(Chest. 2002;122:1622-1626.)
© 2002
American College of Chest Physicians
Structural Changes of the Airway Wall Impair Respiratory Function, Even in Mild Asthma*
Kumiko Shiba, MD, PhD;
Keita Kasahara, MD, PhD;
Hiroaki Nakajima, MD, PhD and
Mitsuru Adachi, MD, PhD
* From the First Department of Internal Medicine (Drs. Shiba, Kasahara, and Adachi), Showa University School of Medicine, Tokyo; and Department of Respiratory Disease (Dr. Nakajima), Showa University Northern Yokohama Hospital, Yokohama City, Kanagawa, Japan.
Correspondence to: Keita Kasahara, MD, PhD, First Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan; e-mail: kasa3561{at}med.showa-u.ac.jp
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Abstract
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Study objectives: To clarify whether structural changes of the airway wall impair respiratory function in patients with mild asthma, and to determine whether mild asthma should be treated with inhaled steroids.
Setting: Showa University Hospital in Tokyo.
Patients: Thirteen healthy nonatopic volunteers (control subjects), 26 patients with mild asthma treated with a bronchodilator alone without oral or inhaled corticosteroids or antiallergic agents, and 10 patients with mild-to-moderate asthma treated with inhaled corticosteroids.
Measurements: We measured the thickness of the epithelial reticular basement membrane (Rbm) of the airway wall in bronchial biopsy specimens from patients with asthma and from healthy control subjects. We also performed spirometry and histamine challenge tests to evaluate airflow obstruction and airway hyperresponsiveness.
Results: The thickness of the Rbm in patients with mild asthma was significantly greater than that in healthy control subjects and was negatively correlated with the FEV1 as a percentage of FVC and the provocative concentration of histamine that caused a 20% decrease in FEV1 from the post-saline solution baseline value. Moreover, the Rbm was thicker in patients with mild asthma not treated with inhaled steroids than in patients with mild-to-moderate asthma treated with inhaled steroids.
Conclusions: The thickness of the Rbm is increased even in mild asthma and is correlated with airway obstruction and hyperresponsiveness. Our results suggests that anti-inflammatory treatment with inhaled steroids should be started in the early stage of bronchial asthma to prevent structural changes from occurring in the airway wall.
Key Words: asthma • basement membrane • steroid inhalation • structural changes • thickness of the airway wall
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Introduction
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Most treatment guidelines1
2
3
4
recommend that mild asthma be treated mainly with bronchodilators and without inhaled corticosteroids. However, some studies have suggested that inflammation and structural changes of the airway are already present when symptoms of asthma first appear.5
6
The inflammation and structural changes of the airway may induce airway hyperresponsiveness or limit airflow. Inhaled steroids are recommended by most guidelines to inhibit inflammation of the airway in moderate or severe asthma. However, the ability of inhaled steroids to reverse structural change or improve airway hyperresponsiveness remains controversial.7
8
9
If treatment with inhaled steroids were started late, airway inflammation might continue and induce airway hyperresponsiveness and structural changes. We performed the present study to clarify whether thickening of the epithelial reticular basement membrane (Rbm) of the airway wall impairs respiratory function in patients with mild asthma, and to determine whether mild asthma should be treated with inhaled steroids.
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Materials and Methods
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Subjects
Subjects included 13 healthy nonatopic volunteers (control subjects, group 1), 26 patients with mild asthma treated with a bronchodilator alone without oral or inhaled corticosteroids or antiallergic agents (group 2), and 10 patients with mild-to-moderate asthma treated with inhaled corticosteroids and without oral steroids or antiallergic agents (group 3) [Table 1
]. Asthma was diagnosed and classified according to the Guidelines for the Diagnosis and Management of the Asthma, Expert Panel Report II, 1997.2
The patients with mild asthma had no history of severe asthmatic attacks and had never been hospitalized for treatment. All subjects were nonsmokers, and COPD, bronchiectasis, and inactive pulmonary tuberculosis were excluded by symptoms, physical examinations, chest radiography, and CT. All control subjects were without a history of wheezing or asthma and had normal spirometric findings. We further classified the 26 patients with mild asthma (group 2) into two groups: those in whom asthma had been diagnosed 
12 months before the start of the study (group 2a), and those in whom asthma had been diagnosed > 12 months before the start of the study (group 2b) [Table 2
]. The 10 patients with mild-to-moderate asthma treated with inhaled steroids and without oral steroid or antiallergic agents (group 3) had received diagnoses > 12 months before the study started and had begun daily inhalation of 
600 mg of beclomethasone dipropionate (BDP) on diagnosis of asthma. All subjects were informed of the details of this study and gave informed consent before the beginning of the experiment. This study was approved by the Showa University Ethics Committee. The procedures used in our study were in accordance with the recommendations of the Helsinki Declaration of 1974.
Study Design
Patients were screened by history, physical examinations, and respiratory function tests. After we had ensured that each patient had stable asthma and had not changed medications for at least 3 months, a standard histamine challenge test and bronchoscopy were performed. First, we evaluated the relations of Rbm thickness to disease duration, respiratory function, and airway hyperresponsiveness in patients with mild asthma not being treated with inhaled corticosteroid (group 2). Second, we compared Rbm thickness among the four groups (groups 1, 2a, 2b, and 3).
Respiratory Function Tests
Spirometric tests were performed with a spirometer (Autospiro AS- 300; Minato; Osaka, Japan) to measure FVC, FEV1, and peak expiratory flow (PEF). The tests were repeated at least three times, and the highest of the three acceptable measurements was used for analysis.
Histamine Challenges
Bronchial responsiveness to histamine was measured with a method recommended by the Japan Academy of Allergology.10
Subjects inhaled double-increased concentrations of histamine by means of a nebulizer (model 646; DeVilbiss; Somerset, PA) for 2 min during tidal breathing. Increasing concentrations of histamine were administered until FEV1 had decreased by > 20% of the baseline value. Results were expressed as the provocative concentration of histamine causing a 20% decrease in FEV1 (PC20) from the post-saline solution baseline value.
Bronchial Biopsy
No patients had had an asthma attack before fiberoptic bronchoscopy (BF type 240; Olympus; Tokyo, Japan). We used lidocaine (20 mL of 2% solution for local anesthesia), atropine (0.5 mg IM), and midazolam (0.1 mg/kg intravascular infusion slowly) as premedications. At the start of bronchoscopy, the percutaneous oxygen saturation and pulse were monitored by pulse oximeter (Pulsox; Teijin; Tokyo, Japan) and respiratory rate and BP were observed. Four to five biopsy specimens were obtained from the subsegmental bronchial bifurcation in the right lower lung in each subject. The outer surfaces of biopsy specimens were stained with eosin to ensure proper orientation for cross-sectioning. After the specimens were fixed in 10% buffered formalin solution at room temperature and embedded in paraffin, three measurable 5-µm-thick sections were cut from each specimen with a microtome and stained with hematoxylin-eosin. The thickness of the Rbm was determined by dividing the measured area of the entire Rbm (from the base of the bronchial epithelium to the outer limit of the reticular lamina) by the length of the true basement membrane of the Rbm area, as measured with a computerized image (Apple Computer; Cupertino, CA; National Institute of Health image). Average values from three-to-five measurements in three-to-five stained sections per subject were used for analysis. All measurements were done by a single pathologist in a blinded fashion.
Statistical Analysis
All statistical analyses were done with StatView software version 4.5 (Abacus Concepts; Berkeley, CA) on a personal computer. Values are expressed as mean ± SD. Simple regression was used to compare Rbm thickness with duration of asthma, age, FEV1 as a percentage of FVC (FEV1%), and PC20 in patients with mild asthma. The Mann-Whitney U test was used to compare Rbm thickness between patients and healthy control subjects. Differences with p values < 0.05 were considered significant.
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Results
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Subject Characteristics
Characteristics of the subjects, including age, sex, duration of asthma, dose of BDP, Rbm thickness, and respiratory function measurements in 13 healthy control subjects (group 1) and 36 patients with asthma (groups 2 and 3), are shown in Table 1
; the characteristics of groups 2a and 2b are shown in Table 2
. Patients with asthma in each group and healthy control subjects were similar in regards to age and sex.
Thickness of the Rbm in Patients With Mild Asthma and in Healthy Control Subjects
The Rbm was significantly thicker (mean ± SD) in patients with mild asthma not treated with inhaled steroids (6.4 ± 2.3 µm, group 2) than in healthy control subjects (2.6 ± 0.9 µm, group 1) [Table 1
]. Furthermore, the Rbm was thicker in patients with mild asthma diagnosed within 1 year (5.4 ± 1.9 µm, group 2a) than in healthy control subjects (2.6 ± 0.9 µm, group 1) [Tables 1 , 2
and Fig 1
].
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Figure 1.. Thickness of the Rbm. Group 1, healthy control subjects; group 2a, patients with newly diagnosed mild asthma; group 2b, patients with long history of mild asthma; group 3, patients with mild-to-moderate asthma treated with inhaled corticosteroids. *p < 0.0001.
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Correlation Between Rbm Thickness and Disease Duration in Patients With Mild Asthma
The thickness of the Rbm was positively correlated with disease duration in patients with mild asthma (r = 0.54, p = 0.005; Fig 2
, top, A). However, Rbm thickness and age were not correlated (r = - 0.09, p = 0.66; Fig 2
, bottom, B).
Correlation of Rbm Thickness With FEV1% and PC20 in Patients With Mild Asthma
The thickness of the Rbm was negatively correlated with both FEV1% (r = - 0.65, p = 0.004; Fig 3
) and log PC20 (r = - 0.58, p = 0.005; Fig 4
) in patients with mild asthma not treated with corticosteroids.
Effect of Corticosteroid Inhalation on Rbm Thickening in Asthma
The thickness of the Rbm was less in patients with mild-to-moderate asthma for > 12 months treated with inhaled steroids (group 3) than in patients with mild asthma for > 12 months not treated with inhaled steroids (group 2b; Fig 1
).
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Discussion
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Patients with mild asthma have not had severe symptoms or severe airway inflammation. Most recent guidelines1
2
3
4
recommend that mild asthma be treated mainly with bronchodilators and without inhaled corticosteroids. However, we found that in patients with mild asthma not treated with inhaled corticosteroids, the Rbm was thicker than in healthy control subjects. Furthermore, we found that the Rbm was thicker than in healthy control subjects even in patients in whom mild asthma had been diagnosed within 1 year. These results suggest that even patients with mild asthma should be treated to inhibit structural changes of the airway wall.
We found that the thickening of the Rbm was strongly correlated with airflow limitation and airway hyperresponsiveness in mild asthma. Some earlier studies have also suggested that airway structural changes are associated with airflow limitation or airway hyperresponsiveness.11
12
13
Together, these findings suggest that the airway structural changes can impair respiratory function and aggravate asthmatic symptoms even in patients with mild asthma.
We found that the Rbm was much thinner in patients with mild-to-moderate asthma treated with corticosteroid inhalation than in patients with mild asthma not treated with corticosteroids. Several studies have suggested that airway inflammation and injury-repair responses lead to structural changes of the airways,11
14
15
and that airway inflammation and structural changes occur before asthmatic symptoms appear.5
6
The structural changes, which can induce airway obstruction and hyperresponsiveness, increase with the duration of asthma16
17
and may lead to the development of chronic refractory asthma. Although inhalation of steroids can inhibit airway inflammation in asthma, whether it can reverse airway structural changes is controversial.7
8
9
Some studies have reported that early induction of steroid inhalation can decrease airway hyperresponsiveness; however, Boulet et al7
suggested that once asthma becomes symptomatic, airway responsiveness cannot be normalized in most patients, even with high doses of inhaled corticosteroids. However, even if intensive anti-inflammatory treatments cannot reverse thickening of the airway wall, early treatment with inhaled steroids might still inhibit or prevent further thickening of the Rbm. These results suggest that steroid inhalation should be started immediately after diagnosis of asthma to inhibit development of structural changes of airway wall, which might lead to severe or refractory asthma in the future.
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Conclusion
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We found that the Rbm was thicker in patients with mild asthma not treated with corticosteroids than in healthy control subjects or in patients with mild-to-moderate asthma intensively treated with inhaled corticosteroids. The thickening of Rbm correlated with the duration of asthma and with the impairment of respiratory function and airway hyperresponsiveness. These results suggest that treatment with inhaled corticosteroids should be started from the early stage of even mild bronchial asthma.
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Footnotes
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Abbreviations: BDP = beclomethasone dipropionate; FEV1% = FEV1 as a percentage of FVC; PC20 = provocative concentration of histamine causing a 20% decrease in FEV1; PEF = peak expiratory flow; Rbm = epithelial reticular basement membrane
Received for publication November 6, 2001.
Accepted for publication June 14, 2002.
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References
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- National Asthma Education and Prevention Program.. Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report II. 1997,15-24 National Institutes of Health Bethesda, MD.
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- Japanese Society of Allergology.. Guidelines for the diagnosis and management of bronchial asthma. Allergology 1995;50(suppl),1S-42S
- Boulet, LP, Chakir, J, Dube, J, et al Airway inflammation and structural changes in airway hyperresponsiveness and asthma: an overview. Can Respir J 1998;5,16-21[Medline]
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- Trigg, CJ, Manolitsas, ND, Wang, J, et al Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma. Am J Respir Crit Care Med 1994;150,17-22[Abstract]
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Abstract
Introduction
