Maternal and infant dietary patterns are not related to food allergy risk in Singapore children: GUSTO cohort study.

BACKGROUND: We previously reported that delayed allergenic food introduction in infancy did not increase food allergy risk until age 4 years within our prospective cohort. However, it remains unclear whether other aspects of maternal or infant diet play roles in the development of childhood food allergy. OBJECTIVE: Here we examined the relationship between maternal pregnancy and infant dietary patterns and the development of food allergies until age 8 years. METHODS: Among 1152 Singapore GUSTO study mother-infant dyads, the infant's diet was ascertained using food frequency questionnaires at 18 months (M). Maternal dietary patterns during pregnancy were derived from 24-hour diet recalls. Food allergy was determined through interviewer-administered questionnaires at regular time points from infancy to age 8 years (Y) and defined as a positive history of allergic reactions, alongside skin prick tests at M18, Y3, Y5 and Y8. RESULTS: Food allergy prevalence was 2.5% (22/883) at 12 months and generally decreased over time by 8 years (1.9%; 14/736). Higher maternal dietary quality was associated with increased risk of food allergy (p≤0.016), however, odds ratios were modest. Offspring food allergy risk up until 8 years showed no associations with measures of infant diet including timing of solids/food introduction [aOR 0.90 (0.42-1.92)], infant's diet quality [aOR 0.93 (0.88-0.99)] or diet diversity [aOR 0.84 (0.6-1.19)]. Most infants (89%) were first introduced to cow's milk protein within the first month of life, while egg and peanut introduction were delayed (58.3% introduced by mean age 8.8 months and 59.8% by mean age 18.1 months, respectively). CONCLUSIONS: Apart from maternal diet quality showing a modest association, infant's allergenic food introduction, diet quality and dietary diversity were not associated with food allergy development in this Asian paediatric population. Interventional studies are needed to evaluate the efficacy of these approaches to food allergy prevention across different populations.

Growing Up in Singapore with allergies - Lessons learnt from the GUSTO & S-PRESTO cohorts.

Healthcare systems across the world face major challenges due to allergic diseases, known to affect people of all ages. In Singapore, two prominent cohort studies, Growing Up in Singapore Towards healthy Outcomes (GUSTO) and the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO), have made notable advancements to our knowledge and understanding of allergic diseases. These cohorts, which comprised of healthy mother-infant dyads recruited from the healthy Singapore population, have shed light on the complex connections between factors influencing health in early life, preconception and pregnancy, on the pathogenesis of allergic disorders in offspring. GUSTO highlighted significant risk factors in antenatal and early life, such as maternal diet, health and lifestyle choices, as well as infant environmental influences, that contributed to the risk of allergic diseases in the Asian Singaporean population. It also identified differential patterns of allergic disease in comparison to other populations, particularly the role of the microbiome in predicting atopic outcomes. Meanwhile, S-PRESTO further explores the long-term maternal and child outcomes associated with preconception health. Findings seem to suggest that prevention of offspring allergic conditions can be achieved through optimizing maternal health and lifestyle choices before conception. Both studies underscore the significance of early life interventions, preconception health, and personalized approaches to effectively manage and prevent allergies. By leveraging the insights and promising findings from GUSTO and S-PRESTO, future work can drive development of preventative strategies and personalized interventions to reduce burden of allergic diseases in the Singapore population.

Clinical predictors of wheeze trajectories and associations with allergy in Asian children.

BACKGROUND: Childhood wheezing is a highly heterogeneous condition with an incomplete understanding of the characteristics of wheeze trajectories, particularly for persistent wheeze. OBJECTIVE: To characterize predictors and allergic comorbidities of distinct wheeze trajectories in a multiethnic Asian cohort. METHODS: A total of 974 mother-child pairs from the prospective Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort were included in this study. Wheeze and allergic comorbidities in the first 8 years of life were assessed using the modified International Study of Asthma and Allergies in Childhood questionnaires and skin prick tests. Group-based trajectory modeling was used to derive wheeze trajectories and regression was used to assess associations with predictive risk factors and allergic comorbidities. RESULTS: There were 4 wheeze trajectories derived, including the following: (1) early-onset with rapid remission from age 3 years (4.5%); (2) late-onset peaking at age 3 years and rapidly remitting from 4 years (8.1%); (3) persistent with a steady increase to age 5 years and high wheeze occurrence until 8 years (4.0%); and (4) no or low wheeze (83.4%). Early-onset wheezing was associated with respiratory infections during infancy and linked to subsequent nonallergic rhinitis throughout childhood. Late-onset and persistent wheeze shared similar origins characterized by parent-reported viral infections in later childhood. However, persistent wheezing was generally more strongly associated with a family history of allergy, parent-reported viral infections in later childhood, and allergic comorbidities as compared with late-onset wheezing. CONCLUSION: The timing of viral infection occurrence may determine the type of wheeze trajectory development in children. Children with a family history of allergy and viral infections in early life may be predisposed to persistent wheeze development and the associated comorbidities of early allergic sensitization and eczema.

A systematic review of quality and consistency of clinical practice guidelines on the primary prevention of food allergy and atopic dermatitis.

Background and aims: With an increasing number of Clinical Practice Guidelines (CPGs) addressing primary prevention of food allergy and atopic dermatitis, it is timely to undertake a comprehensive assessment of the quality and consistency of recommendations and evaluation of their implementability in different geographical settings. Methods: We systematically reviewed CPGs from 8 international databases and extensive website searches. Seven reviewers screened records in any language and then used the AGREE II and AGREE REX instruments to critically appraise CPGs published between January 2011 and April 2022. Results: Our search identified 2138 relevant articles, of which 30 CPGs were eventually included. Eight (27%) CPGs were shortlisted based on our predefined quality criteria of achieving scores >70% in the "Scope and Purpose" and "Rigour of Development" domains of the AGREE II instrument. Among the shortlisted CPGs, scores on the "Applicability" domain were generally low, and only 3 CPGs rated highly in the "Implementability" domain of AGREE-REX, suggesting that the majority of CPGs fared poorly on global applicability. Recommendations on maternal diet and complementary feeding in infants were mostly consistent, but recommendations on use of hydrolysed formula and supplements varied considerably. Conclusion: The overall quality of a CPG for Food Allergy and Atopic Dermatitis prevention did not correlate well with its global applicability. It is imperative that CPG developers consider stakeholders' preferences, local applicability, and adapt existing recommendations to each individual population and healthcare system to ensure successful implementation. There is a need for development of high-quality CPGs for allergy prevention outside of North America and Europe. PROSPERO registration number: CRD42021265689.

Quality and consistency of clinical practice guidelines on the prevention of food allergy and atopic dermatitis: Systematic review protocol.

Background and aims: Allergy prevention strategies have gained significant traction as a means to attenuate the growing burden of allergic diseases over the past decade. As the evidence base for primary prevention of food allergy (FA) and atopic dermatitis (AD) is constantly advancing, clinical practice guideline (CPG) recommendations on interventions for FA and AD prevention vary in quality and consistency among professional organizations. We present a protocol for a systematic review of CPGs on primary prevention of FA and AD. Methods: We will systematically review and appraise all CPGs addressing primary prevention of FA and AD and report our findings according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases and manual website searches from January 2011 to March 2021 without language or geographical restrictions, and supplemented by author contact, will generate the list of potentially relevant CPGs to screen. Evaluation of the methodological quality, consistency, and global applicability of shortlisted CPGs will be performed by members of the Allergy Prevention Work Group of the World Allergy Organization (WAO) using the Appraisal of Guidelines for Research and Evaluation (AGREE) II and AGREE-REX (Recommendations EXcellence). instruments. Guideline contents, consistency, and quality of the recommendations will be summarised in tabular and narrative formats. We aim to present consolidated recommendations from international guidelines of the highest methodological quality and applicability, as determined by AGREE II and AGREE-REX. Dissemination: This systematic review will provide a succinct overview of the quality and consistency of recommendations across all existing CPGs for FA and AD prevention, as well as crucial perspectives on applicability of individual recommendations in different geographical contexts. Results from this systematic review will be reported in a peer-reviewed journal. It will also inform a position statement by WAO to provide a practical framework to guide the development of future guidelines for allergy prevention worldwide. Prospero registration number: CRD42021265689.

Prevalence of IgE-mediated cow milk, egg, and peanut allergy in young Singapore children.

Background: The rising prevalence of food allergy reported in the United States, UK, and Australia may be attributable to the rise in peanut allergy prevalence. The food allergy prevalence in other parts of the world such as Asia is, however, less well documented. Objective: This study aimed to evaluate the prevalence of cow's milk, egg, and peanut allergies in a general population of Singaporean children below 30 months of age. Methods: A total of 4,115 children from the general population who attended well-baby visits between 2011 and 2015 completed standardized questionnaires to elicit a convincing history of food allergy to estimate the population prevalence of food allergies. Results: The prevalence of a convincing history of cow's milk allergy was 0.51% (95% confidence interval [CI], 0.3-0.7), hen's egg allergy 1.43% (95% CI, 1.1-1.8), and peanut allergy 0.27% (95% CI, 0.12-0.42). Of the 15 of 59 children with a convincing history of hen's egg allergy who consented, 12 (80%) had corroborative positive skin prick tests. Conclusion: The prevalence of food allergy, in particular peanut allergy, in children below 2 years of age is lower in this South East Asian population than reported in Western cohorts. Further research should focus on deciphering differential risk factors for food allergy across different geographical locations.

Allergic sensitization trajectories to age 8 years in the Singapore GUSTO cohort.

Background: Allergic sensitization is linked to allergy development, with early sensitization often associated with worse outcomes. We aimed to identify if distinct allergic sensitization trajectories existed within a diverse and multi-ethnic Asian cohort. Methods: We administered modified ISAAC questionnaires in the first 8 years and conducted skin prick testing at ages 18 months, 3, 5 and 8 years in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. We used latent class analysis to derive allergic sensitization trajectories, and adjusted odds ratios (AOR) to evaluate predictive risk factors and associations with allergic comorbidities. Results: Among 997 children, three trajectories were identified: early food and mite sensitization (16.2%), late mite sensitization (24.2%) and no/low sensitization (59.6%). Early food and mite sensitization was associated with early eczema by 6 months [AOR (95%CI) 4.67 (1.78-12.28)], increased risk of wheeze by 3-8 years (ARR 1.72-1.99) and eczema in the first 8 years of life (ARR 1.87-2.41). Late mite sensitization was associated with female sex [AOR 0.58 (0.35-0.96)], cesarean section [AOR 0.54 (0.30-0.98)], early eczema by 6 months [AOR 3.40 (1.38-8.42)], and increased risk of eczema by 18 months [ARR 1.47 (1.03-2.08)] and 8 years [ARR 1.35 (1.05-1.73)]. Conclusion: Early onset of eczema and early allergic sensitization were strongly associated. Early sensitization, especially to house dust mites, was associated with increased risks of developing wheeze and eczema, pointing to the importance of developing preventive perinatal interventions and effective therapeutics for sensitized toddlers.

Evaluation of Stool Short Chain Fatty Acids Profiles in the First Year of Life With Childhood Atopy-Related Outcomes.

Introduction: Short chain fatty acids (SCFAs) are the main intestinal intermediate and end products of metabolism of dietary fibers/polyphenols by the gut microbiota. The aim of this study was to evaluate the biological implication of stool SCFA profiles determined in the first year of life on the clinical presentation of allergic outcomes in childhood. Methods: From the Growing Up in Singapore Toward healthy Outcomes (GUSTO) cohort, a sub-cohort of 75 participants was recruited. Scheduled questionnaire data was collected for cumulative prevalence of physician-diagnosed eczema, wheezing with the use of nebuliser, and allergen sensitization till the age of 8 years. Stool samples collected at week 3 and months 3, 6 and 12 were quantitated for 9 SCFAs using LC/MS/MS. SCFA data were grouped into lower (below the 25th) and higher (above the 75th percentiles) categories. Generalized Linear Mixed Models was employed to analyse longitudinal association between SCFAs and atopy-related outcomes. Results: Children with lower stool butyric acid levels (≤25th percentile) over the first 3 time points had higher odds ratio (OR) for wheezing (adjOR = 14.6), eczema (adjOR = 13.2), food sensitization (adjOR = 12.3) and combined outcomes of both wheezing and eczema (adjOR = 22.6) till age 8 years, compared to those with higher levels (≥75 percentile). Additionally, lower longitudinal levels of propionic acid (≤25th percentile) over 4 time points in first year of life was associated with recurrent wheezing (≥2 episodes) till 8 years (adjOR = 7.4) (adj p < 0.05). Conclusion: Our results suggest that relatively low levels of gut SCFAs in early life are associated with increased susceptibility to atopic-related outcomes in childhood.

Associations Between Eczema and Attention Deficit Hyperactivity Disorder Symptoms in Children.

Background: Epidemiological studies suggest a link between eczema and attention deficit hyperactivity disorder (ADHD), but underlying mechanisms have not been examined. Objective: We aim to investigate the association between eczema and subsequent ADHD symptoms in the Growing Up in Singapore Towards healthy Outcomes cohort and explore the role of pro-inflammatory cytokines and gut microbiome. Methods: The modified International Study of Asthma and Allergies in Childhood questionnaire and Computerized Diagnostic Interview Schedule for Children Version IV were administered to assess reported eczema within the first 18 months and presence of ADHD symptoms at 54 months, respectively. Skin prick testing at 18 months, cytokines in maternal blood during pregnancy and cord blood and the mediating role of the gut microbiome at 24 months were assessed. Results: After adjusting for confounders, eczema with or without a positive skin prick test was associated with doubling the risk of ADHD symptoms. No differences in maternal and cord blood cytokines were observed in children with and without eczema, or children with and without ADHD. Gut microbiome dysbiosis was observed in children with eczema and children with ADHD. Children with eczema also had lower gut bacterial Shannon diversity. However, the relationship between eczema and ADHD was not mediated by gut microbiome. Conclusion: Early life eczema diagnosis is associated with a higher risk of subsequent ADHD symptoms in children. We found no evidence for underlying inflammatory mechanism or mediation by gut microbiome dysbiosis. Further research should evaluate other mechanisms underlying the link between eczema and ADHD. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT01174875], identifier [NCT01174875].

Associations Between Maternal Distress During Early Life Periods and Offspring Respiratory Infections and Allergic Outcomes.

Background: Increasing evidence suggests that maternal distress is a risk factor for development of respiratory infections and allergic diseases in the offspring. We aim to evaluate the link between maternal distress during critical periods in early life, namely the preconception, pregnancy and postnatal periods, and development of respiratory infections and allergic diseases in the offspring from the Singapore PREconception Study of long Term maternal and child Outcomes (S-PRESTO) cohort. Methods: Maternal perceived distress was evaluated using validated questionnaires including Beck Depression Inventory-II (BDI-II) administered during three time periods: preconception (three months apart at four timepoints), pregnancy (during each trimester) and postnatal (3 and 6 months post-delivery). Child eczema, rhinitis and wheeze outcomes were evaluated using a modified ISAAC questionnaire at ages 3, 6, 12, and 18 months. Child allergic sensitization was determined by skin prick testing at 18 months. Results: Among 332 mother-child pairs studied, higher maternal distress during preconception and pregnancy increased the risks of wheeze development in the first 18 months; for example, preconception and pregnancy BDI-II scores ≥20 were associated with increased risks of wheeze by 18 months [adjusted risk ratios 3.2 (95%CI 1.1-9.4) and 2.5 (1.0-5.9), respectively]. Emotional and practical support from family during preconception decreased the risks of offspring wheeze. No associations were observed between maternal distress and offspring eczema, rhinitis and allergic sensitization. Conclusion: Maternal distress during critical early life periods was associated with offspring wheeze in the first 18 months of life. Supporting maternal mental health even before pregnancy could reduce the risk of offspring wheeze.

Emollients in infancy to prevent atopic dermatitis: A systematic review and meta-analysis.

BACKGROUND: Several studies have evaluated prophylactic emollients as a preventive strategy against atopic dermatitis (AD) and food allergy (FA). We aimed to synthesize the evidence on efficacy and safety of prophylactic emollients started during the first 6 weeks of infancy for prevention of AD and FA. METHODS: MEDLINE, Embase, CINAHL, BIOSIS, and the Cochrane Library databases were searched systematically for randomized controlled trials published between January 2000 and July 2020, which assessed the effects of prophylactic emollients initiated within the first 6 weeks of life on the development of AD within 24 months of age, compared to no treatment. Risk of bias and certainty of evidence were assessed using the Cochrane Collaboration's tool and GRADE process, respectively. RESULTS: Of the 1486 articles identified, 10 studies fulfilled inclusion criteria. In infants given emollients, there was no significant reduction on the development of AD (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.64, 1.10) compared to the control group. However, there was significant benefit of prophylactic emollients (RR 0.75, 95% CI 0.62-1.11) in the high-risk population (n = 8 studies). There was also significant benefit (RR 0.59, 95% CI 0.43, 0.81) in studies (n = 6) where emollients were used continuously to the point of AD assessment; but not when treatment was ceased for an interval before AD assessment. There were no protective effects on FA found. CONCLUSION: The prophylactic application of emollients initiated in early infancy may prevent AD, especially in high-risk populations and when used continuously. We hypothesize that emollients may delay rather than prevent AD.

Fexofenadine: review of safety, efficacy and unmet needs in children with allergic rhinitis.

Allergic rhinitis (AR) is the most common undiagnosed chronic condition in children. Moderate/severe AR symptoms significantly impair quality of life, and cause sleep disruption, absenteeism and decreased productivity. Additionally, untreated AR predisposes children to asthma and other chronic conditions. Although intranasal corticosteroids are the most effective pharmacologic treatment for AR, oral antihistamines are often preferred. First-generation antihistamines may be chosen to relieve AR symptoms as they are inexpensive and widely available; however, they cause sedative and cardiovascular negative effects due to poor receptor selectivity. Therefore, second-generation antihistamines were developed to reduce adverse effects while retaining efficacy. There are fewer clinical trials in children than adults, therefore, efficacy and safety data is limited, particularly in children under 6 years, highlighting the need to generate these data in young children with AR. Fexofenadine, a highly selective second-generation antihistamine, effectively alleviates symptoms of AR, is non-sedating due to decreased blood-brain barrier permeability, and is devoid of cardiovascular side effects. Importantly, fexofenadine relieves the ocular symptoms of allergic conjunctivitis, which occur concomitantly with AR, improving quality of life. Overall, fexofenadine displays a favorable safety profile and results in greater treatment satisfaction in children compared with other second-generation antihistamines. This review aimed to evaluate and compare the safety and efficacy of fexofenadine with other available first- and second-generation antihistamines in children with AR.

Atopic dermatitis trajectories to age 8 years in the GUSTO cohort.

BACKGROUND: The heterogeneity of childhood atopic dermatitis (AD) underscores the need to understand latent phenotypes that may inform risk stratification and disease prognostication. OBJECTIVE: To identify AD trajectories across the first 8 years of life and investigate risk factors associated with each trajectory and their relationships with other comorbidities. METHODS: Data were collected prospectively from 1152 mother-offspring dyads in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort from ages 3 months to 8 years. AD was defined based on parent-reported doctor's diagnosis. An unsupervised machine learning technique was used to determine AD trajectories. RESULTS: Three AD trajectories were identified as follows: early-onset transient (6.3%), late-onset persistent (6.3%) and early-onset persistent (2.1%), alongside a no AD/reference group (85.2%). Early-onset transient AD was positively associated with male gender, family history of atopy, house dust mite sensitization and some measures of wheezing. Early-onset persistent AD was associated with antenatal/intrapartum antibiotic use, food sensitization and some measures of wheezing. Late-onset persistent AD was associated with a family history of atopy, some measures of house dust mite sensitization and some measures of allergic rhinitis and wheezing. CONCLUSION AND CLINICAL RELEVANCE: Three AD trajectories were identified in this birth cohort, with different risk factors and prognostic implications. Further work is needed to understand the molecular and immunological origins of these phenotypes.