucosa, and lips (see Figures 135-5, 135-6, 135-7).
Genital herpes presents with multiple transient, painful vesicles that appear on the penis (see Figures 135-1 and 135-2), vulva (see Figure 135-3), buttocks (Figures 135-4 and 135-11), perineum, vagina or cervix, and tender inguinal lymphadenopathy.6 The vesicles break down and become ulcers that develop crusts while these are healing.
Recurrences typically occur 2 to 3 times a year. The duration is shorter and less painful than in primary infections. The lesions are often single, and the vesicles heal completely by 8 to 10 days.
UV radiation in the form of sunlight may trigger outbreaks, another reason to use sun protection when outdoors. Sunlight triggers recurrence of orolabial HSV-1, an effect that is not fully suppressed by acyclovir.
Recurrent herpes simplex virus on the buttocks of a woman. Note the vesicles and crusts in a unilateral cluster. (Reproduced with permission from Richard P. Usatine, MD.)
The gold standard of diagnosis is viral isolation by tissue culture and PCR testing.2
PCR is extremely sensitive (96%) and specific (99%) and is preferred for all testing.2 It is used for cerebrospinal fluid (CSF) testing in suspected HSV encephalitis or meningitis.2
The culture sensitivity rate is only 50% and depends upon the stage at which the specimen is collected. The sensitivity is highest at first in the vesicular stage and declines with ulceration and crusting. The tissue culture assay can be positive within 48 hours but may take longer.
HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1) type-specific HSV serologic assays are 80%–98% specific. Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection. Type-specific HSV serologic assays might be useful in patients with recurrent symptoms and negative HSV cultures and an asymptomatic patient with a partner with genital herpes. Screening for HSV-1 and HSV-2 in the general population is not indicated.2
The Tzanck test and antigen detection tests have lower sensitivity rates than viral culture and should not be relied on for diagnosis.2
The CDC does not currently recommend routine type 2 HSV testing in someone with no symptoms suggestive of herpes infection (i.e., for the general population).7
If the herpes was acquired by sexual contact, screening should be performed for other sexually transmitted diseases (STDs), such as syphilis and HIV.
Biopsy is usually unnecessary unless no infectious etiology is found for a genital lesion and a malignancy is suspected.
Syphilis produces a painless or mildly painful, indurated, clean-based ulcer (chancre) at the site of exposure. It is best to investigate for syphilis or coexisting syphilis in any patient presenting for the first time with a genital ulcer of unproven etiology (see Chapter 225, Syphilis).
Chancroid produces a painful deep, undermined, purulent ulcer that may be associated with painful inguinal lymphadenitis (see Chapter 225, Syphilis).
Drug eruptions produce pruritic papules or blisters without associated viral symptoms (see Chapter 212, Cutaneous Drug Reactions).
Behçet disease produces ulcerative disease around the mouth and genitals, possibly before onset of sexual activity (Figure 135-12).
Acute paronychia presents as a localized abscess in a nail fold and is the main differential diagnosis in the consideration of herpetic whitlow (see Chapter 202, Paronychia).
Felon—A red, painful infection, usually bacterial, of the fingertip pulp. It is important to distinguish whitlow from a felon (where the pulp space usually is tensely swollen), as incision and drainage of a felon is needed, but should be avoided in herpetic whitlow because it may lead to an unnecessary secondary bacterial infection.
Young man with Behçet syndrome presenting with a painful penile ulcer and aphthous ulcers in his mouth. (Reproduced with permission from Richard P. Usatine, MD.)
Acyclovir is a guanosine analog that acts as a DNA chain terminator which, when incorporated, ends viral DNA replication. Valacyclovir is the l-valine ester prodrug of acyclovir that has enhanced absorption after oral administration and high oral bioavailability. Famciclovir is the oral form of penciclovir, a purine analog similar to acyclovir. They must be administered early in the outbreak to be effective, but are safe and extremely well-tolerated.6 SORⒶ
Antiviral therapy is recommended for an initial genital herpes outbreak. Table 135-1 shows the dosages for antiherpes drugs. Although systemic antiviral drugs can partially control the signs and symptoms of herpes episodes, no therapy eradicates latent virus.8
Acyclovir, famciclovir, and valacyclovir are equally effective for episodic treatment of genital herpes, but famciclovir appears somewhat less effective for suppression of viral shedding.2 SORⒷ
Effective episodic treatment of herpes requires initiation of therapy during the prodrome period or within 1 day of lesion onset. Providing the patient with a prescription for the medication with instructions to initiate treatment immediately when symptoms begin improves efficacy.2 SORⒷ
IV acyclovir therapy at 5 to 10 mg/kg IV every 8 hours for 2 to 7 days followed by oral antiviral therapy to complete at least 10 days of total therapy should be provided for patients who have severe HSV disease or complications.2 SORⒸ
HSV strains resistant to acyclovir have been detected in immunocompromised patients, so other antivirals (e.g., famciclovir) need to be considered in these patients. SORⒸ
Topical medication for HSV infection is generally not effective. Topical penciclovir applied every 2 hours for 4 days reduces clinical healing time by approximately 1 day.1,2
All patients with a first episode of genital herpes should receive antiviral therapy, as even with mild clinical manifestations initially, they can develop severe or prolonged symptoms.
Toxicity of these 3 antiviral drugs is rare, but in patients who are dehydrated or who have poor renal function, the drug can crystallize in the renal tubules, leading to a reversible creatinine elevation or, rarely, acute tubular necrosis. Adverse effects, usually mild, include nausea, vomiting, rash, and headache. Lethargy, tremulousness, seizures, and delirium have been reported rarely in studies of renally impaired patients.9
TABLE 135-1Dosages of Treatments for Genital Herpes Infection2 ||Download (.pdf) TABLE 135-1 Dosages of Treatments for Genital Herpes Infection2
|Drug ||Primary Infection Dosage ||Recurrent Infection Dosage ||Chronic Suppressive Therapy |
|Acyclovir (Zovirax) ||400 mg 3 times daily for 7 to 10 days or 200 mg 5 times daily ||400 mg 3 times daily for 5 days or 800 mg twice daily for 5 days or 800 mg 3 times daily for 2 days ||400 mg twice daily |
|Famciclovir (Famvir) ||250 mg 3 times daily for 7 to 10 days ||125 mg twice daily for 5 days or 1 g twice daily for 1 day or 500 mg once, followed by 250 mg twice daily for 2 days ||250 mg PO twice daily |
|Valacyclovir (Valtrex) ||1 g twice daily for 7 to 10 days ||500 mg twice daily for 3 days or 1 g daily for 5 days ||500 mg to 1 g once daily |
Table 135-2 provides an overview of treatments for herpes labialis.
TABLE 135-2Treatments for Herpes Labialis ||Download (.pdf) TABLE 135-2 Treatments for Herpes Labialis
|Drug ||Dose or Dosage ||Evidence Rating† |
|Episodic oral treatment for recurrences‡ |
|Acyclovir (Zovirax) ||200 mg 5 times per day or 400 mg 3 times per day for 5 days ||A |
|Famciclovir (Famvir) ||1500 mg once for 1 day ||B |
|Valacyclovir (Valtrex) ||2 g twice for 1 day ||B |
|Episodic topical treatment for recurrences‡ |
|Acyclovir cream ||Apply 5 times per day for 4 days ||B |
|Docosanol cream (Abreva) ||Apply 5 times per day until healed ||B |
|Penciclovir cream (Denavir) ||Apply every 2 hours while awake for 4 days ||B |
|Treatment to prevent recurrences |
|Acyclovir ||400 mg twice per day (ongoing) ||A |
|Valacyclovir ||500 mg once per day (ongoing) ||B |
In the treatment of primary orolabial herpes, oral acyclovir (200 mg 5 times daily for 5 days) accelerates healing by 1 day and can reduce the mean duration of pain by 36%.10 SORⒶ
The oral lesions in primary herpes gingivostomatitis can lead to poor oral intake especially in children and the elderly (Figure 135-13). To prevent dehydration, the following medications may be considered. Topical oral anesthetics such as 2% viscous lidocaine by prescription or 20% topical benzocaine over the counter (OTC) may be used to treat painful oral ulcers. SORⒸ A solution combining aluminum and magnesium hydroxide (liquid antacid) and 2% viscous lidocaine has been reported as helpful when swished and spit out several times a day as needed for pain. SORⒸ
Docosanol cream (Abreva) is available without prescription for oral herpes. One randomized controlled trial (RCT) of 743 patients with herpes labialis showed a faster healing time in patients treated with docosanol 10% cream compared with placebo cream (4.1 vs. 4.8 days), as well as reduced duration of pain symptoms (2.2 vs. 2.7 days).11 More than 90% of patients in both groups healed completely within 10 days.11 Treatment with docosanol cream, when applied 5 times per day and within 12 hours of episode onset, is safe and somewhat effective.12
Primary herpes gingivostomatitis in a 4-year-old girl. Note the cluster of ulcers inside the lower lip typical of herpes simplex virus. The patient also had involvement of her gingiva, which were swollen and painful. (Reproduced with permission from Richard P. Usatine, MD.)
Barrier protection using latex condoms is recommended to minimize exposure to genital HSV infections (see "Patient Education" below).
Suppressive therapy with antiviral drugs reduces the frequency of genital herpes recurrences by 70% to 80% in patients with frequent recurrences.2 SORⒶ Traditionally this is reserved for use in patients who have more than 4 to 6 outbreaks per year (see Table 135-1).
Short-term prophylactic therapy with acyclovir for orolabial HSV may be used in patients who anticipate intense exposure to UV light. Early treatment of recurrent orolabial HSV infection with famciclovir 250 mg 3 times daily for 5 days can markedly decrease the size and duration of lesions.13 SORⒶ
The patient should return for follow-up if pain is uncontrolled or superinfection is suspected. The patient should be periodically evaluated for the need for suppressive therapy based on the number of recurrences per year.
Measures to prevent genital HSV infection:
Abstain from sexual activity or limit number of sexual partners to prevent exposure to the disease.
Use condoms to protect against transmission, but this is not foolproof as ulcers can occur on areas not covered by condoms.
Prevent autoinoculation by patting dry affected areas, not rubbing with towel.
Studies show that patients may shed virus when they are otherwise asymptomatic. A link between HSV genital ulcer disease and sexual transmission of HIV has been established. Safer sex practices should be strongly encouraged to prevent transmission of HSV to others and acquiring HIV by the patient.
B. Herpes simplex viruses. Clin Infect Dis.
GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep.
K. Herpes simplex virus infection of the hand. A profile of 79 cases. Am J Med.
et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med.
GJ. Epidemiology of genital herpes infections. Infect Dis Clin North Am.
SL. Management of genital herpes. Am Fam Physician.
Centers for Disease Control and Prevention (CDC). Seroprevalence of herpes simplex virus type 2 among persons aged 14–49 years—United States, 2005–2008. MMWR Morb Mortal Wkly Rep.
V. Interventions for men and women with their first episode of genital herpes. Cochrane Database Syst Rev 2016(8):CD010684.
DH. Treatment of common cutaneous herpes simplex virus infections. Am Fam Physician.
et al. Treatment of recurrent herpes simplex labialis with oral acyclovir
. J Infect Dis.
et al; Docosanol
10% Cream Study Group. Clinical efficacy of topical docosanol
10% cream for herpes simplex labialis: a multi-center, randomized, placebo-controlled trial. J Am Acad Dermatol.
R. Nongenital herpes simplex virus. Am Fam Physician.
et al. Perioral famciclovir
in the treatment of experimental ultraviolet radiation-induced herpes simplex labialis: a double-blind, dose-ranging, placebo-controlled, multicenter trial. J Infect Dis.