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1.  Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines 
Background
The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood.
Objectives
We hypothesized that STRA in children is characterized by airway eosinophilia and mast cell inflammation and is driven by the TH2 cytokines IL-4, IL-5, and IL-13.
Methods
Sixty-nine children (mean age, 11.8 years; interquartile range, 5.6-17.3 years; patients with STRA, n = 53; control subjects, n = 16) underwent fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), and endobronchial biopsy. Airway inflammation, remodeling, and BAL fluid and biopsy specimen TH2 cytokines were quantified. Children with STRA also underwent symptom assessment (Asthma Control Test), spirometry, exhaled nitric oxide and induced sputum evaluation.
Results
Children with STRA had significantly increased BAL fluid and biopsy specimen eosinophil counts compared with those found in control subjects (BAL fluid, P < .001; biopsy specimen, P < .01); within the STRA group, there was marked between-patient variability in eosinophilia. Submucosal mast cell, neutrophil, and lymphocyte counts were similar in both groups. Reticular basement membrane thickness and airway smooth muscle were increased in patients with STRA compared with those found in control subjects (P < .0001 and P < .001, respectively). There was no increase in BAL fluid IL-4, IL-5, or IL-13 levels in patients with STRA compared with control subjects, and these cytokines were rarely detected in induced sputum. Biopsy IL-5+ and IL-13+ cell counts were also not higher in patients with STRA compared with those seen in control subjects. The subgroup (n = 15) of children with STRA with detectable BAL fluid TH2 cytokines had significantly lower lung function than those with undetectable BAL fluid TH2 cytokines.
Conclusions
STRA in children was characterized by remodeling and variable airway eosinophil counts. However, unlike in adults, there was no neutrophilia, and despite the wide range in eosinophil counts, the TH2 mediators that are thought to drive allergic asthma were mostly absent.
doi:10.1016/j.jaci.2012.01.059
PMCID: PMC3381727  PMID: 22385633
Pediatric asthma; eosinophilia; remodeling; severe therapy-resistant asthma; mediators
2.  Serum Vitamin D Levels and Severe Asthma Exacerbations in the Childhood Asthma Management Program Study 
Background
Asthma exacerbations, most often due to respiratory tract infections, are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs. Vitamin D status may play a role in preventing asthma exacerbations.
Objectives
To assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations.
Methods
We measured 25-hydroxyvitamin D (25(OH)D) levels in serum collected from 1,024 mild to moderate persistent asthmatic children at the time of enrollment in a multi-center clinical trial of children randomized to receiving budesonide, nedocromil, or placebo (as-needed beta-agonists), the Childhood Asthma Management Program. Using multivariable modeling we examined the relationship between baseline vitamin D level and the odds of any hospitalization or emergency department (ED) visit over the 4 years of the trial.
Results
35% of all subjects were vitamin D insufficient, as defined by a level ≤ 30 ng/ml 25(OH)D. Mean vitamin D levels were lowest in African-American subjects, and highest in whites. After adjusting for age, sex, BMI, income, and treatment group, insufficient vitamin D status was associated with a higher odds of any hospitalization or ED visit (odds ratio [OR] 1.5 [95% confidence interval [CI]: 1.1 – 1.9] P =0.01).
Conclusion
Vitamin D insufficiency is common in this population of North American children with mild to moderate persistent asthma, and is associated with higher odds of severe exacerbation over a four year period.
doi:10.1016/j.jaci.2010.03.043
PMCID: PMC2902692  PMID: 20538327
Asthma; Vitamin D; inhaled corticosteroids; asthma exacerbations
3.  Effect of Vitamin D and Inhaled Corticosteroid Treatment on Lung Function in Children 
Rationale: Low vitamin D levels are associated with asthma and decreased airway responsiveness. Treatment with inhaled corticosteroids improves airway responsiveness and asthma control.
Objectives: To assess the effect of vitamin D levels on prebronchodilator FEV1, bronchodilator response, and responsiveness to methacholine (PC20, provocative concentration of methacholine producing a 20% decline in FEV1) in patients with asthma treated with inhaled corticosteroids.
Methods: We measured 25-hydroxyvitamin D levels in the serum of children with persistent asthma at the time of enrollment in the Childhood Asthma Management Program. We divided subjects into the vitamin D sufficiency (>30 ng/ml), insufficiency (20–30 ng/ml), and deficiency (<20 ng/ml) groups. Covariates included age, treatment, sex, body mass index, race, history of emergency department visits, hospitalizations, and season that vitamin D specimen was drawn. Our main outcome measures were change in prebronchodilator FEV1, bronchodilator response, and PC20 from enrollment to 8–12 months.
Measurements and Main Results: Of the 1,024 subjects, 663 (65%) were vitamin D sufficient, 260 (25%) were insufficient, and 101 (10%) were deficient. Vitamin D–deficient subjects were more likely to be older, African American, and have a higher body mass index compared with the vitamin D–sufficient and insufficient subjects. In the inhaled corticosteroid treatment group, prebronchodilator FEV1 increased from randomization to 12 months by 140 ml in the vitamin D–deficient group and prebronchodilator FEV1 increased by 330 ml in the vitamin D insufficiency group and by 290 ml in the vitamin D sufficiency group (P = 0.0072), in adjusted models.
Conclusions: In children with asthma treated with inhaled corticosteroids, vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency.
doi:10.1164/rccm.201202-0351OC
PMCID: PMC3480528  PMID: 22798322
asthma; vitamin D; lung function; forced expiratory volume; children
4.  Exhaled breath condensate cysteinyl leukotrienes and airway remodeling in childhood asthma: a pilot study 
Respiratory Research  2006;7(1):63.
Background
It has been suggested that cysteinyl leukotrienes (cysLTs) play an important role in airway remodeling. Previous reports have indicated that cysLTs augment human airway smooth muscle cell proliferation. Recently, cysLTs have been measured in exhaled breath condensate (EBC). The aim of this study was to evaluate the relationship between cysLTs in EBC and another marker of airway remodeling, reticular basement membrane (RBM) thickening, in endobronchial biopsies in children.
Methods
29 children, aged 4–15 years, with moderate to severe persistent asthma, who underwent bronchoscopy as part of their clinical assessment, were included. Subjects underwent spirometry and EBC collection for cysLTs analysis, followed by bronchoscopy and endobronchial biopsy within 24 hours.
Results
EBC cysLTs were significantly lower in asthmatic children who were treated with montelukast than in those who were not (median (interquartile range) 36.62 (22.60–101.05) versus 249.1 (74.21–526.36) pg/ml, p = 0.004). There was a significant relationship between EBC cysLTs and RBM thickness in the subgroup of children who were not treated with montelukast (n = 13, r = 0.75, p = 0.003).
Conclusion
EBC cysLTs appear to be associated with RBM thickening in asthma.
doi:10.1186/1465-9921-7-63
PMCID: PMC1456970  PMID: 16603074
5.  Vitamin D Levels, Lung Function, and Steroid Response in Adult Asthma 
Rationale: Patients with asthma exhibit variable response to inhaled corticosteroids (ICS). Vitamin D is hypothesized to exert effects on phenotype and glucocorticoid (GC) response in asthma.
Objectives: To determine the effect of vitamin D levels on phenotype and GC response in asthma.
Methods: Nonsmoking adults with asthma were enrolled in a study assessing the relationship between serum 25(OH)D (vitamin D) concentrations and lung function, airway hyperresponsiveness (AHR), and GC response, as measured by dexamethasone-induced expression of mitogen-activated protein kinase phosphatase (MKP)-1 by peripheral blood mononuclear cells.
Measurements and Main Results: A total of 54 adults with asthma (FEV1, 82.9 ± 15.7% predicted [mean ± SD], serum vitamin D levels of 28.1 ± 10.2 ng/ml) were enrolled. Higher vitamin D levels were associated with greater lung function, with a 22.7 (±9.3) ml (mean ± SE) increase in FEV1 for each nanogram per milliliter increase in vitamin D (P = 0.02). Participants with vitamin D insufficiency (<30 ng/ml) demonstrated increased AHR, with a provocative concentration of methacholine inducing a 20% fall in FEV1 of 1.03 (±0.2) mg/ml versus 1.92 (±0.2) mg/ml in those with vitamin D of 30 ng/ml or higher (P = 0.01). In ICS-untreated participants, dexamethasone-induced MKP-1 expression increased with higher vitamin D levels, with a 0.05 (±0.02)-fold increase (P = 0.02) in MKP-1 expression observed for each nanogram per milliliter increase in vitamin D, a finding that occurred in the absence of a significant increase in IL-10 expression.
Conclusions: In asthma, reduced vitamin D levels are associated with impaired lung function, increased AHR, and reduced GC response, suggesting that supplementation of vitamin D levels in patients with asthma may improve multiple parameters of asthma severity and treatment response.
Clinical trials registered with www.clinicaltrials.gov (NCT00495157, NCT00565266, and NCT00557180).
doi:10.1164/rccm.200911-1710OC
PMCID: PMC2868500  PMID: 20075384
asthma; vitamin D; glucocorticoids; treatment
6.  Airway remodeling measured by multidetector computed tomography is increased in severe asthma and correlates with pathology 
Chest  2008;134(6):1183-1191.
Background
To prospectively apply an automated, quantitative 3-D approach to imaging and airway analysis to assess airway remodeling in asthma.
Methods
Using the Pulmonary Workstation (VIDA Diagnostics) that enables quantitative airway segment measurements of low-dose, thin section (0.625-1.25 mm) multidetector-row CT (MDCT), we compared airway wall thickness (WT) and area (WA) in 123 subjects participating in a prospective multicenter cohort study, NIH Severe Asthma Research Program (SARP): severe asthma (n=63), mild-moderate asthma (n=35), and normal (n=25). A subset of these subjects underwent fiberoptic bronchoscopy and endobronchial biopsies (n=32). WT and WA were corrected for total airway diameter and area - WT%, WA%.
Results
Subjects with severe asthma had significantly greater WT% than mild-moderate asthma and normals [17.2±1.5 v 16.5±1.6, p=0.014 and 16.3±1.2, p=0.031, respectively] and greater WA% compared to mild-moderate asthma and normal [56.6±2.9 v 54.7±3.3, p=.005 and 54.6±2.4, p=0.003, respectively]. Both WT% and WA% were inversely correlated with baseline FEV1% (r=-0.39, p<0.0001 and -0.40, p<0.0001, respectively) and positively correlated with response to bronchodilator (r=0.28, p=0.002 and r=0.35, p<0.0001, respectively). Airway epithelial thickness on biopsy correlated with WT% (r=0.47, p=0.007) and WA% (r=0.52, p=0.003). In the same individual, there is considerable regional heterogeneity in airway wall thickness.
Conclusion
Severe asthmatics have thicker airway walls on MDCT than mild asthmatics or normals, which correlates with pathologic measures of remodeling and the degree of airflow obstruction. MDCT may be a useful technique for assessing airway remodeling in asthma, but overlap among groups limits the diagnostic value in individual subjects.
doi:10.1378/chest.07-2779
PMCID: PMC2859729  PMID: 18641116
Asthma; airway remodeling; chest CT
7.  Pharmacotherapy of Patients with Mild Persistent Asthma: Strategies and Unresolved Issues 
In studies comparing regular versus on-demand treatment for patients with mild persistent asthma, on-demand treatment seems to have a similar efficacy on clinical and functional outcomes, but it does not suppress chronic airway inflammation or airway hyper-responsiveness (AHR) associated with asthma. Data on the efficacy of a continuous treatment with inhaled corticosteroids (ICS) in preventing the progression of asthma are conflicting. There is the possibility that patients without a regular treatment with ICS may develop a more severe asthma associated with airway structural changes (remodeling) and a progressive loss of lung function. However, the possible clinical and functional consequences of persistent, not controlled, airway inflammation in patients with asthma have to be established. Assessment of asthma control should include inflammatory outcomes, such as fraction of exhaled nitric oxide and sputum eosinophil counts. Until the relationships between symptoms, lung function tests, AHR, airway inflammation, exacerbations, and airway remodeling are clarified, regular treatment seems to be generally more appropriate than on-demand treatment to warrant a greater control of asthma. Select subgroups of patients with mild asthma who are well controlled by regular treatment might adopt the on-demand treatment plan as an intermediate step toward the suspension of controller medication. The increasing evidence for heterogeneity of asthma, the growing emphasis on asthma subphenotypes, including molecular phenotypes identified by omics technologies, and their possible implications for different asthma severity and progression and therapeutic response, are changing the paradigm of treating patients with asthma only based on classification of their disease severity to a pharmacological strategy more focused on the individual asthmatic patient. Pharmacological treatment of asthma is going toward a personalized approach.
doi:10.3389/fphar.2011.00035
PMCID: PMC3139104  PMID: 21808620
asthma; airway inflammation; airway remodeling; inhaled corticosteroids; leukotriene receptor antagonists; non-invasive biomarkers; pharmacological treatment
8.  The Role of Hyaluronan and Hyaluronan Binding Proteins in Human Asthma 
Background
The characteristics of human asthma are chronic inflammation and airway remodeling. Hyaluronan (HA), a major extracellular matrix component, accumulates during inflammatory lung diseases including asthma. Hyaluronan fragments stimulate macrophages to produce inflammatory cytokines. We hypothesized that HA and its receptors would play a role in human asthma.
Objective
To investigate the role of HA and HA binding proteins in human asthma.
Methods
Twenty-one subjects with asthma and 25 normal control subjects underwent bronchoscopy with endobronchial biopsy and bronchoalveolar lavage (BAL). Fibroblasts were cultured, HA and HA synthase expression was determined at baseline and after exposure to several mediators relevant to asthma pathobiology. The expression of HA binding proteins, CD44, TLR2 and TLR4 on BAL macrophages was determined by flow cytometry. IL-8 production by macrophages in response to HA fragment stimulation was compared.
Results
Airway fibroblasts from asthma patients produced significantly increased concentrations of lower molecular weight HA compared to those of normal fibroblasts. Hyaluronan synthase 2 mRNA was markedly increased in asthmatic fibroblasts. Asthmatic macrophages showed a decrease in cell surface CD44 expression and an increase in TLR2 and TLR4 expression. Macrophages from asthmatic subjects showed an increase in responsiveness to low molecular weight HA stimulation, as demonstrated by increased IL-8 production.
Conclusions
HA homeostasis is deranged in asthma with increased production by fibroblasts and decreased CD44 expression on alveolar macrophages. Upregulation of TLR2 and TLR4 on macrophages with increased sensitivity to HA fragments suggests a novel pro-inflammatory mechanism by which persistence of HA fragments could contribute to chronic inflammation and airway remodeling in asthma.
doi:10.1016/j.jaci.2011.04.006
PMCID: PMC3149736  PMID: 21570715
Asthma; Hyaluronan; Cytokines; Fibroblasts; Macrophages
9.  Serum Vitamin D Levels and Markers of Severity of Childhood Asthma in Costa Rica 
Rationale: Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood.
Objectives: To determine the relationship between measured vitamin D levels and both markers of asthma severity and allergy in childhood.
Methods: We examined the relation between 25-hydroxyvitamin D levels (the major circulating form of vitamin D) and markers of allergy and asthma severity in a cross-sectional study of 616 Costa Rican children between the ages of 6 and 14 years. Linear, logistic, and negative binomial regressions were used for the univariate and multivariate analyses.
Measurements and Main Results: Of the 616 children with asthma, 175 (28%) had insufficient levels of vitamin D (<30 ng/ml). In multivariate linear regression models, vitamin D levels were significantly and inversely associated with total IgE and eosinophil count. In multivariate logistic regression models, a log10 unit increase in vitamin D levels was associated with reduced odds of any hospitalization in the previous year (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.004–0.71; P = 0.03), any use of antiinflammatory medications in the previous year (OR, 0.18; 95% CI, 0.05–0.67; P = 0.01), and increased airway responsiveness (a ≤8.58-μmol provocative dose of methacholine producing a 20% fall in baseline FEV1 [OR, 0.15; 95% CI, 0.024–0.97; P = 0.05]).
Conclusions: Our results suggest that vitamin D insufficiency is relatively frequent in an equatorial population of children with asthma. In these children, lower vitamin D levels are associated with increased markers of allergy and asthma severity.
doi:10.1164/rccm.200808-1361OC
PMCID: PMC2675563  PMID: 19179486
10.  Airway TGFβ1 and oxidant stress in children with severe asthma: Association with airflow limitation 
Background
Transforming growth factor beta-1 (TGFβ1) is thought to play a role in airway remodeling in asthma. TGFβ1 expression may be mediated by an excessive burden of reactive oxygen species and oxidant stress.
Objective
Given the profound airway oxidant stress we have previously observed in children with severe asthma, we sought to: 1) quantify TGFβ1 protein and mRNA gene expression in the airways of children with mild-to-moderate and severe atopic asthma; and to 2) determine the relationship of airway TGFβ1 concentrations to oxidant burden (i.e., lipid peroxidation), Th2-mediated eosinophilic inflammation, and airflow limitation.
Methods
Bronchoalveolar lavage fluid was collected from 68 atopic children with asthma (severe asthma, n = 28) and 12 atopic adult controls. Airway TGFβ1 expression and activation were assessed in relation to airway IL-13, 8-isoprostane, and malondialdehyde concentrations. The relationship of airway TGFβ1 expression to airflow limitation in children with asthma was also assessed.
Results
Children with severe asthma had higher total airway concentrations of TGFβ1 that were associated with increased protein and mRNA expression of TGFβ1 in airway macrophages and an increase in the lipid peroxidation biomarkers 8-isoprostanes and malondialdehyde. TGFβ1 activation was also greater in children with severe asthma and was associated with higher airway 8-isoprostane, malondialdehyde and IL-13 concentrations. Total airway TGFβ1 concentrations were further associated with airflow limitation.
Conclusions
Children with severe asthma have increased airway TGFβ1 expression and activation associated with an increased airway oxidant burden. Oxidant stress may mediate the effects of TGFβ1 and promote airway remodeling in children with severe asthma.
doi:10.1016/j.jaci.2011.11.037
PMCID: PMC3268912  PMID: 22206775
Airway remodeling; Asthma; Children; Lung function; Oxidant stress; Transforming growth factor beta-1
11.  Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset 
Thorax  2012;67(12):1061-1066.
Background
Eosinophilic inflammation is implicated in asthma. Eotaxin 1–3 regulate eosinophil trafficking into the airways along with other chemotactic factors. However, the epithelial and bronchoalveolar lavage (BAL) cell expression of these chemokines in relation to asthma severity and eosinophilic phenotypes has not been addressed.
Objective
To measure the expression of the three eotaxin isoforms in bronchoscopically obtained samples and compare them with clinically relevant parameters between normal subjects and patients with asthma.
Methods
Normal subjects and patients with asthma of varying severity recruited through the Severe Asthma Research Program underwent clinical assessment and bronchoscopy with airway brushing and BAL. Eotaxin 1–3 mRNA/protein were measured in epithelial and BAL cells and compared with asthma severity, control and eosinophilic inflammation.
Results
Eotaxin-2 and eotaxin-3 mRNA and eotaxin-2 protein were increased in airway epithelial brushings from patients with asthma and were highest in cases of severe asthma (p values 0.0155, 0.0033 and 0.0006, respectively), with eotaxin-2 protein increased with age at onset. BAL cells normally expressed high levels of eotaxin-2 mRNA/protein but BAL fluid levels of eotaxin-2 were lowest in severe asthma. Epithelial eotaxin-2 and eotaxin-3 mRNA/protein was associated with sputum eosinophilia, lower forced expiratory volume in 1 s and more asthma exacerbations. Airway epithelial cell eotaxin-2 protein differed by asthma severity only in those with late onset disease, and tended to be highest in those with late onset eosinophilic asthma.
Conclusions
Epithelial eotaxin-2 and 3 are increased in asthma and severe asthma. Their expression may contribute to luminal migration of eosinophils, especially in later onset disease, asthma control and severity.
doi:10.1136/thoraxjnl-2012-201634
PMCID: PMC3652589  PMID: 23015684
12.  Airway Lipoxin A4 Generation and Lipoxin A4 Receptor Expression Are Decreased in Severe Asthma 
Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A4 (LXA4) is an arachidonic acid–derived mediator that serves as an agonist for resolution of inflammation.
Objectives: Airway levels of LXA4, as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma.
Methods: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA4 and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA4 receptors were monitored by flow cytometry.
Measurements and Main Results: Individuals with severe asthma had significantly less LXA4 in bronchoalveolar lavage fluids (11.2 ± 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 ± 38.5 pg/ml; P < 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA4 receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes.
Conclusions: Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.
doi:10.1164/rccm.200801-061OC
PMCID: PMC2542432  PMID: 18583575
severe asthma; lipoxins; eicosanoids
13.  Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes 
Thorax  2012;67(11):950-956.
Background
Studies exploring the relationship between prenatal vitamin D exposure and childhood asthma have yielded conflicting results. Higher vitamin D intake during pregnancy has been shown to lower the risk of childhood wheeze, yet a study of maternal late-pregnancy serum 25-hydroxyvitamin D suggested higher serum concentrations may be associated with increased childhood asthma.
Objective
To assess the relationship between mothers’ serum 25-hydroxyvitamin D status and asthma and wheeze phenotypes in their children at age 6 years. Secondly, to explore the relationship between maternal 25-hydroxyvitamin D status and objective measures of childhood atopy and lung function.
Methods
Serum 25-hydroxyvitamin D was measured at 34 weeks’ gestation in the mothers of 860 children born at term. Wheeze was classified as either transient or persistent/late using questionnaire data collated from 6, 12, 24 and 36 months and 6 years. At 6 years spirometry was performed and atopic status was determined by skin prick testing, exhaled nitric oxide was measured in 451 and bronchial hyperresponsiveness in 216 children.
Results
There were no significant associations between maternal late-pregnancy 25-hydroxyvitamin D status and either asthma or wheeze at age 6 years. Maternal vitamin D status was not associated with transient or persistent/late wheeze; no significant association was found between persistent/late wheeze when subdivided according to atopic status. No associations were found with skin sensitisation or lung function.
Conclusions
This study provides no evidence that exposure to higher concentrations of 25-hydroxyvitamin D in maternal serum during late pregnancy increases the risk of childhood asthma, wheeze or atopy.
doi:10.1136/thoraxjnl-2012-201888
PMCID: PMC3679514  PMID: 22707522
asthma epidemiology; asthma; paediatric asthma
14.  Increased Glucocorticoid Receptor β Alters Steroid Response in Glucocorticoid-insensitive Asthma 
Rationale: Glucocorticoids (GCs) are highly effective in the treatment of asthma. However, some individuals have GC-insensitive asthma.
Objectives: To evaluate the functional response to steroids of bronchoalveolar lavage (BAL) cells from sites of airway inflammation from patients with GC-insensitive versus GC-sensitive asthma. As well, to attempt to define the functional role of glucocorticoid receptor (GCR)β (a splicing variant, and dominant negative inhibitor of, the classic GCRα) in controlling GCRα nuclear translocation and transactivation at a molecular level.
Methods and Measurements: Fiberoptic bronchoscopy with collection of BAL fluid was performed on seven patients with GC-sensitive asthma and eight patients with GC-insensitive asthma. GCRα cellular shuttling in response to 10−6 M dexamethasone treatment and GCRβ expression were analyzed in BAL cells by immunofluorescence staining. The effects of overexpression and silencing of GCRβ mRNA on GCRα function were assessed.
Main Results: Significantly reduced nuclear translocation of GCRα in response to steroids was found in BAL cells from patients with GC-insensitive asthma. BAL macrophages from patients with GC-insensitive asthma had significantly increased levels of cytoplasmic and nuclear GCRβ. It was demonstrated that GCRα nuclear translocation and its transactivation properties were proportionately reduced by level of viral transduction of the GCRβ gene into the DO-11.10 cell line. RNA silencing of GCRβ mRNA in human BAL macrophages from patients with GC-insensitive asthma resulted in enhanced dexamethasone-induced GCRα transactivation.
Conclusions: GC insensitivity is associated with loss of GCRα nuclear translocation in BAL cells and elevated GCRβ, which may inhibit GCRα transactivation in response to steroids.
doi:10.1164/rccm.200507-1046OC
PMCID: PMC2662945  PMID: 16387802
asthma; bronchoalveolar lavage cells; glucocorticoid insensitivity; glucocorticoid receptor
15.  Link between vitamin D and airway remodeling 
In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma.
doi:10.2147/JAA.S46944
PMCID: PMC3979801
vitamin D; asthma; airway remodeling; airway smooth muscle; supplementation
16.  Endotoxin Augments Myeloid Dendritic Cell Influx into the Airways in Patients with Allergic Asthma 
Rationale: Epidemiologic studies have shown that exacerbation of asthma is modulated by environmental endotoxin. High levels of endotoxin are associated with asthma symptoms and the current use of asthma medication. However, the underlying mechanisms by which endotoxin modulates asthma are not completely understood.
Objectives: The aim of the study was to test whether endotoxin enhances the response of individuals with allergic asthma to allergen, and to determine if this interaction is associated with increased numbers of antigen-presenting cells in the airways.
Methods: Seventeen subjects with mild allergic asthma underwent segmental challenge with allergen, endotoxin, and the combination of both in three different lung segments via bronchoscopy. The cellular influx including monocytes, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs), as well as the level of cytokines, were assessed in bronchoalveolar lavage fluid obtained 24 hours after segmental challenge. Monocytes, mDCs, and pDCs were isolated and their capacity to induce T cell proliferation was determined.
Measurements and Main Results: Endotoxin enhanced the cellular response to allergen. The combination of allergen and endotoxin resulted in increased numbers of total cells, lymphocytes, neutrophils, eosinophils, monocytes, and mDCs, as well as increased levels of lipopolysaccharide-binding protein, IL-1α, IL-6, and tumor necrosis factor–α in the bronchoalveolar lavage fluid compared with allergen alone. Isolated mDCs but not pDCs induced a strong T cell proliferation in vitro.
Conclusions: Endotoxin augments the allergic inflammation in the lungs of individuals with asthma, and induces an enhanced influx of monocytes and functionally active antigen-presenting mDCs into the respiratory tract.
doi:10.1164/rccm.200706-870OC
PMCID: PMC2427055  PMID: 18388357
dendritic cells; monocytes; bronchoalveolar lavage; endobronchial allergen challenge; mixed lymphocyte culture test
17.  The Effect of Vitamin D Status on Pediatric Asthma at a University Hospital, Thailand 
Purpose
In the USA and Europe, hypovitaminosis D is associated with increased asthma severity, emergency department (ED) visit, and impaired pulmonary function in asthmatic patients. However, in tropical countries, data on the effect of vitamin D status on asthma is limited. This study evaluates the relationship between vitamin D status and the level of asthma control as well as other asthmatic parameters.
Methods
Asthmatic children were evaluated for serum 25-hydroxyvitamin D, pulmonary function tests, a skin prick test, and the level of asthma control.
Results
A total of 125 asthmatic children were recruited (boys, 66.4%). Their mean age±SD was 10.8±3.0 years. Vitamin D statuses were: deficiency (<20 ng/mL) in 19.2% of the patients, insufficiency (20-30 ng/mL) in 44.8%, and sufficiency (>30 ng/mL) in 36%. The vitamin D levels were 25.9±9.4 ng/mL in uncontrolled patients, 29.2±8.6 ng/mL in partly controlled patients, and 27.9±8.0 ng/mL in controlled patients (P>0.05). There were no significant differences in pulmonary function, asthma exacerbation, inhaled-corticosteroid (ICS) dose, anti-inflammatory drugs, or ED visit or hospitalization between different vitamin D statuses. Vitamin D deficiency patients were older and had a delayed onset of asthma than insufficiency or sufficiency patients. There was no significant correlation between serum vitamin D and pulmonary function/doses of ICS.
Conclusions
High prevalences of vitamin D deficiency and insufficiency were found in asthmatic children in Thailand; however, there was no significant relationship between vitamin D status and the level of asthma control or other asthma parameters.
doi:10.4168/aair.2013.5.5.289
PMCID: PMC3756175  PMID: 24003385
Asthma; children; corticosteroid; 25-hydroxyvitamin D; vitamin D
18.  Vitamin D Insufficiency and Severe Asthma Exacerbations in Puerto Rican Children 
Rationale: Vitamin D insufficiency (a serum 25(OH)D <30 ng/ml) has been associated with severe asthma exacerbations, but this could be explained by underlying racial ancestry or disease severity. Little is known about vitamin D and asthma in Puerto Ricans.
Objectives: To examine whether vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, and time outdoors.
Methods: A cross-sectional study was conducted of 560 children ages 6–14 years with (n = 287) and without (n = 273) asthma in San Juan, Puerto Rico. We measured plasma vitamin D and estimated the percentage of African racial ancestry among participants using genome-wide genotypic data. We tested whether vitamin D insufficiency is associated with severe asthma exacerbations, lung function, or atopy (greater than or equal to one positive IgE to allergens) using logistic or linear regression. Multivariate models were adjusted for African ancestry, time outdoors, atopy, and other covariates.
Measurements and Main Results: Vitamin D insufficiency was common in children with (44%) and without (47%) asthma. In multivariate analyses, vitamin D insufficiency was associated with higher odds of greater than or equal to one severe asthma exacerbation in the prior year (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5–4.9; P = 0.001) and atopy, and a lower FEV1/FVC in cases. After stratification by atopy, the magnitude of the association between vitamin D insufficiency and severe exacerbations was greater in nonatopic (OR, 6.2; 95% CI, 2–21.6; P = 0.002) than in atopic (OR, 2; 95% CI, 1–4.1; P = 0.04) cases.
Conclusions: Vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, or markers of disease severity or control.
doi:10.1164/rccm.201203-0431OC
PMCID: PMC3406083  PMID: 22652028
vitamin D; asthma exacerbations; Puerto Ricans; childhood
19.  297 Relationship Between Exhaled Nitric Oxide and Levels of Asthma Control in Asthma Patients Treated with Inhaled Corticosteroid 
Background
While asthma control is defined as the extent to which the various manifestations of asthma are reduced by treatment, current guidelines of asthma recommend assessment of asthma control without consideration of airway inflammation. Our aim was to investigate the relationships between fractional exhaled nitric oxide (FeNO), a reliable marker of airway inflammation, and levels of asthma controls in patients treated with inhaled corticosteroid (ICS).
Methods
We enrolled 71 adult patients with asthma, who had been treated with ICS more than 4 months. Asthma control was assessed by the physician based on the Global Initiative for Asthma guidelines, and by the patients and by using Asthma Control Test (ACT). Statistical analyses were performed to analyze the relationships between FeNO and measures of asthma control and clinical indices for asthma manifestations.
Results
There was no significant difference in FeNO levels between 3 groups according to levels of asthma control (controlled, partly controlled and uncontrolled) determined by the physician (P = 0.81) and by the patients (P = 0.81). In addition, FeNO values were not correlated with the ACT scores (r = 0.031, P = 0.807), while FeNO showed peripheral blood eosinophil counts (P < 0.001).
Conclusions
These findings demonstrated that FeNO levels are not related with the measures of asthma control in patients treated with ICS. Information of airway inflammation from FeNO concentrations seems to be discrepant from levels of asthma control.
doi:10.1097/01.WOX.0000412054.05318.f5
PMCID: PMC3512760
20.  Pathophysiological Features of Asthma Develop in Parallel in House Dust Mite–Exposed Neonatal Mice 
Asthma frequently commences in early life during airway and immune development and exposure to new environmental challenges. Endobronchial biopsies from children with asthma are abnormal, and lung function is maximally reduced by 6 years of age. As longitudinal biopsy studies are unethical in children, the relationship between development of pathology and reduced lung function is unknown. We aimed to establish a novel neonatal mouse model of allergic airways disease to investigate the developmental sequence of the pathophysiologic features of asthma. Neonatal Balb/c mice were challenged three times weekly from Day 3 of life using intranasal house dust mite (HDM) or saline for up to 12 weeks. Weekly assessments of airway inflammation and remodeling were made. Airway hyperresponsiveness (AHR) to methacholine was assessed from Week 2 onward. Total and eosinophilic inflammation was significantly increased in the lungs of HDM-exposed neonates from Week 2 onwards, and a peak was seen at 3 weeks. Goblet cells and peribronchiolar reticulin deposition were significantly increased in HDM-exposed neonates from Week 3, and peribronchiolar collagen was significantly greater from Week 4. HDM-exposed neonates had increased AHR from Week 2 onward. Although inflammation and AHR had subsided after 4 weeks without allergen challenge, the increased reticulin and collagen deposition persisted in HDM-exposed mice. Neonatal mice exposed to intranasal HDM developed eosinophilic inflammation, airway remodeling, and AHR as reported in pediatric asthma. Importantly, all abnormalities developed in parallel, not sequentially, between 2 and 3 weeks of age.
doi:10.1165/rcmb.2008-0396OC
PMCID: PMC3380517  PMID: 19151316
pediatric; remodeling; asthma pathophysiology; mouse model; allergic airways disease
21.  Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma 
Thorax  2005;60(12):1012-1018.
Background: Tumour necrosis factor α (TNFα) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNFα is generated in excess. By contrast, asthma is regarded as a Th2 type disorder, especially when associated with atopy. However, as asthma becomes more severe and chronic, it adopts additional characteristics including corticosteroid refractoriness and involvement of neutrophils suggestive of an altered inflammatory profile towards a Th1 type response, incriminating cytokines such as TNFα.
Methods: TNFα levels in bronchoalveolar lavage (BAL) fluid of 26 healthy controls, 42 subjects with mild asthma and 20 with severe asthma were measured by immunoassay, and TNFα gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma. The cellular localisation of TNFα was assessed by immunohistochemistry. An open label uncontrolled clinical study was then undertaken in 17 subjects with severe asthma to evaluate the effect of 12 weeks of treatment with the soluble TNFα receptor-IgG1Fc fusion protein, etanercept.
Results: TNFα levels in BAL fluid, TNFα gene expression and TNFα immunoreative cells were increased in subjects with severe corticosteroid dependent asthma. Etanercept treatment was associated with improvement in asthma symptoms, lung function, and bronchial hyperresponsiveness.
Conclusions: These findings may be of clinical significance in identifying TNFα as a new therapeutic target in subjects with severe asthma. The effects of anti-TNF treatment now require confirmation in placebo controlled studies.
doi:10.1136/thx.2005.045260
PMCID: PMC1747263  PMID: 16166100
22.  The impact of vitamin D deficiency on immune T cells in asthmatic children: a case-control study 
Background
Vitamin D exerts profound effects on both adaptive and innate immune functions involved in the development and course of autoimmune and inflammatory diseases. As the incidence of vitamin D insufficiency is surprisingly high in the general population, experimental studies have started to investigate whether vitamin D levels (measured as serum 25 hydroxy vitamin D-25[OH]D) are correlated with immune cells and clinical parameters.
Purpose
The aim of the present research was to investigate serum vitamin D status in a case-control study in children with asthma and to study associations between vitamin D levels and certain immunological parameters.
Materials and methods
A case control study of thirty-nine children with clinically controlled asthma was enrolled to assess the relationship between serum vitamin D concentrations and disease activity. Vitamin D was assayed with a radioimmunoassay kit. We evaluated the relationship between vitamin D concentrations and forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and the FEV1/FVC ratio. Correlations between inflammatory mediators, Th1, Th2, Th17, and regulatory T cells (Treg) and vitamin D were investigated.
Results
Only 15.38% of our asthmatic children had a sufficient serum 25(OH)D (≥30 ng/mL) whereas 80% of healthy children expressed sufficient levels. Deficient values of vitamin D (<20 ng/mL) were observed in 17 (43.59%) asthmatic patients (14.40 ± 3.30 ng/mL; P = 0.0001). Deficiency was not observed in controls. Th1/Th2 ratio was significantly correlated to 25(OH) D level (r = 0.698; P = 0.0001). A significant negative correlation was observed between serum interleukin-17 and vitamin D levels in young asthmatics (r = −0.617; P = 0.001). A significant correlation was observed between CD25+Foxp3+ Treg cells and vitamin D values in asthmatics (r = 0.368; P = 0.021).
Conclusion
Even in a southern Mediterranean country, hypovitaminosis D is frequent in children with asthma. Our findings suggest that vitamin D is an important promoter of T cell regulation in vivo in young asthmatics.
doi:10.2147/JAA.S29566
PMCID: PMC3363015  PMID: 22690128
vitamin D; Th17; Treg cells; asthma; children
23.  The Relationship Between Serum 25 Hydroxy Vitamin D Levels and Asthma in Children 
Purpose
Asthma and other allergic disorders have increased over the past decades in nearly all nations. Many studies have suggested the role of vitamin D deficiency in both T-helper1 and T-helper2 diseases; however, the association between vitamin D, allergy, and asthma remains uncertain. In this study, the associations of 25-hydroxy vitamin D3 levels with asthma and with the severity of asthma were evaluated.
Methods
This cross-sectional study was conducted on 50 asthmatic children and 50 healthy controls aged 6-18 years. Serum 25-hydroxy vitamin D3 levels were determined and compared between the two groups. The relationship between serum vitamin D levels and pulmonary function test outcomes and eosinophil counts were examined in asthmatic patients.
Results
Univariate analysis of the relationship between asthma and vitamin D showed that decreased vitamin D levels were associated with significantly increased odds of asthmatic state (P=0.002). In a multivariate analysis after adjustment for age, body mass index, and sex, the relationship between vitamin D and asthma increased. In asthmatic patients, 25-hydroxy vitamin D levels had direct and significant correlations with both predicted FEV1 (R2=0.318; P=0.024) and FEV1/FVC (R2=0.315; P=0.026). There were no associations between vitamin D level and eosinophil counts, duration of disease, and the number of hospitalization or unscheduled visits in the previous year (P>0.05).
Conclusions
These results showed that serum 25-hydroxy vitamin D levels were inversely associated with asthma, and there was a direct and significant relationship between vitamin D levels and pulmonary function test outcomes in asthmatic children. An interventional study in asthmatic patients with low serum vitamin D concentration may establish a causal relationship between asthma and vitamin D.
doi:10.4168/aair.2011.3.4.251
PMCID: PMC3178823  PMID: 21966605
Asthma; vitamin D; allergy
24.  Features of severe asthma in school-age children: Atopy and increased exhaled nitric oxide 
Background
Children with severe asthma have persistent symptoms despite treatment with inhaled corticosteroids (ICSs). The differentiating features of severe asthma in children are poorly defined.
Objective
To identify features of severe versus mild-to-moderate asthma in school-age children using noninvasive assessments of lung function, atopy, and airway inflammation.
Methods
A total of 75 children (median age, 10 years) with asthma underwent baseline characterization including spirometry and lung volume testing, methacholine bronchoprovocation, allergy evaluation, and offline measurement of exhaled nitric oxide (FENO). Twenty-eight were followed longitudinally over 6 months. Participants were assigned to the severe asthma subgroup if they required high-dose ICS plus 2 or more minor criteria.
Results
Children with severe versus mild-to-moderate asthma had more symptoms, greater airway obstruction, more gas trapping, and increased bronchial responsiveness to methacholine. Subjects with severe asthma also had higher concentrations of FENO and significantly greater sensitization to aeroallergens. With long-term study, both the reduction in FEV1 and increase in FENO persisted in the severe versus mild-to-moderate group. Furthermore, despite adjustments in ICS doses, the frequency of exacerbations was significantly higher in subjects with severe (83%) versus mild-to-moderate asthma (43%).
Conclusion
Severe asthma in childhood is characterized by poor symptom control despite high-dose ICS treatment and can be differentiated from mild-to-moderate asthma by measurement of lung function and FENO.
Clinical implications
Clinicians should suspect severe asthma in children with poor response to ICS, airway obstruction, and high FENO.
doi:10.1016/j.jaci.2006.08.019
PMCID: PMC2878140  PMID: 17157650
Children; asthma; atopy; nitric oxide; pulmonary function testing
25.  Exhaled Nitric Oxide is Associated with Allergic Inflammation in Children 
Journal of Korean Medical Science  2011;26(10):1265-1269.
Exhaled nitric oxide (eNO) has been proposed as a noninvasive marker of airway inflammation in asthma. In asthmatic patients, exhaled NO levels have been shown to relate with other markers of eosinophilic recruitment, which are detected in blood, sputum, bronchoalveolar lavage fluid and bronchial biopsy samples. The purpose of this study was to assess the possible relationship between eNO and allergic inflammation or sensitization in childhood asthma and allergic rhinitis. Subjects consisted of 118 asthmatic children, 79 patients with allergic rhinitis, and 74 controls. Their age ranged from 6 to 15 yr old. eNO level, peripheral blood eosinophil count, eosinophil cationic protein (ECP), serum total IgE level and specific IgE levels were measured. Methacholine challenge test and allergic skin prick test for common allergens were performed in all subjects. Atopic group (n = 206, 44.48 ± 30.45 ppb) had higher eNO values than non-atopic group (n = 65, 20.54 ± 16.57 ppb, P < 0.001). eNO level was significantly higher in patients with asthma (42.84 ± 31.92 ppb) and in those with allergic rhinitis (43.59 ± 29.84 ppb) than in healthy controls (27.01 ± 21.34 ppb, P < 0.001) but there was no difference between asthma and allergic rhinitis group. eNO also had significant positive correlations with Dermatophagoides pteronyssinus IgE level (r = 0.348, P < 0.001), Dermatophagoides farinae IgE level (r = 0.376, P < 0.001), and the number of positive allergens in skin prick test (r = 0.329, P = 0.001). eNO had significant positive correlations with peripheral blood eosinophil count (r = 0.356, P < 0.001), serum total IgE level (r = 0.221, P < 0.001), and ECP (r = 0.436, P < 0.001). This study reveals that eNO level is associated with allergic inflammation and the degree of allergic sensitization.
doi:10.3346/jkms.2011.26.10.1265
PMCID: PMC3192335  PMID: 22022176
Exhaled Nitric Oxide; Asthma; Allergic Rhinitis; Allergy; Sensitization

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