Beyond Atopy Multiple Patterns of Sensitization in Relation to Asthma in a Birth Cohort Study

The University of Manchester, Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 02/2010; 181(11):1200-6. DOI: 10.1164/rccm.200907-1101OC
Source: PubMed


The pattern of IgE response (over time or to specific allergens) may reflect different atopic vulnerabilities which are related to the presence of asthma in a fundamentally different way from current definition of atopy.
To redefine the atopic phenotype by identifying latent structure within a complex dataset, taking into account the timing and type of sensitization to specific allergens, and relating these novel phenotypes to asthma.
In a population-based birth cohort in which multiple skin and IgE tests have been taken throughout childhood, we used a machine learning approach to cluster children into multiple atopic classes in an unsupervised way. We then investigated the relation between these classes and asthma (symptoms, hospitalizations, lung function and airway reactivity).
A five-class model indicated a complex latent structure, in which children with atopic vulnerability were clustered into four distinct classes (Multiple Early [112/1053, 10.6%]; Multiple Late [171/1053, 16.2%]; Dust Mite [47/1053, 4.5%]; and Non-dust Mite [100/1053, 9.5%]), with a fifth class describing children with No Latent Vulnerability (623/1053, 59.2%). The association with asthma was considerably stronger for Multiple Early compared with other classes and conventionally defined atopy (odds ratio [95% CI]: 29.3 [11.1-77.2] versus 12.4 [4.8-32.2] versus 11.6 [4.8-27.9] for Multiple Early class versus Ever Atopic versus Atopic age 8). Lung function and airway reactivity were significantly poorer among children in Multiple Early class. Cox regression demonstrated a highly significant increase in risk of hospital admissions for wheeze/asthma after age 3 yr only among children in the Multiple Early class (HR 9.2 [3.5-24.0], P < 0.001).
IgE antibody responses do not reflect a single phenotype of atopy, but several different atopic vulnerabilities which differ in their relation with asthma presence and severity.

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Available from: Adnan Custovic, Oct 01, 2015
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    • "Review childhood asthma development in westernized nations (Simpson et al., 2010), and its rise is associated with a parallel increase in asthma prevalence (Masoli et al., 2004). More recently, an unsupervised statistical approach to pediatric subject clustering, based on the range and degree of their atopic sensitization, revealed that subjects that were predominantly multi-sensitized to common food and aero-allergens had the highest risk of subsequently developing asthma in childhood (Havstad et al., 2014; Simpson et al., 2010). Allergic asthma is a heterogeneous and complex disease, clinically defined as reversible airflow obstruction and immunologically by hyper-activation of the T helper 2 (Th2) arm of the adaptive immune response and the overexpression of the pro-inflammatory cytokines IL-4, IL-5, and IL-13, as well eosinophilia and mast cell infiltration of the airways (Adcock et al., 2008). "
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    ABSTRACT: Asthma and atopy, classically associated with hyper-activation of the T helper 2 (Th2) arm of adaptive immunity, are among the most common chronic illnesses worldwide. Emerging evidence relates atopy and asthma to the composition and function of the human microbiome, the collection of microbes that reside in and on and interact with the human body. The ability to interrogate microbial ecology of the human host is due in large part to recent technological developments that permit identification of microbes and their products using culture-independent molecular detection techniques. In this review we explore the roles of respiratory, gut, and environmental microbiomes in asthma and allergic disease development, manifestation, and attenuation. Though still a relatively nascent field of research, evidence to date suggests that the airway and/or gut microbiome may represent fertile targets for prevention or management of allergic asthma and other diseases in which adaptive immune dysfunction is a prominent feature. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 05/2015; 17(5):592-602. DOI:10.1016/j.chom.2015.04.007 · 12.33 Impact Factor
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    • "The research strategy that has proven most fruitful in progressively elucidating the initiation phase of asthma involves utilization of large cohorts of children, either randomly selected populations or specific “high-risk” groups recruited on the basis of family history of disease susceptibility. These cohorts are tracked throughout childhood and, where feasible, into early adulthood (38–47). In some instances, exemplified by the “farmer-mother” studies in northern Europe whose offspring express very low susceptibility to asthma/allergy (48), this has additionally involved collecting data on maternal environmental exposures during pregnancy and assessing, the impact of these on subsequent disease risk in their offspring. "
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    ABSTRACT: Asthma is a genetically complex, chronic lung disease defined clinically as episodic airflow limitation and breathlessness that is at least partially reversible, either spontaneously or in response to therapy. Whereas asthma was rare in the late 1800s and early 1900s, the marked increase in its incidence and prevalence since the 1960s points to substantial gene × environment interactions occurring over a period of years, but these interactions are very poorly understood (1-6). It is widely believed that the majority of asthma begins during childhood and manifests first as intermittent wheeze. However, wheeze is also very common in infancy and only a subset of wheezy children progress to persistent asthma for reasons that are largely obscure. Here, we review the current literature regarding causal pathways leading to early asthma development and chronicity. Given the complex interactions of many risk factors over time eventually leading to apparently multiple asthma phenotypes, we suggest that deeply phenotyped cohort studies combined with sophisticated network models will be required to derive the next generation of biological and clinical insights in asthma pathogenesis.
    Frontiers in Immunology 09/2014; 5:447. DOI:10.3389/fimmu.2014.00447
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    • "Although some studies have suggested a possible linear dose.response relationship between early life exposure to allergens and the subsequent development of sensitization5,6), the development of atopic sensitization is the result of a complex interplay of genetic and environmental factors1,2,7). Therefore, our review aimed to (1) describe the prevalence of atopic sensitization in infants and young children, (2) describe the change in patterns of sensitization to common allergens across different age groups, and (3) to discuss the determinants of atopic sensitization in infants and young children. "
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    ABSTRACT: Atopic sensitization is a complex phenomenon that changes dynamically with age throughout childhood; its prevalence increases with age in young children. Additionally, with increasing age, the prevalence of sensitization to inhalant allergens and the prevalence of polysensitization to allergens increase. It is also well established that the development of atopic sensitization is the result of a complex interplay of genetic and environmental factors. However, there is considerable heterogeneity in the literature in terms of the effect of different environmental exposures in young children on the subsequent risk of atopic sensitization and allergic diseases. Previous studies on the relationship, in early life, between pet ownership, sex, exposure to secondhand smoke, exposure to traffic-related air pollution components, and atopic sensitization have yielded different results. Recent studies have highlighted the importance of gene-environment interactions, especially during early childhood, on the risk of subsequent atopic sensitization and allergic diseases. Therefore, pediatricians should consider the genetic and environmental determinants of atopic sensitization in infants and young children when diagnosing and treating patients with allergic diseases. Determining ways in which early exposure to these risk factors in young children may be reduced could be beneficial in preventing the likelihood of developing atopic sensitization.
    Korean Journal of Pediatrics 05/2014; 57(5):205-10. DOI:10.3345/kjp.2014.57.5.205
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