The text that follows reviews and discusses the papers published in the Journal on chronic obstructive pulmonary disease (COPD) during 2011. Whenever relevant, works published earlier or elsewhere are included. The reader is referred to the original papers for further details. We have organized the review according to the following subheadings: Risk Factors, Natural History, Physiology, Disease Mechanisms, Phenotypes and Biomarkers, Comorbidities, Management, and Exacerbations.
Gene–environment interactions are key for the development of COPD (1, 2). The following papers addressed them in 2011.
Artigas and colleagues used genotype data from 12 population-based studies that included 3,284 patients with COPD and 17,538 control subjects to investigate the association of COPD with several single-nucleotide polymorphisms (TNS1, GSTCD, HTR4, AGER, and THSD4) and found that three (TNS1, GSTCD, and HTR4) were associated with COPD, although the highest risk score was only 1.6-fold higher in COPD (3).
COPD is a heterogeneous disease (1). To identify genetic determinants of emphysema, Kong and colleagues performed a genome-wide association study in 2,380 patients with COPD in whom the amount of emphysema had been determined by computed tomography (CT) scan (4). They found that a single-nucleotide polymorphism in BICD1 was significantly associated with emphysema. Because BICD1 is associated with telomere length, a marker of cell aging, these observations support the idea that accelerated aging may be involved in the pathogenesis of emphysema (5).
Susceptibility to COPD is not a dichotomous variable, and a range in “degree of susceptibility” exists (6). As a result, some smokers develop the disease earlier than others. Factors associated with the early inception of COPD are poorly understood (7). To investigate them, Foreman and colleagues compared patients with severe early onset (<55 yr) with older (>64 yr) patients with COPD included in the COPDGene Study and found that the former was significantly associated with African American race, maternal COPD, female sex, and cumulative smoking exposure (8).
Despite being the largest minority group in the United States, Hispanics are often not included in COPD clinical trials (9). Bruse and colleagues studied a New Mexican cohort of current and former smokers and found that Hispanic ethnicity was significantly associated with lower odds of COPD and that Hispanic smokers have a reduced risk of rapid decline in lung function. Therefore, to understand COPD susceptibility, populations protected from the disease should be evaluated just as rigorously as those vulnerable to the disease (10).
Andersen and colleagues investigated prospectively the effect of exposure to traffic-related air pollution on the incidence of COPD in 57,053 participants in the Danish Diet, Cancer, and Health cohort (11). Results showed that COPD incidence was significantly associated with nitrogen dioxide levels (hazard ratio [HR], 1.08), particularly in patients with diabetes (HR, 1.29) and asthma (HR, 1.19) (11).
Using a mouse model of vitamin D deficiency, Zosky and colleagues provided direct mechanistic evidence linking vitamin D deficiency and lung development (12). These observations provide the basis for determining if vitamin D therapy prevents the occurrence of chronic pulmonary diseases (13).
De Marco and colleagues examined the incidence and risk factors of COPD in 4,636 subjects without asthma included in the European Community Respiratory Health Survey in whom spirometry was measured when they were 20 to 44 years old and about 8 years later (14). COPD incidence ranged from 1.85 to 2.88 cases/1,000 persons/yr, depending on the diagnostic criteria used (FEV1/FVC < lower limit of normal or < 0.70). Smoking and airway hyperresponsiveness were the two main risk factors for COPD, but other determinants included respiratory infections in childhood and a family history of asthma, indicating that COPD may start early in life (15).
Since the seminal report by Fletcher and Peto in 1977 (16), an accelerated decline of FEV1 has been considered the cornerstone of COPD. Yet, this paradigm has been questioned by several recent studies (6, 17). Casanova and colleagues monitored 1,198 patients with COPD (1,100 men) recruited in Florida and in Tenerife, Spain from 1997 to 2009 (18). They found that FEV1 declined significantly (by 86 ml/yr) in 18% of patients and that higher FEV1 at recruitment (RR, 1.857) and low body mass index (RR, 1.071) were independent predictors of FEV1 decline. They also determined the BODE index and found that the concordance between FEV1 and BODE change was low (κ Cohen, 16%). These results confirmed that the progression of COPD is very heterogeneous (6, 17–20).
Using a new technique called “anatomical optical coherence tomography,” which can measure dimensions and elastic wall properties of central airways with a fiberoptic probe, Williamson and colleagues showed that although airway dimensions were somewhat reduced in asthma, they were no different from control subjects among patients with COPD (21). Although there was a tendency toward increased airway wall compliance in COPD, this was not significant, and these findings are consistent with the fact that COPD involves more peripheral airways (22). Laveneziana and colleagues showed that, in patients with moderate to severe COPD, the intensity and quality of dyspnea can be dissociated and are strongly influenced by mechanical constraints on tidal volume expansion during incremental and constant-load exercise (23).
Several papers shed new light on the underlying disease process in COPD, with identification of new therapeutic targets and biomarkers of disease. There is increasing evidence that emphysema represents accelerated aging of the lung, and some studies have shown telomere shortening and dysfunction in patients with COPD. Amsellem and colleagues have shown that pulmonary vascular endothelial cells from patients with COPD show increased cellular senescence and decreased telomerase activity, with shorter telomeres and increased release of inflammatory cytokines and chemokines (24). This study supports the view that telomere shorting may contribute to chronic inflammation in patients with COPD (25). Telomerase null mice that have short telomeres show increased emphysema and double-strand DNA breaks after exposure to chronic cigarette smoke, with evidence of reduced epithelial repair (26). Interestingly, a family with a telomerase mutation was reported in the same paper to have early-onset emphysema. Shapiro, in an accompanying editorial, stresses the importance of personalized medicine in COPD and of recognizing distinct phenotypes such as this (27).
Several autoantibodies have been reported in patients with COPD. For example, Nunez and colleagues show that a significantly higher proportion of patients with COPD have antinuclear and antitissue antibodies compared with healthy control subjects and that this is related to disease severity (28). Kirkham and colleagues report circulating antibodies to carbonyl-modified proteins, which are correlated with disease severity and provide a link between oxidative stress and autoimmunity in COPD (29). This provides a plausible link between smoking, increased oxidative stress in COPD, and the presence of circulating autoantibodies, although it is not clear whether these autoantibodies play a role in disease activity and progression (30). A new immune abnormality in COPD was described by Polosukhin and colleagues, who found localized reduction in secretory IgA secretion on the surface of small airway epithelium, which was associated with increased CD4+ and CD8+ lymphocyte infiltration (31). As pointed out in an accompanying editorial, this may be a factor predisposing to bacterial colonization of the lower airways in patients with COPD (32). Several types of IL-17–producing cells, including Th17 cells, natural killer cells, and γ/δ T cells, are recognized in lungs, but the role of this cytokine in driving neutrophilic inflammation in COPD is not certain (33).
There is increasing understanding of inflammatory mechanisms in COPD. Sapey and colleagues report abnormal chemokinesis of peripheral blood neutrophils from patients with COPD, and this appears to be improved by a phosphoinositide-3-kinase inhibitor, suggesting that there is an intrinsic abnormality in neutrophil function in COPD (34). MicroRNAs may play a role in COPD through inhibiting gene transcription and translation, and several are differentially expressed in the sputum of patients with COPD compared with smoking and nonsmoking control subjects without COPD. The miRNA let-7C was consistently down-regulated in smokers and in patients with COPD and was linked to increased expression of TNF receptor-2 (35). In patients with very severe COPD, the endopeptidase neprilysin, which breaks down endothelins and other vasoconstrictor peptides, was decreased at sites of pulmonary vascular remodeling (36). This reduction in neprilysin was mimicked in pulmonary vascular smooth muscle cells by hypoxia and oxidative stress, thus linking these stresses with pulmonary hypertension in COPD. There is a reduction in the expression of the proinflammatory transcription factor C/EBPβ in airway epithelial cells of smokers and in normal epithelial cells after smoke exposure, which may result in a reduced inflammatory response, but the relevance of this observation to COPD was not determined (37). Several lines of evidence have implicated matrix metalloproteinase (MMP)-9 in elastolysis and emphysema, but MMP-9 knockout mice do not appear to develop more emphysema after cigarette smoke exposure, according to a study from the St. Louis group (38). Furthermore, although MMP-9 is expressed in macrophages in COPD lungs, this is not well correlated with areas of emphysema, suggesting that MMP-9 inhibition may not be a successful therapeutic strategy. Patients with COPD often have chronic bacterial colonization of the lower airways, and Knobloch and colleagues suggest that Th1-mediated adaptive immunity to short-chain bacterial lipopolysaccharides that is mediated via TLR4 is impaired in smokers and patients with COPD, resulting in decreased secretion of IFN-γ (39). It is not clear how this relates to bacterial colonization because normal smokers who have sterile airways have the same defect as patients with COPD (40).
Genetic studies have identified several developmental genes in the pathogenesis of COPD, including SOX5. SOX5 knockout mice show abnormal lung development with delay in lung maturation, lending this observation some biological plausibility (41). Mutations of the receptor tyrosine kinase c-kit are associated with an emphysema-like disease in mice, and the c-kit inhibitor imatinib was shown to inhibit epithelial clonal expansion (42). Defective function of another growth factor, vascular-endothelial growth factor (VEGF), has been been implicated on the pathogenesis of emphysema, and virus infections (influenza and respiratory syncytial virus), as well as the virus mimic poly(I:C), appear to inhibit VEGF signaling in mice (43). A reduction in VEGF receptors was seen in adiponectin knock-out mice, which develop emphysema and have systemic inflammation, weight loss, osteoporosis, and endothelial cell dysfunction, thus providing a link to COPD comorbidities (44). Another pathway involved in lung development is the WNT/β-catenin pathway. Signaling through this pathway is reduced in alveolar cells from experimental emphysema in mice but also in the lung parenchymal of patients with very severe COPD (45). Stimulation of this pathway with lithium chloride attenuated the development of emphysema and improved lung function, suggesting that activating the WNT/β-catenin pathways may have some therapeutic value. A companion editorial reinforces the importance of examining this repair pathway in COPD and of looking for novel therapeutic approaches to lung regeneration (46).
COPD is a complex disease at the clinical, cellular, and molecular levels (2). Addressing this complexity is of paramount importance for the development of better and more personalized therapy for COPD (1). Recent theoretical (scale-free networks), technological (high-throughput technology, bio-computing), and analytical improvements (systems biology) provide the tools required to progress toward P4 medicine (Personalized, Predictive, Preventive, and Participatory) (1).
Along these lines, the need to identify clinical COPD phenotypes has become the focus of many recent papers (47), such as the one by Celli and colleagues, who investigated potential gender differences in survival, causes of death, and patient-centered outcomes in 1,481 women and 4,631 men with COPD enrolled in the TORCH study (48). They found that, after adjusting for baseline differences, the risk of dying was 16% higher in men than in women, although the differences did not reach statistical significance (HR, 1.16; 95% confidence interval, 0.98–1.39) and causes of death were similar. On the other hand, women reported more exacerbations and worse dyspnea and health status scores than men (48).
Some smokers may have lung function impairment characterized by reduced FEV1 with preserved FEV1/FVC ratio. Yet, because they are systematically excluded from COPD trials, they are poorly characterized. Wan and colleagues found that in the first 2,500 subjects enrolled in the COPDGene study, they accounted for 9% of the total and that they were characterized by increased BMI and airway wall thickness as well as reduced total lung capacity, gas trapping, and bronchodilator responsiveness. The proportion of emphysema varied widely (49). They found a higher proportion of nonwhite subjects and subjects with diabetes (49).
It has been difficult to identify specific biomarkers for COPD in the blood (50, 51), but serum concentrations of the chemokine CCL18, which is produced in lung, are increased in patients with COPD and are correlated with mortality and therefore may serve as biomarkers (52). Endothelial microparticles, which are microvesicles released from apoptotic endothelial cells, are increased in the plasma of smokers with evidence of early emphysema (53), suggesting that this could be a circulating biomarker of early emphysema or a phenotype of COPD associated with endothelial cell apoptosis (54).
Comorbidities, including cardiovascular disease, lung cancer, osteoporosis, and depression, are recognized to have an important impact on the prognosis and management of COPD. Low bone density is strongly correlated with radiological emphysema in current and former smokers, suggesting a possible common mechanistic link (55). However, as pointed out by Cooper in an accompanying editorial, the lack of age-matched control subjects and measures of physical activity makes interpretation difficult (56). Several studies have shown that lung cancer is more common in patients with COPD than in smokers without COPD, but a longitudinal study of patients with COPD over several years gave a surprisingly high prevalence of 16 per 1,000 person-years (compared with 1–1.5 per 1,000 person-years in smokers with normal lung function) (57). Also surprising is that the risk of lung cancer (especially squamous cell cancer) was greater in patients with milder disease and with predominant emphysema. The high prevalence of lung cancer in early COPD suggests that there may be common mechanisms, such as common genetic predispositions to both diseases or common pathogenetic factors, such as growth factors, as discussed in the companion editorial (58). Depression is a common comorbidity in patients with COPD and in a large cohort was found in 26% of patients compared with only 7% in nonsmoking control subjects and was more common in patients with more severe disease, in younger patients, and in female patients (59). In an accompanying editorial, Jones makes the point that diagnosis of depression in patients with COPD is difficult because there is an overlap of symptoms; therefore, specific screening tests are needed and antidepressant therapy may be indicated (60).
The use of inhaled corticosteroids (ICS) increases the incidence of pneumonia in COPD (61). Chen and colleagues investigated if prior ICS use had any effect on clinical outcomes in patients with COPD hospitalized with pneumonia (62). They retrospectively studied 15,768 patients with COPD hospitalized for pneumonia registered in the national administrative databases of the Department of Veterans Affairs (8,271 with ICS and 7,497 without ICS) and found that prior use of ICS was independently associated with decreased risk of short-term mortality and use of mechanical ventilation (62).
Vogelmeier and colleagues investigated, in a 1-year, randomized, double-blind, double-dummy, parallel-group trial, if 18 μg of tiotropium once daily (3,707 patients) was superior to 50 μg of salmeterol twice daily (3,669 patients) in preventing exacerbations in patients with moderate to very severe COPD and a history of exacerbations in the preceding year (63). They found that, compared with salmeterol, tiotropium increased the time to the first exacerbation and reduced the annual number of exacerbations without significant differences in mortality rate (63).
Ekström and colleagues (64) investigated trends in cause-specific mortality in oxygen-dependent COPD in 7,628 patients (53% women) in Sweden who were followed up for a median of 1.7 years. They found that crude overall mortality increased by 1.6%/yr and that causes of death changed with time: risk of death because of respiratory disease and lung cancer decreased by 2.7%/yr and by 3.4%/yr, respectively, whereas that for circulatory disease and for digestive organ disease increased by 2.8%/yr and 7.8%/yr, respectively. These observations emphasize the importance of optimized diagnostics and treatment of comorbidities to decrease morbidity and mortality in COPD (65).
The National Emphysema Treatment Trial (NETT) was a multicenter, prospective, randomized controlled trial that investigated the role of lung volume reduction surgery in COPD (66). The many lessons learned from NETT were reviewed by Criner and colleagues, including the relevance of hyperinflation and small airway disease, as well as nonpulmonary issues, in emphysema (67). The NETT study generated also multiple insights into the preoperative, perioperative, and postoperative management of patients undergoing thoracotomy. Finally, the NETT study has been the starting point of newer investigation on bronchoscopic endobronchial interventions and other techniques less invasive than lung volume reduction surgery to achieve lung reduction that were also reviewed by Criner and colleagues (68).
Two studies in experimental animals that investigated the effects of novel therapies in COPD are worth noting. First, Wright and colleagues showed that, in a guinea pig model, treatment with simvastatin after 3 months of smoke exposure reversed smoke-induced pulmonary hypertension and prevented emphysema but not airway remodeling (69). This study is important because it is the first demonstration that an intervention can reverse a COPD-associated, cigarette smoke–induced anatomic abnormality and because it shows the importance of examining all three anatomic lung compartments when assessing the effects of a potential drug intervention in patients with COPD. Second, Schweitzer and colleagues showed that, in two different murine models of emphysema, systemic delivery of human or mouse adult adipose stem cells was associated with pulmonary (reduced inflammation, cell death, and airspace enlargement) and systemic (rescue of bone marrow hematopoietic progenitor cell function and restoration of weight loss) effects (70).
A new version of the GOLD document was presented in November 2011 (www.goldcopd.org). This updated version, which has yet to be published in a peer-reviewed journal, proposes a novel, multidimensional approach to assess and treat patients with COPD that includes the impact of the disease on the patient well-being (i.e., level of current symptoms) and the risk of future events (mortality and exacerbations) as assessed by the FEV1 value and the annual rate of exacerbations (the highest risk being used to guide therapy). According to this proposal, patients with COPD can be categorized into four GOLD patient types (types A, B, C, and D), each with its specific treatment.
There is no valid, standardized tool for assessing the frequency, severity, and duration of exacerbations of COPD (ECOPD) (71). Leidy and colleagues (72) tested the properties of a new patient-reported outcome diary (Exacerbations of Chronic Pulmonary Disease Tool [EXACT]) in a prospective, two-group, observational study in 222 patients with ECOPD and 188 clinically stable patients with COPD. Their results support that EXACT is reliable, valid, and sensitive to change with exacerbation recovery (72).
ECOPD are heterogeneous events (73). To identify clinical ECOPD phenotypes and to determine biomarkers that recognize them, Bafadhel and colleagues used unbiased cluster analysis in 145 patients (101 men and 44 women) who were followed for 1 year and studied at stable and exacerbation visits (74). The authors identified four distinct clusters (bacterial, viral, eosinophilic, and pauci-inflammatory), and the biomarkers that best identified the first three were sputum IL-1β, serum CXCL10, and percentage peripheral eosinophils, respectively. Whether these biomarkers can be used to direct therapy requires more investigation (73).
Tanabe and colleagues investigated the impact of ECOPD on emphysema progression in a cohort of patients with COPD followed over 2 years and found that emphysema progressed more in patients with than in those without ECOPD (75), highlighting the importance of preventing and treating ECOPD (76).
Mallia and colleagues studied a human model of ECOPD induced by experimental rhinovirus infection in 13 patients with COPD and in 13 control subjects (77). In this novel and unique study (78), the authors showed that, after rhinovirus infection, patients with COPD developed prolonged lower respiratory symptoms, airflow limitation, and systemic and airway inflammation, and that neutrophil markers in sputum were related to clinical outcomes and virus load to inflammatory markers (77).These results strongly support a causal relationship between rhinovirus infection and ECOPD (78).
Finally, Albert and colleagues showed that, in patients with COPD and increased risk of exacerbations, the addition of azithromycin (250 mg daily for 1 yr) in addition to their usual care reduced the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects (79). The potential effects of treatment with azithromycing on microbial resistance patterns are unknown (79).
Over the past 12 months, the Journal has published a large number of high-quality and relevant articles dealing with varied and important aspects of COPD. This is encouraging because, although our understanding, management, and treatment of COPD has improved significantly over the last two decades, there is still a lot to be done to prevent, improve, and eventually cure this prevalent and important disease.
| 1. | Agusti A, Sobradillo P, Celli B. Addressing the complexity of chronic obstructive pulmonary disease: from phenotypes and biomarkers to scale-free networks, systems biology, and P4 medicine. Am J Respir Crit Care Med 2011;183:1129–1137. |
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| 7. | Garcia-Aymerich J. Are we ready to say that sex and race are key risk factors for COPD? Am J Respir Crit Care Med 2011;184:388–390. |
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