Systematic review of the association between short chain fatty acids and allergic diseases.

We performed a systematic review to investigate the current evidence on the association between allergic diseases and short chain fatty acids (SCFAs), which are microbially produced and suggested as one mechanism on how gut microbiome affects the risk of allergic diseases. Medline, Embase and Web of Science were searched from data inception until September 2022. We identified 37 papers, of which 17 investigated prenatal or early childhood SCFAs and the development of allergic diseases in childhood, and 20 assessed SCFAs in patients with pre-existing allergic diseases. Study design, study populations, outcome definition, analysis method and reporting of the results varied between papers. Overall, there was some evidence showing that the three main SCFAs (acetate, propionate and butyrate) in the first few years of life had a protective effect against allergic diseases, especially for atopic dermatitis, wheeze or asthma and IgE-mediated food allergy in childhood. The association between each SCFA and allergic disease appeared to be different by disease and the age of assessment. Further research that can determine the potentially timing specific effect of each SCFA will be useful to investigate how SCFAs can be used in treatment or in prevention against allergic diseases.

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.

Prevalence, risk factors and parental perceptions of gastroesophageal reflux disease in Asian infants in Singapore.

INTRODUCTION: Infant gastroesophageal reflux disease (GERD) is a significant cause of concern to parents. This study seeks to describe GERD prevalence in infants, evaluate possible risk factors and assess common beliefs influencing management of GERD among Asian parents. METHODS: Mother-infant dyads in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) cohort were prospectively followed from preconception to 12 months post-delivery. GERD diagnosis was ascertained through the revised Infant Gastroesophageal Reflux Questionnaire (I-GERQ-R) administered at 4 time points during infancy. Data on parental perceptions and lifestyle modifications were also collected. RESULTS: The prevalence of infant GERD peaked at 26.5% at age 6 weeks, decreasing to 1.1% by 12 months. Infants exclusively breastfed at 3 weeks of life had reduced odds of GERD by 1 year (adjusted odds ratio 0.43, 95% confidence interval 0.19-0.97, P=0.04). Elimination of "cold or heaty food" and "gas producing" vegetables, massaging the infant's abdomen and application of medicated oil to the infant's abdomen were quoted as major lifestyle modifications in response to GERD symptoms. CONCLUSION: Prevalence of GERD in infants is highest in the first 3 months of life, and the majority outgrow it by 1 year of age. Infants exclusively breastfed at 3 weeks had reduced odds of GERD. Cultural-based changes such as elimination of "heaty or cold" food influence parental perceptions in GERD, which are unique to the Asian population. Understanding the cultural basis for parental perceptions and health-seeking behaviours is crucial in tailoring patient education appropriately for optimal management of infant GERD.

Associations between grass pollen exposures in utero and in early life with food allergy in 12-month-old infants.

Birth during pollen seasons may influence food allergy risk but no study has assessed pollen exposure. Using the HealthNuts population-based cohort of 5276 infants, we assessed grass pollen exposures, in utero and up to the first 6 months of life, on hen's egg, sesame and peanut allergy outcomes at 12 months. Cumulative pollen exposure in the first 7 days of life increased risk of peanut sensitization aMOR (adjusted multinomial odds ratio) = 1.21 (95% CI: 1.01-1.44). Exposure between first 4-6 months of life increased risk of hen's egg aMOR = 1.02 (95% CI: 1.004-1.04) and sensitization to all foods aMOR = 1.02 (95% CI: 1.003-1.04). Grass pollen exposure was associated with food challenge diagnosed food allergy, but only among infants with a maternal history of food allergy. Exposure to grass pollen in the intrauterine period and infancy may be important but more studies are needed to replicate these findings.

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.

Children of Asian ethnicity in Australia have higher risk of food allergy and early-onset eczema than those in Singapore.

BACKGROUND: In Western countries, Asian children have higher food allergy risk than Caucasian children. The early-life environmental exposures for this discrepancy are unclear. We aimed to compare prevalence of food allergy and associated risk factors between Asian children in Singapore and Australia. METHODS: We studied children in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort (n = 878) and children of Asian ancestry in the HealthNuts cohort (n = 314). Food allergy was defined as a positive SPT ≥3 mm to egg or peanut AND either a convincing history of IgE-mediated reaction at 18 months (GUSTO) or a positive oral food challenge at 14-18 months (HealthNuts). Eczema was defined as parent-reported doctor diagnosis. RESULTS: Food allergy prevalence was 1.1% in Singapore and 15.0% in Australia (P<0.001). Egg introduction was more often delayed (>10 months) in Singapore (63.5%) than Australia (16.3%; P<0.001). Prevalence of early-onset eczema (<6 months) was lower in Singapore (8.4%) than Australia (30.5%) (P<0.001). Children with early-onset eczema were more likely to have food allergy than those without eczema in Australia [aOR 5.11 (2.34-11.14); P<0.001] and Singapore [aOR4.00 (0.62-25.8); P = 0.145]. CONCLUSIONS: Among Asian children, prevalence of early-onset eczema and food allergy was higher in Australia than Singapore. Further research with larger sample sizes and harmonized definitions of food allergy between cohorts is required to confirm and extend these findings. Research on environmental factors influencing eczema onset in Australia and Singapore may aid understanding of food allergy pathogenesis in different parts of the world.

Global differences in atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder, with a highly variable prevalence worldwide. Recent evidence, however, has shown an increase in prevalence in the Asia Pacific region. Nevertheless, most of the published literature has focused mainly on Western populations, and only few clinical trials have included subgroups of other ethnic populations. Reasons for the observed ethnic and geographical differences in AD are not well established. This calls into question the need for a better understanding of AD pathogenesis and inter-ethnic differences in clinical and immuno-phenotypes. These differences may reflect inherent variability in disease mechanisms between populations, which in turn may impact upon treatment responses such as biologics that are currently tailored mainly to a specific immuno-phenotype (T-helper type 2 dominant). In this article, we reviewed existing literature on the prevalence of AD globally, highlighting differences, if any, in the clinical and immuno-phenotypes of AD between different ethnicities. We discussed genetic and environmental factors that affect AD in different populations and therapeutic considerations. Our review highlights AD as a disease with ethnic-dependent clinical and immunological heterogeneity and calls for greater inclusion of ethnic diversity in future research in order to develop targeted treatments.

Genetic determinants of paediatric food allergy: A systematic review.

BACKGROUND: The genetic determinants of food allergy have not been systematically reviewed. We therefore systematically reviewed the literature on the genetic basis of food allergy, identifying areas for further investigation. METHODS: We searched three electronic databases (MEDLINE, EMBASE and PubMed) on 9 January 2018. Two authors screened retrieved articles for review according to inclusion criteria and extracted relevant information on study characteristics and measures of association. Eligible studies included those that reported an unaffected nonatopic control group, had genetic information and were carried out in children. RESULTS: Of the 2088 studies retrieved, 32 met our inclusion criteria. Five were genome-wide association studies, and the remaining were candidate gene studies. Twenty-two of the studies were carried out in a predominantly Caucasian population with the remaining 10 from Asian-specific populations or unspecified ethnicity. We found FLG, HLA, IL10, IL13, as well as some evidence for other variants (SPINK5, SERPINB and C11orf30) that are associated with food allergy. CONCLUSIONS: Little genetic research has been carried out in food allergy, with FLG, HLA and IL13 being the most reproducible genes for an association with food allergy. Despite promising results, existing genetic studies on food allergy are inundated with issues such as inadequate sample size and absence of multiple testing correction. Few included replication analyses or population stratification measures. Studies addressing these limitations along with functional studies are therefore needed to unravel the mechanisms of action of the identified genes.

The global incidence and prevalence of anaphylaxis in children in the general population: A systematic review.

BACKGROUND: Despite an increasing number of publications from individual countries and regions, there is still no systematic review of the global epidemiology of anaphylaxis in the general paediatric population. METHODS: We conducted a systematic review, using a protocol registered and published with the international prospective register of systematic reviews (PROSPERO). Results were reported following PRISMA guidelines. The search strategy was designed in Medline (ovid) and modified for Embase (ovid) and PubMed. Papers were screened by two independent reviewers following selection and exclusion criteria. Data extraction and risk of bias assessment were completed by the same two reviewers. Studies in adults only or those that did not report data in children separately were excluded. RESULTS: A final total of 59 articles were included. Of these, 5 reported cumulative incidence, 39 reported incidence rate and 17 reported prevalence data. The incidence of anaphylaxis in children worldwide varied widely, ranging from 1 to 761 per 100 000 person-years for total anaphylaxis and 1 to 77 per 100 000 person-years for food-induced anaphylaxis. The definition of anaphylaxis from NIAID/FAAN was the most commonly used. Gender and ethnicity were demographic risk factors associated with anaphylaxis in children. Increasing total or food-induced anaphylaxis incidence over time was reported by 19 studies. CONCLUSION: The reported incidence of anaphylaxis in children varied widely. Studies in developing countries are underrepresented. To accurately compare anaphylaxis incidence between countries and investigate the time trends, further studies using a standardized definition across different countries are required.

Children with East Asian-Born Parents Have an Increased Risk of Allergy but May Not Have More Asthma in Early Childhood.

BACKGROUND: We previously reported that infants with Asian-born parents are 3 times more likely to have IgE-mediated food allergy than those with Australian-born parents. It is unknown whether this translates to the increased risk of other allergic diseases later in childhood and whether ancestry interacts with other risk factors for allergic disease development. OBJECTIVE: To compare prevalence and risk factors for allergic rhinitis, asthma, and aeroallergen sensitization at age 6 between children with East Asian-born and Caucasian-born parents. METHODS: A total of 5276 1-year-old infants were recruited into a population-based longitudinal study of allergy. A total of 4455 children participated in age 6 follow-up (84.4%), including 3015 with Caucasian-born parents and 415 with East Asian-born parents. Children underwent skin prick tests to aeroallergens and questionnaires captured data on asthma, eczema, and allergic rhinitis. RESULTS: Compared with children with Caucasian-born parents, children of East Asian-born parents had more allergic rhinitis (19.9% [95% confidence interval (CI) 14.9-26] vs 9.3% [95% CI 8-10.8], P < .001) and aeroallergen sensitization (64.3% [95% CI 57.5-70.5] vs 34.4% [95% CI 32.2-36.7], P < .001) at age 6. Asthma was similar in both groups (9.1% [95% CI 6.2-13.2] vs 11.7% [95% CI 10.4-13.1]), P = .21. Children with IgE-mediated food allergy and eczema in infancy were 3 times more likely to have asthma and 2 times more likely to have allergic rhinitis at age 6, irrespective of ancestry. CONCLUSIONS: Children of East Asian ancestry born in Australia have a higher burden of most allergic diseases in the first 6 years of life, whereas asthma may follow a different pattern. IgE-mediated food allergy and eczema at age 1 increase the risk of asthma and allergic rhinitis irrespective of ancestry.

Asian children living in Australia have a different profile of allergy and anaphylaxis than Australian-born children: A State-wide survey.

BACKGROUND: Asian children born in Australia have higher rates of eczema and nut allergy than non-Asian children. However, it is not known whether this country of birth differential exists for other allergies or anaphylaxis risk. OBJECTIVE: We investigated the influence of maternal and child's country of birth on the prevalence of parent-reported eczema, asthma, food allergy and being diagnosed by a doctor as being "at risk of anaphylaxis." METHODS: We assessed the relationship between mother and child country of birth and allergies using the 2010 School Entrant Health Questionnaire, completed for 57 005 5-year old children (85.8% response rate) in Victoria, Australia. Analyses were conducted using logistic regression with results presented as odds ratios (OR) with 95% confidence intervals (CIs). RESULTS: Children born in Australia to Asian-born mothers were more likely to have parent-reported food allergy (OR 2.33, 95%CI 1.96-2.77) and eczema (OR 2.04, 95%CI 1.73-2.41), but not more likely to have asthma (OR 0.87, 95% CI 0.74-1.02) than non-Asian children. By contrast, children born in Asia who subsequently migrated to Australia had a lower risk of food allergy (OR 0.33, 95%CI 0.20-0.55), eczema (OR 0.37, 95%CI 0.24-0.57) and asthma (OR 0.29, 95% CI 0.21-0.40). Patterns of anaphylaxis risk differed depending on the trigger. Compared with Australian-born non-Asian children, Australian-born Asian children were more likely to be diagnosed as being at risk of both food-induced and non-food-induced anaphylaxis. For children born in Asia, risk was lower for anaphylaxis to milk, peanut and tree nuts compared to non-Asian children, but higher for soy, wheat and non-food triggers. CONCLUSIONS AND CLINICAL RELEVANCE: Patterns of allergy/anaphylaxis risk and their triggers differed according to both ethnicity and country of birth, suggesting a gene-environment factor is in play. The difference in patterns for asthma compared with other atopic diseases is surprising and warrants further exploration.

Polymorphisms affecting vitamin D-binding protein modify the relationship between serum vitamin D (25[OH]D3) and food allergy.

BACKGROUND: There is evolving evidence that vitamin D insufficiency may contribute to food allergy, but findings vary between populations. Lower vitamin D-binding protein (DBP) levels increase the biological availability of serum vitamin D. Genetic polymorphisms explain almost 80% of the variation in binding protein levels. OBJECTIVE: We sought to investigate whether polymorphisms that lower the DBP could compensate for adverse effects of low serum vitamin D on food allergy risk. METHODS: From a population-based cohort study (n = 5276) we investigated the association between serum 25-hydroxyvitamin D3 (25[OH]D3) levels and food allergy at age 1 year (338 challenge-proven food-allergic and 269 control participants) and age 2 years (55 participants with persistent and 50 participants with resolved food allergy). 25(OH)D3 levels were measured using liquid chromatography-tandem mass spectrometry and adjusted for season of blood draw. Analyses were stratified by genotype at rs7041 as a proxy marker of DBP levels (low, the GT/TT genotype; high, the GG genotype). RESULTS: Low serum 25(OH)D3 level (≤50 nM/L) at age 1 years was associated with food allergy, particularly among infants with the GG genotype (odds ratio [OR], 6.0; 95% CI, 0.9-38.9) but not in those with GT/TT genotypes (OR, 0.7; 95% CI, 0.2-2.0; P interaction = .014). Maternal antenatal vitamin D supplementation was associated with less food allergy, particularly in infants with the GT/TT genotype (OR, 0.10; 95% CI, 0.03-0.41). Persistent vitamin D insufficiency increased the likelihood of persistent food allergy (OR, 12.6; 95% CI, 1.5-106.6), particularly in those with the GG genotype. CONCLUSIONS: Polymorphisms associated with lower DBP level attenuated the association between low serum 25(OH)D3 level and food allergy, consistent with greater vitamin D bioavailability in those with a lower DBP level. This increases the biological plausibility of a role for vitamin D in the development of food allergy.

Immune Modulation by Vitamin D and Its Relevance to Food Allergy.

Apart from its classical function in bone and calcium metabolism, vitamin D is also involved in immune regulation and has been linked to various cancers, immune disorders and allergic diseases. Within the innate and adaptive immune systems, the vitamin D receptor and enzymes in monocytes, dendritic cells, epithelial cells, T lymphocytes and B lymphocytes mediate the immune modulatory actions of vitamin D. Vitamin D insufficiency/deficiency early in life has been identified as one of the risk factors for food allergy. Several studies have observed an association between increasing latitude and food allergy prevalence, plausibly linked to lower ultraviolet radiation (UVR) exposure and vitamin D synthesis in the skin. Along with mounting epidemiological evidence of a link between vitamin D status and food allergy, mice and human studies have shed light on the modulatory properties of vitamin D on the innate and adaptive immune systems. This review will summarize the literature on the metabolism and immune modulatory properties of vitamin D, with particular reference to food allergy.

Environmental and genetic determinants of vitamin D insufficiency in 12-month-old infants.

We aimed to investigate the relationship between genetic and environmental exposure and vitamin D status at age one, stratified by ethnicity. This study included 563 12-month-old infants in the HealthNuts population-based study. DNA from participants' blood samples was genotyped using Sequenom MassARRAY MALDI-TOF system on 28 single nucleotide polymorphisms (SNPs) in six genes. Using logistic regression, we examined associations between environmental exposure and SNPs in vitamin D pathway and filaggrin genes and vitamin D insufficiency (VDI). VDI, defined as serum 25-hydroxyvitamin D3(25(OH)D3) level ≤50nmol/L, was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infants were stratified by ethnicity determined by parent's country of birth. Infants formula fed at 12 months were associated with reduced odds of VDI compared to infants with no current formula use at 12 months. This association differed by ethnicity (Pinteraction=0.01). The odds ratio (OR) of VDI was 0.29 for Caucasian infants (95% CI, 0.18-0.47) and 0.04 for Asian infants (95% CI, 0.006-0.23). Maternal vitamin D supplementation during pregnancy and/or breastfeeding were associated with increased odds of infants being VDI (OR, 2.39; 95% CI, 1.11-5.18 and OR, 2.5; 95% CI, 1.20-5.24 respectively). Presence of a minor allele for any GC SNP (rs17467825, rs1155563, rs2282679, rs3755967, rs4588, rs7041) was associated with increased odds of VDI. Caucasian infants homozygous (AA) for rs4588 had an OR of 2.49 of being associated with VDI (95% CI, 1.19-5.18). In a country without routine infant vitamin D supplementation or food chain fortification, formula use is strongly associated with a reduced risk of VDI regardless of ethnicity. There was borderline significance for an association between filaggrin mutations and VDI. However, polymorphisms in vitamin D pathway related genes were associated with increased likelihood of being VDI in infancy.