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.

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.

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.

Resolution of eicosanoid/cytokine storm prevents carcinogen and inflammation-initiated hepatocellular cancer progression.

Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an "eicosanoid and cytokine storm." AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP, CHOP, and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.

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.

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.

Management of Atopic Dermatitis in Children Younger Than Two Years of Age by Community Pediatricians: A Survey and Chart Review.

OBJECTIVES: To characterize primary care providers' (PCPs) practice patterns for atopic dermatitis (AD) in children <2 years old and determine the need for AD guidelines for PCPs focused on this age group. STUDY DESIGN: This is a mixed-methods study consisting of a survey and a retrospective medical record review of PCP practices in the Chicago metropolitan area. The survey was analyzed using both quantitative and qualitative methods. RESULTS: In the survey (n = 52 respondents), PCPs reported management of AD is different in children <2 years compared with older children (88%). They were more likely to refer to a specialist (65%) and less likely to use high-potency topical corticosteroids (64%). In the chart review, PCP visits for children 2-5 years old (n = 50 914) vs those <2 years old (n = 71 913) for AD, older children had medium- and high-potency topical corticosteroids prescribed more frequently than younger children (0.66% vs 0.37%, P < .01 and .15% vs 0.05%, P < .01, respectively). In the subset of children <2 years of age who also were evaluated by a specialist (n = 109), medium- and high-potency topical corticosteroids were prescribed disproportionately at visits to providers in dermatology (57%) vs allergy (30%) vs pediatrics (15%) (P < .01). PCPs suggested that guidelines for this age group should include recommendations for preferred corticosteroids (39%), allergy management (35%), referral criteria (22%), and assessment of disease severity (11%). CONCLUSIONS: PCP management of AD in children <2 years is different from older children, with possible underuse of medium/high-potency topical corticosteroids. Clear guidelines for this age group are needed.

Product of Investigator Global Assessment and Body Surface Area (IGAxBSA): A practice-friendly alternative to the Eczema Area and Severity Index to assess atopic dermatitis severity in children.

BACKGROUND: Accurately documenting pediatric atopic dermatitis (AD) severity is important, but research tools, such as Eczema Area and Severity Index (EASI), are too time consuming for clinical settings. Product of the Physician Global Assessment and affected percentage of body surface area (PGA×BSA) is a new, rapid measure of psoriasis severity. OBJECTIVE: To evaluate an Investigator Global Assessment and body surface area product (IGA×BSA) as an easy-to-use severity measure for pediatric AD. METHODS: Patient-reported and objective disease severity measures were collected from 195 caretaker/child dyads (child age range, 5-17 years) with almost clear (Validated Investigator Global Assessment for AD [vIGA] of 1) to severe (vIGA of 4) AD. Data were assessed with Spearman coefficients and plots. Severity strata were proposed by using an anchoring approach based on the EASI. RESULTS: IGA×BSA correlates better with the EASI than IGA alone (r = 0.924 vs r = 0.757, P < .001). Bland-Altman plot indicates high and consistent agreement between IGA×BSA and the EASI. Suggested severity strata for IGA×BSA are 0-30, mild; 30.1-130, moderate; and 130.1-400, severe (κ = 0.760). LIMITATIONS: The patient cohort was predominantly from the midwestern United States. CONCLUSIONS: IGA×BSA (using the vIGA) is a simple measure that correlates well with the EASI in patients with mild to severe pediatric AD. Future work is needed to affirm reliability across IGA scales and responsiveness to change.

Neurocognitive function in moderate-severe pediatric atopic dermatitis: A case-control study.

BACKGROUND/OBJECTIVES: Epidemiological studies have shown an increased prevalence of attention deficit hyperactivity disorder (ADHD) in children with atopic dermatitis (AD), but many of the features of ADHD may occur as a result of the poor sleep and itch distraction associated with AD. METHODS: A case-control study was performed in children aged 6-17 years with moderate/severe AD compared with age-/sex-matched healthy controls. Participants were screened for ADHD using Vanderbilt assessments. RESULTS: Seventeen patients with AD and 18 controls completed the study. Two children with AD (11.7%) and one control (5.56%) met screening criteria for ADHD via parent-completed Vanderbilt assessments; AD patients were not significantly more likely to screen positive for ADHD (P = 0.47), or comorbid behavior disorders (P = 0.23). However, AD patients were more likely than controls to exhibit ADHD-associated behaviors, most significantly inattention. CONCLUSIONS: Our AD cohort did not have a significantly increased prevalence of ADHD. Certain neurocognitive symptoms are increased in children with moderate-to-severe AD compared to controls.

Systematic Review and Meta-analysis Comparing Topical Corticosteroids With Vehicle/Moisturizer in Childhood Atopic Dermatitis.

PROBLEM: To determine the safety and efficacy of topical corticosteroid versus vehicle/moisturizer in children under 2 years old (<2 y). ELIGIBILITY CRITERIA: A systematic review and meta-analysis searching PubMed MEDLINE, Embase, Web of Science, Cochrane Database of Controlled Trials, Cochrane Database of Systematic Reviews, DARE, NHS Economic Evaluation, CINAHL, GREAT, and Clinicaltrials.gov. We selected randomized controlled trials (RCTs) comparing topical corticosteroids to vehicle/moisturizer and included children <2 y. Two authors extracted data. SAMPLE: Only one study limited analyses to children <2 y, so our review included participants older than 2 years. Twelve RCTs were included with 2224 participants. Ten studies were industry-sponsored. RESULTS: The proportion of responders to topical corticosteroid across studies was 0.65 (95% CI, 0.54-0.74), as compared to vehicle/moisturizer 0.32 (95% confidence interval (CI), 0.20-0.48). The proportion of adverse events were similar between groups (topical steroids 0.17 (95% CI, 0.08-0.33) vs. vehicle/moisturizer 0.12 (CI 0.02-0.42)). High heterogeneity in treatment response occurred across studies that could not be explained by potential moderators. Mild adrenal suppression occurred in 4 of 157 measured participants (3%) receiving topical corticosteroids. Limitations include the few RCTs on this topic, the inclusion of participants >2 y and outcome measures and reporting methods rarely met CONSORT guidelines. CONCLUSIONS: Topical corticosteroids trended to being more effective and equally safe to vehicle/moisturizers, but generalizability is limited given the dearth of well-designed studies focused on children <2 y. Adverse events from vehicle/moisturizer may be greater than topical corticosteroid due to under treatment. IMPLICATIONS: Further work is needed in this age group.

Sleep disturbance in children with moderate/severe atopic dermatitis: A case-control study.

BACKGROUND: Sleep is disturbed in 60% of children with atopic dermatitis (AD). OBJECTIVE: To characterize sleep in a cohort of children with moderate-to-severe AD and determine methods for assessment of sleep disturbance. METHODS: A case-control study compared children age 6 to 17 years who have moderate-to-severe AD with age- and sex-matched healthy controls. Participants wore actigraphy watches and completed sleep- and disease-specific questionnaires. RESULTS: Nineteen patients with AD and 19 controls completed the study. The patients with AD experienced wake after sleep onset (WASO) for 103 plus or minus 55 minutes as compared with 50 plus or minus 27 minutes in the controls (P < .01). They had a higher frequency of restless sleep, daytime sleepiness, difficulty falling back to sleep at night, and teacher-reported daytime sleepiness. Disease severity correlated well with WASO (total SCORing Atopic Dermatitis score: r = 0.61, P < .01; objective SCORing Atopic Dermatitis score: r = 0.58, P = .01; and Eczema Area and Severity Index: r = 0.68, P < .01). The Children's Dermatology Life Quality Index sleep question correlated with WASO (r = 0.52, P = .03), but self-reported itch severity did not (r = 0.28, P = .30). LIMITATIONS: The study cohort was small. CONCLUSION: Children with moderate-to-severe AD experience more WASO and lower sleep efficiency than healthy controls but similar bedtime and wake time, sleep duration, and sleep onset latency.

Diurnal variations in subcutaneous allergen immunotherapy reactions.

BACKGROUND: Circadian rhythms underlie many immune responses and allergic diseases. Subcutaneous immunotherapy (SCIT) can result in adverse reactions; however, it is unclear whether such reactions have a diurnal pattern. OBJECTIVE: To assess whether the timing of SCIT affects the rate of adverse reactions. METHODS: This study was a retrospective medical record review of adult patients (n = 289) who received SCIT at the Northwestern Medical Faculty Foundation, Chicago, Illinois, during a 10-year period (2004-2014). Injections were given in the outpatient setting. There were a total of 17,457 injections with 574 reactions. Covariates included age, sex, median income, asthma status, vial contents, number of injections, and previous immunotherapy reactions. Logistical regression was used to calculate the odds of having a reaction with time of SCIT administration as the primary determinate. RESULTS: Immunotherapy reactions occurred more frequently after afternoon or evening (pm) injections (328/8721 = 3.8%) vs morning (am) injections (246/8736 = 2.8%), (χ2 = 12.26, P < .01). Systemic reactions, defined as World Allergy Organization grade 1 or higher, did not have diurnal variation (59/8721 = 0.67% for pm vs am 56/8736 = 0.64% for morning; χ2 = 0.08; P = .77). pm injections resulted in higher odds of reaction compared with am injection in a fully adjusted logistic regression model (odds ratio = 1.43; 95% confidence interval, 1.20-1.70; P < .01). When considering time as 4 categories, the highest odds of reaction were noted for the period from 15:01 to 17:30 (odds ratio, 1.55; 95% confidence interval, 1.21-2.00; P < .01). CONCLUSION: pm injections of SCIT are associated with increased cutaneous reaction rates when compared with am injections. In patients experiencing bothersome local reactions, it may be beneficial to administer SCIT in the morning.

Sensitization to mouse and cockroach allergens and asthma morbidity in urban minority youth: Genes-environments and Admixture in Latino American (GALA-II) and Study of African-Americans, Asthma, Genes, and Environments (SAGE-II).

BACKGROUND: Pest allergen sensitization is associated with asthma morbidity in urban youth but minimally explored in Latino populations. Specifically, the effect of mouse sensitization on the risk of asthma exacerbation has been unexplored in Latino subgroups. OBJECTIVE: To evaluate whether pest allergen sensitization is a predictor of asthma exacerbations and poor asthma control in urban minority children with asthma. METHODS: Latino and African American children (8-21 years old) with asthma were recruited from 4 sites across the United States. Logistic regression models evaluated the association of mouse or cockroach sensitization with asthma-related acute care visits or hospitalizations. RESULTS: A total of 1,992 children with asthma in the Genes-environments and Admixture in Latino American (GALA-II) and Study of African-Americans, Asthma, Genes, and Environments (SAGE-II) cohorts were studied. Asthmatic children from New York had the highest rate of pest allergen sensitization (42% mouse, 56% cockroach), with the lowest rate in San Francisco (4% mouse, 8% cockroach). Mouse sensitization, more than cockroach, was associated with increased odds of acute care visits (adjusted odds ratio [aOR], 1.47; 95% CI, 1.07-2.03) or hospitalizations (aOR, 3.07; 95% CI, 1.81-5.18), even after controlling for self-reported race and site of recruitment. In stratified analyses, Mexican youth sensitized to mouse allergen did not have higher odds of asthma exacerbation. Other Latino and Puerto Rican youth sensitized to mouse had higher odds of hospitalization for asthma (aORs, 4.57 [95% CI, 1.86-11.22] and 10.01 [95% CI, 1.77-56.6], respectively) but not emergency department visits. CONCLUSION: Pest allergen sensitization is associated with a higher odds of asthma exacerbations in urban minority youth. Puerto Rican and Other Latino youth sensitized to mouse were more likely to have asthma-related hospitalizations than Mexican youth.

Nocturnal eczema: Review of sleep and circadian rhythms in children with atopic dermatitis and future research directions.

Children with atopic dermatitis (AD) experience significant sleep disruption, and clinically, the disease is noted to worsen in a circadian manner at night. Epidemiologic findings highlight many negative consequences of AD, such as impaired linear growth, which is uniquely related to disturbed sleep. Clinical guidelines currently recommend assessing sleep in patients with AD as a crucial parameter of disease control with appropriate treatment. In this review we describe our current understanding of the roles of sleep cycles and circadian rhythms in the nighttime exacerbation of AD (nocturnal eczema). We present a schematic to explain the mechanism of nocturnal eczema. Treatment options for sleep disturbance and future directions for research are discussed in the context of AD.