Clinical trial NCT03038932: Etiology of Eczema Herpeticum (EH)
Official title: Integrated Extreme Trait Analysis to Understand the Etiology of Eczema Herpeticum (ADRN-06)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Eczema Herpeticum
Keywords: whole genome sequencing (WGS)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Atopic Dermatitis Research Network
name: Rho Federal Systems Division, Inc.
First posted: 2017-02-01
Enrollment: 69
Sex: ALL
Minimum age (years): 3
Maximum age (years): 64
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 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 protocol will also enroll two independent populations of participants 1) children, 3-17 years of age and 2) adults 18-64 years of age. A minimum of 12 recurrent ADEH+ with ≥3 EH episodes, 12 ADEH- and 12 NA participants will be enrolled in each of the two populations.

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Must be a participant already enrolled in the ADRN Registry and provided DNA (ClinicalTrials.gov ID: NCT01494142);
2. Participant and/or parent guardian must be able to understand and provide informed consent;
3. 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.
4. Anti-Herpes Simplex Virus (HSV)-1 or Anti-HSV-2 Immunoglobulin G (IgG) seropositive.

Exclusion Criteria:

1. Inability or unwillingness of a participant and/or parent guardian to give written informed consent or comply with study protocol;
2. Pregnant or lactating women;
3. Known or suspected immunosuppression;
4. Severe concomitant illness(es);
5. History of keloid formation (adults only);
6. History of lidocaine or Novocain allergy (adults only);
7. History of serious life-threatening reaction to latex, tape, or adhesives;
8. 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.
9. Use of biologics within 5 half-lives (if known) or 16 weeks of the Screening Visit;
10. Use of an investigational drug within 5 half-lives (if known) or 8 weeks of the Screening Visit.

Primary outcomes:
measure: 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
timeFrame: 3 years
measure: 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
timeFrame: 3 years
Secondary outcomes:
measure: Gene expression profiles in the dermis
timeFrame: 3 years
measure: Gene expression profiles in the epidermis
timeFrame: 3 years
measure: Gene expression profiles in in keratinocytes
timeFrame: 3 years
measure: Gene expression profiles in fibroblasts
timeFrame: 3 years
measure: Gene expression profiles in peripheral blood Plasmacytoid Dendritic Cells(pDCs)
timeFrame: 3 years
measure: Gene expression profiles in skin tape strip samples
timeFrame: 3 years
measure: Herpes Simplex Virus (HSV) replication in primary keratinocytes
timeFrame: 3 years
measure: Herpes Simplex Virus (HSV) replication in fibroblasts
timeFrame: 3 years
measure: Herpes Simplex Virus (HSV) replication in Plasmacytoid Dendritic Cells (pDCs)
timeFrame: 3 years
measure: Herpes Simplex Virus (HSV) replication in genetically modified cell lines
timeFrame: 3 years
measure: Anti-viral responses in primary keratinocytes
timeFrame: 3 years
measure: Anti-viral responses in fibroblasts
timeFrame: 3 years
measure: Anti-viral responses in Plasmacytoid Dendritic Cells (pDCs)
timeFrame: 3 years
measure: Anti-viral responses in genetically modified cell lines
timeFrame: 3 years
measure: Immune responses in primary keratinocytes
timeFrame: 3 years
measure: Immune responses in fibroblasts
timeFrame: 3 years
measure: Immune responses in Plasmacytoid Dendritic Cells (pDCs)
timeFrame: 3 years
measure: Immune responses in genetically modified cell lines
timeFrame: 3 years
measure: Differentiation markers in primary keratinocytes
timeFrame: 3 years
measure: Differentiation markers in genetically modified keratinocyte cell lines
timeFrame: 3 years
measure: Expression of reporter gene constructs testing non-coding variants
timeFrame: 3 years
measure: Exploratory: Viral carriage
timeFrame: 3 years
measure: Exploratory: Protein expression of epidermal differentiation complex
timeFrame: 3 years
measure: Exploratory: Protein expression of inflammatory genes
timeFrame: 3 years
measure: Exploratory: Lipid profiles
timeFrame: 3 years
measure: Exploratory: Whole-genome DNA methylation profiles from epidermis
timeFrame: 3 years
measure: Exploratory: Whole-genome DNA methylation profiles from dermis
timeFrame: 3 Years
Other outcomes:
Locations:
city: Denver
country: United States
facility: National Jewish Health: Division of Pediatric Allergy and Clinical Immunology
state: Colorado
Study officials:
affiliation: National Jewish Health: Division of Pediatric Allergy and Clinical Immunology
name: Donald Leung, M.D., Ph.D.
role: STUDY_CHAIR
References: