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1.  C-reactive protein as a prognostic marker in chronic obstructive pulmonary disease 
The present study aimed to evaluate whether circulating C-reactive protein (CRP) levels are a biomarker of systemic inflammation and a significant predictor of future chronic obstructive pulmonary disease (COPD) outcome. During the study, 116 patients with stable COPD and 35 age- and gender-matched healthy subjects with normal pulmonary function were observed. Patient follow-up was also performed to evaluate the strength of the associations between CRP levels and future outcomes. The observations from the present study showed that serum CRP levels were significantly higher in stable COPD patients than in control subjects (4.48±0.83 vs. 1.01±0.27 mg/l, respectively; P<0.05). In addition, it was identified that a serum CRP concentration of >3 mg/l is a poor prognostic variable of COPD compared with a CRP concentration of ≤3 mg/l [hazard ratio (HR), 2.71; 95% confidence interval (CI), 1.05–6.99; P<0.05]. A quantitative synthesis of four studies including 1,750 COPD patients was performed and statistically similar results were obtained (HR, 1.54; 95% CI, 1.14–2.07; P<0.01). The present study showed that circulating CRP levels are higher in stable COPD patients and, therefore, may be used as a long-term predictor of future outcomes. These observations highlight the importance of high sensitivity CRP assays in patients with stable COPD.
PMCID: PMC3881036  PMID: 24396422
C-reactive protein; chronic obstructive pulmonary disease; survival
2.  Determination of inflammatory biomarkers in patients with COPD: a comparison of different assays 
Chronic obstructive pulmonary disease (COPD) is an inflammatory pulmonary disorder with systemic inflammatory manifestations that are mediated by circulating acute-phase reactants. This study compared an enzyme-linked immunosorbent assay (ELISA) to a nephelometric technique for the measurement of serum C-reactive protein (CRP) and serum amyloid A (SAA) and investigated how the choice of assay influenced the estimation of inflammation in patients with stable COPD.
CRP and SAA concentrations measured by ELISA and nephelometry in 88 patients with COPD and 45 control subjects were used to evaluate the performance of these methods in a clinical setting.
With both assays, the concentrations of CRP and SAA were higher in COPD patients than in controls after adjustment for age and sex. There was a moderate correlation between the values measured by ELISA and those measured by nephelometry (logCRP: r = 0.55, p < 0.001; logSAA: r = 0.40, p < 0.001). However, the concentrations of biomarkers determined by nephelometry were significantly higher than those obtained with ELISA for CRP (mean difference = 2.7 (9.4) mg/L) and SAA (mean difference = 0.31 (14.3) mg/L).
Although the serum CRP and SAA concentrations measured by ELISA and nephelometry correlated well in COPD patients, the ELISA values tended to be lower for CRP and SAA when compared with nephelometric measurements. International standardization of commercial kits is required before the predictive validity of inflammatory markers for patients with COPD can be effectively assessed in clinical practice.
PMCID: PMC3340310  PMID: 22463705
3.  Systemic inflammation in chronic obstructive pulmonary disease: a population-based study 
Respiratory Research  2010;11(1):63.
Elevated circulating levels of several inflammatory biomarkers have been described in selected patient populations with COPD, although less is known about their population-based distribution. The aims of this study were to compare the levels of several systemic biomarkers between stable COPD patients and healthy subjects from a population-based sample, and to assess their distribution according to clinical variables.
This is a cross-sectional study design of participants in the EPI-SCAN study (40-80 years of age). Subjects with any other condition associated with an inflammatory process were excluded. COPD was defined as a post-bronchodilator FEV1/FVC < 0.70. The reference group was made of non-COPD subjects without respiratory symptoms, associated diseases or prescription of medication. Subjects were evaluated with quality-of-life questionnaires, spirometry and 6-minute walk tests. Serum C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukins (IL-6 and IL-8), alpha1-antitrypsin, fibrinogen, albumin and nitrites/nitrates (NOx) were measured.
We compared 324 COPD patients and 110 reference subjects. After adjusting for gender, age, BMI and tobacco consumption, COPD patients showed higher levels of CRP (0.477 ± 0.023 vs. 0.376 ± 0.041 log mg/L, p = 0.049), TNF-α (13.12 ± 0.59 vs. 10.47 ± 1.06 pg/mL, p = 0.033), IL-8 (7.56 ± 0.63 vs. 3.57 ± 1.13 pg/ml; p = 0.033) and NOx (1.42 ± 0.01 vs. 1.36 ± 0.02 log nmol/l; p = 0.048) than controls. In COPD patients, serum concentrations of some biomarkers were related to severity and their exercise tolerance was related to serum concentrations of CRP, IL-6, IL-8, fibrinogen and albumin.
Our results provide population-based evidence that COPD is independently associated with low-grade systemic inflammation, with a different inflammatory pattern than that observed in healthy subjects.
PMCID: PMC2891677  PMID: 20500811
4.  Local and systemic neutrophilic inflammation in patients with lung cancer and chronic obstructive pulmonary disease 
BMC Immunology  2013;14:36.
Recent investigations suggest that neutrophils play an important role in the immune response to lung cancer as well as chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the amount of neutrophils and markers of their activity in lung cancer and COPD and in coexistence of these two diseases.
In total, 267 persons were included in the study: 139 patients with lung cancer, 55 patients with lung cancer and COPD, 40 patients with COPD, and 33 healthy subjects. Peripheral blood and BAL fluid samples were obtained for cell count analysis and determination of NE, MPO levels and ROS production. NE and MPO levels in the serum and BAL fluid were determined by ELISA. ROS production was analyzed by flow cytometer.
The percentage, cell count of neutrophils and neutrophil to lymphocyte ratio in the peripheral blood were significantly higher in lung cancer patients with or without COPD compared to COPD patients or healthy individuals (P < 0.05). The percentage and cell count of neutrophils in BAL fluid were significantly lower in patients with lung cancer with or without COPD than in patients with COPD (P < 0.05). However, BAL fluid and serum levels of both NE and MPO were significantly higher in patients with lung cancer than COPD patients or healthy individuals (P < 0.05). Neutrophils produced higher amounts of ROS in patients with lung cancer with or without COPD compared with COPD patients or healthy individuals (P < 0.05).
The results from this study demonstrate higher degree of local and systemic neutrophilic inflammation in patients with lung cancer (with or without COPD) than in patients with COPD.
PMCID: PMC3750549  PMID: 23919722
Lung cancer; Chronic obstructive pulmonary disease; Neutrophils; Reactive oxygen species
5.  Lung density on high resolution computer tomography (HRCT) reflects degree of inflammation in smokers 
Respiratory Research  2014;15(1):23.
Smokers have increased cell concentration in the lower respiratory tract indicating a chronic inflammatory state, which in some individuals may lead to development of chronic obstructive pulmonary disease (COPD). Computer tomography (CT) imaging provides means of quantifying pulmonary structure and early signs of disease. We investigated whether lung density on high resolution CT differs between smokers and never-smokers and if this were associated to intensity of inflammation.
Forty smoking volunteers with normal pulmonary function, 40 healthy never-smokers and 40 patients with COPD of GOLD stage I-II, were included. Mean lung attenuation and percentage of pixels in the lung with attenuation between −750 and −900 HU (percentage higher density spectrum (%HDS)) were calculated on inspiratory CT-scans. Markers of systemic inflammation in blood and cell counts in bronchoalveolar lavage (BAL) fluid were recorded.
Lung density expressed as %HDS was increased in smokers (44.0 ± 5.8%) compared to both never-smokers (38.3 ± 5.8%) and patients with COPD (39.1 ± 5.8%), (p < 0.001, for both). Females had denser lungs than males, which was dependent on body height. Cell concentration in BAL were correlated to lung density in smokers (r = 0.50, p < 0.001).
Lung density on CT is associated with cell concentration in BAL in smokers and may mirror an inflammatory response in the lung. Gender difference in lung density is dependent on height. In COPD with emphysema, loss of lung tissue may counterbalance the expected increase in density due to inflammation. The findings may help to interpret high resolution CT in the context of smoking and gender and highlight the heterogeneity of structural changes in COPD.
PMCID: PMC3944780  PMID: 24564813
Inflammation; Attenuation; Lung density; Smoking; CT; Lung function; Gender; Bronchoalveolar lavage
6.  Neutrophil adhesion molecules in experimental rhinovirus infection in COPD 
Respiratory Research  2013;14(1):72.
COPD exacerbations are associated with neutrophilic airway inflammation. Adhesion molecules on the surface of neutrophils may play a key role in their movement from blood to the airways. We analysed adhesion molecule expression on blood and sputum neutrophils from COPD subjects and non-obstructed smokers during experimental rhinovirus infections.
Blood and sputum were collected from 9 COPD subjects and 10 smoking and age-matched control subjects at baseline, and neutrophil expression of the adhesion molecules and activation markers measured using flow cytometry. The markers examined were CD62L and CD162 (mediating initial steps of neutrophil rolling and capture), CD11a and CD11b (required for firm neutrophil adhesion), CD31 and CD54 (involved in neutrophil transmigration through the endothelial monolayer) and CD63 and CD66b (neutrophil activation markers). Subjects were then experimentally infected with rhinovirus-16 and repeat samples collected for neutrophil analysis at post-infection time points.
At baseline there were no differences in adhesion molecule expression between the COPD and non-COPD subjects. Expression of CD11a, CD31, CD62L and CD162 was reduced on sputum neutrophils compared to blood neutrophils. Following rhinovirus infection expression of CD11a expression on blood neutrophils was significantly reduced in both subject groups. CD11b, CD62L and CD162 expression was significantly reduced only in the COPD subjects. Blood neutrophil CD11b expression correlated inversely with inflammatory markers and symptom scores in COPD subjects.
Following rhinovirus infection neutrophils with higher surface expression of adhesion molecules are likely preferentially recruited to the lungs. CD11b may be a key molecule involved in neutrophil trafficking in COPD exacerbations.
PMCID: PMC3726453  PMID: 23834268
Chronic obstructive pulmonary disease; Exacerbations; Respiratory viruses; Neutrophils
7.  Ongoing airway inflammation in patients with COPD who do not currently smoke 
Thorax  2000;55(1):12-18.
BACKGROUND—Inflammatory changes in the airways in chronic obstructive pulmonary disease (COPD) are largely attributed to smoking, yet they may be present even if patients do not currently smoke. The differences in inflammatory cells and the factors contributing to these differences were examined in the airways of patients with COPD who do not currently smoke.
METHODS—Eighteen non-atopic subjects with COPD (14 men) of mean (SD) age 62 (8) years and forced expiratory volume in one second (FEV1) 59 (13)% predicted and 11 non-atopic healthy subjects (eight men) of mean (SD) age 58 (8) years, FEV1 104 (11)% predicted were studied. Sputum induction and bronchoscopy with bronchoalveolar lavage (BAL) and biopsies were performed.
RESULTS—Patients with COPD had more mucosal EG2+ cells (eosinophils) (median (range) 40 (0-190) versus 5 (0-40) cells/mm2, p = 0.049) and CD68+ cells (1115 (330-2920) versus 590 (450-1580) cells/mm2, p = 0.03), and a tendency towards more CD4+ but not CD8+ lymphocytes than healthy controls. Furthermore, patients with COPD had higher percentages of sputum neutrophils (77 (29-94) versus 36 (18-60)%, p = 0.001) and eosinophils (1.2 (0-8.5) versus 0.2 (0-3.1)%, p= 0.008), BAL fluid eosinophils (0.4 (0-1.7) versus 0.2 (0-0.5)%, p = 0.03), and higher concentrations of sputum eosinophilic cationic protein (ECP) (838 (115-23 760) versus 121 (35-218) ng/ml, p<0.001). Concentrations of ECP expressed per eosinophil were not higher. Patients with COPD with high mucosal EG2+ cell numbers also had high mucosal CD4+ cell numbers. Sputum eosinophilia was associated with a decrease in FEV1/VC and BAL fluid eosinophilia with a decrease in mucosal NP57+ cells (neutrophils).
CONCLUSIONS—Subjects with COPD who do not currently smoke have increased numbers of inflammatory cells. Eosinophils are increased in number in the airways in COPD but do not seem to be activated. The increased eosinophil numbers are probably due to recruitment as a result of ongoing inflammation. Macrophages and lymphocytes may play a part in this inflammation.

PMCID: PMC1745599  PMID: 10607796
8.  Prevalence and correlates of osteoporosis in chronic obstructive pulmonary disease patients in India 
Chronic obstructive pulmonary disease (COPD) is a syndrome of progressive airflow limitation caused by the abnormal inflammatory reaction of the airway and lung parenchyma. Osteoporosis is one of the major extrapulmonary manifestations of COPD. The, prevalence of osteoporosis in COPD patients in Indian population is unknown.
To study the prevalence of osteoporosis in COPD and to define various risk factors associated with reduced bone mineral density (BMD) in COPD.
Materials and Methods:
The study was done in the department of Pulmonary Medicine of a tertiary care hospital. All the diagnosed cases of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) guidelines were included in this study. The present study was a prospective study in for a period of 1 year. A brief history of the patients was taken, especially regarding duration of illness, number of exacerbations in the past 3 years, smoking in pack years, and history of steroid use (both systemic and inhaled steroids) after which cumulative dose of steroids was calculated. Spirometry was done in all these patients to stage the severity of COPD according to GOLD criteria. DEXA scan of the lumbar spine was done using bone densitometer to determine osteoporosis. A world Health Organization (WHO) criterion for definition of osteoporosis was applied and patients with T-score of > –2.5 standard deviation (SD) were diagnosed to have osteoporosis, –1 SD to –2.5 SD were diagnosed to have osteopenia and < –1 SD as normal. Statistical analysis for association of COPD with osteoporosis was done using chi-square test. Risk factors for osteoporosis were identified by univariate and multivariate logistic regression analysis.
A total of 102 COPD patients were included in the study. Among these, 68 patients (66.6%) had osteoporosis and 20 patients (19.6%) had osteopenia. Majority (64.7%) of the patients who had osteoporosis had stage III and stage IV COPD disease. It was observed that as the severity grade of COPD increased, the risk of osteoporosis also increased. The bone mineral density (BMD) showed a significant difference among different stages of COPD. As the severity of the stage of COPD increased, BMD decreased. It was also observed that patients with lower body mass index (BMI) had higher prevalence of osteoporosis (37.3%) as compared to overweight patients. On univariate analysis, it was observed that risk factors for osteoporosis were female sex, higher number of exacerbations, BMI, and severity of COPD. After using multivariate logistic regression analysis, stage IV COPD (odds ratio (OR): 34.48, 95% confidence interval (CI): 1.59–1,000, P < 0.02), number of acute exacerbations >3 (OR: 30.3, 95% CI: 4.74–200, P < 0.01), and steroid cumulative dose >1,000 mg (OR: 7.35, 95% CI: 0.92–58.5, P < 0.04) were observed to be significant risk factors for osteoporosis in COPD patients.
In the present study, the prevalence of osteoporosis was 66.6% and another 19.6% had osteopenia. As the severity of COPD increased, the risk of osteoporosis increased. GOLD stage III and stage IV patient had significantly lower BMD as compared to stage I and stage II of COPD disease. Stage IV COPD disease, use of oral or parenteral glucocorticoids, and repeated number of exacerbations were found to be independent risk factors for osteoporosis in COPD patients. Thus, high clinical suspicion and early diagnosis and treatment is required in the evaluation of osteoporosis in COPD patients so that the quality of life can be improved in these patients.
PMCID: PMC4129592  PMID: 25125807
COPD; correlates; DEXA scan; osteoporosis; repeated exacerbations; risk factors
9.  Plasma homocysteine is elevated in COPD patients and is related to COPD severity 
Although recent studies have found that total plasma homocysteine (tHCY) and chronic obstructive pulmonary disease (COPD) are both risk factors for cardiac disease, there have been few studies of plasma homocysteine levels in COPD patients. We tested the hypothesis that total plasma homocysteine (tHCY) would be elevated in patients diagnosed with COPD compared with controls.
We studied 29 COPD outpatients and 25 asymptomatic subjects (controls) over age 55 years with measurement of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), St. Georges Respiratory Questionnaire (SGRQ) score, tHCY and serum C-reactive protein (sCRP).
There was no difference between controls vs. COPD patients in mean age or gender but mean (SD) FEV1 was 2.25 (0.77) vs 1.43 (0.60) L; FEV1% predicted 76.1 (17.2) vs 49.1 (16.3) p < 0.001 in both cases. Median (IQR) tHCY was 8.22 (6.63, 9.55) in controls vs 10.96 (7.56, 13.60) micromol/l for COPD, p = 0.006 and sCRP 0.89 (0.47, 2.55) vs 2.05 (0.86, 6.19) mg/l, p = 0.023. tHCY(log) was also higher in (r, p) smokers (0.448, 0.001), patients with low FEV1% (−0.397, 0.003), males (0.475, <0.001), but high SGRQ Total score (0.289, 0.034), and high sCRP (0.316, 0.038). tHCY(log) was independently related to (regression coefficient, p) sCRP(log) (0.087, 0.024), male gender (0.345, <0.001) and presence of COPD (0.194, 0.031). Median (IQR) tHCY GOLD Stage I and II 8.05 (7.28, 11.04), GOLD Stage III and IV: 11.83(9.30, 18.30); p = 0.023.
Plasma homocysteine is significantly elevated in COPD patients relative to age and sex-matched controls and is related to serum CRP and COPD severity.
PMCID: PMC2695192  PMID: 18229569
COPD; Homocysteine; CRP; SGRQ; FEV1
10.  A new inflammation marker of chronic obstructive pulmonary disease–adiponectin 
This study was undertaken to measure the concentration of adiponectin (APN) in serum and induced sputum in patients with chronic obstructive pulmonary disease (COPD during acute exacerbation (AECOPD) and at stable stage and to determine the role of APN as a marker of inflammation in the pathogenesis of COPD.
All the patients in this prospective study were enrolled from October 2008 to October 2009, including 30 male AECOPD patients from the emergency department, 30 male stable COPD patients from the department of respiratory diseases, and 30 healthy non-smoking male controls from the department of medical examination. The serum and induced sputum were collected from each patient. All of the patients had normal weight (BMI range 18.5-24.9 kg/m2). Patients with severe bronchial asthma, bronchiectasis or autoimmune disease were excluded. Cell count and classification was performed for the induced sputum. The concentrations of APN, IL-8, IL-6 and TNF-α were measured by ELISA. Pulmonary function was tested among the three groups. Comparisons between the groups were conducted by Student’s t test, ANOVA analysis or nonparametric test. Correlation analysis was carried out by Pearson’s product-moment correlation coefficient test or Spearman’s rank-order correlation coefficient test.
The concentrations of APN in the serum or induced sputum in AECOPD patients were significantly higher than those in stable COPD patients or healthy non-smoking controls (P<0.01). The concentration of APN in stable COPD patients was significantly higher than that in healthy non-smoking controls (P<0.01). For the AECOPD patients, APN was positively correlated with IL-8 and TNF-α in the serum and induced sputum (r=0.739, 0.734, 0.852, 0.857 respectively, P<0.05). For the stable COPD patients, APN was also positively correlated with IL-8 and TNF-α in the serum and induced sputum (r=0.751, 0.659, 0.707, 0.867 respectively, P<0.05). In addition, for the AECOPD patients, APN was positively correlated with the percentage of neutrophils in the induced sputum (r=0.439, P<0.05).
APN is involved in the process of systematic and airway inflammation of COPD. This process is related to neutrophils in the airway, IL-8 and TNF-α. APN could be used as a new marker for inflammation of COPD.
PMCID: PMC4129679  PMID: 25214966
Chronic obstructive pulmonary disease; Serum; Induced sputum; Adiponectin; Neutrophil; Interleukin-8; Tumor necrosis factor-a; Interleukin-6
11.  Neutrophilic inflammation and IL‐8 levels in induced sputum of alpha‐1‐antitrypsin PiMZ subjects 
Thorax  2005;61(2):129-133.
Severe alpha‐1‐antitrypsin deficiency (AATD), due to homozygosity for the protease inhibitor (Pi) Z allele, is a genetic risk factor for chronic obstructive pulmonary disease (COPD). In a previous study the sputum of severe AATD subjects with airflow obstruction showed a pattern of cellular inflammation similar to COPD patients. It is uncertain whether heterozygotes for the Z allele or intermediate deficiency (PiMZ) have an increased risk of developing COPD.
Sputum cell counts and the supernatant level of the neutrophil chemoattractant interleukin (IL)‐8 were investigated by sputum induction in 10 non‐smoker asymptomatic PiMZ subjects with normal pulmonary function, 10 patients with stable COPD, and 10 age matched normal subjects. Data are expressed as mean (SD).
The mean (SD) number of neutrophils was significantly higher (p<0.01) in the sputum of PiMZ subjects (84.5 (22.2) ×104/ml) and patients with COPD (126.9 (18.8) ×104/ml) than in matched normal subjects (55.0 (8.7) ×104/ml). IL‐8 levels were increased in PiMZ subjects (828.5 (490.6) ng/ml; median 1003.0 ng/ml; range 1260–100 ng/ml) and in COPD patients (882.5 (524.3) ng/ml; median 934.9 ng/ml; range 1506–258 mg/ml) compared with normal subjects (3.5 (0.5) ng/ml; median 3.5 ng/ml; range 4.5–2.5 ng/ml). There was a significant positive correlation between IL‐8 supernatant concentration and neutrophil count in PiMZ subjects (p = 0.036; r = 0.66). An inverse correlation was observed between the percentage of neutrophils and forced expiratory volume in 1 second (% predicted) in patients with COPD (p = 0.04; r = −0.43).
These findings indicate that PiMZ subjects without airflow obstruction may have an IL‐8 related neutrophilic inflammation in the airways, similar to stable COPD patients, suggesting an increased risk of developing pulmonary changes.
PMCID: PMC2104580  PMID: 16284217
α1‐antitrypsin deficiency; induced sputum; airway inflammation; chronic obstructive pulmonary disease
12.  Accuracy of History, Wheezing, and Forced Expiratory Time in the Diagnosis of Chronic Obstructive Pulmonary Disease 
To determine the accuracy of the history and selected elements of the physical examination in the diagnosis of chronic obstructive pulmonary disease (COPD).
Independent blind comparison of the standard clinical examination (evaluating the accuracy of history, wheezing, and forced expiratory time [FET]) with spirometry. The gold standard for diagnosis of COPD was a forced expiratory volume at 1 second (FEV1) below the fifth percentile (adjusted for patient height and age).
Seven sites in 6 countries, including investigators from primary care and secondary care settings.
One hundred sixty-one consecutive patients with varying severity of disease (known COPD, suspected COPD, or no COPD) participated in the study.
One hundred sixty-one patients (mean age 65 years, 39% female, 41% with known COPD, 27% with suspected COPD, and 32% normal) were recruited. Mean (±SD) FEV1 and forced vital capacity were 1,720 (±830) mL and 2,520 (±970) mL. The likelihood ratios (LR) for the tested elements of the clinical examination (and their P values on χ2 testing) were: self-reported history of COPD, 5.6 (P < .001); FET greater than 9 seconds, 6.7 (P < 0.01); smoked longer than 40 pack years, 3.3 (P = .001); wheezing, 4.0 (P < .001); male gender, 1.6 (P < .001); and age over 65 years, 1.6 (P = .025). The accuracy of these elements was not appreciably different when reference standards other than FEV1 below the 5th percentile were applied. Only 3 elements of the clinical examination were significantly associated with the diagnosis of COPD on multivariate analysis: self-reported history of COPD (adjusted LR 4.4), wheezing (adjusted LR 2.9), and FET greater than 9 seconds (adjusted LR 4.6). Area under the receiver operating characteristic curve for the model incorporating these 3 factors was 0.86.
Less emphasis should be placed on the presence of isolated symptoms or signs in the diagnosis of COPD. While numerous elements of the clinical examination are associated with the diagnosis of COPD, only 3 are significant on multivariate analysis. Patients having all 3 of these findings have an LR of 33 (ruling in COPD); those with none have an LR of 0.18 (ruling out COPD).
PMCID: PMC1495102  PMID: 12220364
chronic obstructive pulmonary disease; clinical examination; spirometry; diagnosis
13.  Increased serum levels of lipocalin-1 and -2 in patients with stable chronic obstructive pulmonary disease 
Despite a number of studies on biomarkers in chronic obstructive pulmonary disease (COPD), only a few disease-related markers have been identified, yet we still have no satisfactory markers specific to innate immune system and neutrophil activation, which is essential in airway inflammation in COPD. Recent biological studies indicated that lipocalins (LCNs) might be involved in airway inflammation and innate immunity; however, results from available studies on the association of LCNs with COPD are not consistent. We carried out a multicenter prospective observational cohort study to investigate the differences in serum levels of LCN1 and LCN2 between subjects with COPD (n=58) and healthy controls (n=29). Several validated inflammatory markers, including C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-8, were measured. The correlation of LCN1 and LCN2 with clinical features such as smoking habits, lung function, symptoms, and disease category was also analyzed. When comparing with healthy controls, serum levels of LCN1 (66.35±20.26 ng/mL versus 41.16±24.19 ng/mL, P<0.001) and LCN2 (11.29±3.92 ng/mL versus 6.09±5.13 ng/mL, P<0.001) were both elevated in subjects with COPD after adjusting for age, sex, smoking habits, and inflammatory biomarkers. Smoking history and tobacco exposure, as quantified by pack-year, had no impact on systemic expressions of LCN1 and LCN2 in our study. Blood levels of LCN1 and LCN2, respectively, were negatively correlated to COPD Assessment Test and Modified Medical British Research Council score (P<0.001). Disease category by Global Initiative for Chronic Obstructive Lung Disease grade 1–4 or group A–D was not associated with levels of LCNs. Patient-reported exacerbations and body mass index were also tested, but no relationship with LCNs was found. In summary, serum concentrations of LCN1 and LCN2 were both elevated in patients with COPD, with their levels correlating to COPD Assessment Test and Modified Medical British Research Council score. These findings warrant large-scale and longitudinal studies to validate LCNs as circulating biomarkers for COPD.
PMCID: PMC4043430  PMID: 24920892
lipocalin-1; lipocalin-2; chronic obstructive pulmonary disease; biomarkers
14.  Adhesion molecules in subjects with COPD and healthy non-smokers: a cross sectional parallel group study 
Respiratory Research  2013;14(1):47.
The aim of the study was to investigate how the expression of adhesion molecules changes as neutrophils migrate from the circulation to the lung and if these changes differ between non-smoking subjects and smokers with and without COPD.
Non-smoking healthy subjects (n=22), smokers without (n=21) and with COPD (n=18) were included. Neutrophils from peripheral blood, sputum and bronchial biopsies were analysed for cell surface expression of adhesion molecules (CD11b, CD62L, CD162). Serum, sputum supernatant and BAL-fluid were analysed for soluble adhesion molecules (ICAM-1, -3, E-selectin, P-selectin, VCAM-1, PECAM-1).
Expression of CD11b was increased on circulating neutrophils from smokers with COPD. It was also increased on sputum neutrophils in both smokers groups, but not in non-smokers, as compared to circulating neutrophils.
Serum ICAM-1 was higher in the COPD group compared to the other two groups (p<0.05) and PECAM-1 was lower in smokers without COPD than in non-smoking controls and the COPD group (p<0.05). In BAL-fluid ICAM-1 was lower in the COPD group than in the other groups (p<0.05).
Thus, our data strongly support the involvement of a systemic component in COPD and demonstrate that in smokers neutrophils are activated to a greater extent at the point of transition from the circulation into the lungs than in non-smokers.
PMCID: PMC3669051  PMID: 23635004
Adhesion molecules; Chronic Obstructive Pulmonary Disease; Neutrophils; Sputum; Bronchoialveolar lavage fluid
15.  Increased oxidative stress in asymptomatic current chronic smokers and GOLD stage 0 COPD 
Respiratory Research  2006;7(1):69.
Chronic obstructive pulmonary disease (COPD) is associated with increased oxidative and nitrosative stress. The aim of our study was to assess the importance of these factors in the airways of healthy smokers and symptomatic smokers without airway obstruction, i.e. individuals with GOLD stage 0 COPD.
Exhaled NO (FENO) and induced sputum samples were collected from 22 current smokers (13 healthy smokers without any respiratory symptoms and 9 with symptoms i.e. stage 0 COPD) and 22 healthy age-matched non-smokers (11 never smokers and 11 ex-smokers). Sputum cell differential counts, and expressions of inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE) were analysed from cytospins by immunocytochemistry. Eosinophil cationic protein (ECP) and lactoferrin were measured from sputum supernatants by ELISA.
FENO was significantly decreased in smokers, mean (SD) 11.0 (6.7) ppb, compared to non-smokers, 22.9 (10.0), p < 0.0001. Induced sputum showed increased levels of neutrophils (p = 0.01) and elevated numbers of iNOS (p = 0.004), MPO (p = 0.003), nitrotyrosine (p = 0.003), and 4-HNE (p = 0.03) positive cells in smokers when compared to non-smokers. Sputum lactoferrin levels were also higher in smokers than in non-smokers (p = 0.02). Furthermore, we noted four negative correlations between FENO and 1) total neutrophils (r = -0.367, p = 0.02), 2) positive cells for iNOS (r = -0.503, p = 0.005), 3) MPO (r = -0.547, p = 0.008), and 4) nitrotyrosine (r = -0.424, p = 0.03). However, no major differences were found between never smokers and ex-smokers or between healthy smokers and stage 0 COPD patients.
Our results clearly indicate that several markers of oxidative/nitrosative stress are increased in current cigarette smokers compared to non-smokers and no major differences can be observed in these biomarkers between non-symptomatic smokers and subjects with GOLD stage 0 COPD.
PMCID: PMC1524947  PMID: 16646959
16.  Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at:
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website:
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website:
The objective of this evidence-based analysis was to determine the effectiveness and cost-effectiveness of smoking cessation interventions in the management of chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Tobacco smoking is the main risk factor for COPD. It is estimated that 50% of older smokers develop COPD and more than 80% of COPD-associated morbidity is attributed to tobacco smoking. According to the Canadian Community Health Survey, 38.5% of Ontarians who smoke have COPD. In patients with a significant history of smoking, COPD is usually present with symptoms of progressive dyspnea (shortness of breath), cough, and sputum production. Patients with COPD who smoke have a particularly high level of nicotine dependence, and about 30.4% to 43% of patients with moderate to severe COPD continue to smoke. Despite the severe symptoms that COPD patients suffer, the majority of patients with COPD are unable to quit smoking on their own; each year only about 1% of smokers succeed in quitting on their own initiative.
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. Smoking cessation can help to slow or halt the progression of COPD. Smoking cessation programs mainly target tobacco smoking, but may also encompass other substances that can be difficult to stop smoking due to the development of strong physical addictions or psychological dependencies resulting from their habitual use.
Smoking cessation strategies include both pharmacological and nonpharmacological (behavioural or psychosocial) approaches. The basic components of smoking cessation interventions include simple advice, written self-help materials, individual and group behavioural support, telephone quit lines, nicotine replacement therapy (NRT), and antidepressants. As nicotine addiction is a chronic, relapsing condition that usually requires several attempts to overcome, cessation support is often tailored to individual needs, while recognizing that in general, the more intensive the support, the greater the chance of success. Success at quitting smoking decreases in relation to:
a lack of motivation to quit,
a history of smoking more than a pack of cigarettes a day for more than 10 years,
a lack of social support, such as from family and friends, and
the presence of mental health disorders (such as depression).
Research Question
What are the effectiveness and cost-effectiveness of smoking cessation interventions compared with usual care for patients with COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on June 24, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations (1950 to June Week 3 2010), EMBASE (1980 to 2010 Week 24), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, and the Centre for Reviews and Dissemination for studies published between 1950 and June 2010. A single reviewer reviewed the abstracts and obtained full-text articles for those studies meeting the eligibility criteria. Reference lists were also examined for any additional relevant studies not identified through the search. Data were extracted using a standardized data abstraction form.
Inclusion Criteria
English-language, full reports from 1950 to week 3 of June, 2010;
either randomized controlled trials (RCTs), systematic reviews and meta-analyses, or non-RCTs with controls;
a proven diagnosis of COPD;
adult patients (≥ 18 years);
a smoking cessation intervention that comprised at least one of the treatment arms;
≥ 6 months’ abstinence as an outcome; and
patients followed for ≥ 6 months.
Exclusion Criteria
case reports
case series
Outcomes of Interest
≥ 6 months’ abstinence
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Nine RCTs were identified from the literature search. The sample sizes ranged from 74 to 5,887 participants. A total of 8,291 participants were included in the nine studies. The mean age of the patients in the studies ranged from 54 to 64 years. The majority of studies used the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD staging criteria to stage the disease in study subjects. Studies included patients with mild COPD (2 studies), mild-moderate COPD (3 studies), moderate–severe COPD (1 study) and severe–very severe COPD (1 study). One study included persons at risk of COPD in addition to those with mild, moderate, or severe COPD, and 1 study did not define the stages of COPD. The individual quality of the studies was high. Smoking cessation interventions varied across studies and included counselling or pharmacotherapy or a combination of both. Two studies were delivered in a hospital setting, whereas the remaining 7 studies were delivered in an outpatient setting. All studies reported a usual care group or a placebo-controlled group (for the drug-only trials). The follow-up periods ranged from 6 months to 5 years. Due to excessive clinical heterogeneity in the interventions, studies were first grouped into categories of similar interventions; statistical pooling was subsequently performed, where appropriate. When possible, pooled estimates using relative risks for abstinence rates with 95% confidence intervals were calculated. The remaining studies were reported separately.
Abstinence Rates
Table ES1 provides a summary of the pooled estimates for abstinence, at longest follow-up, from the trials included in this review. It also shows the respective GRADE qualities of evidence.
Summary of Results*
Abbreviations: CI, confidence interval; NRT, nicotine replacement therapy.
Statistically significant (P < 0.05).
One trial used in this comparison had 2 treatment arms each examining a different antidepressant.
Based on a moderate quality of evidence, compared with usual care, abstinence rates are significantly higher in COPD patients receiving intensive counselling or a combination of intensive counselling and NRT.
Based on limited and moderate quality of evidence, abstinence rates are significantly higher in COPD patients receiving NRT compared with placebo.
Based on a moderate quality of evidence, abstinence rates are significantly higher in COPD patients receiving the antidepressant bupropion compared to placebo.
PMCID: PMC3384371  PMID: 23074432
17.  Enhanced neutrophil response in chronic obstructive pulmonary disease 
Thorax  2001;56(6):432-437.
BACKGROUND—Neutrophils are likely to play a major role in the inflammatory response seen in chronic obstructive pulmonary disease (COPD). This study sought to address the hypothesis that an enhanced neutrophil response to proinflammatory agents in COPD may contribute to their recruitment and activation in the lungs.
METHODS—Circulating neutrophils were obtained from 10 patients with COPD, eight long term smokers with normal lung function, and eight healthy never smoking controls. The in vitro production of reactive oxygen species (ROS) was measured by the NADPH oxidase method (respiratory burst) and the surface expression of several adhesion molecules (Mac-1, LFA-1 and L-selectin) was measured by flow cytometry. Measurements were obtained under basal conditions and after stimulation with phorbol myristate acetate (PMA) and tumour necrosis factor alpha (TNFα). mRNA levels of p22-phox (a subunit of NADPH oxidase) and Mac-1 (CD11b) were also determined by reverse transcriptase polymerase chain reaction (RT-PCR).
RESULTS—Patients with COPD showed enhanced respiratory burst compared with smokers with normal lung function, both under basal conditions (mean (SE) fluorescence intensity (MFI) 15.1 (0.5) v 11.6 (0.5); mean difference -3.4 (95% CI of the difference -5.1 to -1.8), p<0.01) and after PMA stimulation (MFI 210 (7) v 133 (10); mean difference -77 (95% CI of the difference -102 to -52), p<0.01). Mac-1 surface expression was also enhanced in patients with COPD, both under basal conditions (MFI 91 (5) v 45 (3); mean difference -46 (95% CI of the difference -61 to -31), p<0.001) and after stimulation with TNFα (MFI 340 (15) v 263 (11); mean difference -77 (95% CI of the difference -119 to -34), p=0.001). These differences were also apparent when patients with COPD were compared with non-smokers (p<0.05). The mRNA levels of p22-phox and Mac-1 (CD11b) were similar in patients with COPD and smokers with normal lung function, suggesting that the observed differences were due to post-transcriptional regulation.
CONCLUSIONS—These results demonstrate an enhanced neutrophil response to proinflammatory agents in patients with COPD which may contribute to their enhanced recruitment and activation in the lungs of these patients. These findings support those of other studies which have indicated that the neutrophil is likely to play a major role in the pathogenesis of this disease.

PMCID: PMC1746080  PMID: 11359957
18.  Inflammatory features of nasal mucosa in smokers with and without COPD 
Thorax  2004;59(4):303-307.
Background: To investigate whether nasal and bronchial inflammation coexists in chronic obstructive pulmonary disease (COPD), nasal and bronchial biopsy specimens from seven control subjects, seven smokers without COPD, and 14 smokers with COPD were studied.
Methods: Nasal and bronchial biopsy specimens were taken from the same patients during bronchoscopy and squamous cell metaplasia and the thickness of the epithelium and basement membrane were measured. The numbers of eosinophils (EG2), neutrophils (elastase), macrophages (CD68), and CD8 T lymphocytes (CD8/144B) were assessed by immunohistochemistry.
Results: Smokers with and without COPD had squamous metaplasia in the nasal and bronchial epithelium. In all groups the thickness of the nasal epithelium was greater than that of the bronchial epithelium. The thickness of the basement membrane was similar in nasal and bronchial biopsy specimens from smokers with and without COPD, but was greater in the bronchi than in the nasal epithelium of controls. Eosinophil number was higher in the nasal and bronchial mucosa of smokers without COPD than in smokers with COPD or controls. Neutrophil number was higher in the nasal and bronchial mucosa of smokers with COPD than in smokers without COPD or controls. CD8 T lymphocyte numbers were similar in smokers with and without COPD and higher than in controls. There were fewer macrophages in nasal and bronchial biopsy specimens from smokers without COPD than in those with COPD.
Conclusion: Nasal and bronchial inflammation coexists in smokers and is characterised by infiltration of CD8 T lymphocytes. In smokers without COPD this feature is associated with an increased number of eosinophils, while in those with COPD it is linked to an increased number of neutrophils in both nasal and bronchial biopsy specimens.
PMCID: PMC1763801  PMID: 15047949
19.  Peripheral Blood T-Cell Populations in COPD, Asymptomatic Smokers and Healthy Non-Smokers in Indian subpopulation- A Pilot Study 
Background: COPD is a major global health problem affecting 4-10% of Indian adult male population. Immunological processes have been implicated in the pathogenesis of COPD. As compared to healthy smokers, COPD patients have airway inflammation indicated by the presence of CD8+ T cells in the lung. This predominant increase in CD8+ T cells in the lung may be reflected in the peripheral blood. In an attempt to understand why only some smokers develop COPD, we compared the peripheral T-cell markers in COPD patients with that of asymptomatic smokers, and healthy nonsmokers.
Methods: Twenty healthy non-smokers (HNS), 19 asymptomatic smokers (AS) and 21 COPD male patients (age and pack year-matched) were identified after clinical evaluation and spirometry. Blood CD3+, CD4+, CD8+ T-cell populations were measured.
Results: Smokers with COPD had severe airflow limitation (FVC, 69.8+16.7%; FEV1, 47.47+16.9%; FEV1/FVC, 53.1+13.3%). The BMI was found to be significantly lower among patients with COPD (19.1+4.8kg/m2) as compared to AS (23+4.3kg/m2) and HNS (23.7+4.0kg/m2) (p value = 0.003 HS).
The mean CD3+T-cell absolute count in COPD patients (1154.3+582.2), showed a marked decline as compared to that of AS (1251.9+491.6) and HNS (1424.9+352.2). The mean CD4+T-cell counts in COPD patients (652.7+340.5) were also lower when compared to AS (745.7+313.8) and HNS (832.5+220.7). The mean CD8+T-cell counts among COPD patients (424.7+264.3) were, similar to the counts observed among AS (426.9+193.2) and HNS (500.4+191). Though not statistically significant, the absolute counts of CD3+, CD4+ and CD8+ lymphocytes among COPD patients tended to be lower. No significant difference in the CD4+/CD8+ lymphocyte ratio between the patient groups was observed.
Conclusion: Our study indicates that BMI is related to the severity of COPD, hence proving a systemic component to its pathogenesis. However, we found similar percentages of CD8+Tcells in all the study groups suggesting that predominant CD8+ T cells in the airways may be due to its de novo origin rather than recruitment from blood. However, larger studies are needed to clarify the effect of disease severity, beedi smoking and ethnicity.
PMCID: PMC3708210  PMID: 23905115
Chronic obstructive pulmonary disease; Smokers; Peripheral blood T cells; Autoimmune
20.  Predictors of cardiovascular disease in asthma and chronic obstructive pulmonary disease 
Cardiovascular disease (CVD) is a common comorbidity in patients with chronic airway obstruction, and is associated with systemic inflammation and airway obstruction. The aim of this study was to evaluate the predictors of CVD in two different conditions causing chronic airway obstruction, asthma and COPD.
Lung function tests, clinical and echocardiographic data were assessed in 229 consecutive patients, 100 with asthma and 129 with COPD. CVD was classified into: pressure overload (PO) and volume overload (VO). Sub-analysis of patients with ischemic heart disease (IHD) and pulmonary hypertension (PH) was also performed.
CVD was found in 185 patients (81%: 51% COPD and 30% asthmatics) and consisted of PO in 42% and of VO in 38% patients. COPD patients, as compared to asthmatics, had older age, more severe airway obstruction, higher prevalence of males, of smokers, and of CVD (91% vs 68%), either PO (46% vs 38%) or VO (45% vs 30%). CVD was associated with older age and more severe airway obstruction both in asthma and COPD. In the overall patients the predictive factors of CVD were age, COPD, and male sex; those of PO were COPD, BMI, VC, FEV1 and MEF50 and those of VO were age, VC and MEF50. In asthma, the predictors of CVD were VC, FEV1, FEV1 /VC%, and PaO2, those of PO were VC, FEV1 and FEV1 /VC%, while for VO there was no predictor. In COPD the predictors of CVD were age, GOLD class and sex, those of VO age, VC and MEF50, and that of PO was BMI. Sub-analysis showed that IHD was predicted by COPD, age, BMI and FEV1, while PH (found only in 25 COPD patients), was predicted by VO (present in 80% of the patients) and FEV1. In subjects aged 65 years or more the prevalence of CVD, PO and VO was similar in asthmatic and COPD patients, but COPD patients had higher prevalence of males, smokers, IHD, PH, lower FEV1 and higher CRP.
The results of this study indicate that cardiovascular diseases are frequent in patients with chronic obstructive disorders, particularly in COPD patients. The strongest predictors of CVD are age and airway obstruction. COPD patients have higher prevalence of ischemic heart disease and pulmonary hypertension. In the elderly the prevalence of PO and VO in asthma and COPD patients is similar.
PMCID: PMC3844573  PMID: 24004921
Airway obstruction; Asthma; Cardiovascular disease; COPD; Pressure overload; Volume overload
21.  Changes of HMGB1 and sRAGE during the recovery of COPD exacerbation 
Journal of Thoracic Disease  2014;6(6):734-741.
Acute exacerbation of chronic obstructive pulmonary disease is associated with increased airway and systemic inflammation. However, the correlation between acute exacerbation/convalescence of chronic obstructive pulmonary disease (COPD) and simultaneous changes of high mobility group protein B1 (HMGB1) and soluble RAGE (sRAGE) levels has not been clearly clarified. The aim of this study was to assess these issues.
A total of 44 COPD patients were recruited. Following a structured interview, plasma levels of HMGB1, sRAGE, fibrinogen and serum level of high-sensitivity C-reactive protein (hsCRP) were measured in patients with acute exacerbation of COPD (AECOPD) within 24 h of hospitalization and pre-discharge (convalescence). All patients were examined with spirometry in convalescence of COPD.
There was a significant decline in plasma HMGB1 (P<0.01), sRAGE (P<0.05), fibrinogen (P<0.01) and serum hsCRP (P<0.01) levels from acute exacerbation to convalescence phase of COPD. Changes of sRAGE was significantly correlated with changes of HMGB1 (r=0.4, P=0.007). COPD disease status correlated with the ratio of HMGB1/sRAGE, but not gender, age, course of disease, smoking history and FEV1% pred. Levels of HMGB1 and sRAGE were the highest in the current smoker group, and significantly decreased in ex-smoker group in both acute exacerbation and convalescence phase of COPD, however, their levels in never smoker group were higher than ex-smoker group in either phase of COPD.
HMGB1 and sRAGE levels were dynamically changed between exacerbation and convalescence phase of COPD, HMGB1 and sRAGE were likely not only a potential marker in COPD exacerbation but also a therapeutic target for COPD treatment.
PMCID: PMC4073385  PMID: 24976997
Chronic obstructive pulmonary disease (COPD); high mobility group protein B1 (HMGB1); soluble RAGE (sRAGE); biomarker; exacerbation; convalescence
22.  Sex discrepancies in COPD patients and burden of the disease in females: a nationwide study in Greece (Greek Obstructive Lung Disease Epidemiology and health ecoNomics: GOLDEN study) 
The prevalence of chronic obstructive pulmonary disease (COPD) in females appears to be increasing. Recent studies have revealed that the percentage of women with COPD in Greece is approximately 12.5%.
To evaluate the burden of COPD among males and females in Greece through a nationwide cross-sectional survey and to explore sex differences regarding functional characteristics and exacerbation frequency.
Data collection was completed in a 6-month period. The present study followed a nationwide sampling approach of respiratory medicine physicians. The sampling approach included three steps: 1) estimation of expected incidence and prevalence of COPD cases in each prefecture of Greece and in total; 2) estimation of expected incidence of COPD cases per physician in each prefecture; and 3) creation of a frame of three different sampling zones. Following this sampling, data were provided by 199 respiratory physicians.
The participating physicians provided data from 6,125 COPD patients. Female patients represented 28.7% of the study participants. Female COPD patients were, on average, 5 years younger than male COPD patients. Never smokers accounted for 9.4% within female patients, compared to 2.7% of males (P<0.001). Female patients were characterized by milder forms of the disease. Comorbidities were more prevalent in men, with the exception of gastroesophageal reflux (14.6% versus 17.1% for men and women, respectively, P=0.013). Female COPD patients had a higher expected number of outpatient visits per year (by 8.9%) than males (P<0.001), although hospital admissions did not differ significantly between sexes (P=0.116). Females had fewer absences from work due to COPD per year, by 19.0% (P<0.001), compared to males.
The differences observed between male and female COPD patients provide valuable information which could aid the prevention and management of COPD in Greece.
PMCID: PMC3933352  PMID: 24600217
chronic obstructive pulmonary disease; exacerbations; comorbidities
23.  The impact of chronic obstructive pulmonary disease and obesity on length of stay and cost of spine surgery 
Indian Journal of Orthopaedics  2010;44(4):424-427.
Chronic obstructive pulmonary disease (COPD) and obesity may be more common among spine surgery patients than in the general population and may affect hospital cost.
Materials and Methods:
We retrospectively studied the prevalence of COPD and obesity among 605 randomly selected spine surgery inpatients operated between 2005 and 2008, including lumbar microdiskectomy, anterior cervical decompression and fusion and lumbar decompression and fusion patients. The length of hospital stay and hospital charges for patients with and without COPD and obesity (body mass index [BMI]≥30 kg/m2) were compared.
Among 605 spine surgery patients, 9.6% had a history of COPD. There were no statistical difference in the prevalence of COPD between the three spine surgery groups. Obesity was common, with 47.4% of the patients having a BMI≥30 kg/m2. There were no significant differences in obesity rates or BMI values between the three types of spine surgery patients. Obesity rates between patients with and without COPD were 62.1% vs. 45.9%, and were statistically different (P<0.05). Similarly, significant difference (P<0.01) in BMI values between COPD and non-COPD groups, 32.66±7.19 vs. 29.57±6.048 (mean ± std. deviation), was noted. There was significant difference (P<0.01) in cost between nonobese female patients without COPD and those with obesity and COPD in the anterior cervical decompression and fusion (ACDF) group. No association with increased hospital length of stay or cost was found in the other two types of spine surgery or in male ACDF patients.
COPD and obesity seem to additively increase the length of hospital stay and hospital charges in ACDF female patients, an important finding that requires further investigation.
PMCID: PMC2947730  PMID: 20924484
COPD; obesity; spine surgery; length of stay; hospital cost
24.  Plasma YKL-40 and all-cause mortality in patients with chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is hallmarked by inflammatory processes and a progressive decline of lung function. YKL-40 is a potential biomarker of inflammation and mortality in patients suffering from inflammatory lung disease, but its prognostic value in patients with COPD remains unknown. We investigated whether high plasma YKL-40 was associated with increased mortality in patients with moderate to very severe COPD.
Four hundred and ninety-three patients with moderate to very severe COPD were followed prospectively for up to 10 years. Patients were divided into two groups according to plasma YKL-40: concentration higher than the 75th percentile for age-matched healthy subjects (i.e. high levels) and normal levels. Outcome was overall survival (OS) and was evaluated in uni- and multivariate proportional hazards Cox regression analyses and adjusted for factors affecting mortality.
Median plasma YKL-40 was increased in patients with COPD (81 ng/ml, p < 0.001) compared to healthy subjects (40 ng/ml). Patients with high plasma YKL-40 had a hazard ratio (HR) of 1.42 (95% CI: 1.15–1.75, p = 0.001) for all-cause mortality. Multivariate analysis showed that YKL-40 (HR 1.38; 95% CI: 1.11–1.72, p = 0.004), age (HR 1.05; 95% CI: 1.03–1.06, p < 0.0001), Severe COPD (HR 1.35; 95 CI: 1.03-1.76, p = 0.03) very severe COPD (HR 2.19; 95% CI: 1.60 - 2.99 < 0.0001), neutrophil granulocyte count (HR 1.05; 95% CI: 1.01-1.08, p = 0.01), and a smoking history of > 40 years (HR 1.38; 95% CI: 1.11-1.71, p = 0.003) were independent prognostic markers of OS.
High plasmaYKL-40 is associated with increased mortality in patients with moderate to very severe COPD, suggesting a role for YKL-40 as a potential biomarker of mortality in this patient group.
Trial registration NCT00132860.
PMCID: PMC3890498  PMID: 24373580
COPD; Inflammation; Mortality; Prognosis; YKL-40
25.  High Mobility Group Protein B1 (HMGB1) in Asthma: Comparison of Patients with Chronic Obstructive Pulmonary Disease and Healthy Controls 
Molecular Medicine  2011;17(7-8):807-815.
High mobility group protein B1 (HMGB1) has been implicated as an important mediator in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). However, the expression of HMGB1 in plasma and sputum of patients with asthma and COPD across disease severity needs to be defined. The objective of the study was to examine the induced sputum and plasma concentrations of HMGB1 in COPD and asthmatic patients to determine differences in HMGB1 levels between these diseases and their relationship with airway obstruction and inflammatory patterns. A total of 147 participants were enrolled in this study. The participants included 34 control subjects, 61 patients with persistent asthma (according to the Global Initiative for Asthma [GINA] guidelines) and 47 patients with stable COPD (stratified by Global Initiative for Chronic Obstructive Lung Disease [GOLD] status). Spirometry was performed before sputum induction. HMGB1 levels in induced sputum and plasma were determined by enzyme-linked immunosorbent assay. Sputum and plasma concentrations of HMGB1 in patients with asthma and COPD were significantly higher than concentrations in control subjects and were significantly negatively correlated with forced expiratory volume in 1 s (FEV1), FEV1 (% predicted) in all 147 participants. The levels of HMGB1 in induced sputum of COPD patients were significantly higher than those of asthma patients and healthy controls (P < 0.001). This difference was present even after adjusting for sex, age, smoking status, daily dose of inhaled corticosteroids and disease severity. There were no significant differences in HMGB1 levels between patients with eosinophilic and noneosinophilic asthma. HMGB1 levels in asthmatic and COPD patients were positively correlated with neutrophil counts and percentage of neutrophils. In multivariate analysis, the two diseases (asthma and COPD) and disease severity were independent predictors of sputum HMGB1, but not smoking, age or use of inhaled corticosteroids. In conclusion, these data support a potential role for HMGB1 as a biomarker and diagnostic tool for the differential diagnosis of asthma and COPD. The importance of this observation on asthma and COPD mechanisms and outcomes should be further investigated in large prospective studies.
PMCID: PMC3146613  PMID: 21380479

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