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Background: Recent studies support the existence of several entities under the clinical diagnosis of bronchiolitis. Among infants with severe bronchiolitis, distinct profiles have been differentially associated with development of recurrent wheezing by age 3 years. However, their associations with actual asthma remain unclear. Objectives: Our aim was to study the association between severe bronchiolitis profiles identified by using a clustering approach and childhood asthma. Methods: Among 408 children (aged

Background There is evidence that CD4 + CD25 high T-regulatory cells are important for establishing tolerance to allergens, but information in children is limited. Objective To test the hypothesis that greater numbers and function of CD4 + CD25 high T cells are associated with a reduced risk of childhood allergies and wheezing. Methods A cohort of 151 six-year-old children from atopic families was analyzed for peripheral blood CD4 + CD25 high and CD4 + CD25 int T cells by flow cytometry and for clinical and immunologic correlates of atopy. The associations between these variables were assessed by regression analysis. Results Factors positively associated with % CD4 + CD25 high /CD4 T cells were male sex, number of positive allergen-specific IgE tests, total IgE, season, and 1-month average total pollen count preceding blood draw. The percentage of CD4 + CD25 high /total CD4 T cells did not correlate with induced cytokine production, and correlated negatively with suppressive capacity of CD4 + CD25 + T cells ( r = –0.45; P = .034). The percentage of CD4 + CD25 int /CD4 T cells was 54% higher in pollen-sensitized children compared with nonsensitized children in spring ( P = .023 for interaction), and correlated positively with IL-5, IL-10, and IL-13 ( P ≤ .001 for all). Conclusion Our findings suggest that blood CD4 + CD25 high cells are a mixture of activated and regulatory T cells, and that these cells could be seasonally regulated by environmental factors such as pollen exposure. Clinical implications Seasonal increases in CD4CD25 high expression in children with allergy may represent systemic immune activation caused by pollen exposures.

Background Rhinovirus-induced early wheezing has been suggested as a new important risk factor for recurrent wheezing. Objective We sought to investigate the risk factors for recurrent wheezing and to determine post hoc the efficacy of prednisolone in risk groups. Methods We followed for 1 year 118 children (median age, 1.1 years) who had had their first episode of wheezing and had participated in a trial comparing prednisolone with placebo in hospitalized children. Demographics and laboratory data were obtained at study entry. The follow-up outcome was recurrent wheezing (3 physician-confirmed episodes). Results Recurrent wheezing was diagnosed in 44 (37%) children. Independent risk factors were age < 1 year, atopy, and maternal asthma. The probability of recurrent wheezing was higher in rhinovirus than respiratory syncytial virus (RSV)–affected children among placebo recipients (hazard ratio, 5.05; 95% CI, 1.00-25.41). Prednisolone decreased the probability of recurrent wheezing in children with eczema (0.15; 95% CI, 0.04-0.63) but not in those without eczema (1.89; 95% CI, 0.83-4.29; P = .007 for interaction). Prednisolone was associated with less recurrent wheezing in the rhinovirus group (0.19; 95% CI, 0.05-0.71), but not in the RSV (2.12; 95% CI, 0.46-9.76) or in the RSV/rhinovirus-negative groups (2.03; 95% CI, 0.83-5.00; P = .017 for interaction). Conclusion Rhinovirus-induced early wheezing is a major viral risk factor for recurrent wheezing. Prednisolone may prevent recurrent wheezing in rhinovirus-affected first-time wheezers. The presence of eczema may also influence the response to prednisolone. Clinical implications A prospective trial is needed to test the hypothesis that prednisolone reduces recurrent wheezing in rhinovirus-affected wheezing children.

Rhinovirus-induced wheezing is an important risk factor for recurrent wheezing. There are no randomized controlled trials on the effect of systemic corticosteroids in patients with this disease.We sought to study the short- and long-term effects of prednisolone treatment of the first acute, moderate-to-severe, rhinovirus-induced wheezing episode in young children.After confirming rhinovirus from nasopharyngeal aspirate by using PCR, 79 children with a first wheezing episode at age 3 to 23 months were randomized to receive oral prednisolone (first dose of 2 mg/kg, followed by 2 mg/kg/d in 2 divided doses for 3 days) or placebo. The trial was double blind throughout the 12-month follow-up. The primary outcomes were long term: new physician-confirmed wheezing episode within 2 months, number of physician-confirmed wheezing episodes within 12 months, and initiation of regular controller medication for asthma symptoms within 12 months. The primary interaction analysis examined rhinovirus load.Seventy-four patients completed the study (mean age, 13 months; 28% atopic). Long-term outcomes did not differ between groups (all P ≥ .30). For short-term outcomes, the prednisolone group had less cough, rhinitis, noisy breathing, severe breathing difficulties, and nocturnal respiratory symptoms at home within 2 weeks (all P.05). The 25 children with greater than 7000 rhinovirus copies/mL (most sensitive cutoff) benefitted from prednisolone in terms of less risk of physician-confirmed recurrence within 2 and 12 months compared with placebo (both P.05).Prednisolone cannot be routinely recommended for all young children experiencing their first acute, moderate-to-severe, rhinovirus-induced wheezing episode. Prednisolone might be beneficial in a subgroup of children with high viral loads.

Background: The generation and maintenance of allergen specific T cell tolerance is a key step in healthy immune responses to allergens and successful allergen specific immunotherapy. Breaking of peripheral T cell tolerance to allergens can lead to the development of allergies but the mechanisms are not completely understood. Objective: We sought to identify molecular mechanisms that break allergen specific T cell tolerance in human subjects. Methods: Proliferative responses of allergen specific T cells from tonsils and peripheral blood were measured by using tritiated thymidine incorporation and carboxyfluorescein succinimidyl ester (CFSE) dilution experiments. Cytokine levels in cell free supernatants were quantified by using the cytometric bead array and mRNA expression of transcription factors and cytokines was determined by using quantitative PCR. Myeloid dendritic cells (DCs) were characterized by using flow cytometry. Results: In allergic patients the immune profile of the tonsils represents the atopic status of patients with low expression of the TH1 cell specific transcription factor T bet and the cytokine IFN ? as well as IL 10. Human tonsils show very low levels of allergen induced T cell proliferation thus representing a very suitable in vivo model to assess mechanisms of breaking allergen specific T cell tolerance. Triggering of Toll like receptor (TLR) 4 or TLR8 and the proinflammatory cytokines IL 1ß or IL 6 break allergen specific T cell tolerance in human tonsils and peripheral blood through a mechanism dependent on the adaptor molecule myeloid differentiation primary response gene (88) (MyD88). In particular myeloid DCs and stimulations that activate them broke the tolerance of allergen specific CD4+ T cells whereas plasmacytoid DCs and stimulations that activate them such as TLR7 and TLR9 did not have any effect. Tolerance breaking conditions induced by different molecular mechanisms were associated with a mixed cytokine profile with a tendency toward increased levels of IL 13 and IL 17 which are TH2 and TH17 cytokines respectively. Conclusion: Certain innate immune response signals and proinflammatory cytokines break allergen specific CD4+ T cell tolerance in normally unresponsive subjects which might lead to the development or exacerbation of allergic diseases after encountering microbes or inflammatory conditions. © 2012 American Academy of Allergy Asthma Immunology.

Background Tonsils are strategically located in the gateway of both alimentary and respiratory tracts representing the first contact point of food and aeroallergens with the immune system. Tonsillectomy removes only the palatine tonsils and sometimes adenoids. Lingual tonsil is anatomically big and remains lifelong intact. Objective The aim of this study was to demonstrate cellular and molecular mechanisms of oral tolerance induction to food and aeroallergens in human tonsils. Methods Tonsil allergen-specific FOXP3 + regulatory T (Treg) cells, plasmacytoid dendritic cells (pDCs), and myeloid dendritic cells were characterized by flow cytometry and suppressive assays. Intracellular staining, [ 3 H]-thymidine incorporation, and carboxy-fluorescein succinimidyl ester dilution experiments were performed. Tonsil biopsies were analyzed by confocal microscopy. Results CD4 + FOXP3 + Treg cells and pDCs constitute important T- and dendritic cell–compartments in palatine and lingual tonsils. Tonsil pDCs have the ability to generate functional CD4 + CD25 + CD127 − FOXP3 + Treg cells with suppressive property from naive T cells. CD4 + FOXP3 + Treg cells proliferate and colocalize with pDCs in vivo in T-cell areas of lingual and palatine tonsils. Tonsil T cells did not proliferate to common food and aeroallergens. Depletion of FOXP3 + Treg cells enables the allergen-induced proliferation of tonsil T cells, indicating an active role of Treg cells in allergen-specific T-cell unresponsiveness. High numbers of major birch pollen allergen, Bet v 1–specific CD4 + FOXP3 + Treg cells, are identified in human tonsils compared with peripheral blood. A positive correlation between the percentages of FOXP3 + Treg cells and pDCs is observed in tonsils from nonatopic individuals. Conclusion Functional allergen-specific Treg cells are identified both in lingual and in palatine tonsils.