Trajectories of early-onset rhinitis in the Singapore GUSTO mother-offspring cohort.

BACKGROUND: The natural history of childhood rhinitis is not well described. OBJECTIVE: This study aimed to identify different rhinitis trajectories in early childhood and their predictors and allergic associations. METHODS: Rhinitis symptoms were ascertained prospectively from birth until 6 years using standardized questionnaires in 772 participants. Rhinitis was defined as one or more episodes of sneezing, runny and/or blocked nose >2 weeks duration. Latent trajectories were identified using group-based modelling, and their predictive risk factors and allergic associations were examined. RESULTS: Three rhinitis trajectory groups were identified: 7.6% (n = 59) were termed early transient rhinitis, 8.6% (n = 66) late transient rhinitis, and 6.6% (n = 51) persistent rhinitis. The remaining 77.2% (n = 596) were classified as non-rhinitis/reference group. Early transient rhinitis subjects were more likely of Indian ethnicity, had siblings, reported childcare attendance, early wheezing and eczema in the first 3 years of life. Late transient rhinitis was associated with antenatal exposure to smoking, higher maternal education levels, and wheezing at age 36-72 months. Persistent rhinitis was associated with male gender, paternal and maternal history of atopy, eczema, and house dust mite sensitization. CONCLUSIONS & CLINICAL RELEVANCE: Risk factors for early transient rhinitis involve a combination of genetic and early environmental exposures, whereas late transient rhinitis may relate to maternal factors and early respiratory infections independent of atopy. In contrast, persistent rhinitis is strongly associated with atopic risk and likely represents the typical trajectory associated with allergic disorders. Allergic rhinitis symptoms may commence as early as the first year of life and may inform development of early interventive strategies.

Epicutaneous sensitization to food allergens in atopic dermatitis: What do we know?

Atopic dermatitis (AD) is a chronic inflammatory skin disease mainly affecting children, which has no definitive curative therapy apart from natural outgrowing. AD is persistent in 30%-40% of children. Epithelial barrier dysfunction in AD is a significant risk factor for the development of epicutaneous food sensitization, food allergy, and other allergic disorders. There is evidence that prophylactic emollient applications from birth may be useful for primary prevention of AD, but biomarkers are needed to guide cost-effective targeted therapy for high-risk individuals. In established early-onset AD, secondary preventive strategies are needed to attenuate progression to other allergic disorders such as food allergy, asthma, and allergic rhinitis (the atopic march). This review aims to describe the mechanisms underpinning the development of epicutaneous sensitization to food allergens and progression to clinical food allergy; summarize current evidence for interventions to halt the progression from AD to food sensitization and clinical food allergy; and highlight unmet needs and directions for future research.

Establishment of the nasal microbiota in the first 18 months of life: Correlation with early-onset rhinitis and wheezing.

BACKGROUND: Dynamic establishment of the nasal microbiota in early life influences local mucosal immune responses and susceptibility to childhood respiratory disorders. OBJECTIVE: The aim of this case-control study was to monitor, evaluate, and compare development of the nasal microbiota of infants with rhinitis and wheeze in the first 18 months of life with those of healthy control subjects. METHODS: Anterior nasal swabs of 122 subjects belonging to the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) birth cohort were collected longitudinally over 7 time points in the first 18 months of life. Nasal microbiota signatures were analyzed by using 16S rRNA multiplexed pair-end sequencing from 3 clinical groups: (1) patients with rhinitis alone (n = 28), (2) patients with rhinitis with concomitant wheeze (n = 34), and (3) healthy control subjects (n = 60). RESULTS: Maturation of the nasal microbiome followed distinctive patterns in infants from both rhinitis groups compared with control subjects. Bacterial diversity increased over the period of 18 months of life in control infants, whereas infants with rhinitis showed a decreasing trend (P < .05). An increase in abundance of the Oxalobacteraceae family (Proteobacteria phylum) and Aerococcaceae family (Firmicutes phylum) was associated with rhinitis and concomitant wheeze (adjusted P < .01), whereas the Corynebacteriaceae family (Actinobacteria phylum) and early colonization with the Staphylococcaceae family (Firmicutes phylum; 3 weeks until 9 months) were associated with control subjects (adjusted P < .05). The only difference between the rhinitis and control groups was a reduced abundance of the Corynebacteriaceae family (adjusted P < .05). Determinants of nasal microbiota succession included sex, mode of delivery, presence of siblings, and infant care attendance. CONCLUSION: Our results support the hypothesis that the nasal microbiome is involved in development of early-onset rhinitis and wheeze in infants.

Obesity, asthma prevalence and IL-4: Roles of inflammatory cytokines, adiponectin and neuropeptide Y.

BACKGROUND: Obesity is associated with asthma risk and severity, but the underlying biological mechanisms are poorly understood. We hypothesized that cytokine markers of systemic inflammation, and adiponectin and neuropeptide Y (NPY) markers of immuno-modulating and neurohormonal regulation are involved in the obesity-asthma association. METHODS: We explored the relationships between body mass index (BMI), C-reactive protein (CRP), IL-6, TNF-α, adiponectin and NPY with asthma prevalence and IL-4 levels in 70 youth with asthma and 69 age- and gender-matched healthy controls using cross-sectional and longitudinal data. RESULTS: Mean BMI level was higher among patients with asthma than healthy controls (p < 0.001). In logistic regression models controlling for potential confounders, independent associations with asthma prevalence were found for obesity (p = 0.001), increasing tertiles of CRP (linear trend p < 0.001), IL-6 (linear trend p < 0.001) and lowest and highest tertiles of TNF-α (quadratic trend p < 0.05), increasing adiponectin (linear p = 0.022) and decreasing tertiles of NPY (linear trend p = 0.001). Among patients with asthma, NPY level was positively correlated with adiponectin (p < 0.05) and TNF-α (p < 0.05), and levels of NPY and IL-6 were significantly associated with IL-4 level at baseline and 1-year follow-up. CONCLUSIONS: The obesity-asthma association was not explained by systemic inflammation. Specifically, CRP, TNF-a, IL-6, NPY and adiponectin were independently associated with asthma prevalence. NPY and IL-6 were associated with IL-4 marker of allergic airway inflammation in asthma and should be further investigated as prognostic markers of asthma outcomes.

Rhinitis in the first 18 months of life: exploring the role of respiratory viruses.

BACKGROUND: Rhinitis is common in early childhood, but allergic rhinitis is considered a later manifestation of the atopic march. This study aimed to evaluate rhinitis (allergic and non-allergic) in the first 18 months of life, its link with other atopic manifestations and the role of respiratory viruses. METHODS: Subjects (n = 1237) of the Singapore GUSTO birth cohort were followed up quarterly until 18 months of age with questionnaires to screen for rhinitis symptoms lasting at least 2 wk and with monthly calls to positive subjects to detect prolonged/recurrent rhinitis symptoms (total duration ≥ 4 wk). Anterior nasal swabbing for molecular-based virus detection was conducted during these visits and near (within a month) rhinitis episodes. Skin prick testing to common environmental and food allergens was conducted at the 18 month visit. RESULTS: Prolonged/recurrent rhinitis was significantly associated with history of parental atopy (mother: aOR = 2.17; father: aOR = 1.82) and atopic comorbidities of eczema (aOR = 2.53) and wheeze (aOR = 4.63) (p < 0.05), though not with allergen sensitization. Although the frequency of nasal respiratory virus detection during scheduled quarterly visits did not differ between prolonged/recurrent rhinitis and matched controls (p > 0.05), virus detection was higher in swabs obtained within a month following rhinitis episodes in prolonged/recurrent rhinitis subjects compared with scheduled visits (adjusted p = 0.04). CONCLUSIONS: Based on the duration of rhinitis symptoms, this study defined a subset of early childhood rhinitis which was associated with atopic predisposition and comorbidities. Persistent respiratory viral shedding may contribute to the symptomatology. Whether this entity is a precursor of subsequent childhood allergic rhinitis will require longer follow-up.

Maternal PUFA status and offspring allergic diseases up to the age of 18 months.

Studies have suggested that maternal PUFA status during pregnancy may influence early childhood allergic diseases, although findings are inconsistent. We examined the relationship between maternal PUFA status and risk of allergic diseases in early childhood in an Asian cohort. Maternal plasma samples from the Growing Up in Singapore Towards Healthy Outcomes mother-offspring cohort were assayed at 26-28 weeks of gestation for relative abundance of PUFA. Offspring (n 960) were followed up from 3 weeks to 18 months of age, and clinical outcomes of potential allergic diseases (rhinitis, eczema and wheezing) were assessed by repeated questionnaires. Skin prick testing (SPT) was also performed at the age of 18 months. Any allergic disease with positive SPT was defined as having any one of the clinical outcomes plus a positive SPT. The prevalence of a positive SPT, rhinitis, eczema, wheezing and any allergic disease with positive SPT was 14·1 % (103/728), 26·5 % (214/808), 17·6 % (147/833), 10·9 % (94/859) and 9·4 % (62/657), respectively. After adjustment for confounders, maternal total n-3, n-6 PUFA status and the n-6:n-3 PUFA ratio were not significantly associated with offspring rhinitis, eczema, wheezing, a positive SPT and having any allergic disease with positive SPT in the offspring (P>0·01 for all). A weak trend of higher maternal n-3 PUFA being associated with higher risk of allergic diseases with positive SPT in offspring was observed. These findings do not support the hypothesis that the risk of early childhood allergic diseases is modified by variation in maternal n-3 and n-6 PUFA status during pregnancy in an Asian population.

Viewpoint: the future of research in pediatric allergy: what should the focus be?

Allergic diseases have been increasing during the last three decades, and exact reasons for this are still debated. Despite intense ongoing research, a lot of aspects of allergic diseases are still poorly understood, resulting in limitations in current therapeutic approach to allergies. In this viewpoint, important unanswered research questions are raised mainly on novel therapeutic approaches to allergic children, and suggestions for future research are raised. Three aspects of pediatric allergy are distinguished: the prevention, control, and cure.

Prevalence of anxiety and depressive symptoms in adolescents with asthma: a meta-analysis and meta-regression.

It remains unclear whether anxiety and depressive symptoms are more prevalent in adolescents with asthma when compared with healthy individuals. This meta-analysis aimed to evaluate the difference in the aggregate prevalence of depressive and anxiety symptoms between adolescents with asthma and healthy controls and to explore the underlying moderators that potentially explain the heterogeneity of the effect size. A meta-analysis of published work was performed using the random effects model. The differences in aggregate prevalence of depressive and anxiety symptoms between adolescents with asthma and healthy controls were determined. Meta-regression and subgroup analysis were performed to identify factors that may contribute to heterogeneity. A total of eight studies were eligible for analysis. The aggregate prevalence of depressive and anxiety symptoms was significantly higher among 3546 adolescents with asthma than that of 24,884 controls (depression, 0.27; 95% CI, 0.18.6-0.39 vs. 0.13; 95% CI, 0.09-0.19; anxiety, 0.33; 95% CI, 0.19-0.52 vs. 0.21; 95% CI, 0.12-0.33). The risk of developing depression and anxiety is significantly higher among adolescents with asthma when compared with controls (depression: pooled odds ratio, 2.09; 95% CI, 1.65-2.64; p < 0.001; anxiety: pooled odds ratio, 1.83; 95% CI, 1.63-2.07; p < 0.001). Meta-regression revealed that the proportions of Caucasian (p = 0.008) and smokers (p < 0.001) were significant moderators which explained the significant heterogeneity when comparing the risk of developing depressive symptoms among adolescent asthma patients vs. controls while age, gender, and severity of asthma were not significant. Family doctors, pediatricians, and healthcare providers should formulate strategies to detect depressive and anxiety symptoms in adolescents with asthma and offer psychological interventions to reduce the burden of psychiatric comorbidity.

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.

Features of childhood atopic dermatitis.

Eczema or atopic dermatitis (AD) is the most common skin disease in children, and recent data derived from several studies showed that the prevalence of AD is still increasing in most Asian countries. The role of allergic reactions in AD is still a matter of debate. In some children allergy is not involved, while in others allergic reactions can trigger and maintain the skin lesions. Therefore, AD is now considered as a group of skin diseases with as a common feature the existence of a chronic skin inflammation. The underlying mechanisms of AD are not uniform, but differ from patient to patient, and also differ in one patient in time, suggesting the existence of different subtypes of AD, in a complex interplay. From different studies it is now suggested that at least 4 different players are involved in AD. These 4 players are: congenital skin barrier defects, allergy, autoimmunity (i.e. the production of autoantibodies against skin cells), and microbial agent colonization, especially colonization with bacteria, mainly Staphylococcus aureus. Much more needs to be discovered on the mechanisms of AD and other "players" might be discovered soon, as the current "4-player-model" cannot explain all features of AD. Treatment of AD might change in the near future. Today's cornerstones of treatment are still moisturizers (from a young age to prevent further skin barrier dysfunctions and allergic sensitization), local corticosteroids, and antiseptics, but new future therapeutic approaches become very likely.

Compliance with topical nasal medication--an evaluation in children with rhinitis.

It is our impression that children with rhinitis often dislike or struggle with the administration of topical nasal sprays and drops. This study aims to investigate children's acceptance of topical nasal sprays/drops, and to identify patient factors that may affect their acceptance. An interview (by WYZI) questionnaire survey was carried out on parents/guardians of children aged 1-15 with rhinitis, where information on the diagnosis and treatment, patients' use and responses to these medications, and their preferred treatment routes were collected. Two hundred questionnaires were completed, of which 194 were valid for analysis. The mean age of patients was 7.54 yr; male to female ratio was 1:1.6, and Chinese made up the majority (62.4%). About one quarter (24.7%) of children disliked the use of topical nasal sprays/drops sufficiently to affect compliance with the medication. Furthermore, of those who could indicate their preferred route of drug administration (n = 75), 73% indicated a preference for oral medication, while only 11% preferred the nasal route. Topical nasal sprays/drops were more acceptable in older children (7-15 yr) compared to the younger ones (1-6 yr) (OR = 2.383, CI 1.223-4.644). The acceptance of nasal sprays/drops was not associated with gender, ethnic group, concurrent use by other family members, length and amount of usage, and the response to therapy. A substantial proportion of children prescribed topical nasal sprays/drops did not find it acceptable. Age played a significant factor to the acceptance of the use of topical nasal sprays/drops.

A compromised developmental trajectory of the infant gut microbiome and metabolome in atopic eczema.

Evidence is accumulating that the establishment of the gut microbiome in early life influences the development of atopic eczema. In this longitudinal study, we used integrated multi-omics analyses to infer functional mechanisms by which the microbiome modulates atopic eczema risk. We measured the functionality of the gut microbiome and metabolome of 63 infants between ages 3 weeks and 12 months with well-defined eczema cases and controls in a sub-cohort from the Growing Up in Singapore Toward healthy Outcomes (GUSTO) mother-offspring cohort. At 3 weeks, the microbiome and metabolome of allergen-sensitized atopic eczema infants were characterized by an enrichment of Escherichia coli and Klebsiella pneumoniae, associated with increased stool D-glucose concentration and increased gene expression of associated virulence factors. A delayed colonization by beneficial Bacteroides fragilis and subsequent delayed accumulation of butyrate and propionate producers after 3 months was also observed. Here, we describe an aberrant developmental trajectory of the gut microbiome and stool metabolome in allergen sensitized atopic eczema infants. The infographic describes an impaired developmental trajectory of the gut microbiome and metabolome in allergen-sensitized atopic eczema (AE) infants and infer its contribution in modulating allergy risk in the Singaporean mother-offspring GUSTO cohort. The key microbial signature of AE is characterized by (1) an enrichment of Escherichia coli and Klebsiella pneumoniae which are associated with accumulation of pre-glycolysis intermediates (D-glucose) via the trehalose metabolic pathway, increased gene expression of associated virulence factors (invasin, adhesin, flagellin and lipopolysaccharides) by utilizing ATP from oxidative phosphorylation and delayed production of butyrate and propionate, (2) depletion of Bacteroides fragilis which resulted in lower expression of immunostimulatory bacterial cell envelope structure and folate (vitamin B9) biosynthesis pathway, and (3) accompanied depletion of bacterial groups with the ability to derive butyrate and propionate through direct or indirect pathways which collectively resulted in reduced glycolysis, butyrate and propionate biosynthesis.

Management of childhood asthma in Western Australia.

AIMS: The study aimed to determine how childhood asthma is managed in Western Australia by general practitioners (GPs) and specialist paediatricians. METHODS: A questionnaire survey was sent to 992 GPs and specialist paediatricians, asking about practice and preferences regarding maintenance management of childhood asthma and treatment of acute asthma. Questions about asthma in infants, pre-school and school-aged children were asked separately. RESULTS: The overall response rate was 24.7%, with 188/878 (21.4%) of GPs and 44/62 (71.0%) of paediatricians returning the questionnaire. The decision to start maintenance therapy was generally based on symptom frequency and severity. The first choice for maintenance treatment in all age groups was inhaled corticosteroids (ICS). The second most common treatment varied according to age group, with short-acting beta(2)-agonist (SBA) preferred for infants, montelukast or short-acting beta(2)-agonist for pre-schoolers and combination therapy (ICS + long action beta(2)-agonist) for school-aged children. Objective monitoring of lung function with peak flow or spirometry, was used by 40% of GPs and 59% of paediatricians. Acute asthma was primarily managed with inhaled salbutamol and oral corticosteroids. There were few differences in treatment choice between GPs and paediatricians. Many GPs indicated that they did not treat asthma in infants without specialist consultation. CONCLUSIONS: These data show good compliance by the minority of GPs responding to the survey and by paediatricians practising in Western Australia with current Australian asthma management guidelines. Major differences in treatment preferences between the groups were not detected.

Determinants in early life for asthma development.

A reliable screening test in newborns for the subsequent development of bronchial asthma (BA) has not been found yet. This is mainly due to the complexity of BA, being made up by different types and underlying mechanisms. In different studies, a number of risk factors for BA have been identified. These include a positive family history of BA, passive smoking (also during pregnancy), prematurity (including pulmonary infections, RDS and BPD), early viral respiratory infections (such as RSV-bronchiolitis), male gender, early lung function abnormalities and atopic constitution. The major risk factor for persistent BA is an underlying allergic constitution. Therefore, early symptoms and markers of allergy (i.e. The Allergic March) and a positive family history for allergy should be considered as important risk factors for the development of BA.

Parvalbumin--the major tropical fish allergen.

Fish allergy is common in countries where consumption is high. Asian nations are amongst the world's largest consumers of fish but the allergen profiles of tropical fish are unknown. This study sought to evaluate the allergenicity of four commonly consumed tropical fish, the threadfin (Polynemus indicus), Indian anchovy (Stolephorus indicus), pomfret (Pampus chinensis) and tengirri (Scomberomorus guttatus). Immunoglobulin E (IgE) cross-reactivity with parvalbumin of cod fish (Gad c 1), the major fish allergen, was also studied. Detection of tropical fish and cod specific-IgE was performed by UniCap assay, and skin prick tests were also carried out. The IgE-binding components of tropical fish were identified using IgE immunoblot techniques, and cross-reactivity with Gad c 1 was assessed by ELISA inhibition and IgE immunoblot inhibition. Clinically, nine of 10 patients studied were allergic to multiple fish. All patients exhibited detectable specific-IgE to cod fish (10 of 10 skin prick test positive, eight of 10 UniCap assay positive) despite lack of previous exposure. The major allergen of the four tropical fish was the 12-kDa parvalbumin. IgE cross-reactivity of these allergens to Gad c 1 was observed to be moderate to high in the tropical fish studied. Parvalbumins are the major allergens in commonly consumed tropical fish. They are cross-reactive with each other as well as with Gad c 1. Commercial tests for cod fish appear to be sufficient for the detection of tropical fish specific-IgE.

Dynamics of helper CD4 T cells during acute and stable allergic asthma.

Asthma comprises heterogeneous clinical subtypes driven by diverse pathophysiological mechanisms. We characterized the modulation of the inflammatory environment with the phenotype, gene expression, and function of helper CD4 T cells among acutely exacerbated and stable asthma patients. Systemic Th2 immune deviation (IgE and Th2 cytokines) and inflammation (IL-6, CRP) were associated with increased Th17 cells during acute asthma. Th2/Th17 cell differentiation during acute asthma was regulated by the enhanced expression of transcription factors (c-MAF, IRF-4). The development of pathogenic Th2 cells during acute asthma was characterized by the secretion of inflammatory cytokines coupled with Th2 molecules and PPARγ expression. The acquisition of CD15S, CD39, CD101, and CCR4 contributed to the increased heterogeneity of Regulatory T cells during asthma. Two clusters were derived from above cytokines, CD4 T cell phenotypes, and clinical data. Cluster 1, characterized by high eosinophils, Th2 and ILC2 frequencies, and higher exacerbation rates, may represent Th2-high subtype. Cluster 2 represents a more complex subtype; it is constituted by higher neutrophils or Th17 frequencies, higher inhaled corticosteroids dose and poor asthma control. In conclusion, we characterized systematically and longitudinally Th2-high and non-Th2 asthma subtypes and the heterogeneity of CD4 T cells in stable and acute asthma.

Low Food Allergy Prevalence Despite Delayed Introduction of Allergenic Foods-Data from the GUSTO Cohort.

BACKGROUND: There is mounting evidence that early introduction of allergenic food decreases the risk of food allergy development, especially in high-risk infants with eczema. However, there is a lack of data to suggest whether this association holds true in Asian populations. OBJECTIVE: To investigate the relationship between the timing of introduction of allergenic foods and food allergy outcomes in infants in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study. METHODS: The GUSTO cohort recruited 1152 mothers of Chinese, Malay, and Indian ethnicity who had singleton, naturally conceived pregnancies and followed their offspring prospectively. Information on demographic characteristics, child health, infant feeding practices, and a convincing history of IgE-mediated food allergy was obtained from interviewer-administered questionnaires at multiple time points. Corroborative skin prick tests to food allergens were performed at 18 and 36 months. RESULTS: Most of the infants were introduced to egg (49.6%), peanut (88.7%), and shellfish (90.2%) after age 10 months. Food allergy prevalence was, however, very low between age 12 and 48 months: egg, 0.35% to 1.8%; peanut allergy, 0.1% to 0.3%; and shellfish, 0.2% to 0.9%. There were no significant associations between the timing of introduction of allergenic foods and the development of food allergy, adjusted for confounders including breast-feeding and eczema. CONCLUSIONS: Food allergy rates in Singapore are low despite delayed introduction of allergenic foods. Early introduction of allergenic foods may thus not be necessary in populations in which overall food allergy prevalence is low, and thus infant feeding recommendations should be carefully tailored to individual populations.