Best Dx/Best Rx: Herpes Simplex and Herpes Zoster

Herpes Simplex

Martin S. Hirsch, MD
Harvard Medical School and Massachusetts General Hospital, Boston, MA

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

A viral disease caused by both HSV-1 and HSV-2
Humans are the only known natural hosts for HSV, although animals can be infected experimentally
Pathogenesis

Characteristic lesion is a superficial vesicle on an inflammatory base
After initial infection, HSV travels along sensory nerve pathways to ganglion cells, the site of latent infection
After reactivation, HSV reverses course and spreads peripherally by sensory nerve pathways; once virus reaches cutaneous sites, cell-to-cell spread occurs until host immune mechanisms limit further dissemination

Herpes simplex virus 1 (HSV-1)

Primary infection occurs mainly in childhood
Seroprevalence of HSV-1 infection in different populations ranges from 44% in persons 12 to 19 years of age to above 80% in those older than 60 years
Dual infection with HSV-2, found in 10% and 25% of adults
Mode of transmission

Direct contact with infected secretions, usually by oral route
Asymptomatic excretion of virus is common
Autoinoculation to other skin sites also occurs, more often with HSV-2 than with HSV-1
In respiratory care and dental care providers when fingers are placed in patients' mouths; thus, gloves should be worn

Recurrences

Occurs frequently, usually as a result of endogenous reactivation
Lip or perioral, develop in 20% to 40% of the population in the United States
Ocular herpes, 25% to 50% of infections recur within 2 years

Herpes simplex virus 2 (HSV-2)

Infection occurs predominantly in sexually active adolescents and young adults
Seroprevalence of HSV-2 infection in the United States

Increases from less than 6% in those younger than 19 years to more than 25% in those older than 30 years
Changes in sexual mores resulted in age-adjusted seroprevalence in 1990s that was 30% higher than seroprevalence in 1970s
Now detectable in one of five persons older than 12 years

Independent predictors of HSV-2 seropositivity include

Female gender
Black race
Increasing age
Less education
More lifetime sex partners
Prior occurrence of syphilis or gonorrhea
Lack of HSV-1 antibody

Dual infection with HSV-1, found in 10% and 25% of adults
Mode of transmission

Direct contact with infected secretions, usually by genital route
Asymptomatic excretion of virus is common
More efficient from males to females than from females to males
Autoinoculation to other skin sites also occurs, more often with HSV-2 than with HSV-1

Recurrences

Occurs frequently, usually as a result of endogenous reactivation
Of all primary cases of genital herpes in the United States each year, 60% to 80% will recur
Most cases represent reactivation, although exogenous reinfection can also occur
Clinically significant recurrences tend to decrease over time

Clinical syndromes

Oral-labial herpes

Most often asymptomatic in patients younger than 5 years; presents as gingivostomatitis or pharyngitis when symptomatic
Posterior pharyngitis and tonsillitis may be primary problem in adolescents and young adults
Recurrent, a shorter and milder affliction, often heralded by local pain or tingling for a few hours and healing is complete within 8 to 10 days

Ocular herpes

Most infections are caused by HSV-1
May present as unilateral follicular conjunctivitis, bleph aritis, or corneal epithelial opacities; healing is usually complete within 2 to 3 weeks
Recurrences may take form of keratitis, blepharitis, or keratoconjunctivitis
Deep stromal involvement may result in scarring, corneal thinning, and abnormal vascularization, with resultant blindness or rupture of the globe

Genital herpes

HSV-2 is causative agent in 70% to 95% of primary infections
Associated vesicular lesions

In men, often appear on the glans penis or penile shaft
In women, lesions may involve the vulva, perineum, buttocks, cervix, or vagina

Healing may take several weeks; previous infection with HSV-1 may reduce the severity and duration of first episode caused by HSV-2
Extragenital lesions develop during the course of primary infection in 10% to 18% of patients
Urinary retention may occasionally complicate primary infection, particularly in women
Recurrent episodes

Usually shorter and milder than primary episodes but still affect women more severely than men
Fewer occurrences in patients dually infected with HSV-1 and HSV-2

Healing occurs in 6 to 10 days and is usually uncomplicated; frequent asymptomatic shedding occurs, particularly in women

Perianal and anal herpes

Usually caused by HSV-2
An important problem in men who have sex with men
Vesicles and ulcerations may lead to erythematous cryptitis with inguinal adenopathy
Herpes proctitis is often prolonged and severe in patients with AIDS

Herpetic whitlow

Usually involves one digit and is characterized by intense itching or pain followed by formation of deep vesicles that may coalesce
Generally caused by

HSV-2 among general public
HSV-1 among medical and dental personnel

Lesions resolve in 2 to 3 weeks, unless they are incised, in which case healing may be delayed by secondary bacterial infection
Recurrent whitlows commonly appear and are sometimes associated with severe local neuralgia

Encephalitis, is a severe form of HSV infection
Bell palsy, HSV-1 has been implicated as an etiologic agent
Meningitis, recurrent self-limited (Mollaret meningitis), HSV-1 has been implicated as an etiologic agent
Infection in the immunocompromised host

Disorders of T cell-mediated immunity are associated with more severe HSV infections
In clinical settings such as organ transplantation, lymphoreticular neoplasm, or AIDS, HSV infection is often slow to heal and may disseminate cutaneously or to visceral organs
Certain skin conditions, such as eczema and burns, are associated with cutaneous but not visceral dissemination
Intubation or catheterization of debilitated patients may facilitate the spread of infection

Neonatal infection

Between one in 2,500 and one in 10,000 births are complicated by HSV infection, usually HSV-2
Risk of transmission is increased in premature births, after prolonged membrane rupture, and with the use of fetal scalp monitor electrodes
Severe disease

About 40% to 50% of infants born to mothers with primary infections are at risk
Fewer than 8% of infants born to women with recurrent herpes are at risk
Treatment has greatly reduced the mortality from severe infection

Infection becomes apparent several days to weeks after delivery
Newborns often present with vesicles or conjunctivitis, or a syndrome resembling neonatal sepsis may be evident
If untreated, disseminated or central nervous system infection is fatal in more than 70% of patients, whereas localized disease is generally self-limited

Differential Diagnosis

Aphthous stomatitis
Behçet syndrome
Candidiasis
Chancroid
Erythema multiforme
Herpangina
Herpes zoster
Infectious mononucleosis
Stevens-Johnson syndrome
Streptococcal pharyngitis
Syphilis

Best Tests

Physical examination usually sufficient for diagnosis
Laboratory testing for definitive diagnosis

Tissue culture systems

Diagnostic method of choice
Virus cytopathic effect is often detectable within a period of 24 to 48 hours

Immunofluorescence

With monoclonal antibodies to type-specific antigens, for typing of isolates
For direct testing of virus antigens in scrapings or tissue specimens

Immunohistochemistry, for direct testing of virus antigens in scrapings or tissue specimens
Giemsa or Wright stain, scrapings from suspected lesions, for presence of multinucleated giant cells, which indicates infection with HSV or VZV
Serologic techniques that differentiate HSV-1 from HSV-2 infections

Used to confirm diagnosis of primary HSV infection, but are seldom helpful in diagnosing recurrences
Can establish diagnosis in patients with atypical complaints, identify asymptomatic carriers, and identify persons at risk

PCR detection of HSV DNA in CSF

Standard means of diagnosing HSV encephalitis
Results are often positive within 24 hours of onset of symptoms and may remain positive during first week of illness

Best Therapy*

Preventive therapy

Vaccination

No HSV vaccine has been approved for general use
Preliminary studies of glycoprotein-D-adjuvant vaccines suggest efficacy in certain populations

Condom use may prevent sexual transmission when either sexual partner has a history of genital HSV infection
Sunscreen application to susceptible skin areas before exposure to uv light can prevent HSV reactivation
Gloves should be worn by medical and dental personnel who treat HSV-positive patients to prevent contact with infected areas
Cesarean section is indicated to prevent perinatal infection when genital herpes lesions are noted during labor
Acyclovir in late pregnancy may be useful in women with recurrent genital HSV infections

Drug therapy

For primary genital or mucocutaneous herpes (HSV-1 or HSV-2)

Acyclovir

Oral, 200 mg five times daily, for 7-10 days
Intravenous, 5 mg/kg three times daily, for 7-10 days
May be useful in high-dose short-term regimens

Valacyclovir

Oral, 500 to 1,000 mg twice daily
May be used in high-dose (1-2 g), short-term (1-2 day) regimens

Famciclovir

Oral, 250 mg three times daily
Used when its dosing of three times a day is preferred to acyclovir's five times a day

Foscarnet

Intravenous, 40 mg/kg b.i.d. to t.i.d. for 2-3 weeks
For chronic acyclovir-resistant HSV-2 infection

For suppression of severe and frequently recurring genital herpes

Acyclovir, oral, 200 to 400 mg twice daily
Valacyclovir

Oral, 500 to 1,000 mg daily
Has been shown to decrease HSV-2 excretion and transmission to partners

Famciclovir, oral, 250 mg three times daily

For herpes encephalitis, acyclovir, intravenous, in dosage of 10 to 15 mg/kg every 8 hours for 14 to 21 days
For neonatal HSV, acyclovir, intravenous, in a dosage of 20 mg/kg every 8 hours for 14 to 21 days
Acyclovir-resistant HSV infection, in immunocompromised and immunocompetent individuals

Foscarnet

Intravenous, 40 mg/kg every 8-12 hours daily for 2 to 3 weeks
Topical preparations are also under study

Cidofovir, topical preparations are under study
Trifluridine, topical preparations are under study

Best References

Bacon TH, Levin MJ, Leary JJ, et al. Clin Microbiol Rev 16:114, 2003 [PMID 12525428]

Engelberg R, Carrell D, Krantz E, et al. Sex Transm Dis 30:174, 2003 [PMID 12567178]

Scott LL, Hollier LM, McIntire D, et al. Infect Dis Obstet Gynecol 10:71, 2002 [PMID 12530483]

Wald A, Ashley-Morrow R. Clin Infect Dis 35(Suppl 2):S173, 2002 [PMID 12353203]

Whitley RJ, Roizman B. Lancet 357:1513, 2001 [PMID 11377626]

* To obtain additional drug information, click on the DrugInfo tab in the left column, or click on the following link: http://search.medscape.com/drug-reference-search?queryText=

October 2007

Herpes Zoster