American Journal of Respiratory and Critical Care Medicine

The morbidity and mortality of chronic obstructive pulmonary disease (COPD) continues in an uninterrupted fashion; current treatment options are limited, and there is no cure. Failure to diagnose COPD early, poor correlation of airflow obstruction with the extent and type of structural impairment, the number of comorbid conditions, and the lack of an adequate animal model for COPD account for our current inability to transform COPD treatment. Fortunately the tide is beginning to turn. The medical research community has recognized these problems and has embarked on multiple paths of scientific inquiry to understand COPD pathogenesis, the clinical phenotypes, and treatments that are truly novel by using compounds that inhibit pathways of lung injury and aberrant responses of repair. The following are examples of the research work conducted on COPD in 2015 that attempt to address many of the questions that need to be answered to achieve the common goal of not only improving the care of patients with COPD but also curing them of this devastating disease.

Role of Sphingolipids

Alterations in sphingolipid metabolism have been implicated in the pathogenesis of COPD. Mass spectroscopy of plasma samples from 250 subjects was used to determine which sphingolipids are linked to certain COPD phenotypes (1). Eight sphingolipids were associated with emphysema; ceramide, ganglioside, and sphingomyelin were the most significant. Eleven sphingolipids were associated with COPD exacerbations; trihexosylceramide had the strongest association. More work is needed to unravel the complicated biology of sphingolipids and their relationship with COPD phenotypes, such as exacerbation and emphysema.

Pathogenesis of Chronic Bronchitis

Anderson and colleagues hypothesized that dehydration of the mucus layer lining the airways contributes to the symptoms of chronic bronchitis (CB) by decreasing mucus transport (2). They examined mucus hydration in patients with CB compared with smoking and nonsmoking normal subjects. Mucus hydration in CB was threefold lower than the control groups, and those with CB had significantly greater mucin concentration. They also found that mucus dehydration was associated with decreased in vivo mucociliary clearance measured by transbronchial clearance rates and lower FEV1% predicted. These data suggest that increased mucus concentration leads to impaired mucociliary clearance, and impaired mucociliary clearance is associated with worsened lung function.

COPD is driven by inhalation of particulates that provokes airway inflammatory changes leading to neutrophil recruitment. Inflammatory chemokines signal neutrophils to migrate and activate in the airways by using C-X-C chemokine receptor (CXCR) 1 and CXCR2 receptors found on neutrophil cell membranes. The efficacy of MK-7123 to prevent the downstream effects of neutrophilic-mediated airway inflammation was evaluated for its ability to halt COPD progression (3). Doses of 10 or 30 mg/d of MK-7123 did not improve FEV1 (Figure 1) or other outcomes compared with placebo, but post hoc analyses showed a 168-ml increase in FEV1 in current smokers. However, 18% of subjects treated with MK-7123 were withdrawn from the study for low neutrophil counts. This study highlights the importance but also the challenges associated with targeting the innate immune system as a potential therapeutic target in COPD. Other agents that reduce neutrophilic pulmonary inflammation without severely reducing neutrophil activity may be an alternative approach. As an example, Wells and colleagues conducted a 12-week randomized controlled trial of roflumilast versus placebo targeting the acetyl-proline-glycine-proline (AcPGP) pathway to inhibit neutrophilic inflammation (4). Roflumilast treatment reduced sputum AcPGP more than 50% and prolyl by 46% without any change in lung function or quality of life. Future studies will need to determine the therapeutic role of targeting the AcPGP pathway to suppress neutrophilic activity.

COPD is a heterogeneous disease with different radiographic phenotypes; genetic differences may be partially responsible for these phenotypes. Cho and colleagues performed a genome-wide associated study in 12,031 subjects looking for genetic associations with the radiographic phenotypes of emphysema, gas trapping, and airway wall thickness (5). They identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations including HHIP, 15q25, and AGER loci as well as new associations near SERPINA10 and DLC1. Several of these loci—15q25, HHIP, and AGER—had already been associated with COPD, airway obstruction, and emphysema in a general population or with emphysema and soluble receptor for advanced glycation end products levels in COPD. Dijkstra and colleagues used participants from the Dutch-Belgian Lung Cancer Screening Trial (NELSON study) to identify genetic variants associated with increased airway wall thickness (AWT) and then validated the findings in LUSI (German Lung Cancer Screening Intervention Trial) (6). They found three single nucleotide polymorphisms on chromosome 2q and 10q significantly associated with AWT. The genes associated with AWT have variable functions, including airway inflammation, tissue remodeling, and possibly increased susceptibility for COPD. These data suggest that genetic risk factors may be involved in the pathogenesis of specific structural patterns of airways and emphysematous destruction.

In addition, smoking behavior has been recently linked to genetic predilection. Wain and colleagues identified genetic associations with COPD at four novel loci in European-descended patients using the UK Biobank (7). They reported five genome-wide significant signals for smoking behavior. Their data suggest that smoking affects only a small percentage of genes associated with lung function and that the smoking and genetic pathways often act independently.

COPD Onset and Progression

COPD has been historically classified as a disease with progressive airway obstruction predicted by exposure to cigarette smoke or other pollutants, recurrent respiratory infections, and genetic factors. These notions all presuppose that patients with COPD begin adulthood with normal lung function. Using three independent cohorts, Lange and colleagues challenge this concept and report that decreased baseline airflow in adults 40 years old or younger along with relatively normal rates of decline in FEV1 can result in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II COPD (8). Accordingly, about 50% of patients with GOLD stage II COPD may have an FEV1 less than 80% predicted in early adulthood and follow a trajectory of normal FEV1 decline. These findings demonstrate that low FEV1 in early adulthood can be important in the development of COPD and that accelerated decline in FEV1 is not the sole pathway to the presentation of COPD.

Smoking is one factor crucial to the development of emphysema; however, there are no current prognostic tools to determine which smokers will develop emphysema or have progression. The description of clinical and radiologic disease in smokers with normal spirometry was reported by Regan and colleagues (9). In 4,388 subjects enrolled into COPDGene (Genetic Epidemiology of COPD) with FEV1 greater than 80% predicted and FEV1/FVC greater than 0.7, one or more respiratory impairments was found in 54%, with current smoking associated with more respiratory symptoms and more respiratory medication use. Former smokers had more chest computed tomography (CT) evidence of emphysema and gas trapping. Harvey and colleagues provided evidence that smokers with normal spirometry but a low diffusion capacity were at greater risk to develop airflow obstruction (10). In 1,570 actively smoking subjects with normal spirometry, 397 had a low diffusion capacity. Fifty-nine smokers with normal spirometry/diffusion capacity and 46 smokers with normal spirometry/low diffusion capacity were randomly recruited for repeat spirometry. In the normal spirometry/diffusion capacity group, 3% developed GOLD-defined COPD over 45 ± 20 months, whereas 22% of those with normal spirometry/low diffusion capacity developed GOLD-defined COPD over 41 ± 31 months. These data suggest that lung disease and respiratory impairments are common in smokers without evidence of obstruction and that the diffusion capacity could be an early marker for future development of airflow obstruction.

In a cohort of 224 former and active smokers prospectively followed for a period of 3 to 5 years as part of the LES-COPD (Longitudinal Exacerbation Study of COPD), Bhavani and colleagues comprehensively examined pulmonary function tests, quantitative chest CT scans, annual 6-minute-walk distance tests, and T-cell cytokine responses to human lung elastin fragments (11). In multivariate analysis, the rate of emphysema progression was greater in those with lower body mass index. IFN-γ and IL-6 T-cell responses directly correlated with the annual rate of emphysema progression. These data demonstrate that the rate of emphysema progression is highly variable, but active smokers with lean body weight and autoreactive T cells may be at the greatest risk for emphysema progression.

Clinical and Immunological Factors in Progression

B cells are present in lymphoid follicles, and the number of lymphoid follicles inversely correlates with airflow obstruction in COPD (12). Lymphoid follicles result from lymphoid neogenesis (13), but what drives the expansion and development of lymphoid follicles in COPD is not clear.

B-cell activating factor (BAFF) is produced by many different cells and increases B-cell survival and maturation and may have a role in lymphoid follicle genesis. Although BAFF expression is increased in alveolar macrophages and lymphoid follicles in COPD lungs, it is not known if B-cell production of BAFF occurs in COPD and contributes to disease progression. Polverino and colleagues correlated BAFF immunostaining in lymphoid follicles from nonsmoking control subjects, smokers without COPD, and subjects with COPD with the number and size of lymphoid follicles as well as B-cell apoptosis, activation, and proliferation (14). In subjects with mild COPD and smoking control subjects the lymphoid follicles were characterized by apoptotic and limited BAFF-positive cells. Patients with GOLD IV COPD had lymphoid follicles characterized by abundant BAFF-positive cells, few apoptotic cells, higher BAFF levels in serum, and more BAFF-positive cells in bronchoalveolar lavage fluid. Similarly, Seys and colleagues found increased BAFF expression in the lungs of patients with COPD and cigarette-exposed mice (15). Prophylactic administration of a soluble fusion protein of the BAFF receptor that antagonizes BAFF activity in cigarette extract–exposed mice attenuated pulmonary inflammation and destruction of alveolar walls and altered the phenotype of alveolar and interstitial macrophages. These data, in aggregate, suggest that BAFF expression may contribute to COPD progression by promoting B-cell survival and lymphoid follicle expansion, and inhibition of its activity may attenuate pulmonary inflammation and alveolar destruction.

Physical Activity and Disease Progression

Decreased physical activity is a consequence of COPD and occurs early. Waschki and colleagues followed a cohort of patients with COPD over time to assess changes in physical activity and to examine the association of sustained physical inactivity to disease progression (16). They prospectively followed 137 patients with COPD and 26 with CB (normal spirometry) for 2.8 years. There was a decline in physical activity across all GOLD grades, and a higher decline in FEV1 or worsened quality of life were associated with a decline in physical activity. After adjusting for confounders, sustained physical inactivity was related to worsening 6-minute-walk distance and fat-free mass but not worsening FEV1 over time. This study demonstrates that physical activity decreases over time across all levels of COPD and that physical inactivity is associated with declines in 6-minute-walk distance and fat-free mass but not FEV1.

Immune Activation in Alpha-1 Antitrypsin Deficiency

Imbalances of elastase and antielastase activity along with innate lung are believed to cause tissue destruction in patients with alpha-1 antitrypsin deficiency (A1ATD). The adaptive immune response was assessed in subjects with A1ATD and compared with patients with usual COPD and control subjects (17). Lymphoid follicles in both A1ATD and usual COPD were significantly higher when compared with the control groups. B lymphocytes and CD4+ and CD8+ lymphocytes were also significantly increased in A1ATD and usual COPD compared with control subjects. IL-32, a cytokine that has importance in the induction of autoimmunity, was markedly unregulated in A1ATD and usual COPD. These results change the paradigm of A1ATD from protease and antiprotease imbalance to one that is more complex and includes an important adaptive immune inflammatory response pattern involving lymphocytes and lymphoid follicles. Whether A1ATD only predisposes patients to a more severe and rapid progression of COPD that evolves with characteristic changes in adaptive immunity or A1AT has a key role as an immunomodulatory protein that limits disease progression requires further study (18).

Lung Microbiome

Respiratory tract normal flora are important, and disruption of this environment has been suggested to have an important role in the pathogenesis of COPD. Studying the lung microbiome is challenging because sampling the lung’s natural environment necessitates access via the upper airway, which is populated by different flora. Sze and colleagues uniquely addressed this obstacle by combining16S microbiome analysis, human gene expression, and quantitative histology applied to the microCT of explanted lung cores from patients with COPD as well as control subjects (19). This technique allowed them to compare the interaction of microorganisms and their host environment in a local lung region without disruption. Both the Proteobacteria and Actinobacteria expanded in the COPD compared with the control lung sections; however, the Firmicutes and Bacteroidetes phyla contracted in COPD (Figure 2). This decline in microbial diversity was associated with emphysematous destruction and remodeling of alveolar and bronchiolar tissue and infiltration of the lung tissue by CD4+ cells in the lungs of patients with GOLD stage IV disease compared with control subjects.

Influenza frequently precipitates acute exacerbations of COPD, but the cause for the increased susceptibility to influenza in COPD is not well understood. Influenza viruses use host cell-signaling pathways during infection and the phosphoinositide-3-kinase (P13K) pathway is crucial for initial virus entry. Hyperactivation of P13K occurs in COPD, which may explain the increased susceptibility to influenza. Using a combination of human bronchial epithelial cells from patients with COPD and healthy control subjects and a mouse model of cigarette-induced COPD and influenza infection, Hsu and colleagues showed that COPD bronchial epithelial cells were more susceptible to viral entry and replication than were mice with experimental COPD (20). Increased P13K-p110α levels and activity precipitated increased infection and reduced antiviral responses. Conversely, global P13K, specific p110α inhibitors, or exogenous IFN-β restored protective antiviral responses and suppressed influenza infection. These results suggest that patients with COPD have increased susceptibility to influenza from impaired antiviral function mediated by increased P13K-p110α activity.

Lung Cancer

Lung cancer screening with chest CT imaging is recommended based on the NLST (National Lung Screening Trial) demonstrating a 20% reduction in lung cancer deaths. However, because of high false-positive rates, an approach to improve early diagnostic precision of lung cancer in susceptible patients is needed. Young and colleagues compared lung cancer incidence, histology, and stage shift in a subgroup of the NSLT who had baseline spirometry (21). In patients with COPD there was a twofold increase in lung cancer, and there was a trend favoring early diagnosis of lung cancer and avoidance of late-stage lung cancer in comparing chest CT to chest X-ray. In patients with COPD, there were significantly fewer bronchoalveolar cell cancers and significantly more non-small cell lung cancers. The P-IELCAP (Pamplona International Early Lung Cancer Detection Program) and the PLuSS (Pittsburgh Lung Screening Study) databases were analyzed in an attempt to develop a predictive score for lung cancer risk for patients with COPD (22). The risk model used age greater than 60 years, body mass index less than kg/m2, 60 pack-years or more smoking history, and emphysema presence to create a 10-point score (Chronic Obstructive Pulmonary Disease Lung Cancer Screening Score [COPD-LUCSS]): low risk (0–6) and high risk (7–10). In both cohorts, high-risk patients had a 3.5-fold greater risk for lung cancer than low-risk patients (Figure 3). These data highlight that precision may be gained by coupling COPD history, lung function, and imaging data to more precisely define lung cancer risk.

Although hypoxemia is associated with pulmonary hypertension, emphysema has not correlated with pulmonary artery pressure. Dournes and colleagues wanted to determine the clinical and high-resolution CT parameters associated with pulmonary hypertension in COPD (23). Pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mm Hg) was present in 34 of their 60 patients. AWT was greater in those with pulmonary hypertension, whereas there was no difference in the percentage of emphysema between groups. AWT but not percentage emphysema correlated with mean pulmonary artery pressure in those with and without pulmonary hypertension. Multivariate analysis demonstrated that the best model to predict pulmonary hypertension included AWT, PaO2, and the diameter ratio between the pulmonary artery and aorta. AWT explained 19% of the difference, and PaO2 and the diameter ratio between the pulmonary artery and aorta explained only 5 and 3%, respectively. This was the first study to demonstrate a relationship between AWT and pulmonary hypertension; however, the mechanism remains unproven.

There is loss of pulmonary capillaries in emphysematous lung tissue, but there are not adequate data on the pulmonary microvascular blood flow (PMBF) in patients with mild COPD. Hueper and colleagues used gadolinium-enhanced magnetic resonance imaging to assess PMBF in subjects enrolled in a multicenter study (24). PMBF was 38% lower in patients with COPD than in control subjects across all levels of severity. Investigators calculated the PMBF only in regions of the lung without emphysema and found that compared with control subjects those with COPD still had less PMBF (Figure 4). When subjects with COPD were classified as having either emphysema or small airway disease, they found that those with small airway disease alone did not have significantly decreased PMBF. This study suggests that pulmonary microvascular blood flow is abnormal in patients with mild COPD and could represent a pathological process different from small airway disease, because decreased PMBF was not seen in those with predominantly small airway disease.

Exercise Physiology

Patients with mild COPD have troublesome dyspnea and elevated ventilatory equivalent for carbon dioxide (V.e/V.co2) during exercise. The mechanism and clinical consequences of a high V.e/V.co2 have not been well described. Elbehairy and colleagues examined pulmonary gas exchange in patients with mild COPD during incremental exercise (25). They compared 11 patients with mild COPD to 11 age-matched nonsmoking healthy subjects. Patients with COPD had significantly lower V.o2% predicted as well as a higher V.e/V.co2 at maximal exercise and more dynamic hyperinflation. Because of expiratory flow limitation in the patients with COPD, the critical inspiratory reserve volume was met at lower V.e in patients with COPD. This study demonstrated that the physiologic dead space is increased in mild COPD and that increased V.e will maintain arterial blood gas homeostasis. However, this increased V.e leads to earlier mechanical constraints on increasing tidal volume and results in severe dyspnea and cessation of exercise.

Occupational Exposure and COPD

Despite the strong evidence for occupational exposure (OE) as a contributor to COPD, there are few data regarding the effect of OE in those with established COPD. After adjusting for confounders, in a large cohort of subjects at risk for COPD, OE was associated with an increased risk of COPD (26). Those with OE had worse quality of life, more dyspnea, and shorter 6-minute-walk distances. Using a multivariate model there was a significantly increased risk of exacerbations requiring healthcare use with OE. This study highlights the importance of avoidance of all noxious inhaled agents to optimize symptoms and improve quality of life in those with COPD.

GOLD has defined airflow obstruction on spirometry as a fixed FEV1/FVC ratio below 0.70, but this may overestimate the presence of airflow obstruction in elderly populations due to the effects of aging. Some propose using the lower limit of normal (LLN) of FEV1/FVC, and the GLI (Global Lung Initiative) has published equations using the LLN. Vaz Fragoso and colleagues sought to evaluate the phenotype of GLI-defined normal spirometry and compare it with GOLD-defined obstruction using data from COPDGene (27). Among those with GLI-defined normal spirometry, GOLD classified 7.5% as mild COPD, 5.9% as moderate COPD, and 9.1% with a restrictive pattern. Subjects classified as having airflow obstruction by GOLD who were normal by GLI criteria also had normal dyspnea, quality of life, 6-minute-walk distance, percentage emphysema, and percentage gas trapping on CT imaging and were older. A fixed cutoff of FEV1/FVC ratio may lead to an inaccurate diagnosis in older patients, possibly leading to overdiagnosis of COPD. It remains unclear whether the LLN approach should be used in all or only in those above some as-of-yet unidentified age.

Hyperinflation and the Benefits of Lung Reduction

Lung volume reduction surgery (LVRS) has been shown to improve cardiac performance and reduce inflammatory biomarkers. Whether LVRS can improve endothelial dysfunction by reducing lung volumes leading to less systemic inflammation is unclear. Clarenbach and colleagues reported the effects of LVRS on endothelial function and systemic inflammation in patients with emphysema (28). The authors reported that flow-mediated dilation improved in the LVRS group compared with the control group. A reduction in residual volume/total lung capacity was the only parameter independently associated with an improvement in flow-mediated dilation after LVRS. This study confirms prior links between vascular disease and emphysema and provides further information that hyperinflation has protean negative effects on nonpulmonary health status in patients with COPD.

Klooster and colleagues have revisited the technique of endobronchial valve placement in selected hyperinflated patients with heterogeneous and homogenous emphysema with no evidence of collateral ventilation in the ipsilateral treated and nontreated lung lobes (29). At 6 months, patients with heterogeneous and homogenous disease both had significant increases in FEV1, 6-minute-walk distance, and improvements in quality of life compared with the control group. Although patients with heterogeneous disease had more robust improvements, patients with homogenous emphysema by chest CT analyses still had significant improvements. Pneumothorax rates were higher in the endobronchial valve–treated arm, and acute exacerbations were common in both arms. Larger and longer prospective controlled trials are needed to assess the durability of these results and the optimum candidates for treatment.

Regardless of technique chosen, selection of optimum patients for lung reduction is challenging. A retrospective analysis to quantitatively assess a variety of chest CT features was conducted by Schuhmann and colleagues in 146 patients who underwent endobronchial lung reduction (30). Parameters were assessed with the goal to predict a volume reduction of greater than 350 ml in the targeted lobe. In addition, the success of CT measures to predict target lobe reduction was compared with an endobronchial assessment of collateral ventilation. Fissure integrity was the strongest predictor of response but was closely followed by low attenuation clusters and the vessel volume ratio. Quantitative chest CT parameters were comparable to the endobronchial assessment method to predict success in achieving targeted lobe volume reduction. Because both methods were contradictory in about a third of subjects, more precise measures for the selection of patients and optimum lobes for targeted therapy are required.


To improve patient compliance and convenience of inhaled bronchodilator therapy in COPD, a series of new once-daily long-acting β2-agonist/long-acting muscarinic antagonist (LABA/LAMA) combinations have been developed. Two replicate studies, FLIGHT 1 and FLIGHT 2, reported the efficacy and safety of QVA 149 (indacaterol/glycopyrrolate), a fixed-dose combination of an LABA and an LAMA in comparison with its monocomponents and placebo in patients with moderate to severe COPD (31). Indacaterol/glycopyrrolate was superior in terms of FEV1 under the curve from 0 to 12 hours compared with the monocomponents. Indacaterol/glycopyrrolate improved quality of life, dyspnea, and rescue medication use compared with placebo. These data are interesting in that superior therapeutic effects are seen when combining LABA/LAMA and suggest that lower doses of both agents could deliver a beneficial effect. The biologic mechanisms underpinning these clinical results deserve further investigation to exploit optimal clinical outcomes (32).

Whether to use dual long-acting bronchodilators or a combination of a long-acting bronchodilator and an inhaled corticosteroid is also an important current clinical question. Zhong and colleagues examined the effect of a combination of an LABA/LAMA dual bronchodilator (indacaterol/glycopyrronium) as compared with a combination of an LABA/inhaled corticosteroid (ICS; salmeterol/fluticasone) in patients with moderate to severe COPD with a history of no more than one exacerbation in the past year (33). The LABA/LAMA combination demonstrated a statistically significant increase in trough FEV1 and area under the curve of FEV1 from 0 to 4 hours compared with the LABA/ICS group at Week 26. Moderate to severe exacerbations were reduced by 31% in the indacaterol/glycopyrronium group compared with the salmeterol/fluticasone group. Similar changes were seen in both groups in improvement in St. George's Respiratory Questionnaire, use of rescue medications, and improvement in transitional dyspnea score. These data suggest that LABA/LAMA may be an alternative treatment option to LABA/ICS in the management of patients with moderate to severe COPD with a history of no more than one exacerbation in the prior year.

Asthma and COPD Overlap

COPD is a heterogeneous disease with several features overlapping with asthma. Christenson and colleagues examined asthma gene expression in bronchial wall cells of patients with COPD from two prior randomized controlled trials of inhaled glucocorticoid therapy (GLUCOLD [Groningen and Leiden Universities Study of Corticosteroids in Obstructive Lung Disease]) to determine if gene expression signifies therapeutic responsiveness to the administration of inhaled glucocorticoids (34). The group identified a subset of patients with COPD with increased asthma-related genetic signatures called the T-helper type 2 signature (T2S) score. Higher T2S scores were associated with decreased lung function, increased airway wall and blood eosinophil counts, and bronchodilator reversibility, but not asthma history. The high T2S score group showed a significant improvement in hyperinflation with inhaled corticosteroid treatment. These data confirmed that airway gene expression alterations can be found in asthma and COPD, suggesting that T-helper type 2 inflammation is important in a subset of COPD that is not identified by a clinical history of asthma.

COPD Exacerbations

The reduction of acute exacerbations of COPD remains vital. The REACT (Roflumilast and Exacerbations in Patients Receiving Appropriate Combination Therapy) study builds on the body of evidence for roflumilast as add-on therapy in COPD. Martinez and colleagues reported that roflumilast had incremental benefit as add-on therapy to LABA/ICS in moderate/severe COPD with two or more exacerbations in the prior year (35). Their analysis demonstrated a borderline reduction in exacerbation rate, but this may have been related to a lower than expected exacerbation rate in the comparator group. The reduction in exacerbations appeared to be most pronounced for patients who encountered severe exacerbations requiring hospitalization.

The impact of COPD as a comorbid condition in patients hospitalized with acute decompensated heart failure was also reported in 9,748 patients admitted to 11 medical centers with acute decompensated heart failure (36). A history of COPD was reported in 35.9% of patients, who were also less likely to be discharged on β-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in comparison to patients with acute disease other than COPD. Not surprisingly, patients with decompensated heart failure with COPD had a higher rate of death at 1 and 5 years after discharge in comparison to those without a comorbid diagnosis of COPD. These data suggest that the underuse of appropriate medicines to treat heart failure in patients with COPD results in greater morbidity and mortality.

Predicting which patients are at risk for readmission for acute exacerbation of COPD is challenging, with prior history of hospitalization being the best indicator to date. Skeletal muscle weakness and muscle wasting could provide a window into the hospitalized COPD patient’s overall compromised state. Ultrasound assessment of the quadriceps muscle cross-sectional area is a surrogate for lower leg muscle mass and can be performed at the bedside independent of effort. Greening and colleagues reported in patients hospitalized with COPD exacerbation that quadriceps muscle cross-sectional area was independently associated with readmission and death (37). Additionally, patients with the smallest quadriceps muscle spent more days in the hospital. These data suggest that the extrapulmonary manifestations of COPD may have important bearing on major events in the subsequent course of the patient with COPD.

Prolonged symptoms after an exacerbation also herald a worse outcome. In 351 patients with one or more exacerbations, patients with longer symptom duration had worse quality of life, a shorter interval between exacerbation recovery and onset of subsequent exacerbation, and impaired recovery of peak flow 3 months later (38). These data suggest that patients with prolonged symptom duration have worse quality of life and a greater risk of new events.

The importance of early outpatient follow up after COPD hospitalization was again reported in a study of 195 patients with COPD (39). Within 30 days of discharge, only 44% of subjects had an outpatient visit. Not attending the outpatient visit was associated with a significant increased risk of hospitalization within 90 days of discharge. Early follow up post COPD hospitalization appears to reduce exacerbation-related rehospitalization rates in patients with COPD.

The biological pathways and mechanisms that occur in the lung provoking COPD exacerbation are poorly understood. IL-17A is a proinflammatory cytokine that induces the expression of mediators that recruit and activate neutrophils. Roos and colleagues demonstrated that the expression of IL-17A is greater in the distal lung of more severely obstructed patients with COPD compared with never-smokers or smokers without COPD (Figure 5) (40). They also reported a greater dependency on CXCL-12 for lymphoid neogenesis in IL-17A knockout mice. In addition, the investigators found evidence of CXCL-12 expression in the lymphoid follicles of the COPD lung with a trend toward greater concentration of CXCL-12 in patients with COPD than in smokers without airflow obstruction or never-smokers.

Although IL-17A is increased in the lung tissue and sputum of patients with stable COPD, its role in acute exacerbation is unknown. In an experimental mouse model of nontypeable Haemophilus influenzae (NTHi)-induced acute exacerbation and cigarette smoke exposure, airway neutrophilia was associated with an increased expression of IL-17A. In a parallel study in patients with COPD, IL-17A was found to be significantly elevated during NTHi-associated acute exacerbation but normalized to baseline IL-17A levels after resolution. Finally, IL-17A levels were not elevated in patients with COPD when acute exacerbation was associated with non-NTHi organisms isolated from the sputum culture (41). These data suggest that IL-17A is a mediator of neutrophilic inflammation in acute exacerbation, especially in those associated with NTHi organisms.

Some optimism was reported by Ford and colleagues on the trend in mortality from COPD among adults in the United States (42). In an examination of the mortality trends from COPD among U.S. adults from 1968 through 2011, the age-adjusted mortality rate among men peaked in 1999 and then declined, whereas the age-adjusted mortality rate among women increased from 2000 to 2011 and had peaked in 2008. Despite evidence of a narrowing in the sex gap, mortality rates in men continued to exceed those among women; however, there was evidence of a decline in the annualized percentage change in the mortality rates of both white and black men and adults aged 55 to 64 years and 65 to 74 years. These data show that the mortality rate for COPD has decline since 1999 in men and some age groups but continues to rise in women, encouragingly at a reduced pace.

New information from studies of COPD performed over the past year demonstrate that substantial progress is being made in our understanding of the pathogenesis, phenotypic classification, and development of novel therapeutic approaches in the care of patients with COPD. Although a cure for this devastating disease is not yet in sight, the undeterred commitment of researchers, the medical industry, various government and societal funding agencies, and, most importantly, clinical research participants who are afflicted with COPD provide great promise that progress is finally being made in our quest to reverse the downward trajectory of impairment commonly associated with this disease.

1. Bowler RP, Jacobson S, Cruickshank C, Hughes GJ, Siska C, Ory DS, Petrache I, Schaffer JE, Reisdorph N, Kechris K. Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes. Am J Respir Crit Care Med 2015;191:275284.
2. Anderson WH, Coakley RD, Button B, Henderson AG, Zeman KL, Alexis NE, Peden DB, Lazarowski ER, Davis CW, Bailey S, et al. The relationship of mucus concentration (hydration) to mucus osmotic pressure and transport in chronic bronchitis. Am J Respir Crit Care Med 2015;192:182190.
3. Rennard SI, Dale DC, Donohue JF, Kanniess F, Magnussen H, Sutherland ER, Watz H, Lu S, Stryszak P, Rosenberg E, et al. CXCR2 antagonist MK-7123: a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;191:10011011.
4. Wells JM, Jackson PL, Viera L, Bhatt SP, Gautney J, Handley G, King RW, Xu X, Gaggar A, Bailey WC, et al. A randomized, placebo-controlled trial of roflumilast: effect on proline-glycine-proline and neutrophilic inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:934942.
5. Cho MH, Castaldi PJ, Hersh CP, Hobbs BD, Barr RG, Tal-Singer R, Bakke P, Gulsvik A, San José Estépar R, Van Beek EJ, et al.; NETT Genetics, ECLIPSE, and COPDGene Investigators. A genome-wide association study of emphysema and airway quantitative imaging phenotypes. Am J Respir Crit Care Med 2015;192:559569.
6. Dijkstra AE, Postma DS, van Ginneken B, Wielpütz MO, Schmidt M, Becker N, Owsijewitsch M, Kauczor HU, de Koning HJ, Lammers JW, et al. Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses. Am J Respir Crit Care Med 2015;191:547556.
7. Wain LV, Shrine N, Miller S, Jackson VE, Ntalla I, Soler Artigas M, Billington CK, Kheirallah AK, Allen R, Cook JP, et al.; UK Brain Expression Consortium (UKBEC); OxGSK Consortium. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir Med 2015;3:769781.
8. Lange P, Celli B, Agustí A, Boje Jensen G, Divo M, Faner R, Guerra S, Marott JL, Martinez FD, Martinez-Camblor P, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015;373:111122.
9. Regan EA, Lynch DA, Curran-Everett D, Curtis JL, Austin JH, Grenier PA, Kauczor HU, Bailey WC, DeMeo DL, Casaburi RH, et al.; Genetic Epidemiology of COPD (COPDGene) Investigators. Clinical and radiologic disease in smokers with normal spirometry. JAMA Intern Med 2015;175:15391549.
10. Harvey BG, Strulovici-Barel Y, Kaner RJ, Sanders A, Vincent TL, Mezey JG, Crystal RG. Risk of COPD with obstruction in active smokers with normal spirometry and reduced diffusion capacity. Eur Respir J 2015;46:15891597.
11. Bhavani S, Tsai CL, Perusich S, Hesselbacher S, Coxson H, Pandit L, Corry DB, Kheradmand F; Five-Year Prospective Longitudinal Exacerbation Study of Chronic Obstructive Pulmonary Disease (LES-COPD). Clinical and immunological factors in emphysema progression. Am J Respir Crit Care Med 2015;192:11711178.
12. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:26452653.
13. Brusselle GG, Demoor T, Bracke KR, Brandsma CA, Timens W. Lymphoid follicles in (very) severe COPD: beneficial or harmful? Eur Respir J 2009;34:219230.
14. Polverino F, Cosio BG, Pons J, Laucho-Contreras M, Tejera P, Iglesias A, Rios A, Jahn A, Sauleda J, Divo M, et al. B cell-activating factor: an orchestrator of lymphoid follicles in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:695705.
15. Seys LJ, Verhamme FM, Schinwald A, Hammad H, Cunoosamy DM, Bantsimba-Malanda C, Sabirsh A, McCall E, Flavell L, Herbst R, et al. Role of B cell-activating factor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:706718.
16. Waschki B, Kirsten AM, Holz O, Mueller KC, Schaper M, Sack AL, Meyer T, Rabe KF, Magnussen H, Watz H. Disease progression and changes in physical activity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:295306.
17. Baraldo S, Turato G, Lunardi F, Bazzan E, Schiavon M, Ferrarotti I, Molena B, Cazzuffi R, Damin M, Balestro E, et al. Immune activation in α1-antitrypsin-deficiency emphysema: beyond the protease-antiprotease paradigm. Am J Respir Crit Care Med 2015;191:402409.
18. Stockley RA. Immune modulation by α1-antitrypsin: a nice concept, but does it influence outcome? Am J Respir Crit Care Med 2015;191:363364.
19. Sze MA, Dimitriu PA, Suzuki M, McDonough JE, Campbell JD, Brothers JF, Erb-Downward JR, Huffnagle GB, Hayashi S, Elliott WM, et al. Host response to the lung microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:438445.
20. Hsu AC, Starkey MR, Hanish I, Parsons K, Haw TJ, Howland LJ, Barr I, Mahony JB, Foster PS, Knight DA, et al. Targeting PI3K-p110α suppresses influenza virus infection in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;191:10121023.
21. Young RP, Duan F, Chiles C, Hopkins RJ, Gamble GD, Greco EM, Gatsonis C, Aberle D. Airflow Limitation and histology shift in the national lung screening trial: the NLST-ACRIN cohort substudy. Am J Respir Crit Care Med 2015;192:10601067.
22. de-Torres JP, Wilson DO, Sanchez-Salcedo P, Weissfeld JL, Berto J, Campo A, Alcaide AB, García-Granero M, Celli BR, Zulueta JJ. Lung cancer in patients with chronic obstructive pulmonary disease: development and validation of the COPD Lung Cancer Screening Score. Am J Respir Crit Care Med 2015;191:285291.
23. Dournes G, Laurent F, Coste F, Dromer C, Blanchard E, Picard F, Baldacci F, Montaudon M, Girodet PO, Marthan R, et al. Computed tomographic measurement of airway remodeling and emphysema in advanced chronic obstructive pulmonary disease: correlation with pulmonary hypertension. Am J Respir Crit Care Med 2015;191:6370.
24. Hueper K, Vogel-Claussen J, Parikh MA, Austin JH, Bluemke DA, Carr J, Choi J, Goldstein TA, Gomes AS, Hoffman EA, et al. Pulmonary microvascular blood flow in mild chronic obstructive pulmonary disease and emphysema: the MESA COPD study. Am J Respir Crit Care Med 2015;192:570580.
25. Elbehairy AF, Ciavaglia CE, Webb KA, Guenette JA, Jensen D, Mourad SM, Neder JA, O’Donnell DE; Canadian Respiratory Research Network. Pulmonary gas exchange abnormalities in mild chronic obstructive pulmonary disease. implications for dyspnea and exercise intolerance. Am J Respir Crit Care Med 2015;191:13841394.
26. Paulin LM, Diette GB, Blanc PD, Putcha N, Eisner MD, Kanner RE, Belli AJ, Christenson S, Tashkin DP, Han M, et al.; SPIROMICS Research Group. Occupational exposures are associated with worse morbidity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;191:557565.
27. Vaz Fragoso CA, McAvay G, Van Ness PH, Casaburi R, Jensen RL, MacIntyre N, Gill TM, Yaggi HK, Concato J. Phenotype of normal spirometry in an aging population. Am J Respir Crit Care Med 2015;192:817825.
28. Clarenbach CF, Sievi NA, Brock M, Schneiter D, Weder W, Kohler M. Lung volume reduction surgery and improvement of endothelial function and blood pressure in patients with chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med 2015;192:307314.
29. Klooster K, ten Hacken NH, Hartman JE, Kerstjens HA, van Rikxoort EM, Slebos DJ. Endobronchial valves for emphysema without interlobar collateral ventilation. N Engl J Med 2015;373:23252335.
30. Schuhmann M, Raffy P, Yin Y, Gompelmann D, Oguz I, Eberhardt R, Hornberg D, Heussel CP, Wood S, Herth FJ. Computed tomography predictors of response to endobronchial valve lung reduction treatment: comparison with Chartis. Am J Respir Crit Care Med 2015;191:767774.
31. Mahler DA, Kerwin E, Ayers T, FowlerTaylor A, Maitra S, Thach C, Lloyd M, Patalano F, Banerji D. FLIGHT1 and FLIGHT2: efficacy and safety of QVA149 (indacaterol/glycopyrrolate) versus its monocomponents and placebo in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:10681079.
32. Donohue JF. Low doses of long-acting β-agonists/long-acting muscarinic agents with large effects: the FLIGHT study. Am J Respir Crit Care Med 2015;192:10281030.
33. Zhong N, Wang C, Zhou X, Zhang N, Humphries M, Wang L, Thach C, Patalano F, Banerji D; LANTERN Investigators. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int J Chron Obstruct Pulmon Dis 2015;10:10151026.
34. Christenson SA, Steiling K, van den Berge M, Hijazi K, Hiemstra PS, Postma DS, Lenburg ME, Spira A, Woodruff PG. Asthma-COPD overlap: clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;191:758766.
35. Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015;385:857866.
36. Fisher KA, Stefan MS, Darling C, Lessard D, Goldberg RJ. Impact of COPD on the mortality and treatment of patients hospitalized with acute decompensated heart failure: the Worcester Heart Failure Study. Chest 2015;147:637645.
37. Greening NJ, Harvey-Dunstan TC, Chaplin EJ, Vincent EE, Morgan MD, Singh SJ, Steiner MC. Bedside assessment of quadriceps muscle by ultrasound after admission for acute exacerbations of chronic respiratory disease. Am J Respir Crit Care Med 2015;192:810816.
38. Donaldson GC, Law M, Kowlessar B, Singh R, Brill SE, Allinson JP, Wedzicha JA. Impact of prolonged exacerbation recovery in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:943950.
39. Gavish R, Levy A, Dekel OK, Karp E, Maimon N. The association between hospital readmission and pulmonologist follow-up visits in patients with COPD. Chest 2015;148:375381.
40. Roos AB, Sandén C, Mori M, Bjermer L, Stampfli MR, Erjefält JS. IL-17A is elevated in end-stage chronic obstructive pulmonary disease and contributes to cigarette smoke-induced lymphoid neogenesis. Am J Respir Crit Care Med 2015;191:12321241.
41. Roos AB, Sethi S, Nikota J, Wrona CT, Dorrington MG, Sandén C, Bauer CM, Shen P, Bowdish D, Stevenson CS, et al. IL-17A and the promotion of neutrophilia in acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:428437.
42. Ford ES. Trends in mortality from COPD among adults in the United States. Chest 2015;148:962970.
Correspondence and requests for reprints should be addressed to Nathaniel Marchetti, D.O., Department of Thoracic Medicine and Surgery, 745 Parkinson Pavilion, 3401 North Broad Street, Philadelphia, PA 19140. E-mail:

Author disclosures are available with the text of this article at


No related items
Comments Post a Comment

New User Registration

Not Yet Registered?
Benefits of Registration Include:
 •  A Unique User Profile that will allow you to manage your current subscriptions (including online access)
 •  The ability to create favorites lists down to the article level
 •  The ability to customize email alerts to receive specific notifications about the topics you care most about and special offers
American Journal of Respiratory and Critical Care Medicine

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