Eczema herpeticum, or Kaposi’s varicelliform eruption
Eczema herpeticum (EH), sometimes referred to as Kaposi’s varicelliform eruption, is a herpes simplex virus (HSV) infection of the skin that occurs in the setting of an underlying inflammatory dermatosis, most commonly atopic dermatitis . First described (and assumed to be of fungal etiology) in 1887 by Austrian physician Moritz Kaposi, EH presents as an eruption of vesicles that can be accompanied by fever, malaise, and lymphadenopathy . The most frequent sites of infection include the areas of the head, face, neck, and trunk that are already affected by atopic dermatitis. EH can progress to a systemic infection with severe complications, including encephalitis and septic shock. EH is also potentially vision-threatening, as it can rarely advance to severe herpetic ocular disease.
EH can affect patients at any age, but classically presents in childhood. The majority of patients with EH have atopic dermatitis (AD), a common skin condition that affects between 8.7 and 18.1% of the United States pediatric population. About 10 to 20% of patients with atopic dermatitis develop EH. A 2018 analysis of 4,655 children hospitalized in the United States for eczema herpeticum found an association with younger age and non-white ethnicity, particularly African American and Asian ethnicities. There is no predilection for gender.
Etiology and Pathophysiology
Eczema herpeticum and other infections comprise the major complication of atopic dermatitis. This preponderance for infection is multifactorial and attributable to defects in the skin barrier, as well as to inflammation and immune dysregulation. Notably, the skin of patients with AD is especially susceptible to colonization with S. aureus.
Generally speaking, the best understood risk factor for development of EH is disruption of the epidermal barrier. Most adults (~60%) and ~20% of children in the general population have serologic evidence of HSV-1 exposure, suggesting that viral exposure alone is not sufficient to cause EH. Instead, EH occurs in patients with a preexisting erosive dermatosis, which is usually, though not exclusively, atopic dermatitis. Risk factors for the development of EH specifically in patients with atopic dermatitis include more severe and/or early-onset atopic dermatitis, high total serum IgE/peripheral eosinophilia, and atopic comorbidities such as asthma or food allergies. Additionally, a history of S. aureus skin infections is a significant risk factor for the development of EH among patients with atopic dermatitis.
Apart from atopic dermatitis, EH has been described in association with burns, skin grafts, immunocompromise, pemphigus foliaceus, ichthyosis vulgaris, bullous pemphigoid, Darier disease, Grover disease, Hailey-Hailey disease, Sezary syndrome, dyskeratosis follicularis, mycosis fungoides, psoriasis, pityriasis rubra pilaris, rosacea, seborrheic dermatitis, and both allergic and irritant contact dermatitis.
There have been some genetic risk factors found through whole genome sequencing. Silencing genes SIDT2 and RBBP8NL in normal human primary keratinocytes has demonstrated increased replication of HSV-1.
Because EH is most often a complication of atopic dermatitis, and given that HSV exposure among the general population is extremely common, primary prevention of EH can be focused on control of AD flares. This may be achieved by various means, including avoidance of irritants and allergens that can trigger AD, identification and avoidance of food allergens (especially in pediatric patients), and the use of loose-fitting clothing and indoor temperature control to decrease skin irritation.
The diagnosis of eczema herpeticum is clinical and can be supported by various studies, as discussed below.
Eczema herpeticum presents acutely and has the potential to be fatal. Presentation consists of widespread, painful clusters of punctated vesicopustules followed by erosive “punched-out” ulcers with hematic crusts, mostly on the head, neck, and trunk. The episode originates in areas affected by atopic dermatitis or, less commonly, by another dermatologic condition; it then spreads to involve normal skin over one to two weeks. Once the vesicles have crusted over to form eroded pits, healing without scarring occurs over 2-6 weeks. Patients can present with disseminated vesicles, skin breakdown, viremia, fever, and lymphadenopathy, or they may present with exclusively cutaneous findings in the absence of systemic symptoms. Clinicians should be aware of “EH incognito,” a presentation of EH that is easily mistaken for impetigo and most often seen in patients with severe AD and recurrent EH.
The primary ophthalmologic concern in eczema herpeticum is the spread of herpes simplex virus (HSV) to the eye or eyes. The spread of a cutaneous herpes virus infection from the eyelids to the cornea is a known mechanism of herpes keratitis, and up to half of patients with herpetic blepharoconjunctivitis also have a corneal infection. However, cases of ocular disease in the setting of EH are infrequently reported.
Symptoms of HSV eye infection include redness, pain, foreign body sensation, photophobia, tearing, and decreased visual acuity. HSV infection tends to involve both the upper and lower eyelids. Compared to adults, children tend to experience more severe herpetic ocular disease that may be bilateral and associated with multiple corneal or conjunctival dendrites, as well as more severe secondary corneal scarring and astigmatism. Conjunctival involvement can present as injection with acute unilateral follicular conjunctivitis, with or without conjunctival dendrites or geographic ulceration.
Corneal epithelial disease secondary to HSV infection can present as macropunctate keratitis, dendritic keratitis, or a geographic ulcer. Herpetic corneal lesions have heaped edges made up of swollen epithelial cells; these swollen cells stain well with rose bengal or lissamine green, while the central ulceration stains with fluorescein. As epithelial dendrites resolve, subepithelial scars and haze, or “ghost dendrites,” may develop. Corneal sensation may be decreased in HSV infection and can be assessed prior to instillation of topical anesthetic during ophthalmologic examination. Sterile neurotrophic ulceration may also be observed. It may go unresolved or worsen despite antiviral therapy, and may be associated with stromal melting or perforation.
Corneal stromal disease secondary to HSV infection can present as disciform (non-necrotizing) keratitis or, less commonly, necrotizing interstitial keratitis. Uveitis may develop in the setting of corneal stromal disease. Retinal involvement is rare.
Ophthalmologic examination has been recommended as a routine part of EH workup. More information on Herpes Simplex Virus Keratitis can be found here.
Delayed or missed diagnosis of EH can have devastating consequences, including blindness and death. The diagnosis can be confirmed by viral culture, polymerase chain reaction for viral DNA in vesicular fluid, skin scraping for Tzanck smear, or electron microscopy or immunofluorescence to identify HSV-infected cells. However, the sensitivity of these approaches is low and the importance of clinical suspicion and quick intervention cannot be overemphasized, especially in patients with a history of atopic dermatitis. The diagnosis of ocular HSV infection is also clinical and does not require confirmatory testing, but if there is doubt corneal scrapings can be obtained for Giemsa stain of multinucleated giant cells.
Serologic testing has low specificity and is not useful. When impetigo is in the differential, a positive skin surface bacterial culture for Staphylococcus or Streptococcus species does not exclude EH, and is actually a common finding in EH cases.
The differential diagnosis for EH includes:
- Primary varicella infection
- Herpes zoster ophthalmicus
- Eczema vaccinatum
- Eczema coxsackium
- Eczema molluscatum
- Pustular psoriasis
- Drug hypersensitivity reaction
- Bullous lupus erythematosus
Prompt treatment of eczema herpeticum is important to resolve acute symptoms and to prevent or ameliorate complications. The indicated treatment is administration of acyclovir (29). There are no clear guidelines about which patients should be hospitalized to receive intravenous acyclovir versus managed as outpatients with less-bioavailable oral acyclovir (5). Regardless, patients with severe disease and immunocompromised patients should be admitted to receive systemic antiviral therapy. If bacterial superinfection is suspected, treatment should include antibiotics.
Treatment of Ocular Involvement
If the HSV skin infection spreads to involve the eyelid margins, the indicated treatment is ganciclovir 0.15% ophthalmic gel or trifluridine 1% drops added to the eye five times per day. In small children, vidarabine 3% ointment five times per day is useful. These treatments should be continued for one to two weeks until symptoms resolve.
For HSV conjunctivitis, three options for management are ganciclovir 0.15% ophthalmic gel, vidarabine 3% ointment, or trifluridine 1% drops five times per day. Treatment should last one to two weeks, and reevaluation is recommended if the conjunctivitis does not resolve after this period.
For herpes keratitis, options for management include ganciclovir 0.15% ophthalmic gel five times per day, vidarabine 3% ointment five times per day, or trifluridine 1% drops nine times per day. If compliance with these treatments is an issue, for example in pediatric patients, intravenous or oral antiviral agents (e.g. acyclovir) are acceptable alternatives to topical therapy. Cycloplegic agents like cyclopentolate 1% three times per day can be considered if photophobia or anterior chamber reaction is present. The use of topical steroids is contraindicated and should be quickly tapered off. Adjunctive debridement of infected corneal epithelial cells at the slit lamp can be done in addition to antiviral therapy. If epithelial defects do not resolve after 7 to 14 days, topical antiviral therapy should be withdrawn and preservative-free artificial tears or an antibiotic ointment should be used four to eight times per day with close monitoring and follow-up over several days. A lack of resolution after this time should also lead to investigation of possible bacterial coinfection, Acanthomoeba keratitis, noncompliance with therapy, and topical antiviral toxicity. Regarding the latter, it has been suggested that topical ganciclovir gel carries a lower risk of corneal toxicity than trifluridine.
Treatment of corneal stromal disease depends on disease severity. For mild cases of disciform (non-necrotizing) keratitis, antiviral prophylaxis and cycloplegic therapy are recommended. Cycloplegic therapy is similarly recommended for moderate to severe cases, in addition to a topical steroid (do not initiate topical steroid therapy while an active epithelial lesion is present!). If epithelial defects are present, topical antibiotics may be used adjunctively; if intraocular pressure is elevated, aqueous suppressants may be used, avoiding prostaglandin analogues. Necrotizing interstitial keratitis is managed as severe disciform keratitis. Patients with necrotizing interstitial keratitis require daily follow-up or admission to monitor for perforation. If the cornea perforates, tissue adhesive or corneal transplantation may be necessary.
Patients being treated for ocular HSV should follow up for repeat examination two to seven days after initiating treatment, and again every one to two weeks depending on examination findings. The size of any epithelial defect or ulcer, depth of corneal involvement, corneal thickness, intraocular pressure, and anterior chamber reaction should all be evaluated.
Complications and Prognosis
Eczema herpeticum generally has a good prognosis when patients receive prompt intervention with antiviral therapy, but scarring may persist long after resolution of acute symptoms. A common complication of EH is bacterial superinfection, with the most common organisms being Staphylococcus aureus, Streptococcus pyogenes, and Pseudomonas aeruginosa. If the cutaneous HSV infection disseminates, systemic infection can occur with fever, malaise, multiple organ involvement, septic shock, meningitis, and encephalitis; such dissemination has been associated with a mortality rate from 1% to 9%. As discussed above, ocular HSV infection is among the most feared complications of EH, and corneal transplant may be indicated in cases of postherpetic scarring that significantly affects vision. Close monitoring after resolution of an episode of EH is recommended because about 50% of patients experience recurrence.
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