A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis.
ABSTRACT: BACKGROUND:Patients with severe asthma have increased physiologically measured air trapping; however, a study using CT measures of air trapping has not been performed. This study was designed to address two hypotheses: (1) air trapping measured by multidetector CT (MDCT) quantitative methodology would be a predictor of a more severe asthma phenotype; and (2) historical, clinical, allergic, or inflammatory risk factors could be identified via multivariate analysis. METHODS:MDCT scanning of a subset of Severe Asthma Research Program subjects was performed at functional residual capacity. Air trapping was defined as >or= 9.66% of the lung tissue < - 850 Hounsfield units (HU). Subjects classified as having air trapping were then compared to subjects without air trapping on clinical and demographic factors using both univariate and multivariate statistical analyses. RESULTS:Subjects with air trapping were significantly more likely to have a history of asthma-related hospitalizations, ICU visits, and/or mechanical ventilation. Duration of asthma (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.08 to 1.87), history of pneumonia (OR, 8.55; 95% CI, 2.07 to 35.26), high levels of airway neutrophils (OR, 8.67; 95% CI, 2.05 to 36.57), airflow obstruction (FEV(1)/FVC) [OR, 1.61; 95% CI, 1.21 to 2.14], and atopy (OR, 11.54; 95% CI, 1.97 to 67.70) were identified as independent risk factors associated with the air-trapping phenotype. CONCLUSIONS:Quantitative CT-determined air trapping in asthmatic subjects identifies a group of individuals at high risk for severe disease. Several independent risk factors for the presence of this phenotype were identified: perhaps most interestingly, history of pneumonia, neutrophilic inflammation, and atopy.
Project description:RATIONALE AND OBJECTIVES:Previous cross-sectional studies have demonstrated that airway wall thickness and air trapping are greater in subjects with severe asthma than in those with mild-to-moderate asthma. However, a better understanding of how airway remodeling and lung density change over time is needed. This study aimed to evaluate predictors of airway wall remodeling and change in lung function and lung density over time in severe asthma. MATERIALS AND METHODS:Phenotypic characterization and quantitative multidetector-row computed tomography (MDCT) of the chest were performed at baseline and ?2.6 years later in 38 participants with asthma (severe n = 24 and mild-to-moderate n = 14) and nine normal controls from the Severe Asthma Research Program. RESULTS:Subjects with severe asthma had a significant decline in postbronchodilator forced expiratory volume in 1 second percent (FEV1%) predicted over time (P < .001). Airway wall thickness measured by MDCT was increased at multiple airway generations in severe asthma compared to mild-to-moderate asthma (wall area percent [WA%]: P < .05) and normals (P < .05) at baseline and year 2. Over time, there was an increase in WA% and wall thickness percent (WT%) in all subjects (P = .030 and .009, respectively) with no change in emphysema-like lung or air trapping. Baseline prebronchodilator FEV1% inversely correlated with WA% and WT% (both P < .05). In a multivariable regression model, baseline WA%, race, and health care utilization were predictors of subsequent airway remodeling. CONCLUSIONS:Severe asthma subjects have a greater decline in lung function over time than normal subjects or those with mild-to-moderate asthma. MDCT provides a noninvasive measure of airway wall thickness that may predict subsequent airway remodeling.
Project description: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.To examine whether vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, and time outdoors.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.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 FEV(1)/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.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.
Project description:The characteristics that predict progression to overt chronic obstructive pulmonary disease (COPD) in smokers without spirometric airflow obstruction are not clearly defined.We conducted a post hoc analysis of 849 current and former smokers (?20 pack-years) with preserved spirometry from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort who had baseline computed tomography (CT) scans of lungs and serial spirometry. We examined whether CT-derived lung volumes representing air trapping could predict adverse respiratory outcomes and more rapid decline in spirometry to overt COPD using mixed-effect linear modelling.Among these subjects with normal forced expiratory volume in 1?s (FEV1) to forced vital capacity (FVC) ratio, CT-measured residual volume (RVCT) to total lung capacity (TLCCT) ratio varied widely, from 21% to 59%. Over 2.5±0.7?years of follow-up, subjects with higher RVCT/TLCCT had a greater differential rate of decline in FEV1/FVC; those in the upper RVCT/TLCCT tertile had a 0.66% (95% CI 0.06%-1.27%) faster rate of decline per year compared with those in the lower tertile (p=0.015) regardless of demographics, baseline spirometry, respiratory symptoms score, smoking status (former versus current) or smoking burden (pack-years). Accordingly, subjects with higher RVCT/TLCCT were more likely to develop spirometric COPD (OR 5.7 (95% CI 2.4-13.2) in upper versus lower RVCT/TLCCT tertile; p<0.001). Other CT indices of air trapping showed similar patterns of association with lung function decline; however, when all CT indices of air trapping, emphysema, and airway disease were included in the same model, only RVCT/TLCCT retained its significance.Increased air trapping based on radiographic lung volumes predicts accelerated spirometry decline and progression to COPD in smokers without obstruction.
Project description:<h4>Background</h4>Arginases (encoded by ARG1 and ARG2 genes) might play an important role in asthma pathogenesis through effects on nitrosative stress. Arginase expression is upregulated in asthma and varies with T(H)2 cytokine levels and oxidative stress.<h4>Objective</h4>We aimed to examine whether variants in these genes are associated with asthma and whether atopy and exposures to smoking and air pollution influence the associations.<h4>Methods</h4>Among non-Hispanic and Hispanic white participants of the Children's Health Study (n = 2946), we characterized variation in each locus (including promoter region) with 6 tag single nucleotide polymorphisms for ARG1 and 10 for ARG2. Asthma was defined by parental report of physician-diagnosed asthma at study entry.<h4>Results</h4>Both ARG1 and ARG2 genetic loci were significantly associated with asthma (global locus level P = .02 and .04, respectively). Compared with the most common haplotype within each locus, 1 ARG1 haplotype was associated with reduced risk (odds ratio [OR] per haplotype copy, 0.55; 95% CI, 0.36-0.84), and 1 ARG2 haplotype was associated with increased risk (OR per haplotype copy, 1.35; 95% CI, 1.04-1.76) of asthma. The effect of the ARG1 haplotype that was significantly associated with asthma varied by the child's history of atopy and ambient ozone (P(interaction) = .04 and .02, respectively). Among atopic children living in high-ozone communities, those carrying the ARG1 haplotype had reduced asthma risk (OR per haplotype copy, 0.12; 95% CI, 0.04-0.43; P(heterogeneity) across atopy/ozone categories = .008).<h4>Conclusions</h4>ARG1 and ARG2 loci are associated with childhood asthma. The association between ARG1 variation and asthma might depend on atopy and ambient ozone levels.
Project description:IgG Fc receptors (Fc?Rs) play important roles in immune responses. It is not clear whether Fc?R receptors play a role in human asthma and allergy. The aim of current study was to investigate whether functional single nucleotide polymorphisms (SNPs) of Fc?R genes (FCGR) are associated with human asthma and allergy.Functional SNPs of FCGR2A (Fc?RIIA-131His>Arg, rs1801274), FCGR2B (Fc?RIIB-187Ile>Thr, rs1050501), FCGR2C (Fc?RIIC-13Gln>Stop, rs10917661), FCGR3A (Fc?RIIIA-158Val>Phe, rs396991), and FCGR3B variants (Fc?RIIIB NA1 and NA2) were genotyped in an asthma family cohort including 370 atopy positive, 239 atopy negative, and 169 asthma positive subjects. The genotype and phenotype data (asthma, bronchial hyper-responsiveness, and atopy) of subjects were analyzed using family-based association tests (FBAT) and logistic regression adjusted for age and sex.The Fc?RIIA-131His>Arg SNP is significantly associated with atopy in a family-based association test (P = 0.00287) and in a logistic regression analysis (P = 0.0269, OR 0.732, 95% CI: 0.555-0.965). The Fc?RIIA-131His (or rs1801274-A) allele capable of binding human IgG2 has a protective role against atopy. In addition, the rare Fc?RIIB-187Thr (or rs1050501-C) allele defective for the receptor-mediated inhibitory signals is a risk factor for atopy (P = 0.0031, OR 1.758, 95% CI: 1.209-2.556) and IgE production (P<0.001). However, variants of activating Fc?RIIIA (rs396991), and Fc?RIIIB (NA1 and NA2), and Fc?RIIC (rs10917661) are not associated with asthma, BHR, and atopy (P>0.05).Fc?RIIA and Fc?RIIB functional polymorphisms may have a role in the pathogenesis of allergy.
Project description:Brown RH, Henderson RJ, Sugar EA, Holbrook JT, Wise RA, on behalf of the American Lung Association Airways Clinical Research Centers. Reproducibility of airway luminal size in asthma measured by HRCT. J Appl Physiol 123: 876-883, 2017. First published July 13, 2017; doi:10.1152/japplphysiol.00307.2017.-High-resolution CT (HRCT) is a well-established imaging technology used to measure lung and airway morphology in vivo. However, there is a surprising lack of studies examining HRCT reproducibility. The CPAP Trial was a multicenter, randomized, three-parallel-arm, sham-controlled 12-wk clinical trial to assess the use of a nocturnal continuous positive airway pressure (CPAP) device on airway reactivity to methacholine. The lack of a treatment effect of CPAP on clinical or HRCT measures provided an opportunity for the current analysis. We assessed the reproducibility of HRCT imaging over 12 wk. Intraclass correlation coefficients (ICCs) were calculated for individual airway segments, individual lung lobes, both lungs, and air trapping. The ICC [95% confidence interval (CI)] for airway luminal size at total lung capacity ranged from 0.95 (0.91, 0.97) to 0.47 (0.27, 0.69). The ICC (95% CI) for airway luminal size at functional residual capacity ranged from 0.91 (0.85, 0.95) to 0.32 (0.11, 0.65). The ICC measurements for airway distensibility index and wall thickness were lower, ranging from poor (0.08) to moderate (0.63) agreement. The ICC for air trapping at functional residual capacity was 0.89 (0.81, 0.94) and varied only modestly by lobe from 0.76 (0.61, 0.87) to 0.95 (0.92, 0.97). In stable well-controlled asthmatic subjects, it is possible to reproducibly image unstimulated airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability.NEW & NOTEWORTHY There is a surprising lack of studies examining the reproducibility of high-resolution CT in asthma. The current study examined reproducibility of airway measurements. In stable well-controlled asthmatic subjects, it is possible to reproducibly image airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability.
Project description:<h4>Background</h4>Thoracic computed tomography (CT) scans are widely performed in clinical practice, often leading to detection of airway or parenchymal abnormalities in asymptomatic or minimally symptomatic individuals. However, clinical relevance of CT abnormalities is uncertain in the general population.<h4>Methods</h4>We evaluated data from 1361 participants aged ?40 years from a Canadian prospective cohort comprising 408 healthy never-smokers, 502 healthy ever-smokers, and 451 individuals with spirometric evidence of chronic obstructive pulmonary disease (COPD) who had thoracic CT scans. CT images of subjects were visually scored for respiratory bronchiolitis(RB), emphysema(E), bronchial-wall thickening(BWT), expiratory air-trapping(AT), and bronchiectasis(B). Multivariable logistic regression models were used to assess associations of CT features with respiratory symptoms, dyspnea, health status as determined by COPD assessment test, and risk of clinically significant exacerbations during 12 months follow-up.<h4>Results</h4>About 11% of life-time never-smokers demonstrated emphysema on CT scans. Prevalence increased to 30% among smokers with normal lung function and 36%, 50%, and 57% among individuals with mild, moderate or severe/very severe COPD, respectively. Presence of emphysema on CT was associated with chronic cough (OR,2.11; 95%CI,1.4-3.18); chronic phlegm production (OR,1.87; 95% CI,1.27-2.76); wheeze (OR,1.61; 95% CI,1.05-2.48); dyspnoea (OR,2.90; 95% CI,1.41-5.98); CAT score?10(OR,2.17; 95%CI,1.42-3.30) and risk of ?2 exacerbations over 12 months (OR,2.17; 95% CI, 1.42-3.0).<h4>Conclusions</h4>Burden of thoracic CT abnormalities is high among Canadians ?40 years of age, including never-smokers and smokers with normal lung function. Detection of emphysema on CT scans is associated with pulmonary symptoms and increased risk of exacerbations, independent of smoking or lung function.
Project description:BACKGROUND:Imaging variables, including airway diameter, wall thickness, and air trapping, have been found to be important metrics when differentiating patients with severe asthma from those with nonsevere asthma and healthy subjects. OBJECTIVE:The objective of this study was to identify imaging-based clusters and to explore the association of the clusters with existing clinical metrics. METHODS:We performed an imaging-based cluster analysis using quantitative computed tomography-based structural and functional variables extracted from the respective inspiration and expiration scans of 248 asthmatic patients. The imaging-based metrics included a broader set of multiscale variables, such as inspiratory airway dimension, expiratory air trapping, and registration-based lung deformation (inspiration vs expiration). Asthma subgroups derived from a clustering method were associated with subject demographics, questionnaire results, medication history, and biomarker variables. RESULTS:Cluster 1 was composed of younger patients with early-onset nonsevere asthma and reversible airflow obstruction and normal airway structure. Cluster 2 was composed of patients with a mix of patients with nonsevere and severe asthma with marginal inflammation who exhibited airway luminal narrowing without wall thickening. Clusters 3 and 4 were dominated by patients with severe asthma. Cluster 3 patients were obese female patients with reversible airflow obstruction who exhibited airway wall thickening without airway narrowing. Cluster 4 patients were late-onset older male subjects with persistent airflow obstruction who exhibited significant air trapping and reduced regional deformation. Cluster 3 and 4 patients also showed decreased lymphocyte and increased neutrophil counts, respectively. CONCLUSIONS:Four image-based clusters were identified and shown to be correlated with clinical characteristics. Such clustering serves to differentiate asthma subgroups that can be used as a basis for the development of new therapies.
Project description:The coexistence of COPD and asthma is widely recognized but has not been well described. This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma.We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma. These subjects were younger (61.3 vs 64.7 years old, p=0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p=0.0001). More African-Americans reported a history of asthma (33.6% vs 15.6%, p<0.0001). Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p<0.0001). Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT. There were no differences in spirometry or CT measurements of emphysema or airway wall thickness.Subjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life. They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history.ClinicalTrials.gov: NCT00608764.
Project description:BACKGROUND:IgE-mediated responses contribute to allergy and asthma. Little is understood regarding the relationship of tissue IgE to systemic IgE, inflammation or clinical outcomes. OBJECTIVES:To evaluate local IgE expression and cellular inflammation in the proximal and distal lung of normal subjects and subjects with asthma of varying severity and relate those tissue parameters to systemic IgE levels, atopy, lung function, and history of severe exacerbations of asthma. METHODS:Tissue from more than 90 subjects with eosinophilic (SAeo(+)) and noneosinophilic (SAeo(-)) severe asthma, mild asthma and normal subjects were immunostained for IgE, signal-amplifying isoform of IgE receptor (FcepsilonRIbeta) and markers of mast cells, eosinophils, and lymphocytes. Tissue expression of IgE, FcepsilonRIbeta, cellular inflammation, serum IgE, and atopy were compared. Regression models were used to determine the relationship of local and systemic IgE to lung function and severe exacerbations of asthma. RESULTS:Mast cell-bound IgE was present along airways but absent in lung parenchyma. Although the groups were similar in systemic/serum IgE and atopy, local/tissue IgE was highest in SAeo(+) and correlated with eosinophils and lymphocytes (r(s) = 0.52, P < .0001; and r(s) = 0.23, P = .03, respectively). Higher local IgE was associated with better lung function, but also with more severe exacerbations of asthma. CONCLUSION:Local IgE appears to be primarily a component of responses within the mucosal immune compartment and is related to cellular inflammation, lung function, and clinical outcomes in asthma. CLINICAL IMPLICATIONS:Local/airway IgE-related processes rather than systemic markers of atopy may be relevant in determining clinical outcomes in asthma.