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Introduction This paper outlines the study protocol for the Dutch Young People (YP) Face IT Study. Adolescents with a visible difference (ie, disfigurement) often experience challenging social situations such as being stared at, receiving unwanted questions or being teased. As a consequence, some of these adolescents experience adverse psychosocial outcomes and appearance-related distress. To address this appearance-related distress, an online psychotherapeutic intervention, YP Face IT, has been developed. YP Face IT uses social interaction skills training and cognitive-behavioural therapy. The Dutch YP Face IT Study tests whether this intervention is effective in reducing social anxiety and improving body esteem. Methods and analysis Participants are adolescents aged 12-18 with a visible difference and experiencing appearance-related distress. In this two-armed randomised controlled trial, 224 adol

Genital lichen sclerosus (LS), a chronic noninfectious dermatosis, is not rare in pediatric dermatology. The histopathological diagnosis in children and adults in both genital and nongenital LS is considered to be the same and encompasses a broad range of possible characteristics. Clinical manifestations and treatment options of genital LS in children are different depending on gender. The vast majority of boys are treated with circumcision, making for a larger amount of information on the histopathology of genital LS in boys, whereas substantial information on the histopathology of juvenile vulvar LS is lacking. In girls, vulvar LS almost always persists beyond puberty and, therefore, presents a particular challenge to clinicians and cause for concern for the patient. Vulvar LS in childhood and adolescence (juveniles) is underreported, and there are uncertainties with regard to the long-term course of the disease when it occurs at an age when the vulva is still developing. The present study investigates biopsie

Het menselijk lichaam is gekoloniseerd met een diversiteit aan micro-organismen, waaronder bacteriën, virussen, schimmels en gisten. Het microbioom bevindt zich op verschillende plekken van het lichaam, waarbij de samenstelling aan micro-organismen uniek is per locatie. De micro-organismen bevinden zich niet alleen aan de oppervlakte, maar ook in het lichaam waar ze interacties aangaan met humane cellen en een belangrijke rol in fysiologische processen hebben. De afgelopen jaren is er toenemende interesse in het humane microbioom in relatie tot verschillende ziektes, waaronder constitutioneel eczeem (CE).

Background: Comel-Netherton syndrome (NS) is a rare autosomal disease, characterized by severe skin disease, hair shaft defects, atopic diathesis, and increased susceptibility for skin infections. Since patients with NS suffer from recurrent infections, it has been hypothesized that an underlying immunodeficiency attributes to this. Here, we studied clinical and immunological characteristics of the cohort of NS patients in the Netherlands in order to identify whether potential immunodeficiencies result in the increased risk of infectious complications. Methods: Phenotypes were scored for severity of skin condition, specific hair shaft defects, atopy, and recurrent infections. Patients’ blood samples were collected for quantification of serum immunoglobulin (Ig) levels, specific antibodies against Streptococcus pneumoniae, and allergen-specific IgE, as well as detailed immunophenotyping of blood leukocyte and lymphocyte subsets by flow cytometry. Results: A total of 14 patients were included with age range 3-46 years and varying degrees of skin involvement. All patients presented with atopic symptoms (food allergy, n = 13; hay fever, n = 10; asthma, n = 7). Recurrent skin infections were common, particularly in childhood (n = 12). Low levels of specific antibodies against S pneumoniae were found in 10 of 11 evaluated patients. Detailed immunological analysis was performed on 9 adult patients. Absolute numbers of lymphocyte subsets and serum immunoglobulin levels were all within normal ranges. Conclusion: Multidisciplinary evaluation of our national cohort showed no evidence for a severe, clinically relevant systemic immunodeficiency. Therefore, we conclude that in Dutch NS patients the increased risk of infections most likely results from the skin barrier disruption and that increased allergen penetration predisposes to allergic sensitization.

Background: The skin microbiome, characterized by an overgrowth of Staphylococcus aureus, plays an important role in the pathogenesis of atopic dermatitis (AD). Multidisciplinary treatment in alpine climate is known for its positive effect on disease severity in children with AD and can result in a different immune response compared with moderate maritime climate. However, the effect on the composition of the skin microbiome in AD is unknown. Objective: To determine the effect of treatment in alpine climate and moderate maritime climate on the microbiome for lesional and non-lesional skin in children with difficult to treat AD. Results: Alpine climate treatment led to a significant change in the microbiota on lesional skin, whereas no significant change was found after moderate maritime climate. On both lesional and non-lesional skin, we observed a significant increase in Shannon diversity and a significant decrease in both Staphylococcus abundance and S aureus load after alpine climate treatment. The decrease in S aureus was significantly larger on lesional skin following alpine climate treatment compared with moderate maritime climate treatment. Staphylococcus epidermidis load was stable over time. Conclusions and clinical relevance: Alpine climate treatment leads to significant changes in the composition of the skin microbiome in children with AD, mainly caused by a reduction in the Staphylococcus genus. This study shows new perspectives in the potential mode of action for therapies in AD.

Background: Having large congenital melanocytic naevi (CMN) is associated with a psychosocial burden on patients and their parents because of its remarkable appearance and the extra care it may require. Large CMN also pose an increased risk of malignant melanoma or neurocutaneous melanosis. There is a lack of international consensus on what important outcome domains to measure in relation to treatment. This makes it difficult to compare options, to properly inform patients and their parents, and to set up treatment policy for CMN. Therefore, we aim to develop a core outcome set (COS), i.e. the minimum set of outcomes that are recommended to be measured and reported in all clinical trials of a specific health condition. This COS can be used in the follow-up of CMN patients with or without treatment, in clinical research and practice. Methods: In the Outcomes for Congenital Melanocytic Nevi (OCOMEN) projects, we follow the recommendations from the Core Outcome Measures in Effectiveness Trials (COMET) initiative and the Cochrane Skin Core Outcomes Set Initiative (CS-COUSIN). This project entails the following: (i) a systematic review to identify the previous reported outcomes in literature; (ii) focus groups with national and international patients and parents to identify patient-important outcomes; (iii) classification of outcomes into outcome domains; (iv) e-Delphi surveys in which stakeholders (patients/parents and professionals) can rate the importance of domains and outcomes; and (v) an online consensus meeting to finalize the core outcome domains of the COS. Results: The results will be disseminated by means of publication in a leading journal and presentations in international meetings or conferences. We engage international experts in CMN, both patients and professionals, to ensure the international utility and applicability of the COS.

Background Eczema phenotypes and emotional and behavioural problems are highly prevalent in childhood, but their mutual relationship is not fully clear. Objectives To examine the associations of eczema phenotypes with school-age emotional and behavioural problems, and the bidirectional associations of eczema and emotional and behavioural problems from birth until 10 years. Methods This study among 5265 individuals was embedded in a prospective population-based cohort study. Never, early transient, mid-transient, late transient and persistent eczema phenotypes were identified based on parent-reported, physician-diagnosed eczema from age 6 months until 10 years. Emotional (internalizing) and behavioural (externalizing) problems were measured repeatedly using the Child Behavior Checklist from age 15 to 10 years. Cross-lagged models were applied for bidirectional analyses. Results All eczema phenotypes were associated with more internalizing problems and attention problems at age 10 years, compared with never having eczema: range of Z-score differences 014 [95% confidence interval (CI) 001–027] to 039 (95% CI 018–060). Children with early transient eczema had more aggressive behaviour symptoms at age 10 years (Z = 016, 95% CI 005–027). Bidirectional analysis showed that eczema at 0–2 years was associated with more internalizing and externalizing problems at ages 3–6 and 10 years, while, inversely, only internalizing problems at 0–2 years were associated with an increased risk of eczema at age 10 years. Conclusions Eczema phenotypes are very modestly associated with more somatic symptoms and attention problems at school age. Early transient eczema is associated with more aggressive behaviour symptoms. Directional effects seem to occur from early-life eczema to later-life internalizing and externalizing problems, rather than the reverse.

Background: Eczema phenotypes and emotional and behavioural problems are highly prevalent in childhood, but their mutual relationship is not fully clear. Objectives: To examine the associations of eczema phenotypes with school-age emotional and behavioural problems, and the bidirectional associations of eczema and emotional and behavioural problems from birth until 10 years. Methods: This study among 5265 individuals was embedded in a prospective population-based cohort study. Never, early transient, mid-transient, late transient and persistent eczema phenotypes were identified based on parent-reported, physician-diagnosed eczema from age 6 months until 10 years. Emotional (internalizing) and behavioural (externalizing) problems were measured repeatedly using the Child Behavior Checklist from age 1·5 to 10 years. Cross-lagged models were applied for bidirectional analyses. Results: All eczema phenotypes were associated with more internalizing problems and attention problems at age 10 years, compared with never having eczema: range of Z-score differences 0·14 [95% confidence interval (CI) 0·01–0·27] to 0·39 (9

The prevalence of allergic diseases in children is markedly increasing to epidemic proportions. The aim of this study is to describe the presence and examine associated parental and child characteristics of allergic sensitization and

Background: Childhood eczema is variable in onset and persistence. Objectives: To identify eczema phenotypes during childhood, and their associations with early-life environmental and genetic factors. Methods: In this study of 5297 children from a multiethnic population-based prospective cohort study, phenotypes based on parent-reported physician-diagnosed ec

Introduction Topical corticosteroids (TCS) of different potencies are the main treatment to control atopic dermatitis (AD). The Dutch guideline on AD for general practitioners (GPs) recommends a stepwise approach in which treatment steps are tailored to the severity of the disease, starting with the lowest possible potency of TCS. However, it remains unclear whether the recommended stepwise approach is most efficient. This randomised open-label controlled trial aims to determine whether a potent TCS is more effective than a low-potency TCS in the initial treatment of children with a moderate flare-up of AD in primary care. In the observational cohort, the overall aim is to determine the frequency, burden and determinants of flare-ups of AD during follow-up. Methods and analysis The study is an observational cohort study with an embedded pragmatic randomised controlled, open-label trial. Eligible are patients diagnosed with AD (aged 12 weeks to 18 years) who visited the GP for AD or received repeated prescriptions for AD in the previous 12 months; follow-up of the cohort is 1 year. Children are enrolled in the trial if they have a flare-up of AD during follow-up in the cohort. Eligible children are randomised to the intervention group (with a potent TCS once daily) or to the GP guideline group (with a low potency TCS once daily). Primary outcome is the difference in average subjective disease severity over 24 weeks follow-up in the trial, measured with the patient-oriented eczema measure. As secondary outcome, the Eczema Area and Severity Index is measured. Ethics and dissemination This study tests the hypothesis that immediate treatment with a potent TCS during a flare-up of AD leads to faster and more efficacious results as compared with starting with a TCS with low potency with less overall use of TCS. The study protocol is approved by the Medical Ethics Committee (MEC) of the Erasmus Medical Center Rotterdam, the Netherlands (MEC-2017-328). The results of the stu

Background: The atopic syndrome consists of heterogeneous manifestations, in which multiple associated genetic loci have recently been identified. It is hypothesized that immune dysregulation plays a role in the pathogenesis. In primary immunodeficiency diseases (PIDs), which are often monogenic immunodysregulation disorders, the atopic syndrome is a frequently occurring comorbidity. Based on the genetic defects in PIDs, novel gene/pathway-targeted therapies have been evaluated, which could be relevant in the atopic syndrome as well. Therefore, we aimed to define subclasses within the atopic syndrome based on the expression profiles of immune cell lineages of healthy mice. Methods: Overlap between known atopy-related genes as described in the Human Gene Mutation Database and disease-causing genes of monogenic PIDs was evaluated. Clusters of atopy-related genes were based on the overlap in their co-expressed genes using the gene expression profiles of immune cell lineages of healthy mice from the Immunological Genome Project. We analyzed pathways involved in the atopic syndrome using Ingenuity Pathway Analysis. Results: Twenty-two (5.3%) genes were overlapping between the atopy-related genes (n = 160) and PID-related genes (n = 278). We identified seven distinct clusters of atopy-related genes. Functional pathway analysis of all atopy-related genes showed relevance of T helper cell-mediated pathways. Conclusions: This study shows a model to define clusters within the atopic syndrome based on gene expression profiles of immune cell lineages. Our results support the hypothesis that both genetic mechanisms and immune dysregulation play a role in the pathogenesis. It also opens up the possibility for novel therapeutic targets and a more tailored approach towards personalized medicine.

Background: Exposure to microbes may be important in the development of atopic disease. Atopic diseases have been associated with specific characteristics of the intestinal microbiome. The link between intestinal microbiota and food allergy has rarely been studied, and the gold standard for diagnosing food allergy (double-blind placebo-controlled food challenge [DBPCFC]) has seldom been used. We aimed to distinguish fecal microbial signatures for food allergy in children with atopic dermatitis (AD). Methods: Pediatric patients with AD, with and without food allergy, were included in this cross-sectional observational pilot study. AD was diagnosed according to the UK Working Party criteria. Food allergy was defined as a positive DBPCFC or a convincing clinical history, in combination with sensitization to the relevant food allergen. Fecal samples were analyzed using 16S rRNA microbial analysis. Microbial signature species, discriminating between the presence and absence food allergy, were selected by elastic net regression. Results: Eighty-two children with AD (39 girls) with a median age of 2.5 years, and 20 of whom were diagnosed with food allergy, provided fecal samples. Food allergy to peanut and cow's milk was the most common. Six bacterial species from the fecal microbiome were identified, that, when combined, distinguished between children with and without food allergy: Bifidobacterium breve, Bifidobacterium pseudocatenulatum, Bifidobacterium adolescentis, Escherichia coli, Faecalibacterium prausnitzii, and Akkermansia muciniphila (AUC 0.83, sensitivity 0.77, specificity 0.80). Conclusions: In this pilot study, we identified a microbial signature in children with AD that discriminates between the absence and presence of food allergy. Future studies are needed to confirm our findings.

Background: Netherton syndrome is a rare severe skin disease. Clinical experience showed considerable psychosocial burdens among Netherton syndrome patients/families. Their (neuro)psychological functioning has never been investigated. Objective: To investigate neuropsychological/psychosocial functioning of Netherton syndrome patients and parents. Methods: A total of 12 Netherton syndrome patients and/or parents completed neuropsychological tests, semi-structured-interviews, and psychological-questionnaires. Results: Intelligence results showed disharmonic profiles, with below-average scores on processing speed. Neuropsychological problems and unfavorable outcomes on health-related quality of life, illness-appearance-related problems, and negative social consequences among patients/parents were found. Psychopathological (emotional) problems were reported; stigmatization, bullying was common among Netherton syndrome patients. Conclusion: Compared with normative data, Netherton syndrome patients showed neuropsychological and psychosocial problems. Standard follow-up is necessary to identify problems at early stage.

Early-life nutrition is an important modifiable determinant in the development of a child’s immune system, and may thereby influence the risk of allergic sensitization and atopic diseases. However, associations between overall dietary patterns and atopic diseases in childhood remain unclear. We examined associations of diet quality in early life with allergic sensitization, self-reported physician-diagnosed inhalant and food allergies, eczema, and asthma among 5225 children participating in a population-based cohort in the Netherlands. Diet was assessed during pregnancy, infancy, and childhood using validated food-frequency questionnaires. We calculated food-based diet quality scores (0–10 or 0–15), reflecting adherence to dietary guidelines. At age 10 years, allergic sensitization was assessed with skin prick tests. Information on physician-diagnosed inhalant and food allergies, eczema, and asthma was obtained with questionnaires. We observed no associations between diet quality during pregnancy and allergic sensitization (odds ratio (OR) = 1.05 per point in the diet score, 95% confidence interval (CI): 0.99, 1.13), allergies (0.96, 95% CI: 0.88, 1.04), eczema (0.99, 95% CI: 0.93, 1.06), or asthma (0.93, 95% CI: 0.85, 1.03) in childhood. Also, diet quality in infancy or childhood were not associated with atopic outcomes in childhood. Our findings do not support our hypothesis that a healthy dietary pattern in early life is associated with a lower risk of allergic sensitization or atopic diseases in childhood.

Background: Atopic dermatitis (AD) is associated with reduced skin microbial diversity and overgrowth of Staphylococcus (S.) aureus. However, the importance of S. aureus colonisation in the complex pathogenesis remains unclear and studies on the effect of anti-staphylococcal therapy in non-infected AD show contradictory results. Long-term interventions against S. aureus might be needed to restore the microbial balance, but carry the risk of bacterial resistance induction. Staphefekt, an engineered bacteriophage endolysin, specifically kills S. aureus leaving other skin commensals unharmed. Bacterial resistance towards endolysins has not been reported, nor is it expected, which allows us to study its effect as long-term anti-staphylococcal treatment in non-infected AD. Methods: This is a multi-centre, placebo-controlled, double-blinded and randomized superiority trial with a parallel group design. A total of 100 participants, aged 18 years or older, diagnosed with moderate to severe AD and using a topical corticosteroid in the weeks before enrolment are included in the study. The study is executed in the Erasmus MC University Medical Centre Rotterdam in collaboration with the Havenziekenhuis Rotterdam. After a 2-week run-in period to standardize the corticosteroid use with triamcinolone acetonide 0.1% cream, participants will be randomized to either treatment with Staphefekt in a cetomacrogol-based cream or a placebo for 12 weeks, followed by an 8-week follow-up period. The primary objective is to assess the difference in the need for corticosteroid co-therapy between the Staphefekt and the placebo group, measuring the number of days per week of corticosteroid cream (triamcinolone) use. Secondary outcomes include the difference in use of corticosteroid cream measured in grams, differences in clinical efficacy, quality of life (QoL), microbial composition (includi23ng S. aureus) between the Staphefekt and the placebo group, and the safety and tolerability. Discussion

Staphylococcus aureus plays an important role in skin and soft tissue infections and contributes to the pathophysiology of complex skin disorders such as atopic dermatitis. Bacterial resistance against commonly used antibiotics has increased considerably in the last decades demanding alternative treatment approaches. We present 3 cases where patients with chronic and recurrent S. aureus-related dermatoses were successfully treated with Staphefekt SA.100. Staphefekt SA.100 is a recombinant phage endolysin for topical skin application that specifically targets both methicillin-sensitive and methicillin-resistant S. aureus. As a consequence of its specific mechanism of action, bacterial resistance is unlikely to develop. In our 3 cases, resistance induction was not observed. Our results indicate that targeted treatment with Staphefekt might be an attractive alternative for (long-term) classical antibiotic therapy, and confirmatory randomized controlled trials are warranted to evaluate its clinical efficacy and safety.

Background: The role of timing and diversity of allergenic food introduction in the development of childhood allergic sensitization and atopic diseases is controversial. Objective: To examine whether timing and diversity of allergenic food introduction are associated with allergic sensitization, allergy and eczema in children until age 10 years. Materials and methods: This study among 5,202 children was performed in a population-based prospective cohort. Timing (age 6 months vs. >6 months) and diversity (0, 1, 2 and 3 foods) of allergenic food (cow’s milk, hen’s egg, peanut, tree nuts, soy and gluten) introduction were assessed by questionnaires at ages 6 and 12 months. At age 10 years, inhalant and food allergic sensitization were measured by skin prick tests, and physician-diagnosed inhalant and food allergy by questionnaire. Data on parental-reported physician-diagnosed eczema were obtained from birth until age 10 years. Results: Children introduced to gluten at age 6 months had a decreased risk of eczema (aOR (95% CI): 0.84 (0.72, 0.99)), compared with children introduced to gluten at age >6 months. However, timing of allergenic food introduction was not associated with allergic sensitization or physician-diagnosed allergy. Children introduced to 3 allergenic foods at age 6 months had a decreased risk of physician-diagnosed inhalant allergy (0.64 (0.42, 0.98)), compared with children not introduced to any allergenic food at age 6 months. However, diversity of allergenic food introduction was not associated with allergic sensitization, physician-diagnosed food allergy or eczema. Conclusion: Neither timing nor diversity of allergenic food introduction was consistently associated

Staphylococcus aureus might amplify symptoms in chronic inflammatory skin diseases. This study evaluates skin and mucosal colonization with S. aureus in patients with psoriasis, acne and rosacea. A systematic literature search was conducted. Both odds ratios (OR) for colonization in patients versus controls and the prevalence of colonization in patients are reported. Fifteen articles about psoriasis and 13 about acne (12 having a control group) were included. No study in rosacea met our inclusion criteria. For psoriasis, one study out of three controlled studies showed increased skin colonization (OR 18.86; 95 % confidence interval [CI] 2.20–161.99). Three out of the five studies that reported on nasal colonization showed significant ORs varying from 1.73 (95 % CI 1.16–2.58) to 14.64 (95 % CI 2.82–75.95). For acne one of the three studies that evaluated skin colonization reported a significant OR of 4.16 (95 % CI 1.74–9.94). A relation between nasal colonization and acne was not found. Limitations in study design and low sample sizes should be taken into consideration when interpreting the results. Colonisation with S. aureus seems to be increased in patients with psoriasis. This bacterial species, known for its potential to induce long-lasting inflammation, might be involved in psoriasis pathogenesis. Information on acne is limited. Prospective controlled studies should further investigate the role of S. aureus in chronic inflammatory skin diseases.

Background: About 10 to 20% of children in West European countries have atopic dermatitis (AD), often as part of the atopic syndrome. The full atopic syndrome also consists of allergic asthma, allergic rhinitis and food allergy. Treatment approaches for atopic dermatitis and asthma include intermittent anti-inflammatory therapy with corticosteroids, health education and self-management training. However, symptoms persist in a subgroup of patients. Several observational studies have shown significant improvement in clinical symptoms in children and adults with atopic dermatitis or asthma after treatment at high altitude, but evidence on the efficacy when compared to treatment at sea level is still lacking.Methods/Design: This study is a pragmatic randomized controlled trial for children with moderate to severe AD within the atopic syndrome. Patients are eligible for enrolment in t

EHealth potentially enhances quality of care and may reduce health care costs. However, a review of systematic reviews published in 2010 concluded that high-quality evidence on the benefits of eHealth interventions was still lacking. Objective: We conducted a systematic review of systematic reviews and meta-analyses on the effectiveness/cost-effectiveness of eHealth interventions in patients with somatic diseases to analyze whether, and to what possible extent, the outcome of recent research supports or differs from previous conclusions. Methods: Literature searches were performed in PubMed, EMBASE, The Cochrane Library, and Scopus for systematic reviews and meta-analyses on eHealth interventions published between August 2009 and December 2012. Articles were screened for relevance based on preset inclusion and exclusion criteria. Citations of residual articles were screened for additional literature. Included papers were critically appraised using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement before data were extracted. Based on conclusions drawn by the authors of the included articles, reviews and meta-analyses were divided into 1 of 3 groups: suitable, promising, or limited evidence on effectiveness/cost-effectiveness. Cases of uncertainty were resolved by consensus discussion. Effect sizes were extracted from papers that included a meta-analysis. To compare our results with previous findings, a trend analysis was performed. Results: Our literature searches yielded 31 eligible reviews, of which 20 (65%) reported on costs. Seven papers (23%) concluded that eHealth is effective/cost-effective, 13 (42%) underlined that evidence is promising, and others found limited or inconsistent proof. Methodological quality of the included reviews and meta-analyses was generally considered high. Trend analysis showed a considerable accumulation of literature on eHealth. However, a similar percentage of papers concluded that eHealth is e