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Papers by Brittany Grashel

Research paper thumbnail of Low non-lesional filaggrin mediates longitudinal Staphylococcus aureus skin colonization, leading to worse atopic dermatitis clinical outcomes in the MPAACH cohort

The Journal of Allergy and Clinical Immunology, Feb 1, 2023

Research paper thumbnail of Events in Normal Skin Promote Early-Life Atopic Dermatitis—The MPAACH Cohort

The Journal of Allergy and Clinical Immunology: In Practice, Jul 1, 2020

BackgroundNon-lesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesion... more BackgroundNon-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.ObjectiveTo 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.MethodsWe 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.ResultsPathophysiologic 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.ConclusionsThis 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.

Research paper thumbnail of Biofilm propensity of <i>Staphylococcus aureus</i> skin isolates is associated with increased atopic dermatitis severity and barrier dysfunction in the MPAACH pediatric cohort

Allergy, Aug 9, 2020

Background:Atopic dermatitis (AD) patients are often colonized with Staphylococcus aureus, and st... more Background:Atopic dermatitis (AD) patients are often colonized with Staphylococcus aureus, and staphylococcal biofilms have been reported on adult AD skin lesions. The commensal S epidermidis can antagonize S aureus, although its role in AD is unclear. We sought to characterize S aureus and S epidermidis colonization and biofilm propensity and determine their associations with AD severity, barrier function, and epidermal gene expression in the first US early-life cohort of children with AD, the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH).Methods:The biofilm propensity of staphylococcal isolates was assessed by crystal violet assays. Gene expression of filaggrin and antimicrobial alarmins S100A8 and S100A9 was measured in keratinocyte RNA extracted from skin tape strips. Staphylococcal biofilms sampled from MPAACH skin were visualized using scanning electron microscopy.Results:Sixty-two percent of staphylococcal isolates (sampled from 400 subjects) formed moderate/strong biofilms. Sixty-eight percent of subjects co-colonized with both staphylococcal species exhibited strains that formed cooperative mixed-species biofilms. Scanning electron microscopy verified the presence of staphylococcal biofilms on the skin of MPAACH children. Staphylococcus aureus strains showing higher relative biofilm propensity compared with S epidermidis were associated with increased AD severity (P = .03) and increased lesional and nonlesional transepidermal water loss (P = .01, P = .03).Conclusions:Our data suggest a pathogenic role for S aureus biofilms in AD. We found that strain-level variation in staphylococcal isolates governs the interactions between S epidermidis and S aureus and that the balance between these two species, and their biofilm propensity, has important implications for AD. Staphylococcal biofilms are observed on the skin of children with AD in the MPAACH cohort. Staphylococcus aureus strains showing higher relative biofilm propensity (compared with S epidermidis from the same subject) are associated with increased AD severity. Staphylococcus aureus strains showing higher relative biofilm propensity are associated with increased lesional and nonlesional transepidermal water loss. Abbreviations: AD, atopic dermatitis; FLG, filaggrin; MPAACH, Mechanisms of Progression of Atopic Dermatitis to Asthma in Children; SCORAD, scoring atopic dermatitis index; S100A8, S100 Calcium-Binding Protein A8; S100A9, Calcium-Binding Protein A9; TEWL, transepidermal water loss

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

The Journal of Allergy and Clinical Immunology, Feb 1, 2020

RATIONALE: Chronic rhinosinusitis (CRS) associated olfactory dysfunction tends to present with te... more RATIONALE: Chronic rhinosinusitis (CRS) associated olfactory dysfunction tends to present with temporary olfactory improvement after treatment. Predicting the olfactory deterioration after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS) remains a significant challenge. The objective of this study was to evaluate the preoperative superior turbinate eosinophilia in patients with CRS and its association with olfactory deterioration after ESS. METHODS: Prospective study in which 78 patients with CRS underwent an olfactory assessment with Sniffin's Sticks before and 3 months after ESS. Post-operative olfactory deterioration was defined by a decrease in Threshold-Discrimination-Identification (TDI) score over 0 points. Superior turbinates were sampled at the surgery for eosinophilia. Preoperative olfactory cleft opacification (OCO) was assessed by computed tomography and the olfactory cleft endoscopy scale (OCES) score was assessed postoperatively. RESULTS: 29.49% of CRS patients (23/78) presented with olfactory deterioration 3 months post-ESS. Preoperative tissue and blood eosinophil levels and preoperative TDI scores were significantly higher in CRS with olfactory deterioration as compared with CRS without olfactory deterioration. CRS with olfaction deterioration had significantly lower preoperative OCO scores and postoperative OCES scores than did CRS without olfaction deterioration. An absolute count of 23.5 eosinophils per high power field in superior turbinate was the best predictor of olfactory deterioration with the highest area under the ROC curve of 0.901. CONCLUSIONS: Superior turbinate eosinophilia is highly associated with the olfactory deterioration in CRS patients 3 months after ESS.

Research paper thumbnail of Progressive accumulation of hyperinflammatory NKG2D<sup>low</sup>NK cells in early life defines a novel endotype of severe atopic dermatitis

medRxiv (Cold Spring Harbor Laboratory), Jun 5, 2023

Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development... more Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic comorbidities remain ill-defined. Herein, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aero allergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed co-incident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired barrier function. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine TNF-α. These observations provide important new insights into a potential pathophysiological mechanism of atopic march involving altered NK-cell functional responses and define a novel endotype of severe AD.

Research paper thumbnail of Longitudinal Atopic Dermatitis Endotypes: An Atopic March Paradigm That Includes Black Children

The Journal of Allergy and Clinical Immunology, Feb 1, 2022

BACKGROUND The atopic march has been studied mostly in White populations, biasing our current par... more BACKGROUND The atopic march has been studied mostly in White populations, biasing our current paradigms. OBJECTIVE To define the atopic march in Black and White children and explore mechanisms for racial differences. METHODS Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (N=601), we assessed longitudinal sensitization, food allergy, allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), SCORAD, transepidermal water loss (TEWL), skin filaggrin (FLG) expression, exposures and genetic heritability to define AD progression endotypes in Black and White children. RESULTS White MPAACH children were more likely to be sensitized to aero and food allergens (p=0.0001) and over 3-times more likely to develop food allergy (FA) and/or allergic rhinitis (AR) without asthma risk (p<0.0001). In contrast, Black children were over 6-times more likely to proceed to high asthma risk without FA, sensitization, or AR (p<0.0001). White children had higher lesional and non-lesional TEWL (both p<0.001) and decreased non-lesional keratinocyte FLG expression (p=0.02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. CONCLUSIONS Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier, and less sensitization, FA and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR and sensitization. The observed racial differences are likely due, in part, to increased genetic heritability for asthma risk and harmful environmental exposures in the Black children. Collectively, our findings provide a new paradigm for the atopic march that is inclusive of Black children.

Research paper thumbnail of Vitamin D, Skin Filaggrin, Allergic Sensitization, and Race: a Complex Interplay

The Journal of Allergy and Clinical Immunology, Feb 1, 2022

BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin... more BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin D has also been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE To explore the role of circulating vitamin D levels in allergic sensitization. METHODS Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N=323) enrolled in the Mechanisms of Progression from AD to Asthma in Children (MPAACH) cohort, a prospective early-life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in keratinocytes was measured by quantitative PCR. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs. 32.9 ng/ml; p < 0.001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels < 27.2 ng/ml (Rho = -0.45; p=0.026). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels ≥ 27.2 ng/ml. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION Despite lower vitamin D levels in Black participants, sensitization load was associated with non-lesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.

Research paper thumbnail of Vitamin D, skin filaggrin, allergic sensitization, and race

Annals of Allergy Asthma & Immunology, Apr 1, 2022

BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin... more BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin D has also been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE To explore the role of circulating vitamin D levels in allergic sensitization. METHODS Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N=323) enrolled in the Mechanisms of Progression from AD to Asthma in Children (MPAACH) cohort, a prospective early-life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in keratinocytes was measured by quantitative PCR. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs. 32.9 ng/ml; p < 0.001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels < 27.2 ng/ml (Rho = -0.45; p=0.026). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels ≥ 27.2 ng/ml. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION Despite lower vitamin D levels in Black participants, sensitization load was associated with non-lesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.

Research paper thumbnail of Temporal relationships between Staphylococcus aureus colonization, filaggrin expression, and pediatric atopic dermatitis

Allergy

BackgroundAtopic dermatitis (AD) is characterized by Staphylococcus aureus (S. aureus) colonizati... more BackgroundAtopic dermatitis (AD) is characterized by Staphylococcus aureus (S. aureus) colonization. Longitudinal early life data delineating relationships of S. aureus colonization, barrier function, and AD outcomes are lacking. We define longitudinal S. aureus endotypes and AD pathogenesis in early life.MethodsWe defined longitudinal S. aureus skin colonization phenotypes across two annual visits (non‐colonized: V1−V2−, early transient: V1+V2−, late‐onset: V1−V2+, persistent: V1+V2+) in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. We analyzed AD severity, sensitization, and skin barrier function across phenotypes, and performed mediation analyses between colonization and FLG expression.ResultsPersistent S. aureus colonization was associated with increased SCORAD at V1 (33.5 vs. 19.0, p = .004) and V2 (40.1 vs.16.9, p < .001), and lower non‐lesional (NL) FLG at V2 (1.77 vs. 4.09, p = .029) compared to the non‐colonized phenotype, with early tr...

Research paper thumbnail of A New Algorithm Identifying Association of Staphylococcus aureus Strains with Low Expression of Filaggrin in Atopic Dermatitis

The Journal of Allergy and Clinical Immunology, Feb 1, 2023

Research paper thumbnail of Low non-lesional filaggrin mediates longitudinal Staphylococcus aureus skin colonization, leading to worse atopic dermatitis clinical outcomes in the MPAACH cohort

Journal of Allergy and Clinical Immunology

Research paper thumbnail of Airway transcriptome networks identify susceptibility to frequent asthma exacerbations in children

Journal of Allergy and Clinical Immunology

Research paper thumbnail of Progressive Accumulation of Hyperinflammatory NKG2Dlow NK Cells in Early Life Defines a Novel Endotype of Severe Atopic Dermatitis

Journal of Allergy and Clinical Immunology

Research paper thumbnail of LB1033 Thrombin contributes to atopic dermatitis pathogenesis and staphylococcus aureus skin colonization in children

Journal of Investigative Dermatology

Research paper thumbnail of The CARD14 Variant Rs11652075 Interacts with Vitamin D3 to Confer Barrier Dysfunction and Atopic Dermatitis Risk

Journal of Allergy and Clinical Immunology, 2022

Research paper thumbnail of Thrombin and Fibrinogen Play a Critical Role in Atopic Dermatitis Pathogenesis

Journal of Allergy and Clinical Immunology, 2022

Research paper thumbnail of Vitamin D, skin filaggrin, allergic sensitization, and race

Annals of Allergy, Asthma & Immunology, 2022

BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin... more BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin D has also been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE To explore the role of circulating vitamin D levels in allergic sensitization. METHODS Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N=323) enrolled in the Mechanisms of Progression from AD to Asthma in Children (MPAACH) cohort, a prospective early-life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in keratinocytes was measured by quantitative PCR. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs. 32.9 ng/ml; p < 0.001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels < 27.2 ng/ml (Rho = -0.45; p=0.026). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels ≥ 27.2 ng/ml. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION Despite lower vitamin D levels in Black participants, sensitization load was associated with non-lesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.

Research paper thumbnail of Longitudinal atopic dermatitis endotypes: An atopic march paradigm that includes Black children

Journal of Allergy and Clinical Immunology, 2021

BACKGROUND The atopic march has been studied mostly in White populations, biasing our current par... more BACKGROUND The atopic march has been studied mostly in White populations, biasing our current paradigms. OBJECTIVE To define the atopic march in Black and White children and explore mechanisms for racial differences. METHODS Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (N=601), we assessed longitudinal sensitization, food allergy, allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), SCORAD, transepidermal water loss (TEWL), skin filaggrin (FLG) expression, exposures and genetic heritability to define AD progression endotypes in Black and White children. RESULTS White MPAACH children were more likely to be sensitized to aero and food allergens (p=0.0001) and over 3-times more likely to develop food allergy (FA) and/or allergic rhinitis (AR) without asthma risk (p<0.0001). In contrast, Black children were over 6-times more likely to proceed to high asthma risk without FA, sensitization, or AR (p<0.0001). White children had higher lesional and non-lesional TEWL (both p<0.001) and decreased non-lesional keratinocyte FLG expression (p=0.02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. CONCLUSIONS Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier, and less sensitization, FA and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR and sensitization. The observed racial differences are likely due, in part, to increased genetic heritability for asthma risk and harmful environmental exposures in the Black children. Collectively, our findings provide a new paradigm for the atopic march that is inclusive of Black children.

Research paper thumbnail of Events in Normal Skin Promote Early-Life Atopic Dermatitis—The MPAACH Cohort

The Journal of Allergy and Clinical Immunology: In Practice, 2020

What is already known about this topic? Nonlesional skin in atopic dermatitis (AD) is abnormal, b... more What is already known about this topic? Nonlesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and nonlesional skin and the definition of endotypes are poorly understood. What does this article add to our knowledge? This study reveals that events in the nonlesional, not the lesional, skin promote the subsequent development of AD severity and cosensitization, which is a key risk factor for allergic comorbidities. How does this study impact current management guidelines? Our study suggests that management of pediatric AD should include treatment of both lesional and nonlesional skin, because subclinical inflammation in normal-appearing areas may predispose to allergic comorbidities and more severe disease. BACKGROUND: Nonlesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and nonlesional skin and the definition of endotypes are poorly understood. OBJECTIVE: To define lesional and nonlesional 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 cohort. METHODS: We assessed lesional and nonlesional skin transepidermal water loss, filaggrin (FLG) and alarmin (S100A8, S100A9) expression, staphylococcal colonization, and patterns of aeroallergen and food sensitization to define nonlesional and lesional phenotypes and endotypes. RESULTS: Pathophysiologic changes were present in lesional and nonlesional skin and were associated with SCORing for Atopic Dermatitis. Nonlesional skin had features characteristic of diseased skin including low FLG and high alarmin expression, and increased colonization with Staphylococcus aureus. In a multivariate model, nonlesional, but not lesional, FLG expression was associated with the development of cosensitization and moderate to severe AD. Lesional skin was characterized by further deficits in FLG expression (P < .001), but alarmin expression was the same as observed in nonlesional skin. CONCLUSIONS: This study reveals that events in the nonlesional, not the lesional, skin promote the subsequent development of AD severity and cosensitization, which is a key risk factor for allergic comorbidities. 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.

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

Journal of Allergy and Clinical Immunology, 2020

RATIONALE: Chronic rhinosinusitis (CRS) associated olfactory dysfunction tends to present with te... more RATIONALE: Chronic rhinosinusitis (CRS) associated olfactory dysfunction tends to present with temporary olfactory improvement after treatment. Predicting the olfactory deterioration after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS) remains a significant challenge. The objective of this study was to evaluate the preoperative superior turbinate eosinophilia in patients with CRS and its association with olfactory deterioration after ESS. METHODS: Prospective study in which 78 patients with CRS underwent an olfactory assessment with Sniffin's Sticks before and 3 months after ESS. Post-operative olfactory deterioration was defined by a decrease in Threshold-Discrimination-Identification (TDI) score over 0 points. Superior turbinates were sampled at the surgery for eosinophilia. Preoperative olfactory cleft opacification (OCO) was assessed by computed tomography and the olfactory cleft endoscopy scale (OCES) score was assessed postoperatively. RESULTS: 29.49% of CRS patients (23/78) presented with olfactory deterioration 3 months post-ESS. Preoperative tissue and blood eosinophil levels and preoperative TDI scores were significantly higher in CRS with olfactory deterioration as compared with CRS without olfactory deterioration. CRS with olfaction deterioration had significantly lower preoperative OCO scores and postoperative OCES scores than did CRS without olfaction deterioration. An absolute count of 23.5 eosinophils per high power field in superior turbinate was the best predictor of olfactory deterioration with the highest area under the ROC curve of 0.901. CONCLUSIONS: Superior turbinate eosinophilia is highly associated with the olfactory deterioration in CRS patients 3 months after ESS.

Research paper thumbnail of Low non-lesional filaggrin mediates longitudinal Staphylococcus aureus skin colonization, leading to worse atopic dermatitis clinical outcomes in the MPAACH cohort

The Journal of Allergy and Clinical Immunology, Feb 1, 2023

Research paper thumbnail of Events in Normal Skin Promote Early-Life Atopic Dermatitis—The MPAACH Cohort

The Journal of Allergy and Clinical Immunology: In Practice, Jul 1, 2020

BackgroundNon-lesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesion... more BackgroundNon-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.ObjectiveTo 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.MethodsWe 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.ResultsPathophysiologic 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.ConclusionsThis 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.

Research paper thumbnail of Biofilm propensity of <i>Staphylococcus aureus</i> skin isolates is associated with increased atopic dermatitis severity and barrier dysfunction in the MPAACH pediatric cohort

Allergy, Aug 9, 2020

Background:Atopic dermatitis (AD) patients are often colonized with Staphylococcus aureus, and st... more Background:Atopic dermatitis (AD) patients are often colonized with Staphylococcus aureus, and staphylococcal biofilms have been reported on adult AD skin lesions. The commensal S epidermidis can antagonize S aureus, although its role in AD is unclear. We sought to characterize S aureus and S epidermidis colonization and biofilm propensity and determine their associations with AD severity, barrier function, and epidermal gene expression in the first US early-life cohort of children with AD, the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH).Methods:The biofilm propensity of staphylococcal isolates was assessed by crystal violet assays. Gene expression of filaggrin and antimicrobial alarmins S100A8 and S100A9 was measured in keratinocyte RNA extracted from skin tape strips. Staphylococcal biofilms sampled from MPAACH skin were visualized using scanning electron microscopy.Results:Sixty-two percent of staphylococcal isolates (sampled from 400 subjects) formed moderate/strong biofilms. Sixty-eight percent of subjects co-colonized with both staphylococcal species exhibited strains that formed cooperative mixed-species biofilms. Scanning electron microscopy verified the presence of staphylococcal biofilms on the skin of MPAACH children. Staphylococcus aureus strains showing higher relative biofilm propensity compared with S epidermidis were associated with increased AD severity (P = .03) and increased lesional and nonlesional transepidermal water loss (P = .01, P = .03).Conclusions:Our data suggest a pathogenic role for S aureus biofilms in AD. We found that strain-level variation in staphylococcal isolates governs the interactions between S epidermidis and S aureus and that the balance between these two species, and their biofilm propensity, has important implications for AD. Staphylococcal biofilms are observed on the skin of children with AD in the MPAACH cohort. Staphylococcus aureus strains showing higher relative biofilm propensity (compared with S epidermidis from the same subject) are associated with increased AD severity. Staphylococcus aureus strains showing higher relative biofilm propensity are associated with increased lesional and nonlesional transepidermal water loss. Abbreviations: AD, atopic dermatitis; FLG, filaggrin; MPAACH, Mechanisms of Progression of Atopic Dermatitis to Asthma in Children; SCORAD, scoring atopic dermatitis index; S100A8, S100 Calcium-Binding Protein A8; S100A9, Calcium-Binding Protein A9; TEWL, transepidermal water loss

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

The Journal of Allergy and Clinical Immunology, Feb 1, 2020

RATIONALE: Chronic rhinosinusitis (CRS) associated olfactory dysfunction tends to present with te... more RATIONALE: Chronic rhinosinusitis (CRS) associated olfactory dysfunction tends to present with temporary olfactory improvement after treatment. Predicting the olfactory deterioration after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS) remains a significant challenge. The objective of this study was to evaluate the preoperative superior turbinate eosinophilia in patients with CRS and its association with olfactory deterioration after ESS. METHODS: Prospective study in which 78 patients with CRS underwent an olfactory assessment with Sniffin's Sticks before and 3 months after ESS. Post-operative olfactory deterioration was defined by a decrease in Threshold-Discrimination-Identification (TDI) score over 0 points. Superior turbinates were sampled at the surgery for eosinophilia. Preoperative olfactory cleft opacification (OCO) was assessed by computed tomography and the olfactory cleft endoscopy scale (OCES) score was assessed postoperatively. RESULTS: 29.49% of CRS patients (23/78) presented with olfactory deterioration 3 months post-ESS. Preoperative tissue and blood eosinophil levels and preoperative TDI scores were significantly higher in CRS with olfactory deterioration as compared with CRS without olfactory deterioration. CRS with olfaction deterioration had significantly lower preoperative OCO scores and postoperative OCES scores than did CRS without olfaction deterioration. An absolute count of 23.5 eosinophils per high power field in superior turbinate was the best predictor of olfactory deterioration with the highest area under the ROC curve of 0.901. CONCLUSIONS: Superior turbinate eosinophilia is highly associated with the olfactory deterioration in CRS patients 3 months after ESS.

Research paper thumbnail of Progressive accumulation of hyperinflammatory NKG2D<sup>low</sup>NK cells in early life defines a novel endotype of severe atopic dermatitis

medRxiv (Cold Spring Harbor Laboratory), Jun 5, 2023

Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development... more Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic comorbidities remain ill-defined. Herein, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aero allergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed co-incident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired barrier function. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine TNF-α. These observations provide important new insights into a potential pathophysiological mechanism of atopic march involving altered NK-cell functional responses and define a novel endotype of severe AD.

Research paper thumbnail of Longitudinal Atopic Dermatitis Endotypes: An Atopic March Paradigm That Includes Black Children

The Journal of Allergy and Clinical Immunology, Feb 1, 2022

BACKGROUND The atopic march has been studied mostly in White populations, biasing our current par... more BACKGROUND The atopic march has been studied mostly in White populations, biasing our current paradigms. OBJECTIVE To define the atopic march in Black and White children and explore mechanisms for racial differences. METHODS Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (N=601), we assessed longitudinal sensitization, food allergy, allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), SCORAD, transepidermal water loss (TEWL), skin filaggrin (FLG) expression, exposures and genetic heritability to define AD progression endotypes in Black and White children. RESULTS White MPAACH children were more likely to be sensitized to aero and food allergens (p=0.0001) and over 3-times more likely to develop food allergy (FA) and/or allergic rhinitis (AR) without asthma risk (p<0.0001). In contrast, Black children were over 6-times more likely to proceed to high asthma risk without FA, sensitization, or AR (p<0.0001). White children had higher lesional and non-lesional TEWL (both p<0.001) and decreased non-lesional keratinocyte FLG expression (p=0.02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. CONCLUSIONS Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier, and less sensitization, FA and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR and sensitization. The observed racial differences are likely due, in part, to increased genetic heritability for asthma risk and harmful environmental exposures in the Black children. Collectively, our findings provide a new paradigm for the atopic march that is inclusive of Black children.

Research paper thumbnail of Vitamin D, Skin Filaggrin, Allergic Sensitization, and Race: a Complex Interplay

The Journal of Allergy and Clinical Immunology, Feb 1, 2022

BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin... more BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin D has also been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE To explore the role of circulating vitamin D levels in allergic sensitization. METHODS Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N=323) enrolled in the Mechanisms of Progression from AD to Asthma in Children (MPAACH) cohort, a prospective early-life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in keratinocytes was measured by quantitative PCR. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs. 32.9 ng/ml; p < 0.001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels < 27.2 ng/ml (Rho = -0.45; p=0.026). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels ≥ 27.2 ng/ml. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION Despite lower vitamin D levels in Black participants, sensitization load was associated with non-lesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.

Research paper thumbnail of Vitamin D, skin filaggrin, allergic sensitization, and race

Annals of Allergy Asthma & Immunology, Apr 1, 2022

BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin... more BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin D has also been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE To explore the role of circulating vitamin D levels in allergic sensitization. METHODS Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N=323) enrolled in the Mechanisms of Progression from AD to Asthma in Children (MPAACH) cohort, a prospective early-life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in keratinocytes was measured by quantitative PCR. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs. 32.9 ng/ml; p < 0.001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels < 27.2 ng/ml (Rho = -0.45; p=0.026). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels ≥ 27.2 ng/ml. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION Despite lower vitamin D levels in Black participants, sensitization load was associated with non-lesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.

Research paper thumbnail of Temporal relationships between Staphylococcus aureus colonization, filaggrin expression, and pediatric atopic dermatitis

Allergy

BackgroundAtopic dermatitis (AD) is characterized by Staphylococcus aureus (S. aureus) colonizati... more BackgroundAtopic dermatitis (AD) is characterized by Staphylococcus aureus (S. aureus) colonization. Longitudinal early life data delineating relationships of S. aureus colonization, barrier function, and AD outcomes are lacking. We define longitudinal S. aureus endotypes and AD pathogenesis in early life.MethodsWe defined longitudinal S. aureus skin colonization phenotypes across two annual visits (non‐colonized: V1−V2−, early transient: V1+V2−, late‐onset: V1−V2+, persistent: V1+V2+) in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. We analyzed AD severity, sensitization, and skin barrier function across phenotypes, and performed mediation analyses between colonization and FLG expression.ResultsPersistent S. aureus colonization was associated with increased SCORAD at V1 (33.5 vs. 19.0, p = .004) and V2 (40.1 vs.16.9, p < .001), and lower non‐lesional (NL) FLG at V2 (1.77 vs. 4.09, p = .029) compared to the non‐colonized phenotype, with early tr...

Research paper thumbnail of A New Algorithm Identifying Association of Staphylococcus aureus Strains with Low Expression of Filaggrin in Atopic Dermatitis

The Journal of Allergy and Clinical Immunology, Feb 1, 2023

Research paper thumbnail of Low non-lesional filaggrin mediates longitudinal Staphylococcus aureus skin colonization, leading to worse atopic dermatitis clinical outcomes in the MPAACH cohort

Journal of Allergy and Clinical Immunology

Research paper thumbnail of Airway transcriptome networks identify susceptibility to frequent asthma exacerbations in children

Journal of Allergy and Clinical Immunology

Research paper thumbnail of Progressive Accumulation of Hyperinflammatory NKG2Dlow NK Cells in Early Life Defines a Novel Endotype of Severe Atopic Dermatitis

Journal of Allergy and Clinical Immunology

Research paper thumbnail of LB1033 Thrombin contributes to atopic dermatitis pathogenesis and staphylococcus aureus skin colonization in children

Journal of Investigative Dermatology

Research paper thumbnail of The CARD14 Variant Rs11652075 Interacts with Vitamin D3 to Confer Barrier Dysfunction and Atopic Dermatitis Risk

Journal of Allergy and Clinical Immunology, 2022

Research paper thumbnail of Thrombin and Fibrinogen Play a Critical Role in Atopic Dermatitis Pathogenesis

Journal of Allergy and Clinical Immunology, 2022

Research paper thumbnail of Vitamin D, skin filaggrin, allergic sensitization, and race

Annals of Allergy, Asthma & Immunology, 2022

BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin... more BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin D has also been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE To explore the role of circulating vitamin D levels in allergic sensitization. METHODS Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N=323) enrolled in the Mechanisms of Progression from AD to Asthma in Children (MPAACH) cohort, a prospective early-life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in keratinocytes was measured by quantitative PCR. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs. 32.9 ng/ml; p < 0.001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels < 27.2 ng/ml (Rho = -0.45; p=0.026). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels ≥ 27.2 ng/ml. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION Despite lower vitamin D levels in Black participants, sensitization load was associated with non-lesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.

Research paper thumbnail of Longitudinal atopic dermatitis endotypes: An atopic march paradigm that includes Black children

Journal of Allergy and Clinical Immunology, 2021

BACKGROUND The atopic march has been studied mostly in White populations, biasing our current par... more BACKGROUND The atopic march has been studied mostly in White populations, biasing our current paradigms. OBJECTIVE To define the atopic march in Black and White children and explore mechanisms for racial differences. METHODS Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (N=601), we assessed longitudinal sensitization, food allergy, allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), SCORAD, transepidermal water loss (TEWL), skin filaggrin (FLG) expression, exposures and genetic heritability to define AD progression endotypes in Black and White children. RESULTS White MPAACH children were more likely to be sensitized to aero and food allergens (p=0.0001) and over 3-times more likely to develop food allergy (FA) and/or allergic rhinitis (AR) without asthma risk (p<0.0001). In contrast, Black children were over 6-times more likely to proceed to high asthma risk without FA, sensitization, or AR (p<0.0001). White children had higher lesional and non-lesional TEWL (both p<0.001) and decreased non-lesional keratinocyte FLG expression (p=0.02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. CONCLUSIONS Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier, and less sensitization, FA and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR and sensitization. The observed racial differences are likely due, in part, to increased genetic heritability for asthma risk and harmful environmental exposures in the Black children. Collectively, our findings provide a new paradigm for the atopic march that is inclusive of Black children.

Research paper thumbnail of Events in Normal Skin Promote Early-Life Atopic Dermatitis—The MPAACH Cohort

The Journal of Allergy and Clinical Immunology: In Practice, 2020

What is already known about this topic? Nonlesional skin in atopic dermatitis (AD) is abnormal, b... more What is already known about this topic? Nonlesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and nonlesional skin and the definition of endotypes are poorly understood. What does this article add to our knowledge? This study reveals that events in the nonlesional, not the lesional, skin promote the subsequent development of AD severity and cosensitization, which is a key risk factor for allergic comorbidities. How does this study impact current management guidelines? Our study suggests that management of pediatric AD should include treatment of both lesional and nonlesional skin, because subclinical inflammation in normal-appearing areas may predispose to allergic comorbidities and more severe disease. BACKGROUND: Nonlesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and nonlesional skin and the definition of endotypes are poorly understood. OBJECTIVE: To define lesional and nonlesional 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 cohort. METHODS: We assessed lesional and nonlesional skin transepidermal water loss, filaggrin (FLG) and alarmin (S100A8, S100A9) expression, staphylococcal colonization, and patterns of aeroallergen and food sensitization to define nonlesional and lesional phenotypes and endotypes. RESULTS: Pathophysiologic changes were present in lesional and nonlesional skin and were associated with SCORing for Atopic Dermatitis. Nonlesional skin had features characteristic of diseased skin including low FLG and high alarmin expression, and increased colonization with Staphylococcus aureus. In a multivariate model, nonlesional, but not lesional, FLG expression was associated with the development of cosensitization and moderate to severe AD. Lesional skin was characterized by further deficits in FLG expression (P < .001), but alarmin expression was the same as observed in nonlesional skin. CONCLUSIONS: This study reveals that events in the nonlesional, not the lesional, skin promote the subsequent development of AD severity and cosensitization, which is a key risk factor for allergic comorbidities. 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.

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

Journal of Allergy and Clinical Immunology, 2020

RATIONALE: Chronic rhinosinusitis (CRS) associated olfactory dysfunction tends to present with te... more RATIONALE: Chronic rhinosinusitis (CRS) associated olfactory dysfunction tends to present with temporary olfactory improvement after treatment. Predicting the olfactory deterioration after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS) remains a significant challenge. The objective of this study was to evaluate the preoperative superior turbinate eosinophilia in patients with CRS and its association with olfactory deterioration after ESS. METHODS: Prospective study in which 78 patients with CRS underwent an olfactory assessment with Sniffin's Sticks before and 3 months after ESS. Post-operative olfactory deterioration was defined by a decrease in Threshold-Discrimination-Identification (TDI) score over 0 points. Superior turbinates were sampled at the surgery for eosinophilia. Preoperative olfactory cleft opacification (OCO) was assessed by computed tomography and the olfactory cleft endoscopy scale (OCES) score was assessed postoperatively. RESULTS: 29.49% of CRS patients (23/78) presented with olfactory deterioration 3 months post-ESS. Preoperative tissue and blood eosinophil levels and preoperative TDI scores were significantly higher in CRS with olfactory deterioration as compared with CRS without olfactory deterioration. CRS with olfaction deterioration had significantly lower preoperative OCO scores and postoperative OCES scores than did CRS without olfaction deterioration. An absolute count of 23.5 eosinophils per high power field in superior turbinate was the best predictor of olfactory deterioration with the highest area under the ROC curve of 0.901. CONCLUSIONS: Superior turbinate eosinophilia is highly associated with the olfactory deterioration in CRS patients 3 months after ESS.