Risk subgroups and intervention effects among infants at high risk for peanut allergy: A model for clinical decision making.

BACKGROUND: The Learning Early About Peanut Allergy (LEAP) trial showed that early dietary introduction of peanut reduced the risk of developing peanut allergy by age 60 months in infants at high risk for peanut allergy. In this secondary analysis of LEAP data, we aimed to determine risk subgroups within these infants and estimate their respective intervention effects of early peanut introduction. METHODS: LEAP raw data were retrieved from ITNTrialShare.org. Conditional random forest was applied to participants in the peanut avoidance arm to select statistically important features for the classification and regression tree (CART) analysis to group infants based on their risk of peanut allergy at 60 months of age. Intervention effects were estimated for each derived risk subgroup using data from both arms. Our main model was generated based on baseline data when the participants were 4-11 months old. Specific IgE measurements were truncated to account for the limit of detection commonly used by laboratories in clinical practice. RESULTS: The model found infants with higher predicted probability of peanut allergy at 60 months of age had a similar relative risk reduction, but a greater absolute risk reduction in peanut allergy with early introduction of peanut, than those with lower probability. The intervention effects were significant across all risk subgroups. Participants with baseline peanut sIgE ≥0.22 kU/L (n = 78) had an absolute risk reduction of 40.4% (95% CI 27.3, 51.9) whereas participants with baseline peanut sIgE<0.22 kU/L and baseline Ara h 2 sIgE <0.10 kU/L (n = 226) had an absolute risk reduction of 6.5% (95% CI 2.6, 11.0). These findings were consistent in sensitivity analyses using alternative models. CONCLUSION: In this study, risk subgroups were determined among infants from the LEAP trial based on the probability of developing peanut allergy and the intervention effects of early peanut introduction were estimated. This may be relevant for further risk assessment and personalized clinical decision-making.

Defining the window of opportunity and target populations to prevent peanut allergy.

BACKGROUND: Peanut allergy affects 1% to 2% of European children. Early introduction of peanut into the diet reduces allergy in high-risk infants. OBJECTIVE: We aimed to determine the optimal target populations and timing of introduction of peanut products to prevent peanut allergy in the general population. METHODS: Data from the Enquiring About Tolerance (EAT; n = 1303; normal risk; 3-year follow-up; ISRCTN14254740) and Learning Early About Peanut Allergy study (LEAP; n = 640; high risk; 5-year follow-up; NCT00329784) randomized controlled trials plus the Peanut Allergy Sensitization (PAS; n = 194; low and very high risk; 5-year follow-up) observational study were used to model the intervention in a general population. Peanut allergy was defined by blinded peanut challenge or diagnostic skin prick test result. RESULTS: Targeting only the highest-risk infants with severe eczema reduced the population disease burden by only 4.6%. Greatest reductions in peanut allergy were seen when the intervention was targeted only to the larger but lower-risk groups. A 77% reduction in peanut allergy was estimated when peanut was introduced to the diet of all infants, at 4 months with eczema, and at 6 months without eczema. The estimated reduction in peanut allergy diminished with every month of delayed introduction. If introduction was delayed to 12 months, peanut allergy was only reduced by 33%. CONCLUSIONS: The preventive benefit of early introduction of peanut products into the diet decreases as age at introduction increases. In countries where peanut allergy is a public health concern, health care professionals should help parents introduce peanut products into their infants' diet at 4 to 6 months of life.

Dietary Intervention during Weaning and Development of Food Allergy: What Is the State of the Art?

Food allergy (FA) affects approximately 6-8% of children worldwide causing a significant impact on the quality of life of children and their families. In past years, the possible role of weaning in the development of FA has been studied. According to recent studies, this is still controversial and influenced by several factors, such as the type of food, the age at food introduction and family history. In this narrative review, we aimed to collect the most recent evidence about weaning and its role in FA development, organizing the gathered data based on both the type of study and the food. As shown in most of the studies included in this review, early food introduction did not show a potential protective role against FA development, and we conclude that further evidence is needed from future clinical trials.

Early Introduction and Community Transmission of SARS-CoV-2 Omicron Variant, New York, New York, USA.

The Omicron variant of SARS-CoV-2 has become dominant in most countries and has raised significant global health concerns. As a global commerce center, New York, New York, USA, constantly faces the risk for multiple variant introductions of SARS-CoV-2. To elucidate the introduction and transmission of the Omicron variant in the city of New York, we created a comprehensive genomic and epidemiologic analysis of 392 Omicron virus specimens collected during November 25-December 11, 2021. We found evidence of 4 independent introductions of Omicron subclades, including the Omicron subclade BA.1.1 with defining substitution of R346K in the spike protein. The continuous genetic divergence within each Omicron subclade revealed their local community transmission and co-circulation in New York, including both household and workplace transmissions supported by epidemiologic evidence. Our study highlights the urgent need for enhanced genomic surveillance and effective response planning for better prevention and management of emerging SARS-CoV-2 variants.

Early introduction of peanut reduces peanut allergy across risk groups in pooled and causal inference analyses.

BACKGROUND: The Learning Early About Peanut allergy (LEAP) study has shown the effectiveness of early peanut introduction in prevention of peanut allergy (PA). In the Enquiring About Tolerance (EAT) study, a statistically significant reduction in PA was present only in per-protocol (PP) analyses, which can be subject to bias. OBJECTIVE: The aim of this study was to combine individual-level data from the LEAP and EAT trials and provide robust evidence on the bias-corrected, causal effect of early peanut introduction. METHOD: As part of the European Union-funded iFAAM project, this pooled analysis of individual pediatric patient data combines and compares effectiveness and efficacy estimates of oral tolerance induction among different risk strata and analysis methods. RESULTS: An intention-to-treat (ITT) analysis of pooled data showed a 75% reduction in PA (p < .0001) among children randomized to consume peanut from early infancy. A protective effect was present across all eczema severity groups, irrespective of enrollment sensitization to peanut, and across different ethnicities. Earlier age of introduction was associated with improved effectiveness of the intervention. In the pooled PP analysis, peanut consumption reduced the risk of PA by 98% (p < .0001). A causal inference analysis confirmed the strong PP effect (89% average treatment effect relative risk reduction p < .0001). A multivariable causal inference analysis approach estimated a large (100%) reduction in PA in children without eczema (p = .004). CONCLUSION: We demonstrate a significant reduction in PA with early peanut introduction in a large group of pooled, randomized participants. This significant reduction was demonstrated across all risk subgroups, including children with no eczema. Furthermore, our results point to increased efficacy of the intervention with earlier age of introduction.

Reactions to peanut at first introduction in infancy are associated with age ≥8 months and severity of eczema.

BACKGROUND: Previous studies have shown the efficacy of the early introduction of peanut to prevent peanut allergy. Due to the exclusion of infants with sensitization to peanut, it remains unclear what the optimal timing of introduction is. METHODS: The PeanutNL study was performed in 6 pediatric allergology centers in the Netherlands. Infants referred for the clinical early introduction of peanut to prevent peanut allergy underwent skin prick tests for peanut and an oral peanut challenge at a median age of 6 months. RESULTS: One hundred sixty two of 707 infants (23%) who had never eaten peanut before were sensitized to peanut, of which 80 (49%) had wheals of >4 mm. Sixty seven of 707 infants (9.5%) had a positive oral challenge to peanut at first introduction. Multivariate analysis revealed that age (p < .001) and SCORAD eczema severity scores (p = .001) were significant risk factors. Introduction of peanut at ≥8 months in infants with moderate and severe eczema resulted in an increased risk (odds ratio 5.24 (p = .013) and 3.61 (p = .019), respectively) of having reactions to peanut as compared to introduction before 8 months. A family history of peanut allergy and previous reactions to egg were not identified as independent risk factors. CONCLUSION: These results suggest that peanut should be introduced before the age of 8 months to reduce the risk of reactions at first exposure in infants with moderate and severe eczema. Furthermore, since children with severe eczema have the highest risk of reactions, the clinical introduction of peanut should be considered, at the latest at the age of 7 months.

Application of the "1-2-3-4-day" rule to stroke severity at baseline versus at 24 h to start direct oral anticoagulant for atrial fibrillation within 7 days from symptom onset.

INTRODUCTION: The aim of this study is to compare the "1-2-3-4-day" rule applied to stroke severity at baseline versus at 24 h to start DOAC for AF within 7 days from symptom onset. PATIENTS AND METHODS: We conducted a prospective cohort observational study based on 433 consecutive AF-related stroke patients starting DOAC within 7 days from symptom onset. Four groups were identified according to the timing of DOAC introduction: 2-day, 3-day, 4-day, and 5-7-day. RESULTS: Three models of multivariate ordinal regression including unbalanced variables among four groups (enrolment year, dyslipidemia, known AF, thrombolysis, thrombectomy, hemorrhagic transformation, DOAC type) were used to estimate the association of neurological severity categories (reference: NIHSS > 15) at baseline (Brant test: 0.818), at 24 h (Brant test: 0.997), and radiological severity categories (reference: major infarct) at 24 h (Brant test: 0.902) in the direction of earlier DOAC introduction on days (from 5-7-day to 2-day). Number of deaths was higher in early DOAC group than in late DOAC group according to the "1-2-3-4-day" rule (5.4% versus 1.3%, 6.8% versus 1.1%, and 4.2% versus 1.7% when it was applied to baseline neurological severity, 24-h neurological and radiological severity, respectively), but no significant difference was found and deaths were not caused by early DOAC introduction. Rates of ischemic stroke and intracranial hemorrhage were not different between early and late DOAC groups. CONCLUSIONS: The application of "1-2-3-4-day" rule to start DOAC for AF within 7 days from symptom onset differed when applied to baseline neurological stroke severity versus 24-h neurological and radiological severity, but safety and effecacy are similar.

Delayed egg introduction beyond infancy and increased egg allergy risk in childhood.

AIM: Egg is a major food allergen in childhood. Recent studies suggest that early introduction of allergenic foods can decrease the risk of developing egg allergy. The impact of early egg introduction in the general population is unclear. We examined associations between age of infant egg introduction and childhood egg allergy outcomes in a general population. METHODS: The study population consisted of 1217 neonates from Project Viva, a longitudinal pre-birth cohort in eastern Massachusetts area, USA. Mothers reported age of infant egg introduction and child egg allergy using questionnaires and specific IgE to egg white was assayed. We estimated associations between age of infant egg introduction and egg allergy outcomes using Log-binomial regression models, adjusting for socio-demographics and health confounders. RESULTS: Egg allergy at 2 years was significantly higher (8.0% vs. 1.4%, P < 0.0001) in children who had delayed egg introduction beyond infancy, compared with children who were introduced to egg during infancy (adjusted relative risk or aRR 7.58; 95% CI 3.08, 18.61). At 12 years, the risk of egg allergy remained significantly higher (3.9% vs. 1.1%, P = 0.048) in children with delayed egg introduction compared with children introduced to egg during infancy (aRR 4.07; 95% CI 1.20, 13.87). CONCLUSIONS: Infants with delayed introduction of eggs after 12 months had increased risk of egg allergy in childhood (2 years) and the relationship persisted in early adolescence (12 years). Our findings suggest that introduction to eggs before 12 months could contribute to the prevention of egg allergy.

Age and eczema severity, but not family history, are major risk factors for peanut allergy in infancy.

BACKGROUND: Whether to screen high-risk groups before early peanut introduction is controversial. OBJECTIVE: We sought to determine the risk of peanut allergy (PA) before peanut introduction for infants with (1) moderate-severe eczema, (2) another food allergy (FA), and/or (3) a first-degree relative with peanut allergy (FH). METHODS: Infants aged 4 to 11 months with no history of peanut ingestion, testing, or reaction and at least 1 of the above risk factors received peanut skin prick test and, depending on skin prick test wheal size, oral food challenge or observed feeding. RESULTS: A total of 321 subjects completed the enrollment visit (median age, 7.2 months; 58% males); 78 had eczema only, 11 FA only, 107 FH only, and 125 had multiple risk factors. Overall, 18% of 195 with eczema, 19% of 59 with FA, and 4% of 201 with FH had PA. Only 1% of 115 with FH and no eczema had PA. Among those with eczema, older age (odds ratio [OR], 1.3; 95% CI, 1.04-1.68 per month), higher SCORing Atopic Dermatitis score (OR, 1.19; 95% CI, 1.06-1.34 per 5 points), black (OR, 5.79; 95% CI, 1.92-17.4 compared with white), or Asian race (OR, 6.98; 95% CI, 1.92-25.44) and suspected or diagnosed other FA (OR, 3.98; 95% CI, 1.62-9.80) were associated with PA. CONCLUSIONS: PA is common in infants with moderate-severe eczema, whereas FH without eczema is not a major risk factor, suggesting screening only in those with significant eczema. Even within the first year of life, introduction at later ages is associated with a higher risk of PA among those with eczema, supporting introduction of peanut as early as possible.

Randomized trial of early infant formula introduction to prevent cow's milk allergy.

BACKGROUND: Previous research has produced conflicting evidence on the preventive effects of early introduction of cow's milk protein on cow's milk allergy (CMA). OBJECTIVE: Through a randomized controlled trial, we sought to determine whether the early introduction of cow's milk formula (CMF) could serve as an effective strategy in the primary prevention of CMA in a general population. METHODS: We recruited newborns from 4 hospitals in Okinawa, Japan. Participants were randomly allocated to ingest at least10 mL of CMF daily (ingestion group) or avoid CMF (avoidance group) between 1 and 2 months of age. In the avoidance group breast-feeding was supplemented with soy formula as needed. Oral food challenge was performed at 6 months of age to assess CMA development. Continuous breast-feeding was recommended for both groups until 6 months of age. RESULTS: We identified 504 infants for randomization into the 2 groups. In all, the parents of 12 participants declined to receive the intervention, and the study sample comprised 491 participants (242 in the ingestion group and 249 in the avoidance group) for a modified intention-to-treat analysis. There were 2 CMA cases (0.8%) among the 242 members of the ingestion group and 17 CMA cases (6.8%) among the 249 participants in the avoidance group (risk ratio = 0.12; 95% CI = 0.01-0.50; P < .001). The risk difference was 6.0% (95% CI = 2.7-9.3). Approximately 70% of the participants in both groups were still being breast-fed at 6 months of age. CONCLUSIONS: Daily ingestion of CMF between 1 and 2 months of age prevents CMA development. This strategy does not compete with breast-feeding.

Real-World LEAP Implementation.

PURPOSE OF REVIEW: In 2015, findings from the Learning Early About Peanut allergy (LEAP) trial provided the first convincing evidence that peanut allergy may be preventable through early peanut introduction into the infant diet. Here we discuss implementation of the LEAP study findings around the world and emerging evidence of the impacts on infant feeding and food allergy. RECENT FINDINGS: The LEAP findings led to rapid changes in allergy prevention guidelines internationally to recommend early peanut introduction. There is now emerging evidence that this has been followed by a substantial increase in early peanut introduction to infants. Studies investigating the impact of these changes in infant feeding practices on the prevalence of peanut allergy are underway. The LEAP trial represented a significant step forwards in food allergy prevention and new research over the past 5 years has provided insights into how best to implement this intervention in the real world.

Preventing food allergy in infancy and childhood: Systematic review of randomised controlled trials.

BACKGROUND: This systematic review of ways to prevent immediate-onset/IgE-mediated food allergy will inform guidelines by the European Academy of Allergy and Immunology (EAACI). METHODS: The GRADE approach was used. Eleven databases were searched from 1946 to October 2019 for randomized controlled trials (and large prospective cohort studies in the case of breastfeeding). The studies included heterogeneous interventions, populations, and outcomes and so were summarized narratively. RESULTS: Forty-six studies examined interventions to reduce the risk of food allergy in infancy (up to 1 year) or early childhood. The following interventions for pregnant or breastfeeding women and/or infants may have little to no effect on preventing food allergy, but the evidence is very uncertain: dietary avoidance of food allergens, vitamin supplements, fish oil, probiotics, prebiotics, synbiotics, and emollients. Breastfeeding, hydrolyzed formulas, and avoiding cow's milk formula may not reduce the risk of cow's milk protein allergy; however, temporary supplementation with cow's milk formula in the first week of life may increase the risk of cow's milk allergy. Introducing well-cooked egg, but not pasteurized raw egg, from 4 to 6 months probably reduces the risk of hen's egg allergy. Introducing regular peanut consumption into the diet of an infant at increased risk beginning from 4 to 11 months probably results in a large reduction in peanut allergy in countries with a high prevalence. These conclusions about introducing peanut are based on moderate certainty evidence, from single trials in high-income countries. CONCLUSIONS: Sixty percent of the included studies were published in the last 10 years, but much still remains to be understood about preventing food allergy. In particular, there is a need to validate the potential benefits of early introduction of food allergens in a wider range of populations.

Earlier ingestion of peanut after changes to infant feeding guidelines: The EarlyNuts study.

BACKGROUND: Randomized controlled trials demonstrate that timely introduction of peanut to infants reduces the risk of peanut allergy. However, much debate remains regarding how to best achieve earlier peanut introduction at the population level. Our previous study in 2007-2011 (HealthNuts, n = 5300) indicated that few infants were consuming peanut in the first year. Australian infant feeding guidelines were updated in 2016 to recommend introducing peanut before 12 months for all infants. There were no data available on the subsequent effect on peanut introduction or peanut reactions. OBJECTIVE: We sought to assess the consequences of a nonscreening approach to allergenic food introduction in a population-based sample of infants in their first year of life. METHODS: EarlyNuts is a population-based, cross-sectional study of 12-month-old infants in Melbourne, Australia, recruited by using an identical sampling frame and methods to HealthNuts (72% response rate vs 73% response rate in HealthNuts). We report here on the first 860 participants recruited between November 2016 and October 2018. RESULTS: Most infants (88.6%; 95% CI, 86.1% to 90.7%) had introduced peanut by 12 months (median age, 6 months), an increase from 28.4% (95% CI, 27.2% to 29.7%) in the HealthNuts study. By 12 months, the majority of these (76.4%) had consumed peanut more than 4 times, and 28% were eating peanut more than once per week. Preliminary results on parent-reported reactions show that 4.0% of those consuming peanut by 12 months had possible IgE-mediated reactions. CONCLUSIONS: There has been a striking shift toward earlier peanut introduction, with a 3-fold increase in peanut introduction by age 1 year in 2018 compared with 2007-2011.

Update on Early Introduction of Peanut to Prevent Allergy Development: Challenges with Implementation.

PURPOSE OF REVIEW: This review summarizes the evidence leading towards the development of new guidelines that recommend early introduction of peanut to prevent the development of peanut allergy. It also reviews the current understanding of challenges faced with implementation of these recommendations on a widespread basis. RECENT FINDINGS: Prior recommendations to avoid feeding allergenic foods to infants have been updated and reversed. This paradigm shift in advice has created an opportunity on a population level to try and halt the recent increase in prevalence of peanut allergy. However, challenges with implementation of these new guidelines exist in many areas. While evidence supports the early introduction of peanut to prevent allergy development, the application and challenges faced with these recommendations are not fully understood. Persistent efforts from pediatricians and allergists, as well as acceptance from parents, will be necessary in order to make a significant impact on the prevalence of peanut allergy.

Recent advancement to prevent the development of allergy and allergic diseases and therapeutic strategy in the perspective of barrier dysfunction.

Therapeutic strategy in late 20th century to prevent allergic diseases was derived from a conceptual framework of allergens elimination which was as same as that of coping with them after their onset. Manifold trials were implemented; however, most of them failed to verify the effectiveness of their preventive measures. Recent advancement of epidemiological studies and cutaneous biology revealed epidermal barrier dysfunction plays a major role of allergen sensitization and development of atopic dermatitis which ignites the inception of allergy march. For this decade, therapeutic strategy to prevent the development of food allergy has been confronted with a paradigm shift from avoidance and delayed introduction of allergenic foods based on the theoretical concept to early introduction of them based on the clinical and epidemiological evidences. Especially, prevention of peanut allergy and egg allergy has been established with the highest evidence verified by randomized controlled trials, although application in clinical practice should be done with attention. This paradigm shift concerning food allergy was also due to the discovery of cutaneous sensitization risk of food allergens for an infant with eczema revealed by prospective studies. Here we have recognized the increased importance of prevention of eczema/atopic dermatitis in infancy. Two randomized controlled trials using emollients showed successful results in prevention of atopic dermatitis in infancy; however, longer term safety and prognosis including allergy march should be pursued. To establish more fundamental strategy for prevention of the development of allergy, further studies clarifying the mechanisms of interaction between barrier dysfunction and microbial milieu are needed with macroscope to understand the relationship between allergic diseases and a diversity of environmental influences.

Prevention of food allergy - Early dietary interventions.

The prevalence of food allergy has increased over the last 30 years and remains a disease, which significantly impacts on the quality of life of children and their families. Several hypotheses have been formulated to explain the increasing prevalence; this review will focus on the hypothesis that dietary factors may influence the development of food allergy. Historically, the prevention of food allergy has focused on allergen avoidance. However, recent findings from interventional studies have prompted a shift in the mind set from avoidance to early introduction of potentially allergenic foods. This review aims to facilitate a better understanding of contemporary research studies that make use of early introduction of common allergenic foods into infant diets as a preventative strategy against the development of food allergy.

Childcare arrangements and infant feeding practices by family structure and household income among US children aged 0 to 2 years.

The primary objective of this study is to examine the disparities in childcare and infant feeding practices by family structure (single-mother vs. two-parent households) and whether household income level may modify the observed associations by family structure. The cross-sectional data analysis was conducted using a nationally representative sample of children aged 0 to 2 years enrolled in the 2007 National Survey of Children's Health. The analytic sample is children from single mothers (n = 1801, 16.0%) and children from two parents (n = 11 337, 84.0%). Children of single mothers used more non-parental childcare [adjusted odds ratios (AOR) = 2.67, 95% confidence intervals (CI) = 1.99-3.58], especially relative care and centre care, than children of two parents. Lower rates of any breastfeeding for 6 months (AOR = 0.57, 95% CI = 0.43-0.77) and ever breastfed (AOR = 0.66, 95% CI = 0.50-0.89) were reported among children of single mothers than those of two parents. The many observed differences in childcare arrangements and breastfeeding by family structure remained significant in both low- and high-income households. However, children of low-income single mothers had more last-minute changes of childcare arrangement (AOR = 2.34, 95% CI = 1.55-3.52) than children of low-income two-parent households and children of high-income single mothers had more early introduction of complementary foods (AOR = 1.92, 95% CI = 1.12-3.29) than children of high-income two-parent households. This study documented disparities in childcare arrangements and infant feeding practices by family structure, regardless of income level. These findings support the need to for comprehensive policies that address maternal employment leave, childcare support and workplace accommodations and support for breastfeeding for children 0 to 2 years, especially among single mothers, regardless of income.