A topic dermatitis (AD) is a chronic, pruritic, inflammatory skin disorder that affects approximately 11% to 28% of children in developed countries.1–4 With a prevalence of about 17% in the United States, AD is the most common chronic skin disease in our country.5,6 From 1997 to 2004, an estimated 7.4 million office visits in the United States were for AD.7 Emergent office visits are often due to flares of AD, and many of these exacerbations are related to bacterial or viral superinfection. AD is frequently found in association with asthma and allergic rhinitis (rhino-conjunctivitis), and the three together are often referred to as the “atopic triad.”
Skin affected by atopic dermatitis is particularly vulnerable to bacterial and viral infection. Seventy to 90% of atopic patients are colonized with Staphylococcus aureus,8–10 with only a small percentage being methicillin-resistant S. aureus.11,12 Children with AD are more susceptible to and tend to have more molluscum lesions and longer lasting molluscum virus infection than their nonatopic peers.13 Diagnosis of herpes simplex virus and vaccinia virus infection in patients with AD is particularly important because these can lead to life-threatening complications. The factors predisposing atopic skin to infection, and the diagnosis and management of eczema herpeticum and eczema vaccinatum, will be reviewed here (see Table, page 661).
Predisposing Factors for Infection
AD is caused by the complex interaction of multiple factors, including genetic, immune, infectious, environmental, neuroendocrine, as well as a defective epidermal barrier.14 For example, the epidermal barrier function and innate immune system are often disrupted in atopic skin, leading to increased susceptibility to infection.
Endogenous and exogenous factors contribute to the defective epidermal barrier found in patients with AD. Abnormal epidermal synthesis results from decreased ceramides, abnormal keratin proteins, and abnormal expression of cornified envelope proteins. Filaggrin is a critical protein in maintaining an epidermal barrier and hydrated epidermis, and filaggrin mutations are found in many individuals with AD.15,16 Other factors that contribute to the disruption of the skin barrier are exogenous proteases from S. aureus and house dust mites,17,18 and exogenous soaps and detergents that increase local pH and increase activity of endogenous proteases.
The innate immune system is the second line of protection for the host to identify organisms invading the skin. Toll like receptors (TLR) of the innate immune system identify pathogenic organisms through pathogen-associated molecular patterns (PAMPs), such as lipopolysacharides (LPS) on gram-negative bacteria, lipoteichoic acid, and peptidoglycans on gram-positive bacteria, and mannans on yeast or fungi. Polymorphisms in TLRs that predispose to S. aureus infection are found more commonly in AD patients than in control patients.19 Antimicrobial peptides like defensins, cathelicidins, and dermcidin are epidermal proteins that have activity against bacteria, viruses, and fungi. Individuals with AD have decreased expression and function of these peptides, making them more susceptible to cutaneous infection.19
Etiology and Epidemiology
Herpes simplex virus (HSV) is a member of the double stranded DNA Herpesviridae family and consists of herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2). HSV-1 commonly causes herpes labialis (orolabial ulcerations known as “cold sores”), but herpes simplex infection may occur at any mucocutaneous site (see Figure 1, page 660). HSV-1 infection becomes nearly ubiquitous with age. Serum HSV-1 antibody detection is 44% in young adults (12 to 19 years) and increases to 90% in those older than 70 years.20 The prevalence of HSV-1 infection is also influenced by age, race, geographic location, and socioeconomic status. Thirty-five percent of black 5-year-olds are seropositive for HSV-1, while 18% of white children of the same age are seropositive.21 Children in low socioeconomic strata become seropositive earlier than their counterparts in higher socioeconomic strata.22
Figure 1. Herpes Simplex Infection on the Nose of a Teenager. Note the Characteristic Grouped Vesicles on an Erythematous Base. This Was the Primary Infection and Was Quite Inflamed. Figures 1, 3, 4, and 6 Courtesy Mary Wu Chang, MD.
HSV-2 is the most common cause of sexually transmitted genital ulcerations worldwide and affects 26% of women and 18% of men in the United States.20 Risk factors for HSV-2 infection include older age, female gender, black race, poor socioeconomic status, low level of education, a previously contracted sexually transmitted disease, early age at first intercourse, and a higher number of lifetime sexual partners.22 HSV-2 remains the major cause of genital herpes infection, but HSV-1 is becoming more common, likely due to sexual practices.
After primary infection of a mucocutaneous surface, HSV travels via retrograde axonal flow to reach the dorsal root ganglia, where it establishes a latent infection. Reactivation of the virus leads to clinical lesions in the sensory distribution of the affected nerve. Factors, such as psychological stress, exposure to heat, cold, or sunlight, menstruation, fever, immunosuppression, or local tissue trauma can trigger HSV reactivation.
Eczema herpeticum (EH; Kaposi’s varicelliform eruption) is widespread herpes simplex infection arising on skin affected by atopic dermatitis. EH can also complicate other, less common skin disorders characterized by abnormal epidermis, such as Darier’s disease, pemphigus foliaceous, and Hailey-Hailey disease. EH can occur from either primary HSV infection or from HSV reactivation.
Atopic dermatitis patients have a higher risk for EH when they have early onset of AD, head and neck AD, large body surface area involvement with severe eczema, low levels of the cathelicidin LL-37, and/or an R501X mutation in filaggrin.23–27 Whether concomitant food allergies or asthma confer an increased risk for EH is still controversial.23,27 Of note, recent topical steroid treatment has not been shown to be associated with EH.27 Patients with EH have inadequate production of the antiviral proteins interferon-alpha and interferon-gamma in response to HSV exposure.
Any patient with a flare of atopic dermatitis should be carefully inspected for secondary herpes virus infection. EH may proceed unnoticed by the patient or parent, and a high index of suspicion is needed by the clinician. Patients may be misdiagnosed as impetigo due to crusting lesions or as a primary bullous disorder due to the vesicles and erosions.
EH presents as small, monomorphic, dome-shaped papulovesicles that rupture to form “punched-out,” tiny ulcers overlying an erythematous base (see Figure 2; Figure 3, page 662; and Figure 4, page 662). EH is most commonly noted on the head, neck, and upper trunk but can occur anywhere on the skin surface. Grouped monomorphic papulovesicles or erosions, or later, coalescing erosions giving a scalloped border, are diagnostic clues to HSV infection. Erosions can be clean or crusted. Rapid dissemination of herpes lesions can occur in EH. The lesions are not restricted to a single dermatome but can affect any skin inflamed by AD. The herpes infection may take 2 to 6 weeks to heal, in contrast to the usual 7- to 10-day healing time when occurring on normal skin. Patients may have associated fever, malaise, and lymphadenopathy. Topical steroid use is not a predisposing factor for EH in atopic dermatitis.27
Figure 2. Eczema Herpeticum on the Scalp of an 11-Month-Old Boy with Atopic Dermatitis. The Diaper Area Was also Involved. DFA Was Positive for HSV, and the Infant Responded Well to IV Acyclovir. Courtesy of Richard Antaya, MD.
Figure 3, A, B. Widespread Eczema Herpeticum in a Young Boy with Atopic Dermatitis. C. Eczema Herpeticum on the Arm of a 10-Year-Old Boy with Atopic Dermatitis. This Was the Second Episode of Eczema Herpeticum. Note the Clustered, Punched-Out Papules with Central Erosions; Subtle Erythema Is Present. Courtesy Justin Finch, MD.
Figure 4. Recurrent Eczema Herpeticum in a 10-Month-Old Girl with Atopic Dermatitis. Ophthalmology Consultation Was Indicated Due to the Periocular Lesions. This Infant Required Prophylactic Daily Suppressive Dosing of Acyclovir, in Addition to Atopic Dermatitis Therapy.
Involvement of the periocular skin can lead to blepharoconjunctivitis and, less commonly, herpes keratitis. Patients may present with red eye, tearing, photophobia, foreign body sensation, ocular pain, or blurred vision. Left undiagnosed and untreated, herpes keratitis can cause blindness. EH can be complicated by bacterial superinfection, most commonly with S. aureus.28
Although less common in the modern era, visceral involvement can occur in EH and can be life-threatening. Effective treatment of atopic dermatitis helps decrease the frequency and severity of EH.
Early diagnosis of EH is essential to minimize complications. The clinical appearance of EH is characteristic but can be confused with impetigo, primary varicella infection, or eczema vaccinatum. The gold standard for diagnosis of HSV is viral culture. The base of a vesicle unroofed with a sterile 15 blade is rubbed with a culture swab before inoculating a cell culture. Characteristic cytopathic changes of balloon degeneration of cells and necrosis are seen within 48 hours. Immunostaining of the cell culture can further distinguish HSV-1 from HSV-2 infection. The sensitivity and specificity of viral culture depends on the quality of the swab and culture techniques.
A Tzanck smear is a rapid diagnostic test that can confirm a herpesvirus infection. Cells scraped from the base of a freshly unroofed vesicle are Giemsa- or Wright-stained to look for characteristic multinucleated giant cells and intranuclear inclusions (see Figure 5, page 663). Although potentially a very easy and fast bedside test, the specificity and sensitivity are operator dependent.
Figure 5.A,B,C. Tzanck Smear from Scraping of Vesicle Base of Patient in Figure 1 (see Page 660) Shows Characteristic Multinucleated Giant Cells (B and C High Power) Representing Keratinocytes Infected with HSV. .
Direct fluorescence antigen (DFA) testing is becoming the preferred method of diagnosis because it is rapid, inexpensive, and virus specific. Cells from a tissue culture or smear specimen are incubated with a fluorescent tagged antibody against HSV antigens and, if HSV is present, the specimen fluoresces. DFA can distinguish between HSV-1 and HSV-2 infection.
Polymerase chain reaction (PCR) amplification of HSV DNA is highly sensitive and specific, but the test is more expensive and less widely available. PCR has the added benefit of being able to detect HSV from body fluids, such as cerebrospinal fluid.
Serologic testing can be useful to distinguish primary HSV from recurrent HSV. Two separate serum samples are obtained: an acute sample must be obtained within 3 or 4 days of symptom onset, and a convalescent sample is collected several weeks after symptoms resolve. In a primary HSV infection, acute serology should be negative because of the delay in humoral response to infections, and convalescent serology would show immunoglobulin G and M antibodies.
Skin biopsy can diagnose HSV infection even in older lesions. If present, viral cytopathic changes and multinucleated giant cells indicate herpesvirus infection, but do not distinguish between HSV-1, HSV-2, or varicella zoster virus.
Treatment of EH in children centers on prompt initiation of systemic antiviral (acyclovir) therapy together with comprehensive treatment of atopic dermatitis. Topical acyclovir is not effective for EH. If EH is localized and limited, oral acyclovir with close follow-up is appropriate. For neonates, if extensive or severe EH is present, or if compliance is uncertain, intravenous acyclovir is indicated. For adolescents, valacyclovir therapy (approved for patients 12 years and older) or famciclovir therapy (approved for patients older than 18 years) may be considered. Oral antibiotics may be needed if bacterial superinfection exists. Aggressive treatment of AD with bathing and moisturization strategies, judicious topical steroid and/or topical immunomodulator therapy, oral antihistamines, and removal of inciting triggers is also very important. Individuals with frequent recurrence of EH may require daily suppressive dosing of acyclovir for HSV prophylaxis. Suppressive regimens should be reevaluated every 6 months to 1 year to assess effectiveness, need for dosage adjustments for growth or erratic absorption, or for discontinuation of suppressive therapy.
If periocular lesions are present (particularly eyelid lesions), immediate referral to ophthalmology is indicated for complete evaluation and treatment. If herpes keratitis is detected, the ophthalmologist may prescribe antiviral ophthalmic drops (eg, 1% trifluridine, 0.1% iododeoxyuridine, or 3% vidarabine) with close follow-up.
Early recognition and treatment of EH helps to minimize later dyspigmentation and scarring. All patients with EH are at risk for future recurrence of disease. Aggressive control of atopic dermatitis and education of the signs and symptoms of early HSV reactivation is important.
Etiology and Epidemiology
Smallpox is caused by variola virus, a member of the double stranded DNA Orthopoxvirus family. The World Health Organization (WHO) declared that smallpox was successfully eradicated worldwide in 1979. This success was achieved through widespread immunization. After its eradication, smallpox vaccination waned until after September 11, 2001, when concerns over the possible use of smallpox in bioterrorism arose. Starting in 2002, the United States military began immunizing military personnel, and, in 2003, some civilians were also immunized in preparation for possible bioterrorism.
The smallpox vaccine is the live vaccinia virus, also a member of the Orthopoxvirus family. Although effective in preventing smallpox infection, vaccination is associated with a high rate of adverse events, including eczema vaccinatum (EV). Mouse models for EV indicate that local immune dysregulation promote viral dissemination. Interleukin-17 (IL-17) is a proinflammatory cytokine found in high levels in AD skin. Natural killer cells are a major component of the innate immune system that identifies and destroys virally infected cells. Increased IL-17 levels and low natural killer cell activity in eczematous skin allows for vaccinia viral dissemination.29,30
No evidence-based studies are available to guide practitioners regarding if and when to immunize patients with a history of AD. The Centers for Disease Control and Prevention (CDC) states that smallpox vaccination “in the pre-outbreak setting” is contraindicated for individuals with or who have close contact to individuals with “a history of atopic dermatitis, irrespective of disease severity or activity; and active acute, chronic, or exfoliative skin conditions that disrupt the epidermis.”31 As such, a majority of EV cases in the United States result from individuals who inadvertently contact a recently vaccinated individual. The most recent reported case of EV occurred in a 28-month-old with AD whose father was routinely vaccinated through the United States military.32
Eczema vaccinatum presents 3 to 14 days after exposure to vaccinia. Widespread firm, deep-seated vesicles or pustules, all in the same stage of development, may become confluent in areas and tend to favor areas of active dermatitis. Patients may be systemically ill, with fever, malaise, and lymphadenopathy. Supraglottic edema can compromise the airway and be potentially fatal. Skin lesions heal with depressed scars by 21 days.
The most common complication of EV is bacterial superinfection, usually by S. aureus. Periocular lesions may indicate corneal involvement, which manifests as vaccinia keratitis. Vaccinia keratitis may result in corneal ulceration, scarring, and blindness.
The diagnosis of EV can be confirmed through several methods. Vaccinia virus can be cultured from a skin biopsy specimen, a vesicular swab, skin from the top of an unroofed vesicle, or a touch prep (a glass slide repeatedly touched to the base of an unroofed vesicle or pustule). PCR for vaccinia virus is available and can distinguish between vaccinia, variola, and other orthopoxviruses. Characteristic findings of intracytoplasmic inclusions (Guarnieri bodies) in infected cells can be seen histologically on skin biopsy.
Vaccinia immunoglobulin (VIG) is available through the CDC and is pooled immunoglobulin from patients vaccinated with the vaccinia virus. It should be administered as soon after the onset of symptoms as possible. The recommended dose is 0.6 mL/kg administered over a 24- to 36-hour period. Old formulations of VIG needed to be administered intramuscularly, but newer formulations that can be administered intravenously are under development. Cidofovir and an experimental antiviral compound ST-246 have successfully treated EV in the past.32