EPIDEMIOLOGY OF ALLERGIC DISEASE ENDOTYPES

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Pediatric allergy and asthma are a costly public health burden, but so far substantial research efforts have yielded no prevention strategies. A likely reason is that despite longstanding recognition by the medical community that the term 'asthma' refers to a colletcion of diseases, researchers have historically treated the syndrome as a single disease entity. Epidemiologically, the collapse of different phenotypes (observed disease patterns) and endotypes (phenotypes further delineated by pathophysiological processes), into a single category corrupts associations between risk factors and diseases. Thus, progress in allergic disease research has been hampered. Prior attempts have been made to identify such phenotypes and endotypes, but a combination of incomplete data and oversimplified statistical methods have limited progress. We propose to apply sophisticated latent class analyses in a large general risk cohort combined with immunological markers to finely discriminate asthma and allergy disease phenotypes and endotypes and then use this information to conduct risk factor analyses. Using this approach in our WHEALS birth cohort, we have already characterized four classes at age 2 years: 1) Low to No Sensitization; 2) Highly Sensitized; 3) Milk and Egg Dominated Sensitization; and 4) Peanut and/or Inhalant allergen - No Milk Sensitization. Total IgE levels varied between the groups, as did the rates of eczema and doctor diagnosis of asthma (at age 4 years). The Highly Sensitized had the greatest rates, the Low to No Sensitization had the lowest rates, and the other two classes had rates intermediate between the Low and High Sensitization groups. These data suggest the use of latent classes, rather than the use of the "traditional" definition of atopy (any allergen-specific IgE (sIgE) 0.35 IU/mL), more specifically identifies those on a trajectory for allergic disease, yielding advancement in both allergic disease research and clinical care. Using the predominantly (62%) African American birth cohort WHEALS, we will: Aim 1) Determine which early life allergic disease phenotypes identified at age 2 years are associated with lung function (spirometry and methacholine challenge) at age 10 years; Aim 2) a) Identify the allergic disease endotypes for 10 year old children based on annual report of wheeze; lung function, eNO, obesity, cytokines, and white cell counts and extensive immunophenotyping [assessment of cellular markers to identify and quantify activation of regulatory T cells (Tregs), basophils and dendritic cells (DCs)] at age 10 years; and total IgE and sensitization (sIgE and skin prick tests) at ages 2 and 10 years; and, b) Estimate associations between early life risk factors (e.g., delivery type, pet exposure, etc.) and the identified Aim 2a endotypes; and, 3) Compare and contrast the risk factor associations with the endotypes in Aim 2 to the risk factor associations determined using "traditional" definitions of atopy and asthma (doctor diagnosis and medication use and/or symptoms in the last year). Analyses will be performed for all 900 WHEALS cohort children and separately for Black children and White children to assess racial differences.