Eczema herpeticum

INTRODUCTION — 

Eczema herpeticum (EH) is a secondary infection of eczematous skin with human herpes simplex virus (HSV). EH occurs most commonly in the setting of atopic dermatitis (AD) but occasionally can be a complication of other inflammatory skin diseases (eg, Darier disease, Hailey-Hailey disease, mycosis fungoides, autoimmune bullous diseases) or thermal burns. In noneczematous conditions, the synonym "Kaposi varicelliform eruption" is preferred [1,2]. EH is a dermatologic emergency that requires prompt initiation of antiviral therapy.

This topic will discuss the risk factors, clinical manifestations, diagnosis, and management of EH. The epidemiology, clinical manifestations, diagnosis, and management of HSV type 1 (HSV-1) infection are discussed separately.

●(See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)

●(See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)

EPIDEMIOLOGY

Incidence and prevalence — In a United Kingdom population-based cohort study, the incidence rates of EH were 11 to 95 per 100,000 person-years among children and 1.5 to 22 per 100,000 person-years in adults [3]. In this cohort, higher rates were seen in children and adults with more severe atopic dermatitis (AD).

The exact prevalence of EH among patients with AD is unknown. In a multicenter registry restricted to moderate to severely affected AD in adults (n = 893), the prevalence of EH was 22 percent [4].

In the United States, the annual incidence of pediatric hospitalization for EH between 2002 and 2012 ranged from 4 to 7.3 per million children [5]. Risk for hospitalization was highest for infants, toddlers, and preschool children.

Risk factors and associations — Patients with AD and EH have a unique phenotype associated with the following:

●Younger age [5,6]

●Earlier onset of AD [2,7,8]

●Non-White race/ethnicity [5]

●Untreated AD [2]

●Severe disease [7,8]

●Allergic comorbidities such as food allergy, asthma, or allergic rhinitis [7,8]

●Higher rates of sensitization to environmental and food allergens [7]

●Higher total serum immunoglobulin E (IgE) [2,7,8]

●Staphylococcus aureus and molluscum contagiosum skin infection [7,9]

Role of therapies for atopic dermatitis

●Topical corticosteroids and topical calcineurin inhibitors – In a review of 100 patients with EH from Germany, up to 75 percent of patients did not have any prior corticosteroid exposure [2]. In another multicenter study of 224 cases of EH, the use of topical corticosteroids, topical calcineurin inhibitors, systemic corticosteroids, or cyclosporine had no influence on EH development [10]. Of 224 patients, 118 did not receive any systemic treatments, and 55 did not receive any topical anti-inflammatory treatments four weeks prior to EH.

●Systemic corticosteroids and cyclosporine – Indirect evidence from a cohort of patients with EH suggests that the occurrence of EH is independent of systemic treatment [10]. Among 131 cases of EH, 118 did not receive any systemic treatment prior to EH. Ten received corticosteroids, two received cyclosporine, and one received both. A retrospective case-control analysis of patients with or without cyclosporine did not demonstrate an increase in EH risk [11].

●Biologics – A pooled analysis of dupilumab clinical trials suggests that the use of dupilumab was associated with a reduced risk of EH compared with placebo (risk ratio [RR] 0.31, 95% CI 0.12-0.82) [12]. In a randomized trial of dupilumab in children aged six months to five years, there were no significant differences in the number of herpetic infections between the dupilumab and placebo groups (RR 1.17, 95% CI 0.31-4.35) [13].

Similarly, in a pooled analysis of tralokinumab trials, the frequency and rate ratios of EH were reduced compared with placebo (0.3 versus 1.5 percent and 1.2 versus 5.2 events per 100 patient-years of exposure) [14].

●Upadacitinib – In an analysis of safety data of upadacitinib trials, EH occurred in 2.9 per 100 patient-years in the upadacitinib 15 mg group, 2.9 per 100 patient-years in the upadacitinib 30 mg group, and 1.6 per 100 patient-years in the placebo group [15].

●Abrocitinib – In a pooled analysis of data from phase 2/3/extension studies of abrocitinib for AD, the incidence rate of EH per 100 patient-years was 1.56 (95% CI 1.00-2.32) in the 100 mg group (n = 1023), 0.85 (95% CI 0.51-1.32) in the 200 mg group (n = 1981), and 0.71 (95% CI 0.35-1.27) in the variable dose group (n = 798) [16].

●Baricitinib – In an analysis of eight randomized trials of baricitinib for moderate/severe AD, the frequency of EH was 0.2 percent among patients receiving 2 mg, 1.4 percent among those receiving 4 mg, and 0.5 percent among those receiving placebo [17]. Of note, most patients with EH had poor disease control (ie, Validated Investigator Global Assessment [VIGA] scores of 3 to 4) preceding the infection.

PATHOGENESIS

Virology — EH is caused by infection with herpes simplex virus (HSV) type 1 (HSV-1) in most cases. Serologic analysis of 113 patients with atopic dermatitis (AD) and EH showed that 93 percent were positive for HSV-1, whereas only 9 percent were positive for HSV type 2 (HSV-2), confirming that the majority of EH cases are associated with HSV-1 [7]. Although EH can occur in the setting of primary HSV infection, at least 50 percent of cases are attributable to secondary HSV reactivation [10].

HSV-1 infection occurs worldwide and is highly prevalent in the general population. Based on the United States National Health and Nutrition Examination Surveys, the age-adjusted HSV-1 seroprevalence was 58 percent from 1999 to 2004 and declined to 48 percent from 2015 to 2016 among persons aged 14 to 49 years [18,19]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)

Pathogenesis — Despite the high likelihood of environmental HSV-1 exposure among individuals with AD, EH occurs at low frequency, suggesting that other host factors are necessary for its development [20]. These include:

●Immune dysregulation with a T helper type 2 (Th2) polarization – There is an enhanced type 2 response and a reduced type 1 cellular response to HSV in EH [21]. Enhanced type 2 polarity is reflected by elevated IgE, eosinophils, and thymus and activation-regulated chemokine (TARC) levels, as well as greater frequency of allergen sensitization [7]. The impaired type 1 response is reflected by the reduced recruitment of plasmacytoid dendritic cells, which are key producers of type 1 interferon (IFN), vital for antiviral response [22]. In addition, the levels of IFN-gamma and IFN receptor gene expression, as well as upstream regulators of IFN (eg, interferon regulatory factor [IRF] 3 and IRF77), are reduced in EH [23]. Lastly, regulatory T cells are increased in AD and EH cases and may contribute to the progression of EH through its suppressive effects on effector T cells [24].

●Impaired epidermal barrier

•Filaggrin – Loss-of-function variants in FLG, encoding filaggrin, a key protein of the cornified cell envelop, are the strongest genetic risk factor for AD and may also be associated with increased susceptibility to EH. In a study of 278 patients with AD, including 112 with AD and EH, the frequency of two common FLG null variants (R501X and 2282del4) was higher in patients with EH than in those without EH (25 versus 8 percent and 18 versus 9 percent, respectively) [25]. Carriage of both null variants had a stronger association with EH (odds ratio [OR] 10, 95% CI 4.7-22.1). (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on 'FLG variants'.)

•Claudin – Claudin, a transmembrane protein of tight junctions that functions to regulate permeability and entry of water and solutes across the skin, may also impact susceptibility to EH. The expression of claudin 1 and claudin 23 is reduced in AD compared with healthy individuals [26]. This reduction in claudin expression is associated with HSV infection and impacts the spread of the virus across keratinocytes.

●Altered antimicrobial peptide – Antimicrobial peptides, such as cathelicidin (LL-37) and beta-defensins, are found in the skin and play a role in immune defense through their antimicrobial properties. In vitro studies have demonstrated the antiviral activity of cathelicidin against HSV [27]. Lower levels of human beta-defensin and cathelicidin expression have been demonstrated in patients with both AD and EH compared with patients with AD but without EH [27,28].

●Genetics – Variants in genes encoding proteins involved in immunity have been found to predispose to EH. These include:

•IFN-gamma and IFN-gamma receptor [23]

•Stat 6 genes [29]

•Thymic stromal lymphopoietin (TSLP) [30]

•IRF2 [31]

Whole genome sequencing studies have also identified variants in SIDT2 and RBBP8NL genes as associated with recurrent EH [32]. Functional studies showed that these genes are involved in keratinocyte differentiation and responses against HSV-1 infection [32].

CLINICAL FEATURES

●Cutaneous findings – EH presents with disseminated, nongrouped, monomorphic papulovesicles on an erythematous base that progress to pustules, punched-out erosions, and crusts. The evolution of vesicles to erosions occurs after two to seven days, with the active phase lasting one to two weeks.

The face, neck, and trunk are the most commonly affected regions (picture 1A and picture 1B), but any area can be involved (picture 1C and picture 1D). EH lesions are typically limited to areas affected by atopic dermatitis (AD) [10].

●Systemic symptoms – Systemic symptoms (eg, fever, headache, lymphadenopathy) can accompany the eruption in approximately one-half of patients, and inflammatory markers may be elevated [2,6,33].

●Clinical course – Lesions are generally healed after two to six weeks [1,34].

●Complications – Complications of EH include [1,3,5,33-38]:

•Extensive gingivostomatitis, which may impact oral intake

•Ocular involvement (keratoconjunctivitis, keratitis)

•Viremia

•Meningoencephalitis

•Hepatitis

•Lymphopenia, eosinophilia, and lymphadenopathy

•Secondary infection with S. aureus (impetiginization) and bacteremia

●Recurrences – Over 20 percent of patients with EH experience one or more recurrent episodes of EH [10]. AD onset at an early age appears to be a predisposing factor for recurrent EH.

DIAGNOSIS

Clinical — The diagnosis of EH is suspected clinically based on the following:

●Patient history

•Flare of atopic dermatitis (AD) with sudden onset of vesicles or erosions on areas involved by AD

•May be associated with prodromal symptoms (eg, malaise, fever)

●Physical examination

•Monomorphic, nongrouped vesicles and pustules on an erythematous base

•Presence of secondary impetiginization with lesions showing golden-colored crusts

•Extracutaneous involvement (eg, meningoencephalitis)

Laboratory tests — The presence of herpes simplex virus (HSV) in the skin can be confirmed by (see "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis'):

●Polymerase chain reaction (PCR) for viral deoxyribonucleic acid (DNA) – PCR is the preferred method for its higher sensitivity compared with other methods [39-41].

●Tzanck smear.

●HSV antigen detection via indirect immunofluorescence.

●HSV viral culture.

●Electron microscopy.

●Skin biopsy demonstrating viral cytopathic changes as well as multinuclear giant cells with intranuclear inclusions [34].

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of EH includes several infectious and noninfectious inflammatory skin conditions.

●Impetigo – Impetigo can mimic as well as coexist with EH. Impetigo typically presents with yellowish, oozy discharge and golden crusts (picture 2 and picture 3). Bacterial culture can confirm the diagnosis. (See "Impetigo".)

●Eczema coxsackium – Eczema coxsackium can present with extensive vesicles and skin erosions and arises due to superimposed infection caused by coxsackie viruses. Similar to hand, foot, and mouth disease, oral sores and papulovesicles involving the hands and feet may be prominent (picture 4). Polymerase chain reaction (PCR) from skin lesions for both herpes simplex virus (HSV) and enterovirus is recommended when the diagnosis is unclear. (See "Atypical exanthems in children", section on 'Atypical hand, foot, and mouth disease'.)

●Varicella – Varicella (chickenpox) can be distinguished by lesions that are at various stages of development, from papule, vesicle, hemorrhagic crusts, and varioliform scars (picture 5A-B). This is in distinction to the monomorphic appearance of EH. (See "Clinical features of varicella-zoster virus infection: Chickenpox".)

●Contact dermatitis – Contact dermatitis occurs in areas where the external irritant or allergen is in contact with the skin, and lesions tend to be linear and asymmetrical (picture 6A-B). (See "Allergic contact dermatitis: Clinical features and diagnosis" and "Allergic contact dermatitis in children".)

●Flare of atopic dermatitis – EH can be mistaken as a flare of the underlying atopic dermatitis (AD) (picture 7) and must be considered in any patient with AD who presents with recent-onset vesicles and erosions. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

MANAGEMENT

Treatment of the acute episode — EH is a dermatologic emergency that requires prompt initiation of antiviral treatment as soon as the diagnosis is suspected.

●When to admit to hospital – Children and adults with severe EH (eg, extensive disease, involvement of the face and periocular areas, extensive gingivostomatitis that impairs oral intake, signs of central nervous system involvement, and/or severe systemic symptoms) should be treated in a hospital. Delayed treatment is associated with increased risk of complications and prolonged hospitalization [38].

●Choice of antiviral therapy – There are no formal guidelines on antiviral treatment for EH [42,43]. However, there is general consensus among experts that acyclovir is first-line treatment for EH.

Due to its modest oral bioavailability, intravenous administration of acyclovir is recommended in most cases. Oral dosing should only be used in mild/limited disease. In a small multicenter placebo-controlled trial (n = 69), acyclovir 200 mg five times per day for five days was associated with a shorter duration of ulcerations and greater improvement compared with placebo [44].

Alternatives to acyclovir include oral valacyclovir (an oral prodrug of acyclovir with greater bioavailability) and oral famciclovir. In rare cases of acyclovir-resistant herpes simplex virus (HSV), foscarnet is an option.

●Patients with severe/extensive eczema herpeticum – For patients with severe or extensive disease, we suggest treatment with intravenous acyclovir [1,34,45]. Recommended doses are as follows:

•Adults – 5 to 10 mg/kg/dose twice daily for 7 to 14 days

•Children – 5 to 10 mg/kg/dose every eight hours for 7 to 14 days

●Patients with mild/limited eczema herpeticum – Patient with mild disease (eg, involvement of a limited, nonfacial area, mild systemic symptoms) can be treated with oral acyclovir. Recommended doses are as follows:

•Adults – 200 to 400 mg/dose five times per day for 7 to 14 days

•Children – 20 mg/kg/dose five times per day (maximum of 800 mg per dose) for 7 to 14 days

Alternatives to acyclovir include:

•Valacyclovir is given orally at the dose of 1000 mg two or three times per day for five to seven days in adults and 20 mg/kg/dose twice daily (maximum of 1000 mg/dose) for five to seven days in children.

•Famciclovir is not recommended in young children. In adolescents and adults, it is given at the dose of 500 mg twice daily for 5 to 14 days.

●Acyclovir-resistant eczema herpeticum – For acyclovir-resistant EH, intravenous foscarnet can be used in children and adults at the dose of 40 mg/kg/dose three times per day.

Supportive care — For all patients with EH, supportive care includes:

●Routine skin care with nonsoap cleansers and moisturizers. The use of topical corticosteroids or topical calcineurin inhibitors is not contraindicated.

●Assessment and treatment of secondary infection with S. aureus with oral antibiotics (table 1) [45] (see "Impetigo"). It should be noted that EH is often misdiagnosed as bacterial infection, resulting in delay in the administration of appropriate antiviral treatment.

●Referral to ophthalmologist/neurologist or other specialists when systemic involvement is suspected. Facial/periocular involvement by EH warrants prompt ophthalmic examination to exclude cornea involvement.

Long-term antiviral prophylaxis — Long-term suppressive treatment with acyclovir may be considered in patients with recurrent attacks of EH. Acyclovir is given at the dose of 400 mg twice daily in adults and 20 mg/kg/dose twice daily in children [45]. The need for ongoing therapy should be reassessed after 6 to 12 months [45].

MANAGEMENT OF ATOPIC DERMATITIS DURING AN EPISODE OF ECZEMA HERPETICUM — 

There is a lack of studies specifically addressing the management of atopic dermatitis (AD) during an episode of EH. Evidence is derived from observational studies and limited data.

●Topical therapies – The use of topical corticosteroids in patients with EH treated with antiviral therapy is generally felt as safe. In a retrospective cohort of 1331 pediatric patients aged 2 months to 17 years hospitalized for EH, the use of topical corticosteroids or topical calcineurin inhibitors was not associated with a longer length of stay [38]. In a series of 39 patients hospitalized for EH, no unfavorable outcomes (ie, death, admission to intensive care unit, or long-term sequelae) were reported among the 36 patients (92 percent) who were given topical corticosteroids within 24 hours of admission [46].

●Systemic therapies – The decision to continue or interrupt treatments is based on a few observational studies, limited data from clinical trials of systemic treatment of AD (most of which are underpowered for the evaluation and management of rare adverse events), and indirect evidence from studies on other autoimmune diseases.

•Conventional immunosuppressants, such as methotrexate, mycophenolate mofetil, and cyclosporine, should be discontinued in severe infections, such as EH. Systemic corticosteroids should be reduced [34].

•Biologics that target the interleukin (IL) 4/13 pathway (eg, dupilumab) are not associated with an elevated risk of EH. Continuation of treatment should be evaluated in the individual patient [34].

•Janus kinase (JAK) inhibitors should be withheld during an episode of EH [47].

PROGNOSIS — 

Prior to the advent of antivirals, mortality of EH was reported to be as high as 50 percent [48]. With the advent of antiviral treatment, the rates of admission to intensive care units and mortality are very low. In a cohort of 1331 pediatric patients with EH, the intensive care unit admission rate was 4 percent, and mortality was 0.1 percent.

Recurrence of EH occurs in 16 to 50 percent of patients, and 5 percent of patients report more than five episodes [2,6,7,10]. The risk of recurrence is higher in patients with early onset of atopic dermatitis (AD) and in those who experienced a prior episode of EH [6,7].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atopic dermatitis".)

SUMMARY AND RECOMMENDATIONS

●Definition and epidemiology – Eczema herpeticum (EH) is a secondary infection of eczematous skin with human herpes simplex virus (HSV), in most cases HSV type 1 (HSV-1). It occurs more frequently in children than in adults and in patients with severe atopic dermatitis (AD). The estimated prevalence of EH among patients with moderate to severe AD is approximately 20 percent. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical presentation – EH presents with disseminated, nongrouped, monomorphic papulovesicles on an erythematous base that may progress to pustules, punched-out erosions, and crusts (picture 1A-D). Systemic symptoms (eg, fever, headache) occur in approximately one-half of the cases. Complications may include keratoconjunctivitis, meningoencephalitis, hepatitis, and secondary infection with Staphylococcus aureus. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of EH requires a high index of suspicion. In the setting of a disease flare, the acute onset of monomorphic, nongrouped papulovesicles that progress to pustules, punched-out erosions, and crusts, often accompanied by systemic symptoms, suggests the diagnosis. The presence of HSV in the skin can be confirmed by polymerase chain reaction (PCR) for viral DNA. (See 'Laboratory tests' above and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis'.)

●Management of the acute episode – EH is a dermatologic emergency that requires prompt initiation of antiviral treatment.

•Severe/extensive eczema herpeticum – Children and adults with severe disease (eg, extensive disease, severe systemic symptoms, involvement of the face/periocular area, extensive gingivostomatitis affecting oral intake, signs of central nervous system involvement) require hospitalization. For these patients, we suggest intravenous acyclovir rather than oral acyclovir or other antiviral agents (Grade 2C). (See 'Treatment of the acute episode' above.)

-Adults – 5 to 10 mg/kg/dose twice daily for 7 to 14 days

-Children – 5 to 10 mg/kg/dose every eight hours for 7 to 14 days

•Mild/limited eczema herpeticum – For patients with mild EH (eg, involvement of a limited, nonfacial area and mild systemic symptoms), we suggest oral acyclovir (Grade 2C).

-Adults – 200 to 400 mg/dose five times per day for 7 to 14 days

-Children – 20 mg/kg/dose five times per day (maximum of 800 mg per dose) for 7 to 14 days

•Supportive measures – Supportive measures include gentle skin care with nonsoap cleansers and moisturizer and assessment and treatment of secondary infection with S. aureus with oral antibiotics (table 1) (see "Impetigo"). Ophthalmologic referral is indicated for patients with facial/periocular involvement. (See 'Supportive care' above.)

•Long-term antiviral prophylaxis – Long-term suppressive treatment with acyclovir may be considered in patients with recurrent attacks of EH. Acyclovir is given at the dose of 400 mg twice daily in adults and 20 mg/kg/dose twice daily in children. (See 'Long-term antiviral prophylaxis' above.)

●Concurrent management of atopic dermatitis – Concurrent management of AD in patients with EH receiving antiviral therapy includes several considerations:

•The use of topical corticosteroids is generally felt to be safe.

•Conventional immunosuppressants (eg, methotrexate, mycophenolate mofetil, cyclosporine) and Janus kinase (JAK) inhibitors (eg, upadacitinib, baricitinib) should be withheld.

•The decision to continue treatment with biologics that target the interleukin (IL) 4/13 pathway (eg, dupilumab) and are not associated with an elevated risk of EH should be evaluated in the individual patient. (See 'Management of atopic dermatitis during an episode of eczema herpeticum' above.)