Characteristics of Bronchial Asthma with Incomplete Reversibility of Airflow Obstruction

Characteristics of bronchial asthma with incomplete reversibility of airflow obstruction Catherine Hudon, MD; He´le`ne Turcotte, MSc; Michel Laviolette, MD; Guy Carrier, MD; and Louis-Philippe Boulet, MD

Background: Incomplete reversibility of airflow obstruction (IRAO) can be observed in some asthmatic patients without significant smoking history nor evidence of other respiratory condition. The characteristics of this group remain however to be defined. Methods: We compared 18 asthmatic patients with persistent airflow obstruction, defined as an FEV1 ⱕ75% predicted despite optimal corticosteroid treatment, to others with complete reversibility of airflow obstruction, paired for age and gender (CRAO, FEV1 ⬎ 80% of predicted). Results: Mean duration of asthma was 31.6 years for IRAO patients and 17.7 for the CRAO group and mean baseline FEV1 was 48.6 ⫾ 2.6% and 89.3 ⫾ 3.4%, respectively. Patients with IRAO had more severe airflow obstruction and hyperinflation than those with CRAO, while lung compliance and CO diffusion were similar. Overall healthcare use was similar in the two groups, but those with IRAO had a greater global asthma-related discomfort, increased diurnal variation of airflow obstruction and used higher doses of inhaled corticosteroids than those with CRAO. Patients with IRAO had slightly increased airway wall thickness on high resolution chest tomography compared with CRAO. Baseline FEV1, however, was not correlated with the measured airway wall thickness. Conclusion: We found that asthmatic patients with IRAO have a more severe asthma and asthma of longer duration than asthmatic subjects with CRAO. Our data suggest that in asthma, IRAO may result from long-standing airway inflammation and associated structural changes, although this remains to be further documented. Ann Allergy Asthma Immunol 1997;78:195–202.

INTRODUCTION Bronchial asthma is classically characterized by a reversible airflow obstruction and airway hyperresponsiveness attributed to an inflammatory process.1 In most asthmatic patients, expiratory flows normalize with treatment. An incomplete reversibility of airflow obstruction may be found in some asthmatic patients without significant history of smoking or other associated respiratory condition despite optimal bronchodilator and corticosteroid treatment.2–5 From the Unite´ de Recherche, Centre de Pneumologie de l’Hoˆpital Laval, Universite´ Laval, Que´bec, Canada. Supported by the Medical Research Council of Canada. Received for publication June 4, 1996. Accepted for publication in revised form August 22, 1996.

VOLUME 78, FEBRUARY, 1997

Although this subgroup of asthmatic patients has been recognized for many years, the determinants of incomplete reversibility of airflow obstruction and its consequences on clinical outcome are still uncertain. Peat et al showed an increased rate of decline in pulmonary function in patients with asthma compared with the general population.6 Others reported that patients with incomplete reversibility of airflow obstruction usually had more severe and/or prolonged asthma.2,3,4 Structural changes of the airway wall induced by a long-standing bronchial inflammation may be involved in these irreversible functional abnormalities.7,8 This study was set to look at clinical, physiologic, and radiologic features of asthmatic patients with or without incomplete reversibility of airflow obstruction in order to define bet-

ter the characteristics and determinants of incomplete reversibility of airflow obstruction in asthma, as well as its clinical consequences. METHODS Selection of Patients A total of 36 patients attending the Laval Hospital asthma clinic took part in this study. First, we enrolled 18 asthmatic patients with incomplete reversibility of airflow obstruction, eight women and ten men, aged 29 to 64 years (mean 47 ⫾ 3) (Table 1). All had diagnoses of asthma according to the criteria of the American Thoracic Society.9 Although these patients had the typical clinical features of asthma and showed a ⬎15% increase in forced expiratory volume in one second (FEV1) either spontaneously or following treatment, they had had an optimal FEV1 ⬍75% of predicted values for at least 2 years despite maximal bronchodilator and inhaled corticosteroid treatment (this last at a daily dose equivalent to ⱖ1000 ␮g beclomethasone) and, for 16 of them, a 2-week oral corticosteroid treatment at a prednisone dose of ⱖ30 mg daily (mean optimal FEV1: 59.3% of predicted value after maximal treatment). In the two patients who did not agree to take oral corticosteroids, FEV1 had been ⬍75% of predicted for many years despite high-dose inhaled corticosteroids (daily dose equivalent to 1000 ␮g of inhaled beclomethasone for one patient and to 1500 ␮g for the other). These patients were paired according to age and sex to the 18 first consecutive asthmatic patients, recruited from our asthma clinic, who agreed to participate in the study. They were aged 24 to 64 years (mean 47 ⫾ 3). They had completely reversible air-

195

Table 1. Baseline Anthropometric, Clinical, and Physiologic Results in Subjects with IRAO and CRAO, and their Morbidity in the Previous Year

N. of subjects (M/F) Mean age, (yr) Duration of asthma, yr Ex-smokers (ⱕ6 pack-years) Number of emergency room visits, no of subjects 1 2 3 Hospitalization, no of subjects Mean global discomfort related to asthma* No. of atopic subjects Baseline FEV1, L (% pred) FEV1/FVC, % PC20, mg/mL, geometric mean

IRAO

CRAO

18 (10/8) 47 ⫾ 3 32 ⫾ 3 5

18 (10/8) 47 ⫾ 3 18 ⫾ 3 4

2 1 1 3 2.3 ⫾ 0.3

4 1 0 2 1.1 ⫾ 0.2

17 1.5 ⫾ 0.1 (48.6 ⫾ 2.6) 51.6 ⫾ 1.9 †

12 2.8 ⫾ 0.2 (89.3 ⫾ 3.4) 70.1 ⫾ 1.7 1.12

P ⬎.05 .008 ⬎.05 ⬎.05

⬎.05 .02 ⬎.05 ⬍.0001 ⬍.0001

* On a scale from 0 ⫽ none to 5 ⫽ maximal. † Not possible to measure, their FEV1 being too low or unable to stop bronchodilators.

flow obstruction as shown by an FEV1 ⬎80% predicted after bronchodilator and/or corticosteroid treatment. Excluded from this study were women of childbearing potential not using adequate contraception; patients with a significant history of smoking (⬎6 pack-years) or showing either a contraindication to the required tests the presence of any respiratory pathology other than asthma or unstable asthma; and patients who had had an allergic reaction or a respiratory infection within a month of the study. Patients with the reactive airway dysfunction syndrome (RADS) were also excluded, as this syndrome represents a specific entity related to a toxic exposure.10 This study was approved by the Laval Hospital Ethics Committee and all patients signed an informed consent form. Study Design All patients came to the laboratory on two to three different occasions. On the first visit, a questionnaire on the characteristics of asthma was administered. It included a global single rating of asthma-related discomfort (0: none, 1: very mild, 2: mild, 3: moderate, 4: severe, and 5: maximal), medications, triggering factors, time of asthma diagnosis, hospitalizations or emergency room visits in the previous year and

196

smoking habits. Pulmonary function tests and skin prick tests were also performed.11 Peak expiratory flows were recorded twice daily in morning and evening over a period of 2 weeks. On the second visit, a methacholine challenge was performed in patients with complete reversibility of airflow obstruction only. It was not possible to do this test on the asthmatic patients with incomplete reversibility of airflow obstruction because most of them had an FEV1 ⬍60% of predicted and/or had been unable to stop their medication before the test. Sixteen patients with incomplete reversibility of airflow obstruction (nine men and seven women) agreed to have a highresolution chest tomography to measure bronchial wall-thickness (right intermediary bronchus) and look for possible parenchymal or bronchial abnormalities. To avoid unnecessary radiation exposure to the matched group with complete reversibility of airflow obstruction, and since high resolution chest tomography results were already available from a previous study including patients with complete reversibility of airflow obstruction, we used these results for comparison with data from patients with incomplete reversibility of airflow obstruction.12 These patients with complete reversibility of airflow

obstruction had the following characteristics: five women and five men, mean age: 36 ⫾ 5 years, asthma duration: 13 ⫾ 3 years, atopy (as defined below): 7, ex-smokers: 3 (ⱕ6 packyears, the others being nonsmokers), baseline FEV1: 2.9 L (85 ⫾ 3% of predicted) and geometric mean provocative concentration of methacholine causing a 20% fall in FEV1 (PC20): 1.5 mg/mL. All were using a ␤2-agonist on a prn basis; 7 patients also required beclomethasone at a mean daily dose of 857 ⫾ 92 ␮g to control asthma symptoms. Pulmonary Function Tests Three reproducible measurements of FEV1 and forced vital capacity (FVC) were obtained before and after inhalation of 200 ␮g salbutamol with a Vitalograph spirometer. Whole body plethysmography was used to obtain measurements of pulmonary volumes, airway resistance (Raw), specific conductance (SGaw), and lung compliance according to standard procedures.13,14 Carbon monoxide diffusion (DLCO) was measured by the single breath method.15 All patients recorded on a diary card the results of three reproducible peak expiratory flow rate (PEF) measurements taken with a mini-Wright peak flow meter in the morning, at noon, before dinner, and in

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

the evening for a 2-week period. Methacholine challenges were performed according to the method described by Juniper et al.16 The results were expressed as PC20. Allergy Skin Tests Skin prick tests were performed with a battery of common inhalants. Atopic status was defined as the presence of at least one positive reaction (wheal diameter ⱖ3 mm) ten minutes after testing. The atopic index, corresponding to the number of positive responses to skin prick tests (wheal diameter ⱖ3 mm), was calculated for each subject. High-Resolution Chest Tomography High resolution chest tomography was performed using a fourth generation TCT 900 S of Toshiba (Japan) with high-resolution technique according to Mayo et al.17 Non-angulated 2-mm thick slices at 10-mm increments were obtained through the lungs without contrast injection. A section was also obtained with reconstruction centered on the right intermediary bronchus. The matrix size was 512 ⫻ 512 at a pixel size of 0.6 mm. Scanning time was 1 second. Measurements were made in a blinded fashion at the end of inspiration in the supine position. Images were recorded at a window width of 1,600 Hounsfield units and a window level of -600 Hounsfield units. The scans were interpreted without knowledge of their origin (complete or incomplete reversibility of airflow obstruction) and after agreement by two radiologists. The description of bronchiectasis and mucoid impactions was based on the criteria established for high resolution chest tomography by Naidich and coworkers18 and Grenier and colleagues.19 Emphysematous changes were characterized according to the criteria of Foster et al20, and atelectasis and acinar pattern according to those of Naidich et al.21 Bronchial wall thickening was defined according to the criteria described by Naidich et al.21 and Zerhouni.22 Bronchial diameter and wall thickness were calculated at the level of the right intermediary

VOLUME 78, FEBRUARY, 1997

bronchus as follows: internal diameter was the smallest internal diameter measured; wall thickness was not measured in the same axis as adjacent internal bronchial diameter. All measurements were done with the help of an electronic caliper. The total bronchial diameter is the sum of the internal diameter and 2 times the wall thickness, which corresponds to the external diameter. Comparisons between groups are made using the ratio of wall thickness/total bronchial diameter. Analysis Results are expressed as means ⫾ SEM and the significance level is established at P ⬍ .05. Sign tests were used to compare expiratory flows, bronchodilator response, lung volumes, DLCO, lung compliance, Raw, sGaw, mean diurnal variation of PEF, emergency room visits, hospitalizations, and global discomfort related to asthma in patients with incomplete and complete reversibility of airflow obstruction. Paired t test was used to compare the duration of asthma between the two groups. PC20 was measured from individual dose-response curves and geometric mean was used for the group with complete reversibility of airflow obstruction. Spearman’s rank correlation test was used to evaluate possible correlations between baseline pre-bronchodilator FEV1, duration of asthma, and bronchial wallthickening measured on high resolution chest tomography. Unpaired t test on transformed values (rank value) was used to compare bronchial wall thickness of both patients with incomplete and complete reversibility of airflow obstruction. RESULTS Patients’ Characteristics Duration of asthma ranged from 11 to 49 years (mean: 32 ⫾ 3) for patients with incomplete reversibility of airflow obstruction and 2 to 53 years (mean: 18 ⫾ 3) for the group with complete reversibility of airflow obstruction (P ⫽ .008, Table 1). Only five patients with incomplete revers-

ibility of airflow obstruction had previously smoked, four having smoked 6 pack-years and one patient 3 packyears. There were four ex-smokers among the asthmatic group with complete reversibility of airflow obstruction: two patients had smoked 2 packyears and the two others, 3 and 6 pack-years respectively. All patients with incomplete reversibility of airflow obstruction used ␤2agonists and high doses of inhaled corticosteroids (average daily dose of corticosteroid, either beclothasone or budesonide: 1792 ⫾ 172 ␮g, mean duration of inhaled corticosteroid therapy: 2.3 ⫾ 0.5 years). Nine patients were also on theophylline and five on oral prednisone (mean dose: 10.5 ⫾ 2.5 mg/day, mean duration of oral corticosteroid therapy: 9.6 ⫾ 1.6 years; another patient had taken oral corticosteroid for 18 years and had stopped 1 year ago). In the group with complete reversibility of airflow obstruction, 16 patients used a ␤2-agonist on demand and inhaled corticosteroids regularly (mean daily dose equivalent to 808 ⫾ 93 ␮g of beclomethasone, P ⬍ .0001; mean duration of inhaled corticosteroid therapy: 3.5 ⫾ 1.1 years); the two other patients requiring only a ␤2-agonist on a prn basis. Emergency Room Visits, Hospitalizations, and Global Discomfort Related to Asthma One patient with incomplete reversibility of airflow obstruction had made three visits to the Emergency Room in the previous year, another patient had made two, and two patients had each made one. On the other hand, one patient with complete reversibility of airflow obstruction had made two Emergency Room visits in the previous year, and four had made one (P ⬎ .05). Three patients with incomplete and two with complete reversibility of airflow obstruction had had one hospitalization in the previous year. The global discomfort related to asthma was considered more severe in patients with incomplete reversibility of airflow obstruction (mean: 2.33 ⫾ 0.27) than in those with complete reversibility of

197

airflow obstruction (mean: 1.06 ⫾ 0.24) (P ⫽ .02). Allergy Skin Prick Tests Seventeen patients with incomplete reversibility of airflow obstruction and 12 with complete reversibility of airflow obstruction were atopic. The atopic index was higher in the patients with incomplete reversibility of airflow obstruction (9.7 ⫾ 2.0) than in those with complete reversibility of airflow obstruction (5.6 ⫾ 1.6) although this did not reach statistical significance (P ⬎ .05). Sixteen patients with incomplete reversibility of airflow obstruction (89%) and 12 with complete reversibility of airflow obstruction (67%) were sensitized to indoor allergens, while 12 subjects with incomplete and seven with complete reversibility of airflow obstruction were sensitized to pollen. Fourteen patients with incomplete reversibility of airflow obstruction and ten with complete reversibility of airflow obstruction were sensitized to housedust and/or housedust mite. Seven of 18 patients with incomplete reversibility of airflow obstruction had a positive early response to skin prick test to Aspergillus (none in the group with com-

plete reversibility of airflow obstruction), although these subjects had no past history of allergic bronchopulmonary aspergillosis. Expiratory Flows Baseline FEV1 and FVC were lower in patients with incomplete reversibility of airflow obstruction (FEV1 32% to 63% of predicted value, mean: 48.6 ⫾ 2.6%, and FVC 49% to 98%, mean: 70.9 ⫾ 3.1%) than in patients with complete reversibility of airflow obstruction (FEV1 71% to 123%, mean 89.3 ⫾ 3.4%, P ⬍ .0001, FVC 73% to 123%, mean: 97.7 ⫾ 3.3%, P ⫽ .001, Fig 1). Mean FEV1/FVC ratio was lower in the group with incomplete (51.6 ⫾ 1.9) than in the group with complete reversibility of airflow obstruction (70.1 ⫾ 1.7, P ⬍ .0001). The slow vital capacity to forced vital capacity ratio was 1.14 ⫾ 0.04 in the group with incomplete reversibility of airflow obstruction and 1.06 ⫾ 0.02 in the group with complete reversibility of airflow obstruction (P ⫽ .031). Postbronchodilator percentage change in FEV1 from baseline was significantly greater in patients with incomplete than in those with complete reversibility of airflow obstruction:

Figure 1. Baseline FEV1, FVC, TLC, FRC, RV, and DLCO expressed in % of predicted values for patients with incomplete reversibility of airflow obstruction (closed circles, n ⫽ 18) and complete reversibility of airflow obstruction (open circles, n ⫽ 18). Horizontal bar represents mean.

198

24.2 ⫾ 2.5 (n ⫽ 18) and 13.6 ⫾ 2.6 (n ⫽ 17), respectively (P ⫽ .002, Fig 2). When expressed in absolute values, however, response to bronchodilator was not significantly different (incomplete: 363 mL and complete reversibility of airflow obstruction: 399 mL). Methacholine Inhalation Test in Patients with Complete Reversibility of Airflow Obstruction Geometric mean PC20 in patients with complete reversibility of airflow obstruction was 1.12 mg/mL, indicating a mild to moderate airway hyperresponsiveness. Lung Volumes, CO Diffusion, and Airway Resistance Residual volume (RV) was higher in the group with incomplete reversibility of airflow obstruction (136% to 291% of predicted, mean: 209.4 ⫾ 9.1%) than in the group with complete reversibility of airflow obstruction (106% to 209%, mean: 162.8 ⫾ 7.4%; P ⫽ .001, Fig 1). All patients with incomplete reversibility of airflow obstruction and 16 of 18 with complete reversibility of airflow obstruction had an RV ⱖ120% of predicted value. Compared with the predicted values, functional residual capacity (FRC) was slightly increased in both patients with incomplete reversibility (95% to 196% of predicted, mean: 144.3 ⫾ 6.5%) and subjects with complete reversibility of airflow obstruction (86% to 247%, mean: 133.1 ⫾ 8.2%), P ⫽ .03. Total lung capacity (TLC) was similar in the two groups (incomplete reversibility of airflow obstruction: 88% to 148% of predicted, mean: 116.7 ⫾ 3.6%, and complete reversibility of airflow obstruction: 92% to 138%, mean: 119.8 ⫾ 2.7%; P ⬍ .05). Mean baseline DLCO was normal in both groups: 93.1 ⫾ 5.1 of predicted in the group with incomplete reversibility of airflow obstruction and 97.5 ⫾ 4.6 in the group with complete reversibility of airflow obstruction (P ⬎ .05). Four patients with incomplete and three with complete reversibility of airflow obstruction had DLCO ⬍80% of predicted values. In the groups with in-

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

Figure 2. Baseline and postbronchodilator (200 ␮g inhaled albuterol) FEV1 expressed in % of predicted values, for patients with incomplete reversibility of airflow obstruction (IRAO, closed circles, n ⫽ 18) and complete reversibility of airflow obstruction (CRAO, open circles, n ⫽ 17). Bronchodilator response varied from 10% to 50% (mean: 24.2%) in patients with IRAO and from ⫺3% to 37% (mean: 13.6%, P ⫽ .002) in patients with complete reversibility of airflow obstruction. When expressed in absolute value, response to bronchodilator was not significantly different (incomplete: 363 mL and complete reversibility of airflow obstruction: 399 mL).

complete and complete reversibility of airflow obstruction, mean lung compliance (L/cm H2O), baseline Raw (L/s ⫻ cm H2O), and sGaw (s ⫻ cm H2O) were 0.174 ⫾ 0.017 (n ⫽ 16) and 0.207 ⫾ 0.016 (n ⫽ 17) (P ⬎ .05), 4.45 ⫾ 0.26 and 3.18 ⫾ 0.25 (P ⫽ .008), 0.073 ⫾ 0.020 and 0.126 ⫾ 0.045 (P ⫽ .05), respectively. Circadian Changes in PEF Eleven patients with incomplete reversibility of airflow obstruction and four with complete reversibility of airflow obstruction had a mean daily change in PEF ⬎10% during the 2-week study period (mean ⌬PEF). Diurnal variations were more marked in the group with incomplete reversibility of airflow obstruction (3.1% to 36.2%, mean: 13.7 ⫾ 2.2%) than in the group with complete reversibility of airflow obstruction (1.9 to 20.6%, mean: 8.2 ⫾ 1.1%; (P ⫽ .04). Maximal ⌬PEF (maximal daily change in % PEF during that period) were similar in the two groups. In the “incomplete” group: 10.8% to 60.0% (mean: 25.0 ⫾ 2.9%)

VOLUME 78, FEBRUARY, 1997

and in the complete reversibility of airflow obstruction group: 5.0% to 34.8% (mean: 17.3 ⫾ 1.9%); (P ⬎ .05). Fourteen asthmatic patients with incomplete reversibility of airflow obstruction and ten with complete reversibility of airflow obstruction had a maximal ⌬PEF ⬎15%. When the absolute change in PEF was considered, however, the mean and maximum daily changes (in mL) were 41.1 ⫾ 6.5 and 75.6 ⫾ 7.9 in the group with incomplete reversibility of airflow obstruction and 37.6 ⫾ 4.8 and 81.1 ⫾ 8.8 in the group with complete reversibility of airflow obstruction. Also, there were no significant differences in absolute value between the two groups in the mean or maximum daily change in PEF (P ⬎ .05). High Resolution Chest Tomography Abnormalities Of the 16 patients with incomplete reversibility of airflow obstruction who had high resolution chest tomography, three (18.8%) had a normal tomography, seven (43.8%) had bronchial wall

thickening, six (37.5%) discrete bronchial dilatations mainly at upper lobes, four (25.0%) an acinar pattern, three (18.8%) mild focal peripheral air space widening, and three bronchial narrowing (18.8%). Results of bronchial wall thickness measurements showed that right intermediary bronchus wall thickness/bronchial diameter ratio was thicker in the group with incomplete reversibility of airflow obstruction (0.13 to 0.21, mean: 0.18 ⫾ 0.01; n ⫽ 16) than in the previously studied group with complete reversibility of airflow obstruction (0.12 to 0.24, mean: 0.16 ⫾ 0.01; n ⫽ 10), (P ⫽ .008, Fig 3). Mean wall thickness was 2.40 ⫾ 0.08 mm in the group with incomplete reversibility of airflow obstruction and 2.02 ⫾ 0.16 mm in the group with complete reversibility of airflow obstruction (P ⫽ .047). The width of the internal diameter (lumen of the bronchus) was similar in both groups with respective values of 8.91 ⫾ 0.32 mm and 9.00 ⫾ 0.56 mm).

Figure 3. Wall thickness/external diameter ratio of the right intermediary bronchus, measured on high resolution chest tomography for asthmatic patients with incomplete reversibility of airflow obstruction (IRAO, n ⫽ 16) in comparison to a group of previously studied patients (11) with complete reversibility of airflow obstruction (CRAO, n ⫽ 10, P ⫽ .008). Horizontal bar represents mean.

199

Correlations Between the Analyzed Parameters There was a significant negative correlation between the duration of asthma and baseline FEV1 (r ⫽ ⫺0.42, P ⫽ .01, Fig 4). There was no significant correlation between duration of asthma and bronchial wall thickness measured with high resolution chest tomography (r ⫽ 0.35, P ⬎ .05) nor between bronchial wall thickness and baseline FEV1 (r ⫽ 0.1, P ⬎ .05). DISCUSSION This study explored the pathophysiology and the consequences of asthma with an irreversible component of airflow obstruction. We looked at clinical, physiologic, and radiologic features of 18 asthmatic patients with incomplete reversibility of airflow obstruction in comparison to asthmatic patients with complete reversibility of airflow obstruction. We found that incomplete reversibility of airflow obstruction was associated with a long asthma duration and frequent abnormalities on high resolution chest tomography, mainly increased airway wall thickness. Although they had no significant increase in overall healthcare use, patients with incomplete reversibility of airflow obstruction required more medication and had

greater daily PEF fluctuations and global asthma-related discomfort. Some of these observations may suggest that asthma with incomplete reversibility of airflow obstruction is associated with airway structural changes following long-term and/or intense airway inflammation. All but one of the patients with incomplete reversibility of airflow obstruction were sensitized to common allergens compared with two-thirds of the patients with complete reversibility of airflow obstruction. The chronic exposure to a sensitizing substance may possibly have maintained the airway inflammation and induced structural airway changes. Although these physiologic features could also be due to some degree of airway wall edema or other nonstructural changes; this should be further documented. Seven of 18 patients with incomplete reversibility of airflow obstruction had positive early responses to skin prick testing while none of the group with complete reversibility of airflow obstruction had such positivity. These subjects with incomplete reversibility of airflow obstruction had no documented past history of allergic bronchopulmonary aspergillosis, but we should wonder whether sensitization to Aspergillus could have played a role in structural airway changes, which

Figure 4. Correlation (r ⫽ ⫺0.42, P ⫽ .01) between duration of asthma and baseline FEV1 for all patients with either incomplete reversibility of airflow obstruction (closed circles, n ⫽ 18) or complete reversibility of airflow obstruction (open circles, n ⫽ 18).

200

caused a persistent and prolonged airway inflammatory reaction. Changes in airway wall thickness can possibly occur during an asthma exacerbation but our patients had stable asthma with no change in symptoms or medication for at least 1 month. In asthmatic patients, incomplete reversibility of airflow obstruction may be due to current insufficient treatment and unstable asthma or may be associated with chronic obstructive pulmonary disease or other respiratory diseases. This was not, however, the case for our patients. All were considered to be receiving optimal corticosteroid treatment and still had incomplete reversibility of airflow obstruction on what was considered the best asthma control possible. All of them had classic histories of asthma with intermittent wheezing and dyspnea going back, with only one exception, at least 15 years, and in many cases, to childhood. None had a significant smoking history and apart from asthma had no history of chronic pulmonary obstructive disease, cystic fibrosis, allergic bronchopulmonary aspergillosis, bronchiolitis, or other respiratory problem at the time of the study. Their FEV1 had been lower than 75% of predicted value for at least 2 years (in most of them at least 5 years) despite intense corticosteroid treatment, high-dose inhaled corticosteroids (in 18), and oral corticosteroids (in 16). They had neither a significant reduction in CO diffusion nor changes in lung compliance. Although we cannot exclude entirely another associated etiology to explain the component of incomplete reversibility of airflow obstruction, the absence of clinical or radiologic features suggesting such disease and the long follow-up makes this possibility unlikely. High resolution chest tomography abnormalities such as bronchial dilatations and peripheral air space widening were mild, focal, not typical of chronic obstructive pulmonary disease or other respiratory diseases and were probably due to asthma, as suggested by the studies of Paganin et al.23,24 These authors previously reported high resolu-

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

tion chest tomography evaluations in 57 patients with asthma of variable severity and showed bronchial and/or parenchymal abnormalities in 71.9% of patients. In our study, 81.3% of the patients with incomplete reversibility of airflow obstruction had pulmonary abnormalities on high resolution chest tomography. On global high resolution chest tomography analysis, we found a prevalence of peripheral air space widening (18.8%) similar to that found in the study by Paganin et al (17.5%). In contrast, when compared with patients of Paganin and with our previously reported control group of patients with complete reversibility of airflow obstruction, our asthmatic patients with incomplete reversibility of airflow obstruction showed more frequent bronchial wall-thickening.11 This finding is somewhat different from some of our previous observations, where we found no significant difference in airway wall thickness between asthmatic patients with or without irreversible component of airflow obstruction.11 This is probably explained by the facts that in the previous study, the number of patients was smaller13 and more importantly that they had less severe airflow obstruction (mean FEV1: 60.3% ⫾ 2.01 compared with 48.6% ⫾ 2.6 in the present study). We do not know why some asthmatic patients have incomplete reversibility of airflow obstruction while others continue to show complete reversibility of airflow obstruction even after many years. We and others found a significant although weak correlation between the duration of asthma and baseline airway caliber suggesting that the chronicity of asthma may be one of the determinants of bronchial structural changes that cause incomplete reversibility of airflow obstruction.3 Previous severity of the asthmatic inflammatory process may also play a significant role in the appearance of incomplete reversibility of airflow obstruction. Until recently, asthma treatment was mostly based on symptom control with bronchodilators and uncontrolled underlying airway in-

VOLUME 78, FEBRUARY, 1997

flammation may have contributed to airway structural changes. In conclusion, since incomplete reversibility of airflow obstruction develops mainly in patients with prolonged asthma of allergic origin, it is possible that a chronic allergen-induced airway inflammatory process induces persistent bronchial structural changes leading to incomplete reversibility of airflow obstruction. This supports the concept that environmental control and early anti-inflammatory treatment could possibly prevent irreversible change or at least prevent progressive permanent structural alterations that could further impede airway function. ACKNOWLEDGMENTS We are grateful to Serge Simard for his help with the statistical analysis and to Lori Schubert for reviewing the manuscript. REFERENCES 1. McFadden Jr ER, Gilbert IA. Asthma. N Engl J Med 1993;327:1928 –37. 2. Lacronique J. Asthme avec trouble ventilatoire obstructif permanent. Rev Prat 1992;42:2425–9. 3. Brown PJ, Greville HW, Finucane KE. Asthma and irreversible airflow obstruction. Thorax 1984;39:131– 6. 4. Finucane KE, Greville HW, Brown PJE. Irrreversible airflow obstruction; evolution in asthma. Med J Aust 1985; 142:602– 4. 5. Nelson HS. The natural history of asthma. Ann Allergy 1991;66: 196 –203. 6. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in patients with asthma. Eur J Respir Dis 1987; 70:171–9. 7. Wilson JW, Li X, Pain MCF. The lack of distensibility of asthmatic airways. Am Rev Respir Dis 1993;148: 806 –911. 8. Bousquet J, Chanez P, Godard P, Michel FB. Is asthma a disease that remodels the airways? All Clin Immunol News, Jan/Feb 1993;5:5– 8. 9. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary

10.

11.

12.

13.

14.

15.

16.

17.

18.

19. 20.

21.

disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225– 44. Gautrin D, Boulet LP, Boutet M, et al. Is reactive airway dysfunction syndrome (RADS) a variant of occupational asthma? J Allergy Clin Immunol 1993;1:12–22. Boulet LP, Turcotte H, Boutet M, et al. Influence of natural antigenic exposure on expiratory flows, methacholine responsiveness and airway inflammation in mild allergic asthma. J Allergy Clin Immunol 1993;91:883–93. Boulet LP, Be´langer M, Carrier G. Airway responsiveness and bronchialwall thickness in asthma with or without fixed airflow obstruction. Am J Respir Crit Care Med 1995;152: 865–71. Dubois AB, Botelho SY, Bedell GN, et al. A rapid plethysmographic method for measuring thoracic gas volume; a comparison with nitrogen washout method for measuring functional residual capacity. J Clin Invest 1956;35: 322– 6. Dawson A. Elastic recoil and compliance. In: Pulmonary function testing: guidelines and controversies. Clausen JL, ed, Toronto: Academic Press 1982: 193–204. Ayers LN. Carbon monoxide diffusing capacity. In: Pulmonary function testing: indications and interpretations. Wilson AF. ed, Orlando: Grune Straton; 1985:137–51. Juniper E, Cockcroft DW, Hargreave FE. Histamine and methacholine inhalation tests: tidal breathing method. Laboratory procedure and standardization. Canadian Thoracic Society, Lund, Sweden: AB Draco, 1991:24 – 6. Mayo JR, Webb WR, Gould R, et al. High resolution CT of the lungs: an optimal approach. Radiology 1987; 163:507–10. Naidich DP, McCauley DI, Khouri NF, et al. Computed tomography of bronchiectasis. J Comput Assist Tomogr 1982;6:437– 44. Grenier P, Maurice F, Musset D, et al. Bronchiectasis: assessment by thinsection CT. Radiology 1986;161:95–9. Foster WL, Pratt P, Roggli V, et al. Centrilobular emphysema/CT-pathologic correlation. Radiology 1986;159: 27–32. Naidich DP, Zerhouni EA, Siegelman SS. Computed tomography of the thorax. New-York: Raven Press, 1984: 123–34, 207– 40.

201

22. Zerhouni EA. Se´miologie tomodensitome´trique pulmonaire. In: Grenier P, ed. Imagerie thoracique de l’adulte. Paris: Flammarion, 1988;197–204. 23. Paganin F, Trussard V, Seneterre E, et al. Chest radiography and high resolution computed tomography of the

202

lungs in asthma. Am Rev Respir Dis 1992;146:1084 –7. 24. Paganin F, Seneterre E, Chanez, et al. Computed tomography of the lungs in asthma: influence of disease severity and etiology. Am J Resp Crit Care Med 1996;153:110 – 4.

Request for reprints should be addressed to: Dr Louis-Philippe Boulet Hoˆpital Laval 2725 Chemin Sainte-Foy Sainte-Foy, Quebec Canada GIV 4G5

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY