© 2008 American Thoracic Society doi: 10.1164/rccm.200801-167UP
Update in Chronic Obstructive Pulmonary Disease 20071 ELEGI Colt Research Labs, University of Edinburgh/MRC Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, United Kingdom Correspondence and requests for reprints should be addressed to William MacNee, M.B. Ch.B., M.D., F.R.C.P. University of Edinburgh/MRC Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK. E-mail: w.macnee{at}ed.ac.uk There is intense scientific and clinical interest in chronic obstructive pulmonary disease (COPD), which is reflected in the increasing number of articles in scientific journals on this topic. There have been advances in our understanding of the pathogenesis, diagnosis, and assessment and in the applications of current treatments in COPD, but not in the development of new treatments for COPD, particularly those that might retard or reverse its progression. DEFINITION In the most recent international guideline (1), the spirometric classification of severity of disease has been revised and simplified A post-bronchodilator FEV1/FVC < 0.70 is designated as stage I (mild disease), despite controversy that the use of this fixed rate ratio may result in overdiagnosis of COPD as mild disease in the elderly and in underdiagnosis among younger adults (2–4). Although this spirometric classification has some uses, it does not represent a complete assessment of disease severity in terms of functional capacity and does not reflect several systemic features that may have an impact on functional capacity and survival. COPD prevalence varies widely depending on the spirometric criteria used to define the disease (5). An elderly cohort study indicated that subjects classified as normal using the lower limit of normal FEV1/FVC, but abnormal using the fixed ratio, are more likely to die and have COPD-related hospitalization during follow-up (4), suggesting that the fixed FEV1/FVC ratio may identify patients at risk even among older subjects. The National Education Health Program recommends the use of the FEV1/FEV6 for detection of COPD in primary care. The FEV6 is both as sensitive and specific for post-bronchodilator airway obstruction as the traditional FVC maneuver, but only when the definition of airway obstruction includes a low FEV1 (6). Therefore, there are still outstanding issues that need resolution regarding the definition of COPD (4, 7). EPIDEMIOLOGY—RISK FACTORS COPD remains an underdiagnosed or wrongly diagnosed condition in many countries, in part related to the problem of defining airflow limitation (8). "Diagnosed" COPD has a very poor relationship to any measure of spirometrically determined COPD (5). In the PLATINO study in five Latin American cities, 88.7% of subjects with COPD (defined as post-bronchodilator FEV1/FVC ratio < 0.70) had not been previously diagnosed (8). Among those with a prior diagnosis of COPD, only 36.3% had a post-bronchodilator FEV1/FVC ratio of less than 0.70 (8). These data on underdiagnosis/missed diagnosis have been replicated in other areas of the world (9–14). The Burden of Lung Disease (BOLD) initiative uses standardized methods to measure the prevalence of COPD around the world. A BOLD population study in Austria showed an overall prevalence in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage I of 26.1%, which was equal in men and women (15), and in GOLD stage II–IV of 10.7%. However, doctor diagnosis of COPD was reported by only 5.6% of participants. A similar report from China (16) showed an overall prevalence of COPD of 8.2% (12.4% in men and 5.1% in women). Higher prevalence of COPD occurred in smokers, rural residents, elderly patients, those with a lower body mass index, those with childhood pulmonary problems, those with a family history of pulmonary diseases, and in those with poor kitchen ventilation or exposure to occupational dust or biomass fuels. Of those with airflow limitation, only 35.1% reported a diagnosis of bronchitis, emphysema, or COPD, and only 6.5% had undergone spirometry. The effects of outdoor air pollution, and especially particulate air pollution, on hospital admission and mortality from COPD are well documented (17–20), and are reinforced by a study from Hong Kong showing a relative risk for admission for every 10-µg/m2 increase in SO2, NO2, O3, PM10, and PM2.5 of 1.007, 1.0026, 1.34, 1.24, and 1.31, respectively (21). Less well known are the effects of indoor air quality on COPD. Smoking households, where particulate levels are higher, are associated with increased symptom burden and worse health status in patients with COPD (22). An association between indoor air pollution and COPD was reported in a study from China where the prevalence of COPD in both the whole population and subpopulation of nonsmoking women was higher in rural (7.4%) than in urban areas (2.5%), with a significant association with biomass fuel cooking (23). A similar association has been shown in rural Pakistan (24). Occupational exposure to dusts and fumes has been associated with increased risk of COPD (25). A recent longitudinal study showed that ongoing exposure to occupational fumes is associated with a greater decline in lung function in patients with early COPD, suggesting the need for secondary prevention to control occupational fume exposure (26). The prognostic value of symptoms of chronic cough/sputum production for the development of COPD is still debated. In an international cohort with normal lung function, the incidence rate of COPD was 2.8/1,000 cases per year. Subjects reporting chronic cough/sputum at baseline had a nearly threefold increased risk of developing COPD with respect to asymptomatic subjects (27). Studies on diet and COPD risk have been conflicting (28). In a large prospective cohort of 42,917 men in the United States, diet with high intake of fruits, vegetables, fish, and whole grain products was negatively associated with the risk of newly diagnosed COPD, whereas a diet with a high intake of refined grains, cured and red meats, desserts, and French fries was positively associated with the risk of newly diagnosed COPD (29). A further cross-sectional study from the Third National Health and Nutrition Examination study found that consumption of cured meat was associated with airway obstruction and increased odds of COPD (odds ratio, 1.78) (30). This association was confirmed in a further study (31). The hypothesis is that high levels of nitrites in cured meats generate reactive nitrogen species, which may produce lung damage. Until recently, there have been no factors, apart from smoking cessation, that reduce lung function decline. Recent data from the Copenhagen City Heart Study showed that moderate to high physical activity in active smokers was associated with reduced lung function decline and COPD risk (32) (odds ratio, 0.77). The six-minute-walk distance (6MWD) is an important tool in the functional assessment of patients with COPD (33). There is abundant information on the natural history of FEV1 decline, but little information on the temporal behavior of the 6MWD. In 294 patients with COPD, the 6MWD declined by 19% (16 m · yr–1) over 5 years in patients with American Thoracic Society/European Respiratory Society stage III COPD and by 26% (15 m · yr–1) in patients with stage IV disease (34). Several studies have addressed the relevance of COPD phenotypes, particularly using computed tomography (CT) imaging to assess the emphysema and airway phenotypes (35). In patients from the National Emphysema Treatment Trial (NETT) with severe COPD (1,053 patients, 38.8% female), for a given degree of airway obstruction women experienced greater breathless, higher modified Borg score, and lower quality of well-being (36). Overall CT-assessed emphysema was less severe in women, and females had thicker small airway walls, which may account for some of the sex differences in the natural history of COPD (37). Mortality in women with COPD in the Western world (38) increased by 291% and by a more modest 60% in men between 1980 and 2000 (39). The increase in mortality in women may result from increased susceptibility to the effects of tobacco smoke (40).
In a study in In intervention studies, the endurance shuttle-walking test is more responsive than the six-minute-walk test for detecting changes in exercise performance after bronchodilatation (43). Echocardiography has been used as a method of assessing pulmonary arterial pressure. However, in a study of patients with emphysema undergoing lung volume reduction surgery the correlation between pulmonary arterial pressure measured by echocardiography and right heart catheterization was poor, casting doubt on the use of this technique to estimate pulmonary arterial pressure in severe emphysema (44). GENETICS
COPD genetic studies are problematic. Many have been performed on small available population samples with poorly defined COPD phenotypes, resulting in inappropriately positive results. Recent studies have attempted to define COPD phenotypes in more detail. In the Lung Health Study, which included a population of almost 6,000 smokers of Caucasian origin with mild to moderate COPD, there was no significant association between tumor necrosis factor (TNF) or lymphotoxin A (LTA) gene polymorphisms and lung function (45), confirming previous negative findings in whites (46, 47), but contrary to previous reported studies in Asian populations (48). This study highlights the problem of translating results from one population to another. Negative associations were also reported in the Lung Health Study population between polymorphisms of the genes encoding IL-10 and the The response to oxidative stress is considered an important factor in the pathogenesis of COPD (50). Oxidative stress response genes and the transcription factors involved in their regulation were differentially expressed in the bronchial epithelium of subjects with COPD compared with healthy smokers, indicating that oxidative stress defense responses are amplified in patients with COPD (51). Previous studies have suggested that polymorphisms in antioxidant genes may relate to the development of COPD (52). A negative association was reported between polymorphisms in the manganese-superoxide dismutase and catalase genes (53). IL-13 gene polymorphisms have been associated with COPD in some (54), but not in other, populations (49, 55). An interaction between the –1112C/T variant in the promoter region of the IL-13 gene and cigarette smoking has been shown, which may influence lung function in long-term smokers (56). The SERPINE2 gene has previously been evaluated as a susceptibility gene for COPD in two association studies, but with contradictory results (57, 58). An analysis of SERPINE2 single nucleotide polymorphisms (SNPs) in two large independent datasets showed a positive association with COPD spirometry (59). The relationship between genetic polymorphisms and COPD phenotypes has been extended in other studies. In patients with COPD, the ADRB2 gene polymorphism in the β2-agonist gene is related to the degree of variability in short-term bronchodilator responses (60). An SNP in the ADAM33 gene that confers susceptibility to COPD is associated with airway hyperreactivity and airway inflammation in COPD (61). In the NETT population, there was an association between GSTP1, EPHX1, and MMP1 gene polymorphisms and apical predominant distribution of emphysema (62), suggesting that altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution. PATHOGENESIS A number of studies have investigated the mechanisms of the enhanced inflammation that characterizes COPD (63) and involves both innate and adaptive immunity in response initially to inhalation of particles and gases (64). However, the inflammatory response appears to persist after smoking cessation when patients develop COPD (65, 66). This was confirmed in a pooled analysis of data from three bronchial biopsy studies (101 subjects), which found no significant differences in inflammatory responses between smokers and ex-smokers with COPD (67). This inflammatory response, particularly in the later stages of the disease, may result from persistent infection of the lower respiratory tract (65). Chronic infection with Chlamydia pneumoniae was demonstrated by polymerase chain reaction and in situ hybridization in 15% of patients with COPD, in contrast to its absence in control subjects. However, there were no differences in the expression of inflammatory mediators or transcription factors associated with inflammation between noninfected and infected patients with COPD (68). Dendritic cells (DCs) are important in the orchestration of the immune responses (69). DCs accumulate in the airways of patients with COPD with increasing disease severity, and such accumulation is associated with an increase in CCL20, the most potent chemokine for DCs, and in the expression of CCR6, the receptor for CCL20. The interaction between CCL20 and CCR6 may provide a possible mechanism for the accumulation of DCs in the lungs in COPD. Previous studies have suggested increased chemotactic responsiveness or chemotactic activity in airway secretions in COPD as a mechanism for the increase in sputum neutrophils in patients with COPD (70, 71). However, a more recent study found that neither increased chemotactic activity in the airways nor enhanced chemotactic responsiveness of neutrophils explains the increased number of these cells in the airways of patients with COPD (72). In contrast, exhaled breath condensate from patients with COPD has higher neutrophil chemotactic activity than that from normal subjects (73). The single-breath N2 test, a measure of small airway function, correlates with markers of airway inflammation in patients with COPD (74), supporting a role for neutrophilic inflammation in the pathogenesis of small airway dysfunction in COPD. The expression of prostacyclin is decreased in patients with emphysema (75) and mice overexpressing prostaglandin I2 (PGI2) exhibited less endothelial apoptosis after chronic smoke exposure, suggesting that PGI2 may have protective effects in the pulmonary vasculature after acute and chronic cigarette smoke exposure. An imbalance in eicosinoid expression may be important in the endothelial dysfunction associated with COPD and may also have relevance for the development of emphysema, which has been proposed to result from endothelial dysfunction and apoptosis of alveolar capillary endothelial cells (76). Several studies have demonstrated a correlation between the number of CD8 cytotoxic T lymphocytes and the degree of airflow limitation in COPD. However, the mechanism by which lymphocytes contribute to the pathogenesis of COPD is unknown. Granzymes are the major effector protease molecules of CD8+ cytotoxic T lymphocytes and increased granzyme A expression is present in type II pneumocytes in patients with severe COPD (77). Inflammatory cells are increased in bronchial submucosal glands and mucus of large airways in smokers with chronic bronchitis. Plasma cells associated with these glands express IL-4, which is likely to promote mucus hypersecretion (78). Previous studies have shown an association between mucus hypersecretion and death from COPD (79). Morphometric studies of lung samples after lung volume reduction surgery found that those with the greatest small airway luminal occlusion from mucus died earlier than subjects with the least luminal occlusion (80). The hypothesis is that airway occlusion causes pneumonia and results in early death. Protease–antiprotease imbalance is believed to be central to the pathogenesis of emphysema. Matrix metalloproteinase (MMP)-2 expression was increased in the lungs in patients with COPD and increased progressively as lung function worsened and emphysema increased (81), suggesting a role for MMP-2 in tissue remodeling and inflammation in severe COPD. In an animal model of smoke-induced emphysema, a dual MMP-9/MMP-12 inhibitor ameliorated smoke-induced airspace enlargement (82), suggesting MMP-9 and MMP-12 inhibitors as potential therapies in COPD. Overproduction of IL-18 in the lungs induces emphysema in mice (83), raising the possibility that IL-18 antibody may be a potential treatment in COPD. Previous studies measured desmosine, a product of elastin injury in the lungs (84, 85). Using the more sensitive technique of mass spectroscopy, levels of plasma desmosine, isodesmosine, and their free components were increased in the urine in patients with COPD compared with normal subjects (86). These results suggest a biomarker of the protease–antiprotease imbalance that can be used in patients with COPD to follow the course of the disease or therapeutic interventions. SYSTEMIC EFFECTS OF COPD COPD is now recognized as having both local lung and systemic effects (87). The mechanism of these systemic effects is not known, but is believed to be related to enhanced systemic inflammation and oxidative stress (88). Increased expression of surface adhesion molecules (CD11b and CXCR1) on circulating neutrophils in patients with COPD suggests increased systemic inflammation compared with healthy smokers, and there is a relationship between CD11b and CXCR1 expression and the extent of airflow limitation in patients with COPD (89). Serum biomarkers measured by novel protein microarray platforms have been identified in patients with COPD that relate to clinical phenotypes, such as extent of airflow limitation, CO transfer factor, 6MWD, exacerbation frequency, and BODE (Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity) index (90). Serum C-reactive protein (CRP) levels are inversely related to FEV1 and FVC. However, no association was found between baseline CRP levels and decline in FEV1 over a period of 9 years in a community-based cohort (91). Higher levels of systemic inflammation are associated with reduced physical activity in COPD (92), and CRP is a strong predictor of COPD outcomes such as hospitalization and death (93). This raises the possibility of calculation of risks for death or hospitalization in patients with COPD. COPD is an independent risk factor for cardiovascular disease (94). Two studies have shown that arterial wall stiffness, which relates to cardiovascular risk, is increased in patients with COPD compared with smoking control subjects (95, 96) and may be associated with systemic inflammation as measured by CRP (95). These studies suggest that COPD may result in systemic endothelial dysfunction, which may be a mechanism for the enhanced cardiovascular risk in COPD (94). Systemic arterial wall stiffness is also independently related to emphysema as assessed by CT scanning (97, 98). Furthermore, arterial wall stiffness correlates with osteoporosis, another systemic complication of COPD (95). These studies raise the intriguing possibility that mechanisms that result in alveolar wall destruction and emphysema may also produce increased cardiovascular risk and osteoporosis in patients with COPD. A post hoc analysis of the European Respiratory Society study on COPD (EUROSCOP) suggested that long-term inhaled corticosteroids (ICS) lowered the incidence of ischemic heart disease (3 vs. 5% in the placebo group) in patients with mild COPD (99). This is an intriguing finding and is supported by other retrospective database studies (100) and by previous studies suggesting that ICS may reduce systemic inflammation in patients with COPD (101). Further prospective clinical trials are required to verify this finding. COPD is associated with many comorbidities (102). Gastroesophageal reflux assessed by esophageal pH monitoring is present, although often asymptomatic, in 57% of patients with severe COPD (103). Anemia has been shown to be an independent risk factor for reduced functional capacity and increased mortality in COPD (104–106). In a retrospective analysis of hemoglobin levels in a cohort of patients with COPD attending a respiratory clinic (n = 683), anemia was present in 70% of patients and polycythemia in 6% (107). Anemic patients had a significantly higher value on the Medical Research Council dyspnea scale, a lower exercise capacity, and shorter median survival than nonanemic patients. Further studies are required to determine the effect of anemia correction on outcomes in COPD. SKELETAL AND RESPIRATORY MUSCLES Skeletal muscle dysfunction is an established systemic feature of COPD (108). It affects exercise tolerance, leads to disability, and contributes to poor quality of life. Several metabolic derangements have been suggested as mechanisms for this muscle dysfunction (109). A study of skeletal muscle biopsies showed a reduction in the number of mitochondria in patients with COPD, which may contribute to the impaired oxidative capacity of the limb muscles in this setting (110). Mitochondrial dysfunction is particularly prominent in patients with COPD with a low body mass index (111), which may also contribute to the low muscle endurance in this subgroup. Skeletal muscle dysfunction influences outcome in patients with COPD. Quadriceps muscle strength predicts mortality in patients with moderate to severe COPD (112).
Dysfunction of the inspiratory muscles, particularly the diaphragm, occurs frequently in COPD (113), and maximal inspiratory pressure, as a measure of diaphragm function, is an independent determinant of survival in these patients (114). Changes in glycosaminoglycan composition of the diaphragm have been shown in COPD, which may alter growth factor handling and thus reduce levels of contractile protein in the diaphragm in patients with COPD (115). The mechanisms of muscle atrophy in patients are not certain. Overexpression of muscle hypertrophic signaling pathways is present in skeletal muscle in COPD and could represent an attempt to restore muscle mass (116). Intercostal muscle biopsies reveal increased proinflammatory cytokine expression, particularly of TNF- Exercise may enhance systemic inflammation and injury to muscles (118). However, pulmonary rehabilitation has no effect on protein breakdown or inflammation in muscles (119). TREATMENT A number of studies have examined combination therapy with ICS, long-acting β-agonists (LABAs), and long-acting anticholinergics in COPD. The largest and most important of these studies was the TORCH (Towards a Revolution in COPD Health) study (120), which compared the effects of ICS, LABAs, or their combination in patients with moderate to severe COPD over a follow-up period of 3 years with a primary outcome of death. The study failed to show a significant reduction in mortality with combination therapy. This result has to be balanced against other positive findings of combination therapy on secondary outcomes of a greater reduction in exacerbation rates, a significant benefit on health status, in addition to a positive effect of combination therapy on decline in lung function over time, compared with the individual components of therapy. There has been considerable comment on the implications of the trial (121–123). One controversial issue is the apparent increased rate of pneumonia among all patients receiving treatment containing ICS. This effect contrasts with previous ICS studies (ISOLDE [Inhaled Steroids in Obstructive Lung Disease in Europe]) (124) and the present study, which shows a reduction in exacerbations with ICS/LABA (120). The reason for the increased incidence of pneumonia in those treated with ICS is under intense investigation and a definitive answer is not yet available. However, the finding of an increased incidence of pneumonia with ICS is supported by database studies that also suggested increased hospitalization for pneumonia in patients with COPD treated with ICS (125). The controversy over the effects of ICS continues and is further fuelled by the results of the Inhaled Steroids Effect Evaluation in COPD (ISEEC) study, in which a pooled study of data from seven long-term randomized, placebo-controlled ICS trials of more than 12 months' duration in patients with moderate to severe COPD (126) suggested that ICS were more effective in improving lung function in ex-smokers than in current smokers and that women have a larger response to ICS than men. However after 6 months of treatment, ICS did not modify decline in FEV1. The addition of ICS to patients receiving LABAs produced a statistically significant and clinically relevant 35% reduction in COPD exacerbations (127). The addition of combination ICS/LABA therapy does not appear to increase the effect of the long-acting cholinergic bronchodilator tiotropium on exacerbation frequency, but did improve lung function, health status, and hospitalization rate for exacerbations (128). Adding either β-agonist or anticholinergic short-acting bronchodilators to maintenance long-acting anticholinergic (tiotropium) treatment produced significant improvements in the FEV1 (129). Premature discontinuation of treatment has been a problem in many clinical trails and may bias results against effective therapies. This was highlighted in an analysis of a randomized controlled trial in which tiotropium was shown to decrease COPD exacerbations (130). The study showed a higher incident rate of fatal events after premature discontinuation of study medication. Thus, long-term clinical trials in COPD should consider the impact of early discontinuation of trial medications as a potential bias in the results (130). Previous randomized control trials have shown the benefits on mortality of long-term oxygen therapy for patients with COPD and resting chronic hypoxemia (131). With ambulatory oxygen therapy, patients without resting hypoxemia, who desaturate during exercise, show improvement in acute exercise performance (132). However, these short-term laboratory-based acute physiologic responses may not be reflected in symptomatic responses during longer term use of ambulatory oxygen therapy. Four randomized controlled trials evaluating the role of ambulatory oxygen have reported mixed results (133–137). However, n of 1 randomized controlled trials may identify patients who may benefit (138). Short-burst oxygen therapy is widely prescribed in patients with COPD, although with little evidence of benefit. It may shorten recovery time after activities of daily living in a selected group of patients with COPD but the effect is rather small (139). However, there may be a subgroup of patients who may benefit from this treatment (139). Novel therapies for COPD have appeared in clinical trials and in retrospective analysis from databases over the last year. Anti-TNF antibody (infliximab) did not show any benefit in patients with moderate to severe COPD on the Chronic Respiratory Questionnaire Score as a primary endpoint and on the secondary outcomes of prebronchodilator FEV1, 6MWD, transitional dyspnea index, and the rate of moderate to severe exacerbations. A higher incidence of pneumonia and cancers occurred in infliximab-treated subjects, although this was not statistically significant (140). The effects of 1-year treatment with the phosphodiesterase inhibitor rofumilast in severe COPD produced a modest but significant improvement in lung function without changing exacerbation rate or health status (141). However, in patients with very severe disease, fewer exacerbations were experienced with rofumilast treatment (141). Statin therapy may provide a new therapeutic option in COPD because animal studies have shown protection against the development of smoke-induced emphysema (142). Statins may have both local lung and systemic antiinflammatory and antioxidant effects (143–145). Statins have been shown to reduce cardiovascular mortality and may therefore protect against the increased cardiovascular risk that is known to occur in COPD. Statin treatment was associated with slower rates of decline in lung function in elderly subjects (FEV1 decline, 23.9 ml/yr in those not taking statins, and a 10.9-ml/yr decline in FEV1 in those taking statins) (146). These data are supported by further retrospective studies using large databases (147, 148) that have shown an apparent effect of statins on mortality in patients with COPD. Randomized clinical trials are warranted to assess whether these findings can be confirmed prospectively, which may lead to an important new treatment for this population of patients. EXACERBATIONS Exacerbations of COPD (ECOPD) are important events in the natural history of this disease and contribute to increased morbidity and mortality. ECOPD have a major impact on health status (149–151). The time course of the changes in health status during ECOPD has now been identified and can be used to guide future trials and evaluate therapeutic interventions (152). Exacerbations also impact negatively on other patient-centered outcomes as measured by BODE index and its components. This index may be used to assess the functional impact of exacerbations to monitor COPD disease progression (153). ECOPD are not only associated with an increase in local inflammatory responses but also a response in systemic cytokines (154–160). Alterations in systemic cytokine levels correlate with changes in symptoms and in lung function. Prospective evaluation of the value of measuring systemic inflammatory markers, coupled with simultaneous measurement of clinical and physiologic changes, may help to better characterize episodes of ECOPD (161). Biomarkers may also add to the characterization and prediction of outcome of COPD exacerbations. The biomarker copeptin may be a marker of short- and long-term prognosis in patients with severe ECOPD requiring hospitalization (162). Self-reporting of sputum purulence may predict bacterial infection in ECOPD and may help in selecting candidates to receive antibiotic treatment (163). Among the variables that predict future exacerbations are older age, level of airway obstruction, duration of COPD, antibiotic or systemic corticosteroid use of COPD in the previous year, or previous hospitalization for COPD in the previous year (164). Risk factors for rehospitalization and death after severe ECOPD include age, male sex, prior hospitalization, and comorbid conditions, including asthma and pulmonary hypertension (165). CRP concentration 14 days after an exacerbation may predict future recurrent exacerbations (166). Many studies have confirmed that bacterial infection has a role in ECOPD. The positivity rate for bacterial culture varies in different parts of the world: 23% in the United States, 32% in Hong Kong and Asia, 50% in the Netherlands, and 57% in Italy (167–170). The role of atypical pathogens, commonly Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila, in ECOPD remains unclear. Although previous serologic studies suggest that these atypical pathogens may have an important role (171–175), the reliability of some serologic assays have been questioned. Using real-time polymerase chain reaction, a recent study found little evidence for a role for these organisms in ECOPD in the Netherlands (176). An intriguing possibility was provided in a study showing a familial aggregation of exacerbations, suggesting a genetic basis for susceptibility for COPD exacerbations (177), possibly related to genetic alterations in innate immunity. Evidence-based reviews (178) suggest treatment with antibiotics in ECOPD based largely on the classic study of Anthonisen and colleagues (179), which used the number of symptoms, particularly the presence of purulent sputum, to determine the need for antibiotic therapy. The role of antimicrobials in acute exacerbations of COPD does, however, remains controversial (180). A rapid and specific test to identify bacterial lower respiratory tract infections would be a major advance. Procalcitonin, a small protein that is normally undetectable in plasma (181), increases markedly in bacterial infections, but is not increased by inflammation due to autoimmunity or viral infection (182). Previous preliminary, single-center studies provided encouraging evidence for the use of procalcitonin to predict the need for antibiotics in ECOPD (183, 184). Procalcitonin-guided antibiotic treatment can reduce total microbial use in hospitalized exacerbations of COPD without changing clinical success rates (185). These results require replication in other trials but support the use of procalcitonin-guided antibiotic treatment in ECOPD (186). The type of antibiotic therapy that should be used in acute exacerbations of COPD also remains controversial (187). Recent meta-analysis comparing the effectiveness of first-line antimicrobial agents (e.g., amoxicillin, ampicillin, pivampicillin, trimethoprim/sulfamethoxazole, and doxycycline) with second-line antimicrobial agents (e.g., amoxicillin/clavulanic acid, macrolides, second- or third-generation cephalosporins, and quinolones) suggests that second-line antibiotics are more effective, but not less safe when administered to patients with ECOPD (188). Systemic corticosteroids have been shown to be effective in improving clinical outcomes in ECOPD, although the magnitude of the improvements are modest and have the potential for greater side effects. In many centers, corticosteroids are given intravenously, however, and recent studies suggest that oral corticosteroids are equally effective (189). ICS may be a substitute for oral corticosteroids in exacerbations of COPD (190–192). Nebulized budesonide provided similar improvement in pulmonary function tests or arterial blood gases compared with oral corticosteroids in ECOPD, suggesting it is a safe and effective alternative to systemic corticosteroids when treating ECOPD (193). Short-acting β-agonists were assessed in exacerbations of COPD requiring hospitalization (194) and did not demonstrate any deleterious effects on pulmonary gas exchange abnormalities. These results are reassuring and support recommendations in guidelines to increase dose and frequency of bronchodilator therapy during ECOPD. Exacerbations of COPD are associated with an increased neutrophil-predominant inflammatory response in the airways, although in some exacerbations eosinophilic airway inflammation may play a role (195, 196). Corticosteroid treatment to reduce eosinophilic airway inflammation was associated with a reduction in severe exacerbations of COPD (197). Long-acting bronchodilators, particularly long-acting anticholinergics, have been shown to reduce exacerbation frequency (198, 199). The mechanism of this effect is unknown, but does not appear to be related to a reduction in airway or systemic inflammation (200). Pulmonary thromboembolism (PTE) has been previously considered to occur with a high prevalence in exacerbations of COPD (201, 202). A recent study that prospectively assessed patients with exacerbations of COPD for PTE, whether or not clinically suspected, suggested that the incidence of unsuspected PTE is very low in patients admitted with exacerbations of COPD, which would argue against a systematic examination for pulmonary embolism in this population (203). FOOTNOTES Conflict of Interest Statement: W.M. has been reimbursed for attending conferences by GlaxoSmithKline, Zambon, and Boehringer Ingelheim and has received honoraria from GlaxoSmithKline and Zambon for participating as a speaker at various scientific meetings; he serves on an advisory board for GlaxoSmithKline and as a consultant for Pfizer, SMB Pharmaceuticals, and Galen; research grants to support work carried out in W.M.'s laboratory are provided by Pfizer for a Clinical Research Fellow, partial funding for a Respiratory Research Nurse, and a multicenter clinical trial, and by GlaxoSmithKline for partial funding of a Respiratory Research Nurse and a multicenter trial, and by Hoffmann LaRoche for a multicenter clinical trial. Received in original form January 28, 2008; accepted in final form January 28, 2008 REFERENCES
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1-antitrypsin–deficient patients with discordance in lung function between FEV1 and KCO (