Childhood asthma, asthma severity indicators, and related conditions along an urban-rural gradient: a cross-sectional study.

BACKGROUND: Asthma prevalence is generally lower in rural locations with some indication of an urban-rural gradient. However, among children with asthma, certain rural exposures thought to protect against the development of asthma could aggravate the condition. We examined childhood asthma prevalence and related conditions along an urban-rural gradient and also examined the characteristics of those with asthma along the urban-rural gradient. METHODS: In 2013 we completed a cross-sectional survey of 3509 children aged 5-14 years living in various population densities of Saskatchewan, Canada. Location of dwelling was identified as belonging to one of the following population densities: large urban region (approximately 200,000), small urban (approximately 35,000), or rural (small town of <1,500 or farm dweller). Physician-diagnosed asthma and asthma-related symptoms were ascertained from responses in the parental-completed questionnaires. RESULTS: Of the study population, 69% lived in a large urban region, 11% lived in a small urban centre and 20% were rural dwellers. Overall, asthma prevalence was 19.6% with differences in asthma prevalence with differences between locations (large urban = 20.7%; small urban = 21.5%; rural = 15.1%; p = 0.003). After adjustment for potential confounders, the association between location of dwelling and asthma remained significant. Despite a lower prevalence of asthma in the rural area, the prevalence and risk of ever wheeze and having more than 3 wheezing episodes in the past 12 months among those who reported asthma, was higher in rural locations after adjustment for potential confounders. CONCLUSIONS: The results of this study support the evidence of a difference in childhood asthma prevalence between urban and rural locations and that once a child has asthma, certain rural exposures may aggravate the disease.

Inhaled allergen bronchoprovocation tests.

The allergen bronchoprovocation test is a long-standing exacerbation model of allergic asthma that can induce several clinical and pathophysiologic features of asthma in sensitized subjects. Standardized allergen challenge is primarily a research tool, and when properly conducted by qualified and experienced investigators, it is safe and highly reproducible. In combination with validated airway sampling and sensitive detection techniques, allergen challenge allows the study of several features of the physiology of mainly TH2 cell-driven asthma in relation to the kinetics of the underlying airway pathology occurring during the allergen-induced late response. Furthermore, given the small within-subject variability in allergen-induced airway responses, allergen challenge offers an adequate disease model for the evaluation of new (targeted) controller therapies for asthma in a limited number of subjects. In proof-of-efficacy studies thus far, allergen challenge showed a fair positive predicted value and an excellent negative predictive value for the actual clinical efficacy of new antiasthma therapies, underscoring its important role in early drug development. In this review we provide recommendations on challenge methods, response measurements, sample size, safety, and harmonization for future applications.

Induction of type 2 T helper cell allergen tolerance by IL-10-differentiated regulatory dendritic cells.

In mouse models of asthma, therapeutic use of allergen-presenting IL-10-differentiated dendritic cells (DCs) can abrogate airway hyperresponsiveness, and reduce other asthma-related responses to near background. Analogous human DCs can suppress human T cell responses in vitro, but the operative mechanisms are poorly defined. We investigated the ability of IL-10-treated human DCs to induce tolerance among autologous T cells of subjects with asthma and the mechanisms by which they do this. CD14(+) monocyte-derived DCs were differentiated in the presence of IL-10 (DC10) ex vivo from 11 donors with asthma and 4 control donors, and characterized for relevant markers. They were pulsed with specific or irrelevant allergen, and cultured with autologous peripheral blood CD4(+) T cells, either alone or together with autologous immunostimulatory DCs (DC-TNF), and the impact of this treatment on the T-cell responses was assessed for each donor. The DC10 expressed reduced levels of some relevant markers (CD40, CD80, human leukocyte antigen-DR) and stimulatory cytokines (IL-6 and IL-12), but augmented levels of Ig-like transcript-22/CD85j and IL-10 relative to DC-TNF. In cocultures, they dampened DC-TNF-driven T helper (Th) type 2 cell proliferation and cytokine (IL-4, -5, and -13) secretion. They also drove the development from atopic CD4(+)CD25(lo)Foxp3(lo) cells of a population of IL-10-secreting CD25(+)Foxp3(+)LAG-3(+)CTLA-4(+) regulatory T cells (Tregs). These Tregs suppressed stimulatory DC-induced autologous Th2 cell proliferation and cytokine secretion in a contact-dependent manner. Our data indicate that IL-10-treated human DCs induce Th2 cell allergen tolerance ex vivo by driving the differentiation of Tregs.