Jocelyn M Biagini Myers1, Michael G Sherenian1, Asel Baatyrbek Kyzy2, Rosario Alarcon2, Amen An2, Zachary Flege2, David Morgan2, Tammy Gonzalez3, Mariana L Stevens2, Hua He4, John W Kroner2, Daniel Spagna2, Brittany Grashel2, Lisa J Martin5, Andrew B Herr6, Gurjit K Khurana Hershey7. 1. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 2. Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3. Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 4. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 5. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 6. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 7. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: gurjit.hershey@cchmc.org.
Abstract
BACKGROUND: Nonlesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and nonlesional skin and the definition of endotypes are poorly understood. OBJECTIVE: To define lesional and nonlesional endotypes of AD by building the first US-based early-life prospective cohort of children with AD, the Mechanisms of Progression from AD to Asthma in Children cohort. METHODS: We assessed lesional and nonlesional skin transepidermal water loss, filaggrin (FLG) and alarmin (S100A8, S100A9) expression, staphylococcal colonization, and patterns of aeroallergen and food sensitization to define nonlesional and lesional phenotypes and endotypes. RESULTS: Pathophysiologic changes were present in lesional and nonlesional skin and were associated with SCORing for Atopic Dermatitis. Nonlesional skin had features characteristic of diseased skin including low FLG and high alarmin expression, and increased colonization with Staphylococcus aureus. In a multivariate model, nonlesional, but not lesional, FLG expression was associated with the development of cosensitization and moderate to severe AD. Lesional skin was characterized by further deficits in FLG expression (P < .001), but alarmin expression was the same as observed in nonlesional skin. CONCLUSIONS: This study reveals that events in the nonlesional, not the lesional, skin promote the subsequent development of AD severity and cosensitization, which is a key risk factor for allergic comorbidities. Collectively, these data suggest the presence of a subclinical eczema endotype that may predispose to the development of allergic disease in the absence of overt eczema. This may represent a new definition of the atopic march that starts with skin barrier dysfunction rather than eczema.
BACKGROUND: Nonlesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and nonlesional skin and the definition of endotypes are poorly understood. OBJECTIVE: To define lesional and nonlesional endotypes of AD by building the first US-based early-life prospective cohort of children with AD, the Mechanisms of Progression from AD to Asthma in Children cohort. METHODS: We assessed lesional and nonlesional skin transepidermal water loss, filaggrin (FLG) and alarmin (S100A8, S100A9) expression, staphylococcal colonization, and patterns of aeroallergen and food sensitization to define nonlesional and lesional phenotypes and endotypes. RESULTS: Pathophysiologic changes were present in lesional and nonlesional skin and were associated with SCORing for Atopic Dermatitis. Nonlesional skin had features characteristic of diseased skin including low FLG and high alarmin expression, and increased colonization with Staphylococcus aureus. In a multivariate model, nonlesional, but not lesional, FLG expression was associated with the development of cosensitization and moderate to severe AD. Lesional skin was characterized by further deficits in FLG expression (P < .001), but alarmin expression was the same as observed in nonlesional skin. CONCLUSIONS: This study reveals that events in the nonlesional, not the lesional, skin promote the subsequent development of AD severity and cosensitization, which is a key risk factor for allergic comorbidities. Collectively, these data suggest the presence of a subclinical eczema endotype that may predispose to the development of allergic disease in the absence of overt eczema. This may represent a new definition of the atopic march that starts with skin barrier dysfunction rather than eczema.
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