Question

Case Scenario: Your patient has asthma, newly diagnosed. His symptoms are shortness of breath, oxygen saturation of 60% on 3 liters of oxygen, anxiety, and loud breathing. He had a respiratory treatment earlier but has awoken with some severe symptoms.

1. Question: What is air trapping and how is it manifested in this case? Support your answer using specific facts, data, examples, and other information drawn from the textbook and at least one other supplemental source.

Answer 1

Air trapping due to airway closure has been associated with unstable asthma. In addition to airway closure that occurs at lower lung volumes during slow expiration, there may be further closure during a forced expiration because of airway compression. The purpose of this study was to define a reference range from a nonasthmatic population and investigate the characteristics of compressive air trapping in asthma. Spirometry and plethysmography were performed in 117 nonasthmatic subjects (ages 18–87 yr) and 153 asthma subjects (ages 12–72 yr). Air trapping was assessed as residual lung volume and the ratio of forced expiratory vital capacity (FVC) to slow inspiratory vital capacity (iVC) (FVC/iVC). There were no significant age or sex effects on the FVC/iVC ratio in the nonasthmatic subjects, and a fifth percentile lower limit of normal (LLN) of 0.93 was computed. An FVC/iVC ratio less than LLN defined compressive air trapping. Asthma subjects exhibited an age-related decline in the FVC/iVC ratio of 0.0027 per year (P < 0.0001) in a mixed effects model, with additional decreases associated with severe asthma and male sex. FVC/iVC ratios< LLN were infrequent in subjects <30 yr but evident in most asthma subjects >50 yr. Lung residual volumes followed similar patterns of greater elevations in subjects with severe asthma, older age, and male sex. Compressive air trapping occurs frequently in older asthmatics, appearing to be a feature of the natural history of asthma that is greater in severe asthma and men. This component of premature airway closure affects spirometric assessment of airway function and may contribute to asthma symptoms during physical exertion.

Asthma is a chronic inflammatory airway disease, characterized by airflow limitation and airway hyper-responsiveness.However, asthma patients consist of several subgroups defined by etiology, pathology, severity, and response to treatment. High doses of inhaled corticosteroids can relieve airflow obstruction in asthmatics. However, a proportion of patients fail to recover normal lung function. Such persistent airflow obstruction is one of the specific asthma phenotypes and comprises fewer than 5% of all asthmatics.

This subgroup has several characteristics that differ from typical asthma. Eosinophilic airway inflammation is the characteristic abnormality in both atopic and nonatopic asthma. However, recent studies suggest that neutrophils are predominant in the airways of severely affected patients.Additionally, thickening of the reticular basement membrane and increased airway smooth muscle are associated with persistent airflow obstruction in severe asthma.Thus, the examining differences in airway inflammation and airway wall changes may help in predicting the effectiveness of asthma therapies including inhaled corticosteroids in asthma subgroups.

In evaluating airway structural changes in asthma, histological examinations using bronchoscopic biopsies are very useful, but availability is limited in severe asthmatics. For the past two decades, HRCT has been used as a noninvasive method to assess bronchial wall thickness and air trapping to reflect the changes in large and small airways.8 Severe asthma is characterized by thickened bronchial walls and increased air trapping on HRCT.9, 10 These large and small airway changes are considered to be responsible for treatment-refractory, chronic, persistent airway obstructions. However, few studies have evaluated longitudinal morphological changes in these parameters. The purpose of this study was to evaluate large and small airway changes on HRCT for the structural characterization of the unresponsiveness to inhaled corticosteroids, leading to persistent airflow obstruction in patients with asthma.

Materials and methods
Subjects
We enrolled patients with moderate or severe asthma according to the Global Initiative for Asthma (GINA) guidelines11 at a university hospital. Moderate-to-severe asthma was defined as post-bronchodilator forced expiratory volume in 1 s (post-BD FEV1) of <75% of the predicted value, two or more episodes of nocturnal symptoms per week, and limitation of activities with asthma symptoms present.11 Subjects had not taken any inhaled or systemic corticosteroid over the previous 4 weeks before the first HRCT examination. All subjects underwent a standardized assessment, which included complete blood count, total IgE, chest posteroanterior radiography, allergy skin-prick tests, and spirometry.12 Exclusion criteria included respiratory infections within 4 weeks of screening, smoking history of >10 packs per year, chronic obstructive pulmonary disease or post-BD FEV1 of >75% predicted value at screening.

This study was approved by the hospital ethics committee. Written consent was obtained from all patients.

Study design
At screening, the subjects underwent lung function tests and HRCT. Subjects with bronchiectasis, emphysema, or other parenchymal lung diseases on HRCT were excluded. Immediately after examination, systemic and/or inhaled corticosteroid treatment was started, according to GINA guidelines.11 During the study period, all subjects maintained higher doses of inhaled corticosteroids (>1000 μg fluticasone per day) combined with long-acting β-agonists and additional therapies to achieve optimal symptom relief and maximum FEV1 for 12 months or more. When the post-BD FEV1 level reached a maximum, HRCT was reevaluated. Maximal post-BD FEV1 level was defined as <10% variation observed on two or more consecutive FEV1 measurements with a 2-month interval after continuous medications for 12 months or more. Subjects were divided into two groups by post-BD FEV1 % levels: the recovered group with >75%, and the persistent airway obstruction group with <75%.

Thin-slice CT scanning and radiological evaluation
All subjects underwent volumetric thin-section CT scanning of the chest using a 16-slice helical CT (Somatom Sensation 16, software version VA20; Siemens Medical Sohe measurement of HRCT findings has been described previously.13 Inspiration and expiration scans were obtained at the end of full inspiration and at the end of full expiration.14 We used the following parameters: 120 kVp, 180 mAs, 1-mm table feed/rotation, 1-mm collimation, and a 0.5-mm interval. Image data were reconstructed with 1.0-mm thicknesses and 10-mm intervals using a bone algorithm.

Images were viewed at two window levels: −450 HU for bronchial wall area(%) and −700 HU for air trapping(%). All images were displayed at the lung window setting using a picture-archiving and communication system (PACS) work station (Starpacs, Infinitt Technology). These findings were defined according to the glossary of terms recommended by the Fleischner Society.15 Airway images were viewed on a work station using a magnification of 5×, and measurements of outer (D) and internal (L) diameters of the bronchi were made using electronic calipers by two experienced thoracic radiologists. All bronchi with a D diameter of >1.5 mm and a ratio of the long-to-short D diameter < 1.5 were measured on each slice of the end-inspiration scans. Because oblique sections can influence wall thickness, bronchi showing a ratio of the long-to-short D diameter < 1.5 were analyzed.

Wall area(WA) was calculated as a percentage of total airway cross-sectional area according to the following formula13:

To measure air trapping, the lung was divided into six zones (right and left upper, middle, and lower) by one- and two-thirds of the vertical distance between the lung apices and the domes of the diaphragm. Air trapping was defined by the decreased attenuation of pulmonary parenchyma, manifested as a less-than-normal increase in attenuation during expiration, according to the definition of the Fleischner Society.

Thus, lung attenuation and air trapping area measurements were performed on similar anatomical levels at inspiration and expiration. The reader selected HRCT sections according to anatomical landmarks and used the software to measure the difference between inspiratory and expiratory median lung attenuation, calculated for the whole lung, as described previously. Focal areas of relative lucency in the superior segments of the lower lobes were excluded from analysis because they can be seen in normal subjects on expiratory scans.16 The low attenuation areas of emphysema and bullae were also excluded.

Air trapping was calculated as the percentage of the involved area to the cross-sectional area from each zone. Intra- and inter-observer variation were assessed by plotting the difference between the two wall area and air trapping measurements against the mean value of each.17 To assess intra- and inter-observer variability of parameters, the kappa coefficient of agreement (κ) was computed.18

Statistical analysis
Data are expressed as means ± SEM or medians and inter-quartile ranges. The SPSS/PC + program (SPSS, Inc., Chicago, IL) was used for the statistical analyses. Mann–Whitney U test or the chi-squared test was used to compare differences between the recovered group and persistent airway obstruction group. Initial and follow-up differences in variables in the intra-group were determined by using the Wilcoxon signed rank test. Correlations between the data were assessed using Spearman's rank test. Finally, multivariate log-binomial regression models were used because of the presence of common outcome variables to estimate relative risks (RRs) and 95% confidence intervals (CIs) for the presence of persistent airflow obstruction by including the initial wall area (Model 1), the initial air trapping (Model 2), the difference between the initial and follow-up wall area (Model 3) and the difference between initial and follow-up air trapping (Model 4). Models 1 and 2 were adjusted for age, gender, smoking history, atopy, and symptom duration. Model 3 was further adjusted for initial wall area and Model 4 was further adjusted for initial air trapping. P values < 0.05 were considered to indicate statistical significance.

Results
Demographic and physiological characteristics of the study subjects
In total, 32 patients with moderate-to-severe asthma were enrolled; 14 patients developed persistent airway obstruction during treatment (Persistent airway obstruction group; . There was no significant difference in age, gender, frequency of atopy, smoking, or duration of asthma between the two groups. The mean length of follow-up duration was similar between the two groups (2.1 vs. 2.7 years). On the initial day of the study, all study subjects had post-BD FEV1s of <75% predicted. There was no significant difference in lung function, including FVC, FEV1, and FEV1/FVC values, between the two groups (Table 2). At the second HRCT examination, the post-BD FEV1 had not changed in the persistent airway obstruction group from that at the initial examination (55.2 ± 4.4% vs. 59.2 ± 3.0% of the predicted value.