COPD as a heterogeneous disease

COPD can no longer be defined as a condition that only affects the lungs, as there is increasing evidence of extra-pulmonary effects of the disease (1–4), the clinical significance of which is recognized by international guidelines for the diagnosis and treatment of COPD (5,6).

The GOLD guidelines define COPD as ‘a common preventable and treatable disease characterized by persistent airflow limitation that is usually progressive and is associated with an enhanced chronic inflammatory response in the airways and the lung to particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients’ (5). The ATS/ERS guidelines indicate that ‘although COPD affects the lungs, it also produces significant systemic consequences’ (6). The presence of a systemic inflammatory component may provide an explanation for these multiple co-morbidities of COPD that have a significant effect on the morbidity and mortality of this disease (3,4,7) and account for over 50% of the total health care costs of COPD (8).

COPD has therefore been considered a multi-component disease characterized by pulmonary and, in some cases, systemic inflammation (4,8,9). The systemic inflammatory component of COPD needs to be better defined, and there is currently an unmet medical need for therapy directed towards this aspect of COPD. An improved understanding of the inflammatory mechanisms relating to COPD will aid the development of future treatments and enable more effective management of this heterogeneous disease (1,3,9,10).

The need for biomarkers in the management of COPD

Spirometry is the recommended physiological measurement used to characterize COPD, both in the clinic and in clinical trials (5,6). However, while it can be tracked against health outcomes, it is not predictive of disease progression (with a long observation time required to measure a decline in FEV₁) (41–43). In addition, FEV₁ does not provide information on the underlying disease pathology, is relatively poorly related to patient function, is unable to distinguish between different COPD phenotypes, and therefore fails to describe the clinical and pathological heterogeneity which is known to occur in COPD (41).

Traditionally, the assessment of pharmacotherapy efficacy in COPD has relied on pulmonary end-points such as FEV₁. The development of additional efficacy assessments, potentially through the use of biomarkers, may provide a greater understanding of the systemic inflammatory processes, and will be critical in developing new therapeutic interventions to treat COPD and its co-morbidities (8,36). The ideal biomarker is one which is robust, reliable, reproducible and translatable, and which correlates with known and accepted clinical end-points, demonstrates disease specificity, and is responsive to therapeutic intervention, thus giving it utility in both the clinic and in the assessment of treatments (38,41,44,45). To date, potential biomarkers in COPD have been linked to a variety of measures including mortality, exacerbations, and computed tomography (CT) assessment of emphysema (41). However, some of the methods used to measure biomarkers require invasive sampling techniques, show poor sensitivity, and are largely focused on the pulmonary component of COPD (41,44).

This review will focus on plasma and serum biomarkers, which have seen a recent surge in interest due to increased awareness of COPD as a systemic disease. Obtaining blood samples is straightforward and, although measurement techniques can be standardized, there is an inherent variability in blood biomarkers (41,44–47). Some blood biomarkers originate in the lung and may provide disease specificity for COPD or relate to the lung components of the disease (48,49). Due to the complexity of COPD, it is likely that a panel of several markers will be required to characterize the disease state fully (50). Evolving technology is providing improved methods for analysis, enabling panels of selected markers to be analyzed, which may allow the identification of biomarker profiles that differentiate between COPD and controls, and between COPD subtypes (51). The development of high-sensitivity assay techniques will also enable lower levels of biomarkers to be detected (52).

The use of biomarkers that reflect pulmonary and systemic effects of COPD may provide a measure of disease progression—imperative for facilitating short-term proof-of-concept studies that underpin larger, later-phase studies (43,53), while also providing the potential to identify specific phenotypes and evaluate novel pharmacotherapies (38,44,45,54).

Distinguishing disease from non-disease

Serum CRP is deemed the signature biomarker of systemic inflammation and has been found to relate to levels of other inflammatory biomarkers such as IL-6, IL-8, and fibrinogen (11,61). Levels of CRP, although variable, are on average higher in patients with stable COPD compared to healthy smokers or non-smokers. There have been several associations of CRP with COPD disease characteristics and outcomes. However, the clinical utility of CRP as a predictor of COPD outcome is questionable (61). Two independent meta-analyses of cross-sectional studies investigating CRP levels in stable COPD patients versus controls presented conflicting results: one analysis showed a marked difference in the level of serum CRP between COPD patients and control subjects (13), whereas a second analysis found no statistically significant difference in CRP levels between COPD and control (62). In a population-based study, increased CRP levels were observed in stable COPD patients compared with controls (0.477 ± 0.023 versus 0.376 ± 0.041 log mg/L, P = 0.049), even after adjusting for confounding factors such as age, gender, and body mass index (BMI) (11). Variable patient selection and differences in the definition of COPD across studies is believed to contribute to the variability in CRP and other biomarker levels, and their relationship to COPD (11). Results from the Third National Health and Nutrition Examination (NHANES III) study (52,63) showed that 41% of patients with moderate COPD and 52% with severe disease had CRP levels > 3 mg/L, and 6% and 23% had CRP levels > 10 mg/L. High-sensitivity techniques for evaluating biomarkers may help to improve the ability of assays to detect lower CRP levels; an important development since increased risk of co-morbidities, such as CVD, remain at CRP levels < 3 mg/L. Broekhuizen et al. used high-sensitivity (hs)-CRP as a biomarker of impaired energy metabolism, as well as functional capacity in COPD; a median CRP level as low as 1.49 (range 0.36–4.07 mg/L) was measured in patients with stable COPD (52). Measurement of hs-CRP is already recommended for the detection and prevention of CVD in clinical practice and may, therefore, provide a more reliable biomarker for COPD given that CVD is a known co-morbidity of the disease (52).

Adiponectin, a protein specifically derived from adipose tissue, is another possible biomarker of systemic inflammation. It has a protective role against the development of atherosclerosis and insulin resistance, thereby providing a possible link between COPD and the co-morbidities, diabetes and CVD (64). Adiponectin levels have been shown to be significantly higher in stable patients with COPD than in healthy controls (15.55 ± 7.7 ng/mL versus 7.58 ± 3.2 ng/mL, P < 0.001), but did not correlate with the severity of airflow limitation, nor with other inflammatory biomarkers (64).

Matrix metalloproteinases (MMPs) and their associated tissue inhibitors of metalloproteinases (TIMP) may play an important role in COPD pathogenesis with respect to the tissue remodeling in both emphysema and small-airways disease (65). Several combinations of MMP-TIMP have been investigated, and their plasma levels have been associated with multiple COPD phenotypes (65). MMP-9 is a major elastolytic MMP and along with its inhibitor, TIMP-1, has been measured in bronchial alveolar lavage (BAL) and sputum. The level of MMP-9 alone, and its ratio with TIMP-1, correlates negatively with FEV₁ (66,67). The annual change in % predicted FEV₁ is also negatively correlated with MMP-9 (r = –0.288, P < 0.01) and CRP (r = –0.354, P < 0.005) when adjusted for age, sex, CVD, smoking history, and baseline % predicted FEV₁. Both serum CRP and MMP-9 may predict rapid decline in lung function in COPD; levels are increased significantly in ‘rapid-decliners’, and elevated MMP-9 levels have been correlated with disease progression (66,67).

B-type natriuretic peptide (BNP) is a 32-amino acid polypeptide that is released by the heart ventricles in response to cardiac stress and is a known biomarker of heart failure (68,69). BNP also plays a role in several activities of the lung, and plasma levels are augmented in patients with stable COPD without pulmonary hypertension or cor pulmonale (68,69).

Lung-derived inflammatory markers such surfactant protein (SP)-D and plasma CC chemokine (CCL-18)/pulmonary and activation-regulated chemokine (PARC) have all been measured systemically as potential COPD biomarkers, with higher levels observed in COPD patients versus controls (49,70).

Clara cell secretory protein-16 (CC-16) is another lung-derived marker which can be measured systemically and is lower in COPD patients compared with controls (48). Airway epithelial cells form a protective barrier against attack by micro-organisms, but the integrity of the epithelium may be damaged due to inflammatory-related injury caused by COPD (71). Distortion of the airway epithelium can occur due to repeated cycles of bronchoconstriction, which in turn leads to the release of growth factors and to airway remodeling, reflecting behavior similar to that observed during wound repair (71). Given its utility as a biomarker for epithelial cell dysfunction, CC-16 is an ideal candidate for use in longitudinal studies to monitor epithelial repair or to track the progression of COPD in combination with other biomarkers (48).

Markers of oxidative stress have shown limited utility as biomarkers in COPD due to the lack of correlation with disease severity and outcome. However, elevated levels of the lipid peroxidation product 8-isoprostane have been observed in plasma of patients with stable COPD compared with controls (72). Levels of plasma lipid peroxides (TBARS) are also raised in COPD and have a negative correlation with % predicted FEV₁, suggesting a link between lipid peroxidation and disease severity (72).

Biomarkers linked with disease severity

TNF-α is a marker of systemic inflammation which has been associated with COPD severity. Increased levels are observed in severe and very severe COPD (61), as well as in the presence of muscle dysfunction with moderate-intensity exercise, in COPD patients contrary to healthy controls (73). However, TNF-α levels in blood are very variable, and it does not appear to be a very reproducible marker of systemic inflammation.

High concentrations of serum fibrinogen, a systemic marker associated with coronary heart disease, have been observed in COPD, independently of the presence of CVD (11,13). Elevated levels of plasma fibrinogen are associated with reduced pulmonary function (FEV₁) as well as an increase in the rate of hospitalization due to COPD (74). Fibrinogen levels in the stable state may be predictive of an increased risk of exacerbations (39). In a longitudinal study of moderate-to-severe COPD patients, higher levels of plasma fibrinogen were observed in patients with frequent exacerbations (≥ 2.52/year) compared to those with infrequent exacerbations (39). Furthermore, high levels of fibrinogen and neutrophil counts were associated with a faster FEV₁ decline (0.40%/year and 0.097%/year, respectively, as a percentage of predicted FEV₁) (39).

CRP, IL-6, p-selectin, intercellular adhesion molecule (ICAM)-1, and membrane glycoprotein CD40L have all been associated with disease severity in some studies of COPD patients (11,75). Garcia-Rio et al. found that serum concentrations of systemic biomarkers CRP and IL-6 were the most consistent for discriminating COPD severity (11). The Framingham Heart Study showed IL-6 was consistently associated with impaired lung function; a 1-standard deviation (SD) higher concentration of IL-6 was associated with a 41 mL lower FEV₁ (95% confidence interval [CI] 61–20) and borderline 15% higher odds of COPD (odds ratio 1.15, 95% CI 0.99–1.34) (75). Elevated levels of p-selectin were seen in COPD patients compared with controls, although the increase was not statistically significant; a 1-SD higher concentration of p-selectin was associated with a 19 mL lower FEV₁ after adjusting for other biomarkers. ICAM-1 showed a correlation with FEV₁ in smokers; on average, a 34 mL lower FEV₁ was associated with a 1-SD higher level of ICAM when this was the only biomarker included in the model. CD40L, a member of the TNF-α family, showed no correlation with FEV₁, but a higher concentration of this glycoprotein indicated a greater probability of COPD in heavy smokers (75).

The levels of the inflammatory mediator osteoprotegerin (OPG) are significantly lower in patients with COPD than in patients without COPD and, together with soluble TNF receptor-1 (sTNFr-1), is related to disease severity and exacerbation frequency in the preceding 12 months (40). Decreasing levels of CC-16 show a weak correlation with COPD severity in former smokers (48). In contrast, levels of serum SP-D did not correlate with COPD severity, as assessed by the degree of airflow limitation (49).

Biomarkers associated with specific disease phenotypes

Systemic biomarkers have also been explored in relation to different subtypes or phenotypes of COPD including emphysema, airway remodeling, and exacerbations.

Cardiovascular disease

CVD is a leading cause of morbidity and mortality in COPD with outcomes from TORCH and the Lung Health Study demonstrating that over 25% of deaths are due to CVD (86). Indeed, a recent epidemiological study has documented a strong association of CVD diagnosis with COPD regardless of smoking habit, particularly among younger patients (87). Over the past decade it has become evident that systemic inflammation underlies—and may link—these two diseases (11,56).

CRP is independently associated with an increased risk of cardiovascular events including coronary artery disease, myocardial infarction (MI), and angina (4,34). In patients with COPD, elevated CRP is linked with an increased risk of a myocardial injury pattern on electrocardiogram (ECG) (11,22), with CRP levels predicting the incidence of cardiovascular events over 7 to 8 years of follow-up in the longitudinal Lung Health Study (LHS) (56). Elevated levels of cardiac troponin (cTnT) have been associated with COPD and acute exacerbations and may also be a marker of increased risk of MI in COPD (86). High levels of this biomarker appear to be related to increased mortality with an even stronger effect observed in patients with tachycardia (86). As with CRP, high-sensitivity techniques have been explored to enable the detection and measurement of lower levels of cTnT. In patients with coronary artery disease, 98% were shown to have measurable hs-cTnT levels even in the stable state (86).

A number of biomarkers, including CRP, fibrinogen, and the adhesion molecule ICAM-1, are elevated in COPD and are indicators of increased risk of atherogenesis, with some appearing to increase with disease severity (63,88). Cytokines and macrophages are key features related to the development of atheroma, and CRP is a central element of these processes. Macrophages contain CRP receptors and may be produced through monocyte differentiation during atherogenesis, while monocyte adherence to the arterial wall is facilitated by CRP (35). CRP also facilitates the production of foam cells—the building blocks of atherosclerotic plaques—and plays an important role in monocyte differentiation. The formation of these plaques increases the risk of cardiovascular events (9,35). A rise in CRP has also been associated with a rise in fibrinogen, which then increases the pro-thrombotic risk (35,63). Plasma OPG and leptin are also potential biomarkers for CVD in COPD patients. Leptin, a hormone associated with levels of body fat, may promote atherothrombosis, and thus may play a role in the pathogenesis of cardiovascular morbidity and mortality related to impaired lung function (55). Plasma OPG has been associated with the development of atherosclerosis, and initial studies have shown dysregulated OPG levels in COPD (40).

Fibrinogen is a biomarker that is linked with coronary heart disease and smoking. Pulmonary infections occurring in COPD and particularly in smokers induce elevated concentrations of fibrinogen which, in turn, are associated with reduced lung function and an increased risk of COPD, even after stratification for smoking (89).

Elevated concentrations of serum CCL-18/PARC are found in COPD patients and are linked with a higher risk of cardiovascular hospitalization and mortality (46). Levels of circulating platelet–monocyte aggregates (indicating platelet activation, a known risk factor for coronary artery disease) are elevated in stable COPD patients compared with matched controls and are further increased in patients with COPD during acute exacerbations (24). These markers may suggest a novel mechanism to explain the increased cardiovascular risk in COPD.

COPD patients are at higher risk of developing venous thromboembolism (VTE), especially during exacerbations when there is heightened hypoxia and increased systemic inflammation, which are known risk factors for hypercoagulability (90). Elevated levels of thrombin–antithrombin complex, prothrombin activation fragments 1 + 2, and IL-6 were observed in patients with COPD undergoing hypoxic challenge, and this resulted in coagulation activation and an enhanced risk of VTE (90).

Correlations between systemic inflammation and pulmonary hypertension are still tenuous, and the effects on inflammatory markers remain controversial (9,91), but recent findings show higher levels of TNFr-1 (40), TNF-α (91,92), and CRP (92) in patients with this condition. Reduced physical activity, a factor contributing to increased risk of CVD, is also a common aspect of COPD, but correlates only weakly with airway obstruction, suggesting that extra-pulmonary factors may play a more important role. Higher values of systemic inflammatory mediators and left ventricular dysfunction have been associated with reduced physical activity, with IL-6 appearing to have the greatest response to exercise, especially in patients with reduced body weight (9,93).

Cachexia and skeletal muscle abnormalities

Reduced protein turnover is the likely cause for the loss of muscle mass observed in COPD patients, while a combination of lipolysis and increases in plasma leptin levels may cause the loss of fat (9).

TNF-α plays a central role in the development of muscle abnormalities and weight loss in COPD, which do not appear to be caused by increased effort in breathing alone (35,94). Increased levels of circulating pro-inflammatory molecules, including TNF-α, are observed in conditions associated with severe emphysema, such as weight loss, muscle wasting, and cachexia; the last-mentioned resulting in an approximate 50% drop in median survival in COPD patients (35,94,95). Pseudouridine (PSU), IL-6, and sTNF receptor II (sTNF- R75) are all elevated in patients with COPD and have been associated with muscle dysfunction and weight loss, PSU being inversely related to both fat-free mass and skeletal muscle function (96). Elevated levels of CRP and TNF-α are observed in those COPD patients with a low BMI compared with those with normal-to-high BMI, thus indicating the presence of systemic inflammation. CRP and TNF-α are potential indicators of malnutrition in COPD (61).

Significant reductions in the antioxidant capacity of plasma during smoking indicate that oxidative stress affects the systemic circulation as well as the lungs (97). Data have shown that mechanisms involved in pulmonary oxidative stress may also be responsible for systemic effects relating to cachexia in COPD (97). Maximal and submaximal exercise increase IL-6 and oxidative stress in COPD patients who have muscle-wasting compared with COPD patients without muscle-wasting and healthy controls, thus supporting the concept that systemic inflammation and oxidative stress play an important role in the reduction of muscle mass in COPD (98).

Lung cancer

Smoking is the major risk factor for lung cancer. However, recent epidemiological studies have shown a higher risk of developing lung cancer in smokers with COPD than in smokers with normal lung function (99,100).

The mechanism for the link between COPD and lung cancer has not been fully elucidated, but evidence indicates oxidative stress and surfactant dysregulation may play important roles in the development of this co-morbidity (101). In the longitudinal LHS study, CRP levels predicted the incidence of cancer-specific mortality over 7 to 8 years of follow-up (56). SP-D levels in BAL fluid are inversely related to CRP levels (101) and may be another potential biomarker (also measurable in plasma) (49) that can identify smokers at risk of early lung cancer (101). Furthermore, high serum levels of IL-6 and IL-8 were associated with lung cancer, and a combination of IL-8 and CRP was better than either marker alone in predicting the development of lung cancer (102).

Potential biomarkers for other co-morbidities

High levels of CRP and TNF-α have been associated with the development of glucose intolerance and insulin resistance, thereby providing a possible link between COPD and type 2 diabetes (35).

Ageing is a mechanism that may link many of the systemic manifestations of COPD and is itself associated with low-grade systemic inflammation (11,103). Increased arterial stiffness and osteoporosis seen in COPD patients compared with age-matched controls provides evidence that premature ageing is associated with COPD (103–105). Shortened telomere length, a known marker of ageing, is present in peripheral leukocytes in COPD patients compared with smokers, independently of age, and has been negatively correlated with elevated levels of plasma cytokines and IL-6 in patients with COPD (103). A common aspect of ageing and COPD is physical impairment which can render patients unable to participate in social activities, leading to isolation and depression (36). The molecular mechanisms underlying depression in COPD are currently unknown, although there is growing evidence to support the role of systemic inflammatory mediators, IL-6 and the TNF system (36,40). In particular, sTNFr-1 has been linked to persistent inflammation observed in depressive disorders and has been independently associated with depression as well as hypertension—two known co-morbidities of COPD (40).

High concentrations of TNF-α have been linked with osteopenia, another known feature of COPD, giving rise to an increased risk of osteoporosis independent of corticosteroid usage (35). Circulating MMP-9 is an indicator of activated osteoclasts and therefore another possible marker of osteoporosis (106). Metabolic syndrome describes a group of risk factors normally associated with CVD and which are also associated with COPD (8). Elevated levels of hs-CRP and IL-6 are seen in patients with the metabolic syndrome and are linked with a decrease in physical activity independently of impaired lung function; metabolic syndrome, physical activity levels, and GOLD stages have all been shown to be independent predictors of CRP and IL-6 levels (107).

Patients with COPD are at increased risk of peptic ulceration, and, conversely, studies have shown that the presence of peptic ulcers impacts on lung function (35). Activation of inflammatory mediators, induced by increases in bacterium Helicobacter pylori concentration, is observed in gastric conditions such as peptic ulceration and may enhance COPD progression; elevation of the caGa-positive strain of H. Pylori, which stimulates the release of IL-1 and TNF-α, supports this concept (35). There are currently no suitable plasma or serum biomarkers to investigate the systemic effects of gastroesophageal reflux disease in COPD.

Using biomarkers to characterize the systemic effects of COPD

It remains a matter of debate whether systemic inflammation arises as a consequence of spill-over from initial pulmonary inflammation or if both inflammatory mechanisms arise independently (3,36). Biomarkers have been utilized to provide evidence in favor of the systemic inflammation theory, with no relationship yet confirmed between markers in sputum and blood (3,9,35,38,39). COPD as a systemic disease is further supported by growing evidence from genetics (2). Whether systemic inflammation is wholly or partially responsible for the association between COPD and its extra-pulmonary manifestations has yet to be confirmed, and the possibility of reverse causation cannot be discounted (13). Indeed extra-pulmonary manifestations may arise due to mechanisms other than systemic inflammation alone, with the extent of systemic involvement affected by disease phenotypes (2).

The identification and development of suitable systemic biomarkers in COPD is not without its challenges due to the complexity of this multi-faceted disease state and its many confounding factors (43). An example is the controversy surrounding TNF-α as a potential surrogate marker of COPD with data from earlier studies showing elevated concentrations of TNF-α in COPD patients in contrast to more recent data showing no increases in this population when studied over a longer period of time (40).

A number of studies and meta-analyses have shown that patients with stable COPD often display elevated levels of systemic inflammatory markers such as increased circulating leukocytes, CRP, IL-6, IL-8, fibrinogen, and TNF-α (11,12,40,75,108). The prevalence of systemic inflammation in COPD has not been well studied, and many of the earlier published data are derived from short-term, cross-sectional studies with small sample sizes (41). Moreover, there is no agreed consensus on the type, number, and value of inflammatory biomarkers needed to define systemic inflammation, and the definition of systemic inflammation is unclear. These studies show a wide intersubject variation in systemic biomarkers, and are unable fully to establish the relationship between biomarkers and key health outcomes due to the chronic nature of COPD and its co-morbidities (41). Sufficiently large sample sizes are required to allow multivariable adjustments for potential confounders with many published data arising from studies with too small a population to be confirmatory (40). Larger longitudinal studies are needed to identify and validate biomarkers over a longer period of time against clinical outcomes such as mortality, exacerbations, and lung function decline. Recent data from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study (42,109,110) have begun to answer some of these questions on systemic inflammation. In this observational study over 2,000 COPD patients, control smokers, and non-smokers were assessed longitudinally over 3 years, and the reliability of systemic inflammatory biomarkers was evaluated. Many systemic inflammatory biomarkers were found to be reproducible over time, with fibrinogen being the most repeatable systemic inflammatory biomarker (110). As shown in other studies, differences in a number of biomarkers can be shown between COPD subjects and control smokers and non-smokers, including peripheral blood white cell count, IL-6, CRP, and fibrinogen, despite large variability within each group (Figure 1), whereas others such as IL-8 and TNF-α appear to be higher in smokers than in COPD patients (111). When the proportion of COPD patients with 0, 1, or 2 (or more) of these biomarkers (white blood cell count, hs-CRP, IL-6, and fibrinogen) were in the upper quartile of the COPD distribution, then 28% of patients had two or more of these biomarkers elevated at the time of recruitment and 56% of these subjects still had two or more systemic inflammatory biomarkers elevated at 1 year (Figure 2). However, 43% of patients had no raised systemic inflammatory biomarkers at baseline, and 70% of these patients still had none of the systemic biomarkers elevated at 1 year. Thus, in accordance with these data from ECLIPSE and this definition of systemic inflammation, around 16% of COPD patients have sustained systemic inflammation. Those patients with sustained systemic inflammation were more breathless, had a poorer exercise capacity, higher exacerbation rate, and higher mortality than those patients without evidence of persistent systemic inflammation. Interestingly, those patients with sustained systemic inflammation had higher prevalence of cardiovascular disease. Thus, from this study, there may be a systemic inflamed COPD phenotype according to the definition used. This can be described as a phenotype of COPD because it only occurs in a percentage of patients, is stable over time, and is associated with clinical and functional characteristics and poor clinical outcomes. It may be that targeting these individuals with treatment may improve outcomes.

Systemic inflammatory biomarkers and co-morbidities of chronic obstructive pulmonary disease

All authors

William MacNee

https://doi.org/10.3109/07853890.2012.732703

Published online:

11 April 2013

Figure 1. Box plot (log scale) of the different biomarkers determined at baseline in COPD patients, smokers with normal lung function, and non-smokers. Reproduced with permission from Agusti et al. PLoS One. 2012;7:e37483 (111).

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Systemic inflammatory biomarkers and co-morbidities of chronic obstructive pulmonary disease

All authors

William MacNee

https://doi.org/10.3109/07853890.2012.732703

Published online:

11 April 2013

Figure 2. Proportion of patients with none, one, or two (or more) biomarkers (WBC count, CRP, IL-6, and fibrinogen) in the upper quartile of the COPD distribution, at baseline (left bars) and after 1 year follow-up (right bars). Reproduced with permission from Agusti et al. PLoS One. 2012;7:e37483 (111).

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Data from the ECLIPSE study have also shown that the addition of a panel of selected systemic inflammatory biomarkers to established clinical measures increases the capacity to predict mortality in this condition (112).

Using biomarkers to manage the therapeutic intervention of COPD

Robust, reliable, systemic biomarkers that correlate to known and accepted clinical outcomes will play an important role in the diagnosis and management of COPD and its co-morbidities. Such biomarkers will also be important for the development of novel therapeutic interventions including those that target specific phenotypes and provide personalized treatments (113). Responsiveness to treatment effect is an important aspect of biomarkers to help in the development of novel anti-inflammatory therapies. The most promising systemic biomarkers that have been investigated to date are CCL-18/PARC, fibrinogen, and SP-D. Levels of SP-D, CCL-18/PARC, and CC-16 have been shown to respond to oral and inhaled corticosteroids (49,114,115). SP-D also responds to intravenous corticosteroid, in contrast to CRP and IL-6 which were not affected by intravenous corticosteroid in clinical studies (115,116).

CCL-18/PARC is predominantly secreted from the lungs, making it a relevant marker of COPD. There is increasing evidence from large longitudinal studies of its ability to track clinical outcomes: CCL-18/PARC is associated with mortality, lung function decline, health outcomes (BODE), the occurrence of acute exacerbations, and cardiovascular hospitalizations (46). This, combined with its responsiveness to oral corticosteroids, makes CCL-18/PARC a very exciting biomarker with the potential for use in clinical practice and drug development (46). Similarly, fibrinogen, although not lung-specific, correlates with mortality, exacerbations, and FEV₁ decline in large cohort studies. Elevated levels of fibrinogen, which may be further increased in the presence of pulmonary infections, have been associated with a higher risk of coronary events in COPD patients (40,89). A recent study showed that a p38 mitogen-activated protein kinase inhibitor (losmapimod) decreased plasma fibrinogen in COPD patients (117). Similarly to CCL-18/PARC, SP-D is derived from the lungs and has shown reproducibility as well as sensitivity to oral and inhaled corticosteroid therapy, and is the first biomarker to predict an increased risk of exacerbations in a large prospective trial (49,115).