INTRODUCTION

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Airway structural studies in chronic asthma have emphasized morphologic alterations of injury associated with an ongoing inflammatory process. The structural changes, leading to fibrosis, include denuding of epithelium, deposition of collagen in subepithelial layers, smooth muscle thickening, bronchovascular permeability, edema, goblet cell hyperplasia, and submucosal gland hypertrophy (1). These changes are referred to collectively as airway remodeling (1), potentially leading to irreversible airway obstruction (3, 5).

In a prospective 10-yr follow-up study, Ulrik and Backer (14) reported that a subgroup of treated asthmatics may experience irreversible, very steep rates of decline in FEV₁ despite persistent normal TLC and diffusing capacity. They suggested emphysema did not develop.

The present physiologic study evaluated patients with moderate to severe, chronic persistent asthma who have seemingly irreversible lung function despite aggressive treatment, to determine the mechanisms of airflow limitation. We attempted to explore the contribution of intrinsic airway obstruction, abnormal lung elastic recoil, or both in limiting expiratory airflow. Of 18 patients studied, 15 had marked loss of static lung elastic recoil pressure. This loss was responsible for a 35% to 55% reduction in maximal expiratory airflow.

Physiologic consequences of loss of lung elastic recoil in chronic persistent asthma include hyperinflation, premature airway closure, and abnormal expiratory airflow. The mechanism remains elusive.

	METHODS

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From January to June 1999, we evaluated lung function studies prospectively in 50 asthmatic patients who were tested when clinically stable in a tertiary referral clinic. Subjects were selected subsequently for this study because their FEV₁ was less than 75% predicted and FEV₁/FVC was less than 75% after three inhalations (670 µg) of aerosolized albuterol on two separate occasions, at least 1 mo apart, and because the subsequent value for FEV₁ (L) was within 5% of the original test result. On both visits, all asthmatics continued their usual medications and dosing, which included aerosolized and oral albuterol, aerosolized ipratropium bromide, oral and inhaled corticosteroids, oral theophylline, leukotriene inhibitors, or a combination of these.

All patients satisfied the criteria for at least partially reversible bronchial reactivity, as they previously demonstrated when off short-acting oral or metered-dose inhaler bronchodilators for 6 h and long-acting bronchodilators for 24 to 48 h, an increase in FEV₁ more than 15% from baseline values after three inhalations (670 µg) of aerosolized albuterol. Furthermore, within the previous year or subsequent to testing, during acute episodes of asthma, their FEV₁ was reduced  1.0 L (> 35% predicted FEV₁) from the best value obtained when they were clinically stable. Chronic bronchitis was not diagnosed in any subject. Only one subject was a current mild cigarette smoker (< 30 pack-years); the others never smoked.

Lung Function Studies

Additional lung function studies were obtained only when the value for FEV₁ reflected the highest value achieved for each subject, and when they were clinically stable.

After obtaining informed consent, lung function studies were obtained using similar techniques and equipment to those published recently (15, 16). We used a pressure-compensated flow plethysmograph (model 6200 Autobox; SensorMedics, Inc., Yorba Linda, CA), and results were compared with predicted values (15, 16). All studies were performed after 3 inhalations (670 µg) of aerosolized albuterol. All patients underwent routine lung function studies, including maximal expiratory flow-volume (MEFV) curves and single-breath diffusing capacity for carbon monoxide. Thoracic gas volume and airway resistance were measured with panting frequency  1 Hz in the plethysmograph. Use of this plethysmograph avoids artifact of gas compression in MEFV curves.

As previously published (15, 16), measurements of static lung elastic recoil pressures were obtained in the open plethysmograph with the patient in a sitting position. A 10-cm-long balloon inflated with 0.5 ml air was positioned in the stomach and then withdrawn to the lower third of the esophagus. After at least two inspirations to total lung capacity (TLC), static transpulmonary (mouth-esophageal) pressures were recorded after stepwise, 3-s interruption of exhalation against a closed shutter at different lung volumes. A minimum of five deflation curves was obtained for each patient, and a plot of best visual fit of the pooled data was constructed.

Using techniques reported previously (15) to determine the mechanism of expiratory airflow limitation, we plotted maximal expiratory airflow obtained from the MEFV curve against static lung elastic recoil pressure at corresponding lung volumes and constructed maximal expiratory airflow-static lung elastic recoil pressure (MFSR) curves. The slope of the MFSR curve between 70% and 30% of the forced vital capacity (FVC), extrapolated to the volume axis, represents the conductance of the S intrinsic small airway segment (Gs) (18). It also allows calculation of the transmural pressure (Ptm') where the Gs slope crosses the pressure axis which, presumably, reflects the collapsible airway segment. If the Ptm' is zero, the Gs would equal the conductance of the upstream segment, Gus. Gs reflects a quantitative value for small airway caliber. Normal values were obtained previously in healthy, nonsmoking subjects with normal routine lung function studies (19).

Estimation of Contribution of Loss of Lung Elastic Recoil to Reduction in Maximal Expiratory Airflow

Maximal expiratory airflow has a linear relationship to lung elastic recoil and inversely with the intrinsic resistance offered by the small airways (18). Therefore, any isolated reduction in lung elastic recoil would be expected to adversely affect maximal expiratory airflow to a similar extent. We determined the value for percent predicted of lung elastic recoil at 80% and 70% of TLC in each of the asthmatic patients with fixed expiratory airflow obstruction compared with healthy nonsmokers. We chose these lung volumes because maximal expiratory airflow is effort-independent. Furthermore, by using a pressure-compensated flow plethysmograph, which measures changes in thoracic gas volume, the artifact resulting from gas compression is avoided. Additionally, measurements of static lung elastic recoil at these lung volumes are more accurate and reproducible. The difference between static and dynamic lung elastic recoil at any given lung volume may vary because of time dependence of stress relaxation. However, at 80% and 70% of TLC, reduced maximal expiratory airflow < 3 L/s in the patients studied should minimize this difference. The mean percent predicted for maximal expiratory airflow was similarly calculated, using the same values. For example, we assumed that a 30% reduction in static lung elastic recoil (70% predicted) would cause a similar 30% reduction in maximal expiratory airflow (70% predicted), based on the model that reduction of airflow would be caused exclusively by the reduction of lung elastic recoil.

Transdiaphragmatic Pressures and Neuromuscular Coupling

To measure maximal transdiaphragmatic pressures (Pdi_max), two separate 10-cm-long balloons were positioned simultaneously in the stomach and lower third of the esophagus. A volume of 2 ml of air was injected into the gastric balloon whereas 0.5 ml of air was injected in the esophageal balloon. We measured the pressures generated in the gastric and esophageal balloons (Pgs and Pes) simultaneously during a maximal inspiratory sniff (20), from end-tidal expiration without a nose clip, as well as during maximal inspiratory effort, from end-tidal expiration against a partially occluded airway (21). Maximal transdiaphragmatic pressure was then determined: Pdi_max = Pg  Pes. We also calculated net total diaphragmatic neuromechanical coupling (NMC), which relates respiratory drive, respiratory muscle performance, lung volume, and lung mechanics during tidal breathing (tidal volume [VT]), as previously described by Laghi and coworkers (21). NMC was calculated over 1 min of tidal breathing (VT); NMC = (VT/ TLC)/(Pdi/Pdi_max). The Pdi reflects the transdiaphragmatic pressures during VT from the onset of airflow. Measurements of maximal inspiratory and expiratory mouth pressures (MIP, MEP) were obtained, as previously described (22). This test is an index of overall respiratory muscle strength.

Lung Computed Tomography (CT)

High-resolution, thin-section CT of the lungs was obtained in each subject, using similar techniques as well as scoring areas of emphysema, as previously described (23).

Asthmatic Subjects in Remission

We also studied three asymptomatic asthmatics, one in each age category, who had normal spirometry and static lung volumes, and obtained MEFV curves, static lung elastic recoil pressure curves, and MFSR curves.

	RESULTS

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Results of routine lung function studies are described in Table 1; in 18 adult asthmatics, 12 men, age 59 ± 15 yr (mean ± SD). Asthmatic patients were divided into three age groups. Whereas FVC remained within normal limits or borderline, FEV₁ and the ratio of FEV₁/FVC were moderately to severely reduced. The MEFV curve was abnormal in all asthmatic subjects, especially at lower lung volumes (Figure 1) compared with age-matched control subjects (19). Hyperinflation was present at residual volume (RV), FRC, and TLC. Spearman's correlation coefficient between RV/TLC, percent predicted and FEV₁, percent predicted was 0.59, p < 0.01; specific airway conductance (SGaw) was 0.50, p < 0.03; Gs was 0.49, p < 0.04. Diffusing capacity was normal or elevated. Plethysmographic measurements of airway resistance were markedly abnormal (Table 1).

View larger version (19K): [in this window] [in a new window]   Figure 1.   Results of maximum expiratory flow volume curves in asthmatic patients with fixed abnormal spirometry. All asthmatics had abnormal expiratory airflow limitation at both high and low lung volumes compared with mean ± 1.64 SD of age-matched control subjects.

Static lung elastic recoil at TLC was borderline or significantly reduced in all age groups. Compared with age-matched control subjects, there was significant loss of static lung elastic recoil, especially at lower lung volumes in 3 of 4 asthmatics age 30 to 49 yr, all five asthmatics age 51 to 60 yr, and 7 of 9 age 61 to 82 yr (Figure 2).

View larger version (8K): [in this window] [in a new window]   Figure 2.   Result of static expiratory pressure volume curves. Fifteen of the 18 asthmatics studied demonstrated loss of lung elastic recoil compared with mean ± 1.64 SD of age-matched control subjects.

Analysis of MFSR curves (Figure 3) indicates that maximal expiratory airflow limitation in most asthmatics was the result of combined loss of lung elastic recoil and concurrent, intrinsic small airway obstruction or collapse. In four of nine elderly asthmatics and only at low lung volumes was airflow limitation accounted for completely by loss of lung elastic recoil. Values for Gs as an index of small airway caliber were reduced in asthmatics as a group compared with age-matched control subjects.

View larger version (19K): [in this window] [in a new window]   Figure 3.   Results of maximum expiratory airflow-static lung elastic recoil pressure curve. In only 4 of 18 asthmatics was expiratory airflow limitation accounted for by loss of lung elastic recoil at low lung volumes. In the remaining 14 cases, maximal expiratory airflow limitation was predominantly due to intrinsic airway obstruction or collapse. The slope of the Gs line was extrapolated to Pst() axis.

The results of the estimated reduction in maximal expiratory airflow, based on reduction in static lung elastic recoil pressures, appear in Table 2. At 80% of TLC, the loss of lung elastic recoil was responsible for approximately 35% reduction in maximal expiratory airflow. The other 42% reduction in maximal expiratory airflow was due to intrinsic small airway obstruction. At 70% of TLC in the subjects age 31 to 49 yr, the majority of airflow limitation was caused by intrinsic small airway obstruction. However, in asthmatics age 51 to 75 yr, loss of lung elastic recoil was responsible for approximately 50% of the reduction in maximal expiratory airflow.

The three asymptomatic asthmatics in remission, one in each group with normal spirometry, had normal MEFV curves, pressure-volume curves, and flow-pressure curves (data not shown).

Values for MIP and MEP (Table 3), and Pdi_max using sniff and partially occluded airway techniques (Table 3), were normal despite lung hyperinflation. Values for diaphragmatic neuromechanical coupling were abnormal in three of six subjects. Thin-section CT of the lungs demonstrated emphysema scores  15, indicating little or no emphysema (23).

	DISCUSSION

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Results of the present study in subjects with chronic persistent asthma, who were clinically stable, but have persistent FEV₁ less than 75% predicted despite extensive treatment regimen, demonstrated unexpectedly a significant loss of lung elastic recoil in 15 of 18 patients. The high incidence of loss of lung elastic recoil was not anticipated in view of the current literature with emphasis on pathologic airway remodeling in asthmatics with fixed abnormal spirometry (1). The loss of lung elastic recoil presumably reflects unexplained physiologic alveolar- lung parenchymal abnormalities that could not be accounted for by emphysema or loss of alveolar-capillary surface area in view of the normal high-resolution, thin-section CT lung and normal diffusing capacity, respectively. Based upon our previous structure-function studies (16, 17, 23), including high-resolution, thin-section CT correlative studies with lung morphology (16, 23), it is unlikely that lung CT scores  15 and normal diffusion would miss advanced pathologic emphysema.

The mechanisms causing loss of lung elastic recoil in chronic asthma in the absence of obvious emphysema remain elusive. Previous investigators have reported transient loss of lung elastic recoil during an acute, spontaneous (24) or antigen-induced (27) asthmatic attack, with return to normal values in most cases with relief of airflow obstruction. Alternatively, Woolcock and Read (31) and Finucane and Colebatch (32) noted persistent loss of lung elastic recoil in five of 10 and four of 10 asthmatics respectively, who had recovered from their asthma attack, and despite normal airway resistance.

McCarthy and Sigurdson (9) reported marked loss of lung elastic recoil in 12 of 16 chronic stable asthmatic patients whose FEV₁ ranged from 49 to 77% predicted, but who had reversible bronchospasm with aerosolized isoprenaline. Furthermore, the loss of lung elastic recoil was believed to contribute solely to airflow limitation in at least eight of 16 asthmatics.

In all of the previous studies reporting loss of lung elastic recoil (9, 31, 32), lung parenchymal imaging techniques were not available to evaluate the integrity of the lung. Alternatively, Bogaard and coworkers (33) reported normal lung elastic recoil in 37 asthmatics whose FEV₁ was less than 1.64 SD from predicted value.

TLC is determined by the outward force of inspiratory muscle pressures to balance the inward elastic recoil forces of the lung and chest wall. Concomitant with an increase in chest-wall outward elastic recoil during acute asthma (27), an increase in inspiratory muscle strength and force of contraction (24, 27, 28), or loss of lung elastic recoil during acute (24) or chronic (31, 32) asthma, would cause hyperinflation and increased TLC. It would be anticipated that inspiratory muscles would be shortened and presumably operating at a mechanical disadvantage in the presence of hyperinflation. Yet, in the present study, global inspiratory muscle pressures and transdiaphragmatic pressures were normal despite hyperinflation, suggesting normal or increased inspiratory muscle strength, similar to observations in chronic obstructive pulmonary disease (34).

Despite the load imposed upon the diaphragm due to chronic airway obstruction, a near normal ventilatory output (i.e., VT sized for TLC) for a given diaphragmatic contraction (i.e., Pdi sized for Pdi_max) as measured by diaphragm neuromuscular coupling was observed in three of six asthmatics.

Whether tissue forces or stress relaxation associated with chronic bronchoconstriction and hyperinflation are causative for loss of lung elastic recoil remains speculative. Rodarte and coworkers (35) noted loss of lung elastic recoil in normal subjects who increased their FRC that was attributed to stress relaxation. Pellegrino and coworkers (36) noted a reduction in lung elastic recoil during dynamic hyperinflation with induced bronchoconstriction, possibly due to airway closure. Despite our inability to completely explain the loss of lung elastic recoil in chronic, stable asthmatics, its high incidence and contributory role to airflow limitation suggest a greater role than previously appreciated.

The lung CT in every patient demonstrated no or minimal evidence of emphysema despite the increased TLC and hyperinflation. Kinsella and coworkers (37) have previously demonstrated the ability of high-resolution, thin-section lung CT to distinguish hyperinflation in chronic asthma from emphysema. Alternatively, Biernacki and coworkers (38) reported that chronic nonatopic asthmatics, who were life-long nonsmokers, had lower lung CT density scores than normal control subjects. However, there was no significant correlation between lung CT density scores and any lung function study.

The current study extends our recent observations of marked loss of lung elastic recoil in chronic-smoking patients with severe airflow limitation who do not have asthma or emphysema, but who exhibit pathologic evidence of chronic small airway disease (16). The unexpected high incidence of loss of lung elastic recoil in chronic, persistent asthma suggests physiologic alveolar-lung alteration remodeling and emphasizes the need for further evaluation of the mechanism involved and its clinical and physiologic consequences.