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Background: Recent discoveries have led to the suggestion that enhancing skin barrier from birth might prevent eczema and food allergy., Objective: To determine the cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children at 2 years from a health service perspective. We also considered a 5-year time horizon as a sensitivity analysis., Methods: A within-trial economic evaluation using data on health resource use and quality of life captured as part of the BEEP trial alongside the trial data. Parents/carers of 1394 infants born to families at high risk of atopic disease were randomised 1:1 to the emollient group, which were advised to apply emollient (Doublebase Gel or Diprobase Cream) to their child at least once daily to the whole body during the first year of life or usual care. Both groups received advice on general skin care. The main economic outcomes were incremental cost-effectiveness ratio (ICER), defined as incremental cost per percentage decrease in risk of eczema in the primary cost-effectiveness analysis. Secondary analysis, undertaken as a cost-utility analysis, reports incremental cost per Quality-Adjusted Life Year (QALY) where child utility was elicited using the proxy CHU-9D at 2 years., Results: At 2 years, the adjusted incremental cost was £87.45 (95% CI -54.31, 229.27) per participant, whilst the adjusted proportion without eczema was 0.0164 (95% CI -0.0329, 0.0656). The ICER was £5337 per percentage decrease in risk of eczema. Adjusted incremental QALYs were very slightly improved in the emollient group, 0.0010 (95% CI -0.0069, 0.0089). At 5 years, adjusted incremental costs were lower for the emollient group, -£106.89 (95% CI -354.66, 140.88) and the proportion without eczema was -0.0329 (95% CI -0.0659, 0.0002). The 5-year ICER was £3201 per percentage decrease in risk of eczema. However, when inpatient costs due to wheezing were excluded, incremental costs were lower and incremental effects greater in the usual care group., Conclusions: In line with effectiveness endpoints, advice given in the BEEP trial to apply daily emollient during infancy for eczema prevention in high-risk children does not appear cost-effective., (© 2023 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin condition with an unpredictable clinical course, associated with a significant impact on quality of life. The pathophysiology of AD involves a complex interplay between impaired skin barrier function, immune dysregulation, genetic susceptibility and environmental factors. Advances in understanding of the immunological mechanisms that underpin AD have heralded the recognition of multiple novel therapeutic targets to bolster the systemic treatment armamentarium for patients with severe AD. This review examines current and future directions of non-biologic systemic treatments for AD, with a focus on their mechanism of action, efficacy and safety, and the key considerations to help inform treatment decisions. We summarize new developments in small molecule systemic therapies which have the potential to further advance our management of AD in this new era of precision medicine., (© 2023 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Observational studies suggest an increased risk of eczema in children living in hard versus soft water areas, and there is, therefore, an interest in knowing whether softening water may prevent eczema. We evaluated the feasibility of a parallel-group assessor-blinded pilot randomized controlled trial to test whether installing a domestic ion-exchange water softener before birth in hard water areas reduces the risk of eczema in infants with a family history of atopy., Methods: Pregnant women living in hard water areas (>250 mg/L calcium carbonate) in and around London UK, were randomized 1:1 antenatally to either have an ion-exchange water softener installed in their home or not (ie to continue to receive usual domestic hard water). Infants were assessed at birth and followed up for 6 months. The main end-points were around feasibility, the primary end-point being the proportion of eligible families screened who were willing and able to be randomized. Clinical end-points were evaluated including frequency of parent-reported doctor-diagnosed eczema and visible eczema on skin examination. Descriptive analyses were conducted, and no statistical testing was performed as this was a pilot study., Results: One hundred and forty-nine families screened were eligible antenatally and 28% (41/149) could not have a water softener installed due to technical reasons or lack of landlord approval. Eighty of 149 (54%) were randomized, the primary end-point. Two participants withdrew immediately after randomization, leaving 39 participants in each arm (78 total). Attrition was 15% (12/78) by 6 months postpartum. All respondents (n = 69) to the study acceptability questionnaire reported that the study was acceptable. Fifty-six of 708 (7.9%) water samples in the water softener arm were above the hard water threshold of 20 mg/L CaCO 3 . At 6 months of age 27/67 infants (40%) developed visible eczema, 12/36 (33%) vs. 15/31 (48%) in the water softener and control groups, respectively, difference -15% (95% CI -38, 8.3%), with most assessments (≥96%) remaining blinded. Similarly, a lower proportion of infants in the water softener arm had parent-reported, doctor-diagnosed eczema by 6 months compared to the control arm, 6/17 (35%) versus 9/19 (47%), difference -12% (95% CI -44, 20%)., Conclusion: A randomized controlled trial of water softeners for the prevention of atopic eczema in high-risk infants is feasible and acceptable., Trial Registration: NCT03270566 (clinicaltrials.gov)., (© 2021 John Wiley & Sons Ltd.)

Background: Non-IgE-mediated Cow's Milk Allergy (CMA) has a prevalence of less than 1% in children. Guidelines developed to help non-specialists diagnose CMA may lead to misattribution of normal symptoms and contribute to overdiagnosis of CMA. We sought to establish the frequency of symptoms during infancy associated with non-IgE-mediated CMA, using the international Milk Allergy in Primary Care (iMAP) guideline as representative of CMA guidelines more generally., Method: Secondary analysis of the Enquiring About Tolerance (EAT) randomized controlled trial (ISRCTN 14254740; 1303 exclusively breastfed 3-month-old healthy infants). Key outcomes were ≥2 iMAP symptoms associated with 'mild-moderate' and 'severe' non-IgE-mediated CMA., Results: Whilst breastfeeding and parental atopy rates were higher than the general population, participants were otherwise similar to the population of England and Wales. Two or more non-IgE CMA symptoms were reported by 25% families for mild-moderate and 1.4% for severe symptoms each month between ages 3 and 12 months, peaking at 38% with ≥2 mild-moderate and 4.3% ≥2 severe symptoms at three months, when participants were not directly consuming cow's milk. 74% of participants reported ≥2 mild-moderate symptoms and 9% ≥2 severe symptoms in at least one month during this period. At six months there was no evidence of difference in the proportion of children with ≥2 symptoms between those consuming (29.5% mild-moderate, 1.8% severe) and not consuming cow's milk (35.3% mild-moderate, 2.2% severe). Mean monthly reporting of ≥2 symptoms was also no different between those with (15.8% mild-moderate, 1.1% severe) or without eczema at baseline (16.7% mild-moderate, 1.3% severe)., Conclusions: Guideline-defined symptoms of non-IgE-mediated CMA are very common in infants. Guidelines may promote milk allergy overdiagnosis by labelling normal infant symptoms as possible milk allergy., (© 2021 John Wiley & Sons Ltd.)

Background: Hard domestic water has been reported to worsen atopic eczema (AE) and may contribute to its development in early life., Objective: To review the literature on the relationship between the effect of water hardness (high calcium carbonate; CaCO 3 ) on (a) the risk of developing AE, (b) the treatment of existing AE and (c) skin barrier function in human and animal studies., Design , Data Sources and Eligibility Criteria: We systematically searched databases (MEDLINE, Embase, Cochrane CENTRAL, GREAT and Web of Science) from inception until 30/6/2020. Human and animal observational and experimental studies were included. The primary outcomes were risk of AE and skin barrier function. Studies were meta-analysed using a random effects model. Evidence certainty was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach., Results: Sixteen studies were included. Pooled observational data from seven studies on 385,901 participants identified increased odds of AE in children exposed to harder versus softer water (odds ratio 1.28, 95% CI 1.09, 1.50; GRADE certainty: very low). Two mechanistic studies in humans reported higher deposition of the detergent sodium lauryl sulphate in those exposed to harder versus softer water. Two randomized controlled trials comparing water softeners with standard care did not show a significant difference in objective AE severity with softened water (standardized mean difference 0.06 standard deviations higher, 95% CI 0.16 lower to 0.27 higher; GRADE certainty: moderate)., Conclusions & Clinical Relevance: There was a positive association between living in a hard water (range: 76 to > 350 mg/L CaCO 3 ) area and AE in children. There is no evidence that domestic water softeners improve objective disease severity in established AE. There may be a role of water hardness in the initiation of skin inflammation in early life, but there is a need for further longitudinal and interventional studies., (© 2020 John Wiley & Sons Ltd.)

Background: Despite the high disease burden of eczema, a contemporary overview of the patterns and trends in primary care healthcare utilization and treatment is lacking., Objective: To quantify primary care consultations, specialist referrals, prescribing, and treatment escalation, in children and adults with eczema in England., Methods: A large primary care research database was used to examine healthcare and treatment utilization in people with active eczema (n = 411,931). Management trends and variations by age, sex, socioeconomic status, and ethnicity were described from 2009 to 2018 inclusive., Results: Primary care consultation rates increased from 87.8 (95% confidence interval [95% CI] 87.3-88.3) to 112.0 (95% CI 111.5-112.6) per 100 person-years over 2009 to 2018. Specialist referral rates also increased from 3.8 (95% CI 3.7-3.9) to 5.0 (95% CI 4.9-5.1) per 100 person-years over the same period. Consultation rates were highest in infants. Specialist referrals were greatest in the over 50s and lowest in people of lower socioeconomic status, despite a higher rate of primary care consultations. There were small changes in prescribing over time; emollients increased (prescribed to 48.5% of people with active eczema in 2009 compared to 51.4% in 2018) and topical corticosteroids decreased (57.3%-52.0%). Prescribing disparities were observed, including less prescribing of potent and very potent topical corticosteroids in non-white ethnicities and people of lower socioeconomic status. Treatment escalation was more common with increasing age and in children of non-white ethnicity., Conclusion and Clinical Relevance: The management of eczema varies by sociodemographic status in England, with lower rates of specialist referral in people from more-deprived backgrounds. There are different patterns of healthcare utilization, treatment, and treatment escalation in people of non-white ethnicity and of more-deprived backgrounds., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Whilst eczema is a common inflammatory skin condition, we lack contemporary estimates of disease incidence and prevalence across the lifespan., Objective: To estimate the incidence and prevalence of eczema in children and adults in England and variation by sociodemographic factors (sex, socio-economic status, ethnicity, and geography)., Methods: We used the Royal College of General Practitioners Research and Surveillance Centre primary care research database of 3.85 million children and adults registered with participating general practitioner practices between 2009 and 2018 inclusive. Eczema incidence was defined as the first-ever diagnosis of eczema recorded in the primary care record, and eczema prevalence was defined as fulfilment of criteria for active eczema (two eczema records appearing in the primary care record within any one-year period)., Results: Eczema incidence was highest in infants younger than 1 year (15.0 per 100 person-years), lowest in adults aged 40-49 (0.35 p/100 person-years), and increased from middle age to a second smaller peak in people 80 years or older (0.79 p/100 person-years). Eczema prevalence was highest in children aged 2 (16.5%) and lowest in adults aged 30-39 (2.8%). Eczema incidence was higher in male infants (<2) and male adults older than 70; for all other ages, incidence was higher in females. Eczema was more common in Asian and black ethnic groups than in people of white ethnicity. Higher socio-economic status was associated with a greater incidence of eczema in infants younger than 2, but the reverse was seen for all other age groups. Both incidence and prevalence of eczema were greater in urban settings and in North-West England., Conclusions and Clinical Relevance: Eczema has a bimodal distribution across the lifespan. We observed differences in incidence and prevalence of eczema by ethnicity, geography, sex, and socio-economic status, which varied in magnitude throughout life., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Conflicting findings from studies evaluating associations of allergic disease with child behaviour require longitudinal studies to resolve., Objective: To estimate the magnitude of associations of atopic dermatitis (AD) in infancy, and symptoms of asthma and AD at 6.5 years, with child behaviour at 6.5 years., Methods: Secondary cohort analysis of the Promotion of Breastfeeding Intervention Trial (PROBIT). PROBIT enrolled 17 046 infants at birth and followed them up at 6.5 years (n = 13 889). Study paediatricians collected data on infantile AD at repeated follow-up examinations during the first year of life. At 6.5 years, paediatricians performed skin prick tests and parents reported asthma and AD symptoms during the prior year. In addition, parents and teachers completed the Strength and Difficulties Questionnaire, which includes scales on hyperactivity/inattention, emotional problems, conduct problems, peer problems and prosocial behaviours., Results: Physician-diagnosed AD in the first year of life was not associated with increased risk for behavioural problems at 6.5 years. Emotional problems at 6.5 years were more common among children with AD symptoms (OR: 2.24, 95% CI: 1.62-3.12) and asthma symptoms (OR: 1.45; 95% CI: 1.07-1.96) during the past year at 6.5 years and ORs for children with symptoms of more severe AD and asthma were also higher. AD in the past year was also associated with probable hyperactivity/inattention disorder at 6.5 years (OR: 2.05; 95% CI: 1.09-3.84). Other subscales of the SDQ were not related to asthma or AD symptoms during the past year., Conclusions and Clinical Relevance: Children with AD symptoms were at higher risk for concomitant hyperactivity/inattention and emotional disorder, and children with asthma symptoms were at higher risk of having concomitant emotional problems. However, AD during infancy did not predict childhood behaviours., (© 2019 John Wiley & Sons Ltd.)

Background: Observational evidence suggests that infection with helminths protects against allergic disease and allergen skin sensitization. It is postulated that such effects are mediated by helminth-induced cytokine responses, in particular IL-10., Objective: We tested this hypothesis in a rural area of central Vietnam where hookworm infection is endemic., Methods: One thousand five hundred and sixty-six schoolchildren aged 6-17 were randomly allocated to receive either anti-helminthic therapy or a placebo at 0, 3, 6, and 9 months. We compared changes in the prevalence of exercise-induced bronchoconstriction, allergen skin sensitization, flexural eczema on skin examination, questionnaire-reported allergic disease (wheeze and rhinitis symptoms), and immunological parameters (hookworm-induced IFN-gamma, IL-5, IL-10) between 0 and 12 months., Results: One thousand four hundred and eighty-seven children (95% of these randomized) completed the study. The most common helminth infections were hookworm (65%) and Ascaris lumbricoides (7%). There was no effect of the therapy on the primary outcome, exercise-induced bronchoconstriction (within-participant mean percent fall in peak flow from baseline after anti-helminthic treatment 2.25 (SD 7.3) vs. placebo 2.19 (SD 7.8, P=0.9), or on the prevalence of questionnaire-reported wheeze [adjusted odds ratio (OR)=1.16, 95% confidence interval (CI) 0.35-3.82, P=0.8] and rhinitis (adjusted OR=1.39, 0.89-2.15, P=0.1), or flexural dermatitis on skin examination (adjusted OR=1.15, 0.39-3.45, P=0.8). However, anti-helminthic therapy was associated with a significantly higher allergen skin sensitization risk (adjusted OR=1.31, 1.02-1.67, P=0.03). This effect was particularly strong for children infected with A. lumbricoides at baseline (adjusted OR=4.90, 1.48-16.19, P=0.009). Allergen skin sensitization was inversely related to hookworm-specific IL-10 at baseline (adjusted OR=0.76, 0.59-0.99, P=0.04). No cytokine tested, including IL-10, changed significantly after the anti-helminthic therapy compared with the placebo., Conclusion: A significant reduction in worm burden over a 12-month period in helminth-infected children increases the risk of allergen skin sensitization but not of clinical allergic disease. The effect on skin sensitization could not be fully explained by any of the immunological parameters tested.

Allergic diseases are rare in areas with high helminth parasite exposure and common where helminth exposure is lacking or significantly reduced, such as urban areas of developing countries and industrialized nations. Studies suggest that helminths induce a systemic immuno-modulatory network, including regulatory T cells and anti-inflammatory IL-10, which might play a key role in the protection against the allergic phenotype. Here, we review the current cross-sectional, birth cohort, and intervention study evidence for a protective effect of helminth infection on allergy. There is increasing evidence for a causal relationship between helminth infection and reduced skin prick test responsiveness to allergens. Cross-sectional studies have shown a consistent negative relationship, and these results have been confirmed in several, although not all, intervention studies. The immunological basis for this protective effect is less clear. Recent studies do not support the mast-cell IgE saturation hypothesis, but suggest that protection is associated with IL-10 production. As for allergic disease, cross-sectional studies support a negative relationship between clinical asthma and infection with some helminth species, particularly hookworm, but more studies are required to draw conclusions for eczema and rhinitis. In addition, none of the few intervention studies to date have demonstrated an increase in clinical allergy after helminth treatment, and further studies are needed. Furthermore, we are only beginning to understand the host genetic factors that are potentially involved. A genetically predetermined T-helper type 2 cell-dominated cytokine milieu reduces parasite burden and may enhance host survival in an environment where helminth parasites are prevalent. Lack of parasite exposure in such hosts might lead to hypersensitivity to seemingly minor environmental allergen stimuli. Large birth cohort studies in helminth-endemic areas that use epidemiological, genetic, and immunological tools are required to further examine how helminth parasites affect the development of atopy and allergic disease. Intervention studies with hookworm in parasite-naïve allergic individuals are currently ongoing in the United Kingdom to test the above hypotheses further.

Background: Allergic diseases, including atopic dermatitis (AD), are increasingly becoming a clinical problem in developing countries., Objective: We investigated the prevalence of AD symptoms and the effects of potential environmental aetiologies in rural and urban areas of Jimma in southwestern Ethiopia., Methods: Information on allergic disease symptoms and lifestyle factors was gathered in an interviewer-led cross-sectional questionnaire-based population survey of 9844 urban and 3032 rural participants of all ages. A one-in-four subsample underwent skin prick testing for hypersensitivity to Dermatophagoides pteronyssinus, mixed threshings, and aspergillus., Results: Around 95% of those eligible took part in the survey. Lifetime cumulative prevalence of AD symptoms was generally low with an overall prevalence of 1.2%, but was higher in the urban (1.5%) than in the rural area (0.3%; odds ratio (OR)=4.45 [95% CI 2.34-8.47]). AD symptoms were strongly associated with wheeze (adjusted OR=22.03 [15.45-31.42]) and rhinitis symptoms (61.94 [42.66-89.95]). Of several environmental exposures assessed, residence in a house made of brick (rather than mud) walls with wooden (rather than clay) floor, exposure to cigarette smoke as a child, having lived outside of Jimma in the past, and being of the Tigrean ethnic group were associated with an increased risk of AD symptoms., Conclusion: Although the overall prevalence of AD symptoms was low in this Ethiopian population, a marked urban-rural gradient was evident. Lifestyle factors linked to urbanization were associated with an increased risk of AD symptoms.