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.

Those selected for treatment by LVRS were placed on a preoperative rehabilitation program, and the measurements of body mass index, FEV₁, FVC, subdivisions of lung volume, diffusing capacity for carbon monoxide (Dl_CO), and arterial partial pressure of oxygen (Pa_O2) used in the analyses were obtained after the rehabilitation period close to the time of surgery. Quality of life was determined using the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Short Form-36 (SF-36) and St. George's Respiratory Questionnaire (SGRQ), and health utility was assessed by the Quality of Well Being scale (QWB) (9). The presence of cough and sputum production was determined from specific questions about these symptoms in the SGRQ, and the severity of dyspnea was quantified using the University of California, San Diego, Shortness of Breath Questionnaire (UCSD SOBQ) (10).

Lung tissue samples removed from these 101 patients by LVRS were fixed in formalin immediately after resection and processed for into paraffin blocks at the site where the LVRS took place. The methods of tissue preparation for the 101 non-LVRS cases are published in detail elsewhere (2). Briefly, histologic sections cut from the paraffin blocks were stained using Movat's pentachrome method (11), and all of the small conducting airways in this tissue cut in reasonable cross-section were analyzed (12). Digital images of the airway histology were captured using a Nikon light microscope (Nikon Microphot, Tokyo, Japan) equipped with a JVC3-CCD KY F-70 digital camera (Diagnostic Instruments, Inc., Yokohama, Japan), linked to a computer to record and store the images. None of the clinical, radiologic, lung function, or steroid treatment data were available to the persons making the histologic measurements until this assessment was complete.

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).

A linear regression analysis (13) was performed on the entire 202 cases to confirm the relationships between FEV₁ and airway thickness, and FEV₁ and lumen content from our previous report (2). The 101 cases treated by LVRS were then divided into quartiles according to the percentage of occlusion of the fully expanded lumen of their small airways and all of the variables were compared using analysis of variance (ANOVA) followed by Tukey's post hoc test (Table 1) (14). Separate analyses were performed where cases were ranked and divided into quartiles based on either airway wall thickness or the percentage of airways containing lymphoid follicles. In addition, the variables in Table 1 were examined as potential predictors of survival using a Cox proportional hazards model (15). To facilitate valid comparisons, all continuous variables were included as quartiles. A forward stepwise selection procedure was then used to determine which variables best predicted survival, retaining only those variables that, in univariate analysis, provided a P value of 0.25 or less. These variables were included one by one into a multivariate model using a stepwise selection process, retaining only those variables that, in the multivariate analysis, provided a P value of 0.15 or less.

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.

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, Dl_CO, Pa_O2 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).

A Kaplan-Meier survival analysis (Figure 1) showed a shortened median survival in the quartile of subjects who had the most severe luminal occlusion. The median time of follow-up was 79 months (95% confidence interval [CI], 68–90 mo). The median survival time was shortest in the quartile with the most severe luminal occlusion (median survival time, 48 mo; 95% CI, 24–71 mo). The median survival time was longest in the group with the least luminal occlusion (> 92 mo). All of the variables listed in Table 1 were evaluated for their relationship with survival. As described in Methods, only those variables that had a univariate P value of 0.25 or less were retained for multivariate analysis. In a stepwise model, only age (P = 0.027) and post-bronchodilator FEV₁ (P = 0.031) were significant covariates. The Cox regression analysis revealed that the patients in the quartile with the highest luminal content had a risk of mortality that was over three times higher than the quartile with the lowest luminal content (adjusted hazard ratio, 3.28; 95% CI, 1.55–6.92; P = 0.002) after adjustments for a variety of factors (see Methods).

Figure 1. An adjusted Kaplan-Meier survival plot of the 101 cases of severe (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage 3) and very severe (GOLD stage 4) chronic obstructive pulmonary disease, indicating that median survival was shortened in the quartile with the most severe occlusion of the fully expanded lumen (hazard ratio, 3.28; 95% confidence interval, 1.55–6.92; P = 0.002) after adjustments for variety of factors cited in Methods. Note that the smoothing of the curves that occurs with correction for confounding variables to allow accurate comparisons between the quartile groups makes the survival rate in the first 90 days appear higher than it was really was.

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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.

Table 2 shows the data concerning patient demographics, physiology, symptoms, and health status, as well as the small airway dimensions for the 94 of the 101 LVRS patients in whom sufficient data were available to analyze the effect of steroid treatment on airway histology. The patients whose treatment included oral ± inhaled steroids were slightly less dyspneic but had a shorter 6-minute-walk, an elevated white blood cell count, and a reduced quality of life compared with the other two groups. Although neither form of corticosteroid therapy had an effect on lumenal content or wall thickness, there was a negative association between steroid therapy and the percentage of airways containing lymphoid follicles (P = 0.051 for ANOVA), with pairwise comparisons showing a significant difference between the group that received oral ± inhaled steroids and the non–steroid-treated subjects (P = 0.019).