Rationale: Neutrophilic inflammation is understood to be of pathogenetic importance in chronic obstructive pulmonary disease (COPD) and may be quantified using 18-fluorodeoxyglucose positron emission tomography–computed tomography (18FDG PET-CT) as a noninvasive, spatially informative biomarker.
Objectives: To assess the potential usefulness of 18FDG PET-CT as a surrogate measure of pulmonary neutrophilic inflammation in patients with usual COPD and α1-antitrypsin deficiency (AATD).
Methods: 18FDG PET-CT imaging was performed in 10 patients with usual COPD, 10 patients with AATD, and 10 healthy control subjects. Pulmonary 18FDG uptake was estimated by three-dimensional Patlak graphical analysis as an indicator of pulmonary neutrophilic glycolytic activity. Patients with AATD were treated with 12 weekly intravenous infusions of AAT augmentation therapy before repeat imaging. 18FDG uptake, lung physiology, lung density, and systemic markers of inflammation were compared for all groups at baseline and, in patients with AATD, at baseline and on treatment.
Measurements and Main Results: 18FDG uptake in the upper lung of patients with usual COPD was greater compared with the healthy control group (P = 0.009) and correlated with measures of disease severity (FEV1% predicted, r = −0.848, P = 0.001; FEV1/FVC, r = −0.918, P < 0.001; Kco% predicted, r = −0.624, P = 0.027; 15th percentile point, r = −0.709, P = 0.011). No significant difference was observed between measurements at baseline and on treatment in patients with AATD.
Conclusions: Quantitative 18FDG PET-CT has a potential role as an imaging biomarker in mechanistic and interventional studies in patients with usual COPD. The data support previous evidence of distinct functional characteristics of neutrophils in COPD.
Clinical trial registered with https://eudract.ema.europa.eu/index.html (EudraCT 2007-004869-18).
18Fluorodeoxyglucose positron emission tomography–computed tomography (18FDG PET-CT) is a noninvasive molecular imaging technique that may provide spatial, quantitative data on pulmonary neutrophilic activity.
Quantitative PET-CT imaging demonstrated that pulmonary 18FDG uptake is significantly greater in patients with stable chronic obstructive pulmonary disease (COPD) compared with patients with α1-antitrypsin deficiency and healthy control subjects. 18FDG uptake was greater in the upper lung region and, in subjects with usual COPD, correlated with physiologic measures of disease severity, in particular, emphysema. The data support the use of this clinical tool for mechanistic and therapeutic studies in usual COPD and suggest that it may be most applicable to patients with moderate to severe COPD and an emphysematous phenotype.
Chronic obstructive pulmonary disease (COPD) is a major and increasing global healthcare problem (1), and modification of disease progression through pharmacotherapy remains the elusive “Holy Grail” of COPD management. This elusiveness is a reflection of the complexity of COPD pathogenesis, the heterogeneity of clinical phenotype, and the practical difficulties associated with the assessment of pathogenetic mechanisms in vivo.
Current understanding of the pathogenesis of emphysema in usual COPD (2) originates from recognition of an association between α1-antitrysin deficiency (AATD) and the development of emphysema. The original description of the imbalance between antiproteases and neutrophil-derived proteases that could account for early-onset emphysema in AATD has conventionally been extrapolated to the pathogenesis of usual COPD (3), and the central role occupied by the neutrophil (4–7) is considered to be comparable in both diseases. Traditional understanding of disease causation in these two conditions is of a common inflammatory pathogenesis that differs primarily in the severity of inflammation and proteolytic damage, which, in turn, reflects the level of antiprotease defense. Consequent to this fundamental unifying concept of disease pathogenesis, neutrophil-related inflammation remains a key pharmacotherapeutic target for disease modification within the lung in both COPD and AATD.
Notwithstanding this aim, studies of antiinflammatory agents have been disadvantaged by a lack of valid clinical outcome measures. For example, bronchoalveolar lavage is invasive and modifies respiratory physiology and pathology in COPD, plasma and urine biomarkers (8–10) are confounded by systemic processes (11), and exhaled breath condensate and sputum are not informative on locality and are also principally representative of central airspaces (12, 13). There is, therefore, a need to develop new methods that are noninvasive and allow repeated assessment without any modification of the disease processes they endeavor to measure.
Molecular imaging using 18fluorodeoxyglucose positron emission tomography–computed tomography (18FDG PET-CT) can generate both quantitative and spatial data of pulmonary glucose uptake (14) that may represent a noninvasive, repeatable biomarker of pulmonary neutrophilic inflammation. The technique has been explored in several respiratory diseases (15–20), including a study in COPD. Using small numbers (n = 6), pulmonary neutrophilic inflammation has been shown to be significantly greater in patients with COPD with an emphysematous phenotype than patients with asthma and healthy control subjects (17).
The purpose of the current study (Evaluation and Control of Lung Inflammation assessed with PET Scanning in Emphysema and Alpha 1-AntiTrypsin Deficiency [ECLIPSE-AATD]) was to use 18FDG PET-CT to quantify and determine the distribution of pulmonary neutrophilic inflammation in patients with usual COPD and AATD relative to healthy control subjects. Some of the results of these studies have been previously reported in the form of an abstract (21).
Subjects with usual COPD (PiM phenotype) and healthy control subjects were recruited from outpatient clinics and by newspaper advertisement. Patients with AATD (AAT serum concentration < 11 μM and PiZ phenotype) were recruited from the UK “ADAPT” registry.
All participants were at least 18 years old; inclusion criteria for subjects with COPD included FEV1 below 80% of the predicted value (22) and an FEV1/FVC ratio of less than 70%. Patients were excluded if they had an FEV1 below 30% predicted, had smoked within the previous 12 months, or experienced an exacerbation in the 8 weeks before the study (see Table E1 in the online supplement for full criteria).
This was a single-center, exploratory, open-label study of cross-sectional design to compare quantitative 18FDG PET-CT imaging in 10 patients with usual COPD, 10 patients with AATD, and 10 healthy control subjects. In addition, patients with AATD were treated with 12 weekly infusions of augmentation therapy using intravenous α1-antitrypsin (Prolastin; Talecris Biotherapeutics, Raleigh-Durham, NC; 60 mg/kg body weight), and imaging was repeated within 24 to 48 hours of the final infusion. The study was approved by the Hammersmith and Queen Charlotte’s and Chelsea Research Ethics Committee. All patients gave written informed consent.
Screening assessment included clinical history and examination, complete blood count, plasma biochemistry, urinalysis, electrocardiogram, chest radiograph and post-bronchodilator lung function (CareFusion, San Diego, CA). Patients with AATD were seen every week for clinical assessment and to receive augmentation therapy.
Before imaging, subjects fasted for 6 hours and avoided inhaled corticosteroids in the preceding 12 hours. A resume of recent symptoms and physical examination was conducted immediately before PET-CT imaging to confirm clinically stability and the absence of an exacerbation within the preceding 8 weeks.
Imaging was performed with a General Electric Discovery STE PET-CT instrument, incorporating a Lightspeed 8-slice CT scanner. Volumetric CT imaging was performed, followed by PET imaging with a free-breathing protocol over 56 minutes, immediately after an intravenous bolus injection of 18FDG. Plasma 18FDG activity was derived from venous blood sampling, performed at intervals during the scan. Quantification of total and regional pulmonary 18FDG uptake was determined by three-dimensional Patlak analysis (23) of the ratio of lung tissue PET signal to plasma radioactivity, normalized to Patlak-determined intercept (see online supplement for methodology). The spatial distribution of 18FDG uptake from apex to base was determined by subdivision of the axial slices into equal thirds to represent the upper, middle, and lower lung. CT lung densitometry was performed using Pulmo-CMS (Medis Medical Imaging, Leiden, Netherlands) to assess emphysema severity and distribution, quantified as described by Bakker and colleagues (24).
High-sensitivity C-reactive protein (hs-CRP) measurements (as a marker of systemic inflammation) were determined from baseline plasma samples using a commercial enzyme-linked immunosorbent assay (Quantikine; R&D Systems Inc; Minneapolis, MN). 18FDG uptake by circulating neutrophils was quantified from venous blood samples acquired during PET imaging using a phosphor imaging method and normalized for circulating neutrophil count (25) (see online supplement).
Groups were initially delineated using a fixed ratio for FEV1/FVC of 0.7 to define COPD (26). Comparison of 18FDG between the groups was made using the Student t test (SPSS, Inc, Chicago, IL) and, for nonparametric data, using the Mann-Whitney U test. A post hoc analysis was performed in which COPD was defined using the lower limit of normal (LLN) to reflect a contemporary definition of COPD (27). Statistical significance was set at P < 0.05.
Comparison of the groups indicated that they were matched for age and that there were no statistically significant differences in physiological and radiological indices of emphysema severity between usual COPD and the AATD groups (see Table 1 and the online supplement). Regional values for 15th percentile point (Perc15) and the locality index demonstrated a predominance of basal emphysema in the AATD group and a predominance of apical emphysema in the COPD group. Data from one healthy control subject was excluded from analysis because of an error in blood sampling that led to inaccuracy in the plasma radioactivity-by-time curve.
|AATD||Usual COPD||Control Subjects||P Value|
|Age, yr||57.2 (2.9)||66.1 (1.8)||61.0 (2.4)||0.052|
|FEV1, L||1.7 (0.2)||1.7 (0.3)||3.4 (0.2)||0.912|
|FEV1, % predicted||51.5 (5.7)||59.4 (5.4)||112.3 (3.3)||0.280|
|FVC, % predicted||114.5 (5.2)||104.6 (3.0)||118.4 (4.3)||0.089|
|FEV1/FVC ratio||33.9 (3.4)||43.9 (4.1)||75.5 (2.3)||0.052|
|TLC, % predicted||116.6 (2.7)||111.1 (3.4)||101.5 (3.7)||0.218|
|DlCO/Va, % predicted||60.4 (6.8)||64.9 (7.1)||105.7 (5.9)||0.579|
|VI-950 HU, %||24.2 (2.6)||20.2 (2.8)||3.7 (0.4)||0.393|
|Perc15, HU||−973.1 (6.6)||−962.5 (10.9)||−871.2 (5.8)||0.529|
|Upper zone Perc15, HU||−954.5 (8.7)||−974.5 (13.0)||−878.3 (9.8)||0.218|
|Middle zone Perc15, HU||−972.0 (7.7)||−964.4 (11.6)||−879.3 (5.7)||0.593|
|Lower zone Perc15, HU||−977.6 (7.7)||−951.0 (11.0)||−855.1 (5.7)||0.063|
|Emphysema locality index, HU/part*||−18.0 (11.5)||31.3 (9.9)||NA||0.001|
|Blood neutrophils,(106 cells/ml)||3.5||4.4||3.6||0.052|
|Inhaled steroid dose, μg†||1,520||1,400||0||0.739|
All subjects with AATD had a PiZ phenotype and none had previously received AAT augmentation therapy. One subject with AATD did not complete treatment due to the development of a widespread skin rash after the first infusion with Prolastin and hence was excluded from the analysis. Three patients with AATD had an acute exacerbation during the 12-week treatment period that required management on an outpatient basis with a course of antibiotics and systemic steroids. In two of these cases the exacerbation resolved 6 weeks before the repeat PET-CT scan, and in the third case resolution of symptoms occurred 3 weeks before imaging.
The mean (± 1 SD) injected dose of 18FDG for PET imaging was 122.0 ± 10.2 MBq, and the mean total dose for imaging was 4.3 mSv. Pulmonary 18FDG uptake in the whole lung was not significantly different between the groups when COPD was defined using a fixed ratio of FEV1/FVC (Figure 1) but was significantly higher in the COPD group compared with the healthy control group (P = 0.009) when defined using the LLN (see online supplement). 18FDG uptake in the upper lung was greater in patients with usual COPD (0.0061 ± 0.0016/min) compared with the healthy control group (0.0045 ± 0.0009/min, P = 0.009; Figures 2 and 3) and correlated with FEV1 % predicted (r = −0.848, P = 0.001) (Figure 4), FEV1/FVC (r = −0.918, P < 0.001) (Figure 5), Kco % predicted (r = −0.624, P = 0.027), and Perc15 (r = −0.709, P = 0.011) (Figure 6). The distribution of emphysema in the usual COPD group was predominantly apical, as demonstrated by the locality data (see Table 1). There was no difference in 18FDG uptake at baseline (0.0033 ± 0.0013/min) and on treatment (0.0036 ± 0.0012/min) in the patients with AATD (Figure 1).
18FDG uptake in circulating neutrophils was lower in the COPD group (3.06 ± 1.62; Figure 7) compared with the AATD group (6.93 ± 3.43; P = 0.022) but just failed to reach significance compared with the healthy control group (7.36 ± 5.69; P = 0.091). Hs-CRP concentrations (Figure 8) were greater in the usual COPD (8.26 ± 8.61 g/L) group compared with the healthy control group (3.57 ± 6.60 g/L; P = 0.032) but not the AATD group (2.45 ± 2.48 g/L; P = 0.063).
The current study describes significant differences in pulmonary 18FDG uptake assessed using quantitative 18FDG PET-CT in patients with usual COPD compared with patients with COPD associated with α1-antritrypsin deficiency and healthy control subjects. Regional differences were seen in pulmonary 18FDG uptake, and, in patients with COPD, there was a correlation between 18FDG uptake and clinical measures of disease severity. Pulmonary 18FDG uptake in patients with AATD was comparable to that seen in healthy control subjects and was not altered by 12 weeks’ treatment with augmentation therapy. Uptake of 18FDG by circulating neutrophils was lower in patients with usual COPD than the other two groups despite evidence of a systemic inflammatory response in patients with usual COPD, as demonstrated by a higher mean serum hs-CRP concentration.
Our data support previous studies that have shown increased pulmonary uptake of 18FDG in patients with COPD (17, 28) and provides more convincing evidence that this relates to the presence of emphysema. The methodology used in the current study enabled the construction of a detailed voxel-based, three-dimensional Patlak map that allowed calculation and visualization (see example in Figure 8) of regional pulmonary 18FDG uptake. We used this approach to demonstrate that the greatest signal occurred in the upper lung in patients with COPD and that there was an axial gradient of 18FDG uptake. The coincident predominance of emphysema and 18FDG uptake in the upper lung, and the correlation between quantitative 18FDG PET-CT and clinical measures of COPD severity, in particular with measures of emphysema severity, suggest that the signal that is seen in quantitative 18FDG PET-CT in patients with usual COPD may relate to the presence of centrilobular emphysema. The use of this methodology also afforded a means of identifying and excluding “artifactual” extrapulmonary uptake arising from thoracic wall, diaphragmatic, and cardiac motion. Consequently, the method of quantitative image analysis that we used was likely more effective at eliminating higher signal originating from extrapulmonary tissue, such as myocardium, than that of the previous studies, and was therefore more representative of true pulmonary 18FDG uptake than previously used methods that averaged 18FDG uptake over the whole field of view to generate a single Patlak plot.
Comparison of the summated 3D Patlak data for whole lung analysis with the results of previous studies (17, 28) suggests that, in the current study, the patients with COPD could be less clearly demarcated from the healthy control subjects, although this distinction became much clearer when using the LLN to define COPD. The most likely explanation for this difference is that, unlike the previous study that examined patients with moderate to severe COPD (17), we included patients with mild COPD. When we performed an additional post hoc analysis (n = 7) that excluded COPD patients with an FEV1 greater than 60%, the demographics of the group, and the results, were comparable to that of the study by Jones and colleagues (17) (data not shown). These data suggest that future studies of COPD using this imaging modality should further explore the influence of disease stage and phenotype on 18FDG uptake.
Pulmonary uptake of 18FDG has been shown to relate to neutrophilic activity in animal models of lobar pneumonia (18) and fibrosis (14), and, consequently, it may be appropriate to conclude that 18FDG PET-CT is a valid noninvasive biomarker of pulmonary neutrophilic activity in usual COPD. These findings are also consistent with the concept that neutrophilic inflammation is of central importance in the pathogenesis of usual COPD (2). However, the current data are not consistent with the conventional understanding that the neutrophilic inflammation in COPD associated with AATD is comparable in nature but more severe than that seen in usual COPD. Patients with severe AATD have a greater degree of airways inflammation compared with usual COPD (6, 7). Consequently, it would be expected that pulmonary 18FDG uptake would be greater in AATD than in usual COPD and that both patient groups would have greater pulmonary 18FDG uptake than healthy control subjects. The protease–antiprotease theory of emphysema pathogenesis in AATD has recently come under scrutiny from the challenging proposal of an inflammatory mechanism driven by the in situ formation of antitrypsin polymers within the lung (29). Nevertheless, this still assumes the same final common pathway of increased neutrophilic inflammation relative to usual COPD irrespective of whether in situ polymer formation is the principal mechanism. Consequently, an alternative explanation is required to account for the apparent disparity between accepted data showing higher levels of neutrophilic inflammation in AATD than in usual COPD and the findings of the current study.
The use of radioisotopes is a relatively novel approach to the noninvasive quantification of lung inflammation, and, although there is good evidence that the methodology provides reliable and clinically relevant data, the results of some studies have been unexpected albeit informative. For example, in studies of patients with bronchiectasis, although indium-111 labeled granulocytes indicate significant migration of neutrophils, as evidenced by a correlation between the loss of isotope from the body and sputum volume and the extent of bronchiectasis on CT (30), there is little 18FDG uptake on PET imaging (18). Jones and colleagues, in a subsequent study, provided some explanatory evidence for this by demonstrating that 18FDG uptake is associated with some but not all neutrophil activities requiring energy (31). Consequently, a lack of increased 18FDG uptake cannot necessarily equate with a lack of neutrophil activity. Although this may allow for the disparity evident between the data for patients with AATD in the current and aforementioned studies (5), a further explanation is required to account for the unexpected difference identified in the uptake of 18FDG seen in patients with usual COPD compared with AATD.
The fundamental characteristics of emphysema associated with AATD are sufficiently similar to those seen in patients with usual COPD to have justified the belief that pathogenesis of both conditions is comparable albeit with quantitative differences (32). For example, neutrophil elastase has been shown to cause all of the pathognomic features of COPD (2), and greater levels of free neutrophil elastase are found in severe AATD (6) consistent with increased proteolytic damage. However, the phenotype of predominantly basal panlobular emphysema seen typically in AATD differs sufficiently from the predominantly apical centrilobular emphysema seen typically in usual COPD to suggest that there are important qualitative differences in pathogenesis. In particular, deficiency of AAT itself can explain the process in the absence of abnormal neutrophils. This idea has been explored in studies of neutrophil function that have identified differences in the behavior of neutrophils from patients with COPD compared with those from patients with AATD. Neutrophils from patients with COPD have been shown to demonstrate more rolling, tethering, and transendothelial migration under flow (33) and relatively higher levels of surface expression of adhesion molecules (33, 34) than those from patients with AATD. More importantly, the migratory behavior and structural responses of neutrophils from patients with COPD are fundamentally different from those from patients with AATD and control subjects, and may relate to altered phosphoinositide 3-kinase (PI3K) function (35). The increased neutrophil migration speed and aberrant migration pathways that were seen in the neutrophils from patients with COPD could be normalized by incubation of the neutrophils with a PI3K inhibitor. This is of particular relevance to the current study, because the enhanced uptake of 18FDG by neutrophils in vitro has been shown to be dependent on PI3K activity and to be reduced by the addition of a PI3K inhibitor (36). Furthermore, the uptake of 18FDG was independent of respiratory burst activity. Consequently, the increased uptake of 18FDG seen in patients with usual COPD in the current and previous PET imaging studies may reflect the fundamental difference in neutrophil function in these patients. Clearly, further extensive studies will be necessary to explore this possibility and to understand the mechanism responsible for the apparent paradox in 18FDG signal seen with quantitative PET imaging in usual COPD and AATD.
It is well established that the number and activation of circulating neutrophils are increased (34, 37, 38) and that the level of circulating inflammatory mediators is increased (39–42) in patients with usual COPD. The role and mechanism of this systemic inflammation in the systemic features of COPD has not been established, but there is indirect evidence that it arises from overspill of inflammation from the lungs (43). Irrespective of whether this is the case, it was expected in the current study that the level of hs-CRP and the uptake of 18FDG by circulating neutrophils would be increased in patients with COPD. The method of phosphorimaging used in the current study has been shown to be a sensitive index of the activation of circulating primed neutrophils (25, 31). Consequently, the finding that 18FDG uptake by circulating neutrophils was not increased coincident with increased levels of serum hs-CRP in patients with COPD suggests that, even in the presence of a systemic inflammatory response, priming of neutrophils occurs mainly within the lung in COPD. Further studies are required to explore this possible explanation.
In conclusion, significant differences in pulmonary 18FDG uptake were demonstrated between patients with stable COPD and both healthy control subjects and patients with AATD, which may reflect fundamental differences in neutrophil function. Pulmonary 18FDG uptake was greatest in the upper lung in patients with COPD and correlated with clinical measures of COPD, in particular, emphysema. Quantitative 18FDG PET-CT offers a methodology to translate in vitro neutrophilic studies into clinic research and represents a potential noninvasive tool for clinical studies of antiinflammatory therapies in usual COPD. However, although published evidence indicates that the neutrophils in COPD are abnormally active in their migratory and degranulation functions (which would be consistent with our findings), the cellular processes associated with the uptake and use of glucose by neutrophils in COPD require further characterization to interpret quantitative 18FDG PET-CT studies.
The authors thank Dr. Hazel Jones for her advice and support on technical issues relating to the performance of quantitative PET imaging.
|1.||Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, Schmid V, Buist S. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 2006;27:397–412.|
|2.||Stockley RA. Neutrophils and the pathogenesis of COPD. Chest 2002;121:151S–155S.|
|3.||Fujita J, Nelson NL, Daughton DM, Dobry CA, Spurzem JR, Irino S, Rennard SI. Evaluation of elastase and antielastase balance in patients with chronic bronchitis and pulmonary emphysema. Am Rev Respir Dis 1990;142:57–62.|
|4.||Ilumets H, Rytila PH, Sovijarvi AR, Tervahartiala T, Myllarniemi M, Sorsa TA, Kinnula VL. Transient elevation of neutrophil proteinases in induced sputum during COPD exacerbation. Scand J Clin Lab Invest 2008;68:618–623.|
|5.||Damiano VV, Tsang A, Kucich U, Abrams WR, Rosenbloom J, Kimbel P, Fallahnejad M, Weinbaum G. Immunolocalization of elastase in human emphysematous lungs. J Clin Invest 1986;78:482–493.|
|6.||Hill AT, Bayley DL, Campbell EJ, Hill SL, Stockley RA. Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency. Eur Respir J 2000;15:886–890.|
|7.||Morrison HM, Kramps JA, Burnett D, Stockley RA. Lung lavage fluid from patients with alpha 1-proteinase inhibitor deficiency or chronic obstructive bronchitis: anti-elastase function and cell profile. Clin Sci (Lond) 1987;72:373–381.|
|8.||Luisetti M, Ma S, Iadarola P, Stone PJ, Viglio S, Casado B, Lin YY, Snider GL, Turino GM. Desmosine as a biomarker of elastin degradation in COPD: Current status and future directions. Eur Respir J 2008;32:1146–1157.|
|9.||Pinto-Plata V, Toso J, Lee K, Park D, Bilello J, Mullerova H, De Souza MM, Vessey R, Celli B. Profiling serum biomarkers in patients with COPD: associations with clinical parameters. Thorax 2007;62:595–601.|
|10.||Walter RE, Wilk JB, Larson MG, Vasan RS, Keaney JF, Lipinska I, O’Connor GT, Benjamin EJ. Systemic inflammation and COPD: the Framingham Heart Study. Chest 2008;133:19–25.|
|11.||Turino GM. COPD and biomarkers: the search goes on. Thorax 2008;63:1032–1034.|
|12.||Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR, et al.. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 2008;31:416–469.|
|13.||Barnes PJ, Chowdhury B, Kharitonov SA, Magnussen H, Page CP, Postma D, Saetta M. Pulmonary biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:6–14.|
|14.||Jones HA, Boobis AR, Hamacher K, Coenen HH, Clark JC. PET imaging of pulmonary fibrosis. J Nucl Med 2003;44:483–484, author reply 484.|
|15.||Brudin LH, Valind SO, Rhodes CG, Pantin CF, Sweatman M, Jones T, Hughes JM. Fluorine-18 deoxyglucose uptake in sarcoidosis measured with positron emission tomography. Eur J Nucl Med 1994;21:297–305.|
|16.||Groves AM, Win T, Screaton NJ, Berovic M, Endozo R, Booth H, Kayani I, Menezes LJ, Dickson JC, Ell PJ. Idiopathic pulmonary fibrosis and diffuse parenchymal lung disease: implications from initial experience with 18F-FDG PET/CT. J Nucl Med 2009;50:538–545.|
|17.||Jones HA, Marino PS, Shakur BH, Morrell NW. In vivo assessment of lung inflammatory cell activity in patients with COPD and asthma. Eur Respir J 2003;21:567–573.|
|18.||Jones HA, Sriskandan S, Peters AM, Pride NB, Krausz T, Boobis AR, Haslett C. Dissociation of neutrophil emigration and metabolic activity in lobar pneumonia and bronchiectasis. Eur Respir J 1997;10:795–803.|
|19.||Labiris NR, Nahmias C, Freitag AP, Thompson ML, Dolovich MB. Uptake of 18fluorodeoxyglucose in the cystic fibrosis lung: a measure of lung inflammation? Eur Respir J 2003;21:848–854.|
|20.||Chen DL, Ferkol TW, Mintun MA, Pittman JE, Rosenbluth DB, Schuster DP. Quantifying pulmonary inflammation in cystic fibrosis with positron emission tomography. Am J Respir Crit Care Med 2006;173:1363–1369.|
|21.||Subramanian D, Jenkins L, Edgar R, Stockley R, Parr D. The evaluation and control of lung inflammation assessed with PET scanning in emphysema - alpha-1 antitrypsin deficiency (ECLIPSE-AATD) trial. Am J Respir Crit Care Med 2011;183:A6152.|
|22.||Quanjer PH, Tammeling GJ, Cotes JE, Fabbri LM, Matthys H, Pedersen OF, Peslin R, Roca J, Sterk PJ, Ulmer WT, et al.. Symbols, abbreviations and units. Working party standardization of lung function tests, European Community for Steel and Coal. Eur Respir J Suppl 1993;16:85–100.|
|23.||Patlak CS. The effect of the previous generation on the distribution of gene frequencies in populations. Proc Natl Acad Sci USA 1953;39:1063–1068.|
|24.||Bakker ME, Putter H, Stolk J, Shaker SB, Piitulainen E, Russi EW, Stoel BC. Assessment of regional progression of pulmonary emphysema with CT densitometry. Chest 2008;134:931–937.|
|25.||Jones HA, Choudhury M, Harris DN. In vivo measurement of circulating leucocyte activation in patients following cardiopulmonary bypass. Nucl Med Biol 2004;31:965–969.|
|26.||Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al.. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532–555.|
|27.||Swanney MP, Ruppel G, Enright PL, Pedersen OF, Crapo RO, Miller MR, Jensen RL, Falaschetti E, Schouten JP, Hankinson JL, et al.. Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction. Thorax 2008;63:1046–1051.|
|28.||Chen DL, Azulay D-O, Atkinson JJ, Yusen RJ, Brody SL, Kozlowski J, Thomas BT, McCarthy TJ, Danto SI, Miller JP, et al.. Reproducibility of positron emission tomography (PET)-measured [18F]Fluorodeoxyglucose ([18F]FDG) uptake as a marker of lung inflammation in chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 2011;183:A6449.|
|29.||Gooptu B, Ekeowa UI, Lomas DA. Mechanisms of emphysema in alpha1-antitrypsin deficiency: molecular and cellular insights. Eur Respir J 2009;34:475–488.|
|30.||Currie DC, Pavia D, Agnew JE, Lopez-Vidriero MT, Diamond PD, Cole PJ, Clarke SW. Impaired tracheobronchial clearance in bronchiectasis. Thorax 1987;42:126–130.|
|31.||Jones HA, Cadwallader KA, White JF, Uddin M, Peters AM, Chilvers ER. Dissociation between respiratory burst activity and deoxyglucose uptake in human neutrophil granulocytes: implications for interpretation of (18)F-FDG PET images. J Nucl Med 2002;43:652–657.|
|32.||Abboud RT, Vimalanathan S. Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema. Int J Tuberc Lung Dis 2008;12:361–367.|
|33.||Woolhouse IS, Bayley DL, Lalor P, Adams DH, Stockley RA. Endothelial interactions of neutrophils under flow in chronic obstructive pulmonary disease. Eur Respir J 2005;25:612–617.|
|34.||Noguera A, Batle S, Miralles C, Iglesias J, Busquets X, MacNee W, Agusti AG. Enhanced neutrophil response in chronic obstructive pulmonary disease. Thorax 2001;56:432–437.|
|35.||Sapey E, Stockley JA, Greenwood H, Ahmad A, Bayley D, Lord JM, Insall RH, Stockley RA. Behavioral and structural differences in migrating peripheral neutrophils from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011;183:1176–1186.|
|36.||Paik JY, Ko BH, Choe YS, Choi Y, Lee KH, Kim BT. PMA-enhanced neutrophil [18F]FDG uptake is independent of integrin occupancy but requires PI3K activity. Nucl Med Biol 2005;32:561–566.|
|37.||Burnett D, Chamba A, Hill SL, Stockley RA. Neutrophils from subjects with chronic obstructive lung disease show enhanced chemotaxis and extracellular proteolysis. Lancet 1987;2:1043–1046.|
|38.||Noguera A, Busquets X, Sauleda J, Villaverde JM, MacNee W, Agusti AG. Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:1664–1668.|
|39.||Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004;59:574–580.|
|40.||Churg A, Wang RD, Tai H, Wang X, Xie C, Wright JL. Tumor necrosis factor-alpha drives 70% of cigarette smoke-induced emphysema in the mouse. Am J Respir Crit Care Med 2004;170:492–498.|
|41.||Di Francia M, Barbier D, Mege JL, Orehek J. Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994;150:1453–1455.|
|42.||Karadag F, Karul AB, Cildag O, Yilmaz M, Ozcan H. Biomarkers of systemic inflammation in stable and exacerbation phases of COPD. Lung 2008;186:403–409.|
|43.||Sinden NJ, Stockley RA. Systemic inflammation and comorbidity in COPD: A result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 2010;65:930–936.|
Funded by an unrestricted educational grant from Talecris Biotherapeutics Ltd. Talecris was acquired by Grifols Inc as of June 2011.
Author Contributions: Conception, hypotheses delineation, and design of the study: R.A.S., D.G.P. Acquisition of the data or the analysis and interpretation of such information: D.R.S., L.J., R.E., N.Q., R.A.S., D.G.P. Writing the article or substantial involvement in its revision before submission: D.R.S., R.A.S., D.G.P.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201201-0051OC on July 26, 2012