Background-To prospectively apply an automated, quantitative 3-D approach to imaging and airway analysis to assess airway remodeling in asthma.

Background The development of asthma after respiratory syncytial virus (RSV) bronchiolitis has been demonstrated in case-control studies, although the determinants of post-RSV asthma remain undefined. Objectives We sought to evaluate the potential determinants of physician-diagnosed asthma after severe RSV bronchiolitis during infancy. Methods We enrolled 206 children during an initial episode of severe RSV bronchiolitis at 12 months of age or less in a prospective cohort study and followed these children for up to 6 years. In a subset of 81 children, we analyzed CCL5 (RANTES) mRNA expression in upper airway epithelial cells. Results Forty-eight percent of children had physician-diagnosed asthma before the seventh birthday. Independent determinants significantly associated with increased risk for physician-diagnosed asthma by the seventh birthday included maternal asthma (odds ratio [OR], 5.2; 95% CI, 1.7-15.9; P = .004), exposure to high levels of dog allergen (OR, 3.2; 95% CI, 1.3-7.7; P = .012), aeroallergen sensitivity at age 3 years (OR, 10.7; 95% CI, 2.1-55.0; P = .005), recurrent wheezing during the first 3 years of life (OR, 7.3; 95% CI, 1.2-43.3; P = .028), and CCL5 expression in nasal epithelia during acute RSV infection (OR, 3.8; 95% CI, 1.2-2.4; P < .001). White children (OR, 0.19; 95% CI, 0.04-0.93; P = .041) and children attending day care (OR, 0.18; 95% CI, 0.04-0.84; P = .029) had a decreased risk of physician-diagnosed asthma. Conclusions Approximately 50% of children who experience severe RSV bronchiolitis have a subsequent asthma diagnosis. The presence of increased CCL5 levels in nasal epithelia at the time of bronchiolitis or the development of allergic sensitization by age 3 years are associated with increased likelihood of subsequent asthma.

Asthma is a chronic inflammatory airway disorder characterized by airway hyperresponsiveness and reversible airflow obstruction. Subgroups of asthma patients develop airflow obstruction that is irreversible or only partially reversible and experience an accelerated rate of lung function decline. The structural changes in the airways of these patients are referred to as airway remodeling. All elements of the airway wall are involved, and remodeled airway wall thickness is substantially increased compared to normal control airways. Airway remodeling is thought to contribute to the subphenotypes of irreversible airflow obstruction and airway hyperresponsiveness, and it has been associated with increased disease severity. Reversal of remodeling is therefore of paramount therapeutic importance, and mechanisms responsible for airway remodeling are feasible therapeutic targets for asthma treatment. This paper will focus on our current understanding of the mechanisms of airway remodeling in asthma and potential targets for future intervention.

Background Immune response following viral infection usually involves Th1-mediated response; however, severe respiratory syncytial virus (RSV) infection appears to be associated with the development of asthma, a Th2-predominant phenotype. Objective To understand the early and subsequent immunologic response to a serious RSV infection in children over time. Methods 206 previously healthy infants hospitalized with severe RSV bronchiolitis were enrolled in a prospective cohort called the RSV Bronchiolitis in Early Life (RBEL) study. Peripheral blood T cells were obtained immediately following RSV infection and at 2, 4 and 6 years of age, stimulated with PMA and ionomycin, and analyzed for interleukin (IL)-2, -4, and - 13 and interferon-γ (IFN-γ) by flow cytometry and real time PCR. Results 48% (n=97) of the children developed asthma (physician-diagnosed) and 48% (n=97) had eczema by age 6. 32% (n=48 of 150) developed allergic sensitization by 3 yrs of age. Children with asthma had lower IL-13 expression at 6 yrs of age than those without (p=0.001). IFN-γ, IL-2 and -4 levels did not differ by asthma or eczema status during follow-up (all p>0.05). Allergic sensitization was not associated with differences in cytokine levels during follow-up (all p>0.05). Conclusion Severe RSV infection early in life is associated with a high incidence of asthma and eczema. Contrary to expectations, subsequent immunologic development in those who developed asthma, eczema or allergic sensitization was not associated with a Th2 phenotype in the peripheral blood.

Asthma leads to chronic airway inflammation that shares pathological features of chronic rejection after lung transplantation. Due to significant role of autoimmunity in chronic rejection, we hypothesized that immunity to self-antigens may also be present in asthma. The goal was to define immune responses to self-antigens in patients with asthma. Blood and clinical data were collected from 99 asthmatics and 60 controls. Serum was analyzed for antibodies (Abs) to Collagen V (ColV) by ELISA and correlated with disease severity. Asthmatics' sera were tested in human protein array to determine immune responses to other self-antigens. Asthmatics had higher concentration of Abs to ColV (predominantly IgG isotype) compared to control (p < 0.01). These Abs correlated with severe asthma (p<0.01) and corticosteroid use (p=0.032). Additionally, Abs to novel self-antigens epidermal group factor receptor (EGFr), activin A type 1 receptor, and alpha-catenin (α-catenin) were detected in asthmatics. We conclude that Abs to self-antigens (ColV, EGFr, Activin A type 1 receptor, and α-catenin) are present in asthmatics sera correlating with clinical disease. Epithelial damage from airway inflammation during asthma may result in exposure of cryptic self-antigens or their determinants resulting in immune response to self-antigens and these may contribute to pathogenesis of asthma.

1Background: Children who have severe RSV bronchiolitis as infants have an increased prevalence of asthma in childhood. The RBEL cohort did not show an overall increase in T helper 2 (Th ) cytokines (Interleukin (IL)-4 and 13) in children who were diagnosed with asthma by 2 age 6, but there was a notable reduction in lung function in those with asthma ( ). Castro M et al, J Allerg Clin Immunol 2008 Rationale: To compare cytokine levels (IL-2, 4, 13 and interferon-γ) at time of entry in the RBEL study and at age 6 years to lung function obtained at age 6 years in patients with severe RSV bronchiolitis. Methods: 206 infants hospitalized at St. Louis Children's Hospital with severe RSV bronchiolitis were enrolled in the RBEL cohort. Peripheral blood mononuclear cells were obtained at time of entry, and at 2, 4, and 6 years of age and were analyzed for IL-2, 4, 13 and interferon-γ by flow cytometry and real-time PCR. Spirometry before and after bronchodilator and methacholine bronchoprovocation challenge were performed at age 6 years. Results: There was an inverse relationship noted between FEV % predicted and interferon-γ levels at age 6 years in patients with definite 1 asthma (physician-diagnosis of asthma and PC <3.2 mg/mL) (n=26; Spearmann correlation coefficient=-0.5; p=0.0083). There was no 20 relationship between lung function at 6 years of age and the other studied cytokine levels obtained at time of entry in the group with definite asthma (all p>0.05). Conclusion: Following severe RSV bronchiolitis, children diagnosed with asthma do not have a Th dominant cytokine response in the 2 peripheral blood nor do cytokine responses appear to relate to subsequent lung function. Funded By: NIH HL61895, M01RR00036

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