Abstract
Excessive airway narrowing is a cardinal feature of asthma, and results in closure of airways. Therefore, asthmatic patients in whom airway closure occurs relatively early during expiration might be prone to severe asthma attacks. To test this hypothesis, we compared closing volume (CV) and closing capacity (CC) in a group of asthmatic patients with recurrent exacerbations (more than two exacerbations in the previous year; difficult-to-control asthma), consisting of 11 males and two females, aged 20 to 51 yr, with those in a group of equally severely asthmatic controls without recurrent exacerbations (stable asthma) consisting of 13 males and two females aged 18 to 52 yr. Both groups used equivalent doses of inhaled corticosteroids and were matched for sex, age, atopy, postbronchodilator FEV1, and provocative concentration of methacholine causing a 20% decrease in FEV1. They were studied during a clinically stable period of their disease. The patients inhaled 400 μ g salbutamol via a spacer device, after which TLC and RV were measured by multibreath helium equilibration, together with the slope of Phase 3 (dN2), CV, and CC, by single-breath nitrogen washout. CV and CC were expressed as ratios of VC and TLC, respectively, and all data are presented as % predicted (mean ± SEM). There was no difference in TLC in patients with difficult-to-control asthma and those with stable asthma (106.7 ± 4.0% predicted versus 101.7 ± 4.3% predicted, p = 0.40), RV (113.1 ± 7.8% predicted versus 100.9 ± 7.1% predicted, p = 0.26), or dN2 (142.7 ± 16.3% predicted versus 116.0 ± 20.2% predicted, p = 0.23). In contrast, CV and CC were increased in the patients with difficult-to-control asthma as compared with the group with stable asthma (CV: 159.5 ± 26.8% predicted versus 98.8 ± 12.5% predicted, p = 0.024; CC: 114.0 ± 6.4% predicted versus 99.9 ± 3.6% predicted, p = 0.030). These findings show that asthmatic individuals with recurrent exacerbations have increased CV and CC as compared with equally severely asthmatic but stable controls, even after bronchodilation during well-controlled episodes. The findings imply that airway closure at relatively high lung volumes under clinically stable conditions might be a risk factor for severe exacerbations in asthmatic patients.
Excessive airway narrowing is a cardinal feature of bronchial asthma, and is considered to be the most important pathophysiologic determinant in fatal asthma (1, 2). It is supposed to be associated with mucosal infiltration of inflammatory cells, airway-wall submucosal thickening, and smooth-muscle hypertrophy in both large and small airways, as observed in patients dying from asthma (3-5).
Similar histopathologic and morphologic abnormalities can be demonstrated, although they are less prominent, in the peripheral airways of patients with moderate asthma (4-9). These structural changes are likely to have functional consequences, such as the absence of a plateau on the dose– response curve for inhaled methacholine or histamine, reflecting a predisposition to excessive airway narrowing (10, 11).
Small-airway pathology is likely to induce airway closure (5, 10-13), potentially giving rise to air trapping during exacerbations of asthma (11, 14, 15). Hence, early airway closure seems to be a key factor in the pathogenesis of fatal asthma.
We hypothesized that airway closure occurring at high lung volumes (e.g., relatively early during expiration) during clinically stable episodes of asthma might predispose to severe asthma attacks. To test this hypothesis, we compared the occurrence of early airway closure in patients with severe asthma with recurrent exacerbations and patients with severe but stable asthma, by assessing the closing capacity (CC) and closing volume (CV) in these two groups of patients.
Two groups of patients with severe bronchial asthma participated in the study. The first group, with severe asthma (difficult-to-control asthma), consisted of 13 patients (11 males and two females, aged 20 to 51 yr), who during the preceding 12 mo had had recurrent (two or more) exacerbations requiring a course of oral corticosteroids for at least 7 d despite regular high-dose inhaled corticosteroid maintenance therapy (beclomethasone dipropionate [BDP]/budesonide [BUD] 800 μg twice daily or fluticasone propionate [FP] 500 μg twice daily). The group of asthmatic subjects without recurrent exacerbations (stable asthma) consisted of 15 control patients (13 males and two females, aged 18 to 52 yr), of whom 13 were individually matched with subjects with severe asthma and using equivalently high doses of inhaled corticosteroid therapy, and were also without a history of exacerbations during the previous year.
Classification of asthma severity was based on history, symptoms, clinical features, and medication requirement according to international guidelines (16). FEV1 in both subject groups was within the normal range (> 70 % predicted) (17) after inhalation of 400 μg salbutamol per metered dose inhaler (MDI) connected to an aerosol chamber. All patients were hyperresponsive to inhaled methacholine (MCh), as shown by a provocative concentration causing a 20% decrease in FEV1 (PC20 MCh) of less than 8 mg/ml (18). Atopic status was assessed by specific IgE titers in response to a panel of common aeroallergens (Phadiatop; Pharmacia, Woerden, The Netherlands).
The thirteen pairs of patients were individually matched for age (within 10 yr), postbronchodilator FEV1 (70 to 85% predicted or ⩾ 85% predicted), and PC20 MCh (within two doubling doses), and for at least one of the following two criteria: sex and atopic status (atopy or no atopy). In addition, two more patients with stable severe asthma but who could not be individually matched were included in the study. Patient characteristics are summarized in Table 1.
| Difficult-to-Control Asthma | Stable Asthma | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient | Age (yr) | Sex | Atopy | FEV1(% pred ) | PC20 MCh (mg/ml ) | Patient | Age (yr) | Sex | Atopy | FEV1(% pred ) | PC20 MCh (mg/ml ) | |||||||||||
| 1 | 45 | F | Yes | 93.1 | 4.6 | 1 | 52 | F | No | 113 | 5.802 | |||||||||||
| 2 | 24 | F | Yes | 104.4 | 0.158 | 2 | 25 | F | Yes | 91.1 | 0.403 | |||||||||||
| 3 | 29 | M | Yes | 71.9 | 0.216 | 3 | 36 | M | Yes | 83.6 | 0.110 | |||||||||||
| 4 | 51 | F | Yes | 118.9 | 0.273 | 4 | 45 | F | No | 108.1 | 0.405 | |||||||||||
| 5 | 26 | F | No | 123.5 | 0.391 | 5 | 18 | F | Yes | 107.1 | 1.137 | |||||||||||
| 6 | 47 | M | Yes | 73.5 | 0.238 | 6 | 39 | F | Yes | 79.5 | 0.842 | |||||||||||
| 7 | 20 | F | Yes | 80 | 0.782 | 7 | 20 | F | Yes | 77.7 | 0.228 | |||||||||||
| 8 | 25 | F | Yes | 118.8 | 0.037 | 8 | 19 | F | Yes | 105.4 | 0.042 | |||||||||||
| 9 | 32 | F | Yes | 89.3 | 0.066 | 9 | 23 | F | Yes | 103.6 | 0.044 | |||||||||||
| 10 | 26 | F | Yes | 85.9 | 2.821 | 10 | 18 | M | Yes | 118 | 1.360 | |||||||||||
| 11 | 23 | F | Yes | 71.7 | 0.136 | 11 | 26 | F | Yes | 71.7 | 0.062 | |||||||||||
| 12 | 25 | F | Yes | 91.6 | 0.431 | 12 | 25 | F | Yes | 98.9 | 1.154 | |||||||||||
| 13 | 32 | F | Yes | 90.8 | 0.555 | 13 | 33 | F | Yes | 107.1 | 1.218 | |||||||||||
| 14 | 51 | F | Yes | 91.8 | 0.636 | |||||||||||||||||
| 15 | 26 | F | Yes | 100.5 | 0.263 | |||||||||||||||||
| Mean | 31.2 | 93.3 | 0.320 | 30.1 | 97.1 | 0.392 | ||||||||||||||||
| SEM | 2.8 | 5.0 | 0.55 | 3.0 | 3.6 | 0.52 | ||||||||||||||||
None of the patients had a history of other respiratory disease than asthma, nor did they use any other pulmonary medications than inhaled corticosteroids and short-acting β2-agonists or ipratropium bromide on demand for their asthma during the study. All patients were nonsmokers or ex-smokers (for more than 12 mo, with a smoking history of less than 5 pack-years). The patients were matched and included during a clinically stable period of their disease, and had not had symptoms of a respiratory tract infection for at least 4 wk before the study. The study was approved by the Hospital Medical Ethics Committee of the Leiden University Medical Center, and informed consent was given by all patients.
Inclusion criteria were checked and matching was completed during two screening visits. Long-acting β2-agonists and theophylline preparations, if used, were discontinued at least 72 h before the first screening visit. On the first visit, pre- and postbronchodilator FEV1 was measured and on the second visit a MCh challenge test was performed. The inhaled corticosteroid medication of all patients was changed to FP 500 μg twice daily (Rotadisk; Glaxo Welcome bv., Zeist, The Netherlands) for at least 4 wk in order to standardize antiinflammatory therapy. Before the subsequent third visit, the patients kept a diary to record morning and evening peak expiratory flow (PEF) measurements, in order to ascertain clinical stability of their disease. Mean diurnal peak flow (PEF) variation during the last week before the study began had to be less than 15% (16). At the third visit, medication compliance was confirmed by counting the FP blisters used by each patient. Thereafter the patients inhaled salbutamol 400 μg per MDI connected to a spacer device at least 20 min before multibreath helium equilibration and subsequent single-breath nitrogen (N2) tests were performed.
Patients were instructed to make morning and evening PEF measurements at home, using a Mini-Wright peakflow meter (Clement Clarke, Ltd., UK) before taking bronchodilator medication (16). PEF was measured three times in the upright position, and the best value was recorded. Spirometry was performed in the laboratory to measure the slow inspiratory VC and postbronchodilator FEV1 with a dry rolling-seal spirometer (Morgan Spiroflow, Kent, UK) (17).
Airway hyperresponsiveness to MCh was assessed through Cockcroft's tidal breathing method (18). In short, MCh aerosols were inhaled in doubling concentrations (0.015 to 8 mg/ml) by tidal breathing for 2 min at 5-min intervals. The challenge test was discontinued if FEV1 dropped 20% or more from baseline. The PC20 MCh was calculated by linear interpolation of the log dose–response curves (18).
TLC, FRC, and RV were assessed with a standardized multibreath helium equilibration test (Masterscreen FRC; Jaeger, Breda, The Netherlands) (17). The nitrogen single-breath test was done with a dry rolling-seal spirometer (Morgan Spiroflow) filled with 100% oxygen and equipped with an N2 meter (Morgan) connected to the mouthpiece, allowing continuous sampling as described previously (19, 20). During this test, patients performed a slow, full inspiratory and expiratory VC maneuver at inspiratory and expiratory flow rates of approximately 0.5 L/s. The expiratory N2 concentration was plotted against volume changes between TLC and RV, and the slope (dN2) of the N2 alveolar plateau was calculated by having a blinded observer draw the best-fit line through Phase 3 of the expiratory volume–concentration curve (20). The first departure from this straight line was considered as indicative of airway closure, and CV (Phase 4) and CC = RV+CV) were calculated (19). This procedure has previously been validated in our laboratory (20). The measurements were accepted only if the VC during the single-breath N2 test was within 10% of the VC measured at spirometry. All volumes were corrected for body temperature–pressure–saturation with water vapor (btps).
CV and CC were expressed as ratios to VC (CV/VC) and TLC (CC/ TLC), respectively (19, 20). Unless otherwise stated, data are expressed as mean ± SEM. Differences and correlations were assessed with parametric and nonparametric tests, as appropriate. Differences were considered to be statistically significant at a value of p < 0.05. Sample size estimations made with published data (21) showed that 13 patients in each group would allow the statistical power to detect a difference between the groups of at least 25% in CV/VC and 6% in CC/TLC, respectively (two-sided α = 0.05, one-sided β = 0.80).
Patient characteristics are summarized in Table 1. Sex and atopy were equally distributed in the two groups. As expected, there were no significant differences in age (p = 0.81), postbronchodilator FEV1 (p = 0.53), or PC20 MCh (p = 0.70) in patients with difficult-to-control and those with stable asthma. In addition, duration of asthma did not differ between the group with difficult-to-control asthma (18.7 yr [range: 3 to 50 yr]) and the group with stable asthma (18.4 yr [range: 3 to 38 yr]), (p = 0.95). There was no significant difference in FEV1 or PC20 MCh at study entry and after 4 wk of FP treatment.
The mean diurnal PEF variation during the week preceding the measurements of lung volumes did not differ in the patients with difficult-to-control asthma (5.2 % ± 0.26%) and those with stable asthma (3.6 ± 0.16%) (p = 0.25).
VC, FRC, RV, and RV/TLC also did not differ significantly in the two groups (Table 2, Figure 1). However, both CV/VC and CC/TLC were significantly increased in the group with difficult-to-control asthma as compared with the group with stable asthma, by an average of 62 % (p = 0.024) and 14 % (p = 0.030), respectively (Table 2, Figure 1). These results are consistent with data obtained when paired statistical analyses were done on data from the 13 individually matched pairs of patients.
| Parameter (% pred ) | Difficult-to-control Asthma | Stable Asthma | p Value | |||
|---|---|---|---|---|---|---|
| FEV1 | 89.0 ± 4.6 | 92.9 ± 4.3 | 0.54 | |||
| TLC | 106.7 ± 4.0 | 101.7 ± 4.3 | 0.40 | |||
| FRC | 98.6 ± 6.6 | 98.7 ± 4.5 | 0.99 | |||
| RV | 113.1 ± 7.8 | 100.9 ± 7.1 | 0.26 | |||
| RV/TLC | 103.5 ± 4.7 | 95.8 ± 3.8 | 0.21 | |||
| dN2 | 142.7 ± 16.3 | 116.0 ± 20.2 | 0.23 | |||
| CV/VC | 159.5 ± 26.8 | 98.8 ± 12.5 | 0.024 | |||
| CC/TLC | 114.0 ± 6.4 | 99.9 ± 3.6 | 0.030 |
Fig. 1. Results of lung volume measurements of patients with difficult-to-control asthma (hatched bars) and patients with stable asthma (open bars). All parameters are expressed as % predicted values (mean ± SEM). RV/TLC = ratio of RV to TLC; dN2 = slope of Phase 3; CV/VC = ratio of closing volume to vital capacity; CC/TLC = ratio of total lung capacity to closing capacity.
[More] [Minimize]In the two groups considered collectively, it appeared that CC/TLC was correlated with diurnal PEF variation (r = 0.47, p = 0.013) (Figure 2A), FEV1 (r = −0.50, p = 0.007) (Figure 2B), RV/TLC (r = 0.77, p < 0.001), and dN2 (r = 0.60, p = 0.001). In addition, CV/VC was correlated with diurnal PEF variation (r = 0.45, p = 0.018) and dN2 (r = 0.41, p = 0.028). No significant correlation was observed between CC/TLC or CV/VC and age (r = −0.24, p = 0.22 and r = −0.23, p = 0.23, respectively), duration of asthma (r = 0.04, p = 0.83, and r = 0.14, p = 0.49, respectively), or PC20 MCh (r = −0.29, p = 0.072, and r = −0.34, p = 0.13, respectively).
Fig. 2. Correlation between CC and diurnal peak flow variation (A), and between CC and FEV1 (B). CC/TLC = ratio of closing capaicty to total lung capacity. Closed diamonds: difficult-to-control asthma; open diamonds: stable asthma.
[More] [Minimize]The results of the present study show that asthmatic subjects with recurrent exacerbations have early airway closure during expiration, as demonstrated by increased CV and CC in comparison with patients with severe but stable asthma. No other lung volume test distinguished the two groups from one another. CC, and to a lesser extent CV, were related to diurnal peak flow variation, FEV1, and RV/TLC. These data indicate that individuals with severe asthma with recurrent exacerbations are prone to airway closure, despite previous inhalation of a β2-agonist during a well-controlled, clinically stable period. This suggests that such patients are at risk of excessive airway narrowing.
The results of our study confirm and extend the findings of others, who observed a trend toward an increased CV in asthmatic subjects (9), which normalized after inhalation of β2- agonists (22). Other studies comparing CV or CC in patients with mild asthma and normal subjects suggested increased values of these parameters in the former group, but the data did not reach statistical significance (15, 23). To our knowledge, the present study is the first to compare two groups of patients with severe asthma, being indicative of preferential airway closure in the subgroup of patients with recurrent exacerbations. Our results are in line with the observation of Ferrer and colleagues (24), who demonstrated a persistent ventilation–perfusion mismatch after recovery from an asthma exacerbation, even after normalization of FEV1, thereby suggesting a functional impairment in the periphery of the lung in difficult-to-control asthma.
Particular attention was given to methodologic aspects of the present study. The patients were carefully matched for factors that might affect airway closure, including sex (20, 25), age (15, 25), smoking (20), FEV1 (25), airway responsiveness (11), and antiinflammatory therapy (26). Furthermore, neither the duration of asthma nor the diurnal PEF variation differed significantly between the two groups as examined retrospectively.
We determined the subjects' static lung volumes by multibreath helium equilibration instead of whole-body plethysmography. It could be argued that this might have led to underestimation of lung volumes. However, such error is almost negligible after adequate helium equilibration in the absence of nonventilated airspaces at lung volumes above FRC (17). We carefully ensured such equilibration by prolonging the helium wash-in until a constant concentration was reached in the closed circuit (change less 0.02% helium over a period of 30 s) (17). Furthermore, it cannot be excluded that body plethysmography leads to an overestimation of FRC and RV (and consequently of CC) in cases of a large degree of parallel inhomogeneity of ventilation (27).
We had previously validated the evaluation of CV by single-breath N2 washout (20), and this enabled us to reach adequate statistical power in the present study (21). All measurements were made after standardized inhalation of salbutamol, in order to prevent possible variability in airway closure caused by smooth-muscle tone (22, 28). As is customary, the values of CV and CC were expressed as ratios to VC and TLC, respectively, and were presented as percentages of predicted values (20, 25).
The increased CV and CC in patients with recurrent exacerbations of asthma are indicative of early airway closure during expiration, and are compatible with persistence of small-airways pathology even during clinically well-controlled periods of disease (29). The correlations between diurnal PEF variation, FEV1, and RV/TLC, respectively, and airway closure suggest that these parameters are related, although the latter two parameters were far more sensitive in detecting a propensity to air trapping. Results from in vitro and in vivo animal studies indicate that airway closure occurs in the small airways (30, 31). Moreover, several studies show evidence of (sub)mucosal and peribronchial inflammation with thickening of the small airways in asthma (5, 8, 9, 32), together with airway smooth-muscle hypertrophy (33, 34). The functional consequence of this is a greatly increased luminal narrowing (11, 12, 34), which may become sustained by the secondary development of a contractile latch-state of the smooth muscle (35).
In addition, it cannot be excluded that any or all three of a loss of elastic recoil (36), decreased airway elastance (37), or a surfactant abnormality (38) might play a role in airflow limitation in the peripheral airways. The last of these possibilities is supported by a recent study of Kurashima and coworkers, who showed a surfactant dysfunction in sputum of patients with an asthma exacerbation (39). When they are considered collectively, at least some of the mechanisms promoting airway closure are still manifest in patients with difficult-to-control asthma. This points toward ongoing inflammation in the small airways, which is not sensitively detected by conventional techniques for evaluating lung function.
The clinical relevance of this study is, first, that assessment of CV and CC might be useful in determining asthma severity and in estimating the risk of a patient's developing frequent exacerbations. Others have postulated that the decrease in FVC at the PC20 MCh during bronchoprovocation testing provides similar information (40). This is not unexpected, since a reduction in FVC during bronchoconstriction is likely to be determined by closure of small airways at low lung volumes (2, 12). Second, the results of this study emphasize the importance, in patients with severe asthma, of treatment with inhaled corticosteroids, which reduces excessive airway narrowing (26). The aim of inhaled therapy in these patients should be to deliver antiinflammatory medication to the peripheral airways. Administration of corticosteroids from a pressurized MDI in combination with a spacer device might perhaps be a first choice for this. This warrants further investigation.
We conclude that asthmatic patients with recurrent exacerbations have an increased CV and CC as compared with controls with severe but stable asthma. This is indicative of small-airway pathology in patients with difficult-to-control asthma, even after bronchodilation during well-controlled episodes of disease. Hence, the measurement of airway closure might give additional information about the clinical control of asthma as well as the risk of excessive airway narrowing and subsequent exacerbations. This suggests that delivery of antiinflammatory medication to the small airways in this subgroup of patients with severe asthma is of specific clinical relevance.
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