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The Proceedings of the American Thoracic Society 6:137-145 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200809-114GO
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Nonmedical Therapy for Chronic Obstructive Pulmonary Disease

Kevin M. Chan1, Fernando J. Martinez1 and Andrew C. Chang2

1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, and 2 Department of Surgery, Section of Thoracic Surgery, University of Michigan Health System, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Fernando J. Martinez, M.D., M.S., Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, 3916 Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0360. E-mail: fmartine{at}med.umich.edu

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a category of diseases with chronic airflow obstruction and hyperinflation. The GOLD committee and the American Thoracic Society/European Respiratory Society have published detailed, evidence-based reviews of management, providing stepped-care algorithms for pharmacologic and nonpharmacologic therapy. Over the past several decades, this has led to numerous nonpharmacologic approaches to ameliorate symptoms in these patients.

Key Words: COPD • LVRS • lung transplantation • emphysema

HISTORY OF NONMEDICAL THERAPY FOR EMPHYSEMA

Detailed discussions of the surgical history of emphysema management have been published (1). These approaches reflected the state of knowledge for their era. Early investigators attempted to improve thoracic mobility, with procedures including costochondrectomy and transverse sternotomy, with unpredictable results (2). Subsequently, techniques were developed to decrease the size of the thoracic cage, to improve diaphragmatic architecture and function, or support the membranous trachea using various prosthetic devices, although practical considerations limited widespread use of these techniques (2).

Brantigan and colleagues attempted to reduce hyperinflation by surgically reducing lung volume (3, 4). Although symptomatic improvement was reported, significant operative mortality limited widespread application. The current era of surgical lung volume reduction was ushered in by Cooper and colleagues, who reported dramatic improvement after bilateral lung volume reduction surgery (LVRS) performed via median sternotomy (5). Subsequently, multiple investigators reported more limited improvement (6). The results of the National Emphysema Treatment Trial (NETT) (7–9) and other randomized trials (10–12) have provided more definitive recommendations regarding the role of LVRS in patients with advanced emphysema.

The process of promoting atelectasis in hyperinflated segments of emphysematous lung by bronchoscopic means was first described by Ingenito and colleagues using the instillation of biocompatible substances to form scar tissue (13). Bronchoscopic endobronchial blockade (14) has subsequently become the most studied technique of bronchoscopic LVRS using one-way valves to prevent air from entering isolated segments while allowing gases and secretions to escape (15, 16). Alternatively, the presence of increased collateral alveolar flow in patients with emphysema has led to the investigation of the endoscopic creation of bronchoparenchymal passages (17). Multicenter trials evaluating these techniques are ongoing (15, 16, 18, 19).

Since the advent of pulmonary transplantation in the 1960s (20) and its widespread implementation in the 1980s, COPD has been the primary indication for transplantation in approximately 37% of patients undergoing operation (21). Patterson and coworkers reported successful double lung transplantation (DLT) in patients with COPD (22), while Mal and colleagues reported successful single lung transplantation (SLT) in patients with COPD (23). Although SLT remains the predominant surgical therapy for advanced COPD (1), the proportion of patients undergoing bilateral transplantation for COPD continues to increase (21).

TECHNIQUES FOR NONMEDICAL THERAPY FOR COPD

Bullectomy or LVRS without Giant Bullae
Multiple techniques have been used to achieve resection of localized bullae, including standard lateral thoracotomy, bilateral resection via median sternotomy (MS), and video-assisted thoracoscopy (VATS). Similarly, the approach to LVRS has included median sternotomy (24), standard thoracotomy, and VATS (25). Laser ablation has fallen out of favor due to higher complication rates (26). In general, comparative studies have suggested greater improvement with bilateral procedures (27). NETT investigators prospectively confirmed similar morbidity and mortality with bilateral VATS or MS, although the overall length of stay was longer for MS and more patients with MS were living independently by 30 days after surgery (8).

Bronchoscopic LVRS
Three bronchoscopic LVRS systems are undergoing evaluation to accomplish surgical LVRS without the concomitant surgical morbidity. The techniques of placement of one-way valves in selected airways (16, 19) and the instillation of a biologically active fibrin glue (18) aim to induce collapse of diseased areas with the intent of reducing lung volumes. The creation of a communication between segmental bronchi and emphysematous lung parenchyma (28) is meant to offer an extra-anatomic means of expiratory air flow and focuses on patients with homogeneous emphysematous change (28).

Lung Transplantation
Controversy continues to revolve around the optimal transplant procedure in patients with COPD (29), although recent data suggest improved long-term outcomes in patients with COPD treated with DLT versus SLT (30). For example, data from the Registry of the International Society of Heart and Lung Transplantation reveals significantly better survival after DLT for COPD, even when stratified by age (21). The implementation of an allocation policy based on urgency, the "Lung Allocation Score" (LAS), in 2005 has altered the patient wait list composition from the previous wait time–based prioritization for lung transplant candidates over 12 years of age (31). Although the primary goal of this allocation policy is to minimize wait list mortality, such a priority score might allow for more accurate patient stratification to address questions such as determining the optimal surgical approach for patients with COPD. As more intermediate- and long-term data regarding outcomes after implementation of the LAS become available, modification of the LAS may lead to continued improvement in organ allocation, wait list mortality, and ultimately patient survival.

WHAT ARE THE RESULTS OF NONPHARMACOLOGIC THERAPIES?

Bullectomy
Bullectomy appears to be of short-term benefit in highly selected patients (32). None of the 22 studies reviewed included a control group and most were retrospective in nature. Improvements in hypoxemia and hypercapnea were most frequently reported, while improvement in airflow was more heterogeneous. When measured, total lung capacity, residual volume and trapped gas generally decreased. In highly selected patients, cor pulmonale reversed if hypoxemia and hypercapnea were present. Most authors described improvement in dyspnea. Little long-term follow-up data have been reported. In general, maintenance of improvement was generally noted, although in many of the patients a gradual worsening was noted over the years (33–37).

LVRS without Giant Bullae
Since the early report of Cooper and colleagues in 1995 (5), numerous reports of outcomes after LVRS have appeared in the literature (6, 38). The results of several randomized, controlled trials have clarified results of LVRS (10–12, 39–42). The National Emphysema Treatment Trial (NETT) was a large prospective, randomized, multicenter study comparing optimum medical therapy with optimum therapy plus LVRS (7). Of 3,777 patients considered for entry, 1,218 were randomized to treatment. During interim analysis, a subgroup of 140 patients were identified with forced expiratory volume in 1 second (FEV1) of 20% or less predicted, and either homogenous distribution of emphysema or carbon monoxide diffusing capacity (DLCO) of 20% or less predicted (43). The patients within this subgroup randomized to LVRS experienced higher 30-day operative mortality (16%) compared with no deaths within 30 days of randomization to medical therapy. This "high-risk" group of patients experienced a greater risk for mortality (relative risk [RR], 3.9; 95% confidence interval [CI], 1.9–9.0) after LVRS compared with counterparts treated medically. Small improvements were noted in FEV1, exercise capacity, and six-minute-walk distances after LVRS among survivors, compared with patients undergoing medical therapy. Thereafter, such "high-risk" patients were deemed not eligible for randomization (43).

Of the remaining patients randomized, with over 4 years of median follow-up, the NETT research group has demonstrated that LVRS confers durable improvement in survival and functional performance(Figure 1) (9, 44). Patients with upper lobe predominant emphysema and low post-rehabilitation exercise capacity (< 25 watts for women, < 40 watts for men) undergoing operation had a significant survival advantage (overall RR, 0.57; P < 0.01). Patients with upper lobe predominant emphysema and a high postrehabilitation exercise capacity or patients with non–upper lobe predominant emphysema and a low postrehabilitation exercise capacity did not experience a survival advantage or disadvantage (7, 9). However, regarding this latter group of patients, homogeneous emphysema alone was found to confer increased odds of 90-day mortality, regardless of postrehabilitation exercise capacity (odds ratio [OR], 2.99; P = 0.009) (44). Patients with non–upper lobe predominant emphysema and a high postrehabilitation exercise capacity, as reported initially (7), experienced an increased risk of death after LVRS (RR, 2.06, P = 0.02) but at longer-term follow-up (9), this difference was no longer statistically significant (RR, 1.10; P = 0.79). Finally, patients with upper lobe predominant emphysema treated surgically were more likely to improve their exercise capacity compared with medically treated patients (Table 1).


Figure 1
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  		Figure 1. Kaplan-Meier estimates of the cumulative probability of death as a function of years after randomization to lung volume reduction surgery (LVRS, shaded line) or medical treatment (solid line) in the National Emphysema Treatment Trial. The P value is for the Fisher exact test for the difference in the proportions of patients who died during the 4.3 years (median) follow-up in all patients randomized. Reprinted by permission from Reference 9.

 

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  		TABLE 1. RESULTS OF BILATERAL LUNG VOLUME REDUCTION SURGERY COMPARED WITH MEDICAL THERAPY IN PATIENTS WITH SEVERE EMPHYSEMA

 
In comparison to initial reports, the majority of case series have confirmed significant mean improvements in spirometry, although to a lesser extent than initially suggested (38). Reported changes in pulmonary function clearly indicated a short-term improvement in spirometry favoring surgery over medical therapy. This was exemplified by the results of two randomized trials (Figures 2a and 2b). In general, bilateral LVRS has resulted in greater short-term improvement. One multicenter prospective study that compared unilateral VATS LVRS with bilateral VATS LVRS noted that pulmonary function improvement favored the bilateral approach (47). The results of laser procedures appeared to be worse than stapling techniques (26, 48). Prospectively collected data from the NETT confirmed similar functional benefits between bilateral LVRS performed using MS or VATS (8).


Figure 2
Figure 2
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  		Figure 2. (A) Absolute change in FEV1% predicted in patients treated with surgery (SG) compared with those treated with continued training (TG). Reprinted by permission from Reference 42. (B) Histograms of changes from base line in FEV1 after 24 months of follow-up. Baseline measurements were performed after pulmonary rehabilitation. Patients previously identified as high-risk were excluded. Patients who were too ill to complete the procedure, or who declined to complete the procedure but did not explain why, were included in the "missing" category. P values were determined by the Wilcoxon rank-sum test. The degree to which the bars are shifted to the upper left of the chart indicates the degree of relative benefit of lung volume reduction surgery over medical treatment. The percentage shown in each quadrant is the percentage of patients in the specified treatment group with a change in the outcome falling into that quadrant. This was an intention-to-treat analysis. Reprinted by permission from Reference 7.

 
Variability in improved FEV1 has been well described. Figure 2b illustrates the heterogeneous spirometric response for the NETT 24 months after randomization to surgery or medical therapy. A significant proportion of patients experienced little improvement in FEV1, even in the short term. Although data are limited, lung volumes have generally decreased during short-term follow-up, while changes in DLCO have been modest (38). Changes in resting arterial blood gases have ranged from significant improvements in PaO2 and decreases in PaCO2 to little change (38, 49). Data regarding long-term functional follow-up are limited. Brenner and coworkers noted a greater decrease in FEV1 (0.255 ± 0.057 L/yr) in those patients experiencing the greatest improvement in the initial 6 months after surgery, whereas the lowest rate of drop in FEV1 appeared in those with the least initial improvement (45). In addition, Yusen and colleagues have shown, in a prospective evaluation of bilateral LVRS in 200 patients (50), that a majority of patients still exhibited spirometric improvement 3 and 5 years after surgery.

Most available data have described consistent improvements in simple measures of exercise capacity such as timed measures of walk distance (7, 38). Several groups have reported consistent, short-term, increases in maximal work load, VO2 and VE (38). The NETT investigators confirmed an increase in maximal achieved wattage during oxygen supplemented cycle ergometry in surgically patients; lesser improvement was noted in patients that continued aggressive medical management (7). Dolmage and colleagues (51) reported improved peak VO2 and power with a greater minute ventilation and tidal volume. Importantly, this study confirmed an improvement in operational lung volumes among patients undergoing operation. Limited data are available regarding long-term maintenance of improvements in exercise capacity. Compared with preoperative values, a higher six-minute-walk distance has been noted in surgically treated patients (52, 53). NETT investigators noted that surgical patients, in contrast to medically treated patients, were more likely to maintain improved maximal wattage during oxygen-supplemented cardiopulmonary exercise testing during long-term follow-up (9).

Dyspnea improvement has been reported by several groups using the Medical Research Council dyspnea scores or the transitional dyspnea index (TDI) (38). NETT investigators have presented detailed assessment of breathlessness using the University of California Shortness of Breath Questionnaire (UCSD SOBQ) (Figure 3); a heterogenous response was noted, although a clear benefit is noted in the surgical treated group compared with medically managed patients (7). Results of formal health status measurement have been presented by others (54). Short-term improvement using the Medical Outcomes Survey-Short Form 36 (SF-36) and the Nottingham Health Profile have been reported. Improvement in health status has also been reported with disease-specific instruments (38). The Canadian controlled trial reported clear improvement in health status measured with the Chronic Respiratory Disease Questionnaire (CRQ) in patients treated surgically compared with a matched group randomized to medical therapy (11), while NETT investigators noted significant improvement in the St. George's Respiratory Questionnaire (SGRQ) of surgically treated patients compared with medically treated patients (7). Long-term SGRQ follow-up from this sentinel study has been reported which supports a beneficial response favoring surgically treated patients (9).


Figure 3
Figure 3
Figure 3
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  		Figure 3. Histograms of changes from baseline in the UCSD SOBQ after (A) 6, (B) 12, and (C) 24 months of follow-up. Baseline measurements were performed after pulmonary rehabilitation. Patients previously identified as high-risk were excluded. Patients who were too ill to complete the procedure, or who declined to complete the procedure but did not explain why, were included in the "missing" category. P values were determined by the Wilcoxon rank-sum test. The degree to which the bars are shifted to the upper left of the chart indicates the degree of relative benefit of lung volume reduction surgery over medical treatment. The percentage shown in each quadrant is the percentage of patients in the specified treatment group with a change in the outcome falling into that quadrant. This was an intention-to-treat analysis. Reprinted by permission from Reference 7.

 
The multi-dimensional BODE index, described in 2004 by Celli and coworkers (55), was developed as a predictor of mortality for patients with COPD. The elements that compose the index include: body mass index, degree of airflow obstruction (FEV1), dyspnea, and exercise capacity. Assessment of dyspnea can be determined by the Medical Research Council dyspnea score as devised in the original BODE index (55) or by the UCSD SOBQ used in the "modified BODE" (mBODE) index (56). Patients undergoing LVRS were more likely to have a measurable decline in the BODE index at 1 and 2 years (57, 58). Imfeld and colleagues have reported from a single institutional experience that a decrease in postoperative BODE index was associated with decreased mortality after bilateral thoracoscopic lung volume reduction (59). Recently, the NETT investigators reported that longitudinal assessment using the mBODE of patients enrolled in the NETT could be used as a predictor for mortality after either medical or surgical intervention for COPD (56).

Hogg and colleagues (60) also demonstrated that patients with COPD with radiographic and pathologic evidence of small airway disease were at risk for earlier mortality after LVRS than patients without such disease (hazard ratio, 3.28; 95% CI, 1.55–6.92). Patients reporting preoperative corticosteroid use appeared to have reduced histologic evidence of ongoing inflammatory changes, although this did not appear to affect airway wall thickening or bronchial luminal mucus plugging. In addition to the functional outcome measures described above, the NETT research group has also reported that patients undergoing LVRS were less likely to experience an acute COPD exacerbation with a risk reduction of 0.30 (95% CI, 0.13–0.48) over 3 years of follow-up after undergoing operation (61).

Bronchoscopic LVRS
Clinical trials are underway to evaluate three bronchoscopic lung volume reduction systems aimed at producing segmental atelectasis/collapse in patients with severe emphysema. The greatest experience to date has been published on the Emphasys (Emphasys Medical, Redwood City, CA) endobronchial valve (EBV) (15, 16, 62–66). The implant is a silicone-based, one-way valve mounted on a nitinol stent (16). The intent of this device is to prevent air from entering the blocked segment while allowing the venting of expired gas and secretions, leading to atelectasis of the isolated emphysematous segments with subsequent reduction in lung volume (16). A third generation valve termed the "Zephyr" endobronchial valve is deployed through the working channel of a flexible bronchoscope and offers less resistance to expiratory flow than previous models (67). Toma and colleagues published the first pilot study of unilateral volume reduction by endobronchial valve insertion (15). On average, 3.1 valves were placed in eight patients with a median FEV1 of 0.79 liters (24% predicted). After 4 weeks, FEV1 increased by 34% and the median DLCO by 29%. Upper lobe collapse was noted in 50% of the patients, and improvement in lung function was greatest in these patients with signs of collapse. Two patients developed an ipsilateral pneumothorax and three had exacerbations of their disease (15). Snell and coworkers reported a similar pilot trial in which 4 to 11 valves were placed in patients with a mean FEV1 of 0.72. Diffusing capacity increased and upper lobe perfusion fell in this patient group without evidence of segmental collapse or other change in pulmonary function (62). Symptomatic improvement was noted in four patients. One episode of pneumonia, three episodes of COPD exacerbation, and one pneumothorax occurred after the procedure (62). Since then, three small, single-center series have been published (63–65), followed by the results of a registry report on 98 patients treated with the Emphasys endobronchial valve (16). After 90 days of follow up, residual volume decreased by 4.9%, FEV1 increased by 11%, FVC increased by 9%, and six-minute-walk distance improved by 23%. Greater improvement was noted in unilateral LVRS, lobar exclusion recipients, and patients with a baseline FEV1 less than 30% predicted or a residual volume (RV) greater than 225% predicted (16). There were eight serious complications (8.2%), including one death (1%). The most common complications were COPD exacerbations (17%), followed by pneumothoraces (5%) and pneumonia (5%) (16). Interestingly, the majority of patients did not develop segmental collapse, yet physiologic improvement was noted. The presence of collateral air circulation, which has been described in patients with diseased emphysematous lungs (17), may account for the lack of anatomic change. In an elegant study by Hopkinson and colleagues, physiologic parameters were evaluated in 19 patients in whom unilateral EBV LVRS was performed (64). Four weeks after the procedure, functional residual capacity and diffusing capacity significantly improved, as did cycle endurance at 80% of peak workload. This was associated with a reduction in end-expiratory volume and dynamic hyperinflation, indirectly indicating a lower resistance to air flow through the EBV anatomic airway, thereby reducing air trapping at peak exercise (64). Decreased upper lobe ventilation and increased lower lobe wash out rates have also been documented by 133Xenon ventilation scintigraphy in EBV-treated patients without evidence of segmental collapse (68). Therefore, the physiologic results of this procedure may be dependent on the reduction of anatomic airway resistance caused by the EBV in comparison to collateral air flow. When collateral airway resistance is greater than anatomic resistance, segmental collapse will occur, which leads to the greatest physiologic benefit (64). Two-year data have been described in a study of five patients, in which one of five patients retained a significant response to FEV1 and three of five retained a response to FVC of greater than or equal to 12% or greater than or equal to 150 ml from baseline (66). In addition, improvement in six-minute-walk distance was observed at 1 month follow up and in the BODE index at 3 months after the procedure. Significant improvement was also noted in the St. George Respiratory Questionnaire at 3 and 6 months in three of four domains (66).

The Intrabronchial Valve (IBV; Spiration, Inc., Redmond, WA) is an implantable device also designed to obstruct airflow into targeted segments of diseased emphysematous lung (19). It is designed as a one-way valve built on six nitinol struts covered by polyurethane in the shape of an umbrella to allow conformation and sealing to the airways with minimal pressure on the mucosa (19). In a pilot study of 28 patients followed for 6 months, improvement in the St. George's Respiratory Questionnaire was seen with a mean change of –6.8 points from baseline (19). No physiologic parameters were noted to improve. Complications developed in 17% of the patients, with periprocedural arrhythmia, bronchospasm, pneumonia, and COPD exacerbations occurring most frequently (19). No pneumothoraces were reported.

Since collateral ventilation may inhibit the maximal effect of LVRS after endobronchial valve placement, the instillation of a biocompatible substance into targeted areas that cause collapse of diseased segments has been postulated to be more effective (13, 18). The results of a phase I trial on six patients with heterogeneous emphysema and a mean FEV1 of 0.99 L using this technique termed "biological lung volume reduction," have recently been reported (18). Instillation of a primer used to deactivate surfactant and detach epithelial cells, followed by a washout solution, then instillation of a fibrinogen suspension combined with thrombin was done in two (three patients) or four (three patients) unilateral targeted subsegments (18). Although results at 3 months after the procedure revealed improvement in mean FVC (+7.2%), RV (–7.8%), RV/TLC (–6.6%), six-minute-walk distance (+14.5%), and dyspnea score, a clinically significant change in the FVC was only seen in two patients and in the six-minute-walk distance in one patient (18). No change in FEV1 was found. Anticipated radiographic change was not uniformly noted, and a dose–response effect was found based on physiologic improvement and the number of subsegments treated (18). No serious adverse events were reported.

The principles of the loss of elastic recoil, anatomic airway collapse, together with the demonstration of collateral ventilation in emphysematous lungs led Lausberg and colleagues to explore the feasibility of creating bronchoparenchymal passages to facilitate expiration and reduce dynamic hyperinflation (17). Using a radiofrequency catheter to create an opening and a balloon expandable coronary stent to maintain bronchoparenchymal communication in ex vivo human lungs, significant improvement was noted in the FEV1 from a mean of 245 cc to 447 cc after three stents and 666 cc after five stents (17). The procedure has been refined and reported in a pilot study performed on 35 patients with diffuse emphysema followed for at least 6 months (28). A median of eight stents were placed in patients with a median FEV1 of 0.74 liters. Although significant improvement was noted 1 month after the procedure in many physiologic parameters, significant improvement was maintained at 6 months only in residual volume (–0.40 L) and the Modified Medical Research Council Dyspnea Score (–0.5 points) (28). Better results were found in patients with an RV/TLC ratio of greater than 0.67, indicating that the degree of hyperinflation may be important for procedural selection (28). There was one death (2.6%) due to major bleeding, with a 7.9% rate of serious intraoperative adverse events (pneumomediastinum, 5.3%). COPD exacerbations and respiratory infections occurred in 32.4% and 27% of patients, respectively (28).

Lung Transplantation
Long-term results of lung transplantation have been limited by significant complications that impair survival. Data from the Registry of the International Society for Heart and Lung Transplantation suggests 82% 1-year, 49% 5-year, and 19% 10-year survival for patients with emphysema (21). While patients with emphysema enjoy the greatest survival advantage in the first year after lung transplantation, they have the lowest survival rate at 10 years (21). Given the high morbidity and mortality associated with lung transplantation, careful patient selection is crucial (69). Furthermore, controversy exists regarding whether a survival benefit is noted after lung transplantation for COPD (70–76).

In a recent report of 463 patients comprising a single institutional experience, Mason and colleagues evaluated differences in spirometry determination between single (n = 269) and double (n = 194) lung transplantation between 1990 and 2005 (77). Although relatively few patients with COPD (29/183) underwent double lung transplantation (DLT), the authors observed that patients with COPD experienced the greatest increase in post-transplantation spirometry after DLT when compared with patients undergoing DLT for other indications. As discussed by the authors, this improvement might be a reflection of the increased total lung capacity for patients with obstructive lung disease. In contrast, for patients undergoing single lung transplantation (SLT), those with COPD experienced the least incremental improvement in postoperative spirometry determinations, possibly reflective of altered respiratory physiology, such as native lung hyperinflation and mediastinal shift toward the transplanted lung. In addition, patients receiving SLT appeared to have more rapid worsening of spirometry measurements than those receiving DLT, who had stable lung function as long as 5 years postoperatively, particularly for patients with COPD, possibly reflecting continued functional native lung deterioration among patients undergoing SLT.

Consistent spirometric improvement after both SLT and DLT has been reported with lesser improvement generally reported for SLT compared with DLT (78, 79). Documentation of long-term results of pulmonary function is scarce. In general, early reports noted that some patients demonstrated stability in FEV1 improvement while others experienced a decline in pulmonary function after several months (80, 81). The importance of obliterative bronchiolitis (OB) on this loss of lung function has been recently reviewed (82, 83). Bronchiolitis obliterans syndrome (BOS) has been defined physiologically as a persistent 20% or greater drop in postoperative FEV1, in the absence of other acute conditions (airway complications, infection, congestive heart failure, reversible airway reactivity, and systemic disease) (84). Furthermore, BOS can be staged according to the drop in FEV1 from the peak, post-transplant value. A decrease in pulmonary function with BOS is particularly likely in SLT compared with DLT recipients (85).

Numerous investigators have reported improved six-minute-walk distance after both SLT and DLT (79, 80). Exercise after SLT or DLT appears to be limited by aerobic capacity and not by ventilatory restriction. Most reports support peripheral muscle dysfunction as the predominant cause of exercise limitation after lung transplantation (86–88). The cause of this peripheral muscle dysfunction after transplantation remains unclear, although chronic disease, drug therapy, disuse, and poor nutrition have all been invoked (89–91). Reports of long-term exercise data after lung transplantation are few. Improvement in six-minute-walk distance after transplantation for COPD has been reported to be maintained up to 4 years after transplantation (92). The same group has published a 13-year experience with lung transplantation in COPD (93). These authors noted a mild decrease in six-minute-walk distance 5 years after transplantation, although continued stability up to 7 years after surgery in DLT recipients has been described (94). A significant limitation to exercise remains for patients after lung transplantation, although the effect of long-term aerobic training has not been described in this patient population.

Limited data are available detailing changes in health status after lung transplantation. In general, improvement in health status has been reported (46, 95, 96). Pretransplant anxiety and psychopathology predicted post-transplant adjustment, with greater anxiety predicting worse post-transplant quality of life (97). Importantly, recipients with BOS experience decrements in health status, particularly in physical and social functioning and bodily pain (46, 98, 99). Long-term data reporting improved health-related quality of life (HRQL) after transplantation have been reported (94, 100). After a mean follow up of 2 years, significant improvement in 7 of 8 subscales of the SF-36 were noted but remained below that of the general population in one study (100). Three- to 5-year post-transplant survivors reported more frequent affective, neurocognitive, and physical appearance issues. Headaches and depression were also more common when compared with patients earlier in their transplant course (100). These symptoms had a greater influence on women, resulting in a lower percentage gain in quality of life than men (101).

Lung Transplantation versus LVRS
Given the overlap of selection criteria for lung transplantation and LVRS, it is evident that careful consideration for the optimal surgical procedure needs to take place for individual patients with COPD. Recent data have suggested that multidimensional approaches to stratifying disease severity is a better approach to prognostication in COPD (102). Figure 4a illustrates how an increasing quartile of BODE score is associated with a worse prognosis in a large cohort of patients with COPD (55). Similarly, in the NETT medically treated cohort, a group that in many ways resembles patients with COPD eligible for transplantation, increasing BODE score is associated with worse prognosis (103) (Figure 4b). Such patients, particularly those with non–upper lobe predominant obstructive lung disease, who also are at greater risk for earlier mortality (Table 1), might be considered as more suitable transplant candidates in future iterations of the lung allocation scoring system, although more extensive evaluation of outcomes should be undertaken.


Figure 4
Figure 4
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  		Figure 4. A. Kaplan-Meier survival curves for four quartiles of the body mass index, degree of airflow obstruction, dyspnea, and exercise capacity index (BODE) for a cohort of 625 patients with chronic obstructive pulmonary disease. Quartile 1 is a score of 0–2, quartile 2 is a score of 3–4, quartile 3 is a score of 5–6, while quartile 4 is a score of 7–10. Reprinted by permission from Reference 55. (B) Kaplan-Meier estimates of the probability of death as a function of the number of years after randomized patients for medically treated patients in the NETT segregated by modified BODE index. The P value was derived from the log rank test for the comparison between subgroups over a median follow-up period of 3.9 years. The curve labels reflect the ranges of BODE scores. Reprinted by permission from Reference 103.

 
CONCLUSIONS

Extensive literature has been published regarding surgical therapies for advanced COPD, with the most widely accepted directed at relief of hyperinflation. Bullectomy and LVRS are established surgical techniques for a very limited number of patients. Bronchoscopic LVRS may offer benefits similar to that of surgical LVRS without the concomitant morbidity; but outcomes are as yet unproven. The patients with the poorest long-term outcomes appear to be those with the most abnormal respiratory function. Lung transplantation may serve as a viable therapeutic option for some of these patients with COPD.

FOOTNOTES

Conflict of Interest Statement: K.M.C. is a co-investigator of a multi-center clinical trial sponsored by Broncus Technologies ($55,702 direct costs in 2008). F.J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.C.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Institution is a site for multi-center EASE trial sponsored by Broncus Technologies (Mountain View, CA).

(Received in original form September 30, 2008; accepted in final form October 8, 2008)

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