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The relationship between infant skin health and food allergy pathogenesis is the focus of intense research activity, on the basis that interventions to improve infant skin health may potentially lead to the prevention of food allergy. Current evidence does not provide conclusive findings on the mechanisms of food allergy development but does support the possibility that food allergy develops through transcutaneous sensitisation to allergenic peptides. In this article, we review the evidence for this model of food allergy development, assess strategies currently being tested for prevention of food allergy through cutaneous interventions, and identify key knowledge gaps which might be explored in future work. Keywords: Atopic dermatitis, Food allergy, Infant, Prevention, Skin barrier

Background Atopic eczema is a common childhood skin problem linked with asthma, food allergy and allergic rhinitis that impairs quality of life. Objectives To determine whether advising parents to apply daily emollients in the first year can prevent eczema and/or other atopic diseases in high-risk children. Design A United Kingdom, multicentre, pragmatic, two-arm, parallel-group randomised controlled prevention trial with follow-up to 5 years. Setting Twelve secondary and four primary care centres. Participants Healthy infants (at least 37 weeks’ gestation) at high risk of developing eczema, screened and consented during the third trimester or post delivery. Interventions Infants were randomised (1 : 1) within 21 days of birth to apply emollient (Doublebase Gel®; Dermal Laboratories Ltd, Hitchin, UK or Diprobase Cream®) daily to the whole body (excluding scalp) for the first year, plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). Families were not blinded to allocation. Main outcome measures Primary outcome was eczema diagnosis in the last year at age 2 years, as defined by the UK Working Party refinement of the Hanifin and Rajka diagnostic criteria, assessed by research nurses blinded to allocation. Secondary outcomes up to age 2 years included other eczema definitions, time to onset and severity of eczema, allergic rhinitis, wheezing, allergic sensitisation, food allergy, safety (skin infections and slippages) and cost-effectiveness. Results One thousand three hundred and ninety-four newborns were randomised between November 2014 and November 2016; 693 emollient and 701 control. Adherence in the emollient group was 88% (466/532), 82% (427/519) and 74% (375/506) at 3, 6 and 12 months. At 2 years, eczema was present in 139/598 (23%) in the emollient group and 150/612 (25%) in controls (adjusted relative risk 0.95, 95% confidence interval 0.78 to 1.16; p = 0.61 and adjusted risk difference −1.2%, 95% confidence interval −5.9% to 3.6%). Other eczema definitions supported the primary analysis. Food allergy (milk, egg, peanut) was present in 41/547 (7.5%) in the emollient group versus 29/568 (5.1%) in controls (adjusted relative risk 1.47, 95% confidence interval 0.93 to 2.33). Mean number of skin infections per child in the first year was 0.23 (standard deviation 0.68) in the emollient group versus 0.15 (standard deviation 0.46) in controls; adjusted incidence rate ratio 1.55, 95% confidence interval 1.15 to 2.09. The adjusted incremental cost per percentage decrease in risk of eczema at 2 years was £5337 (£7281 unadjusted). No difference between the groups in eczema or other atopic diseases was observed during follow-up to age 5 years via parental questionnaires. Limitations Two emollient types were used which could have had different effects. The median time for starting emollients was 11 days after birth. Some contamination occurred in the control group (< 20%). Participating families were unblinded and reported on some outcomes. Conclusions We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children. Emollient use was associated with a higher risk of skin infections and a possible increase in food allergy. Emollient use is unlikely to be considered cost-effective in this context. Future research To pool similar studies in an individual patient data meta-analysis. Trial registration This trial is registered as ISRCTN21528841. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information. Plain language summary Eczema is a troublesome itchy skin condition affecting 1 in 5 children and 1 in 10 UK adults. There is no cure and affected children are more likely to develop food allergies. We wanted to see if we could prevent eczema by protecting the skin of babies at higher risk of developing eczema (with an immediate relative with eczema, asthma or hay fever) with moisturisers used to treat dry skin. Previous research suggested that protecting the skin barrier might also prevent food allergy. One thousand three hundred and ninety-four families took part in a study; half of them were asked to apply moisturiser every day to their newborn baby for the first year and half to look after their baby’s skin in the normal way. At the age of 2 years, we did not see any difference in how common eczema was between the two groups: 23% had eczema in the moisturiser group and 25% in the normal care group. It did not matter how we defined eczema – whether examined by a researcher or parent report. We did not find any differences in related conditions like asthma or hay fever either. We found that children using moisturisers had seen their doctor slightly more often for mild skin infections. There was a hint that food allergy might have been increased in the moisturiser group, but there was not enough data to be sure. We followed up the children to age 5 years, but we still did not find any benefits from using moisturisers in early life. Since this study, other similar research has been done using newer types of moisturisers, but their results are the same. This study shows that using daily moisturisers on healthy babies with a high risk of eczema does not prevent eczema. It is one less thing for busy families to worry about. Scientific summary Background Eczema, also known as atopic eczema (AE) or atopic dermatitis, is a common inflammatory skin disease that typically starts in early life. Eczema affects around 20% of children and 10% of adults in developed countries. Although most cases are mild, moderate to severe disease can have a major impact on the quality of life of an affected child and their family. The main symptom of this systemic inflammatory disease is itching which leads to scratching, bleeding, secondary infection as well as sleep loss and the social stigma of a visible skin disease. Genetic factors such as mutations in the gene encoding filaggrin (FLG) – a protein that is important for maintaining skin barrier function – have been shown to be important in increasing eczema risk, severity and persistence. Epidemiological studies showing that eczema is more common in smaller families, migrant populations and in higher socioeconomic status also suggest that the environment is critically important in determining disease expression. Eczema is closely related to other ‘atopic’ conditions including asthma, hay fever and food allergy. Some evidence suggests that the impaired skin barrier caused by eczema in early life is an important route for the development of food allergy as a result of sensitisation through the skin. Treatment of eczema depends on severity: mild eczema can be treated with emollients (moisturisers) and weak topical corticosteroids. Moderate eczema usually needs potent topical corticosteroids and other anti-inflammatory treatments such as topical tacrolimus, whereas severe eczema is treated by ultraviolet light or systemic treatments including ciclosporin, methotrexate, dupilumab and an emerging pipeline of new biologics. While good progress has been made with treatment, prevention of eczema remains challenging. Strategies include avoidance of allergens (foods and house dust mite) during pregnancy and early life, exclusive breastfeeding, or different timing of introducing solids, but these have not shown convincing preventative effects. Probiotics and prebiotics have shown some benefit, but the exact strain or combination and timing of intervention remain unclear. One previously unexplored eczema prevention strategy is enhancement of the skin barrier in early life. The hypothesis is that enhancing the skin barrier could interrupt an early cascade of inflammatory events that can lead to chronic auto-immune eczema and potentially prevent skin sensitisation to common allergens that can lead to food allergy. Two small pilot studies suggested that protecting the skin of babies who had a first-degree relative with eczema, asthma or hay fever with emollients could prevent the development of eczema in the first year of life. We wanted to see whether daily emollient application for the first year of life in such high-risk babies can prevent eczema and other allergic diseases in a sustained and convincing way by means of a definitive pragmatic randomised controlled trial. Objectives The primary objective was to determine whether advising parents to apply emollient daily for the first year of life could prevent eczema at 2 years of age when compared with standard skin-care advice alone in children at high risk of developing eczema. Secondary objectives included evaluating whether prophylactic use of emollients would delay the onset of eczema or reduce eczema severity when compared to standard skin-care advice, whether any preventive effect at age 2 years was sustained up to age 5 years and to determine the safety and cost-effectiveness of such a strategy. We also sought to determine whether emollients could prevent the development of other associated allergic conditions including food allergy, asthma and hay fever up to the age of 5 years. Methods We conducted a multicentre, pragmatic, two-arm parallel group randomised controlled prevention trial which recruited participants from 12 hospitals and 4 general practices in the UK. Participants were infants of at least 37 weeks’ gestation at high risk of developing eczema defined by having at least one first-degree relative with a parental report of doctor-diagnosed eczema, allergic rhinitis or asthma. Mothers had to be 16 years or older, and the consenting adult had to understand English. We excluded babies with a severe widespread skin condition that would make eczema assessment difficult; a serious health issue that would make it difficult for the family to take part in the trial; or a condition that would make the use of emollient inadvisable. Informed consent was obtained from mothers during pregnancy, or mother, father or guardian post delivery. The intervention group was advised to use one of two study emollients (Doublebase Gel® or Diprobase Cream®) at least once daily to the whole body (excluding the scalp) until the child reached 1 year, plus standard skin-care advice (designated the ‘emollient group’). The control group was advised to use standard skin-care advice only. Standard skin-care guidance, in booklet and video format at the time of randomisation, provided advice to use mild cleansers and shampoos specifically formulated for infants, and to avoid soap, bubble bath and baby wipes, and was given to both groups. Intervention adherence was measured at 3, 6 and 12 months and defined as satisfactory if emollients were applied at least three to four times per week to most of the child’s body. A similar definition was used to define contamination in the control group. The primary outcome was presence of eczema in the last year when the baby was aged 2 years, defined as meeting the United Kingdom Working Party (UKWP) Diagnostic Criteria for AE for children under 4 years. Secondary outcomes encompassed other ways of defining eczema including any parental report of a clinical diagnosis of eczema up to 2 years, parent completion of UKWP criteria at 1 and 2 years, and presence of visible eczema at 2 years recorded by a nurse masked to treatment allocation. Other eczema secondary outcomes included time to onset of eczema (based on first parent report of clinician diagnosis and first topical corticosteroid or immunosuppressant prescription); severity of eczema measured by trained nurses using the Eczema Area and Severity Index at 2 years and parent-reported Patient-Oriented Eczema Measure at 1 and 2 years. Other secondary outcomes included parent-reported wheezing and allergic rhinitis between 1 and 2 years; allergic sensitisation (masked skin prick tests) to milk, egg, peanut, cat dander, grass pollen or dust mite at 2 years; parent-reported food allergy; parental report of clinical diagnosis of food allergy at 1 and 2 years; and allergy to milk, egg or peanut at 2 years confirmed either by oral food challenge or for cases in which no oral food challenge was done, an expert panel of experienced paediatric allergists masked to treatment allocation. The panel decisions were made using an algorithm, validated using data from a previous trial, which incorporates all available data including skin prick test results, previous reaction history, frequency of food ingestion and allergy tests done outside the trial. The main economic outcome measure was incremental cost per percentage decrease in risk of eczema at 2 years in a cost-effectiveness analysis (CEA). Cost–utility analyses using quality-adjusted life-years (QALYs) derived from the proxy Child Health Utility instrument-9 domains (CHU-9D) for the child was also conducted as a secondary analysis. Safety outcomes were parent-reported skin infections (parents were asked what the doctor called the infection) and emollient-related infant slippages during the intervention period (year 1). Tertiary outcomes at 3, 4 and 5 years were to evaluate if emollients in early life could also prevent later-onset allergic diseases including asthma, hay fever and food allergy, and to see whether any early possible benefits of eczema prevention were sustained. Outcomes included parental-reported presence of eczema; severity of eczema; wheezing; allergic rhinitis; food allergy symptoms and clinical diagnoses of asthma, allergic rhinitis and food allergy. Randomisation (1 : 1) within 21 days of birth was performed using computer-generated pseudo-random code with permuted blocks of randomly varying size and concealed from the trial investigators via a web-based randomisation system. Randomisation was stratified by recruiting centre and number of first-degree relatives with eczema, asthma or hay fever (1, 2 or > 2). Research nurses conducting outcome assessments were masked to participant treatment allocation. Families were not masked to the allocated interventions and were reminded not to reveal allocation to research nurses. The trial was powered to detect a relative reduction of 30% in the primary outcome at the 5% significance level (two-sided) with 90% power assuming that 30% of children in the control group would have eczema and 20% attrition, resulting in a sample size of 1282. The target sample size was reached faster than anticipated at which point the Trial Steering Committee permitted that all pregnant mothers who had already consented to the trial could be randomised on the birth of the baby giving a maximum possible sample size of 1400. We analysed participants as randomised regardless of adherence with allocation using available data (i.e. without imputation for missing data) with sensitivity analyses for missing data. The adjusted relative risk (RR) and risk difference for the primary outcome were estimated using generalised estimating equations with the binomial family and log/identity link respectively, with an exchangeable correlation matrix to account for randomisation stratification by centre and number of immediate family members with atopic disease (one, two, or more than two) included as a covariate. A number of planned subgroup analyses for the primary outcome were conducted including according to FLG genotype, to test the hypothesis that FLG null genotype affects response to intensive emollient use from birth. Results One thousand three hundred and ninety-four newborns were randomised between 19 November 2014 and 18 November 2016; 693 to the emollient group and 701 to the control group. Primary outcome data at 2 years were collected for 1210 infants (87%). Unblinding of research nurses prior to skin examination occurred for 12 infants in the intervention group and 6 in the control group. Adherence in the emollient group was 88% (466/532) at 3 months, 82% (427/519) at 6 months and 74% (375/506) at 12 months. In the control group, contamination due to self-directed use of emollients was reported for 18% (82/457), 17% (62/372) and 15% (49/324) at 3, 6 and 12 months, respectively, for infants who did not have a parental report of a doctor diagnosis of eczema. At age 2 years, eczema was present in 139 (23%) of 598 infants in the emollient group and in 150 (25%) of 612 infants in the control group [adjusted RR 0.95, 95% confidence interval (CI) 0.78 to 1.16; p = 0.61; adjusted risk difference −1.2%, 95% CI −5.9% to 3.6%]. All sensitivity analyses conducted, including using multiple imputation for missing primary outcome data, were consistent with the primary analysis. There was no evidence of an interaction effect with allocated group for the primary eczema outcome in any of the subgroup analyses (including FLG genotype). Other eczema definitions supported the results of the primary analysis. Eczema severity and time to onset of eczema were also similar in the two groups. Mean number of skin infections per child in year 1 was 0.23 [standard deviation (SD) 0.68] in the emollient group versus 0.15 (SD 0.46) in the control group; adjusted incidence rate ratio 1.55 (95% CI 1.15 to 2.09). Infant slippage incidents were reported for 15/584 (2.6%) in the emollient group and 11/584 (1.9%) in the control group. Food allergies to milk, egg or peanut at 2 years were confirmed in 41/547 (7.5%) infants in the emollient group and 29/568 (5.1%) in the control group (adjusted RR 1.47, 95% CI 0.93 to 2.33). The largest difference was in the proportion of infants with confirmed food allergy to egg, with an adjusted RR of 1.56 (95% CI 0.92 to 2.65). Results of other measures of food allergy and food sensitisation were similar. The proportion of infants with allergic rhinitis, wheezing and allergic sensitisation to cat dander, grass pollen and dust mite was similar between groups at 2 years. The differences in quality of life (using CHU-9D for the child and EuroQol-5 Dimensions, five-level version for the main carer) between the two groups were very small. Although the emollient intervention period was the first year of life, parents in the emollient group continued to report more frequent moisturiser application through to 5 years than in the control group. By 5 years, 188/608 (31%) parents in the emollient group had reported a clinical diagnosis of eczema in their child since 12 months, compared with 178/631 (28%) in the control group (adjusted RR 1.10, 95% CI 0.93 to 1.30). A diagnosis of food allergy by 5 years was reported for 92/609 (15%) allocated to emollients and 87/632 (14%) allocated to control (adjusted RR 1.11, 95% CI 0.84 to 1.45). Similarly, the percentage of parents reporting that their child had a clinical diagnosis of asthma or allergic rhinitis by 5 years were similar in the two groups. In the complete-case CEA mean cost was £398.23 (SD 1408.39) per child in the emollient group (n = 598) and £312.16 (SD 1105.04) in the control group (n = 610). When intervention use was combined with other health resource use, the adjusted incremental cost was £87.45 (95% CI −54.31 to 229.27). The adjusted difference in the proportion of children without eczema at 2 years was 0.0164 (95% CI −0.0329 to 0.0656) higher in the emollient group compared to the control group. The adjusted incremental cost per percentage decrease in risk of eczema was £5337 at 2 years. Adjusted QALYs for children were very slightly improved (i.e. higher) in the emollient group at 2 years. Conclusions We found no evidence of a useful preventive effect of emollients for eczema at our primary outcome time of 2 years. The failure to show a reduction in eczema was consistent regardless of how eczema was assessed. Some evidence of an increase in skin infections during the intervention period and a possible increase in food allergy at age 2 years was observed. No benefit was observed for time to onset of eczema or eczema severity, and no benefits were observed for eczema, asthma, hay fever or food allergy in longer-term follow-up to 5 years. Emollient use is unlikely to be considered cost effective in this context. Inclusion of individual patient data from all similar eczema prevention studies in further meta-analysis may provide a clearer assessment of whether emollients can prevent eczema and related diseases and provide more certainty about potential harms. Implications for health care The study does not support the use of emollients to prevent eczema and has found a small signal of possible harms, so this intervention cannot be recommended for health care or public health use. As the study relates to prevention of eczema, emollients should continue to be used as part of standard treatment for eczema. Trial registration This trial is registered as ISRCTN21528841. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information.

Neutrophils are short-lived cells of the innate immune system and represent 50-70% of the circulating leucocytes. Their primary role is antimicrobial defence which they accomplish through rapid migration to sites of inflammation followed by phagocytosis, degranulation, and the release of neutrophil extracellular traps (NETosis). While previously considered terminally differentiated cells, they have been shown to have great adaptability and to play a role in conditions ranging from cancer to autoimmunity. This review focuses on their role in allergic disease. In particular: their role as potential amplifiers of type 1 hypersensitivity reactions leading to anaphylaxis; their involvement in alternative pathways of food and drug allergy; their role in allergic rhinitis and asthma and neutrophil dysfunction in atopic dermatitis. The use of potential biomarkers and therapeutic targets is also discussed with a view to guiding future research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

Background: Cow's milk allergy (CMA) overdiagnosis in young children appears to be increasing and has not been well characterised. We used a clinical trial population to characterise CMA overdiagnosis and identify individual-level and primary care practice-level risk factors., Methods: We analysed data from 1394 children born in England in 2014-2016 (BEEP trial, ISRCTN21528841). Participants underwent formal CMA diagnosis at ≤2 years. CMA overdiagnosis was defined in three separate ways: parent-reported milk reaction; primary care record of milk hypersensitivity symptoms; and primary care record of low-allergy formula prescription., Results: CMA was formally diagnosed in 19 (1.4%) participants. CMA overdiagnosis was common: 16.1% had parent-reported cow's milk hypersensitivity, 11.3% primary care recorded milk hypersensitivity and 8.7% had low-allergy formula prescription. Symptoms attributed to cow's milk hypersensitivity in participants without CMA were commonly gastrointestinal and reported from a median age of 49 days. Low-allergy formula prescriptions in participants without CMA lasted a median of 10 months (interquartile range 1, 16); the estimated volume consumed was a median of 272 litres (26, 448). Risk factors for CMA overdiagnosis were high practice-based low-allergy formula prescribing in the previous year and maternal report of antibiotic prescription during pregnancy. Exclusive formula feeding from birth was associated with increased low-allergy formula prescription. There was no evidence that practice prescribing of paediatric adrenaline auto-injectors or anti-reflux medications, or maternal features such as anxiety, age, parity and socioeconomic status were associated with CMA overdiagnosis., Conclusion: CMA overdiagnosis is common in early infancy. Risk factors include high primary care practice-based low-allergy formula prescribing and maternal report of antibiotic prescription during pregnancy., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Loss-of-function mutations in the skin barrier protein filaggrin (FLG) are a major risk for atopic dermatitis (AD). The pathogenic sequence of disturbances in skin barrier function before or during the early development of AD is not fully understood. A more detailed understanding of these events is needed to develop a clearer picture of disease pathogenesis. A robust, noninvasive test to identify babies at high risk of AD would be important in planning early intervention and/or prevention studies., Objectives: To ascertain whether a noninvasive measurement of skin barrier function at day 2 after birth and at 2 months predicts the development of AD at 1 year. Furthermore, to determine whether increases in transepidermal water loss (TEWL) predate the development of clinical AD., Methods: A total of 1903 infants were enrolled in the Cork Babies After Scope: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints Birth Cohort study from July 2009 to October 2011. Measurements of TEWL were made at birth (day 2) and at 2 and 6 months. The presence of AD was ascertained at 6 and 12 months, and disease severity was assessed by using the SCORing Atopic Dermatitis clinical tool at 6 months and by using both the SCORing Atopic Dermatitis clinical tool and Nottingham Severity Score at 12 months. A total of 1300 infants were genotyped for FLG mutations., Results: At 6 months, 18.7% of the children had AD, and at 12 months, 15.53%. In a logistic regression model, day 2 upper quartile TEWL measurement was significantly predictive of AD at 12 months (area under the receiver operating characteristic curve, 0.81; P < .05). Lowest quartile day 2 TEWL was protective against AD at 12 months. An upper quartile 2 month TEWL was also strongly predictive of AD at 12 months (area under the receiver operating characteristic curve, 0.84; P < .05). At both ages, this effect was independent of parental atopy, FLG status, or report of an itchy flexural rash at 2 months. Associations were increased when parental atopy status or child FLG mutation status was added into the linear regression model., Conclusions: Impairment of skin barrier function at birth and at 2 months precedes clinical AD. In addition to providing important mechanistic insights into disease pathogenesis, these findings have implications for the optimal timing of interventions for the prevention of AD., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)