Skin barrier dysfunction associates with type 2 inflammatory diseases: Evidence from a birth cohort

The "epithelial barrier hypothesis" formulates that disturbance of epithelial barriers may cause tissue inflammation and microbial dysbiosis, playing a role in many chronic noncommunicable diseases.1 Transepidermal water loss (TEWL) represents the amount of water that escapes from the stratum corneum per skin area and may be used to measure skin barrier integrity, with few studies addressing TEWL and allergic diseases. Therefore, we aimed to assess differences in skin barrier integrity according to the presence of type 2 inflammatory diseases in a large birth cohort. We analyzed data from 3458 Generation 21 birth cohort participants on their 13-year follow-up assessment, 51.9% of whom were male (Table S1). Patients and their caregivers fulfilled questionnaires assessing demographical data and self-reported medical diagnoses of asthma, allergic rhinitis, eczema, and food allergy (Data S1). TEWL (g/m2h) was performed in a standardized fashion using a validated open-chamber system (Tewameter® TM300 probe [Courage & Khazaka GmbH, Germany] connected to MPA 580 system of the same manufacturer) previously described.2 An average of two consecutive readings was recorded on the dorsum of the hand, the volar forearm, and the antecubital flexure for 1 min in an environmentally controlled room (temperature 21°C and relative humidity at 50%), in a moisturizer and lesion-free skin. Intraclass correlation coefficient (ICC) and standard error of measurement (SEM) were calculated for each location. TEWL values measured in all locations were consistent and had moderate agreement (Table S2). Tanner staging, a widely used system for categorizing adolescents' physical development and maturation during puberty,3 was obtained at the clinical examination considering five stages of development based on breast growth (females), testicular volume, and pubic and armpit hair growth (Table S3). Simple and multiple linear regression models were constructed to identify major factors related to the outcome. All study phases complied with the Ethical Principles for Medical Research Involving Human Subjects expressed in the Declaration of Helsinki. The ISPUP Ethics Committee approved the 13-year evaluation, and the study follows the EU General Data Protection Regulation under close supervision of the Data Protection Office of ISPUP. A written informed consent was obtained from each participant caregiver. In subjects with allergic rhinitis and food allergy, increased values of TEWL were seen in antecubital flexure and volar forearm, respectively, in males and females. The combination of food allergy and eczema in females was associated with a higher TEWL at the dorsum of the hand (Table 1). The maximum likelihood estimates of the multiple regression model (Table 2) showed that male gender, higher testicular volume in males, higher armpit hair in general, and medical diagnosis of allergic rhinitis, asthma, food allergy, and eczema were the important factors influencing skin barrier. It is important to notice that the model captured only about 10%–23% of the variation in TEWL. Moreover, the diagnosis of asthma was the only variable associated with a lower TEWL when assessing antecubital flexure. There is emerging evidence that epithelial barrier disruption, induced by environmental toxic substances and subepithelial tissue inflammation, seems to be the cornerstone in developing many chronic inflammatory diseases.1, 4, 5 The nomenclature for hypersensitivity reactions was recently reviewed and includes a type V hypersensitivity, denoting the peculiarities of the epithelial barrier defects common to several allergic conditions.6 In our study, higher TEWL was seen in males and in the presence of allergic diseases, supporting the association between T2 inflammatory diseases and an epithelial barrier disruption and showing that gender in this age group affects skin water loss. Although it is recognized that gender has an important contribution to TEWL, the most recent systematic review and meta-analysis assessing it in healthy adults did not discuss gender influence.7 We suspect that considering gender in the TEWL analysis might impact the interpretation of these results and should be further assessed in the future across different age ranges. The influence of anatomical regions in TEWL values is noteworthy, as previously described.8 Our study recorded skin water loss in body locations commonly used in dermatologic studies. Notably, the antecubital flexure, frequently affected in patients with eczema, was the body location displaying the most consistent results when comparing the presence or absence of all four allergic diseases in this cohort. Other factors, such as exercise, might also interfere with TEWL results. A previous cohort of swimmers and football players presented a significant increase in TEWL immediately and 30 minutes after training among swimmers (p < .001), compared with football players.9 In our study, we did not assess the possible effects of exercise on TEWL data, as its measurement was obtained at rest. Our study has a few limitations. The evaluated cohort was from the same age, limiting the inference of reference values. Moreover, as a cross-sectional study, it was impossible to assess variations of TEWL related to growth, season, and development of allergic diseases. We acknowledge the relatively small numbers of participants with a diagnosis of allergic conditions, which may hamper the statistical significance of the results when we analyze patients with more than two allergic conditions, but this limitation is reflective of the population prevalence rates within our unique longitudinal birth cohort dataset. This population was also from the same geographic location, which might hamper the application of these values to other populations. We acknowledge the limitation of using self-reported medical diagnoses instead of doctor-diagnosed conditions, but this method was chosen for practicality and cost-effectiveness in a large cohort study, and we mitigated this by employing trained interviewers and ensuring well-informed respondents, with our findings being consistent with previous studies. Type 2 comorbidities were defined based on reported medical diagnosis with no information regarding disease severity; however, we have combined more than one allergic disease for analysis to see its influence on TEWL outcomes. Few patients had more than one allergic disease; nevertheless, a stronger association was seen, particularly with allergic rhinitis and food allergy, frequently linked with a type 2 profile. Lastly, we did not assess the presence of filaggrin mutations in this cohort. However, recent research does not show a direct association between the increase of TEWL and filaggrin loss of function, and TEWL can be associated with different clinical patterns.10 Nonetheless, this study presents important strengths. This is the first assessment of TEWL values on a birth cohort study with this dimension and using Tanner staging, showing that these teenagers had different sexual maturation rates and were at distinct stages of their adolescence development, thus making the results more omnibus in terms of adolescence's period studied. The estimation of TEWL was performed with an extensively used open-chamber device, allowing the detection of even subtle skin barrier changes, and all measures were conducted under controlled environmental conditions in skin free of moisturizers and visible lesions, reducing the influence of exogenous-related factors. The determination of TEWL in this large cohort of adolescents suggests the contribution of gender and allergic comorbidities to the increase in epidermal water loss. It favors that epithelial barrier disruption could play a role in inflammatory chronic conditions. Further longitudinal research is necessary to identify the utility of TEWL determination as a diagnostic tool for allergic comorbidities and as a predictive tool or even a measure of response to treatment. Daniela Brandão Abreu: Conceptualization; methodology; investigation; writing – original draft; formal analysis. Francisca Castro Mendes: Conceptualization; investigation; writing – review and editing; methodology. Diana Silva: Conceptualization; writing – review and editing; validation. Henrique Barros: Writing – review and editing; funding acquisition; supervision; validation. André Moreira: Conceptualization; writing – review and editing; supervision; validation. We gratefully acknowledge the families enrolled in Generation XXI for their kindness, the participating hospitals, and their staff for their help and support, and all previous and current research and field team members for their enthusiasm and perseverance. National funds supported this work through FCT—Fundação para a Ciência e a Tecnologia, IP, under the projects 2022.07363. PTDC—Development of an individual risk assessment tool for school-age asthma prediction. G21 was funded by Programa Operacional de Saúde—Saúde XXI, Quadro Comunitário de Apoio III and Administração Regional de Saúde Norte (Regional Department of Ministry of Health). It has support from the Portuguese Foundation for Science and Technology and the Calouste Gulbenkian Foundation. The authors declare no conflict of interest in relation to this study. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/pai.14218. The data from Generation XXI are not publicly available due to privacy or ethical restrictions. The data can be made available for research proposals upon request to the Generation XXI Executive Committee ([email protected]). Further information about Generation XXI can be obtained via the Generation XXI website [www.geracao21.com] or by emailing [email protected]. Data S1: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.