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 y 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. OBJECTIVES: We examined the relationship between maternal pregnancy and infant dietary patterns and the development of food allergies until age 8 y. METHODS: Among 1152 Singapore Growing Up in Singapore Towards healthy Outcomes study mother-infant dyads, the infant's diet was ascertained using food frequency questionnaires at 18 mo. Maternal dietary patterns during pregnancy were derived from 24-h diet recalls. Food allergy was determined through interviewer-administered questionnaires at regular time points from infancy to age 8 y and defined as a positive history of allergic reactions, alongside skin prick tests at 18 mo, 3, 5, and 8 y. RESULTS: Food allergy prevalence was 2.5% (22/883) at 12 mo and generally decreased over time by 8 y (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 ≤8 y showed no associations with measures of infant diet including timing of solids/food introduction (adjusted odds ratio [aOR]: 0.90; 95% confidence interval [CI]: 0.42, 1.92), infant's diet quality (aOR: 0.93; 95% CI: 0.88, 0.99) or diet diversity (aOR: 0.84; 95% CI: 0.6, 1.19). Most infants (89%) were first introduced to cow milk protein within the first month of life, while egg and peanut introduction were delayed (58.3% introduced by mean age 8.8 mo and 59.8% by mean age 18.1 mo, 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 pediatric population. Interventional studies are needed to evaluate the efficacy of these approaches to food allergy prevention across different populations.

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.

OPINION: Primary prevention of allergy - Will it soon become a reality?

It is generally accepted that allergic diseases are not curable and not preventable, but mainly controllable using pharmacotherapy (i.e. symptomatic medication). Recent research, however, demonstrated that a number of specific interventions can lead to (partial) primary prevention of allergy, especially of atopic dermatitis (AD) and food allergy (FA). Three types of primary prevention strategies have been successfully studied: early administration of bacterial products (most studies are on probiotics), early moisturizing in infants at risk for AD and early exposure to allergenic foods (peanut and egg). Results of these studies indicate that the stage might have been set. Surely, much more research needs to be carried out before advice can be given in clinical practice. This opinion article discusses the three types of beneficial interventions and gives ideas for future research, which might show the way for better strategies in primary prevention of allergic diseases.

Atopic Dermatitis in Early Life: Evidence for at Least Three Phenotypes? Results from the GUSTO Study.

BACKGROUND: Atopic dermatitis (AD) has been highlighted as a likely first step in the 'atopic march', emphasizing the need to define predisposing factors. METHODS: We evaluated AD risk factors and phenotypes in an Asian mother-offspring cohort . We defined three phenotypes of doctor-diagnosed AD based on the time of onset of the disease: early AD occurring within the first 6 months of life, AD occurring between 6 and 12 months and late-onset AD starting after the age of 12 months. RESULTS: Maternal allergic history was associated with an increased risk of developing early-onset AD (adjusted odds ratio (aOR) 20.46, 95% confidence interval (CI) 2.73-153.15, p < 0.01). Maternal allergic history and attendance at a daycare centre increased the odds of the development of AD between 6 and 12 months (aOR 4.19, 95% CI 1.01-17.45, p = 0.049 and aOR 11.42, 95% CI 1.49-87.50, p = 0.02, respectively). Risk factors associated with increased odds of late-onset AD from 12 months were the consumption of probiotics between the age of 9 and 12 months and antibiotic treatment in the first 6 months of life (aOR 4.32, 95% CI 1.07-17.45, p = 0.04 and aOR 3.11, 95% CI 1.10-8.76, p = 0.03, respectively). Early-onset AD was associated with an increased risk of developing allergic sensitization (aOR 46.51, 95% CI 3.44-628.81, p < 0.01). CONCLUSION: We found that early-onset AD was mainly associated with familial factors, while late-onset AD was associated with the consumption of antibiotics or probiotics. The findings support the concept that different phenotypes of AD exist in young children.

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.

Pediatric sublingual immunotherapy efficacy: evidence analysis, 2009-2012.

OBJECTIVE: To perform a structured analysis of the latest scientific evidence obtained for the clinical efficacy of sublingual immunotherapy (SLIT) in children. DATA SOURCES: PubMed, Embase, reference lists from reviews, and personal databases were reviewed for original articles on clinical trials with SLIT in patients younger than 18 years published from January 1, 2009, through December 31, 2012, using broad search and medical subject heading terms. STUDY SELECTIONS: Clinical trials, irrespective of their design, of SLIT in the treatment of respiratory and food allergy in patients 18 years or younger were selected. Clinical outcomes (symptom scores, medication use, provocation tests, pulmonary function tests, skin prick tests, and adverse events) and immunologic changes were tabulated. Quality of each trial and total quality of compounded evidence was analyzed with the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Of 56 articles, 29 met the inclusion criteria. New evidence is robust for the precoseasonal tablet and drop grass pollen SLIT efficacy in allergic rhinitis and scarce for seasonal asthma. Some evidence for Alternaria SLIT efficacy is appearing. For house dust mite (HDM) SLIT in asthma, there is high-quality evidence for medication reduction while maintaining symptom control; evidence for HDM SLIT efficacy in allergic rhinitis is of moderate-low quality. There is moderate evidence for efficacy of dual grass pollen-HDM SLIT after 12 months of treatment and 1 year after discontinuation. Specific provocation test results (nasal, skin) improve with grass pollen and HDM SLIT but nonspecific bronchial provocation testing does not. Food oral immunotherapy is more promising than food SLIT. Possible new surrogate markers have been reported. No anaphylaxis was found among 2469 treated children. CONCLUSION: Evidence for efficacy of SLIT in children with respiratory or food allergy is growing.

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.

The influence of childhood atopic dermatitis on health of mothers, and its impact on Asian families.

This study examines maternal perceptions of paediatric atopic dermatitis (AD) on family and determines risk factors including severity of AD, maternal physical and mental health (MH), quality of life of patients and sociodemographics which predict a negative family impact. A cross-sectional assessment using the Dermatitis Family Impact Questionnaire Scale to assess the impact of AD on family, Infant's Dermatitis Quality of Life Index (<5-yrs old) or Children's Dermatitis Life Quality Index (5-17 yrs old) was used to measure health-related quality of life (HRQOL) of paediatric patients with AD. A 12-item Short-Form Health Survey (SF-12) was used to assess physical and MH of their mothers. Risk factors of adverse family impact were assessed using multiple regression analysis. One hundred and four patients with AD and their mothers were studied. Their mean ages (+/-s.d.) were respectively 6.4 +/- 4.3 and 37.2 +/- 6.6 yrs. In multiple regression analysis, Severity Scoring of Atopic Dermatitis (SCORAD) appeared to be associated with negative family impact and the association remained significant after adjustment for bio-psycho-social factors and HRQOL of patients. The association remained insignificant after adjustment for physical and MH of the mothers. Our results show that the severity of paediatric AD leads to negative family impact through reduction of physical and MH of the mothers, and is independent of patients' HRQOL and sociodemographics. The current approach for managing paediatric AD in Asian society could include early multidisciplinary intervention, aiming at enhancing physical and MH of mothers while minimizing negative impact on family and social isolation. Further research will be welcomed as the results of this study mainly applied to Asian society which could be different to populations from other geographic areas.

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.

Specific profiles of house dust mite sensitization in children with asthma and in children with eczema.

Sensitization to house dust mites (HDM) is highly prevalent among the young atopic population in Singapore. Previously published data suggest that individuals with skin allergies show preferred sensitization to Dermatophagoides pteronyssinus while individuals with pure respiratory allergies show preferred sensitization to Blomia tropicalis. The aim of our study was to compare the sensitization profiles between children with asthma and those with eczema to D. pteronyssinus and B. tropicalis and their specific allergens. A total of 60 children, 30 with asthma and 30 with eczema were recruited. IgE levels specific for a panel of HDM allergens from the two mite species were measured using enzyme-linked immunosorbent assay. The asthma group showed highest sensitization to Blo t5 while the eczema group showed highest sensitization to Der p5. Comparison between the two disease groups showed that the eczema group had significantly higher IgE levels for Der p (p = 0.042) and its allergens Der p1 (p = 0.019) and Der p5 (p = 0.001). Generally, the eczema group was more sensitized to the panel of allergens compared to the asthma group. Individuals with asthma and those with eczema showed different sensitization profiles to HDM. These findings highlighted possible mechanisms for different manifestation of allergy.