Background: Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood. Objective: We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity. Methods: We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases- funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures. Results: S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C C18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C C16:0 C16:0/ C16:0/C C16:0/C18:0 C16:0/C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S aureus abundance and ELOVL6 expression by day 21. Conclusion: CERS1 is a unique molecular biomarker of S aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter-chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6. (J Allergy Clin Immunol 2025;155:479-90.)

Atopic dermatitis (AD) is characterized by type 2 inflammation, chronic pruritus and Staphylococcus aureus (SA) skin colonization and infections.SA is thought to play a role in AD severity.We characterized the changes in the host-microbial interface in AD subjects following type 2 blockade. Participants (N=71) with moderate-severe AD were enrolled in a RDBPC study (dupilumab vs placebo; 2:1) at Atopic Dermatitis Research Network centers. Bioassays were performed at multiple timepoints: SA and virulence factor quantification, 16s rRNA microbiome, serum biomarkers, barrier function, skin transcriptomic analyses and PBMC phenotyping. Dupilumab treatment resulted in significant SA reductions after only 3 days; 11 days before clinical improvement. Those with the greatest SA reductions had the best clinical outcomes, and reductions correlated with CCL17 reductions. Reductions in SA cytotoxins (day 7), increases in skin-homing Th17 subsets (day 14), and increased expression of genes relevant for IL-17, neutrophil and complement pathways (day 7) were also observed. Dupilumab very rapidly reduced SA abundance which correlated with reductions in the type 2 biomarker, CCL17. Immunoprofiling and transcriptomics suggest a role for Th17 immunity, while transcriptomic analysis also points to a role for neutrophil and complement activation as potential mechanisms to explain these findings.

Disease severity in atopic dermatitis (AD) is negatively influenced by S. aureus (SA). SA can be inhibited by antimicrobial molecules made by some strains of coagulase-negative Staphylococcus (AM+CoNS). A lack of AM+CoNS correlates with SA abundance and disease severity in AD. A previous clinical trial showed autologous AM+CoNS could reduce SA on AD skin within 24 hrs. Recently, some CoNS were also found to inhibit expression of SA toxins by blocking quorum sensing through production of autoinducing peptides (AIPs). For this reason, a single strain of S. hominis(SHA9) that produces both AMs and an AIPwas selected for further testing of safety and potential therapeutic efficacy in mice and humans. Application ofSHA9 to OVA-sensitized Balb/c FLGft/ftmice reduced SA survival by >99% (P<.05). In these mice, SHA9 was also a potent anti-inflammatory agent and suppressedIL-4 by 89.6%, IL-13 by 84.6% and TSLP by 87.3% (P<.05). SHA9 also increased skin cathelicidin expression by 9.2 fold (P<.01) to provide enhanced host defense. Efficacy was in part due to the action of AIP; genetic deletion of AMs from SHA9 did not completely eliminate the anti-inflammatory activity but did diminish the capacity to eliminate SA. SHA9 was also evaluated in a double-blind, vehicle-controlled phase 1 clinical trial on 54 moderate to severe SA-positive AD adult subjects. SHA9 or vehicle was applied BID to upper extremities for 7 days and skin swabs were obtained for up to 11 days. No difference in adverse events was observed between active and vehicle groups. Compared to vehicle, SHA9 reduced SA abundance on lesional skin by 99% at day-7 (P<.001). This reduction persisted up to day-11 (99%, P<.001) and correlated with a decrease in local EASI at day-9 (P=.001) and day-11 (P=.007). These data show the safety and efficacy of a highly-defined and rationally selected member of the skin microbiome to manage AD.

Background: Cockroach is one of the most important sources of indoor allergens and can lead to IgE sensitization and development of rhinitis and asthma. Objective: We sought to perform a cockroach allergen component analysis to determine the allergens and antibody levels and patterns of sensitization associated with asthma and rhinitis. Methods: Antibody (IgE, IgG, and IgG(4)) levels to total cockroach and 8 cockroach allergens were determined in 2 groups of cockroach-sensitized 10-year-old children with (n = 19) or without (n = 28) asthma and rhinitis. Allergen-specific antibody levels were measured in streptavidin ImmunoCAPs loaded with each of the recombinant allergens from groups 1, 2, 4, 5, 6, 7, 9, and 11, and total cockroach-specific IgE levels were measured with the i6 ImmunoCAP. Results: IgE antibody levels to cockroach allergens and extract, but not IgG or IgG(4) antibody levels, differed between subjects with and without asthma and rhinitis. Specifically, recognition of more cockroach allergens with higher allergen-specific IgE levels was associated with disease. Variable patterns of sensitization with no immunodominant allergens were found in both groups. There was a good correlation between the sum of allergen-specific IgE and total cockroach IgE levels (r = 0.86, P < .001). Conclusions: Component analysis of 8 cockroach allergens revealed significant differences in IgE reactivity associated with the presence of asthma and rhinitis. Allergen-specific IgE titers and sensitization profiles were associated with asthma and rhinitis.

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.

SummaryBackgroundAtopy is an established risk factor for asthma, and an elevated eosinophil level is a hallmark of atopic and non‐atopic asthma. Whether atopy and eosinophils act independently or interact to influence asthma has clinical and public health implications.ObjectiveTo investigate the relationship between atopy and eosinophils in asthma.MethodsData on current asthma, atopy (IgE positive to ≥ 1 allergen), and blood eosinophil percent (dichotomized at the median) were obtained for persons aged ≥ 6 years from the National Health and Nutrition Examination Survey 2005–2006. Interaction on an additive scale was evaluated by estimating the prevalences of asthma for combinations of atopy (yes or no) and eosinophil percent (high or low) and calculating the excess prevalence due to interaction.ResultsFor all ages combined, the adjusted prevalences of asthma were 4.6%, 7.6%, 6.9% and 17.2% for persons with neither factor, atopy alone, a high eosinophil percent alone and both factors respectively. The excess prevalence of asthma due to interaction was 7.2%, indicating synergism. The excess prevalence was greatest in children aged 6–17 years (15.3%), and it decreased with each older age category until it was absent in adults aged ≥ 55 years (−0.2%). In children, 94% of asthma cases attributable to the 2 factors were attributable to the interaction, whereas in the oldest adults, no cases were attributable to the interaction.Conclusions and Clinical RelevanceInteraction between atopy and an elevated eosinophil level in asthma cases was very strong in children but absent in the oldest adults, which suggests different mechanistic pathways for these factors by age and supports the notion that asthma is a heterogeneous disease. In addition, the age‐dependent interaction between the factors has potential implications for the selection of asthma patients for treatments that would target either IgE or a high eosinophil level.

Multiplex cytokine ELISA systems represent a major advance in research methods, but the large amount of data generated by repeated sampling in birth cohorts creates new challenges for the analysis of relationships between cytokines, postnatal exposures, and atopy-related outcomes. Improved methods are needed to analyze the evolution of time-related patterns of cytokine production. Participants in the Urban Environment and Childhood Asthma longitudinal birth cohort study had mononuclear cell responses of nine cytokines measured in cord blood and at ages 1 and 3 years. Responses were measured to panels of innate and adaptive stimulants, resulting in a large data matrix. Factor, cluster, and principal component analyses were compared as data reduction techniques and to discern patterns of response. Cytokine responses were correlated with each other at each time point but not across years. Responses clustered by cytokine at birth, and by stimulant in years 1 and 3. For example, cord blood IL-13 responses to cockroach, dust mite and tetanus were strongly correlated, whereas at years 1 and 3, IL-4, IL-5 and IL-13 responses to cockroach were correlated with each other. The three data reduction methods revealed similar, but not identical, response patterns. Rather than assuming independence and adjusting for multiple comparisons, interpretation of complex, multi-dimensional, cytokine response data may be enhanced by using statistical methods that explore clustering of responses. Such multivariable analyses are able to retrieve the most salient features of these combinations and can help identify the development of Th2-like cytokine response patterns associated with postnatal exposure to allergens.