Pulmonary and Critical Care Updates

Update in Chronic Obstructive Pulmonary Disease 2005

Leonardo M. Fabbri, Fabrizio Luppi, Bianca Beghe, and Klaus F. Rabe
Section of Respiratory Diseases, Department of Oncology, Haematology, and Pulmonology, University of Modena and Reggio Emilia, Modena; Section of Respiratory Diseases, Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy; and Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands

Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease that has a large impact on quality of life for patients and their families and kills millions of people worldwide (13). Even though there have been signicant advances in the understanding and management of COPD (4, 5), suggesting that the disease may be largely preventable, it remains only marginally treatable. This is probably because COPD is due to a slowly progressive destructive process of the lung that is poorly reversible when manifested clinically, and because it has systemic effects and frequent comorbidities that should be managed more comprehensively (6). The interest in COPD by the medical and scientic community has increased dramatically in the last decade, as reected by the number of publications in both pulmonary and general medical journals. This review aims to summarize and highlight progress in the understanding of COPD in 2005. Although we found most of the articles interesting, we had to be selective, and we take full responsibility for the choices we have made.

DEFINITION
COPD is dened as a disease state characterized by progressive airow limitation that is not fully reversible, and is associated with an abnormal inammatory response of the lungs to noxious particles or gases, primarily cigarette smoke (1, 2). In 2004, the American Thoracic Society/European Respiratory Society guidelines introduced in the denition the concept that, although COPD affects the lungs, it also produces signicant systemic consequences (2). In the last 2 years there has been an increasing number of publications emphasizing the systemic nature of COPD (714) and the frequent and important chronic comorbidities (1518) that may contribute signicantly to its severity and mortality (1922).

(15). Two large epidemiologic studies, in which the diagnosis of COPD was established using spirometry, evaluated COPD prevalence in 2005. In a nationwide Korean survey involving 9,243 subjects, Kim and colleagues (28) reported that the prevalence of COPD, determined by criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), was 17.2% among subjects older than 45 years. Prevalence increased with increasing age, especially in males, in those with more than 20 pack-years of smoking, and in low-income subjects. Most of the COPD found was mild to moderate (FEV1 50%), and only a minority of the subjects were previously diagnosed and received appropriate treatment. Similarly, COPD was largely underdiagnosed in a Swedish epidemiologic study (29). Menezes and colleagues (30) reported wide variability in COPD prevalence between ve major cities in Latin America Sao Paulo (Brazil), Santiago (Chile), Mexico City (Mexico), Montevideo (Uruguay), and Caracas (Venezuela)in people 40 years of age or older, with the highest prevalence in Montevideo (almost 20%) and the lowest in Mexico City (7.8%; Table 1). The reasons for the lower prevalence of COPD in Mexico City remain unclear, although high altitude might contribute.

GENETICS
Although the most important risk factor for COPD is cigarette smoking, not all smokers develop COPD, suggesting that genetic factors may be involved (31). To date, severe deciency of 1-antitrypsin (PiZZ) is the only proven genetic factor for the disease, and association studies between the heterozygous forms of the 1-antitrypsin phenotype (PiMZ) and COPD or the decline of lung function have yielded controversial results. Albeit infrequently, 15 new single-nucleotide polymorphisms (SNPs) with six haplotypes in the SERPINA 1 gene (more commonly known as 1-antitrypsin) have been suggested to be a strong risk factor for COPD (32). Several candidate genes have been investigated (31), including genes encoding matrix metalloproteinases (MMPs). A gene encoding a member of the A disintegrin and metalloprotease (ADAM) family (ADAM33), a group of proteins involved in cell adhesion, cell fusion, cell signaling, and proteolysis, is associated with excessive decline of lung function in individuals with asthma (33) and in the general population (34), suggesting that it may be a susceptible gene for the development of xed airow limitation, a characteristic of COPD. MMP-9 may be involved in the development of emphysema and in the degradation of extracellular matrix components such as gelatin, collagens (IV, V, XI, XVII), and elastin. The human MMP-9 gene is located on chromosome 20q11.113.1, and MMP-9 is synthesized as a proenzyme with a molecular mass of 92 kD. Among several polymorphic changes reported in the regulatory region, the C-1562T polymorphism increases the promoter activity of MMP-9. Although this polymorphism is not associated with development of xed airow limitation, the

EPIDEMIOLOGY
COPD is underdiagnosed and undertreated, resulting in underestimation of the burden of this disease (23). If COPD is detected early, intervention in behavioral risk factors, particularly cigarette smoking, will prevent further deterioration of lung function (2426). The prevalence of COPD is highest in countries where cigarette smoking, for example, is still very common (27). Prevalence data based on the presence of airow limitation provide an accurate estimate of the burden of clinically signicant COPD

(Received in original form March 1, 2006; accepted in final form March 7, 2006 ) Correspondence and requests for reprints should be addressed to Leonardo M. Fabbri, M.D., Department of Respiratory Diseases, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy. E-mail: fabbri.leonardo@ unimo.it Am J Respir Crit Care Med Vol 173. pp 10561065, 2006 DOI: 10.1164/rccm.2603005 Internet address: www.atsjournals.org

Pulmonary and Critical Care Updates TABLE 1. PREVALENCE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN FIVE MAJOR LATIN AMERICAN CITIES ACCORDING TO GOLD STAGES
Prevalence, % (95% CI ) Sao Paulo (Brazil) Stage Stage Stage Stage Stage 0 I II III IV 25.3 10.1 4.6 0.9 0.2 (22.728.0) (8.012.1) (3.35.8) (0.41.5) (0.00.5) Santiago (Chile) 33.6 11.0 4.9 0.7 0.3 (31.236.0) (9.212.8) (3.66.1) (0.21.1) (0.00.7) Mexico City (Mexico) 23.2 5.2 1.9 1.5 0.2 (20.825.6) (3.86.6) (0.92.9) (0.00.9) (0.00.5) Montevideo (Uruguay) 19.1 12.5 6.4 0.6 0.1 (16.421.7) (10.314.8) (4.98.0) (0.01.0) (0.00.3) Caracas (Venezuela) 23.1 6.4 4.9 0.7 0.1 (20.425.8) (4.97.9) (3.66.3) (0.21.2) (0.00.2)

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Definition of abbreviations: CI Data from Reference 30.

confidence interval; GOLD

Global Initiative for Chronic Obstructive Lung Disease.

T allele is signicantly associated with the development of upper lungdominant emphysema in patients with COPD (35). Considering that emphysema may develop in the early stages without affecting lung function (36), the results of this study further suggest that metalloproteinases may be involved in at least some aspects of the pathogenesis of COPD (37). Emphysema may result not only from the destructive activity of the inammatory process but also from a genetic predisposition to proteolysis of elastin due to a variant in the terminal exon of human elastin. This has been described by Kelleher and colleagues in a pedigree of patients with severe early-onset COPD (38). Phospholipases A2 (PLA2s) are enzymes responsible for mobilization of fatty acids, including arachidonic acid, from phospholipids. Large quantities of secretory PLA2s (sPLA2s) are released in the plasma of patients with systemic inammatory diseases (39). Disorders associated with high levels of extracellular sPLA2s are characterized by a signicant increase in plasma or tissue concentrations of proinammatory cytokines, such as tumor necrosis factor (TNF- ) and interleukin 1 . To date, 10 sPLA2 isoforms (IB, IIA, IIC, IID, IIE, IIF, III, V, X, and XII) have been isolated. A biological feature of the group II subfamily sPLA2s is that almost all isoforms are associated with an inammatory and immune process that may have systemic effects. Takabatake and colleagues (40) have shown that the individual susceptibility to loss of body weight in patients with COPD may be attributed to the genetic variance of the group II subfamily sPLA2s. The results of this study suggest that sPLA2-IID may be one of the susceptibility genes that contribute to body weight loss in patients with COPD, because SNP10 is the mutant site that causes the amino acid change in the sPLA2-IID gene.

genesis of COPD. Baraldo and coworkers reported a decreased expression of transforming growth factor (TGF)- RII associated with bronchial gland enlargement in smokers with COPD, and suggested that the absence of TGF- signaling may induce structural changes in the bronchial glands, which, in turn, may promote mucus hypersecretion (44).
Oxidative Stress

PATHOGENESIS
Inflammatory Mechanisms

COPD is a chronic inammatory disease characterized by an increase in neutrophils, macrophages, and T lymphocytes (especially CD8 ) in various parts of the lung, which are driven by inammatory mediators, particularly cytokines, chemokines, and oxidants (41). This abnormal inammatory reaction to risk factors is believed to be responsible for the most important pathologic abnormalities of COPD, bronchiolitis and emphysema (36, 41). Several studies in 2005 explored inammatory mechanisms in COPD. Lundblad and colleagues (42) showed that experimentally induced overexpression of TNF- causes pathologic changes consistent with both emphysema and pulmonary brosis combined with general lung inammation, with alterations in both lung structure and function. Woodruff and colleagues (43), using an integrative genomics approach, observed that smoking induces a remarkably consistent and distinctive pattern of alveolar macrophage activation that might be relevant in the patho-

Environmental factors related to COPD (4549), the most important being active (25, 50) and passive (51) cigarette smoking, act through the generation of oxidative stress and/or reduction of antioxidant capacity (8, 52). Furthermore, some drugs may reduce antioxidant capacity in the lung and increase oxidative stress and thus increase the risk of COPD (53). McKeever and colleagues (54) showed that acetaminophen, a drug that reduces antioxidant capacity in the lung, is associated with a dose-dependent increased risk of COPD and asthma and with decreased lung function, providing further evidence of the broader importance of oxidant and antioxidant processes in the pathogenesis of both asthma and COPD. Focusing on the role of oxidative stress in COPD and the relationship with metabolism of arachidonic acid, Santus and colleagues (55) reported that enhanced oxidative stress in patients with COPD is paralleled by the increased ability of neutrophils to synthesize the chemotactic factor leukotriene B4 and may ultimately contribute to the inltration and activation of neutrophils into the airways, particularly in conjunction with exacerbations (56, 57). Yasuda and colleagues (14) also showed that increased arterial blood carboxyhemoglobin may contribute to the severity of COPD through systemic inammation and production of reactive oxygen species. Antioxidant treatment is effective in reducing oxidant stress (8, 58), as measured by urinary excretion of the isoprostanes, and might lead to an improved control of airway inammation in COPD. Interestingly, oxidative stress may not only be involved in lung inammation but may also extend its effect to dysfunction of respiratory skeletal muscles (59), particularly in hypoxic conditions (60). Pulmonary rehabilitation, an effective treatment option for COPD (61), may improve exercise capacity, at least in part, by reducing systemic oxidative stress (62). However, the clinical implications of these studies are still unclear. In fact, a large, randomized, placebo-controlled, 3-year clinical trial has shown no clinically signicant effects of treatment with the antioxidant acetylcysteine in patients with COPD (63).
Mechanisms of Steroid Resistance

Unlike patients with asthma, those with COPD are poorly responsive to the antiinammatory actions of corticosteroids (64, 65). The mechanisms of steroid resistance in COPD are unclear. Elastase-induced neutrophilia in rats is steroid resistant and is

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associated with a lack of nuclear factor- B pathway activation (66). Furthermore, histone deacetylase activity is decreased in the lungs and airways of patients with COPD (67) and is inversely related to the severity of the disease (Figure 1), suggesting that the steroid-resistant inammatory response in the respiratory tract of patients with COPD might be related to reduced histone deacetylase activity (68, 69).
Immune Mechanisms

CD8 lymphocytes have been related to the progressive reduction of pulmonary function in both COPD (41) and asthma (70). CD4 lymphocytes are also increased in COPD, particularly in severe cases (36). Taraseviciene-Stewart and colleagues (71) demonstrated that intraperitoneal injection of xenogeneic endothelial cells in immunocompetent rats causes an antiendothelial cell humoral response, inux of CD4 lymphocytes into the lung, apoptosis of alveolar septal cells, activation of MMPs, and emphysema, suggesting that alveolar septal cell destruction might result from (auto)immune mechanisms (72). Severe emphysema is associated with apoptosis of alveolar epithelial cells (73), and inammation involving T lymphocytes that are composed of oligoclonal CD4 lymphocytes (72). These T cells accumulate in the lung secondary to conventional antigenic stimulation and thus might be involved in the persistent pulmonary inammation characteristic of severe emphysema. Taken together, these observations suggest that immunologic CD4 lymphocytes may be involved in the development of COPD, and they point to a possible immune mechanism of lung inammation in COPD that characteristically persists even after cessation of risk factors (e.g., cigarette smoking) (26). Adrenomedullin is a potent vasodilator peptidestrongly expressed in basal epithelial cells and type II pneumocytesthat

regulates cell growth and survival. Interestingly, continuous infusion of adrenomedullin improves elastase-induced emphysema in mice, at least in part through mobilization of bone marrow cells and direct protective effects on alveolar epithelial cells and endothelial cells (74). Similarly, in a complex animal model of emphysema in mice, the addition of hepatocyte growth factor to the emphysematous lung accelerates alveolar and vascular repair, leading to compensatory lung growth (75). Interestingly, vascular endothelial growth factor and its receptors have been shown to affect peripheral vascular and airway remodeling processes in an autocrine and/or paracrine manner (76). Statins are 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors used clinically as lipid-lowering agents. They also have antiinammatory properties in several models of human disease (77). In particular, simvastatin attenuates lung parenchymal destruction, inammatory inltration, and pulmonary hypertension experimentally induced by chronic cigarette smoking in rats (78). Because statins are often used to treat cardiovascular diseases and the metabolic syndrome, frequent comorbidities in patients with COPD, their antiinammatory properties should be explored further.

ASSESSMENT OF SEVERITY AND RESPONSE TO TREATMENT

Although there is increasing evidence that COPD is a systemic disease (714) and that it is often associated with signicant comorbidities (1518), lung function, in particular FEV1, remains the reference marker for diagnosis, assessment of severity, and prognosis. Other lung function parameters may also be useful in assessing COPD. Casanova and colleagues (79) observed that the ratio of inspiratory to total lung capacity is an independent

Figure 1. Specimens of lung tissue obtained from patients with increasing clinical stages of chronic obstructive pulmonary disease had a graded increase in interleukin-8 mRNA and histone-4 acetylation at the interleukin-8 promoter (A ) and a reduction in histone deacetylase (HDAC) activity (B ). In contrast, there was no difference in total tissue histone acetyltransferase (HAT) activity among these groups (C ). Furthermore, HDAC activity was significantly correlated with FEV1 and the FEV1:FVC ratio (D ). Reproduced by permission from Reference 67.

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risk factor for mortality in patients with COPD, suggesting that this ratio may be a better assessment tool than FEV1. Indeed, inspiratory capacity and lung volumes may better reect the functional response and the improvement of symptoms and exercise tolerance induced by bronchodilator agents in a disease, such as COPD, that is characterized by poorly reversible airow limitation (80, 81). In response to increasing concern about the limitations of an evaluation of COPD severity based on lung function, there is a continuous search for additional functional, clinical, and biological markers for a more comprehensive and accurate assessment of the disease (82, 83). A multidimensional grading system, the BODE index (Body mass index, airow Obstruction, Dyspnea, and Exercise capacity), has been shown to be a stronger predictor than FEV1 of the risk of hospitalization and death among patients with COPD (84), suggesting that it might provide useful prognostic information (85). Serum C-reactive protein is increased in COPD, decreases after treatment with steroids, and is related to the presence of comorbidities, and thus might contribute to a more accurate assessment of the systemic effects and comorbidities in this disorder (86). Patients with COPD are markedly inactive in daily life and are often characterized by a downward spiral of symptom-induced inactivity, leading to deconditioning and muscle weakness (87), which results in spending less and less time walking and standing as compared with sedentary healthy elderly subjects (88). Because functional exercise capacity is the strongest correlate of physical activity in daily life, exercise testing is recommended for a more comprehensive evaluation of severity and response to treatment. Indeed, exercise testing, particularly the endurance shuttle test, is a sensitive test for detecting changes in exercise capacity induced by bronchodilators (89) and rehabilitation (61). COPD, particularly when severe, may be associated with mild to moderate pulmonary hypertension. Among 998 patients who underwent right heart catheterization between 1990 and 2002 during a period of clinical stability, Chaouat and colleagues (90) reported severe pulmonary hypertension (pulmonary artery mean pressure of 40 mm Hg) in less than 5% of patients. Such patients have severe exertional dyspnea, a short life expectancy, hypocapnia, very low DlCO, and hemodynamic alterations reminiscent of those seen in idiopathic pulmonary hypertension; thus, they should be classied and treated identically to patients with idiopathic pulmonary hypertension (91, 92).

and elevated levels of ubiquitin-conjugated proteins, suggesting accelerated muscle protein degradation. In addition, the remaining contractile proteins in these bers are dysfunctional, and the calcium sensitivity of force generation is reduced. These abnormalities could all contribute to muscle weakness, particularly at submaximal activation, even in patients with mild to moderate COPD (97). The development of muscle fatigue during exercise varies from patient to patient, suggesting heterogeneous mechanisms, and may be reversed by different exercise training programs (61, 98, 99). Patients with greater susceptibility to muscle fatigue have changes in muscle enzymatic proles during exercise, including adenine nucleotide loss (100) and capillarization with preferential reliance on glycolytic metabolism, perhaps explaining, at least in part, the increased contractile muscle fatigue (101). Furthermore, passive tension generation of diaphragm single bers is reduced in patients with COPD; this has been recently linked to alternative splicing of the titin gene, resulting in increased length of the elastic PEVK segment (titin segment rich in proline [P], glutamate [E], valine [V], and lysine [K]) (102). Abdominal muscle strength in the presence of quadriceps weakness is preserved in stable outpatients with COPD, suggesting that disuse and consequent deconditioning contribute to the development of quadriceps muscle weakness, and/or that activity protects the abdominal muscles from systemic myopathic processes (9).

HORMONES
In men, aging and chronic illness are often associated with hypogonadism, which is part of a more complex metabolic syndromecharacterized by central obesity, insulin resistance, dyslipidemia, and hypertensionthat is highly prevalent and associated with increased risk of diabetes mellitus and cardiovascular disease (103). Patients are dened as being hypogonadal when androgen deciency is combined with otherwise unexplained fatigue or diminished energy, vitality, or a sense of wellbeing. Similarly, male patients with COPD may develop hypogonadism due at least in part to primary testicular dysfunction and/ or hypofunctioning of the hypothalamicpituitarygonadal axis. The low circulating levels of testosterone are positively related to quadriceps muscle weakness, but not to exercise intolerance (104); hypogonadism per se does not seem to worsen respiratory symptoms, quality of life, or respiratory or limb muscle performance and exercise capacity in COPD (105, 106). Although short-term testosterone replacement may increase lean body mass and strength in men with severe COPD and low testosterone levelsincluding an improvement in strength amplied by concomitant resistance training (107)long-term benets and adverse effects must be investigated further before testosterone replacement can be recommended as a treatment in such patients (107, 108).

IMAGING
Airow limitation in COPD is in part the result of inammation and remodeling of small airways (i.e., bronchiolitis) and emphysema, and individual patients may have predominantly bronchiolitis or emphysema (1, 2, 36). Imaging, particularly the highresolution computed tomography (HRCT) chest scan, may accurately assess the dimensions of the large and intermediate-sized airways and, albeit less accurately, may predict the dimensions of the smaller airways, which are the most important site of airway obstruction in COPD (93). When combined with comprehensive lung function and lung inammation, assessment of emphysema by HRCT chest scan may provide more accurate phenotyping of patients with COPD (94, 95). In addition, HRCT chest scan would allow the identication of lower lobe bronchiectasis (96).

EXACERBATIONS
Exacerbations of symptoms are a major cause of morbidity, mortality, impaired quality of life, and increased health care costs for patients with COPD (1, 2, 109, 110). The development of respiratory symptoms, particularly dyspnea, is related to worsening of airow obstruction and lung hyperination (111), whereas resolution of dyspnea after acute exacerbations is associated mainly with reduction in lung hyperination as reected by an increase in inspiratory capacity (112). Patients with frequent exacerbations spend less time outdoors and are more likely to become housebound, further compromising their quality of

RESPIRATORY AND SKELETAL MUSCLES

Systemic effects of COPD involve respiratory and skeletal muscles (714). In patients with COPD, the functional impairment of the diaphragm is associated with loss of myosin heavy chain

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life (113). Most exacerbations are precipitated by either bacterial or viral infections (114, 115). Although infections clearly have the ability to induce airway inammation (116) and worsen respiratory symptoms, the role of bacteria in COPD exacerbations and the use of antibiotics remain controversial (1, 2, 117). Bacteria frequently colonize the airways of patients with severe COPD; thus, the simple identication of bacteria in sputum during an exacerbation is insufcient to explain a worsening of symptoms or lung function (117, 118). However, COPD exacerbation could be explained by an increase in bacterial load, a change in bacterial location, or the presence of new, more virulent, or more proinammatory bacterial species or strains (115); for example, gram-negative infections are associated with failure to respond to noninvasive ventilation in severe COPD exacerbations (119). A pooled analysis of data from studies that used protected specimen brush sampling conrmed the role of potentially pathogenic microorganisms by showing that exacerbations in patients with COPD are associated with the overgrowth of these microorganisms and particularly with the appearance of Pseudomonas aeruginosa in the lower airway (120). As compared with colonizing strains, Haemophilus inuenzae strains isolated during COPD exacerbations induce more airway inammation and are more virulent, suggesting that the bacteria infecting the airway may contribute to worsening of symptoms and decrease of airway function by increasing airway inammation (121). Moraxella catarrhalis may cause up to 10% of exacerbations of COPD, thus accounting for approximately 2 to 4 million episodes annually. M. catarrhalis is cleared efciently after a short duration of carriage, and patients develop strain-specic protection from subsequent reacquisition of the same strain (122). Up to 40% of cases of acute respiratory illness in patients with COPD are associated with a viral respiratory tract infection, mainly with picornaviruses, coronaviruses, and inuenza viruses (123). There is increasing evidence that viral infections may be involved in exacerbations not only of asthma but also of COPD (124). Interestingly, the frequency of viral infections in children is directly correlated with the number of adult hospitalizations for COPD, and the frequency of adult hospitalizations for COPD is decreased when children are on school holidays (i.e., less exposed to viral infections). This suggests that exacerbations of COPD may be causally related to epidemics of viral infections (125).

PHARMACOLOGIC TREATMENT
Only the symptoms of COPD can be treated pharmacologically because, with the exception of smoking cessation (24, 25, 126) and continuous long-term oxygen treatment (127), no pharmacologic intervention modies the natural history of COPD (1, 2). The primary outcomes of the most recent long-term pharmacologic studies in COPD are prevention of exacerbations and/or hospitalization. Tiotropium, a long-acting anticholinergic agent, reduces the frequency of exacerbations and the use of health care resources in patients with moderate to severe COPD who are already receiving regular care; this conrms the importance of long-acting bronchodilators in the regular treatment of COPD (128). Because the effect of individual long-acting bronchodilators on exacerbations is relatively small, the next step is to investigate whether a combination of bronchodilators with different mechanisms of action may provide some additive or synergistic effect. Interestingly, the combination of tiotropium and formoterol provides a clinically relevant additive bronchodilator effect in patients with COPD (129). Inhaled steroids, particularly in combination with bronchodilators (130), may also reduce the frequency and severity of exacerba-

tions in patients with severe COPD (131). Withdrawal of inhaled steroids is associated with acute and persistent deterioration in lung function and dyspnea and with an increase in mild exacerbations (132). In contrast, it is still unclear whether the combination of inhaled steroids and long-acting bronchodilators has additive effects on lung function and/or exacerbations (130). Interestingly, the combination of salmeterol and uticasone has a signicant antiinammatory effect in both current and former smokers with COPD, suggesting that at least part of the clinical and functional effect might be related to suppression of inammation (133). Low body weight in patients with COPD is associated with impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rate when compared with adequately nourished individuals with this disease. Nutritional support may therefore be a useful part of their comprehensive care. However, a meta-analysis provided no evidence that nutritional support has a signicant effect on anthropometric measures, lung function, or exercise capacity in patients with stable COPD (134, 135). By contrast, repeated administration of ghrelin, a novel growth hormonereleasing peptide that is reduced in COPD (136), may improve body composition, muscle wasting, and functional capacity in cachectic patients with COPD, thus possibly reversing some of the systemic aspects of COPD (137). Observational studies have shown an association between inhaled corticosteroids and a reduction in mortality and rehospitalization (138), and a recent meta-analysis of long-term trials with inhaled steroids reported a signicant effect of inhaled corticosteroids in reducing mortality from all causes in patients with COPD (139). A large, randomized, controlled clinical trial (140) is testing this hypothesis prospectively; the results of this pivotal study are expected by mid-2006. If the effect of inhaled steroids in reducing mortality in patients with COPD is conrmed in this study, their role in treatment might change signicantly. Interestingly, treatments used for COPD (e.g., inhaled steroids) may have systemic effects and affect comorbidities of COPD (11, 138, 139, 141), and treatments used for comorbidities of COPD (e.g., statins for cardiovascular diseases and the metabolic syndrome) may have antiinammatory effects in the lung (77, 78). Taken together, these observations suggest that a more comprehensive approach should be taken for individual chronic diseases that may occur in the same patient, with the aim to develop new strategies not only for prevention (3), but also for an appropriate diagnosis, assessment of severity, and management of the individual patient with different comorbid conditions (6, 142).

NEW DRUGS
The only novel agents that might become available for COPD in the next few years are inhibitors of phosphodiesterase 4 (PDE4), particularly roumilast and cilomilast. Phosphodiesterases are a family of enzymes involved in the degradation of cyclic adenosine monophosphate, which is a natural modulator of inammation and a potential target for new antiinammatory agents. PDE4 inhibitors possess antiinammatory activity in vitro in a range of inammatory cell types relevant to COPD and asthma, as well as in a wide range of animal models in vivo (143). In patients with moderate to severe COPD, long-term treatment with roumilast improves FEV1 and other lung function parameters and reduces the rate of mild exacerbations (Figure 2) (144). Similarly, cilomilast maintains pulmonary function, improves health status, and reduces the rate of COPD exacerbations (145). Cilomilast reduces the number of CD8 T cells in the airway mucosa of patients with COPD (146), and roumilast partially reduces acute and chronic lung inammation and fully prevents

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Figure 2. Treatment with 250 or 500 g of roflumilast increased post-bronchodilator FEV1 from baseline, whereas a decline was recorded with placebo (A ). Increases from baseline in prebronchodilator FEV1 were also noted with both doses of roflumilast, whereas a decline was recorded with placebo (B ). Data are least squares means SE. * p 0.05 versus baseline. Reproduced by permission from Reference 144.

parenchymal destruction induced by cigarette smoke in mice (147). Whether these antiinammatory effects are relevant for COPD treatment remains to be established. The cytokine TNF- plays a key role in the pathogenesis of many chronic inammatory diseases, including COPD (42, 148), and TNF- antagonists have been extensively studied in different chronic inammatory diseases (148, 149). Unfortunately, the rst study of iniximab, a chimeric monoclonal antibody that neutralizes the biological activities of TNF- in patients with COPD, published in 2005, showed no clinically benecial effects in a small group of patients with mild to moderate COPD, and thus additional studies in larger groups of patients with more advanced disease must be performed to investigate whether this drug has some benecial effects in COPD (150). Retinoic acid induces alveolar regeneration in rodent models of experimental emphysema (151). Clinical trials are being performed with various retinoids in patients with emphysema in the hope that alveolar regeneration may also repair emphysematous lesions in humans. It has been hypothesized that new treatments that alter surface tension, increase recoil, and promote medical volume reduction may result in improved respiratory function in patients with emphysema, but more research is required, particularly on the micromechanics of the emphysematous lung with respect to both tissue and surface tension properties (152).

certainty remains as to the modalities of reevaluation of these patients to maintain or withdraw this long-term treatment, as some may no longer meet eligibility criteria at some time after the initial prescription (153, 154). Reassessment of applicants for domiciliary oxygen after a long period of stability will identify a signicant proportion of patients who are no longer eligible, thus reducing costs and use of resources without affecting quality of life or mortality in patients with COPD (155).

LUNG VOLUME REDUCTION SURGERY

Lung volume reduction surgery (LVRS) is used to treat patients with severe emphysema by removing the most damaged areas of the lung, thus reducing hyperination. Although LVRS has been shown to improve mortality, exercise capacity, and quality of life in selected patients with COPD, it is associated with signicant morbidity and an early mortality rate of about 5%. For these reasons, and because the procedure poses an unacceptable risk in patients with the most severe disease, alternatives have been studied, including bronchoscopic lung volume reduction and endobronchial valve placement. These techniques have been shown to improve mean exercise capacity and reduce dynamic hyperination in a subgroup of patients with COPD (156). The pathophysiologic changes occurring in emphysematous patients after LVRS have been extensively studied in the last few years. Patients with no increase in lung function, as assessed by FEV1 after LVRS, have thicker epithelial layers, more interstitial and peribronchial brosis, vascular sclerosis, and goblet cell hyperplasia, and less bullous disease, suggesting that, in these patients, the main determinant of airow limitation may be airway remodeling that is unaffected by LVRS (157). Improved diaphragm function may contribute to functional improvement after LVRS, because LVRS results in increased diaphragm

OXYGEN THERAPY
Two multicenter randomized clinical trials have rmly established that selected patients with COPD with chronic hypoxemia live longer when they receive domiciliary oxygen (127). As a result, health care systems in many countries include public funding of domiciliary oxygen for eligible applicants. However, un-

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10. Oudijk EJ, Nijhuis EH, Zwank MD, van de Graaf EA, Mager HJ, Coffer PJ, Lammers JW, Koenderman L. Systemic inammation in COPD visualised by gene proling in peripheral blood neutrophils. Thorax 2005;60:538544. 11. Sin DD, Lacy P, York E, Man SF. Effects of uticasone on systemic markers of inammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:760765. 12. Tapson VF. The role of smoking in coagulation and thromboembolism in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:7177. 13. Wouters EF. Local and systemic inammation in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:2633. 14. Yasuda H, Yamaya M, Nakayama K, Ebihara S, Sasaki T, Okinaga S, Inoue D, Asada M, Nemoto M, Sasaki H. Increased arterial carboxyhemoglobin concentrations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:12461251. 15. Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, Schmid V, Buist S. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 2006;27:397412. 16. Rutten FH, Moons KG, Cramer MJ, Grobbee DE, Zuithoff NP, Lammers JW, Hoes AW. Recognising heart failure in elderly patients with stable chronic obstructive pulmonary disease in primary care: cross sectional diagnostic study. BMJ 2005;331:1379. 17. Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc 2005;2:811. 18. Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell AL. Patterns of comorbidities in newly diagnosed COPD and asthma in primary care. Chest 2005;128:20992107. 19. Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979 to 2001. Chest 2005;128:20052011. 20. Nizet TA, van den Elshout FJ, Heijdra YF, van de Ven MJ, Mulder PG, Folgering HT. Survival of chronic hypercapnic COPD patients is predicted by smoking habits, comorbidity, and hypoxemia. Chest 2005;127:19041910. 21. Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr 2005;82:5359. 22. Stoller JK, Tomashefski J Jr, Crystal RG, Arroliga A, Strange C, Killian DN, Schluchter MD, Wiedemann HP. Mortality in individuals with severe deciency of alpha1-antitrypsin: ndings from the National Heart, Lung, and Blood Institute Registry. Chest 2005;127:11961204. 23. Pauwels RA, Rabe KF. Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet 2004;364:613620. 24. Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE. The effects of a smoking cessation intervention on 14.5year mortality: a randomized clinical trial. Ann Intern Med 2005;142: 233239. 25. Willemse BW, Postma DS, Timens W, ten Hacken NH. The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inammation. Eur Respir J 2004;23:464476. 26. Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W. Effect of 1-year smoking cessation on airway inammation in COPD and asymptomatic smokers. Eur Respir J 2005;26: 835845. 27. Xu F, Yin X, Zhang M, Shen H, Lu L, Xu Y. Prevalence of physiciandiagnosed COPD and its association with smoking among urban and rural residents in regional mainland China. Chest 2005;128:28182823. 28. Kim DS, Kim YS, Jung KS, Chang JH, Lim CM, Lee JH, Uh ST, Shim JJ, Lew WJ. Prevalence of chronic obstructive pulmonary disease in Korea: a population-based spirometry survey. Am J Respir Crit Care Med 2005;172:842847. 29. Lindberg A, Jonsson AC, Ronmark E, Lundgren R, Larsson LG, Lundback B. Prevalence of chronic obstructive pulmonary disease according to BTS, ERS, GOLD and ATS criteria in relation to doctors diagnosis, symptoms, age, gender, and smoking habits. Respiration (Herrlisheim) 2005;72:471479. 30. Menezes AM, Perez-Padilla R, Jardim JR, Muino A, Lopez MV, Valdivia G, Montes de Oca M, Talamo C, Hallal PC, Victora CG. Chronic obstructive pulmonary disease in ve Latin American cities (the PLATINO study): a prevalence study. Lancet 2005;366:1875 1881. 31. Molno NA. Genetics of COPD. Chest 2004;125:19291940. 32. Chappell S, Daly L, Morgan K, Guetta Baranes T, Roca J, Rabinovich R, Millar A, Donnelly SC, Keatings V, MacNee W, et al. Cryptic

length, which in turn causes lower motor unit ring rates and reduced breathing effort, thus contributing to improved quality of life and exercise performance (158).

CONCLUSIONS
The number and quality of manuscripts that we selected for this review reect the importance of COPD and the interest of the medical and scientic community in this disease. Progress was made in 2005 in all areas of research, but if we had to identify the most important scientic contributions, we would say that they were the new data on epidemiology (30), genetics (33), mechanisms of steroid resistance (67), and new treatment options (144). However, we also believe that the most striking conceptual change that resulted from studies published in 2005 is the concept of COPD as a systemic disease with frequent and important comorbidities that may dramatically contribute to its severity and mortality (1518) and that might be affected by treatment (138142). This evolving concept will necessarily inuence the future of the existing important international initiatives on COPD (13), possibly merging them into a more general initiative on respiratory diseases (e.g., the Global Alliance for Respiratory Diseases [159]) or chronic diseases (160).
Conflict of Interest Statement : L.M.F. has been paid lecture fees by Altana, AstraZeneca, Boehringer Ingelheim, Schering-Plough, MSD, Roche, Novartis, and Pfizer; has served on the advisory boards of Altana, Schering-Plough, Chiesi, Novartis, Boehringer Ingelheim, and Pfizer; and has received grant support to his university from Boehringer Ingelheim, Miat, Schering-Plough, Pfizer, UCB, Altana, Menarini, Chiesi, GSK, MSD, AstraZeneca, and the Italian Ministry for University and Research. F.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.F.R. has been consulting, has been participating in advisory board meetings, and has received lecture fees from AstraZeneca, Boehringer, Chiesi Pharmaceuticals, Pfizer, Novartis, Altana Pharma, Merck, Sharpe, and Dohme (MSD) and GlaxoSmithKline (GSK). He holds no stock or other equities in pharmaceutical companies. The Department of Pulmonology, and thereby K.F.R. as head of the department, has received grants from Altana Pharma ($222,616), Novartis ($90,640), Bayer ($61,762), AstraZeneca ($113,155), Pfizer ($406,000), MSD ($118,000), Exhale Therapeutics ($90,000), Boehringer Ingelheim ($90,000), Roche ($120,000), and GSK ($299,495) in 2001 until 2005. Acknowledgment : The authors thank Ms. Mary McKenney for editing the manuscript and Dr. Elisa Veratelli for her scientific secretarial assistance.

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