Is there a direct link between skin barrier dysfunction and asthma?
Authors: Alexandra F. Santos
Journal: Allergy (2024)

The atopic march describes the sequential presentation of different atopic conditions throughout childhood.1 Typically, children develop atopic eczema and food allergy in infancy, recurrent wheezing/asthma later and allergic rhinitis later on (Figure 1). Whilst the concept of atopic march can be useful clinically to remind clinicians that children with one atopic condition have a higher risk of developing another, and to remind them to enquire about other atopic diseases when taking a clinical history, not all children follow this sequence or develop all four atopic conditions during their life-time. Atopic dermatitis and asthma share the feature that many affected children do not have associated IgE-mediated allergy but, in others, IgE-mediated allergy to food or airborne allergens can induce exacerbation of the underlying condition. It is well established that IgE sensitisation results from an aberrant Th2-biased immune response to allergens and is more likely to happen in abraded skin, especially in inflamed skin affected with atopic dermatitis, particularly sensitisation to food allergens. The inception of sensitisation to airborne allergens is less well understood in asthma. Predictive factors that could help clinicians delineate the prognosis and adopt early intervention measures to halt the unfavourable immune response and, ultimately, the atopic march, would be useful. Similarly, it would be helpful to have biomarkers to support the diagnosis of asthma in early childhood and to predict its evolution over the life course. In this issue of Allergy, Färdig et al2 report post hoc analyses from the PreventADALL study that revealed that impaired skin barrier function and lower lung function at age 3 months increase the risk of asthma at age 3 years. Further validation of these associations in other patient cohorts is needed before they can be used clinically for diagnosis or prognosis. These associations suggest a link between dysfunctional skin barrier and asthma, and lower lung function and asthma. It is, however, unclear whether these are two separate associations (for instance, one linked to allergic sensitisation and another to perturbed lung physiology) and whether dysfunctional skin barrier is linked to asthma through increased risk of allergic sensitisation or independently of allergic sensitisation. The separate concepts that skin barrier disfunction predisposes to allergic sensitisation and that allergic sensitisation predisposes to asthma are not new. Studies with animal models have previously demonstrated that skin exposure to allergens (such as ovalbumin) induce systemic Th2-like immune response with IgE sensitisation and subsequent airway inflammation after inhalation allergen challenge.3 Mice with impaired skin barrier have greater susceptibility to atopic dermatitis, allergic sensitisation and Th2 lung inflammation following ovalbumin exposure, compared to mice with unaffected skin barrier.4 Clinical studies linking allergen skin exposure and Th2 immune response are many; for instance, studies of patients with filaggrin loss-of-function mutations, which is a well-recognised risk factor for atopic dermatitis and allergic sensitisation, namely to foods, such as peanut, and later development of food allergy.5 In this context, increased environmental exposure to peanut in children with atopic dermatitis and filaggrin mutations was associated with an increased risk of peanut allergy.6 However, clinical studies linking skin barrier dysfunction and subsequent asthma are rarer. A recent study identified genes associated with childhood asthma that have the skin as a target tissue, suggesting that early-onset asthma can result from an impaired barrier function of the skin and possibly other epithelia.7 In a previous systematic review of the literature and meta-analyses, there was no association between filaggrin gene defects and asthma in patients without atopic dermatitis.8 It was interesting to see that, in the study by Färdig et al,2 for a fillagrin mutation at age 3 months to be associated with an increased risk of asthma at age 3 years, some clinical expression of atopic or allergic disease needed to be present, such as atopic dermatitis or allergic sensitisation. A similar report was made for eczema but, despite the well-articulated definitions, the distinction between eczema and atopic dermatitis in the PreventADALL study is not completely clear. In any case, this need for some clinical expression of atopic dermatitis or evidence of allergic sensitisation for filaggrin mutation to increase the risk of asthma suggests shared skin and lung barrier defects and/or an underlying systemic immunological mechanism. The PreventADALL study was a randomised-controlled trial that assessed whether early food introduction and skin emollients, separately or in combination, prevented food allergy.9 In this manuscript, the authors report post hoc analyses done as if it was an observational population-based study. The authors confirmed that no interactions were observed between skin and lung conditions, the study interventions and asthma at age 3 years and thus the use of the whole population was justified to provide a larger sample size. It would have been good to complement the statistical analyses presented in this paper with mechanistic studies exploring the biological link between skin barrier defect and asthma. Is the link between the two happening via systemic Th2 inflammation and IgE sensitisation to the allergen? Or could there be a more general barrier defect shared between the skin and the lung? In any case, the fact that skin barrier dysfunction can predispose to asthma opens potential novel opportunities for asthma prevention through skin interventions. Frequent use of soaps and chemicals, exposure to skin irritants, certain environmental conditions and other factors can impair the skin barrier.10 The epithelial barrier hypothesis proposes that this is a major driver of the recent increase in allergic diseases seen in the past few decades. It is possible that use of emollients and other interventions, namely environmental, to improve the skin barrier can prevent not only atopic dermatitis and allergic sensitisation but also asthma. If skin barrier dysfunction is indeed central to the inception of atopic diseases and the atopic march, preventing it and restoring skin barrier function could have a key primary prevention role with much impact on childhood morbidity, and even mortality, for allergic diseases and asthma. Alexandra F. Santos reports grants from Medical Research Council (MR/M008517/1; MC/PC/18052; MR/T032081/1), Food Allergy Research and Education (FARE), the Immune Tolerance Network/National Institute of Allergy and Infectious Diseases (NIAID, NIH), Asthma UK (AUK-BC-2015-01), BBSRC, Rosetrees Trust and the NIHR through the Biomedical Research Centre (BRC) award to Guy's and St Thomas' NHS Foundation Trust, during the conduct of the study; personal fees from Thermo Scientific, Nestle, Nutricia, Infomed, Novartis, Allergy Therapeutics, IgGenix, Mabylon, Stallergenes, Buhlmann, as well as research support from Buhlmann and Thermo Fisher Scientific through a collaboration agreement with King's College London. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.