The Mechanisms of Atopic Dermatitis to Asthma in Children (MPAACH) Cohort: Novel Atopic Dermatitis Endotypes

Non-lesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and non-lesional skin and the definition of endotypes are poorly understood. Our objective was to define lesional and non-lesional 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 (MPAACH) cohort. We assessed lesional and non-lesional skin TEWL, filaggrin (FLG) and alarmin (S100A8, S100A9) expression, staphylococcal colonization, and patterns of aeroallergen and food sensitization to define non-lesional and lesional phenotypes and endotypes. Pathophysiologic changes were present in lesional and non-lesional skin and were associated with SCORAD. Non-lesional skin had features characteristic of diseased skin including low FLG and high alarmin expression, and increased colonization with S. aureus. In a multivariate model, non-lesional, but not lesional, FLG expression was associated with the development of co-sensitization and moderate-severe AD. Lesional skin was characterized by further deficits in FLG expression (p<0.001), but alarmin expression was the same as observed in non-lesional skin. This study reveals that events in the non-lesional, not the lesional skin, promote the subsequent development of AD severity and co-sensitization, which is a key risk factor for allergic co-morbidities. 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.