BASICSCecilia M. Kipnis, MD
BASICS
DESCRIPTION
• Chronic, recurrent infection of any area innervated by the sacral ganglia
• Due to herpes simplex virus (HSV) type 1 or 2
• HSV-1 causes anogenital and orolabial lesions.
• HSV-2 causes anogenital lesions.
• Primary episode: occurs in the absence of preexisting antibodies to HSV-1 or HSV-2 (may be asymptomatic)
• First episode nonprimary: initial genital eruption; preexisting antibodies are present.
• Reactivation: recurrent episodes
• Synonym(s): herpes genitalis
EPIDEMIOLOGY
• Predominant age of infection 15 to 30 years; prevalence increases with age due to cumulative likelihood of exposure.
• Predominant sex: female > male
• Predominant race: non-Hispanic blacks
Incidence
>700,000 new cases per year in the United States
Prevalence
• Overall prevalence of HSV-2 is 10–40% in the general population and up to 60–95% in the HIV-positive population (1).
• Up to 90% of seropositive persons lack formal diagnosis.
• >50 million are infected with HSV-2 in the United States.
ETIOLOGY AND PATHOPHYSIOLOGY
• HSV is a double-stranded DNA virus of the Herpetoviridae family (1).
• Spread via genital-to-genital contact, oral-to-genital contact, and via maternal–fetal transmission (2).
• Incubation is 4 to 7 days after exposure.
• Risk of transmission highest when lesions are present
• Viral shedding is possible in the absence of lesions, increasing the risk of transmission since precautions may not be followed (abstinence, condom use). Viral shedding occurs intermittently and unpredictably.
• HSV infection increases the risk for HIV.
RISK FACTORS
• Risk increases with age, number of lifetime partners, history of sexually transmitted infections (STIs), history of HIV, sexual encounters before the age of 17 years, and partner with HSV-1 or HSV-2.
• Infection with HSV-1 increases the risk of being infected with HSV-2 by 3-fold.
• Immunosuppression, fever, stress, and trauma increases risk of reactivation.
COMMONLY ASSOCIATED CONDITIONS
Syphilis, HIV, chlamydia, gonorrhea, and other STIs
DIAGNOSIS
HISTORY
• Many patients are asymptomatic (74% of HSV-1 and 63% of HSV-2) or do not recognize clinical manifestations of disease (2).
• If symptoms are present during primary episode, they are often more severe, longer in duration, and associated with constitutional symptoms.
• Common presenting symptoms (primary episode): multiple genital ulcers, dysuria, pruritus, fever, tender inguinal lymphadenopathy, headache, malaise, myalgias, cervicitis/dyspareunia, urethritis (watery discharge)
• First episode, nonprimary: In general, symptoms are less severe than primary episode.
• Common presenting symptoms for recurrent episodes: prodrome of tingling, burning, or shooting pain (2 to 24 hours before lesion appears); single ulcer; lesion can be atypical in appearance; dysuria; pruritus (lasting 4 to 6 days on average)
• Recurrent episodes are more frequent with HSV-2 than with HSV-1, especially the first year after infection. Recurrences are less frequent over time.
• Less common presentations: constipation (from anal involvement causing tenesmus), proctitis, stomatitis, pharyngitis, sacral paresthesias
PHYSICAL EXAM
• Lesions occur in “boxer short” distribution and within anus, vagina, and on cervix.
• Lesion may appear as papular, vesicular, pustular, ulcerated, or crusted; can be in various stages
• Inguinal lymphadenopathy
• Extragenital manifestations include meningitis, recurrent meningitis (Mollaret syndrome), sacral radiculitis/paresthesias, encephalitis, transverse myelitis, and hepatitis
Pediatric Considerations
• Neonatal infection occurs in 20 to 50/100,000 live births; 80% of infections result from asymptomatic maternal viral shedding during an undiagnosed primary infection in the 3rd trimester.
• Transmission ranges from 30–50% if the primary episode is near time of delivery. Neonatal disease is associated with high morbidity and mortality.
• Suspect sexual abuse with genital lesions in children.
DIFFERENTIAL DIAGNOSIS
• HIV; syphilis; chancroid
• Herpes zoster
• Ulcerative balanitis
• Granuloma inguinale
• Lymphogranuloma venereum
• Cytomegalovirus; Epstein-Barr virus
• Drug eruption
• Trauma
• Behçet syndrome
• Neoplasia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
• Confirm clinical diagnosis with laboratory testing
• Viral isolation from lesion (swab or scraping)
– Culture and PCR are preferred (3)[A].
– Use Dacron or polyester-tipped swabs with plastic shafts (cotton tips/wood shafts inhibit viral growth and/or replication) (1).
– Culture by unroofing vesicle to obtain fluid sample. Specificity >99%; sensitivity depends on sample: 52–93% for vesicle, 41–72% for ulcer, 19–30% for crusted lesion (1,3).
– Culture requires timely transport of live virus to the laboratory in appropriate medium at 4°C.
– PCR has the greatest sensitivity (98%) and specificity (>99%) but is also expensive and not readily available. It can increase detection rates by up to 70% (4). Used primarily for CSF (1)
• Type-specific serologic assays
– Western blot (gold standard) and type-specific IgG antibody (glycoprotein G) enzyme-linked immunosorbent assay (ELISA) are used to discriminate between HSV-1 and HSV-2 (3)[B].
– Western blot is >97–99% sensitive and specific but labor intensive and not readily available (1,3).
– ELISA 81–100% sensitive; 93–100% specific (1).
– Seroconversion occurs 10 days to 4 months after infection (3). Antibody testing is not necessary if a positive culture or PCR has been obtained.
– IgM antibody testing is not useful because HSV IgM is often present with recurrent disease and does not distinguish new from old infection.
– Screening with type-specific antibody in the general population is not recommended (3) but may be considered in:
Asymptomatic patients with HIV infection
Discordant couples (one partner with known HSV, the other without)
Patients with recurrent symptoms but no active lesions
TREATMENT
GENERAL MEASURES
• Ice packs to perineum, sitz baths, topical anesthetics
• Analgesics, NSAIDs
MEDICATION
Antiviral medications should be started within 72 hours of onset of symptoms (including prodrome). If presentation is >72 hours, antivirals may be helpful if new lesions continue to form or patient is experiencing significant pain.
First Line
• Acyclovir (4)[A]: the most studied antiviral in genital herpes. Decreases pain, duration of viral shedding, and time to full resolution
– Primary episode
400 mg PO TID for 7 to 10 days
200 mg PO 5 times a day for 7 to 10 days
Longer if needed for incomplete healing
200 mg 5 times per day for 5 days
400 mg TID for 5 days
800 mg BID for 5 days
800 mg TID for 2 days
– Daily suppression
400 mg BID
– Severe, complicated infections requiring IV therapy
5 to 10 mg/kg/dose q8h until clinical improvement; switch to PO therapy to complete a 10-day course.
– HIV infection: 400 mg PO 3 to 5 times per day until clinical resolution is attained
– Precautions
Modify dose in renal insufficiency.
• Valacyclovir (Valtrex) (4)[A]: prodrug of acyclovir, improved bioavailability, less frequent dosing
– Primary episode
1 g PO BID for 7 to 10 days
– Episodic therapy
500 mg PO BID for 3 to 5 days
1 g PO daily for 5 days
– Daily suppression
500 mg PO daily
1 g PO daily
• Famciclovir (Famvir) (4)[A]
– Primary episode
250 mg PO TID for 7 to 10 days
– Episodic therapy
125 mg PO BID for 5 days
1 g PO BID for 1 day
– Daily suppression: 250 mg PO BID
ISSUES FOR REFERRAL
• For acyclovir-resistant HSV, in consultation with infectious disease specialist (4)[A]:
– Foscarnet: 40 mg/kg/dose IV q8h until clinical resolution
Associated with significant toxicity
– Cidofovir: 5 mg/kg IV once weekly
Pregnancy Considerations
• SCREENING: Pregnant women who test antibody negative for HSV-1 and HSV-2 should avoid sexual contact in the 3rd trimester if their partner is antibody positive.
• SUPPRESSIVE THERAPY: Pregnant women with a history of genital herpes should be offered suppression treatment starting at 36 gestational weeks until delivery to decrease reactivation rate. Goal is to reduce the risk of neonatal infection. Recommended regimens to continue until delivery:
– Acyclovir 400 mg PO TID
– Valacyclovir 500 mg PO BID
• Monitor for outbreaks during pregnancy and examine for any lesions at the onset of labor. C-section is recommended if prodromal symptoms or lesions are present at onset of labor to reduce neonatal transmission.
Pediatric Considerations
• High-risk infants include those with active symptoms or lesions, those delivered vaginally with maternal lesions present, and those born during a primary maternal episode. Monitor closely; obtain diagnostic laboratory specimens (HSV PCR and ocular, nasal, anal, and oral cultures). If symptomatic, will require prolonged treatment:
– Acyclovir 20 mg/kg IV q8 for 14 days if skin or mucosal lesions, 21 days if disseminated or CNS disease (4)[A]
• Low-risk infants who are asymptomatic can be observed while obtaining serum HSV PCR and ocular, nasal, anal, and oral cultures.
• Infants with possible HSV infection should be isolated from other neonates; maternal separation is not necessary and breastfeeding is not contraindicated.
ONGOING CARE
GENERAL PREVENTION
• Use barrier contraception and avoid sexual contact when symptoms/lesions are present to decrease risk of transmission.
• Abstinence is the only means of complete protection.
Patient Monitoring
Test for HIV and other STIs.
PATIENT EDUCATION
• Counseling is extremely important for treating subsequent outbreaks and for reducing risk of transmission:
– Treatment options include daily suppressive therapy versus episodic therapy
– Alert partners of history prior to sexual activity
– Avoid sexual contact when symptoms or lesions are present.
– Viral shedding and thus transmission can occur even when symptoms/lesions are NOT present.
Shedding is increased with HSV-2 disease and with HIV.
– Condom use 100% of the time can reduce the risk of transmission of HSV-2 by 30% (6)[A].
– Sexual activity between concordant couples (i.e., both partners with the same type of herpes [HSV-1 or HSV-2]) does not increase risk of outbreaks.
– Alert physician of history in pregnancy.
• Herpes Resource Center: http://www.ashasexualhealth.org/stdsstis/herpes/
• Centers for Disease Control and Prevention: http://www.cdc.gov/
PROGNOSIS
• Resolution of signs/symptoms: 3 to 21 days
• Average recurrence rate is 1 to 4 episodes per year (2).
• Antivirals do not eliminate virus from body but can reduce transmission, shedding, and outbreaks.
Pediatric Considerations
Neonatal infection survival rates: localized >95%, CNS 85%, systemic 30%
COMPLICATIONS
Behavioral issues include lowered self-esteem, guilt, anger, depression, fear of rejection, and fear of transmission to partner.
REFERENCES
1. LeGoff J, Péré H, Bélec L. Diagnosis of genital herpes simplex virus infection in the clinical laboratory. Virol J. 2014;11:83.
2. Hofstetter AM, Rosenthal SL, Stanberry LR. Current thinking on genital herpes. Curr Opin Infect Dis. 2014;27(1):75–83.
3. Geretti AM. Genital herpes. Sex Transm Infect. 2006;82(Suppl 4):iv31–iv34.
4. Centers for Disease Control and Prevention. 2015 sexually transmitted diseases treatment guidelines. http://www.cdc.gov/std/tg2015. Accessed October 6, 2016.
5. ACOG Committee on Practice Bulletins. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 82 June 2007. Reaffirmed 2016. Management of herpes in pregnancy. Obstet Gynecol. 2007;109(6):1489–1498.
6. Martin ET, Krantz E, Gottlieb SL, et al. A pooled analysis of the effect of condoms in preventing HSV-2 acquisition. Arch Intern Med. 2009;169(13):1233–1240.
ADDITIONAL READING
• Dhankani V, Kutz JN, Schiffer JT. Herpes simplex virus-2 genital tract shedding in not predictable over month or years in infected persons. PLoS Comput Biol. 2014;10(11):e1003922.
• Gnann JW Jr, Whitley RJ. Genital herpes. N Engl J Med. 2016;375(7):666–674.
• Money D, Steben M. SOGC clinical practice guidelines: guidelines for the management of herpes simplex virus in pregnancy. Number 208, June 2008. Int J Gynaecol Obstet. 2009;104(2):167–171.
• Tavares F, Cheuvart B, Heineman T, et al. Meta-analysis of pregnancy outcomes in pooled randomized trials on a prophylactic adjuvanted glycoprotein D subunit herpes simplex virus vaccine. Vaccine. 2013;31(13):1759–1764.
• Tobian AA, Grabowski MK, Serwadda D, et al. Reactivation of herpes simplex virus type 2 after initiation of antiretroviral therapy. J Infect Dis. 2013;208(5):839–846.
SEE ALSO
Algorithm: Genital Ulcers
CODES
ICD10
• A60.00 Herpesviral infection of urogenital system, unspecified
• A60.04 Herpesviral vulvovaginitis
• A60.09 Herpesviral infection of other urogenital tract
CLINICAL PEARLS
• Genital herpes can be caused by HSV-1 and HSV-2.
• Many seropositive individuals are unaware that they are infected.
• Most primary episodes are asymptomatic.
• Viral shedding occurs in the absence of lesions.
• Regular (100%) condom use decreases transmission significantly.