Clinical trial NCT01429311: Interferon Responses in Eczema Herpeticum
Official title: Investigation of Reduced Interferon Responses in Peripheral Blood Mononuclear Cells of Participants With Atopic Dermatitis and a History of Eczema Herpeticum (ADRN-01)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Atopic Dermatitis
Eczema Herpeticum
Herpes Simplex Infections
Eczema Vaccinatum
Keywords: Atopic Dermatitis
Eczema herpeticum
Interferon gamma
IFNγ
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Atopic Dermatitis Research Network
First posted: 2011-09-07
Enrollment: 84
Sex: ALL
Minimum age (years): 6
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 40 ADEH+, 40 ADEH-, and 40 non-atopic controls ages 6 to 65 years. Initially, 20 ADEH- and 20 non-atopic control participants will be gender- and age-matched (plus or minus 10 years) to 20 ADEH+ participants. Afterwards, additional participants will be enrolled such that the gender ratio and the age distribution of the ADEH+ participants will be similar to that of the ADEH- and non-atopic control participants

Brief summary: Atopic dermatitis (AD) is a chronic skin disorder characterized by recurrent viral skin infections. A small subset of patients with AD suffer from disseminated viral infections, e.g., eczema herpeticum (ADEH+), after herpes simplex infection (HSV) or eczema vaccinatum (EV) after smallpox vaccination. Interferon gamma (IFNγ) plays a critical role in the innate and acquired immune responses by activating macrophages, enhancing natural killer cell activation, and promoting T cell differentiation, as well as regulating B cell isotype switching to immunoglobulin (Ig) G2a. Recent studies have demonstrated that IFNγ generation was significantly decreased after stimulation with HSV ex vivo. The purpose of this study is to determine if deficient IFNγ induction leads to susceptibility to HSV infection in ADEH+ patients.

Detailed description: The investigators hypothesize that defective IFNγ responses in peripheral blood mononuclear cells (PBMCs) from ADEH+ patients results from aberrant pattern recognition receptors (PRR) signaling in antigen-presenting cells (APCs) resulting in low level production of IL-12, an essential cytokine for IFNγ generation. This study will compare results from 40 ADEH+, 40 ADEH-, and 40 non-atopic participants.

Study procedures will typically be completed in one visit; however, participants may be asked to return for additional unscheduled visit(s) occurring as frequently as every 3 months for the duration of the study to provide an additional blood sample for further characterization of immune mechanisms leading to reduced IFNγ responses in ADEH+.

Eligibility criteria: Participant Inclusion Criteria:

Participants who meet all of the following criteria are eligible for enrollment:

* have a history of AD with or without a history of Eczema Herpeticum (EH) as diagnosed using the Atopic Dermatitis Research Network (ADRN) Standard Diagnostic Criteria OR

  --are non-atopic as diagnosed using the ADRN Standard Diagnostic Criteria
* are willing to sign the informed consent form or whose parent or legal guardian is willing to sign the informed consent form (age appropriate) prior to initiation of any study procedure
* are willing to sign the assent form, if age appropriate.

Participant Exclusion Criteria:

Participants who meet any of the following criteria are not eligible for enrollment:

* have a history of any systemic illness (e.g., immunodeficiency disorders such as human immunodeficiency virus \[HIV\] or lupus erythematosus) other than the condition being studied
* have an active systemic malignancy, excluding uncomplicated non-melanoma skin cancer
* have any skin disease other than AD that might compromise the stratum corneum barrier (e.g., bullous disease, psoriasis, cutaneous T cell lymphoma \[also called Mycosis Fungoides or Sezary syndrome\], dermatitis herpetiformis, Hailey-Hailey, or Darier's disease)
* have a first degree relative already enrolled in the study
* are determined not to be eligible in the opinion of the Investigator.

Participants who meet any of the following criteria are not eligible for enrollment but may be reassessed:

* have active eczema herpeticum at the Enrollment Visit
* have taken systemic immunosuppressive drugs including cyclosporine or oral steroids within 30 days of the Enrollment Visit
* have a fever ≥ 38.5 degrees Centigrade (ºC) (101.3 ºF) at the Enrollment Visit.

Primary outcomes:
measure: Expression of IFNγ and Interleukin-12 (IL-12), in response to stimulation with Herpes Simplex Virus 1 (HSV-1), Vaccinia Virus (VV), and Pattern Recognition Receptors (PRR) agonists
timeFrame: Day 1
Secondary outcomes:
measure: Cell surface expression of Major Histocompatibility complex (MHC) class I and class II and co-stimulatory molecules on CD14+ cells in response to IFNγ and Interferon-alpha (IFNα) stimulation
timeFrame: Day 1
measure: Production of IL-18 and IFNα protein and mRNA by CD14+ cells following stimulation with HSV-1, VV, or PRR agonists
timeFrame: Day 1
measure: Production of IFNγ protein by Cluster of Differentiation 8 (CD8+) T cells in response to stimulation with recombinant human cytokines including but not limited to IL-12, IL-18, and IFNα
timeFrame: Day 1
measure: Protein expression of IFNγ receptor and IFNα/β receptor on CD14+ cells
timeFrame: Day 1
measure: Immunodominant HSV-1 peptide repertoires
timeFrame: Day 1
measure: High-throughput gene expression profiling to analyze ribonucleic acid (RNA) from HSV-1 stimulated and sham stimulated CD14+ monocytes
timeFrame: Day 1
measure: Production of protein and RNA of IFN family members and any related pro- or anti-inflammatory cytokines/chemokines in response to stimulation of PBMCs or purified monocytes
timeFrame: Day 1
measure: Expression of MHC and co-stimulatory molecules on CD14+ cells in response to stimulation with HSV-1, VV, or PRR agonists
timeFrame: Day 1
measure: Viral titer of VV as determined by plaque assay following incubation of virus with PBMCs
timeFrame: Day 1
measure: Gene expression profiles and gene variant profiles of PBMCs stimulated with HSV-1 as assayed by RNA-seq
timeFrame: Day 1
Other outcomes:
Locations:
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
Study officials:
affiliation: National Jewish Health
name: Donald Leung, PhD, M.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gao L, Bin L, Rafaels NM, Huang L, Potee J, Ruczinski I, Beaty TH, Paller AS, Schneider LC, Gallo R, Hanifin JM, Beck LA, Geha RS, Mathias RA, Barnes KC, Leung DYM. Targeted deep sequencing identifies rare loss-of-function variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum. J Allergy Clin Immunol. 2015 Dec;136(6):1591-1600. doi: 10.1016/j.jaci.2015.06.047. Epub 2015 Sep 3.
citation: Bin L, Edwards MG, Heiser R, Streib JE, Richers B, Hall CF, Leung DY. Identification of novel gene signatures in patients with atopic dermatitis complicated by eczema herpeticum. J Allergy Clin Immunol. 2014 Oct;134(4):848-55. doi: 10.1016/j.jaci.2014.07.018. Epub 2014 Aug 23.