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Original Research: COPD |

Increased Systemic Inflammation Is a Risk Factor for COPD Exacerbations* FREE TO VIEW

Karin H. Groenewegen, MD; Dirkje S. Postma, MD, PhD; Wim C. J. Hop, PhD; Pascal L. M. L. Wielders, MD; Noel J. J. Schlösser, MD; Emiel F. M. Wouters, MD, FCCP; for the COSMIC Study Group
Author and Funding Information

*From the Department of Respiratory Medicine (Drs. Groenewegen and Wouters), University Hospital Maastricht, Maastricht; Department of Respiratory Medicine (Dr. Postma), University Medical Center Groningen, University of Groningen, Groningen; Department of Epidemiology and Biostatistics (Dr. Hop), Erasmus Medical Center Rotterdam, Rotterdam; Department of Respiratory Medicine (Dr. Wielders), Catharina Hospital Eindhoven, Eindhoven; and Department of Respiratory Medicine (Dr. Schlösser), Central Military Hospital Utrecht, Utrecht, the Netherlands.

Correspondence to: Karin H. Groenewegen, MD, Department of Respiratory Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands; e-mail: ksi@lung.azm.nl


*From the Department of Respiratory Medicine (Drs. Groenewegen and Wouters), University Hospital Maastricht, Maastricht; Department of Respiratory Medicine (Dr. Postma), University Medical Center Groningen, University of Groningen, Groningen; Department of Epidemiology and Biostatistics (Dr. Hop), Erasmus Medical Center Rotterdam, Rotterdam; Department of Respiratory Medicine (Dr. Wielders), Catharina Hospital Eindhoven, Eindhoven; and Department of Respiratory Medicine (Dr. Schlösser), Central Military Hospital Utrecht, Utrecht, the Netherlands.


Chest. 2008;133(2):350-357. doi:10.1378/chest.07-1342
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Background: COPD is characterized by episodic increases in respiratory symptoms, so-called exacerbations. COPD exacerbations are associated with an increase in local and systemic inflammation. Data of a previously published study in a well-characterized COPD cohort were analyzed to define predictive factors of acute exacerbations, particularly focusing on systemic inflammation.

Objective: To determine if an elevated systemic inflammatory status measured at baseline is related to the occurrence of acute exacerbations in patients with COPD.

Methods: The occurrence of moderate (requiring oral prednisolone) and severe exacerbations (requiring hospitalization) was prospectively recorded over 1 year. At the beginning of the study, lung function values (FEV1, FVC, functional residual capacity, and diffusion capacity of the lung for carbon monoxide [Dlco]) and serum levels of C-reactive protein, fibrinogen, lipopolysaccharide binding protein, tumor necrosis factor (TNF)-α, and its soluble receptors (soluble TNF receptors 55 and 75) as markers of systemic inflammation were determined.

Results: Two hundred seventy-seven person-years of follow-up were analyzed in the total group of 314 patients: 186 patients were responsible for 411 exacerbations (374 moderate and 37 severe). Multivariate analyses showed that a higher initial fibrinogen level and a lower FEV1 predicted a higher rate of both moderate and severe exacerbations. Additional independent predictors of a severe exacerbation were a higher number of prestudy severe exacerbations and lower Dlco. A higher number of prestudy moderate exacerbations was the only additional independent risk factor for the rate of moderate exacerbations.

Conclusion: This study demonstrates that besides lung function impairment systemic inflammation manifested by elevated fibrinogen levels is an independent risk factor for exacerbations of COPD. Attenuation of systemic inflammation may offer new perspectives in the management of COPD patients to reduce the burden of exacerbations.

Figures in this Article

COPD is characterized by episodic increases in respiratory symptoms, so-called exacerbations. These episodes contribute considerably to the increased morbidity, mortality, and health-care costs associated with this disease.14 The definition of acute exacerbation of COPD is largely based on reported symptomatology by the patient, mostly an increase in dyspnea, cough, and sputum production. Different studies58 have reported that airway inflammation increases in acute exacerbations.

Besides an increase in airway inflammation, COPD exacerbations are associated with an increase in systemic inflammation. It has been established that stable COPD is associated with low-grade systemic inflammation as demonstrated by an increase in blood leukocytes,6 acute-phase proteins C-reactive protein (CRP)6and fibrinogen,7 and inflammatory cytokines.2,8 During acute exacerbations of COPD, higher levels of interleukin-6 as well as acute-phase proteins CRP, fibrinogen, and lipopolysaccharide binding protein (LBP) have been demonstrated, declining again during recovery.7,9

It is now recognized that exacerbations are an important outcome in COPD because patients prone to frequent exacerbations have impaired health status,3 reduced physical activity levels,10increased lower airway bacterial colonization,11and accelerated lung function decline.1213 Thus, identification of patients at risk for development of acute exacerbations is important because it could lead to more appropriate therapeutic interventions or more specific treatment of identifiable risk factors. A number of risk factors for acute exacerbations have been described: hypercapnia,1415 previous hospital admissions,3,14 current smoking,14 impaired health status,3,16 pulmonary hypertension15 and hypoxia,14 low body mass index (BMI),17 and low FEV1.,14 Most of these factors have been identified in COPD patients who were hospitalized for an acute exacerbation. However, limited prospective data are available on patients who have moderate exacerbations with treatment out of the hospital.

We hypothesized that besides lung function characteristics, an elevated systemic inflammatory status is related to the occurrence of acute exacerbations in COPD. We analyzed data of a 1-year prospective study in a well-characterized COPD cohort to define predictive factors of acute exacerbations, including both moderate and severe exacerbations, particularly focusing on systemic inflammation.

Study Design

This study is a secondary study of the COSMIC study (COPD and Seretide: a Multi-Center Intervention and Characterization), a multicenter trial to investigate the effects of steroid withdrawal in comparison with combination therapy (long-acting β2-agonist salmeterol and inhaled steroid fluticasone) during a 1-year follow-up period.18 The COSMIC study had a multicenter, randomized, double-blind, parallel-group design. All patients received combined salmeterol (50 μg) and fluticasone (500 μg) bid (in the morning and evening) via an inhaler during a 3-month run-in period. Thereafter, patients were randomized to a 12-month treatment with either salmeterol/fluticasone (SFC) or salmeterol alone. Inhaled salbutamol was used as relief medication, and anticholinergics and methylxanthines in constant dose were allowed throughout the study. After the 3-month run-in period, at the randomization visit systemic inflammatory parameters were measured next to previously described clinical parameters.18

Patients

Inclusion and exclusion criteria have been previously described.18 In short, entry criteria were as follows: age 40 to 75 years, established history of COPD, current or ex-smokers with at least 10 pack-years, prebronchodilator FEV1 30 to 70% of predicted, FEV1/FVC < 88% for men and < 89% for women, and reversibility of 400 μg with salbutamol < 10% of FEV1 percentage of predicted. Importantly, all patients had a history of at least two documented COPD exacerbations in the year preceding the study inclusion. Patients requiring systemic corticosteroids or antibiotics or hospitalization for lower respiratory tract infection and/or COPD exacerbation in the 3-month run-in period were also excluded. Three hundred fourteen of the randomized patients were included in this substudy. Approval from ethics committees at each participating site and written informed consent from all patients were obtained.

Measurements
Static and Dynamic Lung Volumes:

FEV1, FVC, and peak expiratory flow were calculated from the flow-volume curve using a spirometer (Masterlab; Jaeger; Würzburg, Germany). The Tiffeneau index was calculated as FEV1/FVC. Lung function parameters were expressed as percentage of reference values.19After stopping of short-acting bronchodilating medication for 6 h and long-acting β-agonists and study medication for 12 h, reversibility was assessed by inhaling 400 μg of salbutamol using a spacer; reversibility was expressed as percentage of the predicted FEV1 values. Dynamic lung volumes were measured before and 10 min after administration of salbutamol. Functional residual capacity (FRC) was determined by the closed-circuit, multibreath, helium dilution method. Diffusion capacity of the lung for carbon monoxide (Dlco) was measured using the single-breath method and corrected for hemoglobin by the equation given by Cotes et al.20

Exacerbations:

All exacerbations were recorded prospectively during the 12-month follow-up period. Symptoms and use of additional medication and/or hospital admission were recorded in the patient’s chart by the study physician. An exacerbation was defined as follows: worsening of the patient’s symptoms of cough, sputum production, and/or breathlessness requiring a change in medication. Exacerbations were classified according to severity as moderate or severe. In case of a moderate exacerbation, treatment with a standardized course of prednisolone tablets of 30 mg/d for 10 days was indicated. At the discretion of the physician, a moderate exacerbation was additionally treated with a 10-day course of antibiotics. Severe exacerbations required hospitalization of the patient, based on the discretion of the physician.

Inflammatory Markers:

Blood was collected in an evacuated tube containing ethylenediamine tetra-acetic acid (Sherwood Medical; St Louis, MO) and immediately placed on melting ice. Plasma was separated from blood cells by centrifugation for 10 min within 2 h after collection in a refrigerated centrifuge (speed between 3,000 and 5,000 revolutions per minute), without use of the brake. The separated plasma was centrifuged for 5 min, with use of the brake. Plasma samples were stored at – 70°C until analysis.

High-sensitivity CRP was assessed by a particle-enhanced immunonephelometry (BN Prospec; Dade-Behring; Liederbach, Germany). The detection limit for high-sensitivity CRP was 0.175 mg/L (range, 0.175 to 1,100 mg/L), depending on the dilution (N Hs CRP, catalog No. OQIY 13; supplement reagent OUMU; Dade-Behring). Reference values were 0.26 to 7.24 mg/L.21Fibrinogen was assessed using a coagulation analyzer (Sysmex CA-7000; Dade-Behring) according to the Clauss method and calculated from ethylenediamine tetra-acetic acid to citrate plasma values. The measuring range was 0.3 to 10.0 g/L, and the reference range was 1.7 to 4.0 g/L. LBP and the soluble tumor necrosis factor (TNF) receptors (soluble TNF receptor 55 [sTNF-R55], soluble TNF receptor 75 [sTNF-R75]) were measured by enzyme-linked immunosorbent assay, as described previously.22

Lower detection limits for the assays were 1 ng/mL for LBP, 40 ng/mL for sTNF-R55, and 70 ng/mL for sTNF-R75. TNF-α was determined with a high-sensitivity enzyme-linked immunosorbent assay (Quantikine; R&D Systems; Minneapolis, MN), with a lower detection limit of 0.5 pg/mL for total TNF-α.

Statistical Analysis

The predictive values of inflammatory parameters, gender, smoking status (current/former), pack-years, and lung function parameters FEV1, Dlco, and FRC (all expressed as percentage of predicted) were analyzed separately for severe and moderate exacerbations. Also, the documented number of moderate and severe exacerbations during the year before entry into the study was analyzed for predictive values. Definition of these exacerbations was the same as for the follow-up period.

As there were few patients (n = 5) with more than one severe exacerbation, Kaplan-Meier curves and log-rank tests were calculated to evaluate the time until the first severe exacerbation. Cox proportional hazards model was used to evaluate various variables simultaneously regarding the time until the first severe exacerbation.

Many patients had more than one moderate exacerbation. Therefore, Poisson regression was performed as primary analysis to evaluate relations between the annual rate of moderate exacerbations during follow-up and various variables (SAS PROC GENMOD; SAS Institute; Cary, NC), allowing for overdispersion. Exacerbation data were analyzed up to the time of withdrawal or completion of the study.

Other analyses were performed using statistical software (SPSS for Windows, version 11.5; SPSS; Chicago, IL). To eliminate the influence of outlying observations for CRP, TNF-α, sTNF-R55, sTNF-R75, and LBP, these parameters were logarithmically transformed in all analyses. Spearman correlation coefficients (r) are given; p = 0.05 (two-sided) was considered the limit of significance in all analyses.

Patient demographic data and baseline characteristics are summarized in Table 1 . During the 1-year follow-up period, 69 patients withdrew. This occurred after a mean follow-up of 23 weeks. Of the total group of 314 patients, a total of 277 person-years was analyzed (mean follow-up, 0.88 years per patient). Of these 314 patients, 128 patients had neither a moderate nor a severe exacerbation during follow-up; 31 patients had a total of 37 severe exacerbations, with the number per patient ranging from 1 to 2.

One hundred seventy-nine patients had a total of 374 moderate exacerbations, with the number per patient ranging from 1 to 10. No differences in exacerbation rates were found between the salmeterol and SFC treatment groups with respect to severe, moderate, or total number of exacerbations. The total (moderate and severe) mean annual exacerbation rates were 1.61 and 1.36 for the salmeterol and SFC treatment groups, respectively (rate ratio, 1.2; 95% confidence interval [CI], 0.9 to 1.6; p = 0.23). Furthermore, no differences could be demonstrated between both treatment arms for the time until the first severe or first moderate exacerbation. Since there were no differences between the two groups, all further analyses were performed in the two treatment groups combined.

Smokers had a slightly higher LBP (p = 0.02) and lower TNF-α (p = 0.03) than nonsmokers. There were no significant differences in fibrinogen, CRP, and soluble TNF receptors between smokers and nonsmokers.

Severe Exacerbations
Univariate Analysis:

Table 2 shows levels of inflammatory parameters in the total group and stratified according to whether or not a severe exacerbation had occurred during the treatment period of 1 year. Table 2 shows a significantly higher median value of fibrinogen in patients having a severe exacerbation. Kaplan-Meier curves with patients grouped according to median level of fibrinogen showed an increase of the exacerbation rate with a higher fibrinogen level (Fig 1 ). Univariate Cox regression did not reveal any relation between severe exacerbations and the other inflammatory parameters.

Univariate analysis of the lung function parameters showed that FEV1, Dlco, and FRC were all significantly related to the occurrence of a severe exacerbation. Figure 2 shows Kaplan-Meier curves according to FEV1, Dlco, and FRC. Univariate analysis did not show any relationship with BMI, gender, age, or smoking history.

It was found that the documented occurrence of severe exacerbations during the year before entry into the study was related to the occurrence of severe exacerbations during the follow-up period. Of the group of 271 patients who had no prior severe exacerbation, 8% had severe exacerbations during follow-up. This percentage was 27% in the group of 43 patients who had at least one prior severe exacerbation (p < 0.001).

Multivariate Analysis:

In multivariate Cox regression of the three lung function parameters FEV1, Dlco, and FRC, it was found that FEV1 and Dlco were the two major predictive factors independently related to the occurrence of a severe exacerbation. Simultaneous evaluation of fibrinogen level, FEV1, and Dlco showed that these three factors were all significantly predictive. This analysis further showed that also the number of documented prior severe exacerbations was predictive (Table 3 ). The number of prior moderate exacerbations was not predictive (p = 0.13). None of the other investigated factors, including treatment group, was of significant importance when these four variables were taken into account.

Moderate Exacerbations
Univariate Analysis:

In univariate analysis, none of the inflammatory parameters was significantly associated with the time until the first moderate exacerbation; FEV1 was the only lung function parameter associated. The percentage of patients with a moderate exacerbation within 12 months was 67% in patients below and 52% in those above the median FEV1 of 46% predicted (p = 0.010). None of the demographic data, except the number of documented moderate exacerbations during the year before entry into study, showed an association with the time until first moderate exacerbation. With an increasing number of prior moderate exacerbations, the percentage of patients who had a moderate exacerbation during the follow-up period increased. The percentage of patients with moderate exacerbations within 1 year was 56% when the number of moderate exacerbations in the previous year was two or less (n = 231), 68% when the number of moderate exacerbations in the previous year was three (n = 56), and 76% if the number of moderate exacerbations in the previous year was four or more (n = 27), with p value for trend = 0.005.

Of the inflammatory parameters measured, only fibrinogen showed an association with the number of moderate exacerbations in the follow-up period. Univariate Poisson regression showed that the annual rate of moderate exacerbations increased with a factor of 1.2 (p = 0.042) for each increase with 1 U (1 g/L) of fibrinogen. Of the lung function parameters, only baseline FEV1 (percentage of predicted) was related to the number of moderate exacerbations. With each 10% points increase, the annual rate decreased by 15% (p = 0.01). There was also a significant relation of the number of moderate exacerbations with the number of moderate exacerbations during the prestudy year (p < 0.001) but not with the prior number of severe exacerbations (p = 0.13).

Multivariate Analysis:

Simultaneous evaluation of FEV1, fibrinogen, and number of prestudy exacerbations showed that these three factors were all independently related to the rate of occurrence of moderate exacerbations (Table 4 ). The number of prestudy severe exacerbations was not predictive (p = 0.45). Fibrinogen levels did not correlate with FEV1 (r = 0.01, p = 0.91) or number of prestudy moderate exacerbations (r = 0.03, p = 0.63).

For all analyses, prebronchodilator FEV1 values were used. Prebronchodilator and postbronchodilator FEV1 correlated strongly (r = 0.95, p < 0.001). Similar results in the analyses for severe and moderate exacerbations were obtained when postbronchodilator FEV1 was evaluated instead of prebronchodilator FEV1.

We investigated which factors predict acute COPD exacerbations and in particular the role of systemic inflammation in the occurrence of these acute events. We found that higher fibrinogen levels are significantly predictive for the occurrence of severe as well as moderate exacerbations. Further independent predictors for severe acute exacerbations were FEV1, Dlco, and the number of prestudy severe exacerbations, whereas FEV1 and the number of prestudy moderate exacerbations were independent predictors for moderate acute exacerbations.

Besides being a measure of lung function, FEV1 is the parameter used in clinical practice to define the severity of COPD, regardless of the underlying pathophysiology. Since FEV1 reflects both disease in the airway wall and loss of alveolar attachments caused by emphysema, it is not surprising that FEV1 is an important predictor for acute exacerbations. The occurrence of acute exacerbations was significantly higher in our patients with lower FEV1, confirming previous data.14 A recent report by Pinto-Plata et al23 showed that FEV1 was significantly correlated to changes in inflammatory cytokines in patients hospitalized for an acute exacerbation.

The fact that the number of prestudy exacerbations is significantly predictive for an acute exacerbation is also in line with previous studies.3,14,24 Interestingly, the number of severe exacerbations in the year before entry into the study predicted for the occurrence of a severe but not a moderate exacerbation, while the number of moderate exacerbations in the year before entry into the study predicted for the occurrence of a moderate but not a severe exacerbation.

Fibrinogen is an acute-phase reactant and a blood-clotting factor, synthesized by hepatocytes, and released into the circulation in response to interleukin-6. Previous studies2526 have reported that COPD patients have higher systemic fibrinogen levels than healthy control subjects, independently of smoking. These levels increase even further during COPD exacerbations.7 Elevated fibrinogen levels have been associated with reduced FEV1 and increased risk of COPD.,26Also, in a large sample of the general population in the United States, both smoking and reduced FEV1 were related to increased systemic inflammation, measured by CRP and fibrinogen.27

These findings fit with a shift of the hemostatic balance to favor the activation of coagulation in COPD. Different studies2832 have suggested this prothrombotic condition to exist in COPD; other studies25,2829 have demonstrated increased platelet activation in COPD patients. Markers of the hypercoagulation thrombin-antithrombin III complex, fibrinopeptide A, and plasminogen activator inhibitor-1 have been shown to be significantly higher in COPD patients than in healthy control subjects.30This shift in the hemostatic balance can be further distorted during acute exacerbations due to increased rate of platelet aggregability as a consequence of acute disturbances in gas exchange.3132 In this study, we extend the present knowledge regarding fibrinogen by demonstrating that this clotting factor is an independent predictor of acute exacerbations.

Further prospective studies have to explore the relationship between these increased fibrinogen levels and possible exacerbation-related thromboembolic and cardiovascular morbidity. This is of interest because fibrinogen has been identified as an independent prognostic factor for cardiovascular morbidity.33 At this point, the clinical implication of these results is limited because no intervention that influences fibrinogen levels has been reported.

Interestingly, we found that Dlco was independently related to the occurrence of severe but not moderate exacerbations of COPD. How can we reconcile this association?

Dlco is a summative physiologic outcome parameter, reflecting parenchymal abnormalities, changes in pulmonary vascular bed, or underlying cardiac function. It can be hypothesized that patients with more impaired Dlco are prone to more severe worsening of the physical condition,3435 and thus hospitalization for acute exacerbations.36Dlco disturbances can be considered as an indirect marker of parenchymal destruction such as occurs in patients undergoing lung volume reduction surgery and transplantation.37 At least in these patients, progressive inflammatory changes have been associated with more severe lung function impairment.38 Future prospective studies need to explore differences in exacerbation pattern in COPD patients with different lung function impairment in order to better delineate specific COPD phenotypes.

A potential weakness of this study is that the data were originally sampled for another purpose. The study was not powered to investigate the comparison between treatment with or without inhaled corticosteroids regarding exacerbation rates. Favorable effects of inhaled corticosteroids cannot be excluded in view of the resulting wide 95% CI for the exacerbation rate ratio. Measurement of inflammatory markers was performed when all patients were in stable state and all patients had used inhalation steroids and long-ting β2-agonist for 3 months. Therefore, it can be assumed that our patients were maximally stable when systemic inflammatory parameters were measured.

Last but not least, it is important to realize that these results may not be applicable to all populations of COPD patients. The patients in this study were selected by two or more previous exacerbations in the preceding year. The results of this study may therefore be limited to a subgroup of frequent exacerbators.

This prospective study in COPD patients, initially selected based on the occurrence of at least two exacerbations in the year preceding entry of the study, indicates that airflow limitation, as well as fibrinogen as a marker of systemic inflammation, are related to a higher number of both moderate and severe exacerbations. Patients with impaired Dlco are found to be at higher risk for hospitalization for acute exacerbations.

This study demonstrates that besides lung function impairment systemic inflammation manifested by elevated fibrinogen levels is identified as an independent risk factor for acute exacerbations of COPD. Attenuation of systemic inflammation may offer new perspectives in the management of COPD patients in order to reduce the burden of exacerbations.

Abbreviations: BMI = body mass index; CI = confidence interval; CRP = C-reactive protein; Dlco = diffusing capacity of the lung for carbon monoxide; FRC = functional residual capacity; LBP = lipopolysaccharide binding protein; SFC = salmeterol/fluticasone; sTNF-R55 = soluble tumor necrosis factor receptor 55; sTNF-R75 = soluble tumor necrosis factor receptor 75; TNF = tumor necrosis factor

Glaxo-Smith-Kline provided funding for this study.

Dr. Groenewegen has no conflict of interest to declare. Dr. Postma has received honoraria for speaking engagements and research funding from AstraZeneca and GlaxoSmithKline. Dr. Hop is a regular biostatistical consultant to GSK. Dr. Wielders’ research institute has received grants for research purposes from AstraZeneca and GSK. Dr. Schloesser has no conflict of interest to declare. Dr. Wouters has received honoraria for speaking engagements and research funding from AstraZeneca and GlaxoSmithKline.

Table Graphic Jump Location
Table 1. Baseline Characteristics of the 314 Evaluated Patients*
* 

Data are presented as No. (%), mean ± SD, or median No. (range).

 

During year before entry into the study (total had to be at least 2 as inclusion criterium).

Table Graphic Jump Location
Table 2. Levels of Inflammatory Mediators in the Total Group of Patients According to the Presence of Severe Exacerbation*
* 

Data are presented as median (range).

 

Mann-Whitney test for the comparison of the severe exacerbation groups (yes vs no).

 

Fibrinogen data were not available in for 45 patients.

Figure Jump LinkFigure 1. Kaplan-Meier curves for the time until the first severe exacerbation according to above or below the median fibrinogen level. Tick marks denote patients withdrawing or completing study; p = 0.002.Grahic Jump Location
Figure Jump LinkFigure 2. Kaplan-Meier curves for the time until the first severe exacerbation according to FEV1 percentage of predicted (%pred) [below the median of 46% vs above, left panel], Dlco percentage of predicted (below the median of 65% vs above, middle panel), and FRC percentage of predicted (below the median of 124% vs above, right panel); p = 0.005, p < 0.001, and p = 0.02, respectively.Grahic Jump Location
Table Graphic Jump Location
Table 3. Multivariate Cox Regression Analysis for Prediction of a Severe Exacerbation During the 1-Year Treatment Period
* 

Per 10-percentage-point increase.

 

Per unit (grams per liter) increase.

 

Per additional occurrence in year before entry in study.

Table Graphic Jump Location
Table 4. Multivariate Poisson Regression Analysis for Prediction of the Annual Rate of Moderate Exacerbations
* 

Per 10-percentage-point increase.

 

Per unit (grams per liter) increase.

 

Per additional occurrence in year before entry into study.

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Wedzicha, JA, Syndercombe-Court, D, Tan, KC Increased platelet aggregate formation in patients with chronic airflow obstruction and hypoxaemia.Thorax1991;46,504-507. [PubMed]
 
Wedzicha, JA, Cotter, FE, Empey, DW Platelet size in patients with chronic airflow obstruction with and without hypoxaemia.Thorax1988;43,61-64. [PubMed]
 
Danesh, J, Lewington, S, Thompson, SG, et al Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.JAMA2005;294,1799-1809. [PubMed]
 
Pauwels, RA, Buist, AS, Ma, P, et al Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD); executive summary.Respir Care2001;46,798-825. [PubMed]
 
Rodriguez Roisin, R Toward a consensus definition for COPD exacerbations.Chest2000;117,398s-401s. [PubMed]
 
Vermeeren, MA, Schols, AM, Wouters, EF Effects of an acute exacerbation on nutritional and metabolic profile of patients with COPD.Eur Respir J1997;10,2264-2269. [PubMed]
 
Park, KJ, Bergin, CJ, Clausen, JL Quantitation of emphysema with three-dimensional CT densitometry: comparison with two-dimensional analysis, visual emphysema scores, and pulmonary function test results.Radiology1999;211,541-547. [PubMed]
 
Hogg, JC, Chu, F, Utokaparch, S, et al The nature of small-airway obstruction in chronic obstructive pulmonary disease.N Engl J Med2004;350,2645-2653. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Kaplan-Meier curves for the time until the first severe exacerbation according to above or below the median fibrinogen level. Tick marks denote patients withdrawing or completing study; p = 0.002.Grahic Jump Location
Figure Jump LinkFigure 2. Kaplan-Meier curves for the time until the first severe exacerbation according to FEV1 percentage of predicted (%pred) [below the median of 46% vs above, left panel], Dlco percentage of predicted (below the median of 65% vs above, middle panel), and FRC percentage of predicted (below the median of 124% vs above, right panel); p = 0.005, p < 0.001, and p = 0.02, respectively.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Baseline Characteristics of the 314 Evaluated Patients*
* 

Data are presented as No. (%), mean ± SD, or median No. (range).

 

During year before entry into the study (total had to be at least 2 as inclusion criterium).

Table Graphic Jump Location
Table 2. Levels of Inflammatory Mediators in the Total Group of Patients According to the Presence of Severe Exacerbation*
* 

Data are presented as median (range).

 

Mann-Whitney test for the comparison of the severe exacerbation groups (yes vs no).

 

Fibrinogen data were not available in for 45 patients.

Table Graphic Jump Location
Table 3. Multivariate Cox Regression Analysis for Prediction of a Severe Exacerbation During the 1-Year Treatment Period
* 

Per 10-percentage-point increase.

 

Per unit (grams per liter) increase.

 

Per additional occurrence in year before entry in study.

Table Graphic Jump Location
Table 4. Multivariate Poisson Regression Analysis for Prediction of the Annual Rate of Moderate Exacerbations
* 

Per 10-percentage-point increase.

 

Per unit (grams per liter) increase.

 

Per additional occurrence in year before entry into study.

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Wedzicha, JA, Cotter, FE, Empey, DW Platelet size in patients with chronic airflow obstruction with and without hypoxaemia.Thorax1988;43,61-64. [PubMed]
 
Danesh, J, Lewington, S, Thompson, SG, et al Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.JAMA2005;294,1799-1809. [PubMed]
 
Pauwels, RA, Buist, AS, Ma, P, et al Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD); executive summary.Respir Care2001;46,798-825. [PubMed]
 
Rodriguez Roisin, R Toward a consensus definition for COPD exacerbations.Chest2000;117,398s-401s. [PubMed]
 
Vermeeren, MA, Schols, AM, Wouters, EF Effects of an acute exacerbation on nutritional and metabolic profile of patients with COPD.Eur Respir J1997;10,2264-2269. [PubMed]
 
Park, KJ, Bergin, CJ, Clausen, JL Quantitation of emphysema with three-dimensional CT densitometry: comparison with two-dimensional analysis, visual emphysema scores, and pulmonary function test results.Radiology1999;211,541-547. [PubMed]
 
Hogg, JC, Chu, F, Utokaparch, S, et al The nature of small-airway obstruction in chronic obstructive pulmonary disease.N Engl J Med2004;350,2645-2653. [PubMed]
 
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