Etiology of Eczema Herpeticum (EH)

• ClinicalTrials.gov Identifier: NCT03038932
• Recruitment Status: Completed
• First Posted: February 1, 2017
• Last Update Posted: January 14, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Atopic Dermatitis Research Network; Rho Federal Systems Division, Inc.
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

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.

Condition or disease
Eczema Herpeticum

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.

Study Design

• Study Type: Observational
• Actual Enrollment: 69 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Integrated Extreme Trait Analysis to Understand the Etiology of Eczema Herpeticum (ADRN-06)
• Actual Study Start Date: February 22, 2017
• Actual Primary Completion Date: November 24, 2020
• Actual Study Completion Date: November 24, 2020

Groups and Cohorts

Group/Cohort
Discovery Cohort; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 3 years ]
   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.
2. 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 [ Time Frame: 3 years ]
   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.

Secondary Outcome Measures :

1. Gene expression profiles in the dermis [ Time Frame: 3 years ]
2. Gene expression profiles in the epidermis [ Time Frame: 3 years ]
3. Gene expression profiles in in keratinocytes [ Time Frame: 3 years ]
4. Gene expression profiles in fibroblasts [ Time Frame: 3 years ]
5. Gene expression profiles in peripheral blood Plasmacytoid Dendritic Cells(pDCs) [ Time Frame: 3 years ]
6. Gene expression profiles in skin tape strip samples [ Time Frame: 3 years ]
7. Herpes Simplex Virus (HSV) replication in primary keratinocytes [ Time Frame: 3 years ]
   HSV replication will be assessed by HSV copy number by Polymerase Chain Reaction (PCR) or RNA sequencing.
8. Herpes Simplex Virus (HSV) replication in fibroblasts [ Time Frame: 3 years ]
   HSV replication will be assessed by HSV copy number by Polymerase Chain Reaction (PCR) or RNA sequencing.
9. Herpes Simplex Virus (HSV) replication in Plasmacytoid Dendritic Cells (pDCs) [ Time Frame: 3 years ]
   HSV replication will be assessed by HSV copy number by Polymerase Chain Reaction (PCR) or RNA sequencing.
10. Herpes Simplex Virus (HSV) replication in genetically modified cell lines [ Time Frame: 3 years ]
    HSV replication will be assessed by HSV copy number by Polymerase Chain Reaction (PCR) or RNA sequencing.
11. Anti-viral responses in primary keratinocytes [ Time Frame: 3 years ]
    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])
12. Anti-viral responses in fibroblasts [ Time Frame: 3 years ]
    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])
13. Anti-viral responses in Plasmacytoid Dendritic Cells (pDCs) [ Time Frame: 3 years ]
    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]).
14. Anti-viral responses in genetically modified cell lines [ Time Frame: 3 years ]
    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]).
15. Immune responses in primary keratinocytes [ Time Frame: 3 years ]
    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]).
16. Immune responses in fibroblasts [ Time Frame: 3 years ]
    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]).
17. Immune responses in Plasmacytoid Dendritic Cells (pDCs) [ Time Frame: 3 years ]
    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]).
18. Immune responses in genetically modified cell lines [ Time Frame: 3 years ]
    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])
19. Differentiation markers in primary keratinocytes [ Time Frame: 3 years ]
    Differentiation markers (e.g. filaggrin (FLG), involucrin, loricrin, and Human Beta-Defensins (HBDs)).
20. Differentiation markers in genetically modified keratinocyte cell lines [ Time Frame: 3 years ]
    Differentiation markers (e.g. filaggrin (FLG), involucrin, loricrin, and Human Beta-Defensins (HBDs)).
21. Expression of reporter gene constructs testing non-coding variants [ Time Frame: 3 years ]
22. Exploratory: Viral carriage [ Time Frame: 3 years ]
    Viral carriage will be assessed by presence of viral sequencing reads.
23. Exploratory: Protein expression of epidermal differentiation complex [ Time Frame: 3 years ]
    Protein expression of epidermal differentiation complex will be measured by Mass Spectroscopy of skin tape strips.
24. Exploratory: Protein expression of inflammatory genes [ Time Frame: 3 years ]
    Protein expression of inflammatory genes will be measured by Mass Spectroscopy of skin tape strips.
25. Exploratory: Lipid profiles [ Time Frame: 3 years ]
    Lipid profiles will be measured by mass spectroscopy of skin tape strips.
26. Exploratory: Whole-genome DNA methylation profiles from epidermis [ Time Frame: 3 years ]
27. Exploratory: Whole-genome DNA methylation profiles from dermis [ Time Frame: 3 Years ]

Biospecimen Retention:   Samples With DNA

Blood and Skin Tissue

Eligibility Criteria

• Ages Eligible for Study: 3 Years to 64 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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.

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.

Contacts and Locations

Locations

United States, Colorado

National Jewish Health: Division of Pediatric Allergy and Clinical Immunology

Denver, Colorado, United States, 80206

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Atopic Dermatitis Research Network

Rho Federal Systems Division, Inc.

Investigators

• Study Chair: Donald Leung, M.D., Ph.D.; National Jewish Health: Division of Pediatric Allergy and Clinical Immunology

More Information

Additional Information:

ClinicalTrials.gov Record for Atopic Dermatitis Research Network Registry 

National Institute of Allergy and Infectious Diseases (NIAID) website 

Atopic Dermatitis Research Network (ADRN) information 

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03038932
• Other Study ID Numbers: DAIT ADRN-06
• First Posted: February 1, 2017
• Last Update Posted: January 14, 2021
• Last Verified: January 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

whole genome sequencing (WGS)

Additional relevant MeSH terms:

Kaposi Varicelliform Eruption; Eczema; Dermatitis; Skin Diseases; Skin Diseases, Eczematous; Herpes Simplex; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Skin Diseases, Viral; Skin Diseases, Infectious