Eczema herpeticum (EH) is a disseminated herpes simplex virus (HSV) infection occurring in areas of pre-existing inflammatory skin disease. It was first described in 1887 by Austrian dermatologist Moritz Kaposi 4). It is also known as Kaposi varicelliform eruption.
Herpes simplex virus type 1 accounts for over 90% of cases 1). The most common underlying condition is atopic dermatitis (AD), and approximately 3% of AD patients experience EH in their lifetime 4). It can occur at any age but is typically more common in childhood. An analysis of 4,655 hospitalized children in the United States showed associations with younger age and non-white race (especially African American and Asian).
If it progresses to systemic infection, it can cause encephalitis or septic shock. The mortality rate in untreated cases is reported to be 6–10% 1). In infants, severe cases of EH with seborrheic dermatitis as the underlying condition complicated by streptococcal sepsis have been reported 6).
Adults can also develop EH. Although more common in children, adults with atopic dermatitis or other barrier defects are also affected. Cases have been reported, such as a 19-year-old man with EH complicated by herpetic keratitis 2), and a 32-year-old man who developed drug-induced pustulosis during EH 3). A fulminant case of EH in a 22-year-old man using the JAK inhibitor baricitinib has also been reported 5).
Systemic symptoms include fever, malaise, and lymphadenopathy. Patients often complain of pain in the skin lesions. If the eye is involved, symptoms include redness, photophobia, tearing, foreign body sensation, and decreased vision.
Skin Findings
Monomorphic dome-shaped papulovesicles appear in clusters 4). The vesicles then progress to “punched-out” erosions and form hemorrhagic or yellow crusts. Predilection sites are the head, face, neck, and trunk. They spread to normal skin within 1–2 weeks and heal without scarring in 2–6 weeks 1).
A 4-month-old boy with atopic dermatitis initially presented with yellow scales on the scalp, and vesicles spread to the face, extremities, and perineum. Marked eosinophilia and elevated total IgE were noted, and he improved with intravenous acyclovir 1).
Some cases are misdiagnosed as cellulitis. A 19-year-old African American man was treated with broad-spectrum antibiotics for facial cellulitis but did not improve; 24 hours later, photophobia and blurred vision appeared, and a dermatology consultation led to the diagnosis of eczema herpeticum 2).
Ocular Findings
Ocular involvement includes various forms of herpetic keratitis.
Corneal Epithelial Lesions
Dendritic keratitis: Branching epithelial defect with terminal bulbs. The center stains with fluorescein, and the swollen edge stains with rose bengal.
Geographic ulcer: Extensive epithelial defect resulting from enlargement and coalescence of dendritic lesions.
Coarse punctate keratitis: Appears as scattered punctate epithelial infiltrates.
Corneal Stromal and Other Lesions
Disciform keratitis: Presents with round stromal opacity and corneal edema due to immune reaction. Often accompanied by keratic precipitates.
Necrotizing stromal keratitis: Occurs in recurrent cases with vascular invasion and dense opacity. Risk of perforation.
Ghost dendritic lesions: Subepithelial opacities remaining after epithelial healing.
In a 7-month-old infant with EH associated with seborrheic dermatitis, marked edema and blisters were observed on the left eyelid, but corneal lesions were ruled out by ophthalmologic examination 6). In contrast, in a case misdiagnosed as cellulitis, early dendritic lesions were confirmed on the left cornea by fluorescein staining after hospitalization 2).
Children tend to have more severe herpetic eye disease, often presenting with bilateral or multiple corneal dendritic lesions. Corneal hypoesthesia should be assessed before administering topical anesthesia.
The majority of EH cases are caused by herpes simplex virus type 1 1)4). Herpes simplex virus type 2 is a rare cause. Similar conditions caused by Coxsackie A16, vaccinia virus, and varicella-zoster virus have also been reported 4).
The greatest risk factor is disruption of the epidermal barrier.
AD-Related Risk Factors
Severe/early-onset AD: The greater the barrier dysfunction, the higher the risk.
High serum total IgE: An infant case with marked eosinophilia and elevated IgE at the time of first EH has been reported 1).
Peripheral blood eosinophilia: An indicator of Th2 skewing, correlating with EH risk.
Atopic comorbidities: Concurrent asthma or food allergy increases risk.
History of Staphylococcus aureus infection: Cutaneous colonization with S. aureus is an important risk factor for EH.
Other Risk Factors
Skin diseases other than AD: Reported in many conditions including Darier disease, pemphigus, ichthyosis, psoriasis, rosacea, seborrheic dermatitis 6), and contact dermatitis.
Immunosuppressed state: During use of the JAK inhibitor baricitinib, EH has been reported in 0.2–2.8% and herpes simplex virus-1 infection in 3% 5).
Genetic factors: Silencing of the SIDT2 and RBBP8NL genes has been shown to increase herpes simplex virus-1 replication.
The JAK inhibitor baricitinib inhibits type I interferon signaling and has been reported to increase the risk of herpes simplex virus-1 infection to about 3% 5). In a case of a 22-year-old man who developed fulminant EH while taking baricitinib 4 mg/day, the drug was discontinued and intravenous acyclovir led to recovery in 8 days 5). Topical steroids, when used appropriately, do not necessarily directly increase EH risk, but they may mask signs of infection.
The diagnosis of EH is primarily based on clinical findings. In patients with a history of AD who present with acute onset of monomorphic papulovesicles, EH should be suspected promptly. Misdiagnosis as cellulitis can delay treatment initiation 2).
Atypical cases, called “EH incognito,” also require attention. In patients with severe AD or recurrent EH, it can easily be mistaken for impetigo.
| Test Method | Sensitivity Characteristics | Notes |
|---|---|---|
| PCR | High in vesicles | Decreases after 3 days or in crusts 4) |
| Tzanck test | Vesicles 81.6% | Crusts decrease to 62.5%4) |
| Viral culture | Definitive | Difficult in routine clinical practice |
PCR positivity is 100% for vesicles but decreases to 43.7% for crusts4). The sensitivity of the Tzanck test also varies with the temporal changes of the lesion. IgM anti-herpes simplex virus-1 positivity is low at 33% within 7 days of primary infection, but combined with IgG negativity, it can aid diagnosis4).
Ophthalmic evaluation is recommended as part of the standard assessment for EH. Dendritic lesions are confirmed by corneal fluorescein staining. Immunochromatography (Checkmate® Herpes Eye) has 100% specificity but approximately 50% sensitivity; a negative result does not rule out herpes simplex virus infection7). PCR has high sensitivity but may detect spontaneous shedding of herpes simplex virus, and a positive result is not diagnostic7).
| Differential diagnosis | Key differentiating features |
|---|---|
| Impetigo | Characterized by honey-colored crusts |
| Chickenpox | Generalized, polymorphic vesicles |
| Cellulitis | Primarily redness and swelling2) |
Even when impetigo is suspected, a positive bacterial culture does not rule out EH. In EH cases, secondary infection with S. aureus and other bacteria often coexists1)3).
Intravenous acyclovir (5–10 mg/kg/dose, three times daily for 7 days) is the gold standard1)4). For mild cases, outpatient management with oral valacyclovir (1,000 mg twice daily) is an option2). Delay in starting acyclovir is associated with increased hospitalization rates1).
Factors requiring hospitalization include male sex (OR=3.09), fever (OR=5.75), systemic symptoms (OR=2.84), and age under 1 year (OR=7.17)4).
For secondary bacterial infection (commonly S. aureus and Streptococcus), appropriate antibiotics should be used concurrently6). In MRSA-positive cases, vancomycin or linezolid is selected2)3).
Epithelial Keratitis
Acyclovir ophthalmic ointment (3%) applied five times daily is the first-line treatment7). After epithelial lesions resolve, reduce to three times daily and discontinue after 1–2 weeks. In other countries, 0.15% ganciclovir ophthalmic gel (five times daily) or 1% trifluridine eye drops (nine times daily) are also used.
Stromal Keratitis
The principle is combined use of acyclovir ophthalmic ointment and steroid eye drops7). Depending on the degree of inflammation, start with betamethasone 0.1% eye drops and taper gradually. If epithelial defects are present, consider switching to oral steroids.
Necrotizing stromal keratitis
Treatment follows that for severe disciform keratitis. Daily follow-up or hospitalization is necessary to monitor for perforation. If perforation occurs, tissue adhesive or tectonic corneal transplantation is indicated.
Steroid eye drops are contraindicated during active herpetic epithelial lesions because they promote viral replication and worsen corneal damage 2). However, for stromal keratitis after epithelial lesions have resolved, steroid eye drops may be used in combination with antiviral drugs 7). The decision to use them requires evaluation by an ophthalmologist.
In the skin of AD patients, mutations or dysfunction of structural proteins such as filaggrin and claudin lead to disruption of the epidermal barrier 4). This results in transepidermal water loss, changes in skin pH, and imbalance of the skin microbiota.
Th2 cell predominance stimulates IL-4 production, enhancing IgE production, while suppressing Th1 cell differentiation and reducing IFN-γ production 1). Reduced IFN-γ creates an environment favorable for viral replication.
Mutations in adhesion proteins of tight junctions and adherens junctions result in a “loose” state of cell-cell adhesion 4). Nectin-1 is an adherens junction protein and also a receptor for herpes simplex virus. Barrier disruption increases exposure of nectin-1, promoting viral entry into cells 4).
In AD, NK cells with low expression of activating receptors accumulate, with reduced cytolytic activity but increased TNF-α production. Since basolateral adhesion proteins (such as Necl-5 and E-cadherin) are also ligands for NK cell receptors, chronic stimulation due to barrier disruption may induce an exhausted phenotype in NK cells, reducing antiviral immune responses 4).
This hypothesis awaits verification through basic research.
In AD patients, S. aureus skin colonization is frequently observed and contributes to further barrier disruption. EH cases often complicate secondary bacterial infections including MRSA 2)3). In a 7-month-old infant case, sepsis due to S. pyogenes occurred 6).
Baricitinib inhibits Janus kinase (JAK) and blocks the type I interferon signaling pathway 5). This reduces antiviral immunity, increasing the risk of herpes simplex virus-1 infection and EH onset.
The exhaustion hypothesis based on the interaction between basolateral adhesion proteins and NK cell receptors 4) provides a new perspective on the pathogenesis of EH. Future basic research is expected to clarify the relationship between the nectin family and the NK cell activating receptor CD226.
With the widespread use of baricitinib in AD treatment, risk management for EH has become increasingly important 5). Data showing herpes simplex virus-1 infection in 3% and EH in 0.2–2.8% of patients suggest the need for screening and patient education when prescribing JAK inhibitors.
Genome-wide analyses have shown that silencing of SIDT2 and RBBP8NL genes promotes herpes simplex virus-1 replication. In the future, genetic screening may enable identification of patients at high risk for EH.
Currently, there are no unified diagnostic guidelines for EH 4). Cases misdiagnosed as cellulitis 2) highlight the need for improved differential diagnosis in primary care and emergency settings. Establishing a diagnostic algorithm is a future challenge.
For the diagnosis of herpes simplex virus keratitis, immunochromatography and PCR have been shown to be useful 7). The global incidence of herpes simplex virus keratitis is estimated at approximately 1.5 million cases per year 8), making management of ocular complications associated with EH important from a public health perspective.
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