Biomarkers in chronic obstructive pulmonary disease

Biomarkers in chronic obstructive pulmonary disease

Biomarkers in chronic obstructive pulmonary disease SHARON R. ROSENBERG, and RAVI KALHAN CHICAGO, ILL Chronic obstructive pulmonary disease (COPD) is...

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Biomarkers in chronic obstructive pulmonary disease SHARON R. ROSENBERG, and RAVI KALHAN CHICAGO, ILL

Chronic obstructive pulmonary disease (COPD) is a complex disease with multiple phenotypes that cannot be identified through measurement of lung function alone. The importance of COPD risk assessment, phenotype identification, and diagnosis of exacerbation magnify the need for validated biomarkers in COPD. A large number of potential biomarkers have already been assessed and some appear promising, in particular fibrinogen, which is likely to be the first COPD biomarker presented to the Food and Drug Administration for qualification in the drug approval process. Blood fibrinogen and c-reactive protein (CRP) have been associated with the presence of COPD and, in some instances, future risk of developing COPD in targeted populations. Sputum neutrophil counts have been used preliminarily as biomarkers of favorable response to therapy in COPD, but use in clinical settings may be limited. Other potential blood biomarkers include pulmonary and activation-regulated chemokine (PARC/ CCL-18) and the clara cell secretory protein 16 (CC-16). Integrative indices, such as the BODE index, provide a framework to determine prognosis, predict outcome, and may be responsive to therapeutic interventions. Computed tomography provides a means to assess phenotypes and identify the relative extents of small airways disease and emphysema, which themselves may inform prognosis and therapeutic decision making. Fibrinogen and other markers of systemic inflammation are elevated in the context of acute COPD exacerbations and may also identify those at risk of accelerated lung function decline and hospitalization. So far, no single biomarker in COPD warrants wide acceptance emphasizing the need for future investigation of biomarkers in large-scale longitudinal studies. (Translational Research 2012;159:228–237) Abbreviations: AECOPD ¼ acute exacerbations of COPD; BODE ¼ body mass index, airflow obstruction, dyspnea and exercise capacity; CARDIA ¼ coronary artery risk development in young adults; CC-16 ¼ clara cell secretory protein 16; COPD ¼ chronic obstructive pulmonary disease; CRP ¼ c-reactive protein; DLCO ¼ diffusing capacity of the lung for carbon monoxide; ECLIPSE ¼ evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; FEV1 ¼ forced expiratory volume in 1 second; FVC ¼ forced vital capacity; MRC ¼ medical research council; PARC/CCL-18 ¼ pulmonary and activation regulated chemokine; SAA ¼ serum amyloid A; SPD ¼ surfactant protein D

INTRODUCTION: THE COMPLEX NATURE OF COPD

C

hronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the United States, and the only leading cause that is increasing in prevalence.1,2 By 2030, nearly 9 million people will die annually from COPD.3 The symptom

burden faced by those living with COPD and the health care costs associated with the disease are both enormous. COPD is characterized by progressive airflow limitation that is not fully reversible.4 The forced expiratory volume in 1 s (FEV1) both defines and characterizes the severity of the disease5 and is a well known predictor of mortality

From the Asthma and COPD Program, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.

Clair Street, #14-047, Chicago, IL 60611; e-mail: [email protected] northwestern.edu.

Submitted for publication November 14, 2011; revision submitted January 19, 2012; accepted for publication January 19, 2012.

Ó 2012 Mosby, Inc. All rights reserved.

Reprint requests: Ravi Kalhan, MD, MS, Asthma and COPD Program, Northwestern University Feinberg School of Medicine, 676 N St

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1931-5244/$ - see front matter doi:10.1016/j.trsl.2012.01.019

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and morbidity. However, the FEV1 does not correlate well with health status or symptoms.6,7 Historically, the FEV1 is the only accepted marker that meets FDA drug approval criteria for COPD, but given the variability in COPD beyond FEV1, measurement of lung function alone presents obvious limitations when attempting to determine prognosis, predict outcomes, select mostappropriate therapy, or monitor disease activity. This review will focus on the molecular and imaging biomarkers that may be involved in COPD and can be measured in peripheral blood, airway secretions, or via noninvasive imaging. The National Institutes of Health defines a biomarker as ‘‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.’’8 There is a need for molecular, physiologic, and imaging-based biomarkers in COPD that could be used both in identifying specific COPD phenotypes and as surrogate endpoints for clinical trials.9-11 COPD is a multicomponent disease in which limitations exist in distinguishing disease severity from disease activity.12 Although the FEV1 is highly reproducible and relatively easy to obtain, it is not sensitive and does not account for the complex nature of COPD. Traditional measures of lung function such as the FEV1 often may not capture other aspects of disease that contribute to disease activity, which we define as factors that impact daily symptoms, quality-of-life, and prognosis. Examples of factors that may be associated with more ‘‘active’’ disease include weight loss and skeletal muscle dysfunction,13 which when treated through an intervention like pulmonary rehabilitation can be associated with reduced symptom burden, less healthcare utilization, and improved patient sense of well-being without necessarily altering lung function.14 Another example of greater disease activity is the presence of repeated COPD exacerbations, which occur in a subset of patients across the spectrum of FEV1 severity.15 The potential importance of biomarkers in the context of exacerbations is discussed in detail later in this review.15,16-18 In addition, because COPD is defined physiologically by the presence of airflow obstruction (with the finding of a specific value below a cut-off for the FEV1/forced vital capacity [FVC] ratio), there remains no current method to identify subclinical COPD. Even once established and diagnosed, the heterogeneity of COPD, likely characterized by multiple phenotypes each resulting from distinct, albeit likely inter-related mechanisms, and pathophysiology,11 presents a barrier to identifying a single biomarker for this complex disease. Several well-known clinical manifestations serve as examples of COPD phenotypes and when identified may themselves serve as biomarkers of a specific type of COPD

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that has a distinct pathobiology, therapeutic response, or prognosis. Linking such phenotypes with molecular biomarkers would further refine them and result in more efficient identification of various disease subtypes. Perhaps the most obvious manifestation of disease heterogeneity in COPD is the concurrent existence of small airways disease and emphysema19 with variable respective extents of severity20 (Fig). Mucus in the airway lumen, peribronchiolar fibrosis, and presence of inflammatory cells characterize the small airways disease of patients with COPD. Emphysema represents destruction and dilation of respiratory bronchioles beyond the terminal bronchioles. Differential expression of tissue repair genes in the pathogenesis of COPD suggests the pathogenic processes of small airways disease and emphysema are quite different.21 However, current COPD treatment guidelines, which focus on selection of therapies based on the FEV1,5 do not, for the most part, recommend any differences in therapeutic decision making based on the presence of a predominant ‘‘airways phenotype’’ compared with the ‘‘emphysema phenotype’’ with the notable exception of the application of lung volume reduction surgery (LVRS) to individuals with upper-lobe predominant emphysema.22 Computed tomography allows visualization of these pathologic processes and emphasizes the potential for noninvasive radiographic phenotyping23 and investigation of specific radiographic findings as biomarkers of disease prognosis or response to specific therapy. Radiographic COPD phenotype may also be subsequently linked with more efficiently obtained (and sometimes less expensive to measure) serum or urine biomarkers. In addition to the pathologic processes of COPD, the clinical course of patients may identify particular phenotypes. In fact, the clinical course may itself serve as a biomarker that informs prognosis or guides treatment. Because COPD exacerbations present a great burden to both individual patients and the healthcare system, identification of a biomarker that could predict the risk of future exacerbations would be valuable to prescribe exacerbation prevention strategies or target the development of new therapies.24 The most reliable predictor of COPD exacerbations in an individual is a history of prior exacerbations15,25 suggesting a phenotype of exacerbation susceptibility. This phenotype was stable over a 3-year period and reliably predicted by patient recall of events.15 Ideally, then, the presence of an exacerbation would in and of itself be viewed as a biomarker that portends a poor prognosis in COPD and informs clinical decision making focusing on prevention of future exacerbations which is a proven benefit of COPD pharmacotherapy.16,17,26 However, one-half to twothirds of exacerbations are unreported to physicians27 making an easily measured molecular biomarker of

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Fig. Two cases from the authors’ clinical COPD program illustrate the complex nature of COPD not captured by the forced expiratory volume (FEV1) alone. The left panel is a chest computed tomography (CT) scan is a 51-yearold man with an FEV1 of 51% predicted. It demonstrates upper-lobe predominant centrilobular emphysema. The right panel is a CT scan from a 50-year-old woman with an FEV1 of 49% predicted and shows a paucity of emphysema, but some evidence of airway wall thickening and mucous impaction in small airways. Despite having similar FEV1 values, these 2 cases are obviously different in radiographic appearance and clinical disease manifestations.

exacerbation and risk of future exacerbations a potentially valuable tool. The remainder of this review will focus on both molecular and imaging biomarkers that may be used in COPD as they relate to subclinical disease and early risk, measurements of prognosis and disease activity, in particular identification of exacerbations or risk of exacerbations. The relationships between radiographic and molecular biomarkers will also be discussed. It is worth noting that a major effort has been initiated by the COPD Foundation in the United States to qualify blood fibrinogen level as an FDA-accepted biomarker in the COPD drug approval process (http://www. copdfoundation.org/Research/BiomarkersConsortium/ tabid/195/language/en-US/Default.aspx). Although this work has not been finalized, due to its potential importance, we emphasize the potential role of fibrinogen in a variety of contexts. BIOMARKERS OF COPD RISK

The subclinical phase of COPD remains undescribed and therapies, therefore, have not really been tested in early disease. Biomarkers of COPD risk, therefore, would be extremely valuable to identify populations in whom prevention strategies could be targeted. In the longitudinal coronary artery risk development in young adults (CARDIA) study of 2496 adults 18 to 30 years of age at entry without self-report of asthma, we demonstrated that low lung function in early adulthood is associated with lower lung function 20 years later in life.28 In analyses independent of cigarette smoking, we found

that the FEV1 measured at mean age 25-years-old was predictive of the presence of airflow obstruction measured 20 years later at mean age 45 independent of cigarette smoking (adjusted odds ratio [OR] 0.93, 95% confidence interval [CI] 0.92–0.95) per unit change in percent predicted FEV1 at baseline for having FEV1/ FVC less than the lower limit of normal 20 years later). The effect of cigarette smoking on accelerating decline in FEV1 with age was most evident in young adults with pre-existing airflow obstruction.28 A lower FEV1 in young adulthood (even if in the normal range), therefore, may indicate substantial future risk of obstructive lung disease in middle age and identify a population at risk of future lung disease. These data are consistent with the experience reported from the Childhood Asthma Management Program which documented that children with asthma, and often lower lung function, maintain lower lung function into adolescence.29 Cross-sectional studies have documented that increased systemic inflammation is associated with lower lung function in both healthy adults and patients with COPD. Higher CRP levels were associated with lower lung function in 1000 New Zealanders ages 26 to 32 unrelated to smoking, obesity, and asthma.30 Similar inverse findings between CRP and lung function were found among 1131 never smokers without pulmonary disease31 and among participants in the third National Health and Nutrition Examination.32 In older populations, there appears to be an association between systemic inflammation and risk of COPD. In a Dutch study of subjects 55 years of age and older, CRP was associated with increased risk of incident COPD.33 In

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a study of 5247 healthy Swedish men of mean age 46 years, a panel of inflammation sensitive plasma proteins including CRP was associated with increased risk of COPD hospitalization.34 We observed that among CARDIA participants high CRP and fibrinogen in young adulthood were both associated with accelerated decline in the FVC and FEV1 over the subsequent 13 to 15 years.35 There was a positive interaction between cigarette smoking and CRP in an analysis of COPD risk (defined by FEV1/FVC of less than 0.70) and those at the highest risk for developing COPD (10 or more pack-years of smoking cigarettes at year 20, mean age 45-years-old), higher CRP in young adulthood was associated with COPD in middle age (OR per standard deviation of CRP measured at mean age 32 years old 1.53 (95% CI 1.08–2.16) for having FEV1/FVC , 0.70 at mean age 45). We interpreted this finding to indicate that CRP may serve as a valuable biomarker to identify those cigarette smokers who are at greatest risk of developing COPD in the future.35 It is, however, important to note that the utility of a biomarker as a clinical tool for individual patients relies on its predictive sensitivity and specificity. The above associations of lung function and serum markers with risk of future lung disease do not currently justify their use as biomarkers of COPD risk to be used in clinical practice. Since fibrinogen is likely to be the first biomarker qualified for use in drug development, a review of fibrinogen in the context of COPD risk is warranted. In a large sample of the general population in the United States, both smoking and reduced FEV1 were associated with increased systemic inflammation, measured by CRP and fibrinogen.36 Among both healthy individuals and patients with COPD, an inverse association between blood levels of fibrinogen and FEV1 has been reported.30,32,37-40 Although there are clear associations between the presence of COPD and increased levels of fibrinogen, CRP, and a variety of other inflammatory cytokines,41 the usefulness of these blood measurements as biomarkers to be employed in clinical and investigative contexts will rely on further refinement to understand whether they are associated with specific aspects of disease activity, serve as markers of a specific disease phenotype, inform short- or long-term prognosis, or can be used to evaluate therapeutic response. MOLECULAR BIOMARKERS OF DISEASE ACTIVITY, PROGNOSIS, AND THERAPEUTIC RESPONSE

The complexity of COPD challenges the accurate assessment of disease activity and prognosis. Potential biomarkers may allow for risk stratification of established COPD, including identification of those at risk of accelerated loss of lung function or progressive impairment in quality-of-life and a better means to predict

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and assess therapeutic response to pharmacologic therapy. Neutrophils are an attractive biomarker in COPD as they are thought to be mechanistically involved in disease pathophysiology42 and can be measured in the target organ noninvasively.43 Sputum neutrophilia percent increases with smoking and COPD progression.44 Neutrophil counts remain elevated in established COPD even following smoking cessation.45 Neutrophil counts in sputum have been used as a biomarker to evaluate responses to COPD therapies. Over a 3-month period, there was no significant change in sputum neutrophil count between combination fluticasone-salmeterol and placebo.46 Another study showed a lower sputum neutrophil count after 30 months of therapy in the group that received fluticasone compared with the placebo group.47 These data are consistent with the findings of a meta-analysis published in 2005 showing that at least 6 weeks of inhaled corticosteroid therapy results in a reduction of the sputum neutrophil count in patients with stable COPD.36 Sputum neutrophil counts have also been used to assess efficacy of drugs other than inhaled corticosteroids. In a randomized controlled trial, erythromycin was associated with significantly reduced sputum neutrophilia after 3 months and was accompanied by a reduction in COPD exacerbations.48 In a different study, however, there was no reduction in sputum inflammatory markers after 1 year of erythromycin therapy despite a reduction in COPD exacerbations.49 Sputum neutrophil counts have been used to assess low dose theophylline therapy in patients with COPD with conflicting results. In 30 patients with COPD, combination theophylline and fluticasone did not reduce total sputum neutrophil count.50 However, an 8-week study of low dose theophylline was associated with reduced sputum neutrophil count.51 Phosphodiesterase 4 inhibition with 4 weeks of roflumilast treatment reduced the number of neutrophils and eosinophils, as well as soluble markers of neutrophilic and eosinophilic inflammatory activity, in induced sputum samples of patients with COPD. This antiinflammatory effect may in part explain the concomitant improvement in post-bronchodilator FEV1.52 As the FEV1, particularly in more severe COPD, changes minimally, the use of a biomarker in drug efficacy is promising. In the quest for a COPD biomarker of response to therapy, however, reproducibility is vital given its importance in the qualification process. The above data magnifies questions regarding the reproducibility of sputum neutrophil count as a response to COPD therapy. Sputum neutrophils, therefore, may provide mechanistic insights but likely have limited predictive ability for individual patient treatment decisions and their role in serving as surrogate endpoints in clinical trials will require greater refinement.

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Longitudinal studies offer unique insight into the use of biomarkers in established COPD. Two large cohort studies and an intervention study examined the pulmonary and activation regulated chemokine (PARC/CCL18), a lung-predominant inflammatory protein found in serum, with 3 important findings.53 First, PARC/ CCL-18 concentrations were independently associated with the presence of COPD. Second, PARC/CCL-18 concentrations were independently associated with future risk of cardiovascular hospitalization and mortality and with total mortality in COPD. Third, an intervention study showed short-term steroid use modified serum PARC/CCL-18 levels.53 Clara cell secretory protein 16 (CCSP, CC-16) is produced almost exclusively by non-ciliated Clara cells and its main function is to protect the lungs against oxidative stress and carcinogenesis.54 After acute exposure to cigarette smoke, serum levels of CC-16 become elevated55 and can be suppressed by inhaled corticosteroids.56 In a recent study investigating change in FEV1 over time in COPD, a subset of patients were analyzed in whom data on several biomarkers were available. Only CC16 levels were significantly associated with a slower rate of decline in lung function.57 This association was not modified by age, sex, FEV1, current smoking status, or smoking history. Whether this association is biologically meaningful has yet to be determined as it is unknown if the presence of this protein indicates intact small airways or evidence that the protein is directly protecting the airway. Additional work on the relationship between CC-16 and the small airways will determine its potential as a target for new treatments. While sputum and serum provide the majority of COPD candidate biomarker measurements, desmosines may be measured in the urine in addition to the serum and sputum. Desmosine, a crosslink unique to mature elastin, has been extensively discussed as a potentially attractive indicator of elevated lung elastic fiber turnover and a marker of the effectiveness of agents with the potential to reduce elastin breakdown. Two months of tiotropium therapy in a small number of patients with COPD showed a reduction in desmosines in the sputum, plasma, and urine of most patients suggesting lung cholinergic blockade may reduce elastin degradation.58 More recently, after adjustments for age, gender, height, body mass index (BMI), and smoking, urine concentrations of desmosines were significantly associated with all lung function measures, and plasma desmosines with FEV1 and diffusing capacity of the lung for carbon monoxide.59 These cross-sectional data showing associations between desmosines and several lung function variables suggest that desmosines, particularly those measured in the urine, may be a useful biomarker of ongoing lung destruction in COPD. There is, however,

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contrasting literature that desmosine values do not significantly change with supplementation therapy in a-1 antitrypsin therapy.60 BIOMARKERS OF COPD EXACERBATION

Several systemic biomarkers of inflammation and oxidative stress have been studied in acute exacerbations of COPD (AECOPD), but none has gained wide acceptance so far.34,61-67 Because AECOPD accelerate lung function decline and have major implications on the quality of life, morbidity, and mortality of COPD patients, biomarkers contributing to a prompt diagnosis of an imminent or established COPD exacerbation may modify treatment decisions and patient outcomes. Currently, AECOPD are diagnosed based on clinical criteria, when specific symptoms deteriorate beyond day-to-day variability, and their severity is rated according to healthcare resource utilization.5 Identification of a biomarker that has the potential to identify exacerbations and provide prognostic information on the severity of an exacerbation would be quite valuable. The role of fibrinogen in acute exacerbations of COPD warrants discussion. During acute exacerbations of COPD, higher levels of fibrinogen, among other circulating markers, are seen, and they decline with exacerbation recovery.62,68,69 Fibrinogen may also be useful to predict future COPD exacerbations in the short term as a higher initial fibrinogen level was associated with the occurrence of COPD exacerbations over 1year followup and a higher initial fibrinogen and a lower FEV1 predicted a higher rate of both moderate and severe exacerbations.67 In the Copenhagen Heart Study, elevated plasma fibrinogen was associated with increased risk of COPD hospitalization independent of smoking status.39 In a population-based study of initially healthy middleaged men,34 the incidence of hospital admissions for COPD was increased in those with elevated levels of 5 inflammatory plasma proteins, including fibrinogen, over 25 years of follow-up.34 The evaluation of biomarkers in large-scale decisionmaking studies is expected to become an area of intense future investigation. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study helped to establish that a history of 2 or more exacerbations in the prior year is a relatively stable phenotype and predictive of future events.15 Additional biomarker evaluation in this patient group may further identify those at highest risk of lung function decline,70 worse quality of life,71 and increased mortality.72 Donaldson and colleagues73 found that plasma fibrinogen and sputum IL-6 rose faster over time in patients with COPD who had more frequent exacerbations. Further examination of 36 candidate plasma

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biomarker concentrations at baseline and exacerbation in 90 subjects with COPD found 9 biomarkers that were significantly higher at time of exacerbation.63 None of those biomarkers in isolation could provide a better diagnostic performance compared with the presence of any major AECOPD symptoms (dyspnea, sputum volume, or sputum purulence). The use of CRP in combination with 1 or more symptoms of an exacerbation (increased breathlessness, increased sputum volume, increased sputum purulence) outperformed use of CRP alone.63 Several other studies have supported a possible role for CRP in the identification of an AECOPD, however, only with modest diagnostic accuracy. Serum amyloid A (SAA) another acute phase reactant has been evaluated and found to be potentially useful for both the diagnosis of an exacerbation and also its clinical severity.74 The addition of symptoms did not improve the diagnostic performance of SAA, and SAA outperformed CRP. Evaluation of copeptin, a stable portion of the vasopressin precursor, in 167 hospitalized patients with exacerbations of COPD showed that 16% with a copeptin level .40 pmol/L had a significantly longer hospital stay and higher hospital mortality compared with those with copeptin levels ,40 pmol/L.75 The group with elevated copeptin levels were more than 3 times more likely to have another exacerbation requiring admission to the hospital within 6 months.76 Surfactant protein D (SPD) was not useful as a marker of COPD risk in the ECLIPSE study, but the quartile of COPD patients with the highest serum SPD (.1744 ng/mL) reported more exacerbations in the year prior to the baseline test.77 INTEGRATIVE SEVERITY INDICES AS BIOMARKERS

Several integrative measures that incorporate both traditional measures of lung function and other factors that impact an individual’s health status have been developed. The most prominent of these indices is the BODE index first reported by Celli and colleagues. The BODE is a composite of 4 easily measured factors: body mass index, degree of airflow obstruction measured by FEV1, dyspnea as determined by the medical research council (MRC) dyspnea scale, and exercise capacity as determined by distance walked in 6 min (6MWD). The BODE index is a 10-point scale in which higher values reflect greater disease severity, and outperforms FEV1 in predicting all-cause mortality over a 1-year period.78 More recent studies have also pointed to the BODE index as a predictor of hospitalization (again outperforming FEV1),79 and emerging data indicate that the BODE may serve as a useful parameter to assess the effect of therapeutic interventions on

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COPD.80-82 Two additional COPD integrative indices have been developed. The ADO index includes age, dyspnea (MRC scale), and severity of airflow obstruction (FEV1). The discriminatory power of ADO is similar to that of BODE,83 but it has not been evaluated as an indicator of therapeutic response. The DOSE index incorporates dyspnea (MRC scale), obstruction (FEV1), smoking status (current versus former), and exacerbation frequency.84 The inclusion of exacerbations and smoking status distinguishes DOSE from other integrative measures. The DOSE index predicts important future COPD outcomes including hospital admissions, respiratory failure, and exacerbations, but like the ADO it has not been tested in the context of evaluating therapeutic responses. Whether or not the BODE index, like FEV1 alone, correlates with molecular biomarkers requires future investigation. A comparative study of 100 clinically stable patients with COPD and 50 matched healthy smokers evaluated potential serum biomarkers for their ability to identify smokers with COPD and reflect disease severity.85 No single specific serum inflammatory mediator completely correlated with the parameters of the BODE index in patients with stable COPD. Serum MCP-1, however, was associated with multiple components including current smoking status, FEV1, and the 6-min walk distance in patients with stable COPD.85 Emphysema was found to be a predictor of the BODE index in evaluation of high resolution chest CT in patients with COPD.86 IMAGING: EMERGING TECHNOLOGY TO ENHANCE OUR UNDERSTANDING OF COPD

As mentioned, small airways disease and emphysema are 2 pathologic features commonly observed in COPD19 prompting an interest in the identification of quantitative computed tomography as an imaging biomarker to target patient groups or influence specific therapeutic decisions. Emphysema and airway wall thickness CT measurements independently correlate with dyspnea after adjustment for FEV1 percent predicted87 indicating that both findings have equally important impact on disease. It has been shown that airway wall thickness is significantly associated with cough and wheezing.87 High-resolution CT in subjects with severe COPD showed a reduced number of airways in regions of lung undergoing emphysematous destruction and was predictive of a high BODE index.88 These results suggest that CT imaging-based total airway count may be a unique COPD related phenotype in smokers. A recent study showed that airway caliber increases are lower in patients with emphysemapredominant compared to airway-predominant CT subtypes.89 Diminished bronchodilator response in subjects with greater degree of emphysema has been

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reported,90 and these findings suggest that patients with emphysema-predominant CT findings may be less responsive as well. These associations between radiographic phenotype and various clinical responses lend credence to the idea that radiologic findings may be useful biomarkers to classify patients into subgroups which may be particularly responsive to certain therapies, although to-date, we are not aware of robust studies that have tested the effects of therapies in specific subgroups with compelling results. Bignon et al91 were the first investigators to measure small airway narrowing in COPD and Matsuba and colleagues92 confirmed these findings. A recent novel study extends prior data that imaging findings may explain the increased peripheral airway resistance reported in COPD. Multidetector CT was used to compare the number of small airways, terminal bronchioles, and degree of emphysema among various stages of COPD in 14 isolated lungs removed from patients who underwent lung transplantation compared with 4 controls.93 The number of small airways was reduced among all stages of COPD compared with controls as was the number of terminal bronchioles and cross-sectional area at different levels of emphysematous destruction. These findings showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD.93 Whether this novel approach to imaging and its findings in terms of small airways number can be extended to serve as a biomarker for COPD risk, prognosis, or response to therapy remains to be seen. There is extensive data regarding the relation between CT emphysema quantification and several outcomes and disease manifestations as well as mortality. Body mass index and loss of bone mineral density correlate with the extent of emphysema on chest CT.94-96 Patients with greater radiographic emphysema may show more continuous inflammation as evidenced by association of emphysema and elevated sputum neutrophil count97 and relation of tissue neutrophil elastase distribution with emphysema.98 In 251 outpatients with various stages of COPD, emphysema was associated with mortality independent of age, BMI, FEV1, and diffusing capacity.99 A similar finding was previously reported in patients with a-1 antitrypsin deficiency.100 The overall percentage of emphysema as assessed by CT scan was not associated with increased mortality in patients with COPD without a-1 antitrypsin deficiency in the National Emphysema Treatment Trial (NETT).101 It can be argued that the differences in findings between the 2 studies may relate to differences in COPD severity based on GOLD stage, characterization of comorbidities, and CT technique. Variation of serum inflammatory markers in association with CT indices of emphysema and airway disease

was explored in a cohort of current and former smokers and showed several serum inflammatory proteins were significantly associated with FEV1, airway thickening, and parenchymal emphysema.102 The identification of inflammatory markers associated with specific radiographic phenotypes may further sub-classify COPD phenotypes, and if specific enough, may distinguish phenotypes without the need for radiation exposure and cost. In addition to correlation with the BODE index and serum inflammatory markers, CT findings may be associated with pulmonary vascular and cardiac disease in COPD. Quantitative computed tomography measurement of total cross-sectional area of small pulmonary vessels in patients with severe emphysema correlated with mean pulmonary arterial pressure measured by right heart catheterization.103 Airflow obstruction and emphysema have been associated with impaired left ventricular filling.104 These pioneering studies suggest CT may provide a noninvasive means to identify phenotypes and specific groups at risk for comorbid conditions. CONCLUSION

Because of the complexity of COPD and limitations in the traditional measurement of severity, the FEV1, there is a great need to identify COPD biomarkers that inform the complex nature of this very important disease. The FEV1 may measure disease severity, but not activity, and fails to capture a patient’s health status and symptom burden. It has obvious limitations when attempting to predict prognosis and outcome, select most-appropriate therapy, or monitor disease. The disease heterogeneity of COPD, likely characterized by multiple phenotypes resulting from distinct but interrelated mechanisms and pathophysiology, presents a barrier to identifying a single biomarker, although there have been promising findings related to serum biomarkers, integrative disease severity indices, and imaging technologies. Future investigation will continue to advance our understanding of biomarkers related to COPD risk, disease severity, best therapeutic options, prognosis and recognition, and treatment of COPD exacerbations. Sharon R. Rosenberg has received sponsored grants from the Respiratory Health Association of Metropolitan Chicago and the NIH. Ravi Kalhan has served as a consultant for Boehringer-Ingelheim, Forest Laboratories, and AstraZeneca; has received honoraria for lectures from GlaxoSmithKline and AstraZeneca; has received honoraria for development of educational materials from Quantia Communications and Medscape Education; has received industry-sponsored grants from GlaxoSmithKline and Boehringer-Ingelheim; and has received sponsored grants from the Respiratory Health Association of Metropolitan Chicago and the NIH. Both authors have disclosed any financial or personal relationship with organizations that could potentially be perceived as influencing this work and have read the journal’s policy on disclosure of potential conflicts of interest.

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