Low Atopy Research Articles

Proximity to Heavy Traffic Roads and Patient Characteristics of Late of Onset Asthma in an Urban Asthma Center

Background: Traffic-related pollution is associated with the onset of asthma and the development of different phenotypes of asthma. Few studies have investigated the association between traffic proximity and late-onset of asthma (LOA) and early-onset asthma (EOA). This study was conducted to investigate the associations of LOA phenotypes with a function of the distance between residence and heavy traffic roads (HTRs).Methods: The study group consisted of 280 patients who were (LOA: 78.4%) recruited consecutively from a pay-for-performance asthma program to clarify the patient characteristics and proximity to HTRs within 1,000 m from their residences between EOA and LOA in three urban centers in Taiwan. The subsequent analysis focused on patients with LOA (n = 210) linking phenotypes and distance to HTRs.Results: Subjects with LOA tended to be older than those with EOA and had shorter asthma duration, poorer lung function, lower atopy, and less exposure to fumes or dust at home. Patients with LOA were more likely than those with EOA to live within 900 m of two or more HTRs (14.3 vs. 3.4%, p = 0.02). Among patients with LOA, minimum distance to an HTR was negatively associated with numbers of specific IgE as well as positively associated with the age of onset and body weight significantly. A higher proportion of patients with atopy (26.3 vs. 20.6%, p = 0.001. odds ratio [OR]: 2.82) and anxiety/depression (21.0 vs. 18.1%, p = 0.047. OR: 1.81) and a trend of lower proportion of patients with obese (5.7 vs. 12.4%, p = 0.075) were found to be living within 900 m from HTRs.Conclusions: Late-onset of asthma (LOA) tended to live in areas of higher HTR density compared to EOAs. Among patients with LOA living close to HTRs, the interaction between traffic-related pollution, allergy sensitization, and mood status were the factors associated with asthma onset early. Obesity may be the factor for later onset who live far from HTRs.

Endotype of allergic asthma with airway obstruction in urban children

Black and Hispanic children growing up in disadvantaged urban neighborhoods have the highest rates of asthma and related morbidity in the United States. This study sought to identify specific respiratory phenotypes of health and disease in this population, associations with early life exposures, and molecular patterns of gene expression in nasal epithelial cells that underlie clinical disease. The study population consisted of 442 high-risk urban children who had repeated assessments of wheezing, allergen-specific IgE, and lung function through 10 years of age. Phenotypes were identified by developing temporal trajectories for these data, and then compared to early life exposures and patterns of nasal epithelial gene expression at 11 years of age. Of the 6 identified respiratory phenotypes, a high wheeze, high atopy, low lung function group had the greatest respiratory morbidity. In early life, this group had low exposure to common allergens and high exposure to ergosterol in house dust. While all high-atopy groups were associated with increased expression of a type-2 inflammation gene module in nasal epithelial samples, an epithelium IL-13 response module tracked closely with impaired lung function, and a MUC5AC hypersecretion module was uniquely upregulated in the high wheeze, high atopy, low lung function group. In contrast, a medium wheeze, low atopy group showed altered expression of modules of epithelial integrity, epithelial injury, and antioxidant pathways. In the first decade of life, high-risk urban children develop distinct phenotypes of respiratory health versus disease that link early life environmental exposures to childhood allergic sensitization and asthma. Moreover, unique patterns of airway gene expression demonstrate how specific molecular pathways underlie distinct respiratory phenotypes, including allergic and nonallergic asthma.

T-cell phenotypes are associated with serum IgE levels in Amish and Hutterite children

Amish children raised on traditional farms have lower atopy and asthma risk than Hutterite children raised on modern farms. In our previous study we established that the Amish environment affects the innate immune response to decrease asthma and atopy risk. Here we investigated T-cell phenotypes in the same Amish and Hutterite children as in our earlier study to elucidate how this altered innate immunity affects adaptive T cells. Blood was collected from 30 Amish and 30 Hutterite age- and sex-matched children; cells were cryopreserved until analysis. Flow cytometry was used to analyze cell subsets. Atopy was determined based on allergen-specific and total IgE levels. Children exposed to Amish farms had increased activated regulatory CD4+ T-cell phenotypes, whereas conventional CD4 T cellsexpressed lower levels of costimulation molecules and other activation markers. The increase in numbers of circulating activated regulatory CD4+ T cells was associated with an increase in inhibitory receptors on monocytes in Amish, but not Hutterite, children. Strikingly, the Amish children had a higher proportion of CD28null CD8 T cells than the Hutterite children (P<.0001, nonparametric t test), a difference that remained even after accounting for the effects of age and sex (conditional log regression exponential β=1.08, P=.0053). The proportion of these cells correlated with high T-cell IFN-γ production (rs=0.573, P=.005) and low serum IgE levels (rs=-0.417, P=.025). Furthermore, CD28null CD8 T-cell numbers were increased in Amish children, with high expression of the innate genes TNF and TNF-α-induced protein 3 (TNFAIP3) in peripheral blood leukocytes. Amish children's blood leukocytes are not only altered in their innate immune status but also have distinct T-cell phenotypes that are often associated with increased antigen exposure.

Differential effects of obesity on eosinophilic vs. non-eosinophilic asthma subtypes

ABSTRACTObjective: Asthma is a heterogeneous disease composed of multiple disease subtypes. Obesity may worsen asthma, although the mechanism is poorly understood and its effects on different subtypes are not well characterized. We sought to determine whether obesity affects eosinophilic asthma differently from non-eosinophilic asthma. Methods: Charts of 196 persistent asthmatics were reviewed. Subjects were categorized according to BMI (obese ≥ 30 kg/m2) and blood eosinophilia based on two different cutoffs (≥200 or ≥400 cells/µl): eosinophilic, non-obese (E-NO), eosinophilic, obese (E-O), non-eosinophilic, non-obese (NE-NO), and non-eosinophilic, obese (NE-O). We analyzed clinical parameters across these groups to determine associations with obesity and/or eosinophilia. Results: Obesity was highly prevalent in our population (50.5%, 99/196). The majority of asthmatics were female (75.5%), though the ratio was lower in the E-NO group (56%). The NE-NO group was associated with lowest asthma severity, lower atopy, and less medication use. Regardless of eosinophilia, obesity was associated with higher inhaled corticosteroid doses and lower FVC% predicted than their non-obese counterparts. Obesity was associated with reduced FEV1% only in the non-eosinophilic group. Eosinophilia was also associated with reduced FEV1% in the non-obese subjects, but FEV1% was not further reduced in the E-O group compared to the E-NO and NE-O groups. Similar findings were observed regardless of whether the blood eosinophil cutoff was 200 or 400 cells/ µl. Conclusion: Multiple clinical features of asthma are adversely affected by obesity, which may affect eosinophilic and non-eosinophilic subtypes differently.

Asthma susceptibility variants are more strongly associated with clinically similar subgroups

Objective: Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) reproducibly associated with asthma. This study evaluated whether GWAS-nominated SNPs are more strongly associated with asthma patients sharing the same clinical characteristics in order to refine the role of recently identified genes. Methods: Analyses were performed in unrelated French Canadian subjects (566 cases and 416 controls) with data collected on lung function, blood cell counts, atopy, disease history and medication. Previously defined asthma subgroups were used for analysis: 1) older patients with low atopy and low lung function, 2) high atopy, 3) young non-smoking women and 4) high smoking history. Allele frequencies of 68 GWAS-nominated SNPs were compared between controls and cases or controls and subgroups of cases defined by cluster analysis. Results: Twelve GWAS-nominated SNPs demonstrated evidence of replication (p value < 0.05) for association with asthma. In phenotypically similar asthma patients, rs10197862, located in IL1RL1/IL18R1, was the most strongly associated SNP with the high atopy subgroup (p = 0.0009). SNPs located at the IL33 and the STARD3/PGAP3 loci were also associated with the high atopy subgroup. Two SNPs, rs1544791 (PDE4D) and rs3806932 (TSLP), were more strongly associated with the high smoking history subgroup than with asthma or any other subgroups. All 10 SNPs that replicated for asthma per se and within subgroups had lower p values in subgroups. Moreover, 12 SNPs were only replicated in a subgroup. Conclusion: This study shows that the majority of GWAS-nominated SNPs are more strongly associated with homogeneous subgroups of asthma than broadly defined asthma.

A rhinitis phenotype associated with increased development of bronchial hyperresponsiveness and asthma in children

BackgroundAllergic rhinitis (AR) has a wide range of clinical features and may be accompanied by comorbid allergic diseases. ObjectiveTo identify rhinitis phenotypes in school aged children and to predict the prognosis for developing bronchial hyperresponsiveness (BHR) and asthma. MethodsThis prospective follow-up study involved schoolchildren from the Children's Health and Environment Research cohort with current rhinitis, which was defined based on parental-reported, physician-diagnosed rhinitis and symptoms of rhinitis in the previous 12 months. All participants were followed up at 2 and 4 years later. Rhinitis clusters were identified by latent class analysis that used demographic, clinical, and environmental variables. ResultsIn 512 eligible children (age range, 6–8 years), 4 rhinitis phenotypes were identified: cluster 1 (25% of children) was associated with nonatopy and a low socioeconomic status; cluster 2 (36%) was associated with a high-atopic burden but normal lung function; cluster 3 (22%) was associated with a high-atopic burden and impaired lung function; and cluster 4 (17%) was associated with low atopy and a high socioeconomic status. Cluster 3 was associated with the highest total serum IgE levels and blood eosinophil percentages at enrollment and the highest incidence of new cases of BHR (P = .04) and asthma symptoms (P = .005) during follow-up. ConclusionThe rhinitis cluster of schoolchildren with atopy and impaired lung function is associated with allergic march. This identification of distinct rhinitis phenotypes in affected children may help to prevent allergic march in children with rhinitis.

Atopic dermatitis phenotype with early onset and high serum IL-13 is linked to the new development of bronchial hyperresponsiveness in school children.

Atopic dermatitis (AD) is characterized by a heterogeneous clinical spectrum, and some forms of AD are associated with the initial steps of allergic march. The aims of this study were to determine AD phenotypes in school-age children and investigate their associations with the allergic march in each cluster. We included 242 children (6-8 years) with current AD from the Children's HEalth and Environmental Research study, a 4-year prospective follow-up study with 2-year survey intervals. Latent class analysis was used. Serum IL-13 and thymic stromal lymphopoietin (TSLP) levels at the time of enrollment were measured using ELISA. We identified four current AD phenotypes in children, characterized as 'early onset with low atopy' (26.4% of the sample; group 1), 'early onset with high atopy and high eosinophil percentages' (48.3%; group 2), 'late onset with low atopy' (9.9%; group 3), and 'late onset with high atopy and normal eosinophils' (15.3%; group 4). Although groups 2 and 4 demonstrated high atopic burden, children in group 2 showed the persistence of AD and eosinophilia associated with a high prevalence of new cases of bronchial hyper-responsiveness and asthma symptoms during follow-up. The serum IL-13 level was significantly increased in the early-onset AD groups, but there was no significant difference in the serum TSLP levels across all four groups. An allergic march-associated AD phenotype exists that is characterized by early onset of AD with its persistence, increased serum IL-13 levels, high atopy, and a persistently increased blood eosinophil percentage.

Effect of Prenatal Maternal Trait Anxiety on Atopic Dermatitis and Immunoglobulin E Level: Cocoa Study

U E S D A Y 855 Phenotypes of Atopic Dermatitis in School Children Eun Lee, Si Hyeon Lee, Ji-Won Kwon, Song I. Yang, MD, Young Ho Jung, MD, Hyung-Young Kim, Ju-Hee Seo, MD, Byoung-Ju Kim, MD, PhD, Hyo-Bin Kim, MD, PhD, So Yeon Lee, MD, PhD, HoJang Kwon, MD PhD, Soo-Jong Hong, MD, PhD; Department of Pediatrics, Childhood Asthma Atopy Center, Research Center for Standardization of Allergic Diseases, Asan Medical Center, University of Ulsan College of Medicine, Asan Institute for Life Sciences, University of ulsan College of Medicine, Department of Pediatrics, Bundang CHA Medical Center, CHA University College of Medicine, Childhood Asthma Atopy Center, Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, Department of Pediatrics, Pusan National University Yangsan Hospital, Yangsan, Department of Pediatrics, Korea Cancer Center Hospital, Seoul, South Korea, Department of Pediatrics, Hae-undae Paik Hospital, Inje University College of Medicine, Busan, South Korea, Department of Pediatrics,Inje University Sanggye Paik Hospital, Seoul, South Korea, Department of Pediatrics, Hallym University College of Medicine, Seoul, South Korea, Dankook University, Cheonan. RATIONALE: Atopic dermatitis (AD) develops from a complex interplay between environmental and immunologic factors incomplete understanding of its pathophysiology. AD is characterized by heterogeneous features in its onset and severity. The aim was to define the distinct phenotypes of AD children aged 6 to 13 years. METHODS: 242 children diagnosed with AD ever and AD symptoms during the last 12 months were included from the first survey of Children’s Health and Environmental Research survey (n52491). Variables such as personal characteristics, age at onset of AD, treatment during the last 12 months, number of positive skin prick tests (SPTs), total serum IgE levels and eosinophil were included. After 4 years, lung function tests, methacholine provocation tests, and blood test including IgE and eosinophil were performed. RESULTS: We identified 4 AD phenotypes. Class types were characterized as ‘‘early onset with low atopy’’ (26.4% of sample, Group 1), ‘‘early onset with high atopy’’ (48.3%, Group 2), ‘‘late onset with low atopy’’ (9.9%, Group 3), ‘‘intermediate onset with high atopy’’ (15.3%, Group 4). At 4 year follow-up, although group 2 and 4 showed persistently elevated IgE levels, only group 2 showed persistently elevated eosinophil level, increased prevalence of new onset of bronchial hyper-responsiveness (BHR) (13.5%) and new diagnosis of asthma (8.5%), and higher positive SPTs, compared to group 4. CONCLUSIONS: The LCA revealed four distinct AD phenotypes in school children. Cluster analysis of ADmay lead to a better understanding of the pathophysiology of AD, a better prediction of the prognosis, and furthermore, an ideal application of personalized therapy in future.

Multivariate Asthma Phenotypes in Adults: The Quebec City Case-Control Asthma Cohort

Background and Objectives: Asthma is a heterogeneous disease where patient severity can be classified according to various models based on numerous variables. Large collections of well-phenotyped subjects are needed to find distinct clusters of patients for personalized medicine and future genetic studies. The objective of this study is to describe the collection of the Quebec City Case-Control Asthma Cohort and to identify homogeneous subgroups of asthma patients based on clinical characteristics. Methods: This cohort is part of an ongoing project initiated in 2007 to elucidate the genetic basis of asthma. All subjects are randomly recruited at the same site following advertisements. Subjects are unrelated French Canadian white adults 18 years of age or older. Each participant underwent a spirometry, methacholine challenge, and allergy skin-prick tests. Blood was collected for DNA, cell counts and total serum IgE measurements. So far, 982 subjects have been recruited and classified as cases (n = 566) or controls (n = 416). We performed factor and cluster analyses on collected phenotypes from this set to identify subgroups of phenotypically similar asthmatic patients. Results: Factor analysis with 13 variables led to the selection of five factors: lung function, numbers of allergens, blood eosinophil percentage, smoking status and age. K-means cluster analysis on the reduced dataset produced four significantly different groups with the following characteristics: smoking history, low atopy and low lung function, high atopy, and young non-smoking with average atopy. Conclusions: The Quebec City Case-Control Asthma Cohort is a new resource for local and collaborative clinical and genetic research on asthma. This new collection reveals distinct multivariate phenotypes of adult asthma that are likely to be important for future genetic studies and targeted therapies.

Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants

Most infants developing atopic dermatitis have a low risk for atopy. Primary prevention of atopic dermatitis is difficult. To assess the effect of supplementation of an infant and follow-on formula with prebiotic and immunoactive oligosaccharides on the occurrence of atopic dermatitis in the first year of life. Healthy term infants from 5 European countries with low atopy risk were recruited before the age of 8 weeks, either having started with formula feeding or being on full breast-feeding (breast-feeding group). Formula-fed infants were randomized to feeding with a regular formula containing a specific mixture of neutral oligosaccharides and pectin-derived acidic oligosaccharides (prebiotic formula group) or regular formula without oligosaccharides (control formula group). A total of 414 infants were randomized to the prebiotic group and 416 infants to the control group. Atotal of 300 infants were followed in the breast-feeding group. Up to the first birthday, atopic dermatitis occurred in significantly fewer infants from the prebiotic group (5.7%) than from the control group (9.7%; P= .04). The cumulative incidence of atopic dermatitis in the prebiotic group was in the low range of the breast-feeding group (7.3%). In a Cox regression model, the rate of atopic dermatitis was significantly lower by 44% in the prebiotic group versus the control group (P= .04). The number needed to prevent 1 case of atopic dermatitis by supplementation of prebiotics was 25 infants. Formula supplementation with a specific mixture of oligosaccharides was effective as primary prevention of atopic dermatitis in low atopy risk infants.

Exposure to poultry dust and health effects in poultry workers: impact of mould and mite allergens

The aim of the study was to evaluate exposure to moulds and house dust mite Dermatophagoides pteronyssinus in poultry farms, and related health effects in poultry workers (PW). The study involved 41 PW and 45 control office workers. Working environment was evaluated for D. pteronyssinus allergen (Der p 1), moulds and endotoxin. In workers, eye, skin and respiratory symptoms, ventilatory lung function, atopy markers (skin prick test to inhalatory allergens, total IgE) and specific IgG to moulds were assessed. Der p 1 levels ranged <0.1-3.3 microg/g, exposure to fungi was 4.9 x 10(3)-6.8 x 10(4) cfu/m(3), with prevailing Aspergillus, Penicillium and Mucor species, and endotoxin levels ranged 230-284 EU/m(3). In comparison to control subjects, significantly higher prevalence of work-related nose, asthma, eye and skin symptoms, and slight decline in ventilatory lung function was found in PW. PW had significantly higher prevalence of IgG antibodies to moulds comparing to controls (63 vs. 36%, respectively, P = 0.01), especially to Alternaria and Aspergillus species. The prevalence of atopy markers in PW was lower than in population-based studies. Hazardous levels of Der p 1, endotoxin and moulds were determined in poultry houses. High prevalence of work-related symptoms and IgG antibodies to moulds was found in PW. Healthy worker effect is proposed as an explanation of low atopy markers prevalence among PW.

Surfactant protein D alters allergic lung responses in mice and human subjects

Surfactant protein (SP) D has been proposed to be protective in allergic airway responses. We aimed to determine the effect of SP-D deficiency on murine and human airway allergy. Immunologic responses of SP-D gene-deficient mice (Sftpd-/-) at baseline and after 4 intranasal Aspergillus fumigatus exposures were assessed. In addition, the significance of a single nucleotide polymorphism (Met(11)Thr) in the human SP-D gene (known to decrease SP-D function) was investigated. Macrophage and neutrophil bronchoalveolar lavage fluid levels and large airway mucus production were increased in naive Sftpd-/- mice in association with increased lung CCL17 levels and CD4+ T cell numbers. T(H)2-associated antibody levels (IgG1 and IgE) were significantly lower in 4- to 5-week-old Sftpd-/- mice (P < .05). Accordingly, naive Sftpd-/- splenocytes released significantly less IL-4 and IL-13 on anti-CD3/CD28 stimulation (P < .01). After intranasal allergen exposures, a modest decrease in bronchoalveolar lavage fluid eosinophilia and IL-13 levels was observed in Sftpd-/- mice compared with values seen in wild-type mice in association with decreased airway resistance (P < .01). A single nucleotide polymorphism in the SFTPD gene, affecting SP-D levels and pathogen binding, was associated with decreased atopy in black subjects and potentially lower asthma susceptibility in white subjects. Sftpd-/- mice have an impaired systemic T(H)2 response at baseline and reduced inflammation and airway responses after allergen exposure. Translational studies revealed that a polymorphism in the SFTPD gene was associated with lower atopy and possibly asthma susceptibility. Taken together, these results support the hypothesis that SP-D-dependent innate immunity influences atopy and asthma.

How atopic is atopic dermatitis?

BackgroundThe extent to which the phenotype of atopic dermatitis (AD) is truly atopic has been the subject of much debate. ObjectiveWe sought to systematically evaluate the evidence for the value of measurement of IgE antibodies in diagnosing AD and whether knowledge of IgE sensitization increases clinical diagnostic and predictive ability. MethodsWe searched Medline from its inception until September 2003. Only studies that measured atopy as either skin prick test positivity or IgE-antibody sensitization to environmental allergens were included within a descriptive analysis. Because the small number of studies of adequate quality did not allow a formal meta-analysis, we assigned strength of evidence according to predefined quality criteria and ranked studies accordingly. ResultsInclusion of atopy as part of the diagnostic criteria for AD did not enhance the criteria's sensitivity and specificity in relation to the clinical phenotype of AD. The strength of association between atopy and AD varied significantly between hospital studies (47% to 75%; n=14 studies) and was stronger in hospital than in community populations (7.4% to 78%; n=13 studies). Whereas study quality did not have an effect on atopy prevalence in hospital populations, low atopy prevalences in community surveys were seen in less rigidly conducted studies. AD severity was positively associated with the number of positive skin prick test responses or IgE-antibody levels in 7 of 8 studies that measured both. Only one study suggested that IgE-specific sensitization to hen's egg is associated with subsequent development of AD, and 2 studies found that allergen-specific IgE sensitization in patients with AD is a prognostic marker for allergic airway disease in later life. Atopy-associated AD might also have a worse long-term prognosis than AD that is not associated with atopy. ConclusionAlthough atopy is clearly associated with AD, the role of IgE sensitization in AD needs further study. Current evidence suggests that up to two thirds of persons with AD are not atopic, which implies that continued use of the term atopic dermatitis is problematic. Longitudinal studies are needed to compare the treatment response and prognosis of IgE-associated and non–IgE-associated AD.

Highly atopic children: Formation of IgE antibody to food protein, especially peanut

Highly atopic infants often form IgE antibodies toward multiple food protein in the first 2 years of life. They begin producing IgE antibody to inhalant allergens between the first and second year of life. We hypothesized that highly atopic children would be at significant risk of sensitization to peanut. We defined high atopy as serum IgE ≥10 times 1 SD from normal plus multiple positive RASTs. In this study we have characterized the immunologic status of 141 patients by measuring total serum IgE and specific IgE to several allergens, including peanut. These data demonstrated that, independent of clinical history, a positive RAST to peanut was more common in the highly atopic category compared to the low atopy category. Significantly more patients who were highly atopic and had a positive peanut RAST had a positive RAST for egg or milk compared to low atopic patients. More significantly, 33 of the patients had never knowingly received peanut, yet 21 (63.6%) had a positive RAST for peanut, whereas seven (21.2%) had a peanut antibody in the highest RAST category. All these seven patients were considered highly atopic according to the definition above, and three were younger than 2 years of age. These results suggest that highly atopic infants are at special risk for sensitization to peanut, even when they have never received peanut, and that characterization of immunologic sensitization to milk, egg, and peanut will identify the highly atopic infant. At present, it is not clear how these infants became sensitized, but they likely correspond to infants who have been reported as having a reaction to peanut on first known exposure.

HLA-A, B and C and HLA-DR antigens in intrinsic and allergic asthma.

Some 103 patients with asthma and 100 healthy volunteers have been typed for HLA-A, B and C and HLA-DR antigens. The 103 patients consisted of thirty-three with intrinsic asthma, thirty-four with extrinsic asthma, and thirty-six known to have precipitins to Aspergillus fumigatus. No increase in frequency of any of the A, B, C, or DR antigens was found to be significant after correction for the number of comparisons was made. However certain trends comparable to findings in other immunopathic disorders were noted. For example B12 was increased in the allergic asthmatics (46 vs 29% controls) and it is suggested that B12 is associated with the ability to produce the IgE antibodies. A3/B7/DRw2 (which are in linkage disequilibrium) all show a decreased frequency in intrinsic asthma (24, 12 and 9% vs 32, 26 and 24% respectively in controls). Finally B8 and DRw3, which showed a moderate increase in frequency in all three groups of asthmatics, were found in five of seven patients with low atopy but persisting antibodies to A. fumigatus. Further detailed studies of these asthmatic subgroups is warranted.