The Editors' Choice

Abstract

Recent studies have suggested that epidermal barrier dysfunction contributes to the development of atopic dermatitis and other allergic diseases. Horimukai et al (p 824) report the results of a randomized controlled trial investigating whether protecting the skin barrier with a moisturizer during the neonatal period prevents development of atopic dermatitis and allergic sensitization. Approximately 32% fewer neonates who received the moisturizer had atopic dermatitis by week 32 than control subjects (see Figure; P = .012, log-rank test). The authors were not able to show a statistically significant effect of emollient on allergic sensitization based on the serum level of IgE antibody against egg white at 0.34 kUA/L CAP-FEIA equivalents. However, the sensitization rate was significantly higher in infants who had atopic dermatitis than in those who did not (odds ratio, 2.86; 95% CI, 1.22-6.73). Thus daily application of emollient reduces the risk for development of atopic dermatitis by 32 weeks. It might be possible to reduce the prevalence of allergic sensitization by preventing the development of atopic dermatitis. Decades of clinical trials of atopic dermatitis prevention primarily used allergen avoidance, with no standard approach emerging. Simpson et al (p 818) take an alternate approach and take aim at the skin barrier as the site of disease initiation. Emollients are standard flare prevention therapy for established atopic dermatitis (secondary prevention) but have never been used to prevent disease onset (primary prevention). The authors hypothesized that emollient therapy from birth in neonates at high risk for atopic dermatitis could prevent onset by enhancing skin barrier function early in life (see Figure). By using an international collaboration between the United States and the United Kingdom, 124 neonates with a family history of atopic disease were enrolled in a 6-month randomized, controlled feasibility study. At the end of 6 months, the cumulative incidence of atopic dermatitis was 43% in the control group, whereas 22% of babies had atopic dermatitis in the emollient group (relative risk, 0.50; 95% CI, 0.28-0.9; P = .017). All parents in the intervention group found the use of daily emollient acceptable, and there were no emollient-related adverse events. Emollient therapy from birth represents a simple, safe, and low-cost approach to atopic dermatitis prevention. The promising clinical results need confirmation in larger trials of longer duration but suggest that the skin barrier might be an important site for atopic dermatitis initiation. Loss-of-function mutations within the filaggrin gene (FLG-LOF) lead to epidermal barrier dysfunction, making the skin more permeable to environmental allergens and increasing the risk of allergen sensitization and eczema. However, the influence of FLG-LOF on the development of food allergy is uncertain. Venkataraman et al (p 876) explored the time-order relationships between FLG-LOF mutations, food allergy, food sensitization, and eczema using path analysis to determine direct, indirect, and total effects. They found a significant total effect of FLG-LOF on food allergy and food sensitization at 10 and 18 years of age. There was no direct effect of FLG-LOF mutations on food allergy; however, an indirect effect was found through eczema and food sensitization. Overall, the association was strongest for FLG-LOF and eczema in younger children, progressing to food sensitization and food allergy in older children. Thus FLG-LOF mutations can be associated with more persistent forms of childhood food allergy. In conclusion, impaired skin barrier function as a result of both eczema and FLG-LOF seems to be a crucial common factor in the pathogenesis of food allergy. Improvement in barrier function of the skin in early childhood might influence the development of food allergy. A subset of patients with atopic dermatitis (AD) is prone to disseminated herpes simplex virus (HSV) infection (ie, eczema herpeticum [ADEH+]). Biomarkers that identify ADEH+ are lacking. Bin et al (p 848) used an RNA-sequencing approach to evaluate global transcriptional changes of PBMCs from patients with ADEH+ and those with AD without a history of eczema herpeticum (ADEH−). The results demonstrated that PBMCs from patients with ADEH+ had distinct changes to the transcriptome when compared with PBMCs from patients with ADEH− after HSV-1 stimulation: 792 genes were differentially expressed at a false discovery rate of less than 0.05 (ANOVA). Strikingly, 15 type I and type III interferon genes were among the top 20 most downregulated genes in patients with ADEH+. Ingenuity pathway analysis found that the upstream regulators of type I and type III interferons, interferon regulatory factor (IRF) 3 and IRF7, were significantly inhibited in patients with ADEH+ based on the downregulation of their target genes (see Figure). Furthermore, gene expression of IRF3 and IRF7 was also found to be significantly decreased in HSV-1–stimulated PBMCs from patients with ADEH+. Because the IRF3/IRF7-interferon pathways are the most critical innate immune signal pathways for the host to combat invading viruses, these findings indicate that inhibition of the IRF3/IRF7-interferon pathways in patients with ADEH+ contributes to increased susceptibility to disseminated viral infection. Lack et al have proposed that peanut allergy (PA) results from transcutaneous peanut exposure in infants with a disrupted skin barrier, whereas early consumption induces oral tolerance. Filaggrin is a key molecule, deficiencies of which independently increase the risk of eczema and PA and result in skin barrier impairment in infants even before eczema development. In this issue Brough et al (p 867) show that early environmental peanut exposure increases the risk of PA in children genetically predisposed to producing less filaggrin (FLG↓). Children in the Manchester Asthma and Allergy Study were assessed for PA and had genetic studies to determine whether they could produce normal filaggrin levels (FLG↑). Dust samples were collected during the perinatal period/infancy and analyzed for peanut concentration to determine in which groups of children environmental peanut exposure influenced the development of PA. In FLG↑ children environmental peanut exposure did not influence the development of PA. In contrast, in FLG↓ children the risk of PA increased 3-fold for every unit increase in peanut dust concentration and increased many-fold at the highest peanut concentration (see Figure). These data support the hypothesis of transcutaneous sensitization and exemplify the interplay between genes and the environment in development of allergic disease. The recent expansion of newborn screening for early detection of patients with severe combined immunodeficiency has highlighted the clinical quandary of how and when to perform a hematopoietic cell transplantation (HCT) in a very young infant who is lacking an HLA-matched sibling donor. Historically, the majority of recipients of cells from an unrelated donor have been given conditioning chemotherapy. Dvorak et al (p 935) now demonstrate that this is not always required. The retrospective experience of the North American Primary Immune Deficiency Treatment Consortium and the Inborn Errors Working Party of the European Blood and Marrow Transplant Society shows that most patients are able to achieve donor T-cell engraftment, with 5-year survival rates of 71%. Survivors generally had excellent T-cell reconstitution; however, few went on to have freedom from gammaglobulin replacement. The use of serotherapy before HCT was associated with significantly improved outcomes (100%). These data add to the ongoing discussion about the relative need for chemotherapy-based conditioning and highlight the possibility of an initial HCT without conditioning to achieve T-cell reconstitution, followed 2 to 3 years later by a second HCT from the same donor with limited cytoreducing chemotherapy in those patients in whom B-cell immunity is not reconstituted.