Cutaneous Herpes Infections

Human herpes viruses (HHV) encompass multiple double-stranded DNA viruses that are common pathogens to both humans and other animals. The most commonly seen HHVs in clinical practice are human herpes viruses types 1 and 2 (HHV-1 and HHV-2), more commonly known as herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2), and varicella-zoster virus (VZV). In this section, we concentrate on the following viruses:

• Herpes Simplex Viruses (HSV-1 and HSV-2)

  • Nongenital Herpes Simplex Virus (HSV)

  • Genital Herpes Simplex Virus (HSV)

• Varicella-Zoster Virus (VZV)

The following table describes the eight herpes viruses known to infect humans. For more information on the less common herpes viruses, see this NEJM review.

(Reference: Sixth Disease and the Ubiquity of Human Herpesviruses, N Engl J Med 2005, and Dermatology: 3rd Edition, Chapter 80, 2012.)

Herpes Simplex Viruses (HSV-1 and HSV-2)

Diagnostic Testing

When clinical findings are not diagnostic, bedside testing can be done using a Tzanck test, direct immunofluorescence assay (DFA), viral culture, and/or polymerase chain-reaction (PCR) assay.

(Reference: Comparison of Tzanck Smear, Viral Culture, and DNA Diagnostic Methods in Detection of Herpes Simplex and Varicella-Zoster Infection, JAMA 1992, and Diagnosis of Genital Herpes Simplex Virus Infection in the Clinical Laboratory, Virol J 2014.)

Nongenital Herpes Simplex Virus (HSV)

Epidemiology: Nongenital HSV infections are a group of clinical entities caused predominantly by HSV-1 and rarely by HSV-2. HSV-1 is transmitted by both sexual and nonsexual contact. The seroprevalence of HSV-1 is 55%-60% in the United States.

Clinical manifestations:

Herpes Labialis

• Accounts for 90% of HSV-1 infections

• Primary infection: fever, submandibular and cervical lymphadenopathy, multiple and nonclustered painful vesicles on lips, gingiva, palate, tongue (figures 2a and 2b)

• Recurrent eruption: pain and paresthesias followed by grouped vesicles on vermilion border

• Key diagnostic feature: recurrence in the same location (figures 1 and 3)

(Source: Herpes Labialis. N Engl J Med 2014.)

Herpetic Keratitis

• Eye pain, light sensitivity, discharge, gritty sensation

• Fluorescein stain confirms keratitis

(Source: VisualDx 2023.)

Other Nongenital HSV Infections

(Source: Herpetic Whitlow. N Engl J Med 2014.)

(Source: An Outbreak of Herpes Gladiatorum at a High-School Wrestling Camp. N Engl J Med 1991.)

(Source: Severe Herpes Simplex Infection. N Engl J Med 1999.)

Eczema herpeticum (Kaposi varicelliform eruption) is most commonly seen in children with uncontrolled underlying atopic dermatitis.

(Source: Case 14-2012 — A 43-Year-Old Woman with Fever and a Generalized Rash. N Engl J Med 2012.)

(Source: Eczema Herpeticum. N Engl J Med 2017.)

Treatment of nongenital herpes:

• Oral antiviral therapy (e.g., acyclovir or valacyclovir) is the most efficacious modality in primary and recurrent episodes as well as in prevention of recurrence.

  • Antiviral therapy has been shown to decrease time to healing, time to cessation of pain, and days of viral shedding and should be started at first sign of symptoms.

• Topical therapy is less efficacious than oral antiviral therapy but can be used and includes acyclovir, docosanol, and penciclovir creams.

• An overview of antiviral dosing for treating nongenital HSV infections can be found here(table 2).

• Novel therapies for herpes simplex virus, such as pritelivir, are currently in phase 3 trials for treatment in immunocompromised patients.

• Although vaccines against the herpes virus are difficult to raise, new candidates are currently under investigation.

Genital Herpes Simplex Virus (HSV)

Epidemiology: Genital herpes is caused primarily by HSV-2, which is transmitted sexually and has a high recurrence rate (70%-90%). Genital herpes can also be caused by HSV-1, which is typically transmitted via oral-genital sexual practice and has a lower recurrence rate (20%-50%). The seroprevalence of HSV-2 is 16%-25% among people aged 14 to 49 years.

Clinical manifestations:

• Primary: Many cases of genital herpes are asymptomatic. Patients with symptoms experience headache, fever, myalgia, regional lymphadenopathy, and tender genital vesicles.

• Recurrent: Many patients have occult viral shedding without symptoms. Symptomatic episodes are characterized by pain and paresthesias followed by unilateral tender genital vesicles.

(Source: Genital Herpes. N Engl J Med 2016.)

Treatment of genital herpes:

• Acyclovir, famciclovir, and valacyclovir are associated with equivalent efficacy and safety profiles; therefore, the choice is based on dosing regimen, cost, and clinician preference.

• The following table summarizes antiviral indications and dosing for treating genital herpes:

Varicella-Zoster Virus (VZV)

Diagnostic Testing for Herpes Zoster and Primary Varicella

When clinical findings are not diagnostic, bedside testing using a direct immunofluorescence assay (DFA) for VZV antigen or polymerase chain-reaction (PCR) assay are the most reliable. Viral culture for VZV is much less sensitive and specific than for HSV. The accuracy of diagnostic testing for herpes zoster is as follows:

• DFA testing: 82% sensitive and 76% specific

• PCR: 95% sensitive and 99% specific

• Virus culture: 20% sensitive and 99% specific

Primary Varicella

Primary varicella, or chickenpox, represents initial infection with VZV. Since the introduction of a varicella vaccine (approved by the U.S. Food and Drug Administration in 1995), primary varicella has become much less common.

Clinical manifestations:

• Crops of macules proceed to papules, vesicles, and finally crusted ulcers.

• Lesions are in different stages of development (unlike smallpox, where lesions are typically in the same stage) and occur predominantly on the face and trunk.

(Source: Varicella Pneumonia in an Adult. N Engl J Med 2010.)

(Source: Varicella Vaccine and Infection with Varicella-Zoster Virus. N Engl J Med 2005.)

Complications:

• Secondary skin and soft-tissue bacterial infections, encephalitis, pneumonia, and hepatitis are complications of VZV.

Prevention:

• Varicella vaccine (FDA approved in 1995) is now given to all children in the United States in a two-dose schedule at ages 10-15 months and 4-6 years. The vaccine prevents 80% of all disease and 95%-98% of moderate and severe disease.

Treatment:

• Indications for antiviral therapy include age >12 years, chronic pulmonary or cutaneous disorders in children, intake of chronic inhaled or systemic glucocorticoids or chronic salicylates, or immunosuppression.

Herpes Zoster

Herpes zoster (shingles) represents a reactivation of latent VZV leading to spread of the virus along sensory nerve dermatome(s).

Clinical manifestations:

(Source: Herpes Zoster. N Engl J Med 2013.)

(Source: Herpes Zoster. N Engl J Med 2010.)

(Source: Herpes Zoster Ophthalmicus Followed by Contralateral Hemiparesis. N Engl J Med 2002.)

(Source: Herpes Zoster. N Engl J Med 1994.)

(Source: Herpes Zoster Mandibularis. N Engl J Med 2016.)

(Source: Lingual Zoster. N Engl J Med 2011.)

(Source: Zoster of the Tympanic Membrane. N Engl J Med 2011.)

(Source: Herpes Zoster. N Engl J Med 1995.)

Treatment:

• Indications for treatment:

  • age >50 years old

  • moderate-to-severe pain

  • severe rash

  • involvement of face or eye

  • immunocompromised state

• Treatment decreases acute pain and time to resolution but does not decrease risk of postherpetic neuralgia.

• Famciclovir and valacyclovir are preferred over acyclovir, as the former agents have higher bioavailability and levels of antiviral activity in the blood. The following table provides information on the management of herpes zoster with antiviral therapy.

• Evidence suggests an association between use of systemic treatment in patients with psoriasis and increased risk for herpes zoster.

(Source: Herpes Zoster. N Engl J Med 2013.)

Complications:

• Postherpetic neuralgia, defined as pain lasting 90 days after the onset of rash, affects 10%-30% of patients with zoster. For a summary of treatments for postherpetic neuralgia, see table 3 here.

• Other complications include keratitis, facial nerve palsy, sensorineural hearing loss, transverse myelitis, aseptic meningitis, and vasculitis of cerebral vessels leading to stroke.

Prevention:

• Live attenuated herpes zoster vaccine is FDA approved for adults older than 50 years. However, this vaccine is contraindicated in certain populations (e.g., immunocompromised, pregnant, and others). For a summary of recommendations for herpes zoster vaccination, see table 4 here.

• A subunit vaccine(HZ/su) is not a live vaccine and now an option for immunocompromised hosts. Shingrix was approved by the FDA in 2017 for immunocompetent adults ≥50 years of age and approval was expanded in 2021 to include adults aged ≥18 years who are immunocompromised.