Published ahead of print on June 7, 2007, doi:10.1164/rccm.200612-1772OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200612-1772OC
Survival after Lung Volume Reduction in Chronic Obstructive Pulmonary DiseaseInsights from Small Airway Pathology1 University of British Columbia iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Vancouver, British Columbia, Canada; 2 Division of Pulmonary, Allergy, and Critical Care Medicine, Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 3 Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan; 4 Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Medical and Research Center, University of Colorado School of Medicine, Denver, Colorado; 5 Division of Pulmonary and Critical Care Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania; and 6 Baylor College of Medicine, Houston, Texas Correspondence and requests for reprints should be addressed to James C. Hogg, M.D., The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Room 166, 1081 Burrard Street, St. Paul's Hospital, Vancouver, BC, Canada V6Z-1Y6. E-mail: jhogg{at}mrl.ubc.ca
Rationale: COPD is associated with reduced life expectancy. Objectives: To determine the association between small airway pathology and long-term survival after lung volume reduction in chronic obstructive pulmonary disease (COPD) and the effect of corticosteroids on this pathology. Methods: Patients with severe (GOLD-3) and very severe (GOLD-4) COPD (n = 101) were studied after lung volume reduction surgery. Respiratory symptoms, quality of life, pulmonary function, exercise tolerance, chest radiology, and corticosteroid treatment status were assessed preoperatively. The severity of luminal occlusion, wall thickening, and the presence of small airways containing lymphoid follicles were determined in resected lung tissue. Kaplan-Meier survival analysis and Cox proportional hazards models were used to determine the relationship between survival and small airway pathology. The effect of corticosteroids on this pathology was assessed by comparing treated and untreated groups. Measurements and Main Results: The quartile of subjects with the greatest luminal occlusion, adjusted for covariates, died earlier than subjects who had the least occlusion (hazard ratio, 3.28; 95% confidence interval, 1.55–6.92; P = 0.002). There was a trend toward a reduction in the number of airways containing lymphoid follicles (P = 0.051) in those receiving corticosteroids, with a statistically significant difference between the control and oral ± inhaled corticosteroid–treated groups (P = 0.019). However, corticosteroid treatment had no effect on airway wall thickening or luminal occlusion. Conclusions: Occlusion of the small airways by inflammatory exudates containing mucus is associated with early death in patients with severe emphysema treated by lung volume reduction surgery. Corticosteroid treatment dampens the host immune response in these airways by reducing lymphoid follicles without changing wall thickening and luminal occlusion.
Key Words: premature death in COPD • airway remodeling • mucosal immune response • corticosteroids
The emphysematous destruction of the lung's gas-exchanging surface and obstruction to flow in the small conducting airways are responsible for the irreversible airflow limitation that defines chronic obstructive pulmonary disease (COPD) (1). We previously reported a negative association between the severity of the pathology in the small conducting airways and FEV1 over the full range of COPD severity (2). The primary objective of the present study was to test the hypothesis that this pathology might influence survival of patients in a 72-month follow-up period after lung volume reduction surgery (LVRS) (3, 4). A secondary objective was to determine if corticosteroid therapy had any influence on small airway pathology that might provide insight into the recent report that long-term steroid therapy reduces exacerbations of COPD but increases the incidence of pneumonia (5). Preliminary reports on the data contained in this article have been presented in abstract form at the Aspen Lung Conference (6) and at annual meetings of the American Thoracic Society (7, 8).
Patient Population Patients with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages 3 and 4 COPD who were treated by LVRS for advanced emphysema (n = 101) were the subject of this study. Five of these cases from the University of Pittsburgh were treated by LVRS before the start of the National Emphysema Treatment Trial (NETT) and the remaining 96 received this treatment in five sites participating in NETT located at the Universities of Pittsburgh, Michigan, and Colorado, Temple University, and the Baylor College of Medicine. The airway data from these 101 LVRS-treated cases were combined with similar data from 101 cases with milder COPD (GOLD stages 0–2) from the University of British Columbia patient registry and tissue bank to ensure that the cross-sectional regression analysis between airflow limitation and small airway pathology was the same as that observed in our previous report (2). All of the patients who participated in this study provided informed consent under conditions approved by the appropriate committees at the institutions where their surgery was performed. Patient confidentiality was maintained by using unique identifiers to link tissue samples to patient data that could not be traced to any personal identifier.
Preoperative Assessment
Histology The size of the small conducting airways was estimated by measuring the length of the basement membrane and determining lumen area in both the partially collapsed state where the basement membrane was folded and in a simulated fully expanded state calculated by subtracting the area of the epithelium from the area of a circle with a perimeter equal to the airway basement membrane length (2). The severity of the luminal occlusion was expressed by determining the fraction of these lumen areas occluded by inflammatory exudate containing mucus. The thickness of the entire airway wall as well as its epithelial, lamina propria, muscle, and adventitial compartments were determined by dividing their measured areas by the length of the airway basement membrane. The percentage of airways containing a collection of lymphocytes consistent with the formation of a lymphoid follicle was also recorded (2).
Data Analysis
The effect of corticosteroid treatment on the airway histology was determined in 94 of the 101 cases treated by LVRS where sufficient data on corticosteroid treatment were available, by comparing the histology of those who were known not to receive corticosteroid treatment (n = 16) with those who received inhaled corticosteroids only (n = 45), and those who received oral ± inhaled corticosteroid (n = 33) up until the time of their LVRS. Seven of the 101 cases treated by LVRS were not included in this analysis because there was insufficient information to assign them to one of these three categories. The effect of corticosteroids on survival could not be assessed because we were unable to access data concerning the steroid therapy received by these patients during the follow-up period subsequent to LVRS at the time of this writing.
Relationships between Small Airway Pathology and Clinical Data The relationships between FEV1 and both small airway wall thickness (P < 0.001) and the percentage of occlusion of the fully expanded airway lumen by inflammatory exudates containing mucus (P < 0.001) in the 202 cases in this study were similar to our previous report that included 159 of these same cases (2). Table 1 shows the results of the analysis performed on the baseline variables after the LVRS cases were divided into quartiles according to a rank ordering of the severity of the lumen obstruction by intraluminal content. These data show weak relationships between the severity of intraluminal airway occlusion and patient demographics (sex, age, smoking history, and body mass index), function (FEV1, FVC residual volume, DLCO, PaO2 white blood cell count), quality of life, and health status scores (SF-36 PCS, SF-36 MCS, QWB, SGRQ overall score, USD SOBQ, and six-minute-walk test). Stronger relationships were observed between quartiles of intraluminal content and the thickness of the total wall (P = 0.004), airway smooth muscle (P = 0.027), and adventitia (P = 0.006).
Small Airway Pathology and Survival Post-LVRS
The severity of the lumen occlusion measured by histology was not associated with the response to questions in the SGRQ designed to establish a diagnosis of chronic bronchitis, and neither airway wall thickening (P = 0.728) nor the percentage of the airways containing lymphoid follicles (P = 0.531) predicted survival after LVRS.
Impact of Corticosteroid Treatment
The data on from the 202 cases in this study confirm our previous report on 159 cases showing that thickening of the walls of the small conducting airways and occlusion of their lumen by inflammatory exudates containing mucus are negatively associated with FEV1 over the full range of COPD severity (2). They also extend these observations by showing an association between the severity of small airway occlusion by inflammatory exudates containing mucus and early death after LVRS. This association was independent of the LVRS procedure, uninfluenced by correcting for age, level of respiratory symptoms (SGRQ total score, UCSD SOBQ), and level of expiratory flow limitation (FEV1% predicted). The present data also show that treatment with oral ± inhaled corticosteroid therapy had no effect on airway wall thickening or lumen occlusion but was associated with a lowering of the percentage of airways containing lymphoid follicles, which indicates a reduction in the adaptive immune response in the peripheral lung. Chronic bronchitis is defined by excess cough and sputum production and is associated with decreased clearance of mucus from the lower airways, more frequent pneumonias, and premature death (16, 17). However, the SGRQ questions used to establish the presence of chronic bronchitis failed to associate this diagnosis with occlusion of the small airways by inflammatory mucous exudates in the present dataset. This result is consistent with earlier reports on the pathology of COPD showing that the symptoms of chronic bronchitis are more closely associated with pathology in the central rather than the peripheral airways (18, 19). Therefore, we suspect that it is the inflammatory process in the wall and lumen of the small airways (2, 20) that stimulates the local goblet cells to produce the mucus observed in these exudates. Breuer and associates (21) established that neutrophil elastase induces goblet cells to secrete mucus, and Takeyama and colleagues, Lee and colleagues, and Burgel and associates (22–26) extended these observations by showing that elastase secreted by polymorphonuclear leukocytes (PMNs) cleaves several epithelium-bound ligands for the epidermal growth factor receptor (EGFR) responsible for activating the downstream pathways leading to the secretion of mucus. This same group also established that oxygen free radicals generated by the PMNs can bypass EGFR and have a direct effect on mucus secretion. Collectively, these data suggest that PMNs and possibly other inflammatory cells known to infiltrate the wall and lumen of the small airways are capable of stimulating the generation of the mucus observed in these airways. Alternatively, the accumulation of these exudates might have resulted from defective clearance out of the small airways, with the balance between production and clearance probably determining the level of obstruction at any point in time. Unfortunately, we can only comment on the effect of the level of lumen obstruction of these airways because neither production nor clearance could be addressed in this cross-sectional study. The most plausible biological link between the level of airway occlusion and early death in COPD is the increased risk for lower respiratory tract infection. Studies of the cause of death in COPD attribute only 11% of deaths to infection, but it is conceivable that undetected infections of the small airways contribute to the 38% of COPD deaths attributed to respiratory failure (27). Many common respiratory pathogens colonize the upper airways first and enter the lower airways by microaspiration (28). The accumulation of mucus containing exudates in the small airway lumen increases the likelihood of developing infection by slowing the clearance of these organisms and allowing them to replicate to levels where they can invade the tissue and produce infection (28). Furthermore, the fact that early deaths occurred at a mean of 24 months with a CI of 24 to 71 months after surgery indicates these deaths occurred far beyond the 1-month time limit for attributing adverse events to complications arising from the surgical procedure. Sethi and Murphy and their colleagues (29, 30) have shown that the emergence of new strains of organisms that have previously colonized the respiratory tract in COPD are a major source of new infections. These same investigators also demonstrated a sharp increase in the production of sputum IgA and serum IgE antibodies directed against specific microbial proteins from these newly emergent strains (30). We previously attributed the marked increase in the percentage of small airways containing lymphoid follicles to the adaptive immune response to this type of infection (2), and the present results show that steroid therapy is associated with a reduction in the numbers of these follicle-containing airways. Therefore, we postulate that steroid-induced suppression of the host immune response in patients observed in this study might act in conjunction with extensive occlusion of the peripheral airways to account for the increase in pneumonias observed in the recent TORCH trial (5), but further studies will be required to establish this point. In summary, these results show that severe occlusion of the small conducting airways by inflammatory exudates containing mucus is predictive of early death in patients with advanced COPD. We postulate that this airway occlusion may act in association with steroid-induced immune suppression to increase the probability of infection in the lower respiratory tract.
Supported by grants from the Canadian Institute for Health Research (7246), the National Heart, Lung, and Blood Institute (RO1 HL 63117). The National Emphysema Treatment Trial is supported by the National Heart, Lung, and Blood Institute, the Centers for Medicare and Medicaid and the Agencies for Health Research and Quality, and the George H. Love Research Fund at the University of Pittsburgh. Originally Published in Press as DOI: 10.1164/rccm.200612-1772OC on June 7, 2007
Conflict of Interest Statement: J.C.H. served as a consultant to Altana Pharmaceuticals in 2003, 2004, and 2005, and also served on the Canadian advisory board for GlaxoSmithKline (GSK) for 1 year (2003). He has participated as a speaker in scientific meetings and courses organized and financed by various pharmaceutical companies, including AstraZeneca (AZ), Altana Pharmaceuticals, and GSK. He serves as the principal investigator on a jointly sponsored Canadian Institute of Health Research (CIHR) industry-sponsored grant which is one-third supported by CIHR and two-thirds supported by GSK and Merck. This grant application was funded after peer review by the regular CIHR mechanism and the funds received from industry are directly related to the operating costs of the study. F.S.F.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.C.T received grants from AZ, Boehringer Ingelheim, and GSK for the study of prevalence of COPD. D.D.S. has received honoraria for speaking engagements from AZ in 2004 ($3,000) and in 2005 ($11,000), and from GSK in 2004 ($8,000), 2005 ($6,500), and 2006 ($12,000). He has also received unrestricted research funding as either the principal investigator or co-principal investigator from GSK in 2004 for $1.5 million and from AZ in 2007 ($100,000). He also received $1,500 from GSK for consultancy work in 2006. S.A.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.D.P. is the principal investigator of a project funded by GSK to develop computed tomography (CT)–based algorithms to quantify emphysema and airway disease in COPD. With collaborators, he has received Received in original form December 6, 2006; accepted in final form June 5, 2007
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$300,000 to develop and validate these techniques. He is also principal investigator of a Merck Frost–supported research program to investigate gene expression in the lungs of patients who have COPD. He and collaborators have received