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(Chest. 2002;121:715-721.)
© 2002 American College of Chest Physicians

Unsuspected Loss of Lung Elastic Recoil in Chronic Persistent Asthma*

Arthur F. Gelb, MD, FCCP; Jesse Licuanan, MD; Chris M. Shinar, PharmD and Noe Zamel, MD, FCCP

* From the Pulmonary Division (Dr. Gelb), Department of Medicine and Department of Pharmacy Services (Dr. Shinar), Lakewood Regional Medical Center, Lakewood, CA; Department of Medicine (Dr. Licuanan), Overlook Medical Center, Summit, NJ; and Faculty of Medicine (Dr. Zamel), University of Toronto, Toronto, ON, Canada.

Correspondence to: Arthur F. Gelb, MD, FCCP, 3650 E. South St, Suite 308, Lakewood, CA 90712; e-mail: afgelb{at}msn.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To investigate the progression and mechanism(s) for fixed maximum expiratory airflow (max) limitation in patients with chronic persistent asthma.

Methods: When optimally treated and in clinically stable condition, we studied 21 asthmatic patients and classified them into three groups based on the severity of expiratory airflow limitation: (1) group A included 5 asthmatic patients (four women; mean ± SD age, 51 ± 17 years) with mild persistent asthma (FEV1 > 80% predicted) with serial FEV1 measurements obtained prior to the present study for 16 ± 4 years; (2) group B included 11 asthmatic patients (three women; mean age, 64 ± 11 years) with moderate persistent asthma (FEV1 of 60 to 80% predicted) with serial FEV1 measurements for 12 ± 4 years; and (3) group C included 5 asthmatic patients (three women; mean age, 55 ± 16 years) with severe persistent asthma (FEV1 < 60% predicted) with serial FEV1 measurements for 11 ± 5 years.

Results: Lung CT indicated no or trivial emphysema, and diffusion was normal in all asthmatics. There was a marked loss of lung elastic recoil at total lung capacity (TLC) in all asthmatic patients in group B (16 ± 4 cm H2O) and group C (15 ± 5 cm H2O), but none or minimal in group A (22 ± 1 cm H2O) [p < 0.01], and loss of elastic recoil accounted for 34% and 50% of decreased maximal expiratory airflow (max) at 80% and 70% TLC, respectively. Comparison with previous longitudinal data indicated individual asthmatics when in clinically stable condition remained predominantly in the same FEV1 percent predicted classification group as in the current study.

Conclusion: Patients with chronic moderate and severe persistent asthma, despite optimal therapy, have reduced max for many years in part due to (early?) loss of lung elastic recoil from unknown mechanism(s). This challenges current concept of airway remodeling.

Key Words: airflow limitation • airway remodeling • asthma • elastic recoil


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Many symptomatic patients with chronic asthma, despite maximal medical therapy, have irreversible expiratory airflow limitation develop, ie, FEV1 < 80% predicted. Based on the reduction of FEV1, these asthmatic patients are classified as having moderate (60 to 80% predicted) or severe (< 60% predicted), persistent asthma.1 They have near-daily complaints of cough, wheezing, chest tightness, shortness of breath, and/or decreased exercise tolerance despite polytherapy.

Asthma is believed by most investigators to be an "inflammatory" disease of the airways.2 It has been suggested that unchecked, persistent, acute inflammation eventually leads to chronic inflammation and ultimately airway remodeling, luminal narrowing,

For editorial comment see page 673

and fixed expiratory airflow obstruction.2 However, available evidence suggests that there is no correlation between progressive airway changes and longitudinal deterioration of lung function in asthmatic patients.2

We recently reported the unsuspected marked loss of lung elastic recoil not due to emphysema in patients with chronic, stable asthma, which accounted for 25 to 39% of fixed expiratory airflow limitation.3 The present study further explores the mechanism of expiratory airflow limitation in treated patients with chronic, stable asthma. Since these asthmatics had been followed up for many years with longitudinal spirometry, it provided an opportunity to further define the progression of expiratory airflow limitation.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We reviewed the medical records of all asthmatic patients currently receiving treatment in our outpatient clinic to select every patient with longitudinal lung function studies > 5 years. All asthmatics had been treated concurrently by the same physician (A.F.G.), and medications included short-acting and/or long-acting aerosolized and/or oral ß2-agonists, aerosolized ipratropium bromide, oral and/or inhaled corticosteroids, cromoglycate, nedocromil, oral theophylline, and leukotriene inhibitors. At all times, in all asthmatic patients, maximal therapy was used to achieve optimal clinical status and spirometric documented bronchodilation, as judged by FEV1.

Similar to our earlier study,3 all patients satisfied the criteria for at least partially reversible bronchial reactivity.1 Chronic bronchitis was never diagnosed, and only one asthmatic was a current mild cigarette smoker (< 30 pack-years); the others never smoked. Eleven of the 21 asthmatic patients in the present study were previously studied.3 Longitudinal data have never been reported.

Lung Studies
After obtaining informed consent, we measured serial spirometry, maximum expiratory airflow (max)-volume curves, static lung elastic recoil,3 4 5 6 coefficient of retraction,7 max-static lung elastic recoil pressure curves,3 4 8 9 maximum inspiratory and expiratory mouth pressures,10 and lung CT11 in patients with clinically stable asthma using similar techniques and equipment to those recently published.3 4 5 We estimated the contribution of loss of lung elastic recoil to reduction in max as recently reported.3

Briefly, max at effort-independent specific lung volumes (80% and 70% of total lung capacity [TLC]) is directly proportional to the static lung elastic recoil pressure and inversely proportional to the intrinsic resistance of the airways.9 For example, a 20% decrease in measured static lung elastic recoil pressure from normal values at 80% of TLC would be responsible for a 20% decrease in max at that lung volume. Any further decrease in max must be due to increased intrinsic airway resistance (or decreased airway conductance). This relationship provides the opportunity to quantitatively partition the reduction in max into an increased intrinsic airway resistance component vs the contribution due to loss of lung elastic recoil. The inverse of airway resistance is conductance, and the conductance of the S segment determined from flow-pressure curve (GS) is obtained by measuring the slope of the max-static lung elastic recoil curve, obtained at effort-independent lung volumes that crosses the lung elastic recoil pressure axis.9 A reduction in GS from normal values indicates increased intrinsic small airway resistance that cannot be accounted for by loss of lung elastic recoil.

All studies were performed after three inhalations (270 µg) of aerosolized albuterol. Additionally, serial postbronchodilator spirometry had been obtained quarterly in the same laboratory, and the results for yearly FEV1 reflected the highest value achieved for each asthmatic patient when they were in clinically stable condition.

Results of the most recent spirometry study, ie, within the past 6 months in each patient with clinically stable asthma, was used to classify the extent of expiratory airflow limitation. Consistent with previous criteria, mild persistent referred to symptomatic asthmatics with FEV1 > 80% predicted, moderate persistent included FEV1from 60 to 80% predicted, and severe persistent was < 60% predicted.1 Measurements of static lung elastic recoil pressures were obtained in 4 of 5 patients with mild persistent asthma, 10 of 11 patients with moderate persistent asthma, and all 5 patients with severe persistent asthma.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Asthmatic patients were classified into three groups: (1) group A included 5 patients with chronic, stable asthma (four women; mean ± SD age, 51 ± 17 years) who had mild persistent asthma, as per the most recent FEV1 > 80% predicted; (2) group B included 11 patients with chronic, stable asthma (eight men; mean age, 64 ± 11 years) who had moderate persistent asthma, ie, FEV1 60 to 80% predicted; and (3) group C included 5 patients with chronic, stable asthma (2 men; mean age, 55 ± 16 years) who had severe persistent expiratory airflow limitation, ie, FEV1 < 60% predicted. Results of lung function studies are reported in Table 1 . As expected, there was marked abnormalities in expiratory airflow and hyperinflation in asthmatic patients classified as having moderate persistent and severe persistent asthma. Diffusing capacity remained normal in all three groups, indicating normal lung alveolar-capillary surface area. Lung CT was graded <= 15 in every asthmatic patient, indicating no or trivial emphysema.11


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  		Table 1. Results of Lung Function Studies in Patients With Chronic Persistent Asthma*

 
Maximal static lung elastic recoil and coefficient of retraction7 at TLC was normal or borderline in mild persistent asthmatic patients; however, it was markedly decreased in moderate and severe persistent asthmatics. Results of the static lung elastic recoil are reported in Table 2 . At 80% of TLC, only the asthmatics with moderate and severe persistent expiratory airflow obstruction had marked loss of lung elastic recoil, which accounted for 34% of the total reduction in max. The other 66% was due to intrinsic airway obstruction. At 70% of TLC, loss of elastic recoil was responsible for 50% reduction in total max in the asthmatics with moderate and severe airflow limitation. Measurements of the intrinsic airway (S segment) conductance, GS,9 were markedly abnormal in asthmatics with moderate and severe persistent obstruction, whereas patients with mild persistent asthma had normal values. Hysteresis was present between inspiratory and expiratory lung elastic recoil curves.


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  		Table 2. Actual and Estimated Maximal Expiratory Airflow Based on Reduction of Lung Elastic Recoil at 80% and 70% of TLC*

 
Figure 1 demonstrates the results of longitudinal postbronchodilator FEV1 percent predicted in each of the asthmatics obtained when clinically stable and classified on the basis of the most recent FEV1 percent predicted. In almost every asthmatic patient, previous FEV1 percent predicted values, despite variability, were consistent with the most current results. Patients with moderate and severe persistent asthma did not improve over time despite optimal, maximal polytherapy, and patients with mild persistent asthma always remained mild. The five patients with mild persistent asthma were followed up for 16 ± 4 years with 14 ± 5 yearly FEV1 measurements. The 11 patients with moderate persistent asthma were followed up for 12 ± 4 years with 11 ± 4 yearly FEV1 measurements. The patients with severe asthma were followed up for 11 ± 5 years with 8 ± 1.5 yearly FEV1 measurements. Results of maximal inspiratory and expiratory mouth pressures were normal or borderline in all asthmatics despite hyperinflation.



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  		Figure 1. Serial post-aerosol bronchodilator FEV1 percent predicted (%Pred) obtained over many years in patients with persistent asthma currently classified as mild, FEV1 > 80% predicted (top left); moderate, FEV1 60 to 80% (bottom left and top right); and severe, FEV1 < 60% predicted (bottom right). Only asthmatics with current, moderate persistent and severe persistent asthma have marked loss of lung elastic recoil. Top left: the five patients with current, mild persistent asthma have predominantly long-term values for yearly FEV1 > 80% predicted. Bottom left and top right: the 11 patients with current, moderate persistent asthma have predominantly long-term values for yearly FEV1 between 80% and 60% predicted. Within this group, the conditions of four patients deteriorated from mild to moderate over time, and one patient’s condition improved from borderline severe. Bottom right: no patients with severe persistent asthma showed improvement to moderate values.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Results of the present study demonstrate that patients with clinically stable asthma with current moderate (FEV1, 60 to 80% predicted) and severe (FEV1 < 60% predicted) expiratory airflow obstruction, have marked loss of lung elastic recoil (Tables 1 , 2) . This loss of lung elastic recoil is primarily responsible for 46 to 71% of total expiratory airflow reduction (Table 2) . Its contribution in reducing expiratory airflow is even greater than intrinsic airway presumed remodeling and narrowing at low lung volumes. Furthermore, asthmatic patients with current FEV1 < 80% predicted do not appear to have improved significantly over many years despite maximal medical therapy (Fig 1 , bottom left, top right, bottom right). We suspect loss of lung elastic recoil may occur much earlier than expected following recurrent asthmatic attacks and bronchoconstriction, and lead to a component of irreversible expiratory airflow limitation. This is superimposed on fixed or variable bronchoconstriction. In contrast, patients with current, mild persistent asthma with FEV1 > 80% predicted have had similar values over many years and do not have significant loss of lung elastic recoil (Tables 1 , 2 ; Fig 1 , top left).

Previous longitudinal follow-up studies12 13 14 in asthmatic children have demonstrated initial symptoms, need for polytherapy, bronchial hyperresponsiveness, and extent of baseline expiratory airflow limitation greatly influenced the persistence and progression of childhood asthma into adulthood. Only 25% of children with mild asthma subsequently had moderate-to-severe expiratory airflow obstruction develop when studied 20 years later as adults. In contrast, the majority of children with moderate-to-severe asthma had similar or worse asthma as adults.12

All longitudinal adult asthma studies15 16 17 18 have demonstrated more rapid deterioration of FEV1 when compared to normal control subjects, often leading to moderate-to-severe, irreversible expiratory airflow obstruction. Furthermore, prolonged duration of asthma is associated with irreversible expiratory airflow limitation19 20 and hyperinflation due to presumed loss of lung elastic recoil.20

However, irreversible expiratory airflow limitation cannot be readily explained by pathologic large and small airway remodeling that includes epithelial injury, deposition of collagen in subepithelial matrix, hypertrophy and hyperplasia of airway smooth muscle, vascular proliferation, and mucus gland and goblet cell hyperplasia.2 21 22 A recent autopsy study21 of fatal asthma has demonstrated not only the absence of emphysema, but greater large and small airway narrowing with increasing asthma duration, especially in older adults compared to younger adults. However, total wall thickness was not greater in young subjects with fatal asthma compared to control subjects.21 Additionally, autopsy studies23 have reported a disruption of the elastic fiber network in large airways but not small airways in fatal asthma. This would adversely reduce the airway, but not lung recoil. Moreover, "there is no prospective study showing that structural changes, pulmonary function parameters, and indexes of inflammation are related longitudinally."2

The mechanism(s) responsible for the unsuspected loss of lung elastic recoil remain elusive. The normal or elevated diffusing capacity in every patient suggests normal alveolar-capillary surface area. This is in contrast to the reduced diffusing capacity observed in morphologic proven grade >= 35 emphysema, even in subclinical cases when the FEV1 percent predicted is normal or borderline reduced.8 24 Furthermore, based on our previous lung CT structure11 and structure-function correlative studies,8 24 lung CT score <= 15 suggests no or trivial emphysema is present and would not be expected to cause loss of lung elastic recoil. Additionally, Kinsella et al25 showed the ability of high-resolution lung CT to discriminate hyperinflation in asthma from emphysema. The presence of hysteresis noted between the inspiratory and expiratory static lung elastic recoil pressure volume curves in the present study mitigates against surface-active forces causing a loss of lung elastic recoil. Additionally, previous attempts to superimpose hyperinflation with small airway bronchoconstriction and negative pressure around the chest wall did not lead to loss of lung elasticity.26

Previous physiologic studies have reported reversible transient loss of lung elastic recoil and hyperinflation at TLC in some patients during acute attacks of asthma, whether spontaneous in onset,26 27 28 29 or exercise-30 and antigen-induced.31 32 In few cases, persistent loss of lung elastic recoil was noted despite clinical recovery.27 28 McCarthy and Sigurdson33 reported loss of lung elastic recoil in 12 of 16 patients with stable, chronic asthma whose FEV1 ranged from 49 to 77% predicted, but who had reversible bronchoconstriction with aerosolized isoprenaline treatment. Furthermore, the loss of lung elastic recoil was believed to be responsible for the reduction in expiratory airflow in 8 of 16 asthmatics. This is in contrast to the present study, where the asthmatics studied had persistent airflow limitation despite aerosolized albuterol as well as additional bronchodilator polytherapy.

Perhaps, the most unusual observation was the abstract noting loss of lung elastic recoil in children with chronic, symptomatic asthma with normal or borderline lung function, including airway resistance, but with hyperinflation at TLC.34 In contrast, a Dutch study35 noted no loss of lung elastic recoil in 37 adult asthmatics whose FEV1 < 1.64 SD from predicted value.

Autopsy studies of lungs in fatal asthma offer few histologic clues as to the mechanism(s) for loss of lung elastic recoil.21 22 23 However, inflammation in distal airways and lung parenchyma has been noted in biopsy specimens.36 Possibly this could lead to activated neutrophil and/or other elastase-induced mechanical disruption of elastic fibers in lung periphery (J. A. Nadel, MD; personal communication; January 2001). We suspect chronic recurrent bronchoconstriction and hyperinflation are putative causes for mechanical stress relaxation leading to fixed loss of lung elastic recoil, as noted in the present study, and previously in chronic, moderate-to-severe persistent asthma3 27 28 33 and selected patients with chronic, very severe intrinsic small airway disease without emphysema or asthma.5 Most patients with chronic, intrinsic small airway disease, even if severe, do not have loss of lung elastic recoil.5 8 37 38 39 40 Rodarte et al41 noted transient loss of lung elastic recoil in normal subjects breathing at increased functional residual capacity that was attributed to stress relaxation. Similarly, Pellegrino et al42 noted transient loss of lung elastic recoil during dynamic hyperinflation with induced bronchoconstriction. Hoppin43 proposed challenging concepts of stretching of connective tissue to help explain the loss of lung recoil in asthma.

TLC is determined by the outward force of inspiratory muscle pressures to balance the inward elastic recoil forces of the combined lung and chest wall. However, an increase in chest wall outward elastic recoil during acute, exercise-induced asthma has been noted.30 Combined with loss of lung elastic recoil during acute and chronic asthma, hyperinflation and increased TLC would be expected. In the present study, all patients with persistent asthma had at least mild hyperinflation at TLC, but there was no statistical difference between mild vs severe (p > 0.05). 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 and expiratory muscle pressures were normal or borderline in all persistent asthmatics. Moreover, transdiaphragmatic pressures were normal or borderline despite hyperinflation in chronic moderate and severe persistent asthmatics in our previous study,3 suggesting normal or increased inspiratory muscle strength.

In conclusion, results of the present study confirm and extend our earlier observations that patients with chronic, moderate persistent and severe persistent asthma have unsuspected marked loss of lung elastic recoil develop due to unknown mechanism(s). Results of longitudinal spirometry demonstrate variable postbronchodilator FEV1 values, in studied patients with moderate and severe asthma, tend to predominantly remain abnormal over many years despite seemingly optimal therapy. The physiologic burden of loss of lung elastic recoil may occur early and cause fixed expiratory airflow limitation despite maximal medical polytherapy, superimposed on variable bronchoconstriction. Mechanical lung remodeling offers an alternative explanation for persistent expiratory airflow limitation vs pathologic intrinsic airway remodeling in chronic moderate and severe asthma.2 21 23 24 44 Future serial measurements of lung elastic recoil in young adults with stable asthma, as well as deteriorating asthma, may be helpful.


   Acknowledgements
 
The authors thank Jay A. Nadel, MD, Cardiovascular Research Institute, University of California Medical Center, San Francisco, for stimulating discussions; Christy Kirkendall for patient coordination; Randy Newsom, CPFT/RCP, for technical services; and the Mary Decker Foundation.


   Footnotes
 
Abbreviations: GS = conductance of S segment determined from flow-pressure curve; TLC = total lung capacity; max = maximum expiratory airflow

Received for publication May 3, 2001. Accepted for publication August 24, 2001.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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A. F. Gelb, C. F. Taylor, E. Nussbaum, C. Gutierrez, A. Schein, C. M. Shinar, M. J. Schein, J. D. Epstein, and N. Zamel
Alveolar and Airway Sites of Nitric Oxide Inflammation in Treated Asthma
Am. J. Respir. Crit. Care Med., October 1, 2004; 170(7): 737 - 741.
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 ChestHome page
F. C. Sciurba
Physiologic Similarities and Differences Between COPD and Asthma
Chest, August 1, 2004; 126(2_suppl_1): 117S - 124S.
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 Proc Am Thorac SocHome page
S. I. Rennard and S. G. Farmer
Exacerbations and Progression of Disease in Asthma and Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, April 1, 2004; 1(2): 88 - 92.
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 ChestHome page
H. A. Jenkins, R. Cherniack, S. J. Szefler, R. Covar, E. W. Gelfand, and J. D. Spahn
A Comparison of the Clinical Characteristics of Children and Adults With Severe Asthma
Chest, October 1, 2003; 124(4): 1318 - 1324.
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 J. Appl. Physiol.Home page
B. E. McParland, P. T. Macklem, and P. D. Pare
Airway wall remodeling: friend or foe?
J Appl Physiol, July 1, 2003; 95(1): 426 - 434.
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 Am. J. Respir. Crit. Care Med.Home page
L. M. Fabbri, M. Romagnoli, L. Corbetta, G. Casoni, K. Busljetic, G. Turato, G. Ligabue, A. Ciaccia, M. Saetta, and A. Papi
Differences in Airway Inflammation in Patients with Fixed Airflow Obstruction Due to Asthma or Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 418 - 424.
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