Herpes Simplex

Author: Fred F. Ferri, MD

Definition

Herpes simplex is a viral infection caused by the herpes simplex virus (HSV). HSV-1 is associated primarily with oral infections, and HSV-2 causes mainly genital infections. However, either type can infect any site. After the primary infection, the virus enters the nerve endings in the skin directly below the lesions and ascends to the dorsal root ganglia, where it remains in a latent stage until it is reactivated.

Synonyms

Genital herpes
Herpes labialis
Herpes gladiatorum
Herpes digitalis
Oral herpes

ICD-10CM CODES
A60		Anogenital herpesviral (herpes simplex) infections
A60.04		Herpesviral vulvovaginitis
B00		Herpesviral (herpes simplex) infections
B00.1		Herpesviral vesicular dermatitis
B00.82		Herpes simplex myelitis
B00.9		Herpesviral infection, unspecified
P35.2		Congenital herpesviral (herpes simplex) infection

Epidemiology & Demographics

•More than 85% of adults have serologic evidence of HSV-1 infection. The seroprevalence of adults with HSV-2 in the U.S. is 25%; however, only approximately 20% of these persons recall having symptoms of HSV infection.
•Most cases of eye or digital herpetic infections are caused by HSV-1.
•Worldwide, more than 400 million persons have genital herpes caused by HSV-2. In the U.S., one in five adults is infected with HSV-2, and 1 million new infections occur yearly.
•Frequency of recurrence of HSV-2 genital herpes is higher than HSV-1 oral labial infection.
•The frequency of recurrence is lowest for oral labial HSV-2 infections.
•The incidence of complications from herpes simplex (e.g., herpes encephalitis) is highest in immunocompromised hosts.
•Male circumcision significantly reduces the incidence of HSV-2.

Physical Findings & Clinical Presentation

Primary Infection

•Symptoms occur from 3 to 7 days after contact (respiratory droplets, direct contact).
•Constitutional symptoms include low-grade fever, headache and myalgias, regional lymphadenopathy, and localized pain.
•Pain, burning, itching, and tingling last several hours.
•Grouped vesicles, usually with surrounding erythema, appear and generally ulcerate or crust within 48 h (Fig. E1).
•The vesicles are uniform in size (differentiating it from herpes zoster vesicles, which vary in size). Scattered erosions covered with exudate may be noted on genitals (Fig. E2).
•During the acute eruption the patient is uncomfortable; involvement of lips and inside of mouth (Fig. E3) may make it unpleasant for the patient to eat; urinary retention may complicate involvement of the genital area.
•Lesions generally last from 2 to 6 wk and heal without scarring.
•Herpes whitlow is a term generally applied to HSV infection of fingers or toes, although strictly speaking, it refers to HSV infection of the paronychia. Among children, this condition is most commonly seen in infants and toddlers who suck the thumb or fingers and who are experiencing either a symptomatic or a subclinical oral HSV-1 infection (Fig. E4). An HSV-2 herpes whitlow occasionally develops in an adolescent as a result of exposure to infectious genital secretions. The onset of the infection is heralded by itching, pain, and erythema 2 to 7 days after exposure. The cuticle becomes erythematous and tender and may appear to contain pus, although if it is incised, little fluid is present. Incising the lesion is discouraged, as this maneuver typically prolongs recovery and increases the risk for secondary bacterial infection. Lesions and associated pain typically persist for about 10 days, followed by rapid improvement and complete recovery in 18 to 20 days. Regional lymphadenopathy is common, and lymphangitis and neuralgia may occur. Unlike other recurrent herpes infections, recurrent herpetic whitlows are often as painful as the primary infection but are generally shorter in duration.

Figure E1 Herpetic gingivostomatitis.

Multiple erosions with crusting. Note the associated lesions involving the chin.

(From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

Figure E2 Primary herpes simplex.

A, Scattered erosions covered with exudate. B, Numerous erosions appeared 4 days after contact with an asymptomatic carrier.

(From Habif TP: Clinical dermatology, ed 4, Philadelphia, 2004, Mosby.)

Figure E3 Herpes labialis.

Erythematous erosions clustered on the right lower lip in a patient with labial herpes. This young girl also had herpes-associated erythema multiforme.

(From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

Figure E4 Herpes simplex infection of finger (whitlow).

(From Schachner LA, Hansen RC [eds]: Pediatric dermatology, ed 3, Philadelphia, 1988, Mosby, p. 1079.)

Recurrent Infection:

•Generally caused by alteration in the immune system; fatigue, stress, menses, local skin trauma, and exposure to sunlight are contributing factors.
•The prodromal symptoms (fatigue, burning and tingling of the affected area) last 12 to 24 h.
•A cluster of lesions generally evolves within 24 h from a macule to a papule and then vesicles surrounded by erythema; the vesicles coalesce and subsequently rupture within 4 days, revealing erosions covered by crusts.
•The crusts are generally shed within 7 to 10 days, revealing a pink surface.
•The most frequent location of the lesions is on the vermilion border of the lips (HSV-1), the penile shaft or glans penis and the labia (HSV-2), buttocks (seen more frequently in women), fingertips (herpetic whitlow), and trunk (may be confused with herpes zoster).
•Rapid onset of diffuse cutaneous herpes simplex (eczema herpeticum) may occur in certain atopic infants and adults. It is a medical emergency, especially in young infants, and should be promptly treated with acyclovir.
•Herpes encephalitis, meningitis, and ocular herpes can occur in patients with immunocompromised status and occasionally in normal hosts.

Etiology

HSV-1 and HSV-2 are both DNA viruses.

Diagnosis ⬆ ⬇

Differential Diagnosis

•Impetigo
•Behçet syndrome
•Coxsackie virus infection
•Syphilis, chancroid, granuloma inguinale (Table 1)
•Stevens-Johnson syndrome
•Herpangina
•Aphthous stomatitis
•Varicella
•Herpes zoster

TABLE 1 Features of Sexually Transmitted Infections Characterized by Genital Ulcers

	Syphilis	Genital Herpes	Chancroid	Granuloma Inguinale (Donovanosis)
Agent	Treponema pallidum	HSV-1, HSV-2	Haemophilus ducreyi	Klebsiella granulomatis
Incubation	10-90 days	2-14 days	1-10 days	8-80 days
Systemic findings	Primary syphilis: Uncommon Secondary syphilis: Fever, rash, malaise, anorexia, arthralgia, lymphadenopathy	Headache, fever, malaise, myalgia (40%-70%)	None	Local spread only
Inguinal lymphadenopathy	Late, bilateral, nontender, no suppuration	Early, bilateral, tender, no suppuration	Early, rapid, tender, and unilateral; suppuration likely (bubo)	Lymphatic obstruction
Primary lesion	Papule	Vesicle	Papule to pustule	Subcutaneous nodule
Ulcer Characteristics
Number	Usually 1	Multiple	<3	>1, may coalesce
Edges	Distinct	Reddened, ragged	Sharply demarcated, serpiginous borders	Rolled, distinct
Depth	Shallow	Shallow	Shallow	Raised
Base	Red, smooth	Red, smooth	Necrotic	Beefy red, clean
Secretion	Serous	Serous	Purulent	None
Induration	Firm	None	None	Firm
Pain	None	Usual	Often	None
Diagnosis
Serology	MHA-TP or FTA-ABS; VDRL or RPR	Seroconversion (primary infection only)	None	None
Isolation	No in vitro test; rabbit testes inoculation	Culture	Swab of ulcer on selective medium, node aspirates usually sterile	None
Microscopic	Dark-field examination	PCR or fluorescent antibody staining	Gram-negative coccobacilli	Staining of ulcer biopsy material for Donovan bodies
Treatment	Early (primary, secondary and early latent):Benzathine penicillin G (2.4 million U IM) once	Acyclovir or famciclovir or valacyclovir	Aspirate or excise fluctuant nodes	Doxycyclineorazithromycin
	Late latent (>1 yr duration): Benzathine penicillin G (2.4 million U IM) weekly × 3 doses		Incision and drainage of buboes >5 cm Azithromycin or ceftriaxone or ciprofloxacin or erythromycin

FTA-ABS, Fluorescent treponemal antibody-absorption; HSV, herpes simplex virus; IM, intramuscular; MHA-TP, microhemagglutination assay-Treponema pallidum; PCR, polymerase chain reaction; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratory.

From Marcdante KJ et al: Nelson essentials of pediatrics, ed 9, Philadelphia, 2023, Elsevier.

Workup

Diagnosis is based on clinical presentation. Laboratory evaluation confirms diagnosis.

Laboratory Tests

•Direct immunofluorescent antibody slide tests provide a rapid diagnosis.
•Viral culture is the most definitive method for diagnosis; results are generally available in 1 or 2 days. The lesions should be sampled during the vesicular or early ulcerative stage; cervical samples should be taken from the endocervix with a swab.
•Pap smear will detect HSV-infected cells in cervical tissue from women without symptoms.
•Serologic tests for HSV: Immunoglobulin (Ig) G and IgM serum antibodies. Antibodies to HSV occur in 50% to 90% of adults. The presence of IgM or a fourfold or greater rise in IgG titers indicates a recent infection (convalescent sample should be drawn 2 to 3 wk after the acute specimen is drawn).
•Tzanck smear is a readily available test that will demonstrate multinucleated giant cells. However, it is not a highly sensitive test.

Treatment ⬆ ⬇

•Herpes genitalis: Because no cure exists for herpes genitalis, treatment is focused on reducing the number of recurrences through suppressive therapy and on promoting rapid healing when a recurrence is present. In addition, treatment aims to reduce infectivity by reducing viral shedding and to reduce complications, such as urinary retention and aseptic meningitis. Tables 2 and 3 summarize antiviral chemotherapy for HSV infection.
•Herpes labialis: Antiviral therapy shortens the duration of discomfort/pain, hastens healing, and reduces viral shedding, thereby reducing dissemination of HSV. Treatment should be initiated ideally in the prodromal stage and no later than 48 h from the onset of lesions to obtain maximal clinical effect. Oral antiviral agents for herpes labialis include docosanol, famciclovir, and valaciclovir, and they are superior to topical antiviral agents. Topical acyclovir, penciclovir, and docosanol are optional treatments for recurrent herpes labialis, but they are less effective than oral treatments.

TABLE 2 Topical and Oral Antiviral Medications Used for Herpes Simplex Virus Infections *

Drug	Formulation	Regimen	Indication/Comment
Topical
Acyclovir	5% cream (2 g, 5 g)	Apply 5 times/day	Recurrent HL; A: ≥12 yr; 4 days; Rx
	5% ointment (15 g, 30 g)	Apply 6 times/day	Initial GH, localized HSV; A: Adults; 7 days; Rx
Penciclovir	1% cream (1.5 g, 5 g)	Apply q2h (awake)	Recurrent HL; A: ≥12 yr; 4 days; Rx
Docosanol	10% cream (2 g)	Apply 5 times/day	HL; A: ≥12 yr; treat until healed; OTC
Oral (all Rx)
Acyclovir	200-mg capsule		A: ≥2 yr
	400-mg, 800-mg tablet
	200-mg/5-ml susp
		200 mg 5 times/day	Initial GH; 10 days
		200 mg 5 times/day	Recurrent GH; 5 days
		400 mg 2 times/day	Suppression, recurrent GH; up to 12 mo, then reevaluate
Famciclovir	125-, 250-, 500-mg tablet		A: ≥18 yr
		1500-mg single dose	Recurrent HL
		1000 mg 2 times/day	Recurrent GH; 1 day
		250 mg 2 times/day	Suppression, recurrent GH; up to 12 mo
Valacyclovir	500-mg, 1-g caplet		A: Adults and ≥12 yr for HL
		1 g 2 times/day	Initial GH; 10 days
		500 mg 2 times/day	Recurrent GH; 3 days
		500 mg-1 g once daily	Suppressive GH
		2 g 2 times/day	HL; 1 day; both adults and children ≥12 yr

A, Approved; GH, genital herpes; HL, herpes labialis; HSV, herpes simplex virus; OTC, over-the-counter; Rx, by prescription.

^*Approved indications and regimens listed; often used off-label.

From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.

TABLE 3 Antiviral Treatment for Herpes Simplex Virus in the Nonpregnant Patient

	Antiviral Agent
Indication	Valacyclovir	Acyclovir	Famciclovir
First clinical episode	1000 mg bid, 7-10 days	400 mg tid; or 200 mg five times/day, 7-10 days	250 mg tid, 7-10 days
Recurrent episodes	1000 mg daily, 5 days; or 500 mg bid, 3 days	800 mg bid, 5 days; or 800 mg tid, 2 days	125 mg bid, 5 days 500 mg once then 250 mg bid, 2 days; 1000 mg bid, 1 day
Daily suppressive	1000 mg daily (≥10 recurrences/yr) or 500 mg daily (≤9 recurrences/yr)	400 mg bid	250 mg bid

bid, Twice per day; tid, three times per day.

Data from Workowski KA, Bolan GA: Centers for Disease Control and Prevention: sexually transmitted diseases treatment guidelines, 2015, MMWR Recomm Rep 64(RR-03):1-137, 2015; Gershenson DM et al: Comprehensive gynecology, ed 8, Philadelphia, 2022, Elsevier.

Disposition

Most patients recover from the initial episode or recurrences without complications; immunocompromised hosts are at risk for complications (e.g., disseminated herpes simplex infection, herpes encephalitis).

Referral

•Hospital admission in patients with herpes encephalitis or herpes meningitis and in immunocompromised hosts with diffuse herpes simplex infection
•Ophthalmology referral in patients with suspected ocular herpes

Pearls & Considerations ⬆

Comments

•Provide patient education regarding transmission of HSV.
•Condom use offers significant protection against HSV-1 infection in susceptible women.
•Patients should be instructed on the use of condoms for sexual intercourse and on avoiding kissing or sexual intercourse until lesions are crusted. Pericoital application of tenofovir gel, an antiretroviral vaginal gel, has also been shown to reduce the risk of HSV-2 in women. This may be useful in regions of the world where use of condoms is shunned.
•Patients should also avoid contact with immunocompromised hosts or neonates while lesions are present.
•Proper handwashing techniques should be explained.
•Patients with herpes gladiatorum (cutaneous herpes in athletes involved in contact sports) should be excluded from participation in active sports until lesions have resolved.
•Many new HSV-2 infections are asymptomatic. Since HSV-2 antibody tests have become commercially available, an increasing number of persons have learned that they have genital herpes through serologic testing. Persons with asymptomatic HSV-2 infection shed virus in the genital tract less frequently than persons with symptomatic infection, but much of the difference is attributable to less frequent genital lesions because genital lesions are accompanied by frequent viral shedding. The U.S. Preventive Services Task Force (USPSTF) recommends against routine serologic screening for genital HSV infection in asymptomatic adolescents and adults, including those that are pregnant.
•Suppressive treatment of HSV-2 infection lowers the incidence of genital lesions by 70% to 80% but cuts the rate of HSV-2 transmission to uninfected partners by only 50%.
•Pregnancy: Antiviral prophylaxis with acyclovir is recommended from 36 wk of gestation until delivery in women with a history of genital herpes. Elective cesarean delivery should be performed in laboring patients with active lesions to decrease the risk of neonatal herpes.
•Trials involving investigational herpes simplex vaccine have found it to be effective in preventing HSV-1 genital disease and infection, but not in preventing HSV-2 disease or infection.

Related Content

Genital Herpes (Patient Information)
Oral Herpes (Patient Information)

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆