Circadian Rhythms in Skin Barrier Function in Atopic Dermatitis: A Pilot Study.

Atopic dermatitis (AD) is symptomatically worse in the evening, but the mechanism driving nocturnal eczema remains elusive. Our objective was to determine the circadian rhythm of skin barrier function measured by transepidermal water loss (TEWL) in AD patients and explore the molecular underpinnings. A pilot study was performed on a diverse group of AD (n = 4) and control (n = 2) young patients. We used an inpatient tightly controlled, modified, constant routine protocol. TEWL was measured at least every 90 min in the antecubital fossa (lesional) and forearm, while whole blood samples were collected every 4 h. Results show a significant difference in the antecubital fossa TEWL in the AD group versus controls. TEWL in control skin decreases starting a few hours prior to bedtime, both in the antecubital fossa and in the forearm, while in the AD forearm skin, pre-bedtime TEWL increases. We identified 1576 differentially expressed genes using a time-dependent model. The top 20 upregulated gene ontology pathways included neuronal pathways, while the downregulated functional terms included innate immune signaling and viral response. Similar pathways positively correlated with forearm TEWL in controls and inversely with the AD group. Upregulation in sensory perception pathways correlated with increases in lesional (antecubital fossa) TEWL in the evening. Results show skin barrier function worsens in the evening in the AD group, at a time when barrier is normally rejuvenating in healthy skin. This timing and the detection of transcriptomic signatures of sensory perception and diminished viral response might correspond to the nocturnal itch. Larger studies are needed to evaluate these associations in the skin.

The circadian metabolome of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by dry, pruritic skin. Several studies have described nocturnal increases in itching behavior, suggesting a role for the circadian rhythm in modulating symptom severity. However, the circadian rhythm of metabolites in the skin and serum of patients with AD is yet to be described. OBJECTIVE: We sought to assess circadian patterns of skin and serum metabolism in patients with AD. METHODS: Twelve patients with moderate to severe AD and 5 healthy volunteers were monitored for 28 hours in a controlled environment. Serum was collected every 2 hours and tape strips every 4 hours from both lesional and nonlesional skin in participants with AD and location-, sex-, and age-matched healthy skin of controls. We then performed an untargeted metabolomics analysis, examining the circadian peaks of metabolism in patients with AD. RESULTS: Distinct metabolic profiles were observed in AD versus control samples. When accounting for time of collection, the greatest differences in serum metabolic pathways were observed in arachidonic acid, steroid biosynthesis, and terpenoid backbone biosynthesis. We identified 42 circadian peaks in AD or control serum and 17 in the skin. Pathway enrichment and serum-skin metabolite correlation varied throughout the day. Differences were most evident in the late morning and immediately after sleep onset. CONCLUSIONS: Although limited by a small sample size and observational design, our findings suggest that accounting for sample collection time could improve biomarker detection studies in AD and highlight that metabolic changes may be associated with nocturnal differences in symptom severity.

Severe atopic dermatitis, sleep disturbance, and low light exposure.

STUDY OBJECTIVES: Atopic dermatitis (AD) is a chronic inflammatory skin disorder in children. AD worsens at night, particularly in severe disease. Low light exposure contributes to inflammation, poor sleep, and misalignment between circadian (24-hour) rhythms (biological clocks) and social clocks (weekday vs. weekend sleep timing), but has not been evaluated in AD. Our objective was to perform a cross-sectional study to determine whether there is an association between AD severity, recorded light exposure (RLE), and sleep measures in participants with AD and healthy controls. METHODS: Secondary data analysis from two prospective observational studies of 74 participants ages 5-17 years old with severe AD compared to others (healthy controls and mild/moderate AD). Participants wore actigraphy watches for at least 1 weekday and one weekend. Rest/activity and RLE (lux) were obtained from the watches and were analyzed to estimate duration and quality of sleep/light exposure. RESULTS: Participants (n = 74) were on average 10.9 ±â€…3.6 years old, with 45% female, 17% no AD, 27% mild, 32% moderate, and 24% severe AD. On weekends, severe AD participants versus others fell asleep at a similar time (23:52 ±â€…1:08 vs. 23:40 ±â€…1:29 mean clock-time hours ±â€…SD; p = 0.23), had similar sleep-onset latency (8.2 ±â€…8.7 vs. 12.7 ±â€…16.9 minutes; p = 0.28), but woke later (09:12 ±â€…1:04 vs. 08:13 ±â€…1:14 minutes; p < 0.01) resulting in a later sleep-midpoint (04:32 ±â€…0:53 vs. 03:49 ±â€…1:08 minutes; p = 0.02). Severe AD participants had lower levels of daytime RLE than others (mean-over-all-days: 1948.4 ±â€…2130.0 vs. 10341.3 ±â€…13453.8 lux; p = 0.01) and throughout seasons, weekdays, or weekend, yet had similar nighttime RLE. CONCLUSION: Severe AD is characterized by low RLE and sleep disturbance. Low RLE could potentially induce circadian misalignment, contributing to inflammation and worse disease in severe AD. Low RLE can also reflect altered lifestyle and behavior due to atopic disease impacts. Prospective studies are needed to test causality and the potential of bright light as an adjuvant therapy for severe AD.

Assessment and Management of Sleep Disturbances in Atopic Dermatitis: A Review.

Atopic dermatitis (AD) is a chronic burdensome inflammatory skin disease with well-established cutaneous and systemic comorbidities and disease burden. AD particularly has profound impacts on sleep in individuals of all ages. Sleep disturbances (SDs) affect 6.2% of school-age children and 33-87.1% of adults with AD. This narrative review addresses the burden of SD in AD patients, as well as biological mechanisms of SD in AD, including biological clocks influencing sleep, inflammation, and behavior. Approaches for early detection, diagnosis, objective quantification, patient education, and management are reviewed. It is imperative to break the itch-scratch cycle to reduce SDs and improve quality of life in individuals with AD.

Facial atopic dermatitis is associated with sensitization to cow's milk, egg whites, and peanuts in children under 36 months.

Atopic dermatitis (AD) in early childhood often precedes the development of food sensitization and allergy, but the role of treating AD to prevent food allergy remains poorly understood. Our objective was to assess the relationship between facial dermatitis and food sensitization to cow's milk, egg whites, and peanuts in early childhood, as aggressive treatment of facial dermatitis could serve as a potential opportunity for food sensitization prevention. By 3 years of age, food sensitization levels to cow's milk, egg whites, and peanuts were 48% greater in children with facial AD than in children with no facial involvement of their AD. Additional research is needed to determine if facial involvement of AD in infants and young children is associated with increased food allergy.

Perceptions on Management of Atopic Dermatitis in Children Under 2 Years by Community Pediatricians: A Focus Group Study.

Atopic dermatitis (AD) is a common skin condition and is undertreated in children under 2 years, whom there are no specific guidelines for. We sought to understand barriers to AD treatment and primary care pediatricians' (PCPs) suggested solutions. We conducted semi-structured focus groups (n = 5) with PCPs (n = 17) on how the undertreatment of AD can be addressed. Data were analyzed using an inductive qualitative approach. Participants noted that the perceived undertreatment of AD in children under 2 years could be explained by topical corticosteroid (TCS) use hesitancy, lack of caregiver adherence to PCP recommendations, and under-documentation of AD in the electronic medical record (EMR). Proposed suggestions for improving AD management included caregiver and PCP education on TCS safety; stepwise management guidelines for this age group; and EMR aids to help document and manage AD. Research is warranted to create and disseminate clinician-friendly AD management guidelines for this age group.

Patient-reported outcomes for measuring sleep disturbance in pediatric atopic dermatitis: Cross-sectional study of the Patient Reported Outcomes Measurement Information System pediatric sleep measures and actigraphy.

BACKGROUND: Most children with atopic dermatitis (AD) experience sleep disturbance, but reliable and valid assessment tools are lacking. OBJECTIVES: To test the Patient-Reported Outcomes Measurement Information System (PROMIS) sleep measures in pediatric AD and to develop an algorithm to screen, assess, and intervene to reduce sleep disturbance. METHODS: A cross-sectional study was conducted with children with AD ages 5 to 17 years and 1 parent (n = 61), who completed sleep, itch, and AD-specific questionnaires; clinicians assessed disease severity. All children wore actigraphy watches for a 1-week objective sleep assessment. RESULTS: PROMIS sleep disturbance parent proxy reliability was high (Cronbach α = 0.90) and was differentiated among Patient-Oriented Eczema Measure (POEM)-determined disease severity groups (mean ± standard deviation in mild vs moderate vs severe was 55.7 ± 7.5 vs 59.8 ± 10.8 vs 67.1 ± 9.5; P < .01). Sleep disturbance correlated with itch (numeric rating scale, r = 0.48), PROMIS sleep-related impairment (r = 0.57), and worsened quality of life (Children's Dermatology Life Quality Index, r = 0.58), with all P values less than .01. Positive report on the POEM sleep disturbance question has high sensitivity (95%) for PROMIS parent proxy-reported sleep disturbance (T-score ≥ 60). An algorithm for screening and intervening on sleep disturbance was proposed. LIMITATIONS: This was a local sample. CONCLUSIONS: Sleep disturbance in pediatric AD should be screened using the POEM sleep question, with further assessment using the PROMIS sleep disturbance measure or objective sleep monitoring if needed.

Timing of scratch and limb movements during sleep in children with atopic dermatitis.

In this retrospective analysis of children with atopic dermatitis (n = 6) who coincidentally had a video polysomnography, we found that most nocturnal limb movements in children with atopic dermatitis are non-scratch versus scratch, 109.0 ± 67.9 vs. 15.3 ± 5.4 (p = 0.01). Average scratch duration was 8.4 ± 2.7 s, which was not different by sleep stage. Scratch movements are distinct in timing, occurring most often during N2 sleep, in the first third of sleep, and peaking at 90 minutes after sleep onset, corresponding with completion of the first sleep cycle.

Positive Psychology Themes in Interviews of Children With Atopic Dermatitis: Qualitative Study.

BACKGROUND: Atopic dermatitis is a pruritic chronic condition associated with significant sleep disturbance, inattention, and sometimes behavioral problems. Enhancing resiliency in children with atopic dermatitis may promote coping strategies to improve quality of life. Positive psychology is one strategy that can be used to strengthen resiliency. OBJECTIVE: Our objective was to identify positive psychology concepts mentioned by children with atopic dermatitis and their parent to inform strategies to strengthen resiliency in children with atopic dermatitis. METHODS: A total of 20 patient-parent dyads were interviewed to share their experience with atopic dermatitis to help develop a novel psychologic intervention for atopic dermatitis. Patients were 8 to 17 years old and diagnosed with atopic dermatitis. Trained coders analyzed transcripts using a coding dictionary developed based on Seligman's PERMA (positive emotion, engagement, relationships, meaning, and accomplishment) model of positive psychology. The frequency of unprompted mentions of PERMA themes and relevant quotations was captured. Transcripts were also separately coded for resiliency, which is the ultimate goal of PERMA. RESULTS: Positive psychology concepts were mentioned by 100% (20/20) of children and 95% (19/20) of parents. Engagement and relationships, both negative and positive aspects, were the most common unprompted PERMA themes mentioned by children (14/20, 70%) and parents (13/20, 65%). Emotion elicited the most negative comments from children (19/20, 95%) and parents (17/20, 85%). When analyzed for resiliency, 8 participants were identified with at least one resiliency code. On average, participants with a resiliency code mentioned PERMA concepts 9.1 (SD 4.7) times compared to those who mentioned none (mean 5.9, SD 4.6) (P=.14). When participants were stratified by disease severity, on average, more positive psychology concepts were mentioned by patients with mild atopic dermatitis (mean 13, SD 3.0) than those with moderate symptoms (mean 6.2, SD 4.9) or severe symptoms (mean 6.1, SD 4.0) (P=.03). CONCLUSIONS: Among PERMA themes, engagement and relationships are the two most commonly mentioned categories for children with atopic dermatitis. Strategies targeting PERMA such as affirmations and positive reframing may improve psychosocial well-being and resiliency in pediatric atopic dermatitis. Future directions will look at incorporating "positive medicine" into atopic dermatitis treatment to not only relieve symptoms but also strengthen positive aspects of life.

Parent report of sleep health and attention regulation in a cross-sectional study of infants and preschool-aged children with atopic dermatitis.

BACKGROUND/OBJECTIVES: Older children with atopic dermatitis (AD) suffer from poor sleep and attention problems. However, until recently, the dearth of developmentally sensitive assessment tools impeded characterization in younger children. We aimed to characterize sleep and attention problems in young children with AD and identify modifiable factors. METHODS: A cross-sectional study of children with AD aged 1-4 years was stratified by disease severity (Patient-Oriented Eczema Measure), age, and racial/ethnic groups. Developmentally sensitive surveys assessed attention (Multidimensional Assessment Profile of Attention Regulation), sleep, and itch (Patient-Reported Outcomes Measurement Information System). Linear regression models identified predictors of sleep health and attention dysregulation. RESULTS: Parents (n = 60) of children aged 2.78 ± 0.98 years with severe (n = 25), moderate (n = 25), or mild (n = 10) AD were recruited across the United States. Significantly reduced sleep health (T-score ≥ 60) was reported in 86% of children with moderate/severe disease (n = 43), and 50% had ≥5 nights of disturbed sleep per week. A suboptimal sleep environment was identified with 32% of children with too much light, noise, or electronic device usage. With regard to attention regulation, in children with severe AD, 80% had trouble sitting still and 72% of children had trouble paying attention no matter their surroundings. In fully adjusted models, AD severity was a significant predictor of poor sleep health (B = 0.79 [0.31-1.28], p < .01) and attention dysregulation (B = 1.22 [0.51-1.93], p < .01). CONCLUSIONS: More severe AD correlates with poor sleep health and attention dysregulation. In addition to aggressive treatment of AD, clinicians should advise on modifiable sleep hygiene practices and consider screening for attention dysregulation in young children.

Use of technology for the objective evaluation of scratching behavior: A systematic review.

INTRODUCTION: Pruritus is a common symptom across various dermatologic conditions, with a negative impact on quality of life. Devices to quantify itch objectively primarily use scratch as a proxy. This review compares and evaluates the performance of technologies aimed at objectively measuring scratch behavior. METHODS: Articles identified from literature searches performed in October 2020 were reviewed and those that did not report a primary statistical performance measure (eg, sensitivity, specificity) were excluded. The articles were independently reviewed by 2 authors. RESULTS: The literature search resulted in 6231 articles, of which 24 met eligibility criteria. Studies were categorized by technology, with actigraphy being the most studied (n = 21). Wrist actigraphy's performance is poorer in pruritic patients and inherently limited in finger-dominant scratch detection. It has moderate correlations with objective measures (Eczema and Area Severity Index/Investigator's Global Assessment: rs(ρ) = 0.70-0.76), but correlations with subjective measures are poor (r2 = 0.06, rs(ρ) = 0.18-0.40 for itch measured using a visual analog scale). This may be due to varied subjective perception of itch or actigraphy's underestimation of scratch. CONCLUSION: Actigraphy's large variability in performance and limited understanding of its specificity for scratch merits larger studies looking at validation of data analysis algorithms and device performance, particularly within target patient populations.

Circadian disruption and human health.

Circadian disruption is pervasive and can occur at multiple organizational levels, contributing to poor health outcomes at individual and population levels. Evidence points to a bidirectional relationship, in that circadian disruption increases disease severity and many diseases can disrupt circadian rhythms. Importantly, circadian disruption can increase the risk for the expression and development of neurologic, psychiatric, cardiometabolic, and immune disorders. Thus, harnessing the rich findings from preclinical and translational research in circadian biology to enhance health via circadian-based approaches represents a unique opportunity for personalized/precision medicine and overall societal well-being. In this Review, we discuss the implications of circadian disruption for human health using a bench-to-bedside approach. Evidence from preclinical and translational science is applied to a clinical and population-based approach. Given the broad implications of circadian regulation for human health, this Review focuses its discussion on selected examples in neurologic, psychiatric, metabolic, cardiovascular, allergic, and immunologic disorders that highlight the interrelatedness between circadian disruption and human disease and the potential of circadian-based interventions, such as bright light therapy and exogenous melatonin, as well as chronotherapy to improve and/or modify disease outcomes.

Diurnal Variations in Skin Prick Testing.

Background: Prior research suggests that skin prick testing (SPT) might be larger in the afternoon, with unclear clinical significance. Methods: This retrospective chart review analyzed SPT results from patients between June 2008 and June 2017, organized into 4 time groups for analysis (Group 1: 7:00 AM -10:29 AM, Group 2: 10:30 AM -11:59 AM, Group 3: 12:00 PM -2:29 PM, and Group 4: 2:30 PM -8:15 PM). Results: In total, 12,982 (n) patient test results had positive histamine and were included in final analysis. Histamine wheal size was not significantly increased in the PM compared with AM (P = 0.89). Food allergen and aeroallergen wheal sizes were not significantly increased in PM. Histamine erythema size was increased in the PM compared with AM (P ≤ 0.01). Food allergen and aeroallergen erythema sizes trended toward an increase in the PM. Conclusions: There were not significant differences in SPT wheal size based on time of day for histamine, food allergens, or aeroallergens. SPT can be reliably performed at any time of day.

Sleep Disturbance in School-Aged Children with Atopic Dermatitis: Prevalence and Severity in a Cross-Sectional Sample.

BACKGROUND: Atopic dermatitis (AD) causes sleep disturbance but the epidemiology is not known. OBJECTIVE: To estimate the US prevalence of sleep disturbance and its impact on psychological and neurocognitive function. METHODS: We conducted a cross-sectional survey of 180 parent-child dyads with AD using stratified sampling based on disease severity (Patient Oriented Eczema Measure: mild [n = 30), moderate (n = 75) or severe (n = 75]), age, and race (White or Black or African American or other). Symptoms of sleep and psychologic health were assessed using the Patient-Reported Outcome Measurement Information System. To estimate the prevalence of sleep disturbance, we calculated weights using poststratification adjustment making marginal frequencies of AD severity, race, and age similar to marginal frequencies in the 2007 National Survey of Children's Health. Unweighted regression models examined associations with sleep disturbance. RESULTS: In children age 5 to 17 years with AD, we estimated that sleep disturbance occurred in 66.9% (95% confidence interval, 53.3% to 80.5%; 3,116,305 children). The odds of severe sleep disturbance (worse than 95% of US children) were highest in moderate to severe versus mild AD (2.03 [1.00-4.10]; P = .0495; compared with 8.68 [1.82-41.49]; P = .0068). Predictors of parent proxy-reported sleep disturbance were itch intensity (adjusted ß [95% confidence interval] 1.33 [0.62-2.04]) and low income (<$50,000: 6.64 [2.05-11.23]; and $50,000 to less than 100,000: 4.75 [0.35-9.14]). Controlling for disease severity, itch intensity, and significant sociodemographics-parent-proxy, reported sleep disturbance was associated with increased severity of sleep-related impairment, depression, fatigue, and anxiety, in addition to worse inattention and impulsivity. In fully adjusted models, children who self-reported sleep disturbance (T-score ≥60) had increased odds of sleep-related impairment (1.20 [1.11-1.29]), depression (1.13 [1.03, 1.24]), fatigue (1.28 [1.06-1.54]), and anxiety (1.16 [1.02-1.31]). CONCLUSIONS: Sleep disturbance is a common symptom of AD. It affects about 3 million US children and is associated with neuropsychiatric impairment, including depression, anxiety, and inattention. Clinicians should screen for these symptoms in school-aged children, particularly those with moderate to severe AD.

A skin-conformable wireless sensor to objectively quantify symptoms of pruritus.

Itch is a common clinical symptom and major driver of disease-related morbidity across a wide range of medical conditions. A substantial unmet need is for objective, accurate measurements of itch. In this article, we present a noninvasive technology to objectively quantify scratching behavior via a soft, flexible, and wireless sensor that captures the acousto-mechanic signatures of scratching from the dorsum of the hand. A machine learning algorithm validated on data collected from healthy subjects (n = 10) indicates excellent performance relative to smartwatch-based approaches. Clinical validation in a cohort of predominately pediatric patients (n = 11) with moderate to severe atopic dermatitis included 46 sleep-nights totaling 378.4 hours. The data indicate an accuracy of 99.0% (84.3% sensitivity, 99.3% specificity) against visual observation. This work suggests broad capabilities relevant to applications ranging from assessing the efficacy of drugs for conditions that cause itch to monitoring disease severity and treatment response.

Coconut allergy: Characteristics of reactions and diagnostic predictors in a pediatric tertiary care center.

BACKGROUND: Little is known on the clinical manifestations of coconut allergy. Our knowledge to date is mainly based on case reports. OBJECTIVE: To characterize the allergic reactions to coconut and suggest diagnostic cutoffs for specific immunoglobulin E (sIgE) and skin prick testing (SPT) to predict clinically reactive coconut allergy. METHODS: Methods include retrospective chart review at an urban tertiary care center of patients with positive testing result for coconut. Probability curves were computed by logistic regression for SPT and coconut sIgE. RESULTS: Of 275 records reviewed, 69 patients reported coconut reactions and 206 were sensitized only or nonallergic. The reactions occurred with breastfeeding (n = 2), contact (n = 10), or oral ingestion (n = 57). Approximately 50% of oral ingestion reactions were associated with mild/moderate anaphylaxis. Clinical reactivity vs sensitization was more common in topical coconut users (2-fold) (P = .02). Although not statistically significant, there was a trend toward more coconut allergy vs sensitization in Asian and African American patients. The probability of allergy with positive SPT result was approximately 50% and with sIgE was approximately 60%. At an SPT of 9 mm wheal or sIgE of 58 kU of allergen/L, there is a 95% probability of reaction. Cosensitization with tree nuts, legumes, and seeds was common. Macadamia nut had the strongest correlation with coconut (r = 0.81, P < .001, n = 101). CONCLUSION: Although the rate of reactivity to coconut in sensitized individuals is low, half of the reactions from consumption met the criteria for anaphylaxis. Clinicians should be aware of the spectrum of reactions and diagnostic use of sIgE and SPT.