Update in Chronic Obstructive Pulmonary Disease 2019

Contributors to Disease and Disease Mechanisms

Studies of Endophenotype(s) of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is believed to be associated with both intrinsic and exogenous disease determinants. The former comprise genetic (1, 2) and epigenetic (2–4) factors. The latter involve various nonhost disease determinants (5–7), such as pathogens or air pollution. Advancing our understanding, several studies interrogated genetic and epigenetic factors as contributors to clinical manifestations. The studies focused either on a single candidate gene (8–11) or a group of genes (12, 13) with or without previously demonstrated associations with COPD. In line with previous studies (14), several reports converged on the SERPINA1 gene (9, 12, 13). The SERPINA1 (serpin family A member 1) gene encodes the inhibitor of neutrophil elastase, alpha-1 antitrypsin, the genetic deficiency of which causes a monogenic disease with respiratory manifestations similar to those in COPD (15). These observations highlight the prominence of the intrinsic disease component in COPD (14).

In many polygenic diseases, there is the stride to advance the heritability aspect from statistical to causal associations (16, 17), with the latter likely comprising multiple genetic variants. Addressing this in COPD, the studies used “multiomics” techniques or computational models to integrate multiple genetic variants or used composite approaches covering cell lines, animal models, and clinical specimens (11, 12, 18). Two published reports procured their findings or validated these in general population (12, 19), demonstrating the presence of the COPD-associated intrinsic component beyond COPD.

Sakornsakolpat and colleagues (20) examined genome-wide association data from four cohorts enriched for patients with COPD (COPDGene [The Genetic Epidemiology of COPD], NETT [The National Emphysema Treatment Trial], GenKOLS [Genetics of COPD], and TESRA [Treatment of Emphysema with a Gamma-Selective Retinoid Agonist]), looking for potential associations with the Dl_CO, the measure of gas transfer in the lungs. The authors showed significant heritability in subjects with European but not those with African American ancestry. The study power could have been a potential confounder on the latter conclusion. Genetic loci potentially associated with Dl_CO were identified.

Further investigations of COPD endophenotypes could lead to predictive and preventative approaches in COPD.

Innate Immune Cells

Neutrophils have been implicated in driving many of the emphysematous changes in COPD, e.g., through the release of neutrophil elastase. The aberrant neutrophil migration has previously been reported (21) and further confirmed by Dunne and colleagues (22). This report also demonstrated that the PDE4 (phosphodiesterase 4) inhibitor roflumilast was effective at chemoattractant-independent suppression of neutrophil chemotaxis. Even with reservations about using neutrophils ex vivo (23), this study identified a possible mechanism via the EPAC1 (exchange protein directly activated by cAMP 1), potentially revealing a novel target for suppressing neutrophil recruitment.

The macrophage is another key innate immune cell in the lung. Its function in COPD is subdued, with Finney and colleagues (24) suggesting a possible mechanism for this. Specifically, the human rhinovirus was found to impair phagocytosis of Haemophilus influenzae and Streptococcus pneumoniae as well as cytokine release by macrophages of patients with COPD but not those of healthy subjects (24). This study suggested a role for the Toll-like receptor 3 pathway in the suppression of macrophage responses, potentially leading to dysbiosis of the lung microbiome (25).

Airway Epithelium

Several studies examined the role of the airway epithelium as the first barrier to inhaled irritants. Petit and colleagues (26), studying well-differentiated airway epithelial cells from nonsmokers, smokers, and patients with COPD, reported altered intracellular calcium signaling in cells from both latter groups. Intracellular calcium is vital to regulating mucociliary clearance, and the authors showed a critical role for the calcium channel component ORAI3 (ORAI calcium release-activated calcium modulator 3) in the latter process. Downregulated ORAI3 may alter the ciliary beat (27) and thereby reduce the mucociliary clearance, as observed in the airways of patients with COPD.

Also using well-differentiated airway epithelial cells, Feldman and colleagues (28) identified a key role for TGFβ (transforming growth factor β), via SMAD signaling, on mucous cell differentiation. This signaling pathway suppressed differentiation and acted as a gatekeeper, representing a potential target for reducing the goblet cell hyperplasia seen in COPD (29). Certain reservations could be expressed because of the concurrent involvement of TGFβ in remodeling and fibrosis.

Intact airway epithelium is a vital protective barrier for underlying cells, with the inhalation of toxicants disrupting this finely balanced system. Lin and colleagues (30) investigated whether e-cigarette vapor alters epithelial integrity similarly to other inhaled substances, including conventional cigarette smoke. They showed that e-cigarette vapor reduced epithelial integrity and, via CFTR (cystic fibrosis transmembrane regulator), altered the ion transport in epithelial cells. Although the effects on other ion channels remain to be examined (31), this study provides evidence for the potentially harmful effects of e-cigarettes.

In a study of the alveolar epithelium, S100A8 (S100 calcium-binding protein A8) was upregulated after the exposure of alveolar epithelial type II cells to cigarette smoke extract and protected against apoptosis (32). Furthermore, S100A8 was downregulated in cells from patients with emphysema, underscoring the potential protective role.

Smooth Muscle Cells and Lung-Resident Mesenchymal Stem Cells

The airway smooth muscle cell is also altered in COPD, with evidence of hyperproliferation (33, 34). By studying long noncoding RNAs overexpressed in COPD tissues, Zheng and colleagues (35) offered a potential mechanism for this. In particular, COPDA1 was investigated and shown to target the MS4A1 (membrane spanning 4-domains A1) gene. The authors further showed that MS4A1 is a component of the store-operated calcium entry pathway, which can promote cell proliferation. This links the long noncoding RNA COPDA1, via MS4A1, to increased airway smooth muscle cell proliferation, with a potential role in the small airway remodeling observed in COPD (36).

Cruz and colleagues (37) reported similar numbers of lung-resident mesenchymal stem cells (LR-MSC) between healthy lungs and those from patients with COPD, arguing against the previously speculated exhaustion of LR-MSC. However, coculture experiments showed that COPD-derived LR-MSC stimulated proliferation of CD8⁺ T cells. This was associated with smoking because the effect was lost in cells derived from COPD former smokers. These data were substantiated by ex vivo experiments, in which LR-MSC were exposed to cigarette smoke extract, confirming the impairment of the immunomodulatory capacity of LR-MSC by smoking.

Vasculature

In HIV, a lower Dl_CO was associated with more severe coronary artery calcium on computed tomography (CT), and those with both a low Dl_CO and coronary artery calcium had increased mortality and higher circulating markers of endothelial dysfunction (38). Also, there was an association between cigarette smoking and increased volumes of smaller peripheral pulmonary vessels, potentially linking smoking-related lung injury to the vasculature (39). Increased peripheral pulmonary vasculature was also associated with air pollution, specifically, exposure to diesel-related black carbon (40).

The role of ceramides in lung vasculature has been studied by Koike and colleagues (41) in murine emphysema models, human lungs, and cultured endothelial cells. COPD and cigarette exposure impaired the initial steps of ceramide synthesis, triggering autophagy and cell death. This potentially hints to a new therapeutic approach for emphysema (42).

Mucociliary Clearance

CFTR function, via sweat chloride concentrations, has been evaluated in smokers with and without COPD. Higher chloride concentrations were found in individuals with bronchiectasis on CT (43), without a concomitant increase in the prevalence of significant CFTR mutations. Thereby, acquired smoking-related CFTR dysfunction may contribute to bronchiectasis and the small airway phenotype of COPD (43).

In Vivo Models of Disease

A key receptor driving neutrophil recruitment in COPD is the chemokine receptor CXCR2 (CXC chemokine receptor 2) (44). Ligands for this receptor include the chemokines CXCL1 (C-X-C motif chemokine ligand 1) and CXCL8 (both of which are elevated in COPD) (45, 46), and some peptides, such as PGP (proline-glycine-proline) (47). The latter can constitute a chemotactic signal. In a murine model of the cigarette smoke-induced emphysema, Roda and colleagues (48) showed that the PGP-neutralizing peptide l-arginine-threonine-arginine attenuated pulmonary accumulation of both neutrophils and macrophages, suppressing emphysema. Importantly, the CXCR2 receptor expressed by airway epithelial cells appeared to be central to the perpetuation of neutrophilic inflammation by the induction of chemokines and proteases (49). This could be inhibited by l-arginine-threonine-arginine (48), highlighting a potential therapeutic strategy.

Lee and colleagues (50) also used the murine smoke-exposure model and observed that a very brief cigarette smoke exposure protectively upregulated the VEGF (vascular endothelial growth factor). In contrast, chronic exposure to cigarette smoke downregulated VEGF. In mice lacking VEGF, alarmin (IL-33) was released by airway epithelium as the second line of defense. This IL-33 increase is akin to that observed in patients with COPD (51, 52), with this study being the first to link VEGF suppression to IL-33 increase in COPD. This observation, too, may lead to a novel therapeutic option.

Giordano and colleagues (53), in a murine model, sought to investigate the mechanisms of tissue damage and the role of oxidant stress and mitochondrial dysfunction in this pathophysiology. The model was a mouse strain overexpressing AOX (alternative oxidase), an enzyme that essentially bypasses mitochondrial electron transport. After mice exposure to cigarette smoke, the authors showed a protective effect of AOX against tissue destruction. By further testing mouse embryonic fibroblasts overexpressing AOX, Giordano and colleagues showed cytoprotection against cytotoxicity induced by cigarette smoke condensate, likely via reduced expression of intracellular reactive oxygen species. There is a possibility that inhaled AOX may exert benefits in COPD (54).

The role of T cells in the development of emphysema was addressed using an in vivo T-bet (T-box transcription factor) knockout mouse (55). The gene T-bet is important in differentiation of CD4⁺ Th1 cells. The authors showed that this knockout potentiated elastase-induced emphysema, suggesting that CD4⁺ cells are protective. Given the limitations of this model, further studies regarding the role of CD4⁺ cells are required (56). Another study examined the role for autoantibodies against the extracellular matrix in the development of emphysema. Using a murine cigarette smoke-exposure model, Patel and colleagues (57) showed an increase in circulating autoantibodies. To determine whether these could drive emphysema, donor lungs were transplanted. More extensive damage was seen in the recipient mice that had previously been exposed to cigarette smoke, supporting the role of autoantibodies (58).

Complement System and Alpha-1 Antitrypsin Deficiency

Recent evidence reveals a role of the complement system in COPD pathogenesis. Serban and colleagues (59) reported an increased abundance of MASP-2 (mannose-binding lectin [MBL]-associated serine protease 2) in plasma and lung tissue of patients with COPD or alpha-1 antitrypsin deficiency (AATD). The downstream complement factor C4 was activated in plasma of patients with COPD and AATD. In the latter, it was normalized by augmentation therapy.

Campos and colleagues (60) found, in a clinical trial, that a double-dose augmentation therapy in AATD further reduced the hallmarks of protease activity and inflammation in the BAL fluid.

Lung Infections

Leitao Filho and colleagues (61) reported an increased 1-year mortality in patients with COPD hospitalized for an exacerbation when their sputum microbiome was less diverse, such that Staphylococcus was still present and Veillonella absent. This may be informative for personalized risk prediction (62).

Environmental Factors

Apart from tobacco smoking, the leading risk factor for COPD, environmental exposures such as (indoor) biomass burning may also contribute (63, 64). Consequently, household air pollution appears to be of interest in several populations (65).

In a large never-smoking Chinese cohort, the use of solid fuel for cooking was associated with an elevated risk of hospital admission and death (66). In contrast, a change of cooking habits was associated with risk reduction. This conclusion remains ambiguous, however. Thus, a study from rural Malawi (67) attributed respiratory symptoms largely to current or former smoking, tuberculosis history, or CO exposure and did not reveal beneficial effects of using cleaner stoves. It is possible that in COPD, the impact of these environmental factors is much weaker compared with to that of tobacco smoking (68, 69).

Higher amounts of ambient ozone and exposure to fine particulate matter were associated with a faster progression of CT-detected emphysema over 15 years in the MESA (The Multi-Ethnic Study of Atherosclerosis) Lung Study, and ozone predicted a faster decline in lung function over 10 years (70). The mortality related to fine particulate matter decreased over the last decade (71).

Air pollution has been linked to different noninfectious pulmonary diseases (5). The London COPD Cohort recorded and categorized COPD exacerbations for 20 years. An association was reported between elevated ambient nitrogen oxides and increased risk of subsequent viral-type exacerbations (72). Moreover, these exacerbations lasted longer.

Clinical Manifestations

Definition of Disease

A study of more than 9,000 subjects showed that the use of reference equations from the Global Lung Initiative 12 (that include persons 80–95 yr old) instead of the third National Health and Nutrition Examination Survey equations reclassified over 3% of subjects (mostly older individuals) as no longer having obstruction, which was defined as the FEV₁/FVC ratio of below the lower limit of normal (73). The overall agreement between the two sets of reference equations was quite strong, however. It is a reminder of the ease of using a fixed cutoff. The cutoff of the FEV₁/FVC ratio of less than 0.70 was superior in predicting future COPD-related hospitalizations and deaths to other fixed ratios or the lower limit of normal (whether by the third National Health and Nutrition Examination Survey or the Global Lung Initiative 12) (74).

Spirometric Subtypes

COPDGene participants with a bronchodilator responsiveness in both FEV₁ and FVC were found to have less extensive baseline emphysema, more frequent exacerbations, and reduced mortality over 5 years (75). These patients are at high risk of exacerbations and may benefit from a more in-depth study. Another COPDGene study looked at bronchodilator responsiveness (76). A potential caveat was that the study broadened the American Thoracic Society definition to include those with less pronounced increases in FEV₁ or FVC (greater than 9% or 90 ml instead of, respectively, 12% and 200 ml). They found that a bronchodilator responsiveness of FEV₁ was associated with an improved 6-minute-walk distance, fewer symptoms, and fewer exacerbations. A responsive FVC was associated with more symptoms but fewer exacerbations (76). Both COPDGene studies highlight the importance of the particularities of bronchodilator responsiveness, both the metric and criteria.

A new measure of heterogeneity in expiratory airflow, termed the “peak index,” was proposed (77). It normalizes the number of peaks in the forced expiratory flow loop to the total volume exhaled after peak expiratory flow is reached. There were higher values in more severe stages of COPD. After adjusting for baseline FEV₁, this measure was associated with a 4% faster decline in FEV₁ over 5 years.

Imaging

Two imaging-based measures of emphysema and small airway disease (disease probability measure and parametric response mapping), both using inspiratory and expiratory CT scans, were found to have a great agreement with each other (78). These measures were further validated against oscillometry, revealing associations of small airway disease on CT, with peripheral airway resistance and reactance, and of emphysema with acinar heterogeneity.

Asthma–COPD Overlap

The prevalence of asthma–COPD overlap was assessed in a primary care setting in the United Kingdom in patients with the age of 40 years or older, positive smoking history, post-bronchodilator FEV₁/FVC of less than 0.7, and bronchodilator responsiveness by the American Thoracic Society criteria (79). The study found that 33% of those with diagnosis codes for both asthma and COPD had true asthma–COPD overlap, as did 20% of patients with codes for either asthma or COPD or both.

Comorbid Conditions

Cardiovascular comorbidities are common in COPD. In parallel with assessing the prevalence of coexisting conditions, direct functional interactions between the lungs and the heart has been attracting increasing interest. Elevated right heart load as well as reduced right heart size, known as cor pulmonale parvus (80), are both described in COPD. Using 3,506 CT scans from COPDGene, Washko and colleagues (81) described complex relations between emphysema and the right ventricular epicardial volume (RVev). It was shown that the epicardial RVev volume (i.e., chamber + myocardium) was 10% smaller in patients with airflow limitation of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 versus patients with GOLD stage 1. After a multivariable adjustment that also included spirometry indices, patients with more extensive emphysema exhibited a trend toward having a larger RVev volume. This, in turn, was associated with a reduced 6-minute-walk distance. For a given extent of emphysema, associations were shown between the preservation of the distal pulmonary arterial blood vessel volume and RVev volume, with the loss of preservation being associated with increased RVev volume. It was concluded that pulmonary arterial pruning is associated with clinically meaningful increases in RVev volume and relates to exercise capacity and mortality in COPD. Limitations of the study, including the lack of right heart catheterization and the use of noncardiac gated CT image acquisition, have been discussed elsewhere (82).

Apart from the right heart alterations, the left heart involvement has also been documented in COPD. In particular, the occurrence of a decreased left heart size has been described in hyperinflation (83) and emphysema (84), with beneficial effects of lung deflation therapy on chamber size and function (85, 86). Using data from the CLAIM (The Combination of a Long-Acting β₂ Agonist and Long-ActIng Muscarinic Antagonist) study, Vogel-Claussen and colleagues (87) showed an association with an improved pulmonary microvascular blood flow and regional ventilation in patients with COPD and hyperinflation (87, 88).

Several studies showed beneficial effects of β-blocker therapy in patients with both cardiovascular disease and COPD. Observational studies suggested a potential risk reduction of exacerbations and death in COPD. Therefore, the prospective randomized BLOCK (The Beta-Blockers for the Prevention of Acute Exacerbations of) COPD trial has been conducted to investigate the effect of metoprolol on the risk of COPD (89). Notably, the trial had to be stopped early because of not reaching the primary endpoint and for safety concerns. In patients with moderate to severe COPD without established indication for β-blocker use, the time until the first exacerbation was comparable between both study arms.

In patients with COPD and post-traumatic stress disorder, the prescription of benzodiazepines over the short term (less than 90 days) or long term was associated with increased risk of suicide, whereas only short-term use was associated with an overall increased risk of death (90). Predictors of long-term benzodiazepine prescription in this population comprised the lower rates of patient-reported access to mental health care at the center and comorbid generalized anxiety disorder (91). Another study looked at opioid and benzodiazepine use in older patients with COPD, finding that the use of either, or both, classes of medications was associated with more frequent respiratory hospitalizations (92). Careful consideration when prescribing these medications in COPD is warranted, particularly in the presence of other psychiatric comorbidities.

Frailty was also identified as an important factor, which across all severities of COPD, was associated with increased hospitalization, longer duration of stay, and increased mortality (93).

Sex Differences

A study of nearly 50,000 hospitalizations for COPD exacerbation at Veterans Health Administration facilities found that female veterans had higher rates of asthma, drug use, post-traumatic stress disorder, major depression, and bipolar disease (94). The risk factors for readmission included age, comorbid disease, and drug and alcohol use but not sex.

Course of Disease and Lung Function Decline

Apart from cigarette smoking, reasons for variations in COPD progression and lung function decline, covering a broad spectrum of severity, are largely unknown. Using the data from the CARDIA (Coronary Artery Risk Development in Young Adults) Lung Study, lifetime smoking trajectories were associated with the lung function decline and odds of future lung disease (95). Heavy smokers showed the greatest decline in FEV₁ (−42.1 ml/yr) and, in comparison with never-smokers, several times higher odds of obstructive disease and emphysema, with the latter assessed by CT. Smoking cessation led to lower FEV₁ decline (difference of 1.9 ml/yr) and decreased emphysema odds than those in low-rate smokers, despite more lifetime pack-years (9.8 vs. 6.4 pack-years) in those who quit. A logical conclusion was that a safe threshold for smoking intensity does not exist, such that even low-rate smokers exhibit elevated risk for future respiratory disorders. Thus, ongoing smoking, even at low doses, is still the driver of the disease.

An analysis of six U.S. population-based cohort studies (96) revealed an association of albuminuria with faster lung function decline and higher incidence of spirometry-diagnosed COPD and COPD events. This was independent of common risk factors for endothelial dysfunction, such as hypertension, diabetes, or smoking, suggesting endothelial and microvascular mechanisms. Whether these findings hint toward therapeutic targets remains to be shown (97).

Therapy

Inhaled Therapies

The SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD) study found that in nearly half of patients with COPD, inhaled therapy practice departed from the GOLD guideline–based recommendations, most frequently in the overuse of inhaled corticosteroids (mild disease) or the underuse of long-acting bronchodilators (severe disease) (98).

In a real-world study, using administrative data to look at obstructive lung disease hospitalizations, inhaled corticosteroids were found beneficial in reducing hospitalizations both in asthma and COPD with asthma features (99). However, in patients with COPD without asthma features, there was a small but significant risk of hospitalization and a borderline heightened risk of pneumonia (99).

Inhaler technique is not to be underestimated. In one evaluation, nearly half of patients were found to use inhalers incorrectly (100).

Denervation of Cholinergic Nerves

Targeting the airway parasympathetic nervous system has been one of the cornerstones of COPD treatment (101). Drugs like ipratropium, tiotropium, and others have been developed for inhaled application. Departing from that, Slebos and colleagues (102), in a randomized controlled trial, employed radiofrequency ablation via bronchoscopy to denervate the major airways of their vagal afferents and parasympathetic efferents. The primary endpoint, being the rate of respiratory adverse events between 3 and 6.5 months after randomization, was reached. The exacerbation rate in the intervention group was significantly reduced. During the 12.5-month follow-up, there were no safety concerns. A follow-up randomized controlled trial is underway.

Reduction of Hyperinflation and Perfusion/Ventilation

Although interactions between the lungs and heart in COPD are presumed to be of pivotal importance, they are not well understood (88). Recently, two studies showed that lung deflation, induced by one or two long-acting bronchodilators, improves cardiac filling and output (85, 86). In the CLAIM study, not only the consequences for the heart but also regional perfusion and ventilation, could be analyzed by functional lung magnetic resonance imaging. The study by Vogel-Claussen and colleagues (87) suggests that the observed cardiac effects are the consequence of an improvement of pulmonary perfusion and the ventilation–perfusion mismatch. Thus, these data lead to a better understanding of heart and lung interactions. We still need longer-term data from multicenter studies in less selected patients.

Muscle Wasting

Muscle wasting in COPD is associated with increased morbidity and mortality (103). So far, we mostly have rehabilitation to address this condition. In a multicenter, phase 2a, randomized, double-blind, placebo-controlled trial, Polkey and colleagues (104) tested a novel approach, evaluating the effects of bimagrumab on elevating skeletal muscle mass in patients with COPD with low body mass index. Bimagrumab is an activin type II receptor blocker that interferes with myostatin and other negative regulators of muscle mass (104). The primary outcome was an increase in thigh muscle volume, which was measured by magnetic resonance imaging at 8 weeks. In the intervention group, there was a significant improvement of the primary outcome, with the maximal effect at week 16. The secondary parameters, comprising functional improvement (i.e., 6-min-walk distance, hand grip strength, or leg press), also showed significant changes. There were no major adverse events. A larger trial is warranted that focuses on functional parameters, with a study design combining bimagrumab with rehabilitation.

Azithromycin during Acute Exacerbations

Macrolide antibiotics, added to inhaled medication, have been used successfully to prevent COPD exacerbations (105, 106). In this first-ever randomized controlled trial, the treatment with the macrolide azithromycin was initiated in exacerbated patients during hospitalization (107). After 3 days of loading azithromycin at 500 mg daily, administered on top of the usual therapy of antibiotics and oral corticosteroids, the treatment with the macrolide was continued every 2 days with a lower dose of 250 mg orally for a total of 3 months. The primary outcome was the time to the first event of treatment failure, defined as the composite measure of treatment intensification with systemic corticosteroids and/or antibiotics, step-up in hospital care, or readmission for respiratory reasons or all-cause mortality. The treatment failure rate tended to be lower in the azithromycin group. Several secondary endpoints (treatment intensification with corticosteroids and antibiotics or a step-up in hospital care) suggested a benefit of the macrolide treatment. Interestingly, the effects seemed to weaken after the cessation of treatment. In the context of long-term treatment with macrolide antibiotics, there are several safety concerns, ranging from the risk for arrhythmias to the development of macrolide resistance. Therefore, this intervention can only be considered in patients with maximal inhaled treatment who are still at high risk of exacerbations. Subsequent studies need to identify the predictors of positive outcome, the time to start the macrolide, and how long to treat patients (108).