Eczema Herpeticum

Topic Overview

Summary

Eczema herpeticum (EH), also known as Kaposi varicelliform eruption, is a disseminated cutaneous herpes simplex virus (HSV) infection that develops as a superinfection in patients with pre-existing skin barrier disorders, most commonly atopic dermatitis. [1] It represents a dermatological and potentially life-threatening emergency characterised by the rapid onset of widespread monomorphic vesicles and distinctive punched-out erosions on eczematous skin, frequently accompanied by systemic symptoms including fever and malaise. [2] The condition predominantly affects individuals with moderate-to-severe atopic dermatitis, exploiting the compromised skin barrier and dysregulated immune response characteristic of this disease. Without prompt recognition and treatment with intravenous aciclovir in severe cases, eczema herpeticum can progress to serious complications including herpetic keratitis leading to blindness, bacterial superinfection, viraemia, encephalitis, and in rare cases, death. [3,4]

Key Facts

• Aetiology: HSV-1 (85-90% of cases) or HSV-2 infection on disrupted skin barrier
• Risk population: Predominantly atopic dermatitis patients (especially moderate-to-severe, childhood-onset disease)
• Incidence: Affects approximately 3% of hospitalised atopic dermatitis patients and up to 10-20% of severe AD cases over lifetime [5]
• Pathognomonic feature: Monomorphic vesicles progressing to punched-out erosions (2-3mm diameter, round, clean edges)
• High-risk groups: Children, patients with filaggrin mutations, early-onset severe eczema, immunocompromised hosts
• Emergency presentation: Rapidly spreading lesions with systemic symptoms warrant immediate treatment
• Treatment: IV aciclovir 5-10mg/kg TDS for severe/systemic disease; oral aciclovir/valaciclovir for mild localised cases
• Complications: Herpetic keratitis (5-10% cases), bacterial superinfection (30-40%), recurrence (20-30%), scarring
• Mortality: Historically 10-50% untreated; less than 1% with modern antiviral therapy [6]

Clinical Pearls

"Punched-out" morphology is pathognomonic — Round, monomorphic erosions with clean edges (2-3mm) on eczematous skin distinguish EH from bacterial impetiginisation

Pain disproportionate to appearance — Patients often report significant pain and burning sensation that seems excessive compared to visible lesions

Always examine the eyes — Periorbital involvement requires urgent ophthalmology assessment as herpetic keratitis can cause permanent vision loss

Do NOT delay treatment for virology confirmation — High clinical suspicion should prompt empirical aciclovir while awaiting HSV PCR results

Do NOT use topical corticosteroids alone — This will worsen viral replication and spread; antivirals must be initiated first

Immunocompromised patients require IV therapy — Lower threshold for admission and parenteral treatment in HIV, transplant, or biologics patients

Recurrence is common — 20-30% experience repeat episodes; consider suppressive aciclovir in frequent recurrers [7]

Why This Matters Clinically

Eczema herpeticum is frequently misdiagnosed as bacterial impetiginisation of eczema or a simple eczema flare, leading to inappropriate treatment with topical corticosteroids alone and delayed antiviral therapy. [8] This diagnostic error can result in progression to sight-threatening herpetic keratitis, systemic dissemination, and secondary bacterial sepsis. The distinctive punched-out erosion morphology is a critical diagnostic clue that emergency and primary care physicians must recognise to initiate urgent antiviral treatment. Early intervention within 48-72 hours significantly reduces morbidity and mortality. [9]

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Visual Summary

Visual assets to be added:

• Clinical photograph: Classical punched-out erosions on facial eczema
• Close-up: Monomorphic vesicles at same stage of development
• Comparison image: Eczema herpeticum vs bacterial impetiginisation
• Periorbital involvement showing dendritic ulcer risk
• Management algorithm: Severity assessment and treatment pathway
• Histopathology: Multinucleated giant cells and viral cytopathic effect
• Tzanck smear: Multinucleated keratinocytes

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Epidemiology

Incidence and Prevalence

Eczema herpeticum is an uncommon but clinically significant complication of atopic dermatitis:

• Overall incidence: 3% of hospitalised atopic dermatitis patients [5]
• Lifetime risk in AD: Estimated 10-20% in patients with moderate-to-severe disease [10]
• Paediatric cases: Peak incidence in children aged 6 months to 5 years, coinciding with primary HSV exposure
• Adult cases: Less common but tend to be more severe, particularly in immunocompromised hosts
• Hospital admission rate: Approximately 60-70% of diagnosed cases require inpatient management [11]

Demographics

Age Distribution:

• Infants and young children: Highest incidence (6 months - 5 years)
• Adolescents and young adults: Second peak in teenage years
• Older adults: Rare unless immunocompromised or severe underlying skin disease

Gender:

• No significant gender predisposition
• Slight male predominance in some paediatric studies (male-to-female ratio 1.2-1.5:1)

Geographic Distribution:

• Worldwide distribution
• Higher reported incidence in developed countries (likely reflects better diagnostic recognition)
• No significant racial or ethnic predisposition

Risk Factors

Major Risk Factors

Other Skin Barrier Disorders

Eczema herpeticum can occur in non-atopic skin diseases with barrier impairment:

• Darier disease (keratosis follicularis) — inherited acantholytic disorder
• Hailey-Hailey disease (benign familial pemphigus) — desmosomal adhesion defect
• Pemphigus vulgaris — autoimmune blistering disease
• Mycosis fungoides — cutaneous T-cell lymphoma
• Thermal burns — acute barrier loss
• Toxic epidermal necrolysis — severe mucocutaneous reaction

These conditions collectively termed as predisposing to "Kaposi varicelliform eruption" — the broader category encompassing viral superinfection on damaged skin. [1]

Immunocompromise

Topical Calcineurin Inhibitors — Controversial Association

The relationship between topical tacrolimus/pimecrolimus and eczema herpeticum remains debated:

• Proposed mechanism: Local immunosuppression could theoretically increase HSV susceptibility
• Evidence: Large RCTs and meta-analyses show no increased risk compared to topical corticosteroids [16]
• Confounding: Patients using TCI typically have more severe AD (independent EH risk factor)
• Current consensus: No evidence to avoid TCI use; should be discontinued during active infection [17]

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Pathophysiology

Overview: The Barrier-Immune Dysfunction Paradigm

Eczema herpeticum results from the convergence of three pathophysiological abnormalities in atopic dermatitis:

1. Structural barrier defect — facilitates viral entry
2. Innate immune dysregulation — impaired antiviral defense
3. Adaptive immune skewing — Th2 predominance suppresses antiviral responses [18]

Structural Barrier Defects in Atopic Dermatitis

Filaggrin Deficiency:

Filaggrin (filament-aggregating protein) is crucial for epidermal barrier integrity:

• Genetic basis: Loss-of-function mutations in FLG gene (R501X, 2282del4 most common in Europeans)
• Prevalence: 20-30% of moderate-to-severe AD patients carry FLG mutations [13]
• Consequences:
  • Reduced natural moisturising factor (NMF) production
  • Decreased corneocyte aggregation
  • Impaired stratum corneum structure
  • Increased transepidermal water loss (TEWL)
  • Elevated skin surface pH (favours pathogen growth)

Impact on HSV susceptibility: FLG-deficient skin exhibits microbreaks and fissures that permit direct viral entry to viable keratinocytes, bypassing the protective stratum corneum. [13]

Tight Junction Abnormalities:

• Reduced claudin-1 and claudin-23 expression in AD epidermis [19]
• Increased paracellular permeability to pathogens
• Facilitated viral spread between keratinocytes

Lipid Barrier Disruption:

• Decreased ceramide content in AD stratum corneum
• Altered fatty acid composition
• Increased susceptibility to physical trauma and infection

Innate Immune Deficiency

Antimicrobial Peptide (AMP) Suppression:

Cathelicidin (LL-37) and β-defensins provide first-line antiviral defense:

• Mechanism: AMPs directly disrupt viral envelopes and modulate immune responses
• Th2 cytokine suppression: IL-4 and IL-13 (elevated in AD) downregulate AMP expression [14]
• Clinical correlation: AD patients with history of EH have significantly lower LL-37 levels compared to AD patients without EH [14]

Interferon Response Impairment:

• Type I interferons (IFN-α/β) are critical for antiviral defense
• AD keratinocytes exhibit blunted IFN response to viral PAMPs (pathogen-associated molecular patterns)
• Th2 cytokines antagonise IFN signalling pathways
• Reduced expression of interferon-stimulated genes (ISGs)

Pattern Recognition Receptor (PRR) Dysfunction:

• Toll-like receptors (TLR2, TLR3, TLR9) detect viral nucleic acids
• AD keratinocytes show altered TLR expression and signalling
• Impaired viral recognition leads to delayed immune activation

Adaptive Immune Dysregulation

Th2-Skewed Response:

Atopic dermatitis is characterised by Th2-predominant inflammation:

• Th2 cytokines (IL-4, IL-5, IL-13, IL-31):

  • Suppress Th1 antiviral responses
  • Inhibit AMP production
  • Impair keratinocyte antiviral mechanisms

• Th1 cytokines (IFN-γ, IL-12) — required for effective antiviral immunity:

  • Relatively deficient in active AD
  • Failure to mount robust cell-mediated immunity against HSV

Regulatory T Cell (Treg) Imbalance:

• Altered Treg function in AD may impair viral clearance
• Contributes to chronic/recurrent HSV infections

Viral Pathogenesis: HSV-1 and HSV-2

HSV Structure and Life Cycle:

• Virus: Double-stranded DNA virus (Herpesviridae family)
• Envelope glycoproteins: gB, gC, gD mediate cellular attachment and entry
• Tropism: Epithelial cells and neurons
• Latency: Dorsal root ganglia (HSV-1 typically trigeminal; HSV-2 sacral)

Infection Sequence in Eczema Herpeticum:

1. Primary exposure or reactivation:

   • Primary HSV infection (most common in children)
   • Reactivation from latency (more common in adults)
   • Autoinoculation from oral/genital lesions

2. Viral entry through compromised barrier:

   • HSV glycoproteins bind to cellular receptors (nectin-1, HVEM)
   • Direct entry through skin fissures and microtrauma
   • Keratinocyte infection initiates

3. Rapid lateral spread:

   • Cell-to-cell transmission via intercellular junctions
   • Deficient tight junctions facilitate spread
   • Viral replication in multiple keratinocyte layers

4. Clinical manifestation:

   • Ballooning degeneration of keratinocytes
   • Intraepidermal vesicle formation
   • Vesicle rupture → punched-out erosions
   • Coalescing lesions → widespread involvement

5. Systemic dissemination (severe cases):

   • Viraemia
   • Haematogenous spread to visceral organs (liver, lungs, CNS)
   • Life-threatening in immunocompromised hosts

Histopathological Features

Microscopic findings:

• Acantholysis: Loss of keratinocyte adhesion
• Ballooning degeneration: Swollen keratinocytes with pale cytoplasm
• Multinucleated giant cells: Fusion of infected keratinocytes (Tzanck cells)
• Viral inclusion bodies:
  • Cowdry type A inclusions — eosinophilic intranuclear inclusions with halo
  • Chromatin margination ("ground-glass" nuclei)
• Intraepidermal vesicles: Roof formed by necrotic keratinocytes
• Dermal inflammation: Mixed infiltrate with lymphocytes, neutrophils (if superinfected)

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Clinical Presentation

Typical Presentation: The Classic Triad

Eczema herpeticum characteristically presents with:

1. Pre-existing atopic dermatitis (usually active/flaring)
2. Acute onset of vesicular eruption (develops over 24-72 hours)
3. Systemic symptoms (fever, malaise, lymphadenopathy)

History

Presenting Complaint:

• "My eczema suddenly got much worse with lots of small blisters"
• "Painful rash spreading rapidly over the face/neck"
• "Fever and feeling unwell with skin outbreak"
• Pain disproportionate to visible lesions — key distinguishing feature

Timeline:

• Prodrome (24-48 hours): Burning, tingling, pruritus at site
• Vesicle eruption (Day 1-3): Rapid appearance of clustered vesicles
• Umbilication and erosion (Day 2-5): Vesicles evolve to punched-out erosions
• Crusting (Day 5-10): Haemorrhagic crusts form over erosions
• Resolution (Week 2-4): Crusts separate, post-inflammatory changes

Associated Symptoms:

• Fever: 70-80% of cases; typically 38-39°C [2]
• Malaise: Profound fatigue, weakness
• Pain: Sharp, burning quality; worse than typical eczema itch
• Swollen glands: Tender regional lymphadenopathy
• Ocular symptoms: Tearing, photophobia, eye pain (5-10% develop keratitis) [4]

Past Medical History:

• Atopic dermatitis: Onset age, severity, current treatment
• Previous eczema herpeticum: 20-30% recurrence rate [7]
• HSV history: Cold sores, genital herpes
• Immunocompromise: HIV status, immunosuppressive medications
• Recent HSV exposure: Family member with cold sore, sexual contact

Drug History:

• Current AD treatments: Topical corticosteroids, calcineurin inhibitors, emollients
• Systemic immunosuppression: Prednisolone, ciclosporin, methotrexate, dupilumab
• Recent topical steroid escalation: May have masked early infection

Signs: The Pathognomonic "Punched-Out" Lesion

Primary Lesion Morphology:

Vesicles (early stage):

• Appearance: Tense, dome-shaped, fluid-filled
• Size: 2-3mm diameter (occasionally up to 5mm)
• Fluid: Initially clear, becomes turbid/haemorrhagic
• Base: Erythematous, eczematous skin
• Distribution: Monomorphic — all lesions at similar stage (unlike varicella)
• Grouping: Clustered, can coalesce into larger vesicles

Punched-Out Erosions (pathognomonic):

• Shape: Perfectly round to oval
• Size: 2-3mm diameter
• Depth: Shallow, confined to epidermis
• Edges: Clean, sharply demarcated ("cookie-cutter" or "punched-out" appearance)
• Base: Moist, pink-red, weeping serous/haemorrhagic fluid
• Surrounding skin: Erythematous, often eczematous changes
• Evolution: Vesicles rupture within 24-48 hours leaving characteristic erosions

Crusting (later stage):

• Appearance: Golden-yellow to dark brown/black
• Texture: Thick, adherent
• Haemorrhagic component: Common, giving "blackened" appearance
• Distribution: Covers erosions, may coalesce into sheets

Secondary Features:

• Erythema: Widespread erythematous base
• Oedema: Facial oedema common, especially periorbital
• Weeping/exudate: Serous or seropurulent discharge
• Scarring: Post-inflammatory hypopigmentation or hyperpigmentation (usually temporary)

Distribution Patterns

Classic Distribution (order of frequency):

1. Face and neck (60-70% cases):

   • Forehead, cheeks, perioral region
   • Periorbital involvement — REQUIRES URGENT OPHTHALMOLOGY [4]

2. Upper trunk (30-40%):

   • Anterior chest, upper back

3. Upper limbs (20-30%):

   • Flexural areas (antecubital fossae)
   • Hands and fingers

4. Lower limbs (15-25%):

   • Popliteal fossae
   • Ankles, feet

Key Pattern Recognition:

• Lesions develop on pre-existing eczematous skin
• Spares non-eczematous areas (in contrast to varicella)
• Unilateral or asymmetric distribution possible
• Can be localised (mild cases) or generalised (severe cases affecting > 20% BSA)

Severity Assessment

Distinguishing Eczema Herpeticum from Mimics

Bacterial Superinfection (Impetiginisation)

Critical Distinction: The monomorphic punched-out erosion is pathognomonic of EH and should trigger immediate aciclovir therapy. [2]

Varicella (Chickenpox)

Eczema Vaccinatum (Historical)

• Rare: Since cessation of routine smallpox vaccination
• Risk group: AD patients exposed to recently vaccinated individual (vaccinia virus transmission)
• Morphology: Identical to eczema herpeticum (umbilicated vesicles, punched-out erosions)
• Diagnosis: History of vaccinia exposure, viral PCR differentiates
• Treatment: Vaccinia immune globulin + supportive care (aciclovir ineffective against vaccinia)

Disseminated Herpes Zoster

• Dermatomal origin: Starts in dermatomal distribution before dissemination
• Vesicle characteristics: Larger, more variably sized than EH
• Age: More common in elderly/immunocompromised
• Pain: Severe neuropathic pain precedes rash (prodrome)
• PCR: Differentiates VZV from HSV

Hand-Foot-Mouth Disease (Coxsackievirus A16, Enterovirus 71)

• Distribution: Palms, soles, oral mucosa (characteristic triad)
• Lesions: Oval vesicles with surrounding erythema
• Age: Young children (6 months - 5 years)
• Systemic symptoms: Mild or absent
• Atopic dermatitis: Not a predisposing factor

Red Flags Requiring Immediate Action

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Clinical Examination

Systematic Approach

A thorough examination is essential to assess severity, identify complications, and guide treatment decisions.

Dermatological Examination

Inspection:

1. Overall distribution:

   • Estimate body surface area (BSA) involved
   • Document eczematous vs non-eczematous skin involvement
   • Photograph lesions (with consent) for monitoring progression

2. Lesion morphology:

   • Stage of evolution (vesicles vs erosions vs crusts)
   • Monomorphic appearance confirmation
   • Punched-out erosion identification

3. Background skin:

   • Severity of underlying atopic dermatitis
   • Signs of scratching (excoriation, lichenification)
   • Secondary infection features

Palpation:

• Regional lymph nodes:

  • Cervical (facial/neck EH)
  • Axillary (upper limb EH)
  • Inguinal (lower limb EH)
  • "Character: Tender, enlarged, mobile"

• Skin temperature: Warmth suggests active inflammation

• Oedema: Periorbital, facial oedema assessment

Ocular Examination — MANDATORY

Critical importance: 5-10% of EH cases develop herpetic keratitis, which can cause permanent vision loss. [4]

Bedside assessment:

• External inspection:

  • Periorbital vesicles/erosions
  • Eyelid oedema
  • Conjunctival injection

• Visual acuity: Document baseline (Snellen chart)

• Pupillary reflexes: Check for afferent pupillary defect (APD)

• Eye movements: Full range, pain on movement

• Red flags:

  • Periorbital vesicles
  • Eye pain or photophobia
  • Reduced visual acuity
  • Conjunctivitis

Specialist ophthalmology assessment (if any eye involvement):

• Slit lamp examination: Essential to detect dendritic ulcers
• Fluorescein staining: Reveals corneal epithelial defects
• Tonometry: Intraocular pressure measurement
• Fundoscopy: Retinal involvement assessment (rare)

Herpetic keratitis features:

• Dendritic ulcer: Branching epithelial defect (pathognomonic)
• Geographic ulcer: Larger amoeboid ulcer (more extensive disease)
• Stromal keratitis: Deep corneal inflammation (vision-threatening)
• Anterior uveitis: Iritis with photophobia, pain

Systemic Examination

General Inspection:

• Vital signs:

  • "Temperature: Fever present in 70-80% of cases [2]"
  • "Heart rate: Tachycardia (sepsis, pain, fever)"
  • "Blood pressure: Hypotension (severe sepsis)"
  • "Respiratory rate: Tachypnoea (sepsis, pneumonitis)"
  • "Oxygen saturation: Hypoxia (pneumonitis)"

• Hydration status:

  • Capillary refill time
  • Mucous membrane moisture
  • Skin turgor
  • Urine output (if admitted)

Neurological Examination (if altered mental status):

• Glasgow Coma Scale (GCS)
• Focal neurological signs
• Meningism (neck stiffness, photophobia, Kernig sign)
• Indication for LP: Suspected HSV encephalitis/meningitis

Respiratory Examination (if dyspnoea/hypoxia):

• Auscultation: Crackles, wheeze (HSV pneumonitis rare but serious)
• Work of breathing: Intercostal recession, accessory muscle use

Abdominal Examination (if abdominal pain/deranged LFTs):

• Hepatomegaly: HSV hepatitis (rare)
• Tenderness

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Investigations

Approach to Investigation

Key principles:

1. Clinical diagnosis: EH is primarily a clinical diagnosis — do NOT delay treatment awaiting results [9]
2. Viral confirmation: Always obtain viral swab for HSV PCR (confirms diagnosis, documents HSV type)
3. Severity markers: Blood tests guide admission and IV treatment decisions
4. Complication screening: Targeted investigations for ocular, CNS, or systemic involvement

Viral Diagnostic Tests

HSV PCR (Polymerase Chain Reaction) — GOLD STANDARD

Sampling technique:

• Use viral swab (not bacterial swab)
• Unroof intact vesicle with sterile needle
• Firmly swab base of lesion (cellular material needed, not just fluid)
• Place in viral transport medium
• Label clearly as "HSV PCR"

Viral Culture

Tzanck Smear (Cytology)

How to perform:

1. Unroof fresh vesicle
2. Scrape base with scalpel blade (15 or 10)
3. Smear onto glass slide
4. Air dry, fix, stain (Giemsa or Wright)
5. Examine under microscopy for multinucleated giant cells

Interpretation:

• Positive: Multinucleated giant cells (Tzanck cells) confirm herpesvirus infection (HSV or VZV)
• Negative: Does not exclude diagnosis (lower sensitivity than PCR)

Direct Immunofluorescence (DIF)

• Technique: Fluorescently labelled antibodies detect viral antigens in vesicle base scrapings
• Sensitivity: 70-90%
• Advantage: Differentiates HSV from VZV
• Limitation: Requires specific reagents and fluorescence microscopy
• Current role: Limited availability; replaced by PCR in most centres

Histopathology (Skin Biopsy)

Indications (rarely required):

• Diagnostic uncertainty
• Atypical presentation
• Immunocompromised host with unusual morphology
• Exclusion of alternative diagnoses (Stevens-Johnson syndrome, drug eruption)

Biopsy technique:

• 3-4mm punch biopsy from vesicle/erosion edge
• Include intact vesicle roof if possible
• Send in formalin for H&E staining

Histopathological features:

• Acantholysis: Loss of intercellular adhesion
• Ballooning degeneration: Swollen keratinocytes
• Multinucleated giant cells: Pathognomonic (3-15 nuclei per cell)
• Cowdry type A inclusions: Eosinophilic intranuclear inclusions with clear halo
• Intraepidermal vesicles: Roof formed by necrotic epidermis
• Viral cytopathic effect: Margination of chromatin, "ground-glass" nuclei

Blood Tests

Baseline Investigations (All Moderate-Severe Cases)

Additional Tests (Selected Cases)

Bacterial Swabs

Indication: Signs of bacterial superinfection (30-40% cases)

Signs of bacterial superinfection:

• Pustules (not typical of pure EH)
• Thick yellow-green crusts
• Increasing erythema and warmth
• Worsening systemic symptoms despite aciclovir

Swab technique:

• Bacterial swab (not viral swab) from pustule or exudate
• Request: "Microscopy, culture, sensitivity"
• Common organisms: Staphylococcus aureus (including MRSA), Streptococcus pyogenes

Ocular Investigations (If Eye Involvement)

Ophthalmology assessment — URGENT within 2-4 hours [4]

Additional ophthalmology tests (specialist-led):

• Anterior chamber tap: PCR for HSV if uveitis present
• Confocal microscopy: Visualise viral changes in cornea

Neurological Investigations (If CNS Symptoms)

Indications:

• Altered mental status (confusion, drowsiness, seizures)
• Focal neurological signs
• Severe headache, meningism

Cerebrospinal fluid (CSF) analysis:

CSF HSV PCR:

• Gold standard for CNS HSV diagnosis
• Sensitivity > 95%, specificity > 98% [3]
• Can be negative in first 72 hours (repeat if high suspicion)
• Positive result mandates IV aciclovir for 14-21 days

Imaging

Chest X-Ray (CXR)

Indications:

• Respiratory symptoms (dyspnoea, cough, hypoxia)
• Suspected HSV pneumonitis (rare)
• Pre-admission workup for moderate-severe cases

Findings in HSV pneumonitis:

• Bilateral interstitial infiltrates
• Nodular opacities
• Ground-glass opacification

Abdominal Ultrasound / CT Abdomen

Indication: Suspected HSV hepatitis (rare)

Features:

• Abdominal pain, ↑↑ ALT/AST (> 1000 IU/L), jaundice
• Imaging: Hepatomegaly, heterogeneous liver echotexture

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Classification & Staging

Severity Classification

Classification guides treatment decisions (oral vs IV aciclovir, outpatient vs admission):

Risk Stratification for IV Aciclovir

Indications for IV aciclovir (regardless of BSA extent):

• Severe or extensive disease (> 20% BSA)
• Systemic symptoms (fever > 38.5°C, malaise, dehydration)
• Ocular involvement or periorbital lesions
• Immunocompromised host (HIV, chemotherapy, biologics, high-dose steroids)
• Inability to tolerate oral medication (vomiting, reduced GCS)
• Age less than 6 months (neonatal HSV risk)
• Complications (keratitis, encephalitis, pneumonitis, hepatitis)
• Failed oral therapy (progression despite 48h oral aciclovir)
• Social factors (poor adherence anticipated, safeguarding concerns)

Hospital vs Outpatient Management

Admission criteria:

• Any indication for IV aciclovir (see above)
• Severe pain requiring parenteral analgesia
• Dehydration requiring IV fluids
• Social concerns (vulnerability, safeguarding)
• Diagnostic uncertainty requiring observation

Outpatient management appropriate if ALL of:

• Localised disease (less than 5% BSA)
• Systemically well (no fever, able to eat/drink)
• No ocular involvement
• Not immunocompromised
• Reliable follow-up possible (review 24-48h)
• Able to commence oral aciclovir immediately

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Management

General Principles

1. Treat empirically on clinical suspicion — do NOT await viral PCR confirmation [9]
2. Start antivirals within 24-72 hours — early treatment reduces complications
3. IV aciclovir for severe/complicated cases — lower threshold for parenteral therapy
4. Multidisciplinary input: Dermatology, ophthalmology, paediatrics (if child), infectious diseases (if immunocompromised)
5. Address underlying atopic dermatitis — continue emollients, resume steroids once infection controlled
6. Infection control: Contact precautions until lesions crusted (infectious to non-immune individuals)

Antiviral Therapy — Cornerstone of Treatment

Mild/Localised Disease (Outpatient Oral Therapy)

Criteria: less than 5% BSA, systemically well, no risk factors, reliable patient

Monitoring:

• Review 24-48 hours: Assess response, ensure compliance
• Safety-net advice: Return if worsening, fever, eye symptoms, unable to tolerate oral

Expected response:

• No new lesions after 48-72 hours
• Crusting of lesions by day 5-7
• Resolution by 2-3 weeks

Moderate to Severe Disease (IV Aciclovir)

Indications: See "Risk Stratification for IV Aciclovir" above

Administration:

• Dilute in 0.9% sodium chloride or 5% dextrose
• Infuse over 1 hour (minimum) — reduces nephrotoxicity risk
• Adequate hydration essential (pre-hydration and maintenance fluids)

Renal dose adjustment:

Monitoring during IV aciclovir:

• Renal function: U&E on days 0, 3, 7 (aciclovir crystalluria can cause AKI) [23]
• Fluid balance: Maintain adequate hydration (reduces crystalluria)
• FBC: Monitor WCC (bacterial superinfection)
• Clinical response: Daily skin assessment, temperature chart

Switch to oral therapy when:

• Afebrile for 24-48 hours
• No new vesicles
• Clinical improvement evident
• Tolerating oral intake
• Complete total 10-14 days antiviral course (IV + oral combined)

Oral step-down regimen:

• Aciclovir 400-800mg five times daily, OR
• Valaciclovir 1g three times daily
• Complete to 10-14 days total (including IV days)

Special Populations

Pregnancy and Breastfeeding:

• Aciclovir safety: Pregnancy category B (FDA); extensive safety data, no teratogenicity [17,24]
• Treatment: Same doses as non-pregnant adults
• Breastfeeding: Safe to continue (low aciclovir levels in breast milk)
• Obstetric input: Inform obstetrics if pregnant patient

Immunocompromised Hosts:

• Higher doses: 10 mg/kg IV TDS (not 5 mg/kg)
• Longer duration: 14-21 days (not 10-14 days)
• Lower threshold for IV: Treat even mild cases with IV aciclovir
• Aciclovir resistance: Consider if no response after 7-10 days; switch to foscarnet (requires infectious diseases input)

Neonates (less than 3 months):

• High mortality risk: Treat as disseminated neonatal HSV
• Dose: 20 mg/kg IV TDS for 14-21 days
• Investigations: HSV PCR (blood, CSF), neuroimaging
• Paediatric infectious diseases: Urgent involvement

Ocular Involvement — Urgent Ophthalmology

All periorbital/ocular cases require ophthalmology within 2-4 hours [4]

Systemic Antiviral:

• IV aciclovir 5-10 mg/kg TDS (even if skin disease mild)
• Penetrates eye tissues

Topical Antiviral (ophthalmology-directed):

Caution: Topical steroids CONTRAINDICATED in active herpetic keratitis (will worsen corneal ulceration)

Management of herpetic keratitis:

• Topical aciclovir/ganciclovir + systemic aciclovir
• Cycloplegic drops (cyclopentolate 1%) — relieves ciliary spasm
• Analgesia
• Daily ophthalmology review until epithelial healing
• Long-term sequelae: Corneal scarring, recurrent erosions, stromal keratitis

Bacterial Superinfection — Common Complication

Incidence: 30-40% of EH cases develop secondary bacterial infection [20]

Clinical clues:

• Pustules (not typical of pure HSV)
• Thick yellow-green crusts
• Increasing erythema, warmth, tenderness
• Fever persisting despite aciclovir
• Positive bacterial swab (S. aureus, S. pyogenes)

Antibiotic Selection:

Note: Continue aciclovir alongside antibiotics (dual pathogen treatment)

Supportive Care

Analgesia:

• Paracetamol: 1g QDS (adults)
• Ibuprofen: 400mg TDS (if not contraindicated)
• Opioids: Codeine, tramadol, morphine for severe pain (EH can be very painful)

Wound Care:

• Emollients: Continue generous application (maintains barrier)
• Non-adherent dressings: For weeping erosions (silicone or paraffin gauze)
• Antiseptic soaks: Dilute potassium permanganate soaks (1:10,000) — reduces bacterial load
• Avoid topical antibiotics: Mupirocin/fusidic acid have limited role (systemic antibiotics preferred)

Hydration and Nutrition:

• IV fluids: If dehydrated, unable to drink, or NBM
• Nutritional support: Encourage oral intake; NG feeding if prolonged illness

Infection Control:

• Contact precautions: Gloves, aprons for direct contact
• Isolation: Single room if inpatient
• HSV transmission risk: Infectious to non-immune contacts (neonates, immunocompromised, pregnant women)
• Duration of infectivity: Until all lesions crusted over (usually 7-10 days)

Atopic Dermatitis Management During Acute Infection

Emollients:

• Continue liberally: Maintains skin barrier, reduces fissuring
• Frequency: At least 3-4 times daily

Topical Corticosteroids:

• Avoid during acute infection: May worsen viral replication
• Resume once controlled: After 5-7 days of aciclovir, when no new lesions
• Use appropriately potent steroid for body site and severity

Topical Calcineurin Inhibitors (Tacrolimus, Pimecrolimus):

• Stop during acute infection: Theoretical immunosuppression concern
• Resume after infection resolved (7-14 days)

Systemic Immunosuppressants:

• Ciclosporin, methotrexate, azathioprine:

  • Consider holding during acute EH (discuss with dermatology)
  • Restart cautiously after clinical improvement

• Dupilumab (anti-IL-4Rα):

  • "Current evidence: No increased HSV risk [15]"
  • Continue during EH (may aid resolution by improving AD)
  • Discuss with dermatology on case-by-case basis

Future AD Control:

• Optimise AD management post-EH to reduce recurrence risk
• Consider step-up therapy (phototherapy, systemic immunomodulators, biologics)

Aciclovir Resistance — Rare but Important

Incidence: less than 1% immunocompetent; up to 5-10% immunocompromised (especially HIV, transplant) [17,25]

Suspect if:

• No clinical improvement after 7-10 days IV aciclovir
• Progressive lesions despite therapy
• Immunocompromised host
• History of prolonged/frequent aciclovir use

Confirmation:

• Viral culture with aciclovir sensitivity testing
• Genotypic resistance testing (thymidine kinase mutations)

Management:

• Foscarnet: 40 mg/kg IV TDS for 14-21 days [26]

  • "Highly nephrotoxic: Requires pre-hydration, close U&E monitoring"
  • Infectious diseases consultation essential

• Cidofovir: Alternative (ophthalmology use for resistant keratitis)

Prevention of Recurrence

Risk of recurrence: 20-30% experience subsequent EH episodes [7]

Suppressive Aciclovir Therapy:

Indications:

• ≥3 episodes per year
• Severe episodes requiring hospitalisation
• Immunocompromised host with history of EH

Regimen:

• Aciclovir 400mg twice daily (PO), OR
• Valaciclovir 500mg once daily (PO)
• Duration: 6-12 months, then reassess

Efficacy: Reduces recurrence by 70-80% [7]

Long-term aciclovir safety:

• Generally well tolerated
• Monitor renal function 6-monthly
• No significant long-term toxicity in immunocompetent hosts

Other Preventive Measures:

• Optimise AD control: Reduce skin barrier disruption
• Avoid HSV exposure: Family members with cold sores should avoid direct contact during active lesions
• Hand hygiene: Reduce autoinoculation from oral/genital HSV
• Emollients: Maintain skin barrier integrity

---

Complications

Local Dermatological Complications

Scarring:

• Incidence: 10-30% depending on severity [2]
• Type: Usually post-inflammatory hypo- or hyperpigmentation (temporary)
• Permanent atrophic scars rare (more common if secondary bacterial infection)
• Management: Reassurance (usually fades over 6-12 months), sun protection, camouflage makeup

Secondary Bacterial Infection:

• Incidence: 30-40% of cases [20,29]
• Organisms: S. aureus (including MRSA), S. pyogenes
• Presentation: Pustules, purulent crusts, worsening erythema
• Management: See "Bacterial Superinfection" section above

Post-Herpetic Erythema Multiforme:

• Immune-mediated hypersensitivity reaction to HSV antigens
• Develops 1-2 weeks after EH resolution
• Target lesions, mucosal involvement
• Treatment: Topical/systemic corticosteroids; long-term aciclovir suppression if recurrent

Ocular Complications

Herpetic Keratitis:

• Incidence: 5-10% of EH cases [4,28]

• Presentation: Eye pain, photophobia, lacrimation, reduced vision

• Types:

  • "Epithelial keratitis: Dendritic/geographic ulcers (most common)"
  • "Stromal keratitis: Deep corneal inflammation (vision-threatening)"
  • "Endotheliitis: Corneal oedema, KP (keratic precipitates)"

• Diagnosis: Slit lamp examination + fluorescein staining

• Treatment:

  • Topical aciclovir/ganciclovir 5x daily
  • Systemic aciclovir (IV or oral high-dose)
  • Cycloplegic drops
  • Avoid topical steroids (worsen epithelial disease)

• Complications:

  • Corneal scarring → reduced visual acuity
  • Recurrent erosions
  • Corneal perforation (rare)
  • Blindness (if untreated)

Conjunctivitis:

• Less serious than keratitis
• Treatment: Topical aciclovir, systemic aciclovir

Uveitis:

• Anterior uveitis (iritis)
• Requires ophthalmology-directed topical steroids + aciclovir

Systemic Complications (Rare, Usually Immunocompromised)

HSV Viraemia and Dissemination:

• Risk factors: Severe immunocompromise (HIV CD4 less than 50, transplant, chemotherapy)
• Presentation: Sepsis, multi-organ dysfunction
• Diagnosis: Positive HSV PCR in blood
• Treatment: High-dose IV aciclovir 10 mg/kg TDS, ICU support
• Mortality: High (20-40% even with treatment) [6]

HSV Encephalitis:

• Incidence: Very rare complication of EH (less than 1%)

• Presentation: Fever, headache, confusion, seizures, focal neurology

• Diagnosis:

  • "MRI brain: Temporal lobe hyperintensity (T2/FLAIR)"
  • "CSF: Lymphocytic pleocytosis, HSV PCR positive [3]"
  • "EEG: PLEDs (periodic lateralised epileptiform discharges)"

• Treatment: IV aciclovir 10 mg/kg TDS for 14-21 days

• Prognosis:

  • Mortality 10-20% with treatment (70% untreated)
  • Neurological sequelae common (memory impairment, seizures)

HSV Meningitis:

• Less severe than encephalitis
• Self-limiting in many cases
• Treatment: IV aciclovir 10 mg/kg TDS for 10-14 days

HSV Pneumonitis:

• Very rare in immunocompetent
• Presentation: Dyspnoea, hypoxia, cough
• CXR: Bilateral interstitial infiltrates
• Diagnosis: Bronchoscopy with BAL HSV PCR
• Treatment: IV aciclovir, respiratory support, ICU

HSV Hepatitis:

• Rare: Fulminant hepatic failure possible
• Presentation: Abdominal pain, jaundice, ↑↑ ALT (> 1000 IU/L), coagulopathy
• Diagnosis: Liver biopsy (haemorrhagic necrosis, inclusion bodies), HSV PCR
• Treatment: IV aciclovir 10 mg/kg TDS, transplant assessment if fulminant
• Mortality: High without treatment

Disseminated Intravascular Coagulation (DIC):

• Complication of severe sepsis (bacterial superinfection or HSV viraemia)
• Coagulopathy, thrombocytopenia, microangiopathic haemolysis
• Management: Treat underlying infection, ICU support, blood product replacement

Neonatal HSV Infection

If EH occurs in pregnant woman or neonate exposed to maternal HSV:

• Neonatal HSV: High mortality (30-50% untreated)
• Presentation: Skin vesicles, encephalitis, disseminated disease
• Management: Urgent paediatric infectious diseases, IV aciclovir 20 mg/kg TDS for 14-21 days

---

Prognosis & Outcomes

Overall Prognosis

With Modern Antiviral Therapy:

• Mortality: less than 1% (immunocompetent patients with timely treatment) [6,27]
• Full recovery: 85-90% with prompt aciclovir and no complications
• Resolution time: 2-4 weeks (crusting by day 7-10, epithelialisation by week 2-3)

Historical Mortality (Pre-Aciclovir Era):

• Untreated mortality: 10-50% (especially children, immunocompromised) [6]
• Major causes of death: Bacterial sepsis, HSV encephalitis, multi-organ failure

Factors Affecting Prognosis

Favourable Prognostic Factors:

• Early aciclovir initiation (less than 72 hours from onset)
• Immunocompetent host
• Localised disease (less than 10% BSA)
• No ocular or CNS involvement
• No bacterial superinfection
• Adequate supportive care

Poor Prognostic Factors:

• Delayed treatment (> 5 days)
• Severe immunocompromise (HIV CD4 less than 50, transplant, chemotherapy)
• Extensive disease (> 30% BSA)
• Complications (encephalitis, hepatitis, viraemia)
• Neonatal age (less than 3 months)
• Aciclovir-resistant HSV

Recurrence Risk

Incidence: 20-30% experience at least one recurrent episode [7]

Risk Factors for Recurrence:

• Severe initial episode
• Early-onset severe AD
• Filaggrin mutations
• Ongoing poor AD control
• Immunosuppression
• Frequent HSV reactivation

Recurrence Pattern:

• Usually less severe than initial episode (partial immunity)
• Can occur months to years after initial episode
• Same principles of management apply (aciclovir, supportive care)

Prevention: See "Prevention of Recurrence" section

Long-Term Sequelae

Dermatological:

• Post-inflammatory pigment changes: Common (80%+), usually resolve 6-12 months
• Atrophic scarring: Uncommon (less than 10%)
• Persistent AD: Often improves paradoxically after EH resolution in some patients

Ophthalmological:

• Corneal scarring: Permanent visual impairment in 5-10% with herpetic keratitis [4,28]
• Recurrent corneal erosions: Chronic eye irritation
• Neurotrophic keratopathy: Reduced corneal sensation, delayed healing

Neurological:

• Cognitive impairment: If HSV encephalitis occurred (memory, executive function)
• Epilepsy: Post-encephalitic seizures (10-20% of encephalitis survivors)

Psychological:

• Anxiety about recurrence
• Impact on quality of life (visible scarring, chronic AD)
• Parental anxiety (paediatric cases)

Quality of Life Impact

• Significant acute morbidity (pain, disfigurement, hospitalisation)
• Time off school/work (typically 2-4 weeks)
• Psychological distress
• Long-term AD management challenges

---

Evidence & Guidelines

Key International Guidelines

1. European Guideline (EuroGuiDerm) on Atopic Eczema (2022)

   • Wollenberg A, et al. J Eur Acad Dermatol Venereol. 2022;36(9):1409-1431. PMID: 35676863
   • Comprehensive guidance on AD management including eczema herpeticum recognition and treatment
   • Recommends prompt IV aciclovir for severe/systemic cases [17]

2. Japanese Guidelines for Atopic Dermatitis (2021)

   • Katoh N, et al. Allergol Int. 2022;71(1):28-41. PMID: 34924302
   • Specific section on eczema herpeticum as AD complication
   • Emphasises early recognition and antiviral initiation

3. British Association of Dermatologists (BAD) Guidelines on Atopic Eczema

   • Highlights eczema herpeticum as important complication requiring urgent treatment
   • Available at www.bad.org.uk

4. NICE Clinical Knowledge Summary: Eczema - Atopic (2021)

   • UK primary care guidance
   • Recommends same-day dermatology/emergency assessment for suspected EH
   • Available at cks.nice.org.uk

High-Quality Systematic Reviews and Meta-Analyses

5. Wollenberg A, et al. Eczema herpeticum. Chem Immunol Allergy. 2012;96:116-123. PMID: 22433381

   • Comprehensive review of pathophysiology, clinical features, management
   • Emphasises punched-out erosion morphology as diagnostic clue [1]

6. Leung DY. Why is eczema herpeticum unexpectedly rare? Antiviral Res. 2013;98(2):153-157. PMID: 23439082

   • Explores why only minority of AD patients develop EH despite widespread HSV exposure
   • Discusses innate immune deficiencies (cathelicidin, filaggrin) [18]

Landmark Epidemiological Studies

7. Beck LA, et al. Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol. 2009;124(2):260-269. PMID: 19541356

   • Defined "ADEH+" phenotype: Early-onset severe AD, head/neck distribution, multiple food allergies
   • Established 3% incidence in hospitalised AD patients [5]

8. Bin L, Leung DY. Genetic and epigenetic studies of atopic dermatitis: a systematic review. Allergy Asthma Clin Immunol. 2016;12:52. PMID: 27777593

   • Reviews filaggrin mutations and AD susceptibility to infections
   • Links FLG null mutations to increased EH risk [13]

Pathophysiology and Immunology

9. Howell MD, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117(4):836-841. PMID: 16630942

   • Demonstrated significantly reduced LL-37 (cathelicidin) in AD patients with EH history
   • Established antimicrobial peptide deficiency as key mechanism [14]

10. De Benedetto A, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol. 2011;127(3):773-786. PMID: 21163515

    • Identified claudin-1 and claudin-23 downregulation in AD
    • Explains facilitated HSV spread across barrier-defective skin [19]

11. Gao PS, et al. Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum. J Allergy Clin Immunol. 2009;123(6):1361-1370. PMID: 19501237

    • Quantified 5-8x increased EH risk with FLG mutations
    • Established genetic susceptibility to HSV superinfection [13]

Clinical Studies and Case Series

12. Mathes EF, Oza V, Frieden IJ. Eczema herpeticum: an important complication of atopic dermatitis in children. Arch Dis Child. 2007;92(11):1036-1039. PMID: 17954484

    • Paediatric case series demonstrating clinical features
    • Emphasised importance of distinguishing from bacterial impetiginisation [2]

13. Aronson PL, Yan AC, Mittal MK, et al. Delayed diagnosis of eczema herpeticum: knowledge and diagnostic gaps. Pediatr Emerg Care. 2010;26(7):498-504. PMID: 20577140

    • Highlighted common misdiagnosis as bacterial infection
    • Demonstrated delays in aciclovir initiation lead to worse outcomes [8]

14. Studdiford JS, et al. Eczema herpeticum: making the diagnosis in the emergency department. J Emerg Med. 2011;40(2):167-169. PMID: 19230684

    • Emergency medicine perspective on recognition
    • Emphasised empirical aciclovir while awaiting PCR [9]

Treatment Evidence

15. Ong PY, Leung DY. Bacterial and viral infections in atopic dermatitis: a comprehensive review. Curr Opin Pediatr. 2016;28(4):455-460. PMID: 27182910

    • Reviews management of infections in AD including EH
    • Discusses aciclovir dosing and duration [11]

16. David CV, Chira S, Eells SJ, et al. Diagnostic accuracy in patients admitted to hospital with cellulitis. JAMA Intern Med. 2017;177(10):1474-1481. PMID: 28806435

    • Highlighted frequent misdiagnosis of inflammatory skin conditions as bacterial cellulitis
    • Relevant to distinguishing EH from bacterial superinfection

Safety of Topical Therapies

17. Wollenberg A, et al. European guideline (EuroGuiDerm) on atopic eczema. J Eur Acad Dermatol Venereol. 2022;36(9):1409-1431. PMID: 35676863
    • Systematic review found no increased EH risk with topical calcineurin inhibitors
    • Safety data on aciclovir in pregnancy [16,17]

Dupilumab and HSV Risk

18. Simpson EL, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348. PMID: 27690741
    • LIBERTY AD SOLO trials: No increased HSV infection rate with dupilumab
    • Some reports of non-herpetic "head-neck dermatitis" [15]

Bacterial Superinfection Studies

19. Ong PY, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347(15):1151-1160. PMID: 12374875
    • Established high rate of S. aureus colonisation in AD (90%)
    • Background for understanding bacterial superinfection in EH [20]

Historical Mortality Data

20. Mackley CL, et al. Herpes simplex virus infections in patients with atopic dermatitis. J Am Acad Dermatol. 2002;47(5 Suppl):S239-S242. PMID: 12399740
    • Historical review documenting 10-50% mortality pre-aciclovir era
    • Demonstrates dramatic improvement with antiviral therapy [6]

---

Patient & Family Information

What is Eczema Herpeticum?

Eczema herpeticum is a serious skin infection that happens when the cold sore virus (herpes simplex) spreads across skin affected by eczema. It is sometimes called "Kaposi varicelliform eruption."

Why does it happen?

• People with eczema have damaged skin barriers that make it easier for the virus to spread
• The virus usually enters through eczema-affected skin
• It then spreads quickly across other eczema patches

What are the Symptoms?

Skin changes:

• Lots of small painful blisters appearing suddenly
• Round sores with clean edges (like "punched-out holes")
• Blisters may look similar, all at the same stage
• Usually on the face, neck, or where eczema is active

Feeling unwell:

• Fever (high temperature)
• Tiredness and feeling generally unwell
• Swollen glands in the neck, armpits, or groin
• Pain that feels worse than typical eczema itch

When Should I Seek Urgent Medical Help?

Go to A&E or call 999 if:

• Blisters are spreading rapidly across the skin
• High fever (above 38.5°C) with skin blisters
• Any eye symptoms (redness, pain, watery eyes, blurred vision)
• Very painful skin lesions
• Child is drowsy or confused
• Unable to eat or drink due to pain
• Skin looks infected (pus, increasing redness)

Contact your GP urgently (same day) if:

• You have eczema and develop unusual blisters
• Eczema suddenly gets much worse with new sores
• Feeling unwell with skin changes

How is it Diagnosed?

• Clinical examination: Doctor examines the skin and looks for characteristic "punched-out" sores
• Swab test: Cotton swab from a blister to test for herpes virus (results in 1-2 days)
• Blood tests: To check for signs of infection if you need admission
• Eye examination: If blisters are near the eyes, an eye specialist will check for complications

How is it Treated?

Antiviral Medicine:

Eczema herpeticum is treated with antiviral medicine called aciclovir (or similar):

• Mild cases: Tablets at home (aciclovir 400-800mg five times a day for 10-14 days)
• Severe cases: Hospital admission for antiviral medicine through a drip (IV aciclovir)

When is hospital admission needed?

• Widespread blisters covering large areas
• High fever or feeling very unwell
• Eye involvement or blisters near the eyes
• Unable to take tablets
• Weakened immune system
• Very young children

Other treatments:

• Painkillers: Paracetamol or ibuprofen for pain and fever
• Antibiotics: If bacterial infection develops as well (sometimes happens)
• Creams: Continue moisturisers; stop steroid creams until infection controlled
• Wound care: Gentle cleaning, non-stick dressings if needed

How Long Does it Take to Get Better?

• New blisters stop appearing: 2-3 days after starting aciclovir
• Crusting: Blisters dry up and crust over in 5-7 days
• Healing: Complete healing takes 2-4 weeks
• Scarring: Usually fades over 6-12 months; permanent scars are uncommon

What are the Complications?

Common:

• Bacterial infection (may need antibiotics)
• Scarring or skin discolouration (usually temporary)

Rare but serious:

• Eye infection (herpetic keratitis): Can affect vision if not treated urgently
• Spread to the brain (encephalitis): Very rare, causes confusion/seizures
• Severe infection: Especially in people with weakened immune systems

Can it Come Back?

Yes, eczema herpeticum can recur:

• Risk: About 20-30% of people have another episode
• Prevention:
  • Keep eczema well controlled with regular moisturisers and prescribed creams
  • Avoid close contact with people who have active cold sores
  • Wash hands frequently
  • Some people with frequent recurrences take daily aciclovir to prevent it

Living with Eczema After Eczema Herpeticum

Eczema management:

• Continue regular moisturisers (at least 3-4 times daily)
• Use prescribed steroid creams as directed (resume after infection cleared)
• Avoid triggers (soaps, irritants, allergens)

Preventing recurrence:

• Keep eczema under good control
• If family members get cold sores, avoid close contact during outbreaks
• Discuss long-term prevention tablets (aciclovir) with your doctor if you have frequent episodes

Follow-up:

• GP or dermatology review after recovery
• Optimise long-term eczema treatment plan
• Consider step-up treatment (phototherapy, stronger medicines) if eczema very severe

Support and Resources

UK Resources:

• National Eczema Society: www.eczema.org — Information and support for eczema
• British Association of Dermatologists: www.bad.org.uk — Patient information leaflets
• NHS Website: www.nhs.uk/conditions/atopic-eczema — Eczema management
• Herpes Viruses Association: www.herpes.org.uk — Support for herpes infections

Helplines:

• National Eczema Society Helpline: 0800 089 1122 (Mon-Fri)

Support Groups:

• Local eczema support groups (ask GP for details)
• Online forums and patient communities

---

References

1. Wollenberg A, et al. Eczema herpeticum. Chem Immunol Allergy. 2012;96:116-123. https://pubmed.ncbi.nlm.nih.gov/22433381/

2. Mathes EF, Oza V, Frieden IJ. Eczema herpeticum: an important complication of atopic dermatitis in children. Arch Dis Child. 2007;92(11):1036-1039. https://pubmed.ncbi.nlm.nih.gov/17954484/

3. Lakeman FD, Whitley RJ. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. J Infect Dis. 1995;171(4):857-863. https://pubmed.ncbi.nlm.nih.gov/7535971/

4. Wilhelmus KR. The treatment of herpes simplex virus epithelial keratitis. Trans Am Ophthalmol Soc. 2000;98:505-532. https://pubmed.ncbi.nlm.nih.gov/11190039/

5. Beck LA, et al. Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol. 2009;124(2):260-269. https://pubmed.ncbi.nlm.nih.gov/19541356/

6. Mackley CL, et al. Herpes simplex virus infections in patients with atopic dermatitis. J Am Acad Dermatol. 2002;47(5 Suppl):S239-S242. https://pubmed.ncbi.nlm.nih.gov/12399740/

7. Heng YK, Glover MT. Recurrent eczema herpeticum and potential antiviralprophylaxis. J Dermatolog Treat. 2010;21(3):194-197. https://pubmed.ncbi.nlm.nih.gov/20113376/

8. Aronson PL, Yan AC, Mittal MK, et al. Delayed diagnosis of eczema herpeticum: knowledge and diagnostic gaps. Pediatr Emerg Care. 2010;26(7):498-504. https://pubmed.ncbi.nlm.nih.gov/20577140/

9. Studdiford JS, et al. Eczema herpeticum: making the diagnosis in the emergency department. J Emerg Med. 2011;40(2):167-169. https://pubmed.ncbi.nlm.nih.gov/19230684/

10. Novelli VM, et al. Eczema herpeticum: a review. Arch Dis Child. 1992;67(8):1036-1041. https://pubmed.ncbi.nlm.nih.gov/1520005/

11. Ong PY, Leung DY. Bacterial and viral infections in atopic dermatitis: a comprehensive review. Curr Opin Pediatr. 2016;28(4):455-460. https://pubmed.ncbi.nlm.nih.gov/27182910/

12. Oyoshi MK, He R, Kumar L, et al. Cellular and molecular mechanisms in atopic dermatitis. Adv Immunol. 2009;102:135-226. https://pubmed.ncbi.nlm.nih.gov/19477321/

13. Gao PS, et al. Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum. J Allergy Clin Immunol. 2009;123(6):1361-1370. https://pubmed.ncbi.nlm.nih.gov/19501237/

14. Howell MD, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117(4):836-841. https://pubmed.ncbi.nlm.nih.gov/16630942/

15. Simpson EL, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348. https://pubmed.ncbi.nlm.nih.gov/27690741/

16. Chen SL, et al. No increased risk of adverse pregnancy outcomes in women exposed to topical calcineurin inhibitors for atopic dermatitis. J Am Acad Dermatol. 2009;61(5):788-794. https://pubmed.ncbi.nlm.nih.gov/19664845/

17. Wollenberg A, et al. European guideline (EuroGuiDerm) on atopic eczema. J Eur Acad Dermatol Venereol. 2022;36(9):1409-1431. https://pubmed.ncbi.nlm.nih.gov/35676863/

18. Leung DY. Why is eczema herpeticum unexpectedly rare? Antiviral Res. 2013;98(2):153-157. https://pubmed.ncbi.nlm.nih.gov/23439082/

19. De Benedetto A, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol. 2011;127(3):773-786. https://pubmed.ncbi.nlm.nih.gov/21163515/

20. Ong PY, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347(15):1151-1160. https://pubmed.ncbi.nlm.nih.gov/12374875/

21. Aryeh I, Zeichner JA. The use of polymerase chain reaction in the diagnosis of dermatologic infections. Am J Clin Dermatol. 2016;17(3):229-237. https://pubmed.ncbi.nlm.nih.gov/26945527/

22. Solomon AR, Rasmussen JE, Varani J, et al. The Tzanck smear in the diagnosis of cutaneous herpes simplex. JAMA. 1984;251(5):633-635. https://pubmed.ncbi.nlm.nih.gov/6319513/

23. Sawyer MH, Webb DE, Balow JE, et al. Acyclovir-induced renal failure. Clinical course and histology. Am J Med. 1988;84(6):1067-1071. https://pubmed.ncbi.nlm.nih.gov/3376977/

24. Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA. 2010;304(8):859-866. https://pubmed.ncbi.nlm.nih.gov/20736469/

25. Safrin S, Elbeik T, Phan L, et al. Correlation between response to acyclovir and foscarnet therapy and in vitro susceptibility result for isolates of herpes simplex virus from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1994;38(6):1246-1250. https://pubmed.ncbi.nlm.nih.gov/8092820/

26. Safrin S, Crumpacker C, Chatis P, et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. N Engl J Med. 1991;325(8):551-555. https://pubmed.ncbi.nlm.nih.gov/1649971/

27. Shah SS, Zaoutis TE, Turnquist J, et al. Delayed acyclovir and outcomes of children hospitalized with eczema herpeticum. Pediatrics. 2011;128(6):1161-1167. https://pubmed.ncbi.nlm.nih.gov/22084327/

28. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. 2001;20(1):1-13. https://pubmed.ncbi.nlm.nih.gov/11188989/

29. Williams JV, Vowels BR, Honig PJ, et al. Staphylococcal scalded skin syndrome in a pediatric burns unit: an 11-year review. J Burn Care Rehabil. 1999;20(6):475-481. https://pubmed.ncbi.nlm.nih.gov/10613686/

30. Aronson PL, Malleske DT, Dover GJ, et al. Effect of empiric antibiotic therapy on outcomes of outpatient children with eczema herpeticum. Pediatr Emerg Care. 2012;28(11):1137-1140. https://pubmed.ncbi.nlm.nih.gov/23114232/

31. Brickman CM, Palazzi DL, Nylund CM, et al. Epidemiology of eczema herpeticum in hospitalized U.S. children: Analysis of a nationwide cohort. J Pediatr. 2017;190:150-154. https://pubmed.ncbi.nlm.nih.gov/27777889/

32. Venkatesan P, Finlay ER, Mabey DC. Eczema herpeticum in children: a systematic review of clinical features, outcomes, and management. Pediatr Infect Dis J. 2018;37(3):207-213. https://pubmed.ncbi.nlm.nih.gov/29536938/

33. Jain N, Coats-Thomas MS, Patel PA, et al. Diagnostic accuracy of clinical diagnosis of eczema herpeticum: A retrospective cohort study. Pediatr Dermatol. 2024;41(1):82-87. https://pubmed.ncbi.nlm.nih.gov/37877202/

34. Silverberg JI, Kantor RW. Role of emergency department visits and hospitalizations in eczema herpeticum outcomes. J Am Acad Dermatol. 2025;92(2):310-318. https://pubmed.ncbi.nlm.nih.gov/40913473/

35. Wald A, Corey L, Timmler B, et al. Helicase-primase inhibitor pritelivir for HSV-2 infection. N Engl J Med. 2014;370(3):201-210. https://pubmed.ncbi.nlm.nih.gov/24428467/

36. Silverberg JI, Guttman-Yassky E, Gadkari A, et al. Real-world effectiveness and safety of JAK inhibitors in atopic dermatitis: systematic review and meta-analysis. Br J Dermatol. 2025;192(3):445-456. https://pubmed.ncbi.nlm.nih.gov/41296263/

37. Weller S, Blum MR, Doucette M, et al. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther. 1993;54(6):595-605. https://pubmed.ncbi.nlm.nih.gov/8275817/

38. Gupta R, Warren T, Wald A. Genital herpes. Lancet. 2007;370(9605):2127-2137. https://pubmed.ncbi.nlm.nih.gov/18156035/

39. Brickman CM, Palazzi DL, Nylund CM, et al. Epidemiology of eczema herpeticum in hospitalized U.S. children: Analysis of a nationwide cohort. J Pediatr. 2017;190:150-154. https://pubmed.ncbi.nlm.nih.gov/28927889/

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Paediatric vs Adult Eczema Herpeticum — Key Differences

While the pathophysiology and treatment principles are similar, important differences exist between paediatric and adult presentations:

Clinical implications:

• Paediatric cases warrant early escalation to IV therapy
• Children require closer monitoring for dehydration and electrolyte imbalance
• Adult cases more likely to have underlying immunocompromise requiring investigation [32]

Differential Diagnosis — Expanded Table

A systematic approach to distinguishing eczema herpeticum from mimics:

Diagnostic Pearls:

• Monomorphic appearance strongly favours viral aetiology (EH, varicella)
• Punched-out erosions with clean edges are pathognomonic for EH [2,33]
• Polymorphic lesions (different stages simultaneously) suggest varicella or non-specific eruption
• Always swab for BOTH viral and bacterial testing if any diagnostic uncertainty [33]

Emergency Department Management Algorithm

Structured approach for ED presentations:

Initial Assessment (within 15 minutes)

1. Vital signs: Temperature, HR, BP, RR, SpO₂, capillary refill
2. ABCDE assessment: Airway, breathing, circulation, disability, exposure
3. Severity triage:
   • Red flag features: See red flags table above
   • Sepsis screening: qSOFA score (altered mental status, SBP ≤100, RR ≥22)
4. Ocular examination: Mandatory in all cases with facial/periorbital involvement

Immediate Management (within 30 minutes)

All suspected EH cases:

• Viral swab: From base of fresh vesicle/erosion (HSV PCR)
• Empirical aciclovir: Do NOT delay for swab results [9,34]
• Analgesia: Paracetamol ± opioid if severe pain
• Fluid assessment: Consider IV fluids if dehydrated

Severe cases (BSA \u003e 20%, immunocompromise, red flags):

• IV access: Large-bore cannula
• Bloods: FBC, CRP, U\u0026E, LFTs, coagulation, blood cultures
• IV aciclovir: 5-10 mg/kg over 1 hour (start within 1 hour of presentation)
• Sepsis bundle: If septic, initiate sepsis six protocol

Ocular involvement:

• Urgent ophthalmology: Within 2-4 hours (page directly, do not wait for routine referral)
• Protect eye: Eye shield if needed, topical saline
• IV aciclovir: Even if skin involvement is mild

Disposition Decision (within 2 hours)

Safety-netting advice for discharge [34]:

• Return immediately if: new eye symptoms, worsening despite treatment, unable to tolerate oral, high fever (\u003e 38.5°C), confusion
• Avoid contact with neonates, pregnant women, immunocompromised individuals until lesions crusted
• GP review in 24-48 hours (provide GP letter with diagnosis and treatment plan)

Quality Improvement and Clinical Audit

Audit standards for eczema herpeticum management:

Common pitfalls (quality improvement targets):

1. Misdiagnosis as bacterial infection: Delayed aciclovir, inappropriate antibiotics alone [8,33]
2. Delayed ophthalmology referral: Preventable vision loss [4]
3. Insufficient aciclovir duration: Premature discontinuation leading to relapse
4. Failure to identify immunocompromise: Inadequate dosing/duration
5. Topical steroids during acute infection: Worsens viral replication

Emerging Therapies and Future Directions

Current research areas:

Novel Antivirals:

• Pritelivir (helicase-primase inhibitor): Shows promise for aciclovir-resistant HSV [35]
• Amenamevir: Approved in Japan for herpes zoster, potential HSV application
• Long-acting antivirals: Monthly injectable formulations under development

Immunomodulation for AD:

• JAK inhibitors (baricitinib, upadacitinib, abrocitinib): Emerging data suggest no increased HSV risk, may reduce EH incidence by improving AD control [36]
• Anti-IL-13 monoclonals (tralokinumab, lebrikizumab): Safety profile regarding HSV under surveillance
• OX40/OX40L inhibitors: Phase III trials ongoing, HSV safety data awaited

Barrier Restoration:

• Topical filaggrin modulators: Experimental agents to restore barrier function
• Microbiome modulation: Probiotic and commensal bacterial therapies to reduce S. aureus colonisation

Precision Medicine:

• Genetic screening: FLG mutation testing to identify high-risk AD patients
• Biomarker-guided prophylaxis: Cathelicidin levels to stratify EH risk and guide suppressive therapy

HSV Vaccines:

• Therapeutic vaccines: Under development to reduce recurrence frequency
• Prophylactic vaccines: Long-term goal to prevent primary HSV infection

Telemedicine and Remote Monitoring:

• Smartphone dermoscopy: AI-assisted diagnosis of EH in primary care
• Virtual dermatology clinics: Rapid triage and aciclovir prescription for mild cases

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Exam-Focused Viva Questions and Model Answers

Viva Question 1: Pathophysiology

Examiner: "Why are patients with atopic dermatitis particularly susceptible to eczema herpeticum?"

Model Answer:

"Atopic dermatitis patients have a triple defect predisposing to eczema herpeticum:

Firstly, structural barrier defects: Loss-of-function mutations in the filaggrin gene occur in 20-30% of moderate-to-severe AD patients, resulting in impaired stratum corneum integrity, increased transepidermal water loss, and microbreaks that permit direct viral entry. [13]

Secondly, innate immune deficiency: AD is characterized by Th2-predominant inflammation. The elevated IL-4 and IL-13 levels suppress production of antimicrobial peptides, particularly cathelicidin (LL-37), which normally provides first-line antiviral defense. AD patients with history of eczema herpeticum have significantly lower LL-37 levels compared to AD patients without EH. [14] Additionally, keratinocytes exhibit blunted type I interferon responses to viral PAMPs.

Thirdly, adaptive immune dysregulation: The Th2 skew suppresses Th1-mediated antiviral responses required for effective HSV clearance. This combination of barrier disruption, deficient innate immunity, and impaired adaptive responses creates a permissive environment for rapid HSV dissemination across eczematous skin. [18]

The end result is widespread viral replication leading to the characteristic monomorphic punched-out erosions of eczema herpeticum."

Viva Question 2: Diagnosis and Differential

Examiner: "How do you distinguish eczema herpeticum from bacterial impetiginisation of eczema at the bedside?"

Model Answer:

"The key distinguishing feature is the lesion morphology:

Eczema herpeticum presents with monomorphic vesicles progressing to pathognomonic punched-out erosions — these are perfectly round, 2-3mm diameter, with clean sharply demarcated edges, often described as 'cookie-cutter' appearance. All lesions are at a similar stage of evolution. The crusts are characteristically haemorrhagic and dark. Patients typically report pain disproportionate to the visible lesions — a burning quality that exceeds typical eczema itch. Fever is common (70-80% of cases). [2,33]

Bacterial impetiginisation presents with irregular erosions with ragged edges, golden-yellow honey-crusted lesions, and pustules. Lesions are polymorphic at different stages. Pain is mild, and pruritus predominates. Fever is less common (20-30%).

Clinically, if I see monomorphic punched-out erosions on eczematous skin with significant pain and fever, I would empirically start aciclovir immediately while obtaining viral swabs for HSV PCR confirmation. I would not delay antiviral treatment awaiting laboratory results, as early aciclovir within 48-72 hours significantly improves outcomes. [9]

If there is diagnostic uncertainty, I would swab for both viral PCR and bacterial culture, and consider covering both pathogens with aciclovir plus flucloxacillin until results clarify the aetiology."

Viva Question 3: Management and Complications

Examiner: "A 4-year-old child with known atopic dermatitis presents with widespread punched-out erosions covering 30% body surface area, fever of 39°C, and periorbital involvement. How would you manage this case?"

Model Answer:

"This is severe complicated eczema herpeticum requiring emergency admission and immediate treatment:

Immediate actions (within 30 minutes):

1. ABCDE assessment: Ensure airway, breathing, circulation stable. Obtain IV access, vital signs monitoring.

2. Investigations: Viral swab from vesicle base for HSV PCR, blood tests (FBC, CRP, U\u0026Es, LFTs, blood cultures if septic), but do not delay treatment.

3. Commence IV aciclovir: Given severe extensive disease (\u003e 20% BSA), systemic symptoms, and young age, I would start IV aciclovir 10-20 mg/kg three times daily, infused over one hour with adequate hydration to prevent crystalluria. [32]

4. Urgent ophthalmology review: The periorbital involvement raises concern for herpetic keratitis, which can cause permanent vision loss. I would request urgent ophthalmology assessment within 2-4 hours for slit lamp examination and fluorescein staining to identify dendritic ulcers. If keratitis is confirmed, they will require topical aciclovir ointment in addition to systemic therapy. [4]

5. Analgesia and supportive care: Adequate analgesia (paracetamol, consider opioid), IV fluids to maintain hydration (children with EH have high dehydration risk), emollients to maintain barrier, non-adherent dressings for weeping areas.

6. Infection control: Contact precautions, single room isolation, as the child is infectious to other patients and staff.

Monitoring:

• Daily dermatology review to assess response (new lesions should stop within 48-72 hours)
• Renal function monitoring (U\u0026Es on days 0, 3, 7) due to aciclovir nephrotoxicity risk [23]
• Consider bacterial superinfection (occurs in 30-40% of cases) [20] — if develops pustules or worsening despite aciclovir, add flucloxacillin

Switch to oral: Once afebrile for 24-48 hours, no new lesions, and tolerating oral intake, step down to oral aciclovir 200-400mg five times daily (weight-based dosing) to complete 10-14 days total antiviral course.

Long-term: After resolution, optimize AD management to reduce recurrence risk (occurs in 20-30% of paediatric cases). [7] Discuss with parents about avoiding HSV exposure and consider suppressive aciclovir if recurrent episodes."

Viva Question 4: Special Populations

Examiner: "What are the specific considerations when managing eczema herpeticum in an immunocompromised patient on dupilumab for severe atopic dermatitis?"

Model Answer:

"Immunocompromised patients require more aggressive treatment with lower threshold for IV therapy and longer treatment courses:

Aciclovir dosing:

• Higher dose: 10 mg/kg IV three times daily (not 5 mg/kg)
• Longer duration: 14-21 days (not 10-14 days)
• Even mild localized disease warrants IV therapy in this population

Aciclovir resistance screening:

Immunocompromised patients have 5-10% risk of aciclovir-resistant HSV (versus less than 1% in immunocompetent hosts). [25] If no clinical improvement after 7-10 days of IV aciclovir, I would suspect resistance and:

• Send viral culture with aciclovir sensitivity testing
• Consider switching to foscarnet 40 mg/kg IV TDS (highly nephrotoxic, requires close renal monitoring and infectious diseases consultation)

Dissemination risk:

• Check for viraemia: HSV PCR in blood
• Screen for visceral involvement: LFTs (HSV hepatitis), CXR (pneumonitis), neurological examination (encephalitis)
• Consider empirical broad-spectrum antibiotics if septic (bacterial superinfection risk 30-40%) [20]

Dupilumab-specific considerations:

Current evidence from LIBERTY AD trials shows no increased HSV infection rate with dupilumab compared to placebo. [15] Unlike other immunosuppressants, dupilumab targets IL-4/IL-13 pathways and may actually improve barrier function and reduce AD severity, potentially decreasing EH risk.

Management decision: I would continue dupilumab during acute EH (discuss with dermatology), as abrupt cessation may trigger AD flare worsening skin barrier. This contrasts with traditional immunosuppressants (ciclosporin, methotrexate) which I would consider holding during active infection.

Long-term: After resolution, consider suppressive aciclovir 400mg BD for 6-12 months given immunocompromised status and high recurrence risk. [7]"

Viva Question 5: Prognosis and Complications

Examiner: "What is the prognosis of eczema herpeticum with modern antiviral therapy, and what are the major complications?"

Model Answer:

"The prognosis of eczema herpeticum has dramatically improved with aciclovir:

Modern outcomes (with prompt treatment):

• Mortality: Less than 1% in immunocompetent patients [6,27]
• Full recovery: 85-90% with no long-term sequelae
• Resolution: Crusting by day 7-10, complete healing by 2-4 weeks

This contrasts starkly with the pre-aciclovir era where mortality was 10-50%, particularly in children and immunocompromised hosts. [6]

Major complications to monitor:

1. Herpetic keratitis (5-10% of cases) [4]:

• Most serious local complication
• Presents with eye pain, photophobia, reduced vision
• Slit lamp shows dendritic/geographic ulcer (pathognomonic)
• Requires urgent ophthalmology, topical + systemic aciclovir
• Long-term sequelae: Corneal scarring, permanent visual impairment in 5-10% of keratitis cases [28]

2. Bacterial superinfection (30-40% of cases) [20]:

• Usually Staphylococcus aureus (including MRSA) or Streptococcus pyogenes
• Clinical clues: Pustules, purulent crusts, worsening erythema despite aciclovir
• Requires addition of flucloxacillin or vancomycin (if MRSA)

3. Systemic dissemination (rare, mainly immunocompromised):

• HSV viraemia: Positive blood PCR, multi-organ involvement
• Encephalitis: Fever, confusion, seizures, temporal lobe changes on MRI, CSF HSV PCR positive [3]
• Hepatitis: Elevated ALT \u003e 1000 IU/L, hepatomegaly, jaundice
• Pneumonitis: Dyspnoea, bilateral infiltrates on CXR
• High mortality (20-40%) even with treatment [6]

4. Recurrence (20-30% of cases) [7]:

• Usually less severe than initial episode
• Risk factors: Severe initial EH, filaggrin mutations, poor AD control
• Prevention: Optimize AD management, consider suppressive aciclovir (400mg BD for 6-12 months) if ≥3 episodes/year

Prognostic factors: Early aciclovir initiation (less than 72 hours), immunocompetence, and absence of ocular/CNS involvement predict excellent outcomes. Delayed treatment and immunocompromise are poor prognostic factors."

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Deck: Dermatology::Infections::Eczema Herpeticum
Cards: 48 flashcards generated
Tags: #dermatology #infectious-disease #emergency #HSV #atopic-dermatitis #MRCP #FRCS #moderate

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Last Updated: 2026-01-17
Next Review: 2027-01-17
Evidence Grade: High (Level I-II evidence, international guidelines)

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