Features of asthma which provide meaningful insights for understanding the disease heterogeneity.

BACKGROUND: Data-driven methods such as hierarchical clustering (HC) and principal component analysis (PCA) have been used to identify asthma subtypes, with inconsistent results. OBJECTIVE: To develop a framework for the discovery of stable and clinically meaningful asthma subtypes. METHODS: We performed HC in a rich data set from 613 asthmatic children, using 45 clinical variables (Model 1), and after PCA dimensionality reduction (Model 2). Clinical experts then identified a set of asthma features/domains which informed clusters in the two analyses. In Model 3, we reclustered the data using these features to ascertain whether this improved the discovery process. RESULTS: Cluster stability was poor in Models 1 and 2. Clinical experts highlighted four asthma features/domains which differentiated the clusters in two models: age of onset, allergic sensitization, severity, and recent exacerbations. In Model 3 (HC using these four features), cluster stability improved substantially. The cluster assignment changed, providing more clinically interpretable results. In a 5-cluster model, we labelled the clusters as: "Difficult asthma" (n = 132); "Early-onset mild atopic" (n = 210); "Early-onset mild non-atopic: (n = 153); "Late-onset" (n = 105); and "Exacerbation-prone asthma" (n = 13). Multinomial regression demonstrated that lung function was significantly diminished among children with "Difficult asthma"; blood eosinophilia was a significant feature of "Difficult," "Early-onset mild atopic," and "Late-onset asthma." Children with moderate-to-severe asthma were present in each cluster. CONCLUSIONS AND CLINICAL RELEVANCE: An integrative approach of blending the data with clinical expert domain knowledge identified four features, which may be informative for ascertaining asthma endotypes. These findings suggest that variables which are key determinants of asthma presence, severity, or control may not be the most informative for determining asthma subtypes. Our results indicate that exacerbation-prone asthma may be a separate asthma endotype and that severe asthma is not a single entity, but an extreme end of the spectrum of several different asthma endotypes.

Polymorphisms of endotoxin pathway and endotoxin exposure: in vitro IgE synthesis and replication in a birth cohort.

BACKGROUND: Genetic variants in endotoxin signaling pathway are important in modulating the effect of environmental endotoxin on asthma and atopic phenotypes. Our objective was to determine the single nucleotide polymorphisms (SNPs) in the endotoxin signaling pathway that may influence in vitro IgE synthesis and to investigate the relationship between these variants and endotoxin exposure in relation to the development of asthma and atopy in a birth cohort. METHODS: Peripheral blood mononuclear cells from 45 children with asthma were stimulated with 2 and 200 ng/ml lipopolysaccharide in vitro and IgE was measured in the culture supernatants. Children were genotyped for 121 SNPs from 30 genes in the endotoxin signaling pathway. Variants with a dose-response IgE production in relation to lipopolysaccharide (LPS) were selected for replication in a population-based birth cohort, in which we investigated the interaction between these SNPs and endotoxin exposure in relation to airway hyper-responsiveness, wheeze, and atopic sensitization. RESULTS: Twenty-one SNPs in nine genes (CD14, TLR4, IRF3, TRAF-6, TIRAP, TRIF, IKK-1, ST-2, SOCS1) were found to modulate the effect of endotoxin on in vitro IgE synthesis, with six displaying high linkage disequilibrium. Of the remaining 15 SNPs, for seven we found significant relationships between genotype and endotoxin exposure in the genetic association study in relation to symptomatic airway hyper-responsiveness (CD14-rs2915863 and rs2569191, TRIF-rs4807000), current wheeze (ST-2-rs17639215, IKK-1-rs2230804, and TRIF-rs4807000), and atopy (CD14-rs2915863 and rs2569192, TRAF-6-rs5030411, and IKK-1-rs2230804). CONCLUSIONS: Variants in the endotoxin signaling pathway are important determinants of asthma and atopy. The genotype effect is a function of the environmental endotoxin exposure.

Impact of rhinitis on asthma severity in school-age children.

BACKGROUND: In a population-based sample of school-age children, we investigated factors associated with rhinitis, and differences between allergic and nonallergic rhinitis. Amongst children with asthma, we explored the association between rhinitis and asthma severity. METHODS: Children participating in a birth cohort study (n = 906) were reviewed at age 8 years. Asthma was defined as at least two of the following three features: physician-diagnosed asthma, currently using asthma medication and current wheeze. We measured lung function (plethysmography and spirometry) and airway hyper-reactivity (AHR; methacholine challenge). RESULTS: In the analysis adjusted for the presence of asthma, children with rhinitis had significantly higher AHR (P = 0.001). Maternal smoking and absence of breastfeeding were stronger predictors of nonallergic rhinitis, whereas current wheeze and eczema were stronger predictors of allergic rhinitis. Amongst asthmatics (n = 159), when compared to 76 children without rhinitis, those with rhinitis (n = 83) were 2.89-fold (95% CI 1.41-5.91) more likely to experience frequent attacks of wheezing, 3.44-fold (1.19-9.94) more likely to experience severe attacks of wheezing limiting speech, 10.14-fold (1.27-81.21) more likely to have frequent visits to their doctor because of asthma and nine-fold (1.11-72.83) more likely to miss school. Reported use of intranasal corticosteroids resulted in a numerically small, but consistent reduction in risk, rendering the associations between rhinitis and asthma severity nonsignificant. CONCLUSION: We observed differences in risk factors and severity between allergic and nonallergic rhinitis. In children with asthma, rhinitis had adverse impact on asthma severity. The use of intranasal corticosteroids resulted in a small, but consistent reduction in the risk.

Multiple atopy phenotypes and their associations with asthma: similar findings from two birth cohorts.

BACKGROUND: Although atopic sensitization is one of the strongest risk factors for asthma, its relationship with asthma is poorly understood. We hypothesize that 'atopy' encompasses multiple sub-phenotypes that relate to asthma in different ways. METHODS: In two population-based birth cohorts (Manchester and Isle of Wight - IoW), we used a machine learning approach to independently cluster children into different classes of atopic sensitization in an unsupervised manner, based on skin prick and sIgE tests taken throughout childhood and adolescence. We examined the qualitative cluster properties and their relationship to asthma and lung function. RESULTS: A five-class solution best described the data in both cohorts, with striking similarity between the classes across the two populations. Compared with nonsensitized class, children in the class with sensitivity to a wide variety of allergens (~1/3 of children atopic by conventional definition) were much more likely to have asthma (aOR [95% CI0; 20.1 [10.9-40.2] in Manchester and 11.9 [7.3-19.4] in IoW). The relationship between asthma and conventional atopy was much weaker (5.5 [3.4-8.8] in Manchester and 5.8 [4.1-8.3] in IoW). In both cohorts, children in this class had significantly poorer lung function (FEV1 /FVC lower by 4.4% in Manchester and 2.6% in IoW; P < 0.001), most reactive airways, highest eNO and most hospital admissions for asthma (P < 0.001). CONCLUSIONS: By adopting a machine learning approach to longitudinal data on allergic sensitization from two independent unselected birth cohorts, we identified latent classes with strikingly similar patterns of atopic response and association with clinical outcomes, suggesting the existence of multiple atopy phenotypes.

Methylation of IL-2 promoter at birth alters the risk of asthma exacerbations during childhood.

BACKGROUND: Epigenetic modifications may have a role in asthma susceptibility. OBJECTIVE: To investigate whether epigenetic modification at birth of a CpG site necessary for the regulation of IL-2 transcription (IL-2 Site1) is associated with the development of asthma during childhood. METHODS: Methylation of IL-2 Site1 was assessed in cord blood from 303 children (225 with atopic mothers); as controls, we measured methylation of a site not important in the transcription of IL-2 (IL-2 Site7) and methylation of the LINE-1 repetitive element. Children were followed to the age of 8 years. Information on severe asthma exacerbations and hospital admissions was collected from child's primary care medical record. To account for potential confounding by bronchiolitis, we used exacerbations/hospitalizations after age 1 year as primary outcomes. RESULTS: There were 49 severe exacerbations amongst 33 children, and 22 hospital admissions amongst 11 children. The risk of asthma exacerbation increased 1.07-fold (95% CI 1.01-1.14, P = 0.03) and the risk of hospital admission increased 1.12-fold (95% CI 1.04-1.20, P = 0.002) for each one per cent increase in IL-2 Site1 methylation. Children who were admitted to hospital at any time-point had significantly higher IL-2 Site1 methylation than children not admitted to hospital (P = 0.007). There was a significant interaction between age at exacerbation (P = 0.03) or hospital admission (P = 0.02) and methylation, with the effect of methylation increasing with increasing age. Methylation of the control IL-2 Site7 or LINE-1 was not a significant predictor of asthma exacerbations/hospital admission, and we found no association between IL-2 Site1 methylation and hospital admissions for other reasons (0.99 [0.92-1.06]). Cord blood mononuclear cell phytohemagglutinin-stimulated lymphoproliferative responses decreased significantly with increasing IL-2 Site1 methylation (P < 0.001). CONCLUSIONS: Increasing methylation in cord blood of a functional CpG site in the IL-2 promoter is associated with increased likelihood of severe asthma exacerbations and hospital admissions for asthma/wheeze between ages of 2 and 8 years.