Introducing Allergenic Foods in Infants REPLY

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The hygiene hypothesis for allergy – conception and evolution

In 1989, a short paper entitled “Hay fever, hygiene and household size” observed that British children from larger families were less likely to develop hay fever and suggested that this could be because early exposure to infection prevents allergy. This sibship size association for hay fever, since replicated many times in Britain and other affluent countries and confirmed by objective measures of atopy, prompted what has come to be known as the “hygiene hypothesis for allergy”, although that term was not specifically used in the 1989 paper. The present paper reviews the historical roots of the “hygiene hypothesis” and charts its development over more than 30 years. Initial scepticism among immunologists turned to enthusiasm in the mid-1990s as the Th1/Th2 paradigm for allergic sensitisation emerged from animal experiments and the concept of “immunological old friends” became popular from the early 2000s. From the late 1990s, observations of reduced allergy risk among children of anthroposophic families and those brought up on farms suggested that the sibship size effects formed part of a broader range of “hygiene-related” determinants of allergy. Children from large families with farming exposure have approximately sixfold reduction in prevalence of hay fever, indicating the potential strength and epidemiological importance of these environmental determinants. During the 21st century, a wide range of specific microbial, environmental and lifestyle factors have been investigated as possible underlying mechanisms, but sadly none have emerged as robust explanations for the family size and farming effects. Thus, while the “hygiene hypothesis” led to a fundamental reappraisal of our relationship with our microbial environment and to the concept that early exposure, rather than avoidance, is beneficial for developing a healthy immune system, the underlying mechanism for variations in allergy prevalence with family size remains, in Churchillian terms, “a riddle wrapped in a mystery inside an enigma”

An algorithm for diagnosing IgE-mediated food allergy in study participants who do not undergo food challenge.

BACKGROUND: Food allergy diagnosis in clinical studies can be challenging. Oral food challenges (OFC) are time-consuming, carry some risk and may, therefore, not be acceptable to all study participants. OBJECTIVE: To design and evaluate an algorithm for detecting IgE-mediated food allergy in clinical study participants who do not undergo OFC. METHODS: An algorithm for trial participants in the Barrier Enhancement for Eczema Prevention (BEEP) study who were unwilling or unable to attend OFC was developed. BEEP is a pragmatic, multi-centre, randomized-controlled trial of daily emollient for the first year of life for primary prevention of eczema and food allergy in high-risk infants (ISRCTN21528841). We built on the European iFAAM consensus guidance to develop a novel food allergy diagnosis algorithm using available information on previous allergenic food ingestion, food reaction(s) and sensitization status. This was implemented by a panel of food allergy experts blind to treatment allocation and OFC outcome. We then evaluated the algorithm's performance in both BEEP and Enquiring About Tolerance (EAT) study participants who did undergo OFC. RESULTS: In 31/69 (45%) BEEP and 44/55 (80%) EAT study control group participants who had an OFC the panel felt confident enough to categorize children as "probable food allergy" or "probable no food allergy". Algorithm-derived panel decisions showed high sensitivity 94% (95%CI 68, 100) BEEP; 90% (95%CI 72, 97) EAT and moderate specificity 67% (95%CI 39, 87) BEEP; 67% (95%CI 39, 87) EAT. Sensitivity and specificity were similar when all BEEP and EAT participants with OFC outcome were included. CONCLUSION: We describe a new algorithm with high sensitivity for IgE-mediated food allergy in clinical study participants who do not undergo OFC. CLINICAL RELEVANCE: This may be a useful tool for excluding food allergy in future clinical studies where OFC is not conducted

Association of Early Introduction of Solids With Infant Sleep: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The World Health Organization recommends exclusive breastfeeding for 6 months. However, 75% of British mothers introduce solids before 5 months and 26% report infant waking at night as influencing this decision. Objective: To determine whether early introduction of solids influences infant sleep. Design, Setting, and Participants: The Enquiring About Tolerance study was a population-based randomized clinical trial conducted from January 15, 2008, to August 31, 2015, that included 1303 exclusively breastfed 3-month-old infants from England and Wales. Clinical visits took place at St Thomas' Hospital, London, England, and the trial studied the early introduction of solids into the infant diet from age 3 months. Interventions: The early introduction group (EIG) continued to breastfeed while nonallergenic and then 6 allergenic foods were introduced. The standard introduction group (SIG) followed British infant feeding guidelines (ie, exclusive breastfeeding to around age 6 months and to avoid any food consumption during this period). Main Outcomes and Measures: Secondary analysis of an a priori secondary outcome of the effect of early food introduction on infant sleep using the standardized Brief Infant Sleep Questionnaire. Results: Of the 1303 infants who were enrolled in the Enquiring About Tolerance study, 1225 participants (94%) completed the final 3-year questionnaire (618 SIG [95%] and 607 EIG [93%]). Randomization was effective and there were no significant baseline differences between the 2 groups. Following the early introduction of solids, infants in the EIG slept significantly longer and woke significantly less frequently than infants in the SIG. Differences between the 2 groups peaked at age 6 months. At this point, in the intention-to-treat analysis infants in the EIG slept for 16.6 (95% CI, 7.8-25.4) minutes longer per night and their night waking frequency had decreased from 2.01 to 1.74 wakings per night. Most clinically important, very serious sleep problems, which were significantly associated with maternal quality of life, were reported significantly more frequently in the SIG than in the EIG (odds ratio, 1.8; 95% CI, 1.22-2.61). Conclusions and Relevance: In a randomized clinical trial, the early introduction of solids into the infant's diet was associated with longer sleep duration, less frequent waking at night, and a reduction in reported very serious sleep problems. Trial Registration: isrctn.org Identifier: ISRCTN14254740

Inter-Relationship between Rhinitis and Conjunctivitis in Allergic Rhinoconjunctivitis and Associated Risk Factors in Rural UK Children.

OBJECTIVE: Allergic conjunctivitis (AC) is a common condition, especially in childhood. The extent to which it occurs concurrently with or independently from allergic rhinitis (AR) has not been well described. AIM: To examine the inter-relationship between rhinitis and conjunctivitis and the epidemiological risk factors for these conditions in a rural UK population. METHODS: Cross-sectional study of rural school children (aged 5-11 years). Parental questionnaires were used to diagnose allergic outcomes (including conjunctivitis, rhinitis and rhinoconjunctivitis), and to collect data on atopic history, demographic and environmental exposures. Odds ratios of allergic outcome by exposure were examined adjusted for age, sex, breastfeeding, family history of allergy, number of older and younger siblings. RESULTS: Prevalence of conjunctivitis was 17.5%, rhinitis 15.1% and rhinoconjunctivitis 13.0%. Seasonality of symptoms varied by condition: 64.7% of those with conjunctivitis had seasonal symptoms (April-Sept only), 46.7% of those with rhinitis and 92.2% of those with rhinoconjunctivitis. Living on a farm consistently reduced the risk of conjunctivitis (odds ratio 0.47, 95%CI 0.29-0.79, p = 0.004), rhinitis (OR 0.57, 95%CI 0.33-1.01, p = 0.05) and rhinoconjunctivitis (OR 0.57, 95%CI 0.32-1.03, p = 0.06). Exposure to farm animals (particularly in early life), current consumption of unpasteurised milk and playing in a barn or stable significantly reduced the risk of all three conditions. CONCLUSION: More children had parent-reported conjunctivitis than rhinitis. The majority of children with either condition also reported symptoms with the other condition. Farmers' children have less eye and/or nasal symptoms. A number of farming variables linked with the farm microbial environment are likely to be mediating the protective effect

Deaths in people from Black, Asian and minority ethnic communities from both COVID-19 and non-COVID causes in the first weeks of the pandemic in London: a hospital case note review

Objective To undertake a case review of deaths in a 6-week period during the COVID-19 pandemic commencing with the first death in the hospital from COVID-19 on 12th of March 2020 and contrast this with the same period in 2019. Setting A large London teaching hospital. Participants Three groups were compared: group 1—COVID-19-associated deaths in the 6-week period (n=243), group 2—non-COVID deaths in the same period (n=136) and group 3—all deaths in a comparison period of the same 6 weeks in 2019 (n=194). Primary and secondary outcome measures This was a descriptive analysis of death case series review and as such no primary or secondary outcomes were pre-stipulated. Results Deaths in patients from the Black, Asian and minority ethnic (BAME) communities in the pandemic period significantly increased both in the COVID-19 group (OR=2.43, 95% CI=1.60–3.68, p<0.001) and the non-COVID group (OR=1.76, 95% CI=1.09–2.83, p=0.02) during this time period and the increase was independent of differences in comorbidities, sex, age or deprivation. While the absolute number of deaths increased in 2020 compared with 2019, across all three groups the distribution of deaths by age was very similar. Our analyses confirm major risk factors for COVID-19 mortality including male sex, diabetes, having multiple comorbidities and background from the BAME communities. Conclusions There was no evidence of COVID-19 deaths occurring disproportionately in the elderly compared with non-COVID deaths in this period in 2020 and 2019. Deaths in the BAME communities were over-represented in both COVID-19 and non-COVID groups, highlighting the need for detailed research in order to fully understand the influence of ethnicity on susceptibility to illness, mortality and health-seeking behaviour during the pandemic

Fruit, vegetable and vitamin C intakes and plasma vitamin C: cross-sectional associations with insulin resistance and glycaemia in 9-10 year-old children.

AIM: To examine whether low circulating vitamin C concentrations and low fruit and vegetable intakes were associated with insulin resistance and other Type 2 diabetes risk markers in childhood. METHODS: We conducted a cross-sectional, school-based study in 2025 UK children aged 9-10 years, predominantly of white European, South-Asian and black African origin. A 24-h dietary recall was used to assess fruit, vegetable and vitamin C intakes. Height, weight and fat mass were measured and a fasting blood sample collected to measure plasma vitamin C concentrations and Type 2 diabetes risk markers. RESULTS: In analyses adjusting for confounding variables (including socio-economic status), a one interquartile range higher plasma vitamin C concentration (30.9 μmol/l) was associated with a 9.6% (95% CI 6.5, 12.6%) lower homeostatic model assessment of insulin resistance value, 0.8% (95% CI 0.4, 1.2%) lower fasting glucose, 4.5% (95% CI 3.2, 5.9%) lower urate and 2.2% (95% CI 0.9, 3.4%) higher HDL cholesterol. HbA1c concentration was 0.6% (95% CI 0.2, 1.0%) higher. Dietary fruit, vegetable and total vitamin C intakes were not associated with any Type 2 diabetes risk markers. Lower plasma vitamin C concentrations in South-Asian and black African-Caribbean children could partly explain their higher insulin resistance. CONCLUSIONS: Lower plasma vitamin C concentrations are associated with insulin resistance and could partly explain ethnic differences in insulin resistance. Experimental studies are needed to establish whether increasing plasma vitamin C can help prevent Type 2 diabetes at an early stage

Routine infant skincare advice in the UK: A cross-sectional survey.

- We surveyed over 85% of UK public health system maternity care providers in 2022. - Routine UK infant skincare advice is very heterogeneous, often conflicting and not evidence based

Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.

BACKGROUND: Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children. METHODS: We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment. FINDINGS: 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09). INTERPRETATION: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn. FUNDING: National Institute for Health Research Health Technology Assessment