Etiology of Eczema Herpeticum (EH)

Study Overview
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Brief Summary
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Atopic dermatitis, also called eczema, is a disease with dry, scaly, itchy skin. Those with atopic dermatitis may have complications from skin infections such as eczema herpeticum after herpes simplex virus (HSV) infection. Symptoms of eczema herpeticum include fever and clusters of itchy blisters which crust over and form sores. Although exposure to HSV is widespread, most people clear the virus and only a subset of individuals with atopic dermatitis develop eczema herpeticum. The purpose of this study is to determine why some individuals with atopic dermatitis are at higher risk for recurrent skin infections with HSV. The study team will compare how people with atopic dermatitis with a history of recurrent eczema herpeticum, people with atopic dermatitis without a history of eczema herpeticum, and people without atopic dermatitis respond to HSV.

Detailed Description
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This study uses whole genome sequencing (WGS) technology to identify genetic variants that confer risk of recurrent atopic dermatitis with a history of eczema herpeticum (ADEH+), with ≥3 eczema herpeticum (EH) episodes. A small subgroup of individuals with atopic dermatitis (AD) suffer from life-threatening disseminated herpes simplex virus (HSV) skin infections, termed eczema herpeticum (ADEH+). The manifestation of ADEH+ however is not simply a consequence of herpes simplex virus type 1 (HSV-1) infections, since the majority of the US population is latently infected with HSV-1 from an early age. Most importantly, there is a bimodality in the recurrence of eczema herpeticum (EH) episodes; most individuals have only a single episode but a subgroup of ADEH+ individuals has 3 or more episodes. This study aims to conduct an extreme trait investigation of ADEH+ with recurrent EH, ≥3 episodes, compared to AD without a history of eczema herpeticum (ADEH-), using whole genome sequencing.

Official Title
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Integrated Extreme Trait Analysis to Understand the Etiology of Eczema Herpeticum (ADRN-06)

Conditions
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Eczema Herpeticum

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be a participant already enrolled in the ADRN Registry and provided DNA (ClinicalTrials.gov ID: NCT01494142); Participant and/or parent guardian must be able to understand and provide informed consent; A history of Atopic Dermatitis (AD) with a history of eczema herpeticum (ADEH+), as diagnosed using the Atopic Dermatitis Research Network (ADRN) Standard Diagnostic Criteria, with ≥3 episodes of Eczema Herpeticum (EH) OR A history of AD without a history of eczema herpeticum (ADEH-), as diagnosed using the ADRN Standard Diagnostic Criteria, and no immediate family members (mother, father, full siblings, half-siblings, offspring, aunts, uncles, cousins, or grandparents) with a history of EH OR Non-atopic as diagnosed using the ADRN Standard Diagnostic Criteria. Anti-Herpes Simplex Virus (HSV)-1 or Anti-HSV-2 Immunoglobulin G (IgG) seropositive. Exclusion Criteria: Inability or unwillingness of a participant and/or parent guardian to give written informed consent or comply with study protocol; Pregnant or lactating women; Known or suspected immunosuppression; Severe concomitant illness(es); History of keloid formation (adults only); History of lidocaine or Novocain allergy (adults only); History of serious life-threatening reaction to latex, tape, or adhesives; Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study. Use of biologics within 5 half-lives (if known) or 16 weeks of the Screening Visit; Use of an investigational drug within 5 half-lives (if known) or 8 weeks of the Screening Visit.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Discovery Cohort<br>A minimum of 50 recurrent Atopic Dermatitis with a history of Eczema Herpeticum(ADEH+), 500 Atopic Dermatitis without a history of Eczema Herpeticum (ADEH-), and 237 Non-Atopic (NA) European American participants from the Atopic Dermatitis Research Network (ADRN) DNA Repository. The study will learn from this cohort: All Single Nucleotide Variants (SNVs) in ADEH+ ADEH+ specific deleterious SNVs The study will determine the function of: 4. ADEH+ risk variants | |
| Independent populations of participants<br>Two independent populations of participants: Children, aged 3-17 years and Adults 18-64 years of age. A minimum of 12 recurrent Atopic Dermatitis with a history of Eczema Herpeticum (ADEH+) with ≥3 Eczema Herpeticum (EH) episodes, 12 Atopic Dermatitis without a history of Eczema Herpeticum (ADEH-) and 12 Non-Atopic (NA) participants will be enrolled in each of the two populations. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Difference in Frequency of Rare Deleterious Coding Genetic Variants between Subjects with Recurrent Atopic Dermatitis (AD) and a History of Eczema Herpeticum (ADEH+) Compared to Controls - Using Whole Genome Sequencing | Whole genome sequencing methodology will be used to identify differences in frequency of rare deleterious coding genetic variants between recurrent Atopic Dermatitis (AD) subjects with a history of Eczema Herpeticum (ADEH+) and ≥3 Eczema Herpeticum (EH) episodes, versus controls. Controls will include (1) AD subjects without a history of EH (ADEH-); (2) non-atopic (NA) subjects without AD; and (3) general population controls from the Thousand Genomes Project. | 3 years | 
| The Difference in Frequency of Rare Deleterious Non-Coding Genetic Variants between Subjects with Recurrent Atopic Dermatitis (AD) and a History of Eczema Herpeticum (ADEH+) Compared to Controls - Using Whole Genome Sequencing | Whole genome sequencing methodology will be used to identify differences in frequency of rare deleterious non-coding genetic variants between subjects with recurrent Atopic Dermatitis (AD) subjects and a history of Eczema Herpeticum (ADEH+) with ≥3 Eczema Herpeticum (EH) episodes, versus controls. Controls will include (1) AD subjects without a history of EH (ADEH-); (2) non-atopic (NA) subjects without AD; and (3) general population controls from the Thousand Genomes Project. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gene expression profiles in the dermis |  | 3 years | 
| Gene expression profiles in the epidermis |  | 3 years | 
| Gene expression profiles in in keratinocytes |  | 3 years | 
| Gene expression profiles in fibroblasts |  | 3 years | 
| Gene expression profiles in peripheral blood Plasmacytoid Dendritic Cells(pDCs) |  | 3 years | 
| Gene expression profiles in skin tape strip samples |  | 3 years | 
| Herpes Simplex Virus (HSV) replication in primary keratinocytes | HSV replication will be assessed by HSV copy number by Polymerase Chain Reaction (PCR) or RNA sequencing. | 3 years | 
| Herpes Simplex Virus (HSV) replication in fibroblasts | HSV replication will be assessed by HSV copy number by Polymerase Chain Reaction (PCR) or RNA sequencing. | 3 years | 
| Herpes Simplex Virus (HSV) replication in Plasmacytoid Dendritic Cells (pDCs) | HSV replication will be assessed by HSV copy number by Polymerase Chain Reaction (PCR) or RNA sequencing. | 3 years | 
| Herpes Simplex Virus (HSV) replication in genetically modified cell lines | HSV replication will be assessed by HSV copy number by Polymerase Chain Reaction (PCR) or RNA sequencing. | 3 years | 
| Anti-viral responses in primary keratinocytes | Anti-viral responses will be measured by cytokine production and antimicrobial responses (e.g. interferons [IFNs], tumor necrosis factor alpha [TNFalpha], LL-37, human beta-defensins [HBDs]) | 3 years | 
| Anti-viral responses in fibroblasts | Anti-viral responses will be measured by cytokine production and antimicrobial responses (e.g. interferons [IFNs], tumor necrosis factor alpha [TNFalpha], LL-37, human beta-defensins [HBDs]) | 3 years | 
| Anti-viral responses in Plasmacytoid Dendritic Cells (pDCs) | Anti-viral responses will be measured by cytokine production and antimicrobial responses (e.g. interferons [IFNs], tumor necrosis factor alpha [TNFalpha], LL-37, human beta-defensins [HBDs]). | 3 years | 
| Anti-viral responses in genetically modified cell lines | Anti-viral responses will be measured by cytokine production and antimicrobial responses (e.g. interferons [IFNs], tumor necrosis factor alpha [TNFalpha], LL-37, human beta-defensins [HBDs]). | 3 years | 
| Immune responses in primary keratinocytes | Immune responses will be measured by cytokine production and antimicrobial responses (e.g. interferons [IFNs], tumor necrosis factor alpha [TNFalpha], LL-37, human beta-defensins [HBDs]). | 3 years | 
| Immune responses in fibroblasts | Immune responses will be measured by cytokine production and antimicrobial responses (e.g. interferons [IFNs], tumor necrosis factor alpha [TNFalpha], LL-37, human beta-defensins [HBDs]). | 3 years | 
| Immune responses in Plasmacytoid Dendritic Cells (pDCs) | Immune responses will be measured by cytokine production and antimicrobial responses (e.g. interferons [IFNs], tumor necrosis factor alpha [TNFalpha], LL-37, human beta-defensins [HBDs]). | 3 years | 
| Immune responses in genetically modified cell lines | Immune responses will be measured by cytokine production and antimicrobial responses (e.g. interferons [IFNs], tumor necrosis factor alpha [TNFalpha], LL-37, human beta-defensins [HBDs]) | 3 years | 
| Differentiation markers in primary keratinocytes | Differentiation markers (e.g. filaggrin (FLG), involucrin, loricrin, and Human Beta-Defensins (HBDs)). | 3 years | 
| Differentiation markers in genetically modified keratinocyte cell lines | Differentiation markers (e.g. filaggrin (FLG), involucrin, loricrin, and Human Beta-Defensins (HBDs)). | 3 years | 
| Expression of reporter gene constructs testing non-coding variants |  | 3 years | 
| Exploratory: Viral carriage | Viral carriage will be assessed by presence of viral sequencing reads. | 3 years | 
| Exploratory: Protein expression of epidermal differentiation complex | Protein expression of epidermal differentiation complex will be measured by Mass Spectroscopy of skin tape strips. | 3 years | 
| Exploratory: Protein expression of inflammatory genes | Protein expression of inflammatory genes will be measured by Mass Spectroscopy of skin tape strips. | 3 years | 
| Exploratory: Lipid profiles | Lipid profiles will be measured by mass spectroscopy of skin tape strips. | 3 years | 
| Exploratory: Whole-genome DNA methylation profiles from epidermis |  | 3 years | 
| Exploratory: Whole-genome DNA methylation profiles from dermis |  | 3 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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whole genome sequencing (WGS)