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Original Research: PHYSIOLOGIC TESTING |

Conditions Associated With an Abnormal Nonspecific Pattern of Pulmonary Function Tests FREE TO VIEW

Robert E. Hyatt, MD, FCCP; Clayton T. Cowl, MD, FCCP; Julie A. Bjoraker, MD; Paul D. Scanlon, MD, FCCP
Author and Funding Information

*From the Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, MN.

Correspondence to: Robert E. Hyatt, MD, FCCP, Mayo Clinic, 200 First St SW, GO 18E, Rochester, MN 55905; e-mail: hyatt.robert@mayo.edu


Drs. Hyatt, Cowl, and Bjoraker have no conflicts of interest to disclose. Dr. Scanlon has received support from Pharmaceuticals, GlaxoSmithKline, Pfizer, Dey L.P. Pharmaceutical, and Novartis.

This research was supported by the Mayo Clinic, Rochester, MN.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(2):419-424. doi:10.1378/chest.08-1235
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Published online

Background:  Little is known about a fairly frequent abnormal pattern of pulmonary function test results: reduced FEV1 and FVC with a normal FEV1/FVC and normal total lung capacity. We term this a nonspecific pattern (NSP). We sought to identify medical conditions having this pattern and to explore mechanisms producing it.

Methods:  From a database of 80,929 test results, the NSP was found in 7,702 subjects from whom was drawn a random sample of 100 subjects. Medical records and all available tests were examined.

Results:  Airway hyperresponsiveness (AHR) and obesity were common. Two groups of subjects were identified. Group A consisted of 68 subjects with evidence of airway disease, including AHR and chronic lung disease. A volume derecruitment model was proposed to explain their NSP. Group B consisted of 32 subjects with no evidence of airway disease. Restricted expansion of the thorax or lung may explain the NSP in most of these subjects. Forty subjects had repeated tests, and in only 17 were the test results consistently nonspecific.

Conclusions:  In a random sample of 100 subjects with the NSP, the probable underlying cause of the pattern in 68 subjects was airway disease. In most of the remaining 32 subjects, restricted expansion of the thorax or lung may be implicated.

Figures in this Article

In this report, we define a nonspecific pattern (NSP) of pulmonary function test results as a reduced FEV1 and FVC, a normal FEV1/FVC, and a normal total lung capacity (TLC). Restriction is suggested by the normal ratio and reduced FVC but not supported by the normal TLC. Obstruction is suggested by the reduced FEV1 and normal TLC but not supported by the normal ratio. We encountered this pattern in 1972 in a study1 of asymptomatic asthmatic patients. Increasing bronchoconstriction was gradually induced, and in 10 of 15 studies proportional decreases in both FEV1 and FVC initially occurred with no change in TLC. There were parallel shifts of the maximal expiratory flow volume (MEFV) curve. The slope of the MEFV curve is equivalent to the FEV1/FVC. Hence, in 10 of these subjects, obstruction occurred with no change in the FEV1/FVC. This was also noted in several subjects by Cade et al.2 We suggested there was heterogeneous airway constriction with some areas closing early in expiration, while the rest of the lung did not change its emptying pattern.

In our experience, the NSP occurs in 9.5% of patients with complete test results. In 1997, we3 called attention to this constellation of tests that has received little attention in the literature. Stanescu4 suggested the NSP be called the small airways obstruction syndrome and reported 12 subjects.5 The recent American Thoracic Society/European Respiratory Society Task Force report6 addressed the NSP that they believed was uncommon and frequently due to the subject failing to inhale or exhale completely. They classified these subjects, based on the diffusing capacity of the lung for carbon monoxide (Dlco) as having either emphysema or asthma/chronic bronchitis.

Because of this paucity of data, we analyzed a random sample of 100 subjects with the NSP. We sought to exclude early fibrosis or emphysema by requiring a normal Dlco. Our goals were to identify the clinical conditions exhibiting the NSP and to gain insight into the possible mechanism(s) producing this pattern. Some results have been reported in an abstract.7

Subject Selection

We performed a retrospective analysis of subjects studied in our pulmonary function laboratory between 1991 and 2000. Selection criteria were that subjects be ≥ 20 years old with an FEV1 and FVC below the lower limit of normal, and the FEV1/FVC, TLC, and Dlco above the lower limit of normal. All subjects had received a bronchodilator or methacholine challenge.8 Over this time period, bronchodilator tests were routinely performed in all complete test referrals unless the ordering physician requested a methacholine challenge, which happened on 12 occasions. There were 7,702 subjects meeting these criteria from 80,929 subjects with complete test results, a prevalence of 9.5%. A random sample of 100 subjects was selected from the 7,702 subjects for analysis. The study was approved by the Institutional Review Board, and all subjects had given informed consent for their clinical data to be used for research.

Measurements

Spirometry and diffusing capacity were performed by accepted methods. TLC was measured by plethysmography, which also provided a measure of a slow expiratory vital capacity (SVC). Diffusing capacity was by the single-breath method. Normal values for spirometry, TLC, and Dlco were obtained from the same population.910 A positive bronchodilator response required an increase in FEV1 and/or FVC of at least 12% and of at least 200 mL. A positive methacholine challenge was a fall in FEV1 of at least 20%.8 A subject was considered to have airway hyperresponsiveness (AHR) if either test result was positive. We used the FVC in the FEV1/FVC, not the SVC. We also calculated the residual volume (RV) as TLC − FVC. This question is addressed in the “Discussion” section.

Medical records were reviewed, as were other complete tests performed at this institution. The initial test is referred to as the index test.

Flow-volume curves were examined for reproducibility and effort with peak expiratory flows reproducible within 10%. No curves exhibited an abrupt termination.

Statistical Analysis

Variables were compared between groups using the two-sample t test for continuous variables and the χ2 test for categorical variables. In all cases, two-tailed p values <0.05 were considered statistically significant.

Patient Characteristics

Table 1 presents pertinent group data. AHR on the index test was found in 4 of 12 subjects who received methacholine and in 29 of 88 subjects who received a bronchodilator. When we reviewed the medical records and all available test results, evidence of AHR, defined as a clinical diagnosis of asthma and/or a positive bronchodilator or methacholine response, was found in an additional 23 subjects for a total of 56 subjects. Thus, there was a positive bronchodilator response in 40 subjects, a positive methacholine challenge in 6 subjects, and the diagnosis of asthma based on the medical history alone in 10 subjects. Thirty of the 62 men (48%) exhibited AHR, while 26 of the 38 women (68%) exhibited AHR, no significant difference. Chronic lung disease was diagnosed in 16 subjects.

Table Graphic Jump Location
Table 1 Subject Characteristics (n = 100)*

*Data are presented as mean (SD) unless otherwise indicated.

The distribution of body mass index (BMI) by gender is given in Table 2. Obesity (BMI ≥ 30 kg/m2) occurred in 50 subjects equally distributed between the sexes. In the obese subjects, 83% of the women (n = 15) exhibited AHR, compared to 50% of the men (n = 16), a significant difference (p < 0.02).

Table Graphic Jump Location
Table 2 Distribution of BMI by Gender*

*Data are presented as No. (%).

As seen in Table 3, these observations were used in categorizing the majority of subjects. Twenty-six of the subjects in the AHR categories had a clinical diagnosis of asthma. The chronic lung disease category consisted of COPD (n = 11), bronchiectasis (n = 3), silo fillers disease (n = 1), and viral bronchitis (n = 1). COPD was a clinical diagnosis obtained from the patient's chart. The diagnoses in the “Other” category (category 5) are listed in Table 4. In Table 3, in addition to the 52 subjects with the AHR diagnosis, there were 4 subjects in the chronic lung disease category who exhibited AHR, bringing the total to 56. Regarding obesity, in addition to the 38 subjects there were 12 obese subjects in other categories bringing the total to 50.

Table Graphic Jump Location
Table 3 Summary of Patient Diagnosis*

*Data are presented as No. (%). Categories 1, 2, and 3 are designated as group A (airway). Categories 4 and 5 are designated as group B (nonairway).

Table Graphic Jump Location
Table 4 Conditions in “Other” Category

A brief smoking history was obtained at the time of lung function testing. There were 39 never smokers, 49 ex-smokers, and 12 current smokers. There were no striking differences in smoking history among the categories in Table 3.

As seen in Table 1, the mean reduction in FEV1 was relatively mild. Seventy-seven percent of subjects had a FEV1 in the 80 to 60% of predicted range, 21% in the 59 to 50% of predicted range, and 2% in the < 50% of predicted range.

Analysis of Subjects With Tests on Two or More Occasions

Forty of the 100 subjects underwent two or more tests. In 17 of these 40 subjects, the test results were always classified as nonspecific. However, the other 23 subjects showed the following changes: 6 subjects had a normal pattern, 11 had an obstructive pattern, 3 had both normal and obstructive patterns, and 3 had a restrictive pattern. Thus, 58% of the subjects with multiple test results showed on at least one occasion a change from the NSP.

The variability of AHR was evaluated in these 40 subjects. In 18 subjects, there was no change in AHR. However, AHR did change in 22 subjects. Of particular interest were the 26 subjects whose index test result was negative for AHR but 12 of whom had a positive test result at another time. Thus, 46% of subjects with a negative index test result had a positive test result on another occasion.

The strength of the study included having the tests performed by technicians who follow tight quality control and perform thousands of tests a year. Reproducibility of MEFV curves was used to monitor and ensure maximal patient performance. The availability of medical records, often covering many years, was very important in categorizing diagnoses. It was possible to review multiple tests in 40% of the sample. Critical to our analyses was having the TLC measured by body plethysmography. Had we used alveolar volume as a surrogate for TLC, 28% of our sample would have been ruled restrictive.

The NSP as defined here was found in 9.5% of our subjects who had complete test results. This contrasts with the suggestion6 that it is rare and often due to poor performance. Indeed, Aaron et al11 found that in 1,831 subjects, 15% exhibited what we would call the NSP.

The fact that 56% of the sample exhibited AHR was not surprising because we had first encountered the NSP in asymptomatic asthmatic subjects,1 and the fact that 50% of the sample were obese reflected the frequency of obesity in our patient population. AHR with or without obesity, and obesity were present in 59% of the cases. Adding chronic lung diseases raised the number to 75%, leaving 25% with other diagnoses (Table 3).

The NSP occurred most frequently in subjects with mild-to-moderate reductions in FEV1, the mean being 68% of predicted normal. Another interesting feature was the often-transient nature of the NSP as seen in the 40 subjects with multiple test results in which 58% changed pattern. Twenty-three percent at some point reverted to a normal pattern, while most of the others exhibited mild obstruction on at least one occasion.

We now consider possible mechanisms producing the NSP. We classified our subjects into two diagnostic groups. Sixty-eight subjects with obvious airway involvement (categories 1, 2, and 3 in Table 3) are designated group A (airway). Thirty-two subjects with no obvious airway involvement (categories 4 and 5 in Table 3) are designated group B (nonairway).

First we consider the NSP in group A. When a normal subject performs a FVC maneuver, RV is determined at the end of the effort by closure of the peripheral airways and the FEV1/FVC is normal. The subject with COPD has scattered, diseased airways with varying degrees of ventilatory limitation, many of which close during the forced effort. The regions served by these closed airways no longer contribute to the FVC but become part of the increased RV. In addition, the FEV1/FVC is low because flow decreases more than volume. In contrast, we postulate that the subjects in group A have scattered, diseased airways all with markedly reduced ventilation. The remaining airways are relatively normal. We further postulate that the abnormal airways close soon after forced expiration begins, and the regions served by them become part of the increased RV. The remaining lung empties through the uninvolved airways producing a normal FEV1/FVC with proportionate reduction in both flow and volume; thus, the NSP is produced. The reduced ventilation in group A may be secondary to changes such as bronchial inflammation, bronchoconstriction, or mucus accumulation. The involved airways in group A may be small, intermediate, or large.12 This mechanism is similar to that previously proposed.1

A recent imaging study of asthmatic subjects during induced bronchoconstriction was consistent with the closure of segmental or subsegmental airways and not with diffuse airway narrowing.13 The importance of constriction of proximal airways is supported by several other studies.14,15 A lung model16 of constricted airway smooth muscle produced a parallel shift of the MEFV curve, but the constriction involved all airways.

We suggest that closure of the narrowed airways is accelerated by the rapid emptying of relatively normal adjacent regions that decreases the tissue interdependence support they provide. During a SVC, the interdependence support of the uninvolved regions should persist longer, leading to more complete emptying of the slow spaces with an increase in exhaled volume and a reduction in RV.

Another feature is that as areas close during a rapid expiration airflow decreases while resistance and RV increase, all hallmarks of airflow obstruction. We suggest this be termed volume loss or volume derecruitment airway obstruction. This argument is similar to that of Bates and Irvin17 and Lundblad et al,18 who have used the term volume derecruitment airway hyperresponsiveness.

In the derecruitment model, the RV is being determined early and possibly throughout the forced expiration, not just at its termination. Thus, RV becomes time dependent in the sense that it is larger the more rapid the expiration.

We find it difficult to present a unifying mechanism to explain the NSP in group B. The majority of cases do have abnormalities that restrict the normal expansion of either the lung or thorax. Figure 1 illustrates this concept. Obesity, for example, may restrict full thoracic expansion due to the load it imposes on the thorax and abdomen, which is magnified if there is weakness of the respiratory muscles.19 Other conditions interfering with thoracic expansion would be respiratory muscle weakness and structural abnormalities of the chest wall such as scoliosis and chest trauma. Lung expansion would be restricted by space occupying lesions such as larger hiatal hernias. What Figure 1 does not explain is the elevated RV in group B, which was 129% of predicted. Twenty-two of these 32 subjects were smokers, which could increase RV. Weak expiratory muscles may also be a factor as may chest wall abnormalities.

Figure Jump LinkFigure 1 In this schematic drawing, the normal thoracic and lung expansion is represented by the dashed line. The solid line represents a reduced lung expansion (the dark area) due to either a reduction in thoracic expansion or in lung expansion, or a combination of the two. In either case, the FVC and FEV1 are both reduced. However, since the slope of the MEFV curve is unchanged, the FEV1/FVC is also unchanged.Grahic Jump Location

The conditions and mechanism described for group B (nonairway) are suggestive of restriction despite the low normal TLC. Indeed, the percentage of predicted TLC was lower in group B (nonairway) compared to group A (airway), 90.1% vs 96.1%, a significant difference (p < 0.003).

The derecruitment mechanism applied to group A (airway) subjects predicts several other differences between groups A and B (nonairway). The percentage of predicted RV should be greater in group A (airway), and it was: 148% vs 129% (p = 0.002). The difference between the SVC and the FVC should be larger in group A (airway), and it was: 0.353 L vs 0.178 L (p = 0.001).

It has been recommended that the largest vital capacity be used to calculate the FEV1/vital capacity in defining airway obstruction.6 Had we used the FEV1/SVC to classify our subjects, we would have reduced our original sample by almost 50%, with 90% of the reduction being in group A. Furthermore, the decrease in the RV resulting from using TLC − SVC rather than TLC − FVC in group A (airway) would be significant from 3.24 to 2.82 L. Thus, the increased diagnosis of obstruction by using the SVC would be associated with a significant decrease in RV! This raises the pathophysiologic question of whether a reduced FEV1/vital capacity is more important in defining obstruction than an elevated RV. To use a maximal expiratory effort measure, the FEV1, divided by a submaximal inspiratory effort measure seems nonphysiologic. Furthermore, in situations where the SVC exceeds the FVC, the volume added by the SVC has little functional significance because it is rarely utilized during quiet breathing and probably never during exercise in patients with obstruction.20

In summary, we encountered the nonspecific pattern in 9.5% of our subjects. This pattern was often associated with mild impairment of the FEV1 and FVC and could vary over time. Fifty percent of the subjects were obese. Sixty-eight percent had airway hyperreactivity or chronic lung disease. We propose a lung volume derecruitment mechanism to explain the airway obstruction in this group. Thirty-two percent of subjects had no evidence of airway disease. This study reemphasizes that a normal FEV1/FVC with a reduced FEV1 and FVC does not automatically rule out airway obstruction,1,5 and similarly does not automatically rule in pulmonary restriction. The clinician faced with the spirometric findings of a reduced FVC and FEV1 but normal FEV1/FVC should check for airway hyperreactivity by history or by administering a bronchodilator or methacholine. If this does not provide an answer, a measure of TLC to check for restriction should be obtained. If these approaches are negative, conditions in categories 4 and 5 in Table 3 should be considered.

AHR

airway hyperresponsiveness

BMI

body mass index

Dlco

diffusing capacity of the lung for carbon monoxide

MEFV

maximal expiratory flow volume

NSP

nonspecific pattern

RV

residual volume

SVC

slow expiratory vital capacity

TLC

total lung capacity

The authors thank Kenneth O. Parker and Patricia Muldrow for their valuable assistance.

Olive JT Jr, Hyatt RE. Maximal expiratory flow and total respiratory resistance during induced bronchoconstriction in asthmatic subjects. Am Rev Respir Dis. 1972;106:366-376. [PubMed]
 
Cade JF, Woolcock AJ, Rebuck AS, et al. Lung mechanics during provocation of asthma. Clin Sci. 1971;40:381-391. [PubMed]
 
Hyatt RE, Scanlon PD, Nakamura M. Interpretation of pulmonary function tests. 1997; New York, NY Lippincott-Raven:37
 
Stanescu D. Small airways obstruction syndrome. Chest. 1999;116:231-233. [PubMed] [CrossRef]
 
Stanescu DC, Veriter C. A normal FEV1/VC ratio does not exclude airway obstruction. Respiration. 2004;71:348-352. [PubMed]
 
Pellegrino R, Viegi V, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26:948-968. [PubMed]
 
Hyatt RE, Cowl CT, Bjoraker JA, et al. Conditions associated with the “nonspecific” spirometric abnormality [abstract]. Am J Respir Crit Care Med. 2007;175:A608
 
Parker CD, Bilbo RT, Reed CE. Methacholine aerosol as test for bronchial asthma. Arch Intern Med. 1965;115:452-458. [PubMed]
 
Miller A, Thornton JC, Warshaw R, et al. Mean and instantaneous expiratory flows, FVC and FEV1: prediction equations from a probability sample of Michigan, a large industrial state. Bull Eur Physiopathol Respir. 1986;22:589-597. [PubMed]
 
Miller A, Thornton JC, Warshaw R, et al. Single-breath diffusing capacity in a representative sample of the population of Michigan, a large industrial state: predicted values, lower limits of normal, and frequencies of abnormality by smoking history. Am Rev Respir Dis. 1983;127:270-277. [PubMed]
 
Aaron SD, Deles RE, Cardinal P. How accurate is spirometry at predicting restrictive pulmonary impairment? Chest. 1999;115:869-873. [PubMed]
 
Brown RH, Pearse DB, Pyrgos G, et al. The structural basis of airways hyperresponsiveness in asthma. J Appl Physiol. 2006;101:30-39. [PubMed]
 
Samee S, Altes T, Powers P, et al. Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: assessment of response to methacholine and exercise challenge. J Allergy Clin Immunol. 2003;111:1205-1211. [PubMed]
 
King GG, Eberl S, Salome CM, et al. Differences in airway closure between normal and asthmatic subjects measured with single-photon emission computed tomography and Technegas. Am J Respir Crit Care Med. 1998;158:1900-1906. [PubMed]
 
Pellegrino R, Biggi A, Papileo A, et al. Regional expiratory flow limitation studied with Technegas in asthma. J Appl Physiol. 2001;91:2190-2198. [PubMed]
 
Lambert RK, Wilson TA. Smooth muscle dynamics and maximal expiratory flow in asthma. J Appl Physiol. 2005;99:1885-1890. [PubMed]
 
Bates JHT, Irvin CG. Time dependence of recruitment and derecruitment in the lung: a theoretical model. J Appl Physiol. 2002;93:705-713. [PubMed]
 
Lundblad LKA, Thompson-Figueroa J, Allen GB, et al. Airway hyperresponsiveness in allergically inflamed mice: the role of airway closure. Am J Respir Crit Care Med. 2007;175:768-774. [PubMed]
 
Weiner P, Waizman J, Weiner M, et al. Influence of excessive weight loss after gastroplasty for morbid obesity on respiratory muscle performance. Thorax. 1998;53:39-42. [PubMed]
 
Potter WA, Olafsson S, Hyatt RE. Ventilatory mechanics and expiratory flow limitation during exercise in patients with obstructive lung disease. J Clin Invest. 1971;50:910-919. [PubMed]
 

Figures

Figure Jump LinkFigure 1 In this schematic drawing, the normal thoracic and lung expansion is represented by the dashed line. The solid line represents a reduced lung expansion (the dark area) due to either a reduction in thoracic expansion or in lung expansion, or a combination of the two. In either case, the FVC and FEV1 are both reduced. However, since the slope of the MEFV curve is unchanged, the FEV1/FVC is also unchanged.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Subject Characteristics (n = 100)*

*Data are presented as mean (SD) unless otherwise indicated.

Table Graphic Jump Location
Table 2 Distribution of BMI by Gender*

*Data are presented as No. (%).

Table Graphic Jump Location
Table 3 Summary of Patient Diagnosis*

*Data are presented as No. (%). Categories 1, 2, and 3 are designated as group A (airway). Categories 4 and 5 are designated as group B (nonairway).

Table Graphic Jump Location
Table 4 Conditions in “Other” Category

References

Olive JT Jr, Hyatt RE. Maximal expiratory flow and total respiratory resistance during induced bronchoconstriction in asthmatic subjects. Am Rev Respir Dis. 1972;106:366-376. [PubMed]
 
Cade JF, Woolcock AJ, Rebuck AS, et al. Lung mechanics during provocation of asthma. Clin Sci. 1971;40:381-391. [PubMed]
 
Hyatt RE, Scanlon PD, Nakamura M. Interpretation of pulmonary function tests. 1997; New York, NY Lippincott-Raven:37
 
Stanescu D. Small airways obstruction syndrome. Chest. 1999;116:231-233. [PubMed] [CrossRef]
 
Stanescu DC, Veriter C. A normal FEV1/VC ratio does not exclude airway obstruction. Respiration. 2004;71:348-352. [PubMed]
 
Pellegrino R, Viegi V, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26:948-968. [PubMed]
 
Hyatt RE, Cowl CT, Bjoraker JA, et al. Conditions associated with the “nonspecific” spirometric abnormality [abstract]. Am J Respir Crit Care Med. 2007;175:A608
 
Parker CD, Bilbo RT, Reed CE. Methacholine aerosol as test for bronchial asthma. Arch Intern Med. 1965;115:452-458. [PubMed]
 
Miller A, Thornton JC, Warshaw R, et al. Mean and instantaneous expiratory flows, FVC and FEV1: prediction equations from a probability sample of Michigan, a large industrial state. Bull Eur Physiopathol Respir. 1986;22:589-597. [PubMed]
 
Miller A, Thornton JC, Warshaw R, et al. Single-breath diffusing capacity in a representative sample of the population of Michigan, a large industrial state: predicted values, lower limits of normal, and frequencies of abnormality by smoking history. Am Rev Respir Dis. 1983;127:270-277. [PubMed]
 
Aaron SD, Deles RE, Cardinal P. How accurate is spirometry at predicting restrictive pulmonary impairment? Chest. 1999;115:869-873. [PubMed]
 
Brown RH, Pearse DB, Pyrgos G, et al. The structural basis of airways hyperresponsiveness in asthma. J Appl Physiol. 2006;101:30-39. [PubMed]
 
Samee S, Altes T, Powers P, et al. Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: assessment of response to methacholine and exercise challenge. J Allergy Clin Immunol. 2003;111:1205-1211. [PubMed]
 
King GG, Eberl S, Salome CM, et al. Differences in airway closure between normal and asthmatic subjects measured with single-photon emission computed tomography and Technegas. Am J Respir Crit Care Med. 1998;158:1900-1906. [PubMed]
 
Pellegrino R, Biggi A, Papileo A, et al. Regional expiratory flow limitation studied with Technegas in asthma. J Appl Physiol. 2001;91:2190-2198. [PubMed]
 
Lambert RK, Wilson TA. Smooth muscle dynamics and maximal expiratory flow in asthma. J Appl Physiol. 2005;99:1885-1890. [PubMed]
 
Bates JHT, Irvin CG. Time dependence of recruitment and derecruitment in the lung: a theoretical model. J Appl Physiol. 2002;93:705-713. [PubMed]
 
Lundblad LKA, Thompson-Figueroa J, Allen GB, et al. Airway hyperresponsiveness in allergically inflamed mice: the role of airway closure. Am J Respir Crit Care Med. 2007;175:768-774. [PubMed]
 
Weiner P, Waizman J, Weiner M, et al. Influence of excessive weight loss after gastroplasty for morbid obesity on respiratory muscle performance. Thorax. 1998;53:39-42. [PubMed]
 
Potter WA, Olafsson S, Hyatt RE. Ventilatory mechanics and expiratory flow limitation during exercise in patients with obstructive lung disease. J Clin Invest. 1971;50:910-919. [PubMed]
 
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