Herpes

Genital herpes infections are common sexually transmitted infections caused by herpes simplex virus (HSV) type 1 or 2. Herpes simplex virus type 1 is more commonly associated with non-genital herpes, while HSV-2 is more commonly associated with genital herpes. Primary infection often presents with systemic, prodromal symptoms followed by clusters of painful, fluid-filled vesicles on an erythematous base, dysuria, and painful lymphadenopathy. Primary infection can also be asymptomatic. Herpes infections are unique in that the virus is able to remain dormant in the neuronal ganglia, which allows for recurrent infections. Recurrent outbreaks are usually less severe than the initial infection. Treatment is with antiviral therapy, primarily acyclovir.

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Definition

Genital herpes is a mucocutaneous ulcerative disease caused by either herpes simplex virus (HSV) type 1 or 2.

HSV-1:

  • Traditionally associated with gingivostomatitis (“cold sores”) and non-genital infections
  • However, HSV-1 is now also associated with genital herpes. The reason is unknown but thought to be due to a decrease in the number of oral HSV-1 infections, leading people to be more susceptible to genital HSV-1 infections.
  • Usually acquired in childhood

HSV-2:

  • Traditionally (and most commonly) associated with genital herpes
  • Usually acquired after puberty

Epidemiology

  • Worldwide: more prevalent in young adults
  • Centers for Disease Control and Prevention (CDC) estimates (in the United States):
    • Incidence (HSV-1 and -2): approximately 800,000 new cases/year
    • HSV-2:
      • Prevalence: 12% of persons aged 1449 years old
      • Most infected persons are unaware: approximately 88% of infected 1449-year-olds have never been diagnosed
  • Very common in countries that have HIV epidemics
    • Prevalence in HIV populations (in Africa): approximately 70%
    • Because genital herpes causes skin breakdown and ulcerations, it is associated with an increased risk of HIV transmission.
  • Immunodeficient patients are at risk of developing more severe recurrent genital herpes with possible invasive systemic illness.
Epidemiology of Herpes

Global seroprevalence of herpes simplex virus type 2 infection

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Etiology

Causative agent: herpes simplex virus

  • Enveloped
  • Double-stranded, linear DNA
  • Replicates within the nucleus of host cells

Transmission

  • The majority of infections are transmitted by asymptomatic individuals. 
  • Person-to-person transmission during sexual activity, by direct contact with:
    • Mucosal surfaces
    • Genital secretions
    • Oral secretions
    • HSV herpetic lesions
  • Vertical transmission (TORCH infection: Toxoplasmosis, Other agents, Rubella, Cytomegalovirus, and Herpes simplex)
  • Less commonly, can be acquired from non-genital herpetic lesions that are found on the fingers, eyes, or lips of an infected individual

Risk factors

  • Gender: female > male
  • Race: African Americans > Caucasians 
  • Sexual practices
    • New sexual relationships
    • Infrequent condom usage
    • Men who have sex with men (MSM)

Pathophysiology

Primary infection

Primary infection occurs when the virus travels through tiny breaks or even microscopic abrasions in the skin or mucous membranes in the mouth or genital areas.

  • Replication begins in cells of the epidermis and dermis.
    • Virions replicate within the nucleus, forming intranuclear inclusion bodies (Cowdry bodies) that may be visible on a Tzanck smear.
    • Infected cells undergo cell lysis: causes painful vesicles and ulcerations
  • Sensory and autonomic nerve endings are also infected.
    • Once infected, viral particles are transported to nerve cell bodies in the sacral ganglia (via retrograde transport). This transport is independent of virus multiplication and local inflammation.
    • Once in the ganglia, the virus is able to replicate and enter a dormant state known as latency.
      • Protected from the immune system, the virus is able to stay dormant.
      • This allows for the potential of lifelong reactivation.

Recurrent infection

Recurrent infection is due to HSV reactivation.

  • Reactivation can occur due to psychological stress (related to activation by the stress hormones epinephrine and corticosterone), physical illness, immunosuppression, or for no apparent reason.
  • Viral DNA replication begins in the ganglia.
    • Virions then migrate down the affected nerve following a dermatomal distribution.
    • Causes recurrent symptoms of skin vesicles, ulcers, and crusting
Pathophysiology of herpes

Pathophysiology of herpes

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Signs and Symptoms

Genital herpes infection can be symptomatic or asymptomatic/subclinical and is defined as either primary, non-primary, or recurrent.

Primary

  • Occurs in patients with no pre-existing antibodies
  • More common in patients who have recently become sexually active
  • Incubation period: 2–12 days
  • Presentation is variable:
    • Patients may develop a prodrome of systemic features (fever, headache, malaise) with localized pain and itching, dysuria, or tender lymphadenopathy
    • Painful genital ulcers: begins as an erythematous lesion then develops into a group of vesicles and pustules 
    • Distribution in men: prepuce and subpreputial areas of the penis
    • Distribution in women: vagina, vulva, and cervix
  • Healing usually takes place within 1 month and leaves no scarring.

Non-primary

  • Acquisition of HSV-1 in a patient with pre-existing antibodies to HSV-2 (or vice versa)
  • Presentation is usually associated with fewer lesions and fewer systemic symptoms than during primary infection.

Recurrent

  • Occurs due to reactivation of HSV infection
  • Recurrence is more common with HSV-2 and in immunodeficient patients.
  • Presentation is usually less severe, with fewer lesions and shorter duration (7–10 days).
    • Can occur as frequently as 10 times per year
    • Recurrence usually decreases over time.

Other forms of herpetic infections

Other forms of herpetic infections associated with HSV-1 include:

  • Herpetic gingivostomatitis
    • Also known as cold sores
    • Painful, fluid-filled lesions on an erythematous base
  • Herpetic whitlow
    • Herpetic lesions on the finger or hand
    • Most common in:
      • Children with active oral HSV lesions who suck their thumbs
      • Health care personnel or others who don’t wear gloves while feeding patients who cannot feed themselves
      • Dentists and dental hygienists
  • Herpes gladiatorum
    • Herpetic lesions on neck/wrist
    • More common in those participating in contact sports (e.g., wrestlers)

Diagnosis

A diagnosis of genital herpes should be confirmed with laboratory testing. The classic appearance is that of multiple, clear, fluid-filled vesicles on an erythematous base. A diagnostic clue is that the vesicles are painful and tend to be clustered into small groups, although the presentation can vary widely. 

Laboratory testing possibilities include:

  • Polymerase chain reaction (PCR)
    • Preferred if active lesions present; can also detect asymptomatic HSV shedding
    • Has the greatest sensitivity and specificity
  • Direct microscopy: Tzanck smear 
    • Fluid from the vesicles is smeared onto a slide and stained with Giemsa.
    • Reveals multinucleated giant cells, ground glass nuclei, nuclear molding, and, possibly, eosinophilic intranuclear inclusions (type A Cowdry bodies)
  • Viral culture
    • Preferred if active lesions present
    • Lesion should be unroofed and vesicular fluid cultured
    • Sensitivity is only approximately 50%; therefore, PCR is becoming more acceptable as a gold-standard diagnostic modality.
  • Direct fluorescent antibody or type-specific serologic tests 
    • Differentiates HSV-1 and -2
    • Can be used to determine serologic baseline to help determine if a sexual partner has been infected, for example

Management

Antiviral therapy

  • Antiviral therapy is used to shorten the duration of symptoms.
    • Should be started as soon as possible after lesion appearance
    • First-line:
      • Oral acyclovir (TID dosing) 
      • Valacyclovir (BID dosing)
    • For acyclovir-resistant strains: foscarnet
  • For central nervous system (CNS) involvement and systemic disease: IV acyclovir
  • For recurrent infections: Patients are able to self-administer oral antiviral therapy for episodic outbreaks. Patients should begin therapy when prodromal symptoms occur (tingling, paresthesias, or pruritus).
  • Chronic suppressive therapy may be required for those with severe and frequent (> 6 outbreaks/year) outbreaks.

Management in pregnancy

  • Pregnant women who present with HSV lesions should be started on daily antiviral suppressive therapy (acyclovir) at 36 weeks’ gestation.
  • Cesarean delivery is recommended if lesions are present during labor.
  • Decreases but does not eliminate the risk of neonatal HSV infection

Prevention

Prevention is accomplished through patient education, the use of barrier contraceptive devices, and chronic suppressive therapy.

  • Encourage informing sexual partners and the use of barrier contraceptive devices: consistent condom use can decrease HSV-2 transmission by up to 96%!
  • Remember that antiviral therapy does not eradicate the latent virus.
    • Recurrence is expected and will likely be less severe than the initial outbreak.
    • Transmission can occur during asymptomatic periods due to viral shedding.
    • Patients should remain abstinent when lesions or prodromal symptoms present.

Complications

  • Meningitis
    • Accounts for 5% of all viral encephalitis in the United States
    • Most are due to HSV-2
  • Encephalitis
    • HSV causes 10%20% of all sporadic viral encephalitis in the United States
    • > 95% caused by HSV-1
  • Neonatal herpes and encephalitis (can be caused by either HSV-1 or HSV-2)
  • In immunocompromised patients, HSV may cause:
    • Vast skin involvement
    • Chronic herpetic ulcers
    • Widespread mucous membrane damage
    • Systemic infections with involvement of the central and peripheral nervous systems, gastrointestinal (GI) tract, and ocular system

Differential Diagnosis

The differential diagnosis of genital herpes includes the following conditions:

  • Primary syphilis:
    • Caused by the Gram-negative spirochete Treponema pallidum
    • Presents with painless, well-demarcated, indurated ulcerations
  • Chancroid:
    • Caused by the Gram-negative coccobacilli Haemophilus ducreyi
    • Presents as a deep, purulent ulcer with painful lymphadenopathy
  • Granuloma inguinale:
    • Caused by Klebsiella granulomatis; not common in the United States
    • Presents as a painless, beefy-red ulceration that bleeds on contact
  • Chlamydia trachomatis serovars L1-3: the causative agents of lymphogranuloma venereum (LGV)
  • Behcet’s syndrome:
    • Rare vasculitis syndrome
    • Presents with painful oral and genital lesions that often cause scarring, ocular inflammation, arthritis, ulcers of the GI tract, and neurological symptoms

References

  1. Corey L. Herpes simplex virus infections. (2018). In Jameson JL, et al. (Ed.), Harrison’s principles of internal medicine (20th ed). Vol 1, pp 1345-1354. New York, NY: McGraw-Hill.
  2. Albrecht, MA. (2018). Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection. UpToDate. Retrieved September 1, 2020, from https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-genital-herpes-simplex-virus-infection#H24
  3. Panwar, H., Joshi, D., Goel, G., Asati, D., Majumdar, K., & Kapoor, N. (2017). Diagnostic utility and pitfalls of Tzanck smear cytology in diagnosis of various cutaneous lesions. Journal of Cytology, 34(4), 179–182. https://doi.org/10.4103/JOC.JOC_88_16
  4. Kumar R. Understanding and managing acute encephalitis. (2020). F1000Research 2020, 9(F1000 Faculty Rev):60. https://doi.org/10.12688/f1000research.20634.1
  5. Carbo EC, Buddingh EP, Karelioti Igor E, et al. (2020) Improved diagnosis of viral encephalitis in adult and pediatric hematological patients using viral metagenomics. Journal of Clinical Virology. https://reader.elsevier.com/reader/sd/pii/S1386653220303085?token=2F3AE335C3E1F12131389E6306C0494869186CE4D1725BC84168EF5678A93485D3AA79D7E9FA5DEED71B89D859F356FB

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