American Journal of Respiratory and Critical Care Medicine

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a major health care problem and the number of publications in the scientific literature is a reflection of this increased awareness (1). This update cannot do justice to all newly available information, but it does represent a selection of articles that were considered to be of sufficient general interest to warrant further discussion.

The positive aspects in the definition of COPD—initially introduced by the American Thoracic Society/European Respiratory Society statement (2) in 2004—have been adopted in recent updated guidelines defining the disease as preventable and treatable (3). Recent definitions also highlight that significant extrapulmonary effects and comorbidities may contribute to COPD severity in individual patients (49). Clinical management should, therefore, pay careful attention to extrapulmonary effects and comorbidities of COPD, including their effect on the patient's disease severity and quality of life, particularly in the elderly (8, 10, 11).

International guidelines promote the use of post-bronchodilator spirometry values in the definition and classification of severity of COPD. However, post-bronchodilator spirometric reference values have not yet been developed. A recent study (12) aimed to derive reference values for post-bronchodilator FEV1, FVC, and FEV1/FVC in a random sample of a general adult population. Both FEV1 and FVC decreased with age and increased with height. The lower-limit-of-normal (LLN) post-bronchodilator FEV1/FVC exceeded 0.7 for both sexes. Post-bronchodilator prediction equations gave higher predicted FEV1 and FEV1/FVC compared with existing prebronchodilator equations, with a decreasing bronchodilator response with age. This suggests that post-bronchodilator prediction equations can help avoid falsely high FEV1% predicted values with a subsequent underestimation of disease severity.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) advocates the use of a fixed ratio of post-bronchodilator FEV1/ FVC of 0.7, and not the LLN as a threshold for spirometrically defined airflow limitation (3). Because this ratio declines with age, its use may overdiagnose older populations with mild COPD disease. The available comparisons of reference values using the National Health and Nutrition Examination Survey (NHANES) database are problematic because this database does not contain post-bronchodilator values (13). A recent study (14) in 4,965 subjects aged 65 years and older aimed to determine morbidity and mortality among those with an FEV1/FVC ratio of less than 0.7, but above the LLN. Subjects with an FEV1/FVC of less than 0.7 but above the LLN had an increased adjusted risk of death and COPD-related hospitalization during follow-up compared with asymptomatic individuals with normal lung function, thereby suggesting that a fixed FEV1/FVC of less than 0.7 may still identify at-risk patients, even among older adults.

Considering the variability of lung function, absolute changes in FEV1 rather than percentage change could be used to determine whether patients with COPD have improved or worsened lung function between test sessions (15).

Estimating and comparing the prevalence of COPD in different countries are still difficult because of differing definitions (e.g., symptoms vs. spirometry) and thresholds for diagnosis (16, 17). The pooled global prevalence of COPD in adults 40 years or older is approximately 9 to 10%, and is higher in smokers than in nonsmokers, and higher in men than in women (18). Spirometry-defined COPD was present in up to 13.3% of 8,215 subjects older than 35 years, and was mostly (> 80%) undiagnosed, even among people with severe and very severe COPD assessed by spirometry (16). Interestingly, in contrast to previous reports, the presence of chronic cough/phlegm identifies a subgroup of subjects with a high risk of developing COPD, independently of smoking habits (19).

COPD is an important cause of death in many countries and is still increasing because of the expanding epidemic of smoking and the increasingly aging population. A different trend of mortality has been reported in Europe where decreasing mortality from COPD is already being seen in some countries (20). In the United Kingdom, over the past 30 years, mortality from COPD has fallen in men and risen in women, and the remaining sex differences will probably disappear in the near future (21). Women exposed domestically to biomass develop COPD with clinical characteristics, such as impairment of quality of life and increased mortality, similar to those observed in tobacco smokers (22).

Among patients with severe COPD receiving long-term oxygen therapy, women are more likely to die than men. Additional independent predictors of death are lower PaO2 and lower body mass index (BMI) (23). Low fat-free mass index is associated with a poorer prognosis even in patients with COPD with a normal BMI; therefore, assessment of this parameter should be considered in the routine evaluation of these patients (24). Patients with a faster decline in FEV1 are also at modestly increased risk of death and time to a COPD-related hospitalization (25). In patients with severe emphysema, increased mortality is independently associated with more advanced age, lower BMI, oxygen supplementation, and greater hyperinflation (26).

Lomas proposed a new hypothesis relating to the genetics of α1-antitrypsin (α1-AT) deficiency. He proposed that previously protective α1-AT mutants might have become harmful to health. In particular, in the preantibiotic era, the deficiency alleles Z and S, present in more than 20% of some white populations, might have conferred biological advantages by producing α1-AT polymers that were protective against infections as they amplified the inflammatory response that limited invasive respiratory or gastrointestinal infections. By contrast, after the discovery of antibiotics and with the advent of increased smoking habits, the same proinflammatory properties of α1-AT mutants might have become detrimental, as the amplified inflammatory response became responsible for early-onset emphysema due to enhanced inflammation (27).

New advances on the candidate genes for COPD have been reported in 2006—in particular, polymorphisms of genes of oxidative stress (2830), mucins (31), and inflammatory mediators (3235). New single nucleotide polymorphisms in the SERPINA1 (more commonly known as α1-antitrypsin) gene have been found to increase the risk of COPD (36). Hersh and colleagues examined polymorphisms of 22 candidate genes in more than 300 patients with severe COPD from the National Emphysema Treatment Trial (NETT) study, and identified various associations between polymorphisms in four genes and different COPD-related traits, including FEV1, six-minute-walk test, and diffusion capacity of carbon monoxide (DlCO) (37). Although interesting, these studies have the general concerns of all association studies, because they require confirmation in different and larger populations before understanding their role in conferring susceptibility or protection.

By using microarray analysis, Heguy and associates (38) reported that 75 genes were modulated by smoking, with 40 genes up- and 35 down-regulated in alveolar macrophages of smokers as compared with healthy nonsmokers. Of these genes, 69 had not been previously recognized (3942), suggesting that gene expression in alveolar macrophages associated with smoking is more complex than previously believed.

Inhalation of noxious particles, such as cigarette smoke, causes both pulmonary (4345) and systemic (4648) inflammation. This response triggers both innate (43, 45, 49) and adaptive immunity (5052).

Lung Inflammation
Innate immunity.

Cell populations involved in innate immunity (53), including epithelial cells and fibroblasts, respond to challenges with toxic gases and particles by generating a wide variety of cytokines and chemokines that control the migration of inflammatory immune cells into the injured tissue (5456). A net deposition of collagen and elastin in alveolar walls in emphysema and/or COPD has been observed (57, 58), suggesting the importance of fibroblasts for remodeling. Fibroblasts simultaneously bridge the interstitium, linking epithelium and endothelium through apertures in the basal laminae (59, 60). However, in emphysematous regions of the lung, Sirianni and coworkers (60) showed significantly fewer connections between alveolar fibroblasts and type 2 pneumocytes and no contacts between fibroblasts and endothelial cells. This altered structure may have functional consequences, impeding inflammation and compromising maintenance and repair of lung structure and function.

Carnevali and colleagues (61) observed that exposure of human lung fibroblasts to cigarette smoke results in a marked accumulation of clusterin—a heterodimeric glycoprotein of 76–80 kD, widely distributed in the human body, and able to confer protection against various cytotoxic agents—which appears to protect lung fibroblasts against cigarette smoke–induced oxidative stress.

Although an imbalance between oxidants and antioxidants is considered to play a role in the pathogenesis of COPD (62, 63), studies assessing the benefits of antioxidants have yielded mixed results. Foronjy and colleagues (64) demonstrated that a fourfold increase in human copper-zinc superoxide dismutase activity within the lung decreases inflammation, oxidant injury, protease expression, and emphysema formation in response to chronic smoke exposure and elastase administration in mice. Cigarette smoke–induced oxidative stress (6567) also initiates activation of signal transduction systems, such as the redox-sensitive transcription factors nuclear factor (NF)-κB and activator protein 1 (65, 68), which have a central role in regulating many proinflammatory genes (66, 69). In human lung tissue, Szulakowski and coworkers (70) found a smoking-related increase in NF-κB nuclear translocation associated with degradation of the inhibitor of factor kBα (IkBα), and an imbalance between histone deacetylation and acetylation in favor of acetylation. These changes may contribute to the enhanced inflammation in smokers susceptible to the development of COPD (70). Sato and coworkers (71) further underscored the importance of oxidant–antioxidant imbalance in COPD pathogenesis and similarities with aging in a knockout mouse model of senescence.

A novel antiapoptotic function of α1-AT has been observed by Petrache and colleagues (72), extending the therapeutic options for emphysema caused by reduced level or loss of function of α1-AT.

The role of adenosine-receptor (A1, A2A, A2B, and A3) signaling in COPD has been studied (7375), providing potentially novel targets for therapeutic interventions. Varani and associates (76) described the affinity and density of adenosine receptors in the lung parenchyma of patients with COPD, and reported a significant correlation between them and the FEV1/FVC ratio.

Adaptive immunity.

The extent of emphysema in smokers has been related to the number of CD3+ T cells in the alveolar wall, and CD8+ T lymphocytes appeared to be the predominant cell type (55, 7779), supporting a role for adaptive immune responses in the pathogenesis and progression of COPD.

In mice exposed to cigarette smoke, van der Strate and colleagues demonstrated the presence of lymphoid aggregates in the airways and in the lung parenchyma of mice exposed to cigarette smoke, characterized by B-cell follicle cores surrounded by T cells, with the majority being CD4+. The B cells were interspaced by follicular dendritic cells, necessary for antigen presentation and affinity maturation. Furthermore, (oligo)clonal B-cell proliferation has been detected, supporting the hypothesis of a true germinal center reaction (80). Oligoclonal populations of T cells within the lungs of patients with emphysema suggest that response to an antigen plays an important role in the continuing inflammation (78, 81). An aberrant acquired immune response can result from either a defect in the selection, regulation, or death of immune cells (T or B lymphocytes), or from the generation of new (self or foreign) antigens (82); both possibilities could operate in COPD (81, 83). A few studies showed alterations in peripheral blood mononuclear cells in patients with COPD (52, 8489).

Dendritic cells (DCs) play a central role in host immune defense by linking innate to adaptive immune responses (90). Roghanian and coworkers (91) hypothesized that inflammatory mediators, such as neutrophil elastase released into the lung, may modulate DC activity by showing that COPD sputum samples and human neutrophil elastase down-regulate the expression of CD40, CD80, and CD86 on DCs and inhibit LPS-induced DC maturation.

Systemic Inflammation
Innate immunity.

Several articles published in 2006 explored the importance of C-reactive protein (CRP) in COPD, showing that CRP serum levels are increased in patients with COPD independent of cigarette smoking, and that they are reduced in patients with COPD who use inhaled glucocorticosteroids (92). There is also a genetic influence on CRP levels in patients with COPD (93). CRP is considered a strong and independent predictor of COPD outcomes in individuals with airflow limitation (94). CRP is also associated with impaired energy metabolism, impaired functional capacity, distress due to respiratory symptoms (95), and lower quadriceps strength (96). In the presence of exacerbated respiratory symptoms, plasma CRP levels may help to establish the diagnosis of a COPD exacerbation (97).

Adaptive immunity.

An increase in both CD8+ cells (8588) and CD4+ cells (89) has been reported in patients with COPD (8588), highlighting the difficulties in peripheral blood studies in COPD (89).

Abnormalities of skeletal muscle in COPD are due to increased work of breathing, inactivity, systemic inflammation, malnutrition, blood-gas abnormalities and impaired oxygen delivery, electrolyte imbalances, drugs, and comorbid states (98, 99). Respiratory muscles are overloaded due to increased work of breathing (100, 101) and limb muscles are underloaded due to inactivity (102). Whether the abnormalities of skeletal muscle are specific for COPD or are associated with and/or are a consequence of chronic diseases (e.g., chronic heart failure) remains to be established.

Respiratory (103) and peripheral (104) muscles may be affected early in the course of COPD and chronic overload might play a role in preserving normal muscle composition. Skeletal muscle cells of individuals with COPD generate free radicals that may damage genetic material of pulmonary and circulating cells (105). Pulmonary rehabilitation may both increase exercise capacity and reduce exercise-induced oxidative stress (106, 107), with potential beneficial systemic effects (108). However, rehabilitation does not appear to reverse the increased protein breakdown or systemic inflammation associated with COPD (109).

Airflow limitation in COPD is due both to small airway disease (obstructive bronchiolitis) and to parenchymal destruction (emphysema), the relative contributions of which vary among patients (110, 111). Thin-section computed tomography (CT) has been used to quantify emphysema by detecting low-attenuation areas, and the role of CT in diagnosing emphysema has been well established. However, airflow limitation evaluated by FEV1 does not show a good correlation with the severity of emphysema as evaluated by CT (112) because small airway disease appears to contribute significantly to airflow limitation (113). Recent progress in CT technology has made it possible to detect and quantify airway abnormalities (114). Virtual bronchoscopy is a novel CT-based technique that allows a noninvasive intraluminal evaluation of the airways up to about the eighth airway generation (110, 111). Theoretically, thin-section CT can depict the dimensions of airways as small as approximately 1 to 2 mm in inner diameter, suggesting that CT can be used to evaluate airway dimensions in a variety of diseases (110, 111).

Several articles have explored the contribution of various imaging technique for studying airflow limitation in patients with COPD. Hasegawa and colleagues (115) developed a new software for measuring airway dimension using curved multiplanar reconstruction and demonstrated that airway luminal area and wall area significantly correlated with FEV1 (% predicted). The correlation coefficients improved as the airways became smaller in size.

Scintigraphic approaches may be used to assess COPD/emphysema and to provide functional imaging. Ultrafine 133Xe gas particles are being used for ventilation scintigraphy, including single photon emission CT (SPECT), and might be used for evaluating small airway disease and pulmonary emphysema. SPECT imaging has been shown to be more useful than morphologic high-resolution CT in the evaluation of small airway disease, including pulmonary emphysema (116).

Diffusion-weighted hyperpolarized 3He magnetic resonance imaging has been shown to correlate with pulmonary function tests, particularly DlCO (117). Also, dynamic contrast enhanced magnetic resonance imaging may detect abnormalities of the pulmonary peripheral microvasculature (118). These techniques might be useful in the assessment of pulmonary emphysema.

Exacerbations of COPD are defined as events characterized by a change in the patient's baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations and acute in onset, and which may warrant a change in regular medication in a patient with underlying COPD (3). Exacerbation frequency increases with disease severity and is associated with poorer health outcomes as well as a greater burden on the health care system (119).

Airway bacterial and/or viral infections are associated with COPD both in stable conditions (120123) and during exacerbations of symptoms together with acute airway inflammation (32, 124131). The lack of a proven cause–effect relationship between infections, acute inflammation, and exacerbations, and the importance of viral infections may explain why the role of antibiotics in the management of COPD exacerbations still remains controversial (3).

Because respiratory symptoms are nonspecific for COPD, the cause of an acute exacerbation is often difficult to determine (132, 133). Serum biomarkers such as N-terminal–brain natriuretic peptide (nT-BNP) and troponin may help to distinguish between acute dyspnea associated with acute heart failure versus other causes (132138). Also, BNP may be a prognostic marker and a screening parameter for significant pulmonary hypertension in chronic lung disease (139). Likewise, arterial CO2 and respiratory rate may contribute to the assessment of severity of COPD exacerbations (140, 141).

Patients with COPD may be at increased risk of thromboembolism (142) and pulmonary embolism may certainly trigger acute dyspnea in patients with COPD, even if its frequency and importance remain controversial (143145)

Exacerbations are important events in the natural history of COPD and represent one of the main outcomes of treatment of COPD (3). However, the real effect of treatment is difficult to establish, because the definition of COPD exacerbations is broad, and the statistical approach to assess the effect of treatment on exacerbations is complex and subject to bias (146).

Smoking cessation is by far the most important therapeutic intervention in patients with COPD, but smoking cessation rates are still disappointing. In contrast to earlier assumptions (147) suggesting that screening spirometry is useless in COPD because it does not contribute to smoking cessation, a clinical study in primary care demonstrated the efficacy of repeated spirometry and smoking cessation advice by showing higher quit rates in smokers with COPD than in those with normal lung function (148).

Varenicline, a nicotinic acetycholine receptor agonist, is a novel agent for smoking cessation and the first large clinical trial data are reassuring (149, 150). Smokers who achieved abstinence for at least 7 days at the end of 12 weeks of open-label varenicline treatment showed significantly greater continuous abstinence compared with placebo up to Week 52. These results suggest that varenicline may be an efficacious, safe, and well-tolerated agent for maintaining abstinence from smoking. However, to date there is no study available on the use of this agent in patients with COPD.

Meta-analysis has been unable to confirm the role of either influenza or pneumococcal vaccination in the prevention of COPD exacerbations (151153). However, a study on pneumococcal polysaccharide vaccination by inhalation demonstrated the safety of this application in patients with COPD by showing a rapid antibody response (154). Soler and colleagues studied the effect of OM-85, a detoxified immunostimulant derived from eight bacteria, on acute exacerbations in patients with COPD (155). Although the study is relatively small, it describes a surprising 29% decrease in exacerbations in patients with mild disease and extends earlier studies in older patients with more advanced COPD.

A clinical trial in 110 randomized patients using a low dose of 100 mg theophylline twice daily over 1 year demonstrated overall favorable outcomes compared with placebo, including a reduction in COPD exacerbations (156). These findings are supported by a recent clinical trial in 16 patients with COPD investigating the effect of low-dose theophylline versus fluticasone propionate (FP) on the formation of reactive nitrogen species measured in sputum (157). Theophylline had a more pronounced effect on 3-nitrotyrosine formation than the steroid FP, without measurable effects on lung function.

The effect of the fixed combination of salmeterol and FP on lung hyperinflation and exercise endurance was examined in a study protocol involving 185 patients with COPD (FEV1, 41% predicted). The salmeterol/FP combination demonstrated a significant effect on functional residual capacity and increased inspiratory capacity, which correlated with improvement in exercise time (158). The observed effects were comparable to those seen with the long-acting anticholinergic bronchodilator tiotropium.

A large biopsy study involving 140 patients investigated the effect of salmeterol/FP on airway inflammation in COPD (159). In bronchial biopsy samples and in sputum, a broad spectrum of cellular changes were observed and, together with a 173-ml improvement in FEV1, were interpreted as antiinflammatory effects contributing to clinical efficacy. These data were supported by another large, randomized, double-blind trial demonstrating that the long-acting β2-agonist (LABA)/inhaled glucocorticosteroid combination has superior efficacy compared with salmeterol alone on moderate to severe exacerbations in patients with severe COPD (160).

The first COPD trial to address the effect of combination therapy on overall mortality in COPD has been the TORCH trial (TOwards a Revolution in COPD Health) initially involving 6,112 patients with COPD (post-bronchodilator FEV1, 44% predicted) comparing as the primary endpoint the effect of salmeterol/FP versus placebo on mortality over 3 years. The other two treatment arms involved salmeterol only and FP only. As with every trial of this order of magnitude and impact, the study design and unexpected side effects invited comments (161). The study confirmed the efficacy of combination therapy on exacerbations and rescue medication and demonstrated a significant benefit on health status; although it failed in its primary endpoint, the study interestingly showed a change of lung function decline over time (Figure 1) (162). This finding might turn out to be important for long-term treatment of COPD.

TORCH also confirmed, in a large population of patients with moderate–very severe COPD, that the LABA/inhaled glucocorticosteroid combination is more effective than the individual component in reducing the frequency of COPD exacerbations (162) (Figure 2). However, addition of this combination does not increase the effect of a long-acting antimuscarinic, tiotropium, at least on exacerbations (163). In a 1-year trial, the investigators examined the effect of adding salmeterol or salmeterol/FP to an existing therapy with tiotropium as compared with tiotropium alone (163). The primary endpoint was the proportion of patients experiencing a COPD exacerbation. The trial had a high proportion of premature dropouts, which makes interpretation difficult, but the addition of either an LABA or the LABA/inhaled glucocorticosteroid combination did not significantly affect the primary endpoint. The percentage of patients experiencing an exacerbation were 62.8% for tiotropium, 64.8% for the tiotropium–LABA group, and 60% for the tiotropium–LABA/inhaled glucocorticosteroid group. The addition of LABA/inhaled glucocorticosteroid to tiotropium did, however, improve lung function, health status, and hospitalization rate.

Truly novel agents for the treatment of COPD are rare, but a few clinical trials have addressed novel approaches. According to GOLD guidelines (3), none of the existing medications for COPD have been shown to modify the long-term decline in lung function. However, cilomilast, a selective inhibitor of phosphodiesterase-4 (PDE-4), has been shown in a randomized clinical trial (164) to maintain pulmonary function and improve health status, and to reduce the rate of COPD exacerbations during 24 weeks of treatment in patients with moderate to severe COPD. These findings suggest that, in addition to its symptomatic effect, cilomilast might prevent excess decline in lung function associated with COPD (165).

Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal species (166). Unfortunately, animal models do not accurately replicate the complex pathophysiology of human emphysema. Roth and colleagues performed a feasibility study to collect preliminary evidence regarding the effects of retinoids on different measures of human emphysema. They examined 148 subjects with moderate to severe COPD in a randomized, double-blind feasibility study comparing retinoic acid (ATRA) with placebo for 6 months followed by a 3-month crossover period (167). They showed that ATRA resulted in frequent, although usually minor, side effects and no overall improvement in pulmonary function or CT imaging. However, changes in several outcomes were observed in subjects who achieved high retinoid blood levels, suggesting exposure-dependent biological activity that warrants further investigation.

Tumor necrosis factor (TNF)–α appears to play a role in the pathogenesis of COPD as a primary mediator driving the inflammation characteristic of COPD (54). A number of studies have reported increased production of TNF-α in patients with COPD and have related this increase to the systemic manifestations of COPD (46, 48). In 2005, a small pilot study, evaluating the effect of three infusions of infliximab, a TNF-α antagonist, in subjects with COPD demonstrated no beneficial therapeutic response or effect on sputum neutrophils (168). Rennard and colleagues further evaluated the efficacy and safety of infliximab in subjects with moderate to severe COPD (169). In this multicenter, randomized trial they found no treatment benefit as measured by the primary endpoint, Chronic Respiratory Questionnaire total score. Similarly, they found no change in secondary measures, including prebronchodilator FEV1, six-minute-walk distance, Short Form-36 physical component summary score, transition dyspnea index in moderate–severe COPD exacerbations. Although they observed no opportunistic infections and no differences in the occurrence of infections requiring antibiotics, they did find a higher incidence of pneumonia in infliximab-treated subjects and, although not statistically significant, more cases of cancer.

Lung transplantation (LT) and lung volume reduction surgery (LVRS) are the treatments of choice for selected patients with COPD associated with advanced emphysema (170173). The international guidelines for the selection of LT candidates were updated in 2006, and recommended more careful characterization of patients undergoing LT, such as measuring the BODE (Body Mass Index, Obstruction, Dyspnea, Exercise) index (174), and also suggested that more patients with more severe COPD might be considered (175177). LVRS may help to postpone LT up to 4 to 5 years without impairing the chances for subsequent LT (178).

In an article from the NETT database (179), the role of LVRS is questioned for patients with α1-AT deficiency based on the relatively poor outcome of 49 patients studied, compared with the overall result of this large trial. An alternative treatment modality might lie in the use of intrabronchial valves for patients with severe emphysema, and the first limited published clinical data are reassuring (180).

Because both LT and LVRS are associated with high morbidity (181183), impairment in lung mechanical properties (184), and mortality (185), there has been a search for additional treatment approaches, including experimental lung tissue engineering for compensatory growth after surgical resection (186) and minimally invasive surgery alternatives. Airway bypass and bronchoscopy lung volume reduction aim to improve respiratory mechanics through functional exclusion of emphysematous areas of the lung without exposing patients to the risk of conventional surgery (187). The bronchoscopic placement of endobronchial valves for lung volume reduction may represent a safe and effective alternative to conventional LVRS (188), even if proper selection of candidate patients is required (189).

By tackling the systemic consequences and comorbidities of COPD, and the behavioral and educational deficiencies associated with COPD, comprehensive pulmonary rehabilitation programs improve the effects of pharmacologic treatment in patients with COPD, increase exercise performance, reduce symptoms, and improve emotional status and health-related quality of life (190193). The better tolerated interval training exercise is no different from continuous high-intensity exercise for initiating rehabilitation (194), and a 4-week supervision period is as good as 7 weeks of supervision for long-term effects (195).

Long-term oxygen treatment (LTOT) is the only therapy that prolongs life in patients with COPD with severe hypoxemia (PaO2 < 8.0 kPa), but does not have these effects in patients with mild to moderate hypoxemia or in those with only arterial desaturation at night. A reduced use of LTOT increases mortality (196). Women demonstrate a diminished response to LTOT as compared with men (23). Short-term supplementary oxygen before exercise, in addition to improving exercise performance (197), may prevent exercise-induced oxidative stress in normoxemic, muscle-wasted patients with COPD (198).

Controversies still exist concerning the beneficial effects of ambulatory oxygen (199, 200), increasing oxygen flow at night to prevent nocturnal desaturation (201), and prehospital oxygen therapy for COPD exacerbations (202). These concerns are particularly important considering poor adherence of patients with oxygen therapy (203), and the difficulties to monitor LTOT (204).

Considering the limited evidence supporting the role of LTOT (62), and its huge cost, a working group has been convened by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services with the aim to identify areas requiring urgent research to improve the care of patients with COPD (205).

A specialist multidisciplinary approach including the use of noninvasive ventilation has confirmed the importance of noninvasive ventilation in weaning patients with COPD from prolonged invasive ventilation (206). In patients with acute respiratory failure secondary to severe COPD exacerbation who failed noninvasive ventilation, transtracheal open ventilation was shown to be as effective as conventional ventilation (206, 207).

Progress was made in 2006 in all areas of research relating to COPD, but we would consider that the most important contributions were in the area of management. New guidelines have been released, both general (3) and specific for rehabilitation (191) and LT (175), which may contribute to the improvement of care for patients affected by COPD. The largest randomized clinical trial examining the effect of different pharmacologic treatments on mortality in COPD has been published, providing new important data that might affect future treatment of the disease (162). More studies have addressed COPD as a systemic disease with frequent and important comorbidities that may dramatically contribute to its severity and mortality (8). Novel findings have addressed the complexity of acute exacerbations, in particular on the potential role of thromboembolism (143145) and acute heart failure (136).

1. Fabbri LM, Luppi F, Beghe B, Rabe KF. Update in chronic obstructive pulmonary disease 2005. Am J Respir Crit Care Med 2006;173:1056–1065.
2. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932–946.
3. Global Initiative for Chronic Obstructive Lung Disease. A collaborative project of the National Heart, Lung, and Blood Institute, National Institutes of Health, and the World Health Organization [Internet]. Bethesda (MD): National Institutes of Health, National Heart, Lung, and Blood Institute; c2006 [updated 2006 Nov; accessed 2007 Apr]. Available from: www.goldcopd.com
4. Celli BR, Calverley PM, Rennard SI, Wouters EF, Agusti A, Anthonisen N, Macnee W, Jones P, Pride N, Rodriguez-Roisin R, et al. Proposal for a multidimensional staging system for chronic obstructive pulmonary disease. Respir Med 2005;99:1546–1554.
5. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J 2006;28:1245–1257.
6. Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell AL. Patterns of comorbidities in newly diagnosed COPD and asthma in primary care. Chest 2005;128:2099–2107.
7. Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979 to 2001. Chest 2005;128:2005–2011.
8. Fabbri LM, Rabe KF. Complex chronic comorbidities: proceedings of an ERS research seminar held in Rome 11–12 February 2007. [Internet]. Lausanne, Switzerland: European Respiratory Society; c2007 [accessed 2007 Apr]. Available from: www.ersnet.org
9. Fabbri LM, Ferrari R. Chronic disease in the elderly: back to the future of internal medicine. Breathe 2006;3:41–49.
10. Tinetti ME, Bogardus ST Jr, Agostini JV. Potential pitfalls of disease-specific guidelines for patients with multiple conditions. N Engl J Med 2004;351:2870–2874.
11. Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA 2005;294:716–724.
12. Johannessen A, Lehmann S, Omenaas ER, Eide GE, Bakke PS, Gulsvik A. Post-bronchodilator spirometry reference values in adults and implications for disease management. Am J Respir Crit Care Med 2006;173:1316–1325.
13. Hnizdo E, Glindmeyer HW, Petsonk EL, Enright P, Buist AS. Case definitions for chronic obstructive pulmonary disease. COPD 2006;3:95–100.
14. Mannino DM, Sonia Buist A, Vollmer WM. Chronic obstructive pulmonary disease in the older adult: what defines abnormal lung function? Thorax 2007;62:237–241.
15. Herpel LB, Kanner RE, Lee SM, Fessler HE, Sciurba FC, Connett JE, Wise RA. Variability of spirometry in chronic obstructive pulmonary disease: results from two clinical trials. Am J Respir Crit Care Med 2006;173:1106–1113.
16. Shahab L, Jarvis MJ, Britton J, West R. Prevalence, diagnosis and relation to tobacco dependence of chronic obstructive pulmonary disease in a nationally representative population sample. Thorax 2006;61:1043–1047.
17. Roberts SD, Farber MO, Knox KS, Phillips GS, Bhatt NY, Mastronarde JG, Wood KL. FEV1/FVC ratio of 70% misclassifies patients with obstruction at the extremes of age. Chest 2006;130:200–206.
18. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J 2006;28:523–532.
19. de Marco R, Accordini S, Cerveri I, Corsico A, Anto JM, Kunzli N, Janson C, Sunyer J, Jarvis D, Chinn S, et al. Incidence of chronic obstructive pulmonary disease in a cohort of young adults according to the presence of chronic cough and phlegm. Am J Respir Crit Care Med 2007;175:32–39.
20. Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C, Jemal A, Lee TA, Miravitlles M, et al. Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J 2006;27:188–207.
21. Devereux G. ABC of chronic obstructive pulmonary disease: definition, epidemiology, and risk factors. BMJ 2006;332:1142–1144.
22. Ramirez-Venegas A, Sansores RH, Perez-Padilla R, Regalado J, Velazquez A, Sanchez C, Mayar ME. Survival of patients with chronic obstructive pulmonary disease due to biomass smoke and tobacco. Am J Respir Crit Care Med 2006;173:393–397.
23. Machado MC, Krishnan JA, Buist SA, Bilderback AL, Fazolo GP, Santarosa MG, Queiroga F Jr, Vollmer WM. Sex differences in survival of oxygen-dependent patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:524–529.
24. Vestbo J, Prescott E, Almdal T, Dahl M, Nordestgaard BG, Andersen T, Sorensen TI, Lange P. Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City Heart Study. Am J Respir Crit Care Med 2006;173:79–83.
25. Mannino DM, Reichert MM, Davis KJ. Lung function decline and outcomes in an adult population. Am J Respir Crit Care Med 2006;173:985–990.
26. Martinez FJ, Foster G, Curtis JL, Criner G, Weinmann G, Fishman A, DeCamp MM, Benditt J, Sciurba F, Make B, et al. Predictors of mortality in patients with emphysema and severe airflow obstruction. Am J Respir Crit Care Med 2006;173:1326–1334.
27. Lomas DA. The selective advantage of α1-antitrypsin deficiency. Am J Respir Crit Care Med 2006;173:1072–1077.
28. Juul K, Tybjaerg-Hansen A, Marklund S, Lange P, Nordestgaard BG. Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:858–864.
29. Guenegou A, Leynaert B, Benessiano J, Pin I, Demoly P, Neukirch F, Boczkowski J, Aubier M. Association of lung function decline with the heme oxygenase-1 gene promoter microsatellite polymorphism in a general population sample: results from the European Community Respiratory Health Survey (ECRHS), France. J Med Genet 2006;43:e43.
30. Young RP, Hopkins R, Black PN, Eddy C, Wu L, Gamble GD, Mills GD, Garrett JE, Eaton TE, Rees MI. Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function. Thorax 2006;61:394–399.
31. Rousseau K, Vinall LE, Butterworth SL, Hardy RJ, Holloway J, Wadsworth ME, Swallow DM. Muc7 haplotype analysis: results from a longitudinal birth cohort support protective effect of the MUC7*5 allele on respiratory function. Ann Hum Genet 2006;70:417–427.
32. Takabatake N, Shibata Y, Abe S, Wada T, Machiya J, Igarashi A, Tokairin Y, Ji G, Sato H, Sata M, et al. A single nucleotide polymorphism in the ccl1 gene predicts acute exacerbations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:875–885.
33. van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Nolte IM, Boezen HM. Decorin and TGF-beta1 polymorphisms and development of COPD in a general population. Respir Res 2006;7:89.
34. Brogger J, Steen VM, Eiken HG, Gulsvik A, Bakke P. Genetic association between COPD and polymorphisms in TNF, ADRB2 and EPHX1. Eur Respir J 2006;27:682–688.
35. Matheson MC, Ellis JA, Raven J, Johns DP, Walters EH, Abramson MJ. Beta2-adrenergic receptor polymorphisms are associated with asthma and COPD in adults. J Hum Genet 2006;51:943–951.
36. Chappell S, Daly L, Morgan K, Guetta Baranes T, Roca J, Rabinovich R, Millar A, Donnelly SC, Keatings V, MacNee W, et al. Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease. Hum Mutat 2006;27:103–109.
37. Hersh CP, Demeo DL, Lazarus R, Celedon JC, Raby BA, Benditt JO, Criner G, Make B, Martinez FJ, Scanlon PD, et al. Genetic association analysis of functional impairment in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:977–984.
38. Heguy A, O'Connor TP, Luettich K, Worgall S, Cieciuch A, Harvey BG, Hackett NR, Crystal RG. Gene expression profiling of human alveolar macrophages of phenotypically normal smokers and nonsmokers reveals a previously unrecognized subset of genes modulated by cigarette smoking. J Mol Med 2006;84:318–328.
39. Pierrou S, Broberg P, O'Donnell RA, Pawlowski K, Virtala R, Lindqvist E, Richter A, Wilson SJ, Angco G, Moller S, et al. Expression of genes involved in oxidative stress responses in airway epithelial cells of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:577–586.
40. Zandvoort A, van der Geld YM, Jonker MR, Noordhoek JA, Vos JT, Wesseling J, Kauffman HF, Timens W, Postma DS. High ICAM-1 gene expression in pulmonary fibroblasts of COPD patients: a reflection of an enhanced immunological function. Eur Respir J 2006;28:113–122.
41. Reynolds PR, Cosio MG, Hoidal JR. Cigarette smoke-induced EGR-1 upregulates proinflammatory cytokines in pulmonary epithelial cells. Am J Respir Cell Mol Biol 2006;35:314–319.
42. Demeo DL, Mariani TJ, Lange C, Srisuma S, Litonjua AA, Celedon JC, Lake SL, Reilly JJ, Chapman HA, Mecham BH, et al. The serpine2 gene is associated with chronic obstructive pulmonary disease. Am J Hum Genet 2006;78:253–264.
43. Demedts IK, Demoor T, Bracke KR, Joos GF, Brusselle GG. Role of apoptosis in the pathogenesis of copd and pulmonary emphysema. Respir Res 2006;7:53.
44. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653.
45. O'Donnell R, Breen D, Wilson S, Djukanovic R. Inflammatory cells in the airways in COPD. Thorax 2006;61:448–454.
46. Agusti A. Thomas A. Neff lecture: chronic obstructive pulmonary disease: a systemic disease. Proc Am Thorac Soc 2006;3:478–481.
47. Dentener MA, Louis R, Cloots RH, Henket M, Wouters EF. Differences in local versus systemic TNFalpha production in COPD: inhibitory effect of hyaluronan on LPS induced blood cell TNFalpha release. Thorax 2006;61:478–484.
48. Sevenoaks MJ, Stockley RA. Chronic obstructive pulmonary disease, inflammation and co-morbidity: a common inflammatory phenotype? Respir Res 2006;7:70.
49. Spurzem JR, Rennard SI. Pathogenesis of COPD. Semin Respir Crit Care Med 2005;26:142–153.
50. Bracke KR, D'Hulst AI, Maes T, Moerloose KB, Demedts IK, Lebecque S, Joos GF, Brusselle GG. Cigarette smoke-induced pulmonary inflammation and emphysema are attenuated in CCR6-deficient mice. J Immunol 2006;177:4350–4359.
51. D'Hulst AI, Maes T, Bracke KR, Demedts IK, Tournoy KG, Joos GF, Brusselle GG. Cigarette smoke-induced pulmonary emphysema in scid-mice: is the acquired immune system required? Respir Res 2005;6:147.
52. Gadgil A, Zhu X, Sciurba FC, Duncan SR. Altered T-cell phenotypes in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006;3:487–488.
53. Noble PW, Jiang D. Matrix regulation of lung injury, inflammation, and repair: the role of innate immunity. Proc Am Thorac Soc 2006;3:401–404.
54. Mukhopadhyay S, Hoidal JR, Mukherjee TK. Role of TNFalpha in pulmonary pathophysiology. Respir Res 2006;7:125.
55. Sabroe I, Parker LC, Dockrell DH, Davies DE, Dower SK, Whyte MK. Pulmonary perspective: targeting the networks that underpin contiguous immunity in asthma and COPD. Am J Respir Crit Care Med 2006;175:306–311.
56. Molfino NA, Jeffery PK. Chronic obstructive pulmonary disease: histopathology, inflammation and potential therapies. Pulm Pharmacol Ther [online ahead of print] 2006 May 6; doi: 10.1016/j.pupt.2006.04.003.
57. Kranenburg AR, Willems-Widyastuti A, Moori WJ, Sterk PJ, Alagappan VK, de Boer WI, Sharma HS. Enhanced bronchial expression of extracellular matrix proteins in chronic obstructive pulmonary disease. Am J Clin Pathol 2006;126:725–735.
58. Martin-Mosquero C, Peces-Barba G, Rubio ML, Ortega M, Rodriguez-Nieto MJ, Martinez Galan L, Gonzalez-Mangado N. Increased collagen deposition correlated with lung destruction in human emphysema. Histol Histopathol 2006;21:823–828.
59. Walker DC, Behzad AR, Chu F. Neutrophil migration through preexisting holes in the basal laminae of alveolar capillaries and epithelium during streptococcal pneumonia. Microvasc Res 1995;50:397–416.
60. Sirianni FE, Milaninezhad A, Chu FS, Walker DC. Alteration of fibroblast architecture and loss of basal lamina apertures in human emphysematous lung. Am J Respir Crit Care Med 2006;173:632–638.
61. Carnevali S, Luppi F, D'Arca D, Caporali A, Ruggieri MP, Vettori MV, Caglieri A, Astancolle S, Panico F, Davalli P, et al. Clusterin decreases oxidative stress in lung fibroblasts exposed to cigarette smoke. Am J Respir Crit Care Med 2006;174:393–399.
62. Macnee W. Prescription of oxygen: still problems after all these years. Am J Respir Crit Care Med 2005;172:517–518.
63. Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J 2006;28:219–242.
64. Foronjy RF, Mirochnitchenko O, Propokenko O, Lemaitre V, Jia Y, Inouye M, Okada Y, D'Armiento JM. Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice. Am J Respir Crit Care Med 2006;173:623–631.
65. Tuder RM, Yoshida T, Fijalkowka I, Biswal S, Petrache I. Role of lung maintenance program in the heterogeneity of lung destruction in emphysema. Proc Am Thorac Soc 2006;3:673–679.
66. Yang SR, Chida AS, Bauter MR, Shafiq N, Seweryniak K, Maggirwar SB, Kilty I, Rahman I. Cigarette smoke induces proinflammatory cytokine release by activation of NF-κB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol 2006;291:L46–57.
67. Kinnula VL. Focus on antioxidant enzymes and antioxidant strategies in smoking related airway diseases. Thorax 2005;60:693–700.
68. Mossman BT, Lounsbury KM, Reddy SP. Oxidants and signaling by mitogen-activated protein kinases in lung epithelium. Am J Respir Cell Mol Biol 2006;34:666–669.
69. Barnes PJ. Transcription factors in airway diseases. Lab Invest 2006;86:867–872.
70. Szulakowski P, Crowther AJ, Jimenez LA, Donaldson K, Mayer R, Leonard TB, Macnee W, Drost EM. The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:41–50.
71. Sato T, Seyama K, Sato Y, Mori H, Souma S, Akiyoshi T, Kodama Y, Mori T, Goto S, Takahashi K, et al. Senescence marker protein-30 protects mice lungs from oxidative stress, aging, and smoking. Am J Respir Crit Care Med 2006;174:530–537.
72. Petrache I, Fijalkowska I, Zhen L, Medler TR, Brown E, Cruz P, Choe KH, Taraseviciene-Stewart L, Scerbavicius R, Shapiro L, et al. A novel antiapoptotic role for α1-antitrypsin in the prevention of pulmonary emphysema. Am J Respir Crit Care Med 2006;173:1222–1228.
73. Mohsenin A, Blackburn MR. Adenosine signaling in asthma and chronic obstructive pulmonary disease. Curr Opin Pulm Med 2006;12:54–59.
74. Polosa R, Holgate ST. Adenosine receptors as promising therapeutic targets for drug development in chronic airway inflammation. Curr Drug Targets 2006;7:699–706.
75. Sun CX, Zhong H, Mohsenin A, Morschl E, Chunn JL, Molina JG, Belardinelli L, Zeng D, Blackburn MR. Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury. J Clin Invest 2006;116:2173–2182.
76. Varani K, Caramori G, Vincenzi F, Adcock I, Casolari P, Leung E, Maclennan S, Gessi S, Morello S, Barnes PJ, et al. Alteration of adenosine receptors in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:398–406.
77. Sabroe I, Dockrell DH, Vogel SN, Renshaw SA, Whyte MK, Dower SK. Identifying and hurdling obstacles to translational research. Nat Rev Immunol 2007;7:77–82.
78. Taraseviciene-Stewart L, Burns N, Kraskauskas D, Nicolls MR, Tuder RM, Voelkel NF. Mechanisms of autoimmune emphysema. Proc Am Thorac Soc 2006;3:486–487.
79. Vijayanand P, Seumois G, Pickard C, Powell RM, Angco G, Sammut D, Gadola SD, Friedmann PS, Djukanovic R. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N Engl J Med 2007;356:1410–1422.
80. van der Strate BW, Postma DS, Brandsma CA, Melgert BN, Luinge MA, Geerlings M, Hylkema MN, van den Berg A, Timens W, Kerstjens HA. Cigarette smoke–induced emphysema: a role for the B cell? Am J Respir Crit Care Med 2006;173:751–758.
81. Taraseviciene-Stewart L, Douglas IS, Nana-Sinkam PS, Lee JD, Tuder RM, Nicolls MR, Voelkel NF. Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease? Proc Am Thorac Soc 2006;3:687–690.
82. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001;345:340–350.
83. Lee SH, Goswami S, Grudo A, Song LZ, Bandi V, Goodnight-White S, Green L, Hacken-Bitar J, Huh J, Bakaeen F, et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med 2007;13:567–569. [online ahead of print] 2007 Apr 22; doi: 101.1038/nm1583.
84. Reyes E, Prieto A, de la Hera A, de Lucas P, Alvarez-Sala R, Alvarez-Sala JL, Alvarez-Mon M. Treatment with AM3 restores defective T-cell function in COPD patients. Chest 2006;129:527–535.
85. de Jong JW, van der Belt-Gritter B, Koeter GH, Postma DS. Peripheral blood lymphocyte cell subsets in subjects with chronic obstructive pulmonary disease: association with smoking, IgE and lung function. Respir Med 1997;91:67–76.
86. Domagala-Kulawik J, Hoser G, Dabrowska M, Chazan R. Increased proportion of Fas positive CD8+ cells in peripheral blood of patients with COPD. Respir Med 2007;101:1338–1343.
87. Glader P, von Wachenfeldt K, Lofdahl CG. Systemic CD4+ T-cell activation is correlated with FEV1 in smokers. Respir Med 2006;100:1088–1093.
88. Kim WD, Kim WS, Koh Y, Lee SD, Lim CM, Kim DS, Cho YJ. Abnormal peripheral blood T-lymphocyte subsets in a subgroup of patients with COPD. Chest 2002;122:437–444.
89. Koch A, Gaczkowski M, Sturton G, Staib P, Schinkothe T, Klein E, Rubbert A, Bacon K, Wassermann K, Erdmann E. Modification of surface antigens in blood CD8+ T-lymphocytes in COPD: effects of smoking. Eur Respir J 2007;29:42–50.
90. Vermaelen K, Pauwels R. Pulmonary dendritic cells. Am J Respir Crit Care Med 2005;172:530–551.
91. Roghanian A, Drost EM, MacNee W, Howie SE, Sallenave JM. Inflammatory lung secretions inhibit dendritic cell maturation and function via neutrophil elastase. Am J Respir Crit Care Med 2006;174:1189–1198.
92. Pinto-Plata VM, Mullerova H, Toso JF, Feudjo-Tepie M, Soriano JB, Vessey RS, Celli BR. C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax 2006;61:23–28.
93. Hersh CP, Miller DT, Kwiatkowski DJ, Silverman EK. Genetic determinants of C-reactive protein in COPD. Eur Respir J 2006;28:1156–1162.
94. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:250–255.
95. Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM. Raised CRP levels mark metabolic and functional impairment in advanced COPD. Thorax 2006;61:17–22.
96. Yende S, Waterer GW, Tolley EA, Newman AB, Bauer DC, Taaffe DR, Jensen R, Crapo R, Rubin S, Nevitt M, et al. Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects. Thorax 2006;61:10–16.
97. Hurst JR, Donaldson GC, Perera WR, Wilkinson TM, Bilello JA, Hagan GW, Vessey RS, Wedzicha JA. Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:867–874.
98. MacIntyre NR. Muscle dysfunction associated with chronic obstructive pulmonary disease. Respir Care 2006;51:840–847. [Discussion, 848–852.]
99. McKenzie D. To breathe or not to breathe: the respiratory muscles and COPD. J Appl Physiol 2006;101:1279–1280.
100. O'Donnell DE. Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006;3:180–184.
101. Cooper CB. The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function. Am J Med 2006;119:21–31.
102. Wagner PD. Skeletal muscles in chronic obstructive pulmonary disease: deconditioning, or myopathy? Respirology 2006;11:681–686.
103. Ottenheijm CA, Heunks LM, Hafmans T, van der Ven PF, Benoist C, Zhou H, Labeit S, Granzier HL, Dekhuijzen PN. Titin and diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:527–534.
104. Swisher AK, Alway SE, Yeater R. The effect of exercise on peripheral muscle in emphysema: a preliminary investigation. COPD 2006;3:9–15.
105. Maluf SW, Mergener M, Dalcanale L, Costa CC, Pollo T, Kayser M, da Silva LB, Pra D, Teixeira PJ. DNA damage in peripheral blood of patients with chronic obstructive pulmonary disease (COPD). Mutat Res 2007;626:180–184.
106. Mercken EM, Hageman GJ, Schols AM, Akkermans MA, Bast A, Wouters EF. Rehabilitation decreases exercise-induced oxidative stress in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:994–1001.
107. Pinho RA, Chiesa D, Mezzomo KM, Andrades ME, Bonatto F, Gelain D, Dal Pizzol F, Knorst MM, Moreira JC. Oxidative stress in chronic obstructive pulmonary disease patients submitted to a rehabilitation program. Respir Med 2007 (in press).
108. Ventura-Clapier R, Mettauer B, Bigard X. Beneficial effects of endurance training on cardiac and skeletal muscle energy metabolism in heart failure. Cardiovasc Res 2007;73:10–18.
109. Bolton CE, Broekhuizen R, Ionescu AA, Nixon LS, Wouters EF, Shale DJ, Schols AM. Cellular protein breakdown and systemic inflammation are unaffected by pulmonary rehabilitation in COPD. Thorax 2007;62:109–114.
110. Coxson HO, Rogers RM. Quantitative computed tomography of chronic obstructive pulmonary disease. Acad Radiol 2005;12:1457–1463.
111. Coxson HO, Rogers RM. New concepts in the radiological assessment of COPD. Semin Respir Crit Care Med 2005;26:211–220.
112. Baldi S, Miniati M, Bellina CR, Battolla L, Catapano G, Begliomini E, Giustini D, Giuntini C. Relationship between extent of pulmonary emphysema by high-resolution computed tomography and lung elastic recoil in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:585–589.
113. Hogg JC. State of the art: bronchiolitis in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006;3:489–493.
114. de Jong PA, Muller NL, Pare PD, Coxson HO. Computed tomographic imaging of the airways: relationship to structure and function. Eur Respir J 2005;26:140–152.
115. Hasegawa M, Nasuhara Y, Onodera Y, Makita H, Nagai K, Fuke S, Ito Y, Betsuyaku T, Nishimura M. Airflow limitation and airway dimensions in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:1309–1315.
116. Magnant J, Vecellio L, de Monte M, Grimbert D, Valat C, Boissinot E, Guilloteau D, Lemarie E, Diot P. Comparative analysis of different scintigraphic approaches to assess pulmonary ventilation. J Aerosol Med 2006;19:148–159.
117. Fain SB, Panth SR, Evans MD, Wentland AL, Holmes JH, Korosec FR, O'Brien MJ, Fountaine H, Grist TM. Early emphysematous changes in asymptomatic smokers: detection with 3He MR imaging. Radiology 2006;239:875–883.
118. Morino S, Toba T, Araki M, Azuma T, Tsutsumi S, Tao H, Nakamura T, Nagayasu T, Tagawa T. Noninvasive assessment of pulmonary emphysema using dynamic contrast-enhanced magnetic resonance imaging. Exp Lung Res 2006;32:55–67.
119. Donaldson GC, Wedzicha JA. COPD exacerbations: 1. Epidemiology. Thorax 2006;61:164–168.
120. Berenson CS, Garlipp MA, Grove LJ, Maloney J, Sethi S. Impaired phagocytosis of nontypeable Haemophilus influenzae by human alveolar macrophages in chronic obstructive pulmonary disease. J Infect Dis 2006;194:1375–1384.
121. Sethi S. Coinfection in exacerbations of COPD: a new frontier. Chest 2006;129:223–224.
122. Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:991–998.
123. Wilkinson TM, Donaldson GC, Johnston SL, Openshaw PJ, Wedzicha JA. Respiratory syncytial virus, airway inflammation, and FEV1 decline in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:871–876.
124. Mallia P, Johnston SL. How viral infections cause exacerbation of airway diseases. Chest 2006;130:1203–1210.
125. Phua J, Koay ES, Zhang D, Tai LK, Boo XL, Lim KC, Lim TK. Soluble triggering receptor expressed on myeloid cells-1 in acute respiratory infections. Eur Respir J 2006;28:695–702.
126. Cameron RJ, de Wit D, Welsh TN, Ferguson J, Grissell TV, Rye PJ. Virus infection in exacerbations of chronic obstructive pulmonary disease requiring ventilation. Intensive Care Med 2006;32:1022–1029.
127. Proud D, Chow CW. Role of viral infections in asthma and chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2006;35:513–518.
128. Papi A, Luppi F, Franco F, Fabbri LM. Pathophysiology of exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006;3:245–251.
129. Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, Caramori G, Fabbri LM, Johnston SL. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med 2006;173:1114–1121.
130. Martinello RA, Esper F, Weibel C, Ferguson D, Landry ML, Kahn JS. Human metapneumovirus and exacerbations of chronic obstructive pulmonary disease. J Infect 2006;53:248–254.
131. ten Brinke A, Sterk PJ, Masclee AA, Spinhoven P, Schmidt JT, Zwinderman AH, Rabe KF, Bel EH. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 2005;26:812–818.
132. Le Jemtel TH, Padeletti M, Jelic S. Diagnostic and therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol 2007;49:171–180.
133. Abroug F, Ouanes-Besbes L, Nciri N, Sellami N, Addad F, Hamda KB, Amor AB, Najjar MF, Knani J. Association of left-heart dysfunction with severe exacerbation of chronic obstructive pulmonary disease: diagnostic performance of cardiac biomarkers. Am J Respir Crit Care Med 2006;174:990–996.
134. Barnes PJ, Chowdhury B, Kharitonov SA, Magnussen H, Page CP, Postma D, Saetta M. Pulmonary biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:6–14.
135. Grasso S, Leone A, De Michele M, Anaclerio R, Cafarelli A, Ancona G, Stripoli T, Bruno F, Pugliese P, Dambrosio M, et al. Use of N-terminal pro-brain natriuretic peptide to detect acute cardiac dysfunction during weaning failure in difficult-to-wean patients with chronic obstructive pulmonary disease. Crit Care Med 2007;35:96–105.
136. Tung RH, Camargo CA Jr, Krauser D, Anwaruddin S, Baggish A, Chen A, Januzzi JL Jr. Amino-terminal pro-brain natriuretic peptide for the diagnosis of acute heart failure in patients with previous obstructive airway disease. Ann Emerg Med 2006;48:66–74.
137. Januzzi JL Jr. Natriuretic peptide testing: a window into the diagnosis and prognosis of heart failure. Cleve Clin J Med 2006;73:149–152, 155–157.
138. Mueller C, Laule-Kilian K, Frana B, Rodriguez D, Scholer A, Schindler C, Perruchoud AP. Use of B-type natriuretic peptide in the management of acute dyspnea in patients with pulmonary disease. Am Heart J 2006;151:471–477.
139. Leuchte HH, Baumgartner RA, Nounou ME, Vogeser M, Neurohr C, Trautnitz M, Behr J. Brain natriuretic peptide is a prognostic parameter in chronic lung disease. Am J Respir Crit Care Med 2006;173:744–750.
140. Franciosi LG, Page CP, Celli BR, Cazzola M, Walker MJ, Danhof M, Rabe KF, Della Pasqua OE. Markers of disease severity in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2006;19:189–199.
141. Franciosi LG, Page CP, Celli BR, Cazzola M, Walker MJ, Danhof M, Rabe KF, Della Pasqua OE. Markers of exacerbation severity in chronic obstructive pulmonary disease. Respir Res 2006;7:74.
142. Wedzicha JA, Hurst JR. Chronic obstructive pulmonary disease exacerbation and risk of pulmonary embolism. Thorax 2007;62:103–104.
143. Rutschmann OT, Cornuz J, Poletti PA, Bridevaux PO, Hugli OW, Qanadli SD, Perrier A. Should pulmonary embolism be suspected in exacerbation of chronic obstructive pulmonary disease? Thorax 2007;62:121–125.
144. Le Gal G, Righini M. Pulmonary embolism in patients with unexplained exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 2006;145:310 [Author reply, 310.]
145. Tillie-Leblond I, Marquette CH, Perez T, Scherpereel A, Zanetti C, Tonnel AB, Remy-Jardin M. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med 2006;144:390–396.
146. Suissa S. Statistical treatment of exacerbations in therapeutic trials of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:842–846.
147. Wilt T, Niewoehner D, Kim C-B, Kane R, Linabery A, Tacklind J, MacDonald R, Rutks I. Use of spirometry for case finding, diagnosis, and management of chronic obstructive pulmonary disease (COPD). Evidence Report/Technology Assessment No. 121 (prepared by the Minnesota Evidence-based Practice Center under contract no. 290–02–0009) Rockville, MD: Agency for Healthcare Research and Quality; 2005. AHRQ Publication No. 05-e017-2.
148. Stratelis G, Molstad S, Jakobsson P, Zetterstrom O. The impact of repeated spirometry and smoking cessation advice on smokers with mild COPD. Scand J Prim Health Care 2006;24:133–139.
149. Dervaux A, Kanit M, Laqueille X. Efficacy of varenicline for smoking cessation. JAMA 2006;296:2555. [Author reply, 2555–2556.]
150. Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006;296:56–63.
151. Granger R, Walters J, Poole PJ, Lasserson TJ, Mangtani P, Cates CJ, Wood-Baker R. Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006;4:CD001390.
152. Poole PJ, Chacko E, Wood-Baker RW, Cates CJ. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006;3:CD001287.
153. Steentoft J, Konradsen HB, Hilskov J, Gislason G, Andersen JR. Response to pneumococcal vaccine in chronic obstructive lung disease: the effect of ongoing, systemic steroid treatment. Vaccine 2006;24:1408–1412.
154. Meyer P, Menzel M, Muellinger B, Weber N, Haeussinger K, Ziegler-Heitbrock L. Inhalative vaccination with pneumococcal polysaccharide in patients with chronic obstructive pulmonary disease. Vaccine 2006;24:5832–5838.
155. Soler M, Mutterlein R, Cozma G. Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic obstructive pulmonary disease. Respiration 2007;74:26–32.
156. Zhou Y, Wang X, Zeng X, Qiu R, Xie J, Liu S, Zheng J, Zhong N, Ran P. Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology 2006;11:603–610.
157. Hirano T, Yamagata T, Gohda M, Yamagata Y, Ichikawa T, Yanagisawa S, Ueshima K, Akamatsu K, Nakanishi M, Matsunaga K, et al. Inhibition of reactive nitrogen species production in COPD airways: comparison of inhaled corticosteroid and oral theophylline. Thorax 2006;61:761–766.
158. O'Donnell DE, Sciurba F, Celli B, Mahler DA, Webb KA, Kalberg CJ, Knobil K. Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Chest 2006;130:647–656.
159. Barnes NC, Qiu YS, Pavord ID, Parker D, Davis PA, Zhu J, Johnson M, Thomson NC, Jeffery PK. Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease. Am J Respir Crit Care Med 2006;173:736–743.
160. Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:144–149.
161. Rabe KF. Treating COPD:–the TORCH trial, p values, and the dodo. N Engl J Med 2007;356:851–854.
162. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.
163. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O'Donnell D, McIvor A, Sharma S, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007.
164. Rennard SI, Schachter N, Strek M, Rickard K, Amit O. Cilomilast for COPD: results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest 2006;129:56–66.
165. Huang Z, Mancini JA. Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD. Curr Med Chem 2006;13:3253–3262.
166. Massaro D, Massaro GD. Toward therapeutic pulmonary alveolar regeneration in humans. Proc Am Thorac Soc 2006;3:709–712.
167. Roth MD, Connett JE, D'Armiento JM, Foronjy RF, Friedman PJ, Goldin JG, Louis TA, Mao JT, Muindi JR, O'Connor GT, et al. Feasibility of retinoids for the treatment of emphysema study. Chest 2006;130:1334–1345.
168. van der Vaart H, Koeter GH, Postma DS, Kauffman HF, ten Hacken NH. First study of infliximab treatment in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:465–469.
169. Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison J, Mahler D, Saadeh C, Siler T, Snell P, et al. The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:926–934.
170. Stavem K, Bjortuft O, Borgan O, Geiran O, Boe J. Lung transplantation in patients with chronic obstructive pulmonary disease in a national cohort is without obvious survival benefit. J Heart Lung Transplant 2006;25:75–84.
171. Naunheim KS, Wood DE, Mohsenifar Z, Sternberg AL, Criner GJ, DeCamp MM, Deschamps CC, Martinez FJ, Sciurba FC, Tonascia J, et al. Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the national emphysema treatment trial research group. Ann Thorac Surg 2006;82:431–443.
172. Lenfant C. Will lung volume reduction surgery be widely applied? Ann Thorac Surg 2006;82:385–387.
173. Tiong LU, Davies R, Gibson PG, Hensley MJ, Hepworth R, Lasserson TJ, Smith B. Lung volume reduction surgery for diffuse emphysema. Cochrane Database Syst Rev 2006;4:CD001001.
174. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, Pinto Plate V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004;350:1005–1012.
175. Orens JB, Estenne M, Arcasoy S, Conte JV, Corris P, Egan JJ, Egan T, Keshavjee S, Knoop C, Kotloff R, et al. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745–755.
176. Navas B, Santos F, Vaquero JM, Fernandez MC, Redel J, Lama R. Evaluation of patients referred for lung transplantation: fourteen years experience. Transplant Proc 2006;38:2519–2521.
177. Smith PW, Wang H, Parini V, Zolak JS, Shen KR, Daniel TM, Robbins MK, Tribble CG, Kron IL, Jones DR. Lung transplantation in patients 60 years and older: results, complications, and outcomes. Ann Thorac Surg 2006;82:1835–1841. [Discussion, 1841.]
178. Tutic M, Lardinois D, Imfeld S, Korom S, Boehler A, Speich R, Bloch KE, Russi EW, Weder W. Lung-volume reduction surgery as an alternative or bridging procedure to lung transplantation. Ann Thorac Surg 2006;82:208–213. [Discussion, 213.]
179. Stoller JK, Gildea TR, Ries AL, Meli YM, Karafa MT. Lung volume reduction surgery in patients with emphysema and alpha-1 antitrypsin deficiency. Ann Thorac Surg 2007;83:241–251.
180. Wood DE, McKenna RJ Jr, Yusen RD, Sterman DH, Ost DE, Springmeyer SC, Gonzalez HX, Mulligan MS, Gildea T, Houck WV, et al. A multicenter trial of an intrabronchial valve for treatment of severe emphysema. J Thorac Cardiovasc Surg 2007;133:65–73.
181. Force SD, Miller DL, Pelaez A, Ramirez AM, Vega D, Barden B, Lawrence EC. Outcomes of delayed chest closure after bilateral lung transplantation. Ann Thorac Surg 2006;81:2020–2024. [Discussion, 2024–2025.]
182. Hadjiliadis D, Chaparro C, Gutierrez C, Steele MP, Singer LG, Davis RD, Waddell TK, Hutcheon MA, Palmer SM, Keshavjee S. Impact of lung transplant operation on bronchiolitis obliterans syndrome in patients with chronic obstructive pulmonary disease. Am J Transplant 2006;6:183–189.
183. DeCamp MM, Blackstone EH, Naunheim KS, Krasna MJ, Wood DE, Meli YM, McKenna RJ Jr. Patient and surgical factors influencing air leak after lung volume reduction surgery: lessons learned from the National Emphysema Treatment Trial. Ann Thorac Surg 2006;82:197–206. [Discussion, 206–207.]
184. Buduhan G, Tan L, Kasian K, Mink SN. Volume reduction surgery impairs immediate postoperative pulmonary function in canine emphysema. Am J Respir Crit Care Med 2006;174:1310–1318.
185. Swallow EB, Reyes D, Hopkinson NS, Man WD, Porcher R, Cetti EJ, Moore AJ, Moxham J, Polkey MI. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax 2007;62:115–120.
186. Shigemura N, Okumura M, Mizuno S, Imanishi Y, Matsuyama A, Shiono H, Nakamura T, Sawa Y. Lung tissue engineering technique with adipose stromal cells improves surgical outcome for pulmonary emphysema. Am J Respir Crit Care Med 2006;174:1199–1205.
187. Venuta F, Rendina EA, De Giacomo T, Anile M, Diso D, Andreetti C, Pugliese F, Coloni GF. Bronchoscopic procedures for emphysema treatment. Eur J Cardiothorac Surg 2006;29:281–287.
188. Wan IY, Toma TP, Geddes DM, Snell G, Williams T, Venuta F, Yim AP. Bronchoscopic lung volume reduction for end-stage emphysema: report on the first 98 patients. Chest 2006;129:518–526.
189. de Oliveira HG, Macedo-Neto AV, John AB, Jungblut S, Prolla JC, Menna-Barreto SS, Fortis EA. Transbronchoscopic pulmonary emphysema treatment: 1-month to 24-month endoscopic follow-up. Chest 2006;130:190–199.
190. Troosters T, Casaburi R, Gosselink R, Decramer M. Pulmonary rehabilitation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:19–38.
191. Nici L, Donner C, Wouters E, Zuwallack R, Ambrosino N, Bourbeau J, Carone M, Celli B, Engelen M, Fahy B, et al. American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med 2006;173:1390–1413.
192. Lacasse Y, Goldstein R, Lasserson TJ, Martin S. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006;4:CD003793.
193. Paz-Diaz H, Montes de Oca M, Lopez JM, Celli BR. Pulmonary rehabilitation improves depression, anxiety, dyspnea and health status in patients with COPD. Am J Phys Med Rehabil 2007;86:30–36.
194. Puhan MA, Busching G, Schunemann HJ, VanOort E, Zaugg C, Frey M. Interval versus continuous high-intensity exercise in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2006;145:816–825.
195. Sewell L, Singh SJ, Williams JE, Collier R, Morgan MD. How long should outpatient pulmonary rehabilitation be? A randomised controlled trial of 4 weeks versus 7 weeks. Thorax 2006;61:767–771.
196. Cranston JM, Crockett AJ, Moss JR, Alpers JH. Domiciliary oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;4:CD001744.
197. Laude EA, Duffy NC, Baveystock C, Dougill B, Campbell MJ, Lawson R, Jones PW, Calverley PM. The effect of helium and oxygen on exercise performance in chronic obstructive pulmonary disease: a randomized crossover trial. Am J Respir Crit Care Med 2006;173:865–870.
198. van Helvoort HA, Heijdra YF, Heunks LM, Meijer PL, Ruitenbeek W, Thijs HM, Dekhuijzen PN. Supplemental oxygen prevents exercise-induced oxidative stress in muscle-wasted patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:1122–1129.
199. Bradley JM, O'Neill B. Short-term ambulatory oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;4:CD004356.
200. Lacasse Y, Lecours R, Pelletier C, Begin R, Maltais F. Randomised trial of ambulatory oxygen in oxygen-dependent COPD. Eur Respir J 2005;25:1032–1038.
201. Nisbet M, Eaton T, Lewis C, Fergusson W, Kolbe J. Overnight prescription of oxygen in long term oxygen therapy: time to reconsider the guidelines? Thorax 2006;61:779–782.
202. Austin M, Wood-Baker R. Oxygen therapy in the pre-hospital setting for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006;3:CD00534.
203. Cullen DL. Long term oxygen therapy adherence and copd: What we don't know. Chron Respir Dis 2006;3:217–222.
204. Zhu Z, Barnette RK, Fussell KM, Michael Rodriguez R, Canonico A, Light RW. Continuous oxygen monitoring–a better way to prescribe long-term oxygen therapy. Respir Med 2005;99:1386–1392.
205. Croxton TL, Bailey WC. Long-term oxygen treatment in chronic obstructive pulmonary disease: recommendations for future research: an NHLBI workshop report. Am J Respir Crit Care Med 2006;174:373–378.
206. Quinnell TG, Pilsworth S, Shneerson JM, Smith IE. Prolonged invasive ventilation following acute ventilatory failure in COPD: weaning results, survival, and the role of noninvasive ventilation. Chest 2006;129:133–139.
207. Gregoretti C, Squadrone V, Fogliati C, Olivieri C, Navalesi P. Transtracheal open ventilation in acute respiratory failure secondary to severe chronic obstructive pulmonary disease exacerbation. Am J Respir Crit Care Med 2006;173:877–881.
Correspondence and requests for reprints should be addressed to Leonardo M. Fabbri, M.D., Section of Respiratory Diseases, Via del Pozzo 71, 41100 Modena, Italy. E-mail:

Related

No related items
American Journal of Respiratory and Critical Care Medicine
175
12

Click to see any corrections or updates and to confirm this is the authentic version of record