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First published online on February 22, 2007
Chest, doi:10.1378/chest.06-2194
doi:10.1378/chest.06-2194
(Chest. 2007; 131:1372-1378)
© 2007 American College of Chest Physicians
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The Association Between Small Airway Obstruction and Emphysema Phenotypes in COPD*

Won-Dong Kim, MD, FCCP; Sean H. Ling, BSc; Harvey O. Coxson, PhD; John C. English, MD, FCCP; John Yee, MD; Robert D. Levy, MD, FCCP; Peter D. Paré, MD and James C. Hogg, MD, PhD, FCCP

* From the Division of Pulmonary and Critical Care Medicine (Dr. Kim), Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea; The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul’s Hospital (Mr. Ling and Drs. Coxson, Levy, Paré and Hogg), the Department of Surgery (Dr. Yee), and the Department of Pathology (Dr. English), Vancouver General Hospital, University of British Columbia, Vancouver, Canada.

Correspondence to: Won-Dong Kim, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Republic of Korea; e-mail: wdkim{at}amc.seoul.kr

Abstract

Background: Airflow limitation in COPD is due to a variable combination of small airway obstruction and centrilobular emphysema (CLE) and/or panlobular emphysema (PLE), but the relationship between these three different phenotypes is poorly understood. This study compares the severity of small airway obstruction in both forms of emphysema and determines its relationship with FEV1.

Methods: We compared the lung histology of nonsmoking control subjects without emphysema (n = 10) to that of patients with CLE (n = 30) and PLE with (n = 8) and without {alpha}1-antitrypsin (AAT) deficiency (n = 11). The degree of airspace enlargement was measured using the mean interalveolar wall distance (IAWD) [mean linear intercept, Lm], and the evenness of airspace destruction was assessed by the coefficient of variation (CV) of the IAWD. The severity of small airway obstruction was determined by dividing total wall area by the length of the basement membrane to obtain wall thickness.

Results: Lm was greater in all three subgroups of emphysema than in control subjects, and in AAT deficiency than in PLE or CLE. The CV of IAWD was greater in AAT deficiency and CLE than in control subjects and in CLE than in AAT deficiency or PLE. Although small airway wall thickness was greater in CLE and PLE with AAT deficiency than in control subjects, the association between wall thickness and both Lm and FEV1 was observed only in CLE.

Conclusions: Small airway wall thickening occurs in CLE and PLE with AAT deficiency but is more closely associated with degree of emphysema and airflow limitation in CLE.

Key Words: {alpha}1-antitrypsin deficiency • centrilobular emphysema • COPD • emphysema • FEV1 • morphometry • panlobular emphysema • small airway obstruction • small airway wall thickness

The defining physiologic feature of COPD is airflow limitation that is not fully reversible1 due to a variable combination of increased resistance to flow through the small conducting airways2 and/or emphysematous destruction of alveolar walls leading to loss of elastic recoil.3 The principal cause of the increase in airways resistance is small airway obstruction,2 and the main causes of the reduced lung elastic recoil are centrilobular emphysema (CLE) and panlobular emphysema (PLE).

Emphysema has been recognized in association with airway obstruction since the time of Laennec,4 but the relationship between them is poorly understood.5 Reports from the late 1950s and early 1970s demonstrated bronchiolar narrowing6 and changes in the caliber of the small conducting airways in emphysema.7 The classical description of the CLE suggested that the inflammation extended into the parenchyma from the terminal bronchioles and became organized to thicken these structures,8 and a subsequent investigation9 showed CLE was associated with bronchiolar stenoses. However, another study10 showed thickening of the small airway walls in PLE but not in CLE. More recently, a large cross-sectional study11 of patients undergoing lung volume reduction surgery (LVRS) for advanced emphysema showed a clear relationship between the level of FEV1 and thickening of the small airway walls but could not comment on the type of emphysema because the LVRS specimens were not inflated. The concept that the lesions in the small airways are more closely related to CLE than PLE was reintroduced by morphometric studies using microscopic classification of emphysema with measurement of small airway disease pathologic scores121314 or small airway wall dimensions.1516

However, the past studies are based on observational descriptions,8 subjective macroscopic classification of emphysema with indirect measurement of bronchial obstruction on postmortem specimens,7910 semiquantitative visual scoring of small airway pathology,121314 or assessment of calculated wall area.15 We suspect that these differences in technique may be partially responsible for the inconsistent results concerning the relationship between small airway remodeling and type of emphysema, with no one theory being widely accepted.5

The present study sought to confirm and extend these observations using computer-assisted direct measurements of airway wall area and basement membrane length to better define the relationship between small airway remodeling and the various forms of emphysematous destruction. Rather than estimating differences in small airway disease scores1213 or wall area1516 between two groups of CLE and PLE, we investigated the change in small airway wall thickness in relation to the severity of both forms of emphysema. {alpha}1-Antitrypsin (AAT) deficiency is associated with PLE1718 and occasionally with bronchiectasis,19 and others20 have suggested that bronchiolar changes are more frequent in patients with AAT deficiency than in PLE without AAT deficiency. Therefore, we also compared the relationship between small airway wall thickness and degree of emphysema in PLE patients with and without AAT deficiency.

Materials and Methods

Subject Population
The study group consisted of 10 nonsmoking control subjects with normal spirometry and no microscopic emphysema and 49 subjects with a microscopic diagnosis of emphysema. All subjects required lung resection for either small peripheral lung tumors (n = 38), LVRS (n = 3), or lung transplantation for advanced COPD (n = 18) in Vancouver, Canada. All of the subjects gave informed consent for their participation in the study,21 and the protocol was approved by the Hospital and University of British Columbia Clinical Ethics Review Board.

Table 1 summarizes age, gender, smoking status, FEV1, Global Initiative for Chronic Obstructive Lung Disease1 stage, lung volumes, and diffusing capacity of the lung for carbon monoxide (DLCO) in the control group (n = 10), AAT deficiency (n = 8), PLE (n = 11), and CLE (n = 30). The patients with AAT deficiency were younger and showed a tendency of more advanced stage, with the lowest FEV1 and the most abnormal lung volumes and DLCO. CLE patients were heavier smokers.


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  		Table 1. Clinical Characteristics of the Subjects*

 
Pulmonary Function Testing
All pulmonary function tests were done using equipment that met the standards of the American Thoracic Society.

Preparation of Resected Specimens
Lung tissues with AAT deficiency came from 3 right whole lungs and 5 lower lobes, PLE from 2 right or left whole lungs, 5 upper and 4 lower lobes, and CLE from 11 right or left whole lungs, 13 upper lobes, 5 lower lobes, and 1 middle lobe. The lungs or lobes of 41 patients from St. Paul’s Hospital were fixed by intrabronchial infusion of 10% formalin, and the lungs or lobes of 18 patients from the Vancouver General Hospital were fixed by inflation with Bouin fixative; both groups were held at a distending pressure of 20 to 25 cm of fixative for 24 h. Samples of fixed lung tissues were cut sagittally into slices 1 cm thick at the Vancouver General Hospital and into transverse sections 2 cm thick at St. Paul’s Hospital. Randomly selected template tissue blocks, 2.5 x 2 cm, were taken from the slices, ie, 5 for a lobe and 10 for a lung. Samples of fixed tissue were processed into paraffin blocks, cut into sections 4 to 5 µm thick, placed on glass slides, and stained with Movat pentachrome technique.11

Microscopic Criteria Used to Classify Emphysema
Microscopic PLE was diagnosed when the secondary lobules were evenly involved from center to periphery,22 but focal enlargement of alveoli was not regarded as evidence of PLE. Microscopic CLE was diagnosed when sharply demarcated emphysematous spaces at the center of a secondary lobule are associated with intact alveolar ducts and sacs of normal size at the periphery.8 Actual microscopic classification of the specimens was agreed on by two of authors (W.K., J.C.H.).

Measurements of Alveolar and Airway Dimensions
Digital images of the airways and lung parenchyma were separately obtained.11 Measurements of interalveolar wall distance (IAWD) were made on captured images of microscopic fields obtained with a x 10 eyepiece and a x 0.6 objective with digital image analysis software (Media Cybernetics; Carlsbad, CA) using a method described by Thurlbeck.23 IAWD was measured in at least 20 fields from each slide using a single gridline rotated through 90° (10 fields in each direction). The values obtained in each field were used to calculate the coefficient of variation (CV) [SD/mean] of IAWD, which was used to define the evenness or unevenness of lung destruction.12 Mean IAWD, expressed as mean linear intercept (Lm), was used as a measure of the degree of emphysema.

Images of cross-sectioned airways < 2 mm in diameter were examined. Wall area, which included the area bound by the epithelial luminal surface and the connective tissue at the outer limits of the adventitia, was measured with digital image analysis software. Airway wall thickness was used as a measure of airway obstruction and was related to airway size by dividing wall area by basement membrane perimeter.24

Statistical Analysis
Results are expressed as mean ± SD. A nonparametric analysis of variance (Kruskal-Wallis test) was used to evaluate significant differences among the groups; when significance was found, post hoc analysis between groups was performed with nonparametric Mann-Whitney test. The correlation between the variables was determined with the use of nonparametric Spearman rank correlation. To determine whether FEV1 is dependent on wall thickness, the relationship was assessed by simple linear regression. All statistical analyses were performed using software (SPSS, version 12.0.1; SPSS; Chicago, IL); p < 0.05 was considered significant.

Results

Table 2 summarizes the measurements of alveolar dimensions and small airway wall thickness in four groups. Lm was higher in AAT deficiency, PLE, and CLE than in nonsmoking control subjects (p < 0.002, respectively) and also in AAT deficiency than in PLE or CLE (p < 0.01, respectively). CV of IAWD was greater in AAT deficiency and CLE (p < 0.002, respectively) than in control subjects and in CLE than in AAT deficiency or PLE (p < 0.002, respectively). Small airway wall thickness was greater in AAT deficiency and CLE than in control subjects (p < 0.01, respectively), but there was no difference between AAT deficiency, PLE, and CLE.


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  		Table 2. Results of Morphometric Measurement of Parenchyma and Small Airways*

 
Figure 1 shows a correlation between small airway wall thickness and the degree of emphysema in CLE (Spearman r = 0.580, p = 0.001) but not in AAT deficiency (Spearman r = 0.143, p = 0.736) or PLE (Spearman r = 0.264, p = 0.433). This correlation between small airway wall thickness and the degree of emphysema was also not significant even in the combined group of PLE with and without AAT deficiency (Spearman r = 0.416, p = 0.077). Figure 2 shows greater small airway wall thickness in CLE (0.160 ± 0.038 mm) than in AAT deficiency (0.114 ± 0.028 mm) or PLE (0.117 ± 0.025 mm) [p < 0.03, respectively] in patients with severe emphysema arbitrarily defined by Lm > 0.25 mm. Figure 3 shows a relationship between small airway wall thickness and FEV1 in CLE (R2 = 0.433, p < 0.001) but not in AAT deficiency (R2 = 0.002, p = 0.910) or PLE (R2 = 0.285, p = 0.091). This relationship between small airway wall thickness and FEV1 was also not significant even in the combined group of PLE with and without AAT deficiency (R2 = 0.186, p = 0.065).


Figure 1
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  		Figure 1. Correlation between small airway wall thickness and the degree of emphysema as measured by Lm in CLE and PLE with and without AAT deficiency. The solid line indicates the regression line for CLE, the long dashed line indicates the regression line for PLE, the short dashed line indicates the regression line for AAT deficiency, and medium dashed line indicates the regression line for nonsmoking control subjects. There is a stronger correlation in CLE (Spearman r = 0.580, p = 0.001) than in AAT deficiency (Spearman r = 0.143, p = 0.736) or PLE (Spearman r = 0.264, p = 0.433).

 

Figure 2
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  		Figure 2. Small airway wall thickness in all subjects and in a subgroup of patients with severe emphysema with Lm > 0.25 mm. Small airway wall thickness was greater in AAT deficiency and CLE than in nonsmoking control subjects (*p < 0.01, respectively), but there was no difference between AAT deficiency, PLE, and CLE in all cases. Small airway wall thickness in CLE was greater than in AAT deficiency or PLE (+p < 0.03, respectively) in patients with severe emphysema.

 

Figure 3
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  		Figure 3. Relationship between small airway wall thickness and FEV1 in the three types of emphysema. The solid line indicates the regression line for CLE, the long dashed line indicates the regression line for PLE, the short dashed line indicates the regression line for AAT deficiency, and medium dashed line indicates the regression line for nonsmoking control subjects. There is a stronger relationship between small airway wall thickness and FEV1 in CLE (R2 = 0.443, p < 0.001) than in AAT deficiency (R2 = 0.002, p = 0.910) or PLE (R2 = 0.285, p = 0.091).

 
Because of lobar differences in the distribution of emphysema and the fact that only one lobe was available in some cases, wall thickness was compared between upper and lower lobes. These results showed no differences in small airway wall thickness between upper and lower lobes in PLE with and without AAT deficiency (0.093 ± 0.027 and 0.125 ± 0.042 mm, respectively; p = 0.232) and in CLE (0.129 ± 0.049 and 0.118 ± 0.032 mm, respectively; p = 0.711).

Discussion

Emphysema contributes to the decrease in expiratory flow by reducing the elastic recoil pressure available to drive air out of the lungs,3 whereas obstruction in the small airways is most closely associated with a remodeling process that thickens the airway walls.11 However, as both small airway obstruction and emphysema are commonly present within the lungs of individuals with COPD, it is difficult to determine which component of the disease provides the most appropriate therapeutic target.

The present results show that the small airway walls are thicker in both the centrilobular and panlobular emphysematous lung destruction with AAT deficiency. In addition, they show an association between thickening of the small airway walls and severity of emphysema in CLE, which suggests that small airway wall remodeling might progress to centrilobular emphysematous destruction. We extend these findings by showing that although the airways thicken in patients with PLE who had AAT deficiency, there was no relationship between this airway thickening and the severity of emphysema. Furthermore, this difference between these two forms of emphysema was the same for PLE without AAT deficiency. The study also shows a stronger relationship between small airway wall thickening and airflow limitation in CLE, suggesting that small airway obstruction may be the dominant cause of airflow limitation in the centrilobular form,12 and loss of elastic recoil may be the dominant cause of airflow limitation in the panlobular form of emphysema.

The present results are also relevant to the report25 showing that collagen is increased in the lung tissues of CLE and elastin decreased in PLE, and suggest the hypothesis that the inflammatory repair process involving the terminal and respiratory bronchioles of cigarette smokers accounts for the small airway obstruction and destruction of the respiratory bronchioles in the centrilobular form of emphysema; whereas protease-antiprotease imbalance based on neutrophil elastase and AAT might better explain the more uniform destruction of the entire acinus in PLE. The fact that this biochemical imbalance is present in the circulating blood26 is also consistent with preferential location of PLE in the lower lobes because they receive the greatest blood flow in the upright position.

We found no difference in the small airway wall thickness between upper and lower lobes in either form of emphysema. This finding is consistent with a previous report9 showing that the bronchial stenosis associated with the centilobular form is scattered throughout the whole lung, and showing no difference in small airways disease scores between upper and lower lobes.14 The fact that the airway disease is uniformly distributed in the upper and lower lungs and the emphysema favors the upper lobes in the centrilobular form and the lower lobes in the panlobular form suggests that the airways may respond differently than the parenchyma in both forms of emphysema, but more work is needed in this area. Some of our patients with both forms of emphysema had lung function and Lm values that overlapped those of nonsmoking control subjects without emphysema. We attribute this to the fact that the diagnosis of emphysema was based on microscopic criteria observed in samples of lung rather than on the total amount of emphysema present in the lungs. Previous reports indicate that some patients with relatively severe emphysema have very little airflow obstruction27 and that some elderly nonsmokers have senile lungs,28 in whom dilatation of the alveolar ducts might account for an overlap of Lm with those who have mild disease.

We cannot exclude the possibility that differences in the fixatives used at the two hospitals introduced a source of error into these studies. Small differences in the amount of tissue shrinkage associated with different fixatives have been reported, but are thought to be negligible in solid tissues.29 The lungs were inflated with the distending pressure of 20 to 25 cm of fixative at both hospitals which is within normal range of normal transpulmonary pressure.30 Two factors could have influenced the degree of inflation at which the measurements were made. The first is that because maximum elastic recoil pressure is known to decrease with age31 and in emphysema, the inflation pressure of the fixative might have overinflated these lung specimens in some cases. The second is that formalin fixation may allow a greater degree of tissue collapse than Bouin fixative when the tissue is cut to obtain the histologic specimen. We do not believe either of these problems introduce a serious source of error because animal studies have shown that surface area increases only modestly beyond the mid-inflation range32 and the terminal portion of lung pressure-volume curve is quite flat in human lungs. Figure 3 shows that airway wall thickness of some patients with lower FEV1 overlapped those from cases with a higher FEV1. Although this is attributable to the random inhomogeneous distribution of small airway obstruction within individual lungs933 and possible sampling bias of specimens where the entire lung is not available, it may also be due to the fact that some with severe emphysema can have nearly normal spirometry.27 The presence of a lung tumor can influence lung function, but this was minimized in our study by choosing cases where the tumors were small and peripherally located. Medication history of the subjects was not included in the study, but inhaled and systemic corticosteroid treatment has recently been shown not to influence airway remodeling in severe COPD.34

In summary, our data confirm that the small airways thicken in centrilobular and panlobular emphysema with AAT deficiency, and that the extent of the remodeling of the small airways is greater in centrilobular than in the panlobular form. It also establishes that there is no association between small airways wall thickening and the severity of emphysema in the panlobular form of emphysema observed in patients with or without AAT deficiency. Based on these findings, we postulate that close association between small airway wall thickening and the centrilobular form of emphysema might justify their combination as a single target in the development of new therapies for COPD, whereas the small airways represent a secondary target when the panlobular emphysema is the major disease phenotype.

Acknowledgements

The authors thank thoracic surgeons at Vancouver General Hospital (Drs. Guy Fradet, Kenneth Evans, and Richard Finley) and St Paul’s Hospital (Drs. Mary Lynn Brumwell, Hilton Ling, and Robert Miyagashima) for their kind collaboration. We are indebted to Fanny Chu, BSc, and W. Mark Elliott, PhD (St. Paul’s Hospital) for their assistance with morphometric studies.

Footnotes

Abbreviations: AAT = {alpha}1-antitrypsin; CLE = centrilobular emphysema; CV = coefficient of variation; DLCO = diffusing capacity of the lung for carbon monoxide; IAWD = interalveolar wall distance; Lm = mean linear intercept; LVRS = lung volume reduction surgery; PLE = panlobular emphysema

This work was performed at The James Hogg iCAPTURE Center of Cardiovascular and Pulmonary Research, St. Paul’s Hospital, University of British Columbia, Vancouver, Canada.

Drs. Kim, English, Yee, and Levy and Mr. Ling have no conflicts of interest to disclose. Dr. Coxson received $11,000 in 2003 for serving on an advisory board for GlaxoSmithKline. In addition, he is the coinvestigator on two multicenter studies sponsored by GlaxoSmithKline and has received travel expenses to attend meetings related to the project. He has three contract service agreements with GlaxoSmithKline to quantify the CT scans in subjects with COPD. A percentage of his salary between 2003 and 2006 (US $15,000/yr) derives from contract funds provided to a colleague Peter D. Paré by GlaxoSmithKline for the development of validated methods to measure emphysema and airway disease using CT. There is no financial relationship between any industry and the current study.

Dr. Paré is the principal investigator of a project funded by GlaxoSmithKline to develop CT-based algorithms to quantitate emphysema and airway disease in COPD. With collaborators he has received approximately $300,000 to develop and validate these techniques. The funds he has applied solely to the research to support programs and technicians. He is also principal investigator of a Merck Frosst-supported research program to investigate gene expression in the lungs of patients who have COPD. He and collaborators have received approximately $200,000 for this project. These funds have supported the technical personnel and expendables involved in the project.

Dr. Hogg has served as a consultant to Altana Pharmaceuticals in 2003, 2004, and 2005, and also served on the Canadian advisory board for GlaxoSmithKline for 1 year in 2003. He has participated as a speaker in scientific meetings and courses organized and financed by various pharmaceutical companies, including AstraZeneca, Altana Pharmaceuticals, and GlaxoSmithKline. He serves as the principal investigator on a joint Canadian Institute of Health Research and industry-sponsored grant, supported one third by the Canadian Institute of Health Research and two thirds by industry. This grant application was funded after peer review by the regular Canadian Institute of Health Research mechanism, and the funds received from industry are directly related to the operating costs of the study.

Dr. Kim was supported by grant No. F01-2004-000-10180-0 from the Korea Science and Engineering Foundation, Republic of Korea.

Received for publication September 4, 2006. Accepted for publication January 5, 2007.

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