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Implications of the inflammatory response for the identification of biomarkers of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by both local and systemic inflammation. Because inflammation plays a critical role in the development, course and severity of COPD, inflammatory markers have the potential to improve the current diagnostic and prognostic approaches. Local inflammation in COPD is characterized by an infiltration of inflammatory cells, with an increased expression of cytokines, chemokines, enzymes, growth factors and adhesion molecules. Systemic low-grade inflammation is another common but nonspecific finding in COPD. Exacerbations of COPD are acute clinical events accompanied by an exaggerated inflammatory response. Future investigations in the field of COPD biomarkers should take into account different study designs and biochemical assays, disease course and duration, variations in symptom severity and timing of measurement. First draft submitted: 23 June 2015; Accepted for publication: 24 August 2015; Published online: 14 January 2016 Keywords: biomarkers • chronic obstructive pulmonary disease • exacerbations • inflammation

Chronic obstructive pulmonary disease (COPD) is a complex multifactorial disorder resulting from the interplay of multiple risk factors, among which tobacco smoke is considered the most common culprit. COPD is thought to represent the result of an exaggerated local inflammatory response to ongoing tissue injury caused by inhaled particles [1] , which may influence both disease course and symptom severity. In addition, systemic lowgrade inflammation − defined by a significant increase in circulating levels of cytokines and acute phase proteins − is another common but nonspecific finding in COPD [2,3] . Research in COPD-associated systemic inflammation has recently gained momentum because of its association with different comorbid conditions, including the increased risk of cardiovascular disorders commonly observed in this patient group [4] . Finally, exacerbations of COPD are acute clinical events characterized by a worsening of the patient’s respiratory

10.2217/bmm.15.87 © 2016 Future Medicine Ltd

Jose Luis Lopez-Campos*,1,2, Carmen Calero-Acuña1,2, Cecilia Lopez-Ramirez1, María Abad-Arranz1, Eduardo Márquez-Martín1, Francisco Ortega-Ruiz1,2 & Elena Arellano1 1 Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/ Universidad de Sevilla, Seville, Spain 2 CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain *Author for correspondence: Tel.:/Fax: +34 955 013 166 lcampos@ separ.es

symptoms accompanied by an exaggerated inflammatory response that may influence both the type and severity of clinical manifestations. Accordingly, COPD is associated with both local and systemic inflammation, and its exacerbations are mainly considered as inflammatory events. All of these inflammatory processes may modify the mechanics of the lung, ultimately resulting in chronic airflow obstruction and hyperinflation [5] . In turn, mechanical forces can have an impact on certain aspects of COPD pathogenesis [6] . Although inflammation is a core feature of COPD, the exact mechanisms involved and the roles of the different inflammatory components are far less clear. A more detailed characterization of the full repertoire of inflammatory responses in COPD may pave the way for a more in-depth understanding of disease pathogenesis. Unfortunately, the considerable number of inflammatory mediators and their complex interrelationships has pre-

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Review  Lopez-Campos, Calero-Acuña, Lopez-Ramirez et al. vented the development of a simple ­pathogenic model. The aim of the present narrative review is to summarize the current information about local and systemic inflammation in COPD, as well as the role of different inflammatory mediators during COPD exacerbations. Our overall goal is to provide an updated overview of the main characteristics of COPD-related inflammation and highlight future research directions in the field. An increased interest in the complex network of inflammatory molecules involved in COPD will hopefully identify reliable biomarkers that can be used for both disease diagnostics and prognostication. Local inflammation in COPD Figure 1 depicts the traditional age-dependent time course of lung inflammation in subjects with and without COPD. In subjects without COPD, the inflammatory response varies throughout life being influenced by infections and the aging process while remaining within a normal range [1] . A more pronounced local inflammatory environment can be observed in patients with COPD, driven primarily by exposure to tobacco smoke and secondarily by respiratory infections. The initial inflammatory response elicited in the respiratory epithelium by smoke and chronically maintained by continuing exposure is considered the main risk factor for the development of COPD and may induce long-term pathological changes that will eventually lead to disease onset [7] . A discussion on the factors whereby some smokers do not ultimately develop COPD is outside the scope of the present review [8] . However, current evidence indicates that different aspects of the inflammatory response are dysregulated in COPD, ultimately leading to an increased inflammatory load [9] . The main characteristics of COPDrelated inflammation are summarized below. Lung inflammation in COPD is a complex process

Local inflammation in COPD is a complex process characterized by an infiltration of inflammatory cells in the airways, accompanied by an increased expression of cytokines, chemokines, enzymes, growth factors and adhesion molecules [5] . Local inflammatory reactions in COPD involve a number of different cell types, including macrophages, neutrophils, eosinophils, mastocytes, epithelial cells, endothelial cells, dendritic cells, lymphocytes, fibroblasts and pneumocytes  [9–13] . Moreover, local inflammation is closely intertwined with altered cell signaling [5] , increased oxidative stress [14] , protease-antiprotease imbalance  [15] and induction of apoptosis [16] . In addition, growing evidence suggests that local inflammation in COPD may be modulated by genetic factors and

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epigenetic mechanisms [17,18] , the airway microbiota – including the presence of traditional and opportunistic pathogens and dysbiosis – [19–21] , age [22,23] , autoimmune reactions [24] and local hypoxia leading to epithelial–mesenchymal transition (a process by which epithelial cells are converted to a mesenchymal phenotype)  [25] . All of these factors engage in a complex interplay, variously influencing the extent of tissue damage and the clinical expression of COPD. For example, some cases of COPD are characterized by the presence of eosinophilic inflammation (previously considered to be a characteristic feature of asthma), which seems to predict corticosteroid responsiveness during clinical stability and exacerbations [11] . Lung inflammation in COPD is heterogeneous Local inflammation in COPD is typically heterogeneous, being characterized by a wide range of different inflammatory responses. The high degree of heterogeneity in the inflammatory response has been reported in several studies [26,27] and has also been related to clinical expression of the disease. In a small-sized study performed in the Netherlands [28] , the authors studied 18 nonatopic subjects with COPD who underwent sputum induction, bronchoscopy, bronchoalveolar lavage (BAL) and biopsies. The authors identified a significant variability in the inflammatory load, with the neutrophil count in the sputum ranging from 30 to nearly 100%. Moreover, the lymphocyte and eosinophil counts ranged from below 10 to 60% and from 0 to over 80%, respectively [28] . Another study conducted in a sample of 20 Italian nonatopic patients with COPD (either with or without reversible airflow limitation) reported a significant variation in sputum cell counts after a bronchodilator test [29] . Similar variations have been reported for levels of circulating cytokines [30] . Lung inflammation in COPD is compartmentalized

An intriguing characteristic of local inflammation in COPD lies in its compartmentalization. In the lung parenchyma, the inflammatory response is driven by apoptosis as well as an imbalance between elastases and their inhibitors. Conversely, airway inflammation is dominated by thickening of the bronchial wall and fibrosis. Additionally, an increased wall area of small pulmonary vessels driven by intimal thickening and accompanied by adventitial infiltration of CD8 T lymphocytes has been reported in COPD [31,32] . The compartmentalization of COPD inflammation has implications for biomarker discovery [30] , with the results of studies measuring inflammatory biomark-

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Implications of the inflammatory response for the identification of biomarkers of chronic obstructive pulmonary disease 

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Death 2 Infections

Level of inflammation

(d) Level to trigger exacerbation of COPD

(c) Level to trigger COPD

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infections

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Childhood

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Age Figure 1. Purported relations between age, smoke exposure, infections and levels of inflammation in subjects with (red curve) and without COPD (blue curve). Reproduced with permission from [1] .

ers in distinct anatomical compartments not being directly comparable [33] . Therefore, the implications of different cells and biological pathways for biomarker discovery should be interpreted in the context of the compartment being studied (i.e., the upper airway, the main bronchial airway, the small airway, the lung parenchyma and the lung vasculature). Lung inflammation in COPD is associated with different clinical phenotypes

Local inflammatory reactions in COPD result in a wide range of clinical phenotypes with different prognosis and outcomes. Although the relationships between biomarkers of local inflammation and the phenotypic heterogeneity of COPD remain unclear, recent studies have explored the heterogeneity of the inflammatory reactions in relation to specific clinical phenotypes. However, the results of these studies warrant independent confirmation because of the clinical heterogeneity of COPD and the compartmentalization of the inflammatory response [30] . In this scenario, the following three examples are especially illustra-

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tive. The first consists of chronic bronchitis. The core features of COPD patients with chronic bronchitis include persistent sputum production, peculiar clinical features and a distinct profile of airway inflammation. A recent study evaluated sputum cells and mediators in 26 COPD patients who persistently produced sputum as compared with 26 nonpersistent sputum producers  [34] . Persistent sputum producers were characterized by increased sputum neutrophil and eosinophil total cell counts, as well as elevated sputum levels of eotaxin, monocyte chemoattractant protein-1, TNF-α and IL-6, suggesting the presence of a specific inflammatory signature. The presence of airway eosinophilia has also been considered as a distinct phenotype of COPD which is stable over time [26] . Notably, COPD patients who have evidence of eosinophilic inflammation are responsive to specific treatments, including corticosteroids [11,29,35] . In a proof-of-concept trial, Siva and co-workers demonstrated the clinical usefulness of a treatment strategy guided by the number of blood eosinophils  [36] , a finding that was successfully replicated by independent research groups [37,38] . Another

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Review  Lopez-Campos, Calero-Acuña, Lopez-Ramirez et al. distinct phenotype is the association of emphysema and lung fibrosis, an entity that differs from either emphysema or pulmonary fibrosis alone in both biological and clinical terms [39] . It has been suggested that epigenetic mechanisms through which Smad3 regulates matrix metalloproteinase 9 transcription may explain the concomitant occurrence of both conditions [40] . Lung inflammation in COPD is associated with disease severity

Evidence suggests that the extent of bronchial inflammation is associated with disease severity. The progressive airflow limitation in COPD is caused by two main processes, in other words, remodeling of small airways and destruction of the lung parenchyma as a consequence of emphysema [5] . These pathologic changes are caused by chronic inflammation in peripheral sections of the lung, which increases as the disease progresses. In their seminal study, Hogg et al.  [10] demonstrated that the percentage of the airways that contained inflammatory cells increased significantly as COPD progressed. The two pathological components seem to be independent of each other. Moreover, it has been suggested that the pathological process may develop in the airway before the onset of emphysema [41] . Accordingly, a novel grading system for obstructive lung disease based on the results of lung scintigraphy has been recently proposed [42] . Lung inflammation in COPD is more pronounced than in non-COPD smokers

Local inflammation in COPD is driven by an enhanced or abnormal response to inhaled particles or gases (mainly tobacco smoke). Although a similar pattern of inflammation can be observed in smokers without COPD, COPD inflammation seems to be more pronounced and further increases during acute exacerbations [5,9] . The molecular mechanisms underlying the exaggerated inflammatory response in COPD have not been completely elucidated. Exposure to tobacco in COPD is associated with an impaired ability of macrophages to clear respiratory pathogens and apoptotic cells. The number of macrophages in COPD airways is increased but the occurrence of a persistent colonization suggests that bacterial clearance by phagocytosis is defective in COPD [43] . This would ultimately result in an abnormal bacterial colonization and a self-perpetuating cycle of inflammation. Moreover, an aberrant neutrophil migration in COPD has been shown to promote tissue damage as a result of excess proteinase release [44] . An abnormal regulatory T cell response to tobacco smoke and increased Th1 and Th17 cell responses have been also reported in COPD [45] . Altogether, the current

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evidence indicates that COPD is characterized by a multifaceted dysregulation of the inflammatory response, whose net effect is an enhancement of the ­inflammatory load. Lung inflammation in COPD persists after smoking

Research on the potential persistence of local inflammation even after smoking cessation is currently gaining momentum. The effects of smoking cessation on local inflammation in COPD remain controversial. On one hand, there is evidence indicating that the inflammatory process is not halted by tobacco quitting. In this regard, Rutgers and co-workers evaluated 18 nonatopic subjects with COPD who underwent sputum induction and bronchoscopy with BAL and biopsies. The results demonstrated that subjects with COPD who did not currently smoke had an increased numbers of inflammatory cells [28] . Similarly, Gamble and co-workers compared bronchial biopsy inflammatory cell counts in 101 current and former smokers with COPD. No significant differences between current and former smokers were identified in the number of any inflammatory cell type or marker [46] . On the other hand, Li and co-workers used a rat model to evaluate the most appropriate time for smoking cessation. The main findings indicated that smoking cessation at an earlier stage effectively reduced the inflammatory reaction in COPD [47] , suggesting the potential utility of quitting smoking in the early phase of COPD. Similarly, the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study was designed to evaluate the BAL and the induced sputum in 114 current and former smokers with COPD. Although no significant intergroup differences in proinflammatory and anti-inflammatory mediators in BAL and sputum were identified [48] , former smokers with COPD had a higher percentage but a lower number of CD163 + macrophages in the lavage than current smokers. These results suggest that smoking cessation may partially shift the macrophage toward an anti-inflammatory phenotype, which was not accompanied by a decrease in inflammatory parameters. Finally, Wen and co-workers studied 17 smokers and 17 former smokers with COPD and assessed the inflammatory response in different compartments (i.e., sputum, BAL and airway wall biopsies) [49] . The authors found significant compartmentrelated differences in cell type distribution, suggesting that the impact of smoking may be dependent on the anatomical site. Moreover, airway inflammation seems to persist in former smokers with COPD, potentially reflecting subtle changes in the expression of different inflammatory mediators.

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Implications of the inflammatory response for the identification of biomarkers of chronic obstructive pulmonary disease 

Lung inflammation in COPD is resistant to corticosteroids

Controversy still exists on the potential steroid resistance of the local inflammatory response in COPD. Evidence indicates that corticosteroids are not effective in suppressing inflammatory markers in COPD [50,51] . Because this phenomenon may be under epigenetic control through the inactivation of histone deacetylase 2 [52,53] , its occurrence in COPD macrophages is potentially reversible through the use of theophylline [54] . However, the following two observations are noteworthy: although airway histone deacetylase 2 expression is increased by smoking, it was found to be reduced in COPD, and despite a normalized expression of histone deacetylase 2 in former smokers, inhaled steroids did not exert significant effects [53] . Although there is no definite evidence that theophylline may improve the clinical usefulness of inhaled steroids in COPD, the possibility that such a strategy could be useful for a specific subset of patients cannot be excluded [55] . Recent evidence has also supported the potential role of roflumilast N-oxide, a phosphodiesterase 4 inhibitor, for reversing corticosteroid resistance in neutrophils from patients with COPD [56] . Although the potential mechanisms underlying this observation remain unclear, future studies of roflumilast N-oxide in combination with inhaled steroids for COPD patients are warranted. Another noteworthy exception is the eosinophilic-predominant COPD inflammatory subtype, which is corticosteroid-­responsive as ­previously discussed [11,35] . Systemic inflammation in COPD

Initial reports of systemic low-grade inflammation − defined by a significant increase in circulating levels of cytokines and acute phase proteins – in COPD patients dates back from the late nineties [57] . The study of systemic inflammation in COPD has received a great deal of attention in recent years and the main characteristics of this systemic inflammatory response are summarized below. Systemic inflammation in COPD is characterized by mild elevations of different inflammatory mediators Systemic inflammation in COPD is characterized by chronic mild elevations of different inflammatory mediators. In their seminal study, Pinto-Plata et al. [58] reported that serum C-reactive protein (CRP) levels were significantly higher in patients with COPD (5.03 mg/l) than in smokers and former smokers without COPD (2.02 mg/l and 2.24 mg/l, respectively). Starting from the premise that CRP can show an increase of up to 1000-fold after an acute injury [59] , it is evi-

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dent that its elevation in COPD should be considered as mild. This mild increment has also been reported for different types of biomarkers, including chemoattractants, different cytokines and destruction and repair markers [3] . In the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, the differences in serum concentration between COPD patients and smoker controls were 3.2 versus 1.6 mg/l for CRP, 1.5 versus 0.6 pg/ ml for IL-6 or 448 versus 391 mg/dl for fibrinogen, respectively  [60] . Another study quantified the difference in the concentrations of different biomarkers. The results indicated that the standardized mean difference between COPD and control subjects was 0.53 units (95% CI: 0.34–0.72) for CRP, 0.47 units (95% CI: 0.29–0.65) for fibrinogen, 0.44 units (95% CI: 0.20–0.67) for circulating leucocytes and 0.59 units (95% CI: 0.29–0.89) for TNF-α [61] . Systemic inflammation in COPD is heterogeneous

The systemic increase in biomarkers may represent a nonspecific pathway of sustained inflammation, potentially involving different biological pathways [3] . To date, levels of several different molecules have been found to be altered in COPD, including acute phase reactants, chemo-attractants, different inflammatory cytokines, destruction and repair markers, hormones, vitamins, adipokines, surfactant proteins and tissue turnover markers [3,62–64] . The role of all these different biomarkers and their relations with COPD clinical presentation and its different systemic manifestations is currently under scrutiny. Notably, biomarkers of inflammation are characterized by a skewed distribution and show a considerable analytical variability [58] . Moreover, not all inflammatory markers are uniformly elevated in COPD patients, with some subjects showing selective increases only in certain biomarkers [2] . This contributes to the heterogeneity of systemic inflammation in COPD. An important observation is that biomarkers of inflammation do not generally increase in isolation, but are associated with each other within specific networks. In this scenario, proteomics and systems biology have contributed significantly to the identification of complex biomarker signatures. The ECLIPSE study quantified six inflammatory biomarkers in peripheral blood (white blood cells count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) in 1755 patients with COPD, 297 smokers with normal spirometry results and 202 nonsmoking controls [60] . The authors illustrated a network layout of the systemic inflammatory patterns in the three groups of participants. The results indicated that the network was enhanced in patients

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WBC

TNF-α

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COPD (n = 1755) 36% current smokers

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5%

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6%

24%++

18%++

30%++

19%*

*p < 0.001 vs non-smokers

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+p < 0.05; ++p < 0.001 vs smokers

Figure 2. Network layout of the systemic inflammatory response (inflammome) in nonsmokers, smokers with normal lung function, and COPD patients at recruitment. Each node of the network corresponds to one of the six inflammatory biomarkers determined in this study (see color code). The size is proportional to the prevalence of abnormal values (95th percentile of nonsmokers) for each particular biomarker in each study group (precise value reported inside of each node). Two nodes were considered linked if >1% of subjects in the network shared abnormal values of the two biomarkers (being the width proportional to the strength of the association). Reproduced under the Creative Commons Attribution (CC-BY) license from Agusti et al. [60] .

with COPD, with specific patterns of increased (white blood cells count, CRP, IL-6 and fibrinogen) and decreased (IL-8, TNF-α) levels of specific molecules (Figure 2) . These data suggest that a biological network model can be useful for obtaining a comprehensive depiction of the biological processes involved in COPD at the systemic level. Accordingly, it has been reported that a biological network construction can be a useful means for shedding light on lung pathobiology [65] . Systemic inflammation in COPD persists over time

A distinctive feature of systemic low-grade inflammation in COPD is its persistence over time. The participants of the ECLIPSE study followed up over a period of one year to investigate the changes in serum levels of six inflammatory biomarkers under study (white blood cell count, CRP, IL-6, IL-8, fibrinogen and TNF-α). More than half of patients with an increase of two or more inflammatory markers at baseline showed a persistent elevation at the end of the study [60] . More recently, a 3-year prospective study conducted in 53 outpa-

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tients with stable COPD investigated the longitudinal changes in serum CRP and IL-6 levels [66] . Although IL-6 increased significantly over time, no longitudinal changes in mean CRP values were detected. In any case, evidence of a fairly stable systemic inflammatory load in COPD should be interpreted cautiously because of its considerable interindividual variability. Other caveats inherent in the available studies include the lack of multiple serial measurements of serum biomarkers during the follow-up period, the absence of a patientbased analysis and the confounding effect of multiple factors that can easily influence serum levels of acute phase reactants. Many of the studied biomarkers are part of the acute phase reactants superfamily. Serum concentrations of acute phase reactants can be specifically altered by a number of different injuries. Consequently, the availability of only two different measures over time does not rule out a recent exposure to a potential inflammatory stimulus before the analytical determination. In this regard, it would be paramount to distinguish between persistent systemic inflammation and coincident systemic inflammation due to

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Implications of the inflammatory response for the identification of biomarkers of chronic obstructive pulmonary disease 

causes rather than COPD. To rule out transient nonspecific increases in inflammatory markers unrelated to COPD, repeated measures should be performed over a predetermined time and different comorbidities should be taken into account. Systemic inflammation in COPD is related to comorbidities

The presence of systemic inflammation in COPD has been related to its extra-pulmonary manifestations [67] , the most relevant association being with cardiovascular diseases. This association is remarkably reciprocal and should not be solely ascribed to the fact that these are highly prevalent diseases that share common risk factors  [68] . One major link between between COPD and cardiovascular diseases is the deleterious effect of hypoxemia  [69] . A second mechanism is the presence of lung hyperinflation and its impact on cardiovascular function [70] . Additionally, systemic inflammation has shown to accelerate atherosclerosis and consequently increase the risk of adverse cardiovascular events  [71] . Other comorbidities associated with systemic inflammation include – but are not limited to – lung cancer [72] , depression [73] , peripheral muscle impairment  [74] , metabolic syndrome [75] , nutritional abnormalities [76] and osteoporosis [77] . Systemic inflammation in COPD is related to clinical outcomes Systemic inflammation in COPD has been related to both clinical presentation and prognosis [78–80] . The association of systemic inflammatory biomarkers and the main clinical features of COPD has been studied in relation to prognosis [60] , lung function decline [81] , hospital admissions [82] and treatment response [37] . Notably, the inclusion of specific biomarkers of inflammation into the multidimensional evaluation of COPD has been proposed [83,84] . For example, a recent study by Stolz and co-workers demonstrated a significant association of proadrenomedullin with 1-year mortality, which was further improved when the inflammatory marker was combined with the BODE score [83] . Fibrinogen has also been described as a novel marker associated with clinical outcomes. A very recent study examined pooled data from five studies into a common database resulting in 6376 individuals with COPD. These authors found that fibrinogen levels ≥350 mg/dl identified patients at an increased risk of exacerbations and death in the next year, suggesting fibrinogen as a potential useful biomarker for COPD evaluation [85] . Interest in the identification of novel inflammatory prognostic biomarkers of COPD is generally mounting, with the ultimate goal of providing tailored ­therapeutic approaches  [86] .

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Systemic inflammation in COPD needs to be consistently evaluated from an analytical standpoint

An accurate assessment of systemic inflammation in COPD is heavily dependent on the analytical approach. Our group recently determined serum CRP and serum amyloid A (SAA) concentrations as measured by ELISA and nephelometry in 88 patients with COPD and 45 control subjects, with the overall goal of comparing the performances of the two methods in a clinical setting. We found a moderate correlation between values measured by ELISA and those assessed by nephelometry (CRP: r = 0.55, p < 0.001; SAA: r = 0.40, p < 0.001). However, the concentrations determined by nephelometry were significantly higher than those obtained with ELISA for both CRP (mean difference = 2.7 [9.4] mg/l) and SAA (mean difference = 0.31 [14.3] mg/l) [87] . Future studies in the field of systemic inflammation in COPD should address two important unresolved issues related to the analytical variability and the exact source of inflammatory biomarkers. Appropriate sample handling coupled with standardization and harmonization of the biochemical assays is paramount for obtaining reliable and ­reproducible results. Systemic inflammation in COPD has an unknown origin One relevant unresolved issue is related to the origin of systemic inflammation in COPD. The liver has been traditionally considered as their main source of inflammatory molecules. Because the lung itself is capable of synthesizing proinflammatory molecules [33] , it has been also hypothesized that such molecules could be released from lung tissues into the systemic circulation  [88] . However, no significant associations have been identified between airway and systemic concentrations of proinflammatory cytokines [89] . Similarly, the inflammatory loads of induced sputum and plasma were not correlated to each other, putting the ‘leakage hypothesis’ of systemic inflammation into question. Further studies are thus warranted to identify the potential systemic sources of proinflammatory ­molecules in COPD patients. Biomarkers as predictors of exacerbation outcomes

Exacerbations of COPD are acute clinical events characterized by a worsening of the patient’s respiratory symptoms accompanied by an exaggerated inflammatory response. Although the exact causes of such inflammatory bouts remain only partly elucidated, a potential triggering effect of respiratory infections has been proposed (Figure 1) . COPD exacerbations are currently

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Review  Lopez-Campos, Calero-Acuña, Lopez-Ramirez et al. considered heterogeneous both in terms of underlying causes and clinical presentation, ultimately resulting in distinct exacerbation types [90,91] . Moreover, their severity shows a considerable degree of variation. In this scenario, a recent novel approach has been proposed to consider biomarkers of COPD ­exacerbations both in relation to their type and ­severity [92] . Biomarkers of different exacerbation types

Several studies indicate that the inflammatory mechanisms underlying the development of exacerbations in COPD show a high degree of interindividual variation. Although some controversies still exist [93] , the presence of purulent sputum during an exacerbation is generally considered as reflective of its infectious origin [94] . An increased total white cell count is another widely used marker of bacterial infections and has been identified as an independent risk factor for hospitalizations due exacerbations in the ECLIPSE observational cohort study [95] . Although the total white cell count does not seem to predict long-term prognosis after exacerbations  [96] , it can be helpful to identify their infectious origin, albeit not distinguishing between bacterial and viral infections [97] . A small-sized study by Gao et al.  [91] similarly described four inflammatory profiles (i.e., eosinophilic, neutrophilic, mixed granulocytic and paucigranulocytic) based on the predominant cell type ­identified in the sputum. Using cluster analysis of numerous serum and sputum inflammatory biomarkers, Bafadhel et al.  [90] identified four distinct exacerbation types (i.e., bacterial-predominant, viral-predominant, eosinophilpredominant and pauci-inflammatory exacerbations). Interestingly, each type of inflammatory exacerbation seems to be characterized by a specific biomarker, as follows: sputum IL-1β levels for bacterial-predominant exacerbations, blood eosinophilia for eosinophil-predominant exacerbations and serum CXCL10 concentrations for viral-predominant exacerbations. Importantly, a proof-of-concept trial conducted by the same research group demonstrated that a biomarkerdirected treatment strategy of exacerbations based on the peripheral blood eosinophil count could successfully guide their safe and successful treatment with corticosteroids  [98] . Accordingly, peripheral blood eosinophilia is the most commonly studied biomarker of eosinophilic inflammation. In their seminal study, Bafahdel  et al.  [98] used a cut-off value of 2% for peripheral eosinophil count for identifying COPD exacerbations to be treated with corticosteroids. Interestingly, the authors observed a greater improvement in biomarker-negative exacerbations treated with placebo as compared with prednisolone, indicating that

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the peripheral blood eosinophil count may serve as a promising biomarker to guide corticosteroid therapy during exacerbations. CRP has been investigated as a potential biomarker of bacterial exacerbations [99] . However, increased CRP levels may result from a variety of causes, ultimately representing a nonspecific biochemical marker of inflammation. Moreover, elevated CRP concentrations have been independently associated with viral or mixed viral/bacterial infections, but not with ­infections due to bacteria alone [100] . Procalcitonin – the prehormone of calcitonin that behaves as an acute phase reactant – has also been investigated in relation to COPD exacerbations. Serum procalcitonin levels are markedly increased in patients with acute respiratory tract infections but return within the normal range after successful antibiotic treatment [101] . Interestingly, procalcitonin-guided antimicrobial therapy can reduce antibiotic dosage and adverse effects, without compromising the final therapeutic success [102–106] . Although procalcitonin does not seem to distinguish between bacterial, viral and noninfectious causes of COPD exacerbations [107,108] , it can be superior to CRP for identifying the presence of airway infections in patients with exacerbations ­admitted to the intensive care unit [109] . Fractional exhaled nitric oxide (FeNO) − a surrogate marker of eosinophilic airway inflammation − has also been studied during COPD exacerbations [110] . Despite the wide variation in FeNO measurements, there is a trend toward its reduction at follow-up [110,111] accompanied by significant associations with viral infections and sputum eosinophils [112,113] . However, FeNo shows only weak correlations with clinical outcomes and intravenous glucocorticosteroids fail to reduce its levels during exacerbations [110,111] . Periostin − an extracellular matrix protein induced by IL-4 and IL-13 in airway epithelial cells and lung fibroblasts – is a recognized biomarker of Th2-associated airway inflammation and a potential predictor of response to inhaled corticosteroids in patients with eosinophilic infiltration of the airways [114] . Interestingly, serum periostin levels have been shown to be a strong and reliable predictor of airway eosinophilia [115] , making it an attractive biomarker for exacerbations showing an eosinophilic profile. Unfortunately, none of the studies to date have addressed this hypothesis. Biomarkers of exacerbation severity

At least, five different biomarkers have been studied in relation to severity of COPD exacerbation. Adrenomedullin – a potent vasodilator – has been shown to be expressed in bronchial epithelial cells, alveolar macrophages and the pulmonary artery wall [116,117] . Its expres-

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Implications of the inflammatory response for the identification of biomarkers of chronic obstructive pulmonary disease 

sion is induced in response to bacterial injury [118] and predicts long-term prognosis after exacerbations [119] . In the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study, adrenomedullin was identified as a predictor of long-term survival in patients with stable COPD [62,83] . An increase in proadrenomedullin plasma levels >0.84 nmol/l during exacerbations has been also associated with an increased in-hospital mortality [120] and ­admissions to intensive care units [121] . Copeptin – one of the most extensively investigated biomarkers of acute myocardial infarction [122] – have also been studied in exacerbations. One study has associated low level of copeptin (cutoff value: 40 pmol/l) with a reduced length of hospitalization and favorable short and long-term (6 months) clinical outcomes in patients presenting to the emergency department with COPD exacerbations [123] . One small study evaluating 60 patients admitted to a public teaching hospital identified a significant association between CRP concentrations and the severity of COPD exacerbations. Levels >100 mg/ml were associated with an approximately fourfold increased risk of adverse outcomes, including intubation and mechanical ventilation, transfer to the intensive care unit or death in hospital or within 30 days after discharge [124] . B-type natriuretic peptide (BNP) has also been evaluated in a study including 208 patients who presented to the emergency department with an exacerbation of COPD. BNP levels > > 100 pg/ml were significantly associated with the need of ICU care for an increase in BNP of 100 pg/ml. However, BNP levels failed to adequately predict short-term and long-term mortality rates in AECOPD patients [125] . In a more recent prospective cohort study of 99 patients admitted for exacerbations, an association between the N-terminal prohormone of brain natriuretic peptide and mortality has been reported  [126] . In addition, N-terminal probrain natriuretic peptide has been associated with the presence of ischemic heart disease during exacerbations [127] . Finally, troponin has also been evaluated as a prognostic marker during COPD exacerbations. Myocardial injury is common and clinically significant during COPD exacerbations [127] . Different studies indicate that elevated plasma troponin level is significantly associated with increased short-term mortality in COPD [128] . A recent systematic review and meta-analisis evaluated 10 studies on the prognostic role of troponin during exacerbations. The authors showed how troponin is an independent predictor of increased mortality risk [129] . Conclusion Our current understanding of the biological mechanisms underlying COPD inflammation (either during

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Review

stable disease or exacerbations) has increased significantly over the years but remains far from complete. Before focusing on the identification of novel potential inflammatory biomarkers, a more in-depth knowledge of the basic mechanisms of COPD inflammation would be required. Direct comparisons of different studies measuring inflammatory biomarkers in COPD should cautiously be performed because a number of potential confounding factors exist. Finally, inflammatory biomarkers can provide information on both type and severity of exacerbations. Future perspective Although available studies to date have been specifically focused on a restricted number of candidate biomarkers of inflammation, future research in the field should be designed with a more comprehensive, unbiased approach to uncover the largest and most significant inflammatory perturbations occurring in COPD. Identification of biomarkers capable of tracking both local and systemic inflammation in COPD can be achieved through rigorous and well-designed studies. As the field moves forward with biomarker research, we should remain mindful of the biological pathways and the anatomical sites being investigated. At the systemic level, there is now an extensive body of data showing that COPD is associated with a chronic low-grade inflammatory response, although its exact origin remains unclear. The identification of potential factors that are known sources of inflammation and their correlation with an increased risk of COPD will provide mechanistic clues to this research question. Future advances in system biology of COPD will hopefully allow identification of highly sensitive inflammatory markers as high-throughput technologies coupled with rigorous bioinformatics are ­increasingly being used. Acknowledgements The authors are thankful to Enzo Emanuele, MD, PhD (2E Science, Robbio, Italy) for his expert editorial assistance.

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Manuscript editing was funded by Centro de Investigación Biomédica en Red (CIBER), Ministry of Economy, Spain.

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Executive summary • The measurement of biomarkers in chronic obstructive pulmonary disease (COPD) should be considered within the context of the chronic inflammatory load associated with the disease. • Local inflammation in COPD is a complex process characterized by an infiltration of inflammatory cells in the airways, accompanied by an increased expression of different proinflammatory molecules. • An intriguing characteristic of local inflammation in COPD lies in its compartmentalization. • Although systemic inflammation in COPD has important clinical implications, important research gaps still exist. • Further studies are needed to identify the potential systemic sources of proinflammatory molecules in COPD patients. • Exacerbations result in spikes of inflammatory biomarkers, but the question as to whether a return to baseline levels occurs after the exacerbation is resolved remains open. • Biomarkers of COPD exacerbations need to be examined both in relation to their type and severity. innate and adaptive inflammatory immune cells that form lymphoid follicles.

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Implications of the inflammatory response for the identification of biomarkers of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterized by both local and systemic inflammation. Because inflammation plays a critical role in t...
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