The Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary Disease
James C. Hogg, M.D., Fanny Chu, B.Sc., Soraya Utokaparch, B.Sc., Ryan Woods, M.Sc., W. Mark Elliott, Ph.D., Liliana Buzatu, M.D., Ruben M. Cherniack, M.D., Robert M. Rogers, M.D., Frank C. Sciurba, M.D., Harvey O. Coxson, Ph.D., and Peter D. Paré, M.D.
Background Chronic obstructive pulmonary disease (COPD) is amajor public health problem associated with long-term exposureto toxic gases and particles. We examined the evolution of thepathological effects of airway obstruction in patients withCOPD.
Methods The small airways were assessed in surgically resectedlung tissue from 159 patients — 39 with stage 0 (at risk),39 with stage 1, 22 with stage 2, 16 with stage 3, and 43 withstage 4 (very severe) COPD, according to the classificationof the Global Initiative for Chronic Obstructive Lung Disease(GOLD).
Results The progression of COPD was strongly associated withan increase in the volume of tissue in the wall (P<0.001)and the accumulation of inflammatory mucous exudates in thelumen (P<0.001) of the small airways. The percentage of theairways that contained polymorphonuclear neutrophils (P<0.001),macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038),B cells (P<0.001), and lymphoid aggregates containing follicles(P=0.003) and the absolute volume of B cells (P=0.03) and CD8cells (P=0.02) also increased as COPD progressed.
Conclusions Progression of COPD is associated with the accumulationof inflammatory mucous exudates in the lumen and infiltrationof the wall by innate and adaptive inflammatory immune cellsthat form lymphoid follicles. These changes are coupled to arepair or remodeling process that thickens the walls of theseairways.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD)has introduced a five-stage classification for the severityof chronic obstructive pulmonary disease (COPD) based on measurementsof airflow limitation during forced expiration.1,2 Each stageis determined by the volume of air that can be forcibly exhaledin one second (FEV1) and by the ratio of FEV1 to the forcedvital capacity (FVC); lower stages indicate less severe disease.Abnormalities in these tests reflect both the reduction in theforce available to drive air out of the lung as a result ofemphysematous lung destruction3 and obstruction to airflow inthe smaller conducting airways.4,5,6
COPD is attributed to long-term exposure to toxic gases andparticles,1,2 most often related to cigarette smoking. The primaryhost defenses against this stimulus are the innate and adaptiveinflammatory immune responses.7,8 The innate defense systemof the lung includes the mucociliary clearance system9 and theepithelial barrier, supported by the acute inflammatory responsethat follows tissue injury.7,10,11 This response system reactsquickly but lacks specificity, has very limited diversity, andhas no memory.7 The adaptive response provided by the humoraland cellular components of the immune system evolves much moreslowly but is highly specific and very diverse and has an exquisitememory for previous insults.8 The repair process associatedwith both types of response remodels damaged tissue by restoringthe epithelium and microvasculature and adding connective-tissuematrix in an attempt to return the tissue to its previous state.We evaluated the relationship between the progression of COPD,as reflected by the GOLD stage, and the pathological findingsin airways less than 2 mm in internal diameter, which are locatedfrom the 4th to the 12th generation of airway branching in thelung.4,5,6,12
Methods
Specimens and Patient Population
Specimens were obtained from two groups of patients: patientsenrolled in Vancouver, Canada, who required surgical treatmentof small, peripheral lung tumors,13,14,15 and patients enrolledin Pittsburgh, Denver, and Houston,16,17,18 who participatedin the National Emphysema Treatment Trial (NETT). Table 1 showsthe number of patients in each GOLD stage, the clinical anddemographic characteristics, and the type of tissue examined,including the source, the number of airways examined per patient,and the mean length of the basement membrane of airways in eachgroup.
Table 1. Clinical Characteristics of the Patients According to the GOLD Stage of COPD.
Pulmonary Function
The measurements of FEV1 and FEV1:FVC met the American ThoracicSociety standard and have been described previously.13,14,15,16,17,18
Histologic Analysis
The lung tissue obtained from the patients in the NETT was fixedby immersion in formalin, whereas the lungs and lobes resectedfor tumor in patients in Vancouver were first inflated and thenfixed by immersion in formalin. Samples of fixed tissue wereprocessed into paraffin blocks, cut into sections that were4 to 5 µm thick, placed on glass slides, and stained withMovat's pentachrome technique.19 Six complete sets of slidesfrom a subgroup of 40 patients were stained separately to identifypolymorphonuclear neutrophils (NP57, Dako-Cytomation), macrophages(CD68, Dako-Cytomation), eosinophils (Hansel's stain), T-cellsubtypes (CD4 and CD8, NovoCastra Laboratories), and B cells(CD20, Dako-Cytomation). Staining was carried out on an automaticimmunostainer (Dako Autostainer) according to a standard alkalinephosphatase–antialkaline phosphatase method with the useof naphthol AS-BI phosphate (Sigma) and New Fuchsin (Sigma)as substrate. Positive and negative controls were included witheach run.
Digital images of the small conducting airways were obtainedwith the use of a light microscope (Nikon Microphot) equippedwith a digital camera (JVC3-CCD KY F-70, Diagnostic Instruments)linked to a computer and then analyzed with the use of ImagePro Plus digital-image-analysis software (Media Cybernetics).Airways less than 2 mm in diameter were cross-sectioned andexamined.20,21 The maximal luminal area was calculated by determiningthe area enclosed by a circle formed by the full length of thebasement membrane minus the area taken up by the epithelium(this process is termed expansion).20,21 The luminal contentwas expressed as a fraction of the maximal luminal area to correctfor the uncontrolled collapse of the lumen that occurs whenlung tissue is fixed in different ways. Wall thickness includedthe area bound by the epithelial luminal surface and the connectivetissue at the outer limit of the adventitia. The fractionalareas (Vv) taken up by epithelium (from the basement membraneto the luminal surface), lamina propria (from the basement membraneto the outer edge of the smooth muscle), and adventitia (fromthe outer edge of the smooth muscle to the outer edge of theadventitia) were also measured. Because histologic analysisreduces three-dimensional structures to two dimensions, in whichvolumes become areas and surfaces become lines, the ratio oftissue area to the length of the basement membrane was usedto express the ratio of the volume to the surface area (V:SA)or the thickness of the airway wall and its compartments.
We determined the extent of the infiltration of the small airwaysby each type of inflammatory cell by counting the airways aspositive if they contained the inflammatory cells and negativeif they did not. We estimated the total number of each typeof inflammatory cell by measuring their accumulated volume usinga multilevel cascade sampling design.22,23,24 The referencevolume (level 1) for this cascade is the total volume of lungtissue estimated from the electronic record of the preoperativecomputed tomographic (CT) scan. Lung weight was determined bymultiplying the volume of each CT voxel by CT density and thensumming the values for the entire lung. We determined the totaltissue volume by dividing this lung weight by the gas-free tissuedensity (1.065).22 We determined the Vv of the total lung tissuetaken up by small airways by counting the number of points occupiedby small airways in whole-mount images of the histologic sections(level 2), and we determined the Vv of each compartment in theairway wall by counting the number of points at the next levelof magnification (level 3). We then determined the Vv of specificallystained cells present in each airway compartment by countingthe number of points at the next level of magnification (level4). We calculated the absolute volume of a cell of interestin the entire airway wall and compartments by multiplying theVv values from the highest level of magnification (level 4)through the other levels to the reference volume.22,23,24
Statistical Analysis
The correlation between the FEV1 and the numbers of airwayspositive for each type of inflammatory immune cell was determinedwith the use of Poisson regression analysis, after adjustmentfor the total number of airways examined for each type of cell.25The correlation between FEV1 and the volume of each type ofinflammatory cell, wall, or lumen variable was determined withthe use of a univariate analysis based on Spearman's rank correlation.26The strongest correlates with FEV1 from the lumen, wall compartments,and lymphocyte subtypes were then included simultaneously ina multiple linear-regression model.26 All statistical testsperformed were two-sided and used a type I error of 0.05.
Results
The mean (±SE) number of airways examined per patientand the mean basement-membrane length were similar in all fiveGOLD groups (Table 1). Figure 1A shows an airway from a patientwith GOLD stage 4 in which an inflammatory exudate containingmucus nearly fills the airway lumen. Figure 1B shows the sameairway after the lumen has been fully expanded by smoothingout the mucosal folds.20Figure 1C shows the frequency distributionof the ratio of the area of the luminal content to the expandedarea of the lumen before and after correction to full expansionof the lumen in all the patients with GOLD stage 4. Figure 1Dshows the relationship between the severity of the luminal occlusion,calculated after the airway lumen had been fully expanded, andFEV1 for all 159 patients in the study.
Figure 1. Airway from a Patient with GOLD Stage 4 COPD before (Panel A) and after (Panel B) Expansion, the Frequency Distribution of the Ratio of the Luminal Content to the Total Luminal Area in 42 Patients with GOLD Stage 4 COPD (Panel C), and the Relationship between the Forced Expiratory Volume in One Second (FEV1) and the Median Luminal Occlusion in All 159 Patients (Panel D).
Panel A shows a single airway from a patient with the most severe stage of COPD (GOLD stage 4) in which the mucosa is folded because the lung was fixed in a collapsed state (Movat's stain, x4). Panel B shows a reconstructed diagram of the same airway shown in Panel A after the lumen was fully expanded by manipulation of the digital image (Movat's stain, x4).20 Panel C shows the frequency distribution of the ratio of the luminal content to the total luminal area for 562 airways from 42 patients with GOLD stage 4 COPD before and after the luminal area was fully expanded. Although expansion of the lumen shifts the distribution curve to the left, many airways remain partially occluded. Panel D shows the relationship between FEV1 and the median value of luminal occlusion for each of the 159 patients after the luminal area was fully expanded (R=0.505, P=0.001).
Figure 2A shows an airway with a lymphoid follicle containinga germinal center. Figure 2B shows that these structures stainedstrongly for B cells, and Figure 2C shows that the area surroundingthe follicles stained strongly for CD4 cells. Figure 2D showsa remodeled airway in which connective tissue has been depositedin the subepithelium and adventitia of the airway wall.
Figure 2. Pathological Findings in Patients with COPD.
Panel A shows a collection of bronchial lymphoid tissue with a lymphoid follicle containing a germinal center (GC) surrounded by a rim of darker-staining lymphocytes that extend to the epithelium of both the small airway and alveolar surface (Movat's stain, x6). Panel B shows another follicle, in which the germinal center stains strongly for B cells (x6), and Panel C shows a serial section of the same airway stained for CD4 cells, which are scattered around the edge of the follicle and in the airway wall (x6.5). Panel D shows an airway that has been extensively remodeled by connective-tissue deposition in the subepithelial and adventitial compartments of the airway wall. The arrow points to the smooth muscle that separates the subepithelial from the adventitial compartments (Movat's stain, x6).
Figure 3A and Figure 3B show the number of airways that werepositive for polymorphonuclear neutrophils, macrophages, eosinophils,CD4 cells, CD8 cells, and B cells, expressed as a percentageof the total number of airways examined for each type of cell.Figure 3C shows the relationship between FEV1 and total wallthickness over the entire range of FEV1, and Figure 3D showsthe V:SA ratio or thickness of each airway compartment and thepercentage of the airways with lymphoid follicles in each GOLDstage.
Figure 3. Clinical Findings in Patients with COPD According to the GOLD Stage.
Panel A shows the extent of the airway inflammatory response, as measured by the percentage of the airways containing polymorphonuclear neutrophils (PMNs), macrophages, and eosinophils, among patients in each GOLD stage of COPD. Panel B shows similar data for CD4 cells, CD8 cells, and B cells. Panel C shows the association between total wall thickness, measured as the ratio of the volume to the surface area (V:SA), and forced expiratory volume in one second (FEV1) for all 159 patients. Panel D shows the mean (+SE) volume of epithelium, lamina propria, smooth muscle, and adventitial tissue expressed per unit of basement-membrane surface area (V:SA) and the percentage of airways that contained lymphoid follicles in all 159 patients. Patients with GOLD stages 2 and 3 have been combined in Panels A and B to make the number of patients similar in each group. Asterisks indicate P<0.001 for the comparison with patients with GOLD stage 0. Daggers indicate P<0.001 for the comparison with patients with GOLD stage 1. Double daggers indicate P<0.001 for the comparison with patients with GOLD stage 2.
Table 2 summarizes the analysis of the subgroup of 40 patientsin whom inflammatory immune cells were measured. The extentof the response, as reflected by the number of airways containingpolymorphonuclear neutrophils, macrophages, CD4 cells, CD8 cells,B cells, and lymphoid follicles, increased with disease progression,whereas the total accumulated volume of cells only increasedfor B cells and CD8 cells. The univariate analysis involvingall 159 patients (Table 2) shows strong associations betweenthe progression of COPD and the percentage of airways containinglymphoid follicles, the occlusion of the fully expanded lumenby inflammatory mucous exudates, total wall thickness, and thethickness of each of the wall compartments. The multivariateanalysis for both the entire group of patients and the subgroupof 40 patients indicates that thickening of the airway wallshad the strongest association with the progression of COPD.
Table 2. Relationship of FEV1 to Small-Airway Abnormalities.
Discussion
Our results extend those of previous reports4,5,6 by providingquantitative information about the nature of the pathologicalfindings at the site of airway obstruction in relation to theGOLD stage of COPD.1,2 The multivariate analysis indicates thatprogression of COPD from GOLD stage 0 to GOLD stage 4 was moststrongly associated with thickening of the airway wall and eachof its compartments by a repair or remodeling process. The degreeto which the lumen was filled with mucous exudates; the extentof the inflammatory response, as reflected by the number ofthe airways containing acute inflammatory cells (polymorphonuclearleukocytes and macrophages) and lymphocytes (CD4 cells, CD8cells, and B cells) organized into follicles; and the severityof this response, as reflected by the absolute volumes of CD8cells and B cells, were more weakly associated with diseaseprogression.
Our results expand on previous reports that the epithelial barrierof the innate defense system is breached in cigarette smokers10,11by showing that small airways become occluded by inflammatoryexudates containing mucus as COPD progresses. Hypersecretionof mucus is the defining feature of chronic bronchitis and isassociated with an inflammatory process involving the epithelium,gland ducts, and glands of the larger central airways.27,28Although the accumulation of inflammatory exudates in the small-airwaylumen might be attributed to the extension of chronic bronchitisinto the small airways, several studies suggest that this isnot the case. At least two large clinical trials have shownthat the presence of chronic bronchitis does not predict thedevelopment of airflow limitation,29,30 and pathological studiesindicate that central and peripheral airway inflammation canoccur quite independently of each other.27 Collectively, thesedata suggest that the cough and sputum production that defineschronic bronchitis is independent of the disease process inthe small airways that is responsible for airway obstructionin patients with COPD.
The Poisson regression analysis of the number of airways containinginflammatory cells shows that progression of COPD is associatedwith increasing infiltration of the airways by polymorphonuclearneutrophils, macrophages, CD4 cells, and lymphocyte subtypes.However, the cascade analysis showed that the accumulated volumeof inflammatory cells was increased only in the case of CD8cells and B cells. The absence of the accumulation of polymorphonuclearneutrophils, macrophages, and CD4 cells in the airway tissuemay be related to the fact that the patients with severe (GOLDstage 3) and very severe (GOLD stage 4) COPD had all stoppedsmoking an average of nine years earlier and a high percentagehad received some form of corticosteroid therapy.
The observed increase in the absolute volume of CD8 cells andB cells as COPD progressed is consistent with previous results31,32,33and extends such findings by showing an even stronger associationwith the percentage of airways containing lymphoid follicles.The increase in lymphocytes and their organization into folliclesare consistent with increased immune surveillance of the mucosalsurface in patients with COPD, in whom close collaboration amongthe epithelium, antigen-presenting cells, and lymphocytes organizedinto follicles facilitates antigen presentation.34,35 Althoughthe innate immune response can mobilize T cells and B cells,with respect to their organization into follicles, we believethat an adaptive immune response develops in relation to themicrobial colonization and infection known to occur in the laterstages of COPD.36
The strongest association with disease progression was an increasein the volume of the airway wall tissue owing to an increasein epithelium, lamina propria, muscle, and adventitial compartments.The increase in tissue between the epithelial surface and themuscle layer is thought to contribute to nonspecific airwayresponsiveness,37 which is one of the best predictors of therapid decline in FEV1 in patients with COPD.38 The observedincrease in connective tissue in the adventitial compartmentis similar to that reported by Matsuba and Thurlbeck39 and couldcontribute to fixed airway obstruction by preventing the airwaysfrom opening properly during lung inflation. Experiments intransgenic mice have shown that overexpression of cytokinessuch as interleukin-13 results in the activation of transforminggrowth factor , leading to subepithelial and peribronchiolarfibrosis very similar to that reported here.40 A more completeunderstanding of the cytokine pathways that control the depositionof connective tissue in human disease might lead to effectivetreatments.
We conclude that obstruction of the small airways in COPD isassociated with a thickening of the airway wall by means ofa remodeling process related to tissue repair and a malfunctionof the mucociliary clearance apparatus of the innate host defensesystem, which results in the accumulation of inflammatory exudatesin the lumen. We also postulate that colonization and infectionof the lower airways are associated with an adaptive immuneresponse that accounts for the increase in lymphocytes and theirorganization into lymphoid follicles in patients with severe(GOLD stage 3) and very severe (GOLD stage 4) COPD.
Supported by grants from the Canadian Institute for Health Research(7246) and the National Heart, Lung, and Blood Institute (R01HL63117). The National Emphysema Treatment Trial is supportedby the National Heart, Lung, and Blood Institute; the Centersfor Medicare and Medicaid Services and the Agency for HealthResearch and Quality; and the George H. Love Research Fund atthe University of Pittsburgh.
We are indebted to the late Dr. Joe Rodarte for his supportin the early stages of this project and to Dr. Diana Ionescu,Kevin B. Quinlan, Dean English, and Jenny Hards for assistancewith the morphometric studies.
Source Information
From the University of British Columbia, the Centre for Cardiovascular and Pulmonary Research, and St. Paul's Hospital, Vancouver, Canada (J.C.H., F.C., S.U., R.W., W.M.E., L.B., H.O.C., P.D.P.); the National Jewish Research and Medical Center, Denver (R.M.C.); and the University of Pittsburgh Medical Center, Pittsburgh (R.M.R., F.C.S.).
Address reprint requests to Dr. Hogg at Rm. 166, McDonald Research Wing, St. Paul's Hospital, 1081 Burrard St., Vancouver, BC V6Z 1Y6, Canada, or at jhogg{at}mrl.ubc.ca.
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A correction has been published: N Engl J Med 2004;351(13):1367.
, leading to subepithelial and peribronchiolar fibrosis very similar to that reported here.40 A more complete understanding of the cytokine pathways that control the deposition of connective tissue in human disease might lead to effective treatments. 
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