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Introduction: Targeting small airway inflammation could lead to improved clinical outcomes in asthma. Previous observational studies concluded that therapy with extrafine-particle [mass median aerodynamic diameter (MMAD) <2 µm] inhaled corticosteroids (ICS) is associated with similar or better odds of achieving asthma control at lower prescribed doses than fine-particle ICS (MMAD = 2-5 µm). However, while it is believed that the dose-response for ICS reaches a plateau at sub-maximal doses, it is not clear whether such a plateau occurs with extrafine-particle ICS. Methods: To evaluate the potential effect of ICS particle size on dose-response of asthma-related outcomes, we studied severe exacerbation rates in a historical patient cohort of UK adults and adolescents with asthma initiating extrafine- or fine-particle ICS. We extracted electronic medical record data centralized at primary care practices, where information from secondary care and hospitalizations is also aggregated. Data were collected over one baseline (pre-initiation) and one outcome year. Results: Of 32,235 patients with asthma (aged 12-80 years), 54% initiated ICS with extrafine-particle ICS and 46% with fine-particle ICS. Overall, mean age (SD) was 41 (17) years; 60% female; 24% current and 20% ex-smokers. We found a greater ( P < 0.001) reduction in exacerbation rate at higher as compared with lower doses of extrafine-particle ICS: for patients initiating on ≤125 µg/day the reduction was −0.016 (95% CI −0.038, 0.006) exacerbations per year and for those initiating on >250 µg/day the reduction was −0.072 (−0.095, −0.049). No significant dose-response relationship was observed for patients initiating on fine-particle ICS [reduction in exacerbations per year: −0.041 (−0.070, −0.012) at the lowest doses and 0.009 (−0.017, 0.036) at the highest, P = 0.856, despite similar exacerbation rates in the baseline period for both cohorts ( P = 0.40)]. Conclusion: Our findings suggest that extrafine-particle ICS is associated with a reduction in exacerbation rates in a dose-dependent fashion in an adult asthma population. This dose-response relationship was not observed with fine-particle ICS. ENCePP Trial Registration: EUPAS8840. [ABSTRACT FROM AUTHOR]

Although in textbooks asthma and chronic obstructive pulmonary disease (COPD) are viewed as distinct disorders, there is increasing awareness that many patients have features of both. This article reviews the asthma-COPD overlap syndrome. [ABSTRACT FROM AUTHOR]

Background: We previously observed that 30 months of inhaled corticosteroid (ICS) treatment can attenuate FEV1 decline in COPD, but it is unclear whether withdrawal induces a relapse. We hypothesized that FEV1 decline, airway hyperresponsiveness (AHR), and quality of life (QOL) deteriorate after ICS cessation even after prolonged use.Methods: One hundred fourteen patients with moderate to severe COPD finished randomized 6-month or 30-month treatment with fluticasone (500 μg bid), 30-month treatment with fluticasone and salmeterol (500/50 μg bid), or placebo (first part of the Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease [GLUCOLD] study [GL1]). The subsequent 5 years, patients were prospectively followed annually, treated by their physician (GLUCOLD follow-up study [GL2]). Postbronchodilator FEV1, AHR, and QOL were initially recorded at baseline, at 30 months (GL1), and annually during GL2. Analysis was performed by linear mixed-effects models.Results: Among 101 adherent patients during GL1, 79 patients started and 58 completed GL2. Patients using ICSs during GL1, but only using ICSs 0% to 50% of the time during GL2 (n = 56 of 79), had significantly accelerated annual FEV1 decline compared with GL1 (difference GL2-GL1 [95% CI]: 30-month treatment with fluticasone and salmeterol, -68 mL/y [-112 to -25], P = .002; 30-month treatment with fluticasone, -73 mL/y [-119 to -26], P = .002), accompanied by deterioration in AHR and QOL.Conclusions: ICS discontinuation after 30 months in COPD can worsen lung function decline, AHR, and QOL during 5-year follow-up. This suggests that ICS treatment lacks sustained disease-modifying effect after treatment cessation.Trial Registry: ClinicalTrials.gov; No.: NCT00158847; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined whether withdrawal of inhaled corticosteroid (ICS) treatment induces a relapse of forced expiratory volume in one second (FEV1) in chronic obstructive pulmonary disease (COPD) patients. Topics discussed include the findings which suggest that ICS cessation after 30 months in COPD can worsen lung function decline, airway hyperresponsiveness (AHR) and quality of life (QOL).

Chronic obstructive pulmonary disease is mainly a smoking-related disorder and affects millions of people worldwide, with a large effect on individual patients and society as a whole. Although the disease becomes clinically apparent around the age of 40-50 years, its origins can begin very early in life. Different risk factors in very early life—ie, in utero and during early childhood—drive the development of clinically apparent chronic obstructive pulmonary disease in later life. In discussions of which risk factors drive chronic obstructive pulmonary disease, it is important to realise that the disease is very heterogeneous and at present is largely diagnosed by lung function only. In this Review, we will discuss the evidence for risk factors for the various phenotypes of chronic obstructive pulmonary disease during different stages of life. [ABSTRACT FROM AUTHOR]

Cigarette smoking is the main risk factor for COPD (Chronic Obstructive Pulmonary Disease), yet only a subset of smokers develops COPD. Family members of patients with severe early-onset COPD have an increased risk to develop COPD and are therefore defined as “susceptible individuals”. Here we perform unbiased analyses of proteomic profiles to assess how “susceptible individuals” differ from age-matched “non-susceptible individuals” in response to cigarette smoking. Epithelial lining fluid (ELF) was collected at baseline and 24 hours after smoking 3 cigarettes in young individuals susceptible or non-susceptible to develop COPD and older subjects with established COPD. Controls at baseline were older healthy smoking and non-smoking individuals. Five samples per group were pooled and analysed by stable isotope labelling (iTRAQ) in duplicate. Six proteins were selected and validated by ELISA or immunohistochemistry. After smoking, 23 proteins increased or decreased in young susceptible individuals, 7 in young non-susceptible individuals, and 13 in COPD in the first experiment; 23 proteins increased or decreased in young susceptible individuals, 32 in young non-susceptible individuals, and 11 in COPD in the second experiment. SerpinB3 and Uteroglobin decreased after acute smoke exposure in young non-susceptible individuals exclusively, whereas Peroxiredoxin I, S100A9, S100A8, ALDH3A1 (Aldehyde dehydrogenase 3A1) decreased both in young susceptible and non-susceptible individuals, changes being significantly different between groups for Uteroglobin with iTRAQ and for Serpin B3 with iTRAQ and ELISA measures. Peroxiredoxin I, SerpinB3 and ALDH3A1 increased in COPD patients after smoking. We conclude that smoking induces a differential protein response in ELF of susceptible and non-susceptible young individuals, which differs from patients with established COPD. This is the first study applying unbiased proteomic profiling to unravel the underlying mechanisms that induce COPD. Our data suggest that SerpinB3 and Uteroglobin could be interesting proteins in understanding the processes leading to COPD. [ABSTRACT FROM AUTHOR]

Background: Increased airway wall thickness (AWT) and parenchymal lung destruction both contribute to airflow limitation. Advances in computed tomography (CT) post-processing imaging allow to quantify these features. The aim of this Dutch population study is to assess the relationships between AWT, lung function, emphysema and respiratory symptoms. Methods: AWT and emphysema were assessed by low-dose CT in 500 male heavy smokers, randomly selected from a lung cancer screening population. AWT was measured in each lung lobe in cross-sectionally reformatted images with an automated imaging program at locations with an internal diameter of 3.5 mm, and validated in smaller cohorts of patients. The 15th percentile method (Perc15) was used to assess the severity of emphysema. Information about respiratory symptoms and smoking behavior was collected by questionnaires and lung function by spirometry. Results: Median AWT in airways with an internal diameter of 3.5 mm (AWT3.5) was 0.57 (0.44 - 0.74) mm. Median AWT in subjects without symptoms was 0.52 (0.41-0.66) and in those with dyspnea and/or wheezing 0.65 (0.52-0.81) mm (p<0.001). In the multivariate analysis only AWT3.5 and emphysema independently explained 31.1%and 9.5%of the variance in FEV1%predicted, respectively, after adjustment for smoking behavior. Conclusions: Post processing standardization of airway wall measurements provides a reliable and useful method to assess airway wall thickness. Increased airway wall thickness contributes more to airflow limitation than emphysema in a smoking male population even after adjustment for smoking behavior. [ABSTRACT FROM AUTHOR]

Abstract: Multidrug resistance-associated protein-1 (MRP1) reduces the oxidative stress generated by smoking, a risk factor for Chronic Obstructive Pulmonary Disease (COPD). We previously showed that MRP1 variants are associated with the level and decline of annual forced expiratory volume in one second (FEV1) in the general population. Moreover, we showed that MRP1 variants are also associated with FEV1 level and inflammatory markers in COPD patients.We investigate in the current study the association of MRP1 protein expression in bronchial biopsies with FEV1 decline in COPD patients using placebo, or inhaled corticosteroids (ICS) with or without long-acting β2-agonists. Additionally we investigate the association of MRP1 variants with FEV1 decline. MRP1 variants (rs212093, rs4148382, rs504348, rs4781699, rs35621) were genotyped in 110 COPD patients. Associations of MRP1 variants and MRP1 protein expression in bronchial biopsies (obtained at baseline, 6 and 30 months) with FEV1 decline were analyzed using linear mixed-effect models. During 30-month ICS treatment, subjects with a moderate staining for MRP1 had less FEV1 decline than those with a weak staining. In subjects stopping ICS after 6 months followed by 24-month placebo, moderate staining for MRP1 was associated with faster FEV1 decline than in those with a weak staining. None of the variants was associated with FEV1 decline. Our unique study suggests a role of MRP1 protein expression in bronchial biopsies in FEV1 decline occurring selectively in COPD patients with long-term (30-month) ICS therapy. [Copyright &y& Elsevier]

Cigarette smoking is the leading risk factor for lung cancer. To identify genes deregulated by smoking and to distinguish gene expression changes that are reversible and persistent following smoking cessation, we carried out genome-wide gene expression profiling on nontumor lung tissue from 853 patients with lung cancer. Gene expression levels were compared between never and current smokers, and time-dependent changes in gene expression were studied in former smokers. A total of 3,223 transcripts were differentially expressed between smoking groups in the discovery set (n = 344, P < 1.29 x 10-6). A substantial number of smoking-induced genes also were validated in two replication sets (n = 285 and 224), and a gene expression signature of 599 transcripts consistently segregated never from current smokers across all three sets. The expression of the majority of these genes reverted to never-smoker levels following smoking cessation, although the time course of normalization differed widely among transcripts. Moreover, some genes showed very slow or no reversibility in expression, including SERPIND1, which was found to be the most consistent gene permanently altered by smoking in the three sets. Our findings therefore indicate that smoking deregulates many genes, many of which reverse to normal following smoking cessation. However, a subset of genes remains altered even decades following smoking cessation and may account, at least in part, for the residual risk of lung cancer among former smokers. [ABSTRACT FROM AUTHOR]

To cite this article: Koning H, Postma DS, Brunekreef B, Duiverman EJ, Smit HA, Thijs C, Penders J, Kerkhof M, Koppelman GH. Protocadherin-1 polymorphisms are associated with eczema in two Dutch birth cohorts. Pediatr Allergy Immunol 2012: 23: 270-277. Abstract Background: Eczema and asthma share a common genetic background and show linkage to chromosome 5q31-33. Protocadherin-1 ( PCDH1) is located in this region and was identified as a susceptibility gene for bronchial hyper-responsiveness (BHR), a hallmark of asthma. PCDH1 encodes an adhesion molecule, expressed in airway and skin epithelium. We determined whether PCDH1 polymorphisms, previously associated with asthma or BHR, also associated with questionnaire and UK Working Party (UKWP) defined eczema. Methods: Four PCDH1 polymorphisms were genotyped in two Dutch birth cohorts, PIAMA (n = 967) and KOALA Birth Cohort Study (n = 1560). Association with eczema was determined by chi-square tests and generalized estimating equations (GEE). Results: Insertion deletion IVS3-116 was associated with development of UKWP eczema in PIAMA [age 4, OR = 1.90 (1.14-3.18)] and borderline with questionnaire-reported eczema in PIAMA [GEE, OR = 1.33 (0.98-1.81)]. Furthermore, IVS3-116 was associated with questionnaire-reported eczema in KOALA [age 1, OR = 1.44 (1.00-2.07)]. Pooled analysis of questionnaire-reported eczema of both cohorts resulted in a significant association of IVS3-116 with eczema [OR = 1.26 (1.01-1.58)]. Rs3822357 (A-allele) associated with protection for eczema in PIAMA only [questionnaires, OR = 0.19 (0.06-0.63)]. Conclusion: PCDH1 gene variant IVS3-116 associates with eczema in two independent birth cohorts. Combined with previous observations, this indicates a shared genetic susceptibility to BHR, asthma and eczema. [ABSTRACT FROM AUTHOR]

The article discusses a research study on the effectiveness of ciclesonide and a combination of fluticasone propionate and salmeterol in patients with asthma. The study subjects included patients with mild persistent asthma whose ages ranged between 12 and 75 years old. A version of the Asthma Quality of Life Questionnaire was completed by the patients. They were also asked to record their use of salbutamol and their asthma symptoms in electronic diaries.

Arginase probably plays an important role in asthma development, severity and progression. Polymorphisms in arginase 1 and arginase 2 genes have been associated with childhood asthma and FEV1 reversibility to β2 agonists.We investigated the association between arginase 1 and arginase 2 polymorphisms and adult asthma, asthma severity and treatment response in a longitudinal cohort of 200 asthma patients.Patients were studied during 1962-1975 and reexamined during 1990-1999, together with their families. Longitudinal data on lung function and treatment were extracted from medical records. Associations between haplotype-tagging polymorphisms in arginase 1 (n=3) and arginase 2 (n=8) and asthma, asthma severity, acute response to bronchodilators and chronic response to inhaled corticosteroids were analyzed.Two polymorphisms in arginase 2 (rs17249437 and rs3742879) were associated with asthma and with more severe airway obstruction. Increased airway hyperresponsiveness and lower β2 agonist reversibility, but not anticholinergic reversibility, were associated with both arginase 1 and arginase 2. Inhaled corticosteroids slowed down the annual FEV1 decline, which was significantly less effective in homozygote carriers of the C-allele of the arginase 1 polymorphism, rs2781667.We show that previously reported associations between arginase polymorphisms and childhood asthma are also present in adult asthma and the previously found associations with lower reversibility are specific for β2 agonists. Furthermore, we identified associations of arginase 1 and arginase 2 genes with asthma severity, as reflected by a lower lung function, more severe airway hyperresponsiveness, and less long-term response to inhaled corticosteroids. Studies on the functionality of the polymorphisms are warranted to further unravel the complex mechanisms underlying these observations. [ABSTRACT FROM AUTHOR]

Background: Multidrug resistance-associated protein-1 (MRP1) protects against oxidative stress and toxic compounds generated by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (COPD). We have previously shown that single nucleotide polymorphisms (SNPs) in MRP1 significantly associate with level of FEV1 in two independent population based cohorts. The aim of our study was to assess the associations of MRP1 SNPs with FEV1 level, MRP1 protein levels and inflammatory markers in bronchial biopsies and sputum of COPD patients. Methods: Five SNPs (rs212093, rs4148382, rs504348, rs4781699, rs35621) in MRP1 were genotyped in 110 COPD patients. The effects of MRP1 SNPs were analyzed using linear regression models. Results: One SNP, rs212093 was significantly associated with a higher FEV1 level and less airway wall inflammation. Another SNP, rs4148382 was significantly associated with a lower FEV1 level, higher number of inflammatory cells in induced sputum and with a higher MRP1 protein level in bronchial biopsies. Conclusions: This is the first study linking MRP1 SNPs with lung function and inflammatory markers in COPD patients, suggesting a role of MRP1 SNPs in the severity of COPD in addition to their association with MRP1 protein level in bronchial biopsies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Inhalation of adenosine-5′-monophosphate (AMP) causes bronchoconstriction in asthma but not in healthy subjects. Bronchoconstriction upon AMP inhalation is thought to occur by histamine release and subsequent binding to receptors on airway smooth muscle cells. Methods: To explain enhanced sensitivity to AMP in asthma, mast cell expression of the adenosine A2A and A2B receptors and histamine release were measured after incubation of human mast cell line 1 (HMC-1) cells with AMP and the non-specific adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) for 1.5 and 6 h. To establish a Thelper-2 environment resembling the asthma phenotype, HMC-1 cells were additionally cultured with IL-4 and IL-13 alone or stimulated with the combination of both cytokines and AMP and NECA. To study effects of prolonged presence of the inflammatory environment, the cells were pre-incubated overnight (18 h) with IL-4 and IL-13 and additionally stimulated with AMP and NECA for 1.5 or 6 h. Results: AMP and NECA hardly affected adenosine receptor expression but increased IL-8 secretion. Incubation with IL-4 and IL-13 for 6 h increased adenosine A2A receptor expression and histamine secretion, but decreased IL-8 secretion. The combination of IL-4, IL-13, and AMP/NECA for 6 h increased A2B receptor expression and IL-8 secretion. Overnight stimulation with IL-4, IL-13 and subsequent stimulation with AMP/NECA for 1.5 h decreased A2AR expression which was accompanied by increased histamine secretion. Conclusion: These results suggest a role for decreased A2AR expression in enhanced adenosine responsiveness as observed in asthma. [Copyright &y& Elsevier]

The article presents a study on the risk factor for chronic obstructive pulmonary disease (COPD) exacerbations. COPD is characterized by episodic increases in respiratory symptoms called exacerbations. It is associated with an increase in local and systemic inflammation. The study demonstrates that besides lung function impairment, systemic inflammation manifested by elevated fibrinogen levels is an independent risk factor for exacerbations of COPD.

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by defective extracellular matrix (ECM) turnover as a result of prolonged cigarette smoking. Fibroblasts have a central role in ECM turnover. The TGFβ induced Smad pathway provides intracellular signals to regulate ECM production. We address the following hypothesis: fibroblasts have abnormal expression of genes in the Smad pathway in COPD, resulting in abnormal proteoglycan modulation, the ground substance of ECM. Methods: We compared gene expression of the Smad pathway at different time points after stimulation with TGFβ, TNF or cigarette smoke extract (CSE) in pulmonary fibroblasts of GOLD stage II and IV COPD patients, and controls. Results: Without stimulation, all genes were similarly expressed in control and COPD fibroblasts. TGFβ stimulation: downregulation of Smad3 and upregulation of Smad7 occurred in COPD and control fibroblasts, indicating a negative feedback loop upon TGFβ stimulation. CSE hardly influenced gene expression of the TGFβ-Smad pathway in control fibroblasts, whereas it reduced Smad3 and enhanced Smad7 gene expression in COPD fibroblasts. Furthermore, decorin gene expression decreased by all stimulations in COPD but not in control fibroblasts. Conclusion: Fibroblasts of COPD patients and controls differ in their regulation of the Smad pathway, the contrast being most pronounced under CSE exposure. This aberrant responsiveness of COPD fibroblasts to CSE might result in an impaired tissue repair capability and is likely important with regard to the question why only a subset of smokers demonstrates an excess ECM destruction under influence of cigarette smoking. [ABSTRACT FROM AUTHOR]

Background: In asthma, higher chymase positive mast cell (MC-C) numbers are associated with less airway obstruction. In COPD, the distribution of MC-C and tryptase positive mast cells (MC-T) in central and peripheral airways, and their relation with lung function, is unknown. We compared MC-T and MC-C distributions in COPD and controls without airflow limitation, and determined their relation with lung function. Methods: Lung tissue sections from 19 COPD patients (median [interquartile range] FEV1% predicted 56 [23-75]) and 10 controls were stained for tryptase and chymase. Numbers of MC-T and MC-C were determined in different regions of central and peripheral airways and percentage of degranulation was determined. Results: COPD patients had lower MC-T numbers in the subepithelial area of central airways than controls. In COPD, MC-T numbers in the airway wall and more specifically in the epithelium and subepithelial area of peripheral airways correlated positively with FEV1/VC (Spearman's rho (rs) 0.47, p = 0.05 and rs 0.48, p = 0.05, respectively); MC-C numbers in airway smooth muscle of peripheral airways correlated positively with FEV1% predicted (rs 0.57, p = 0.02). Both in COPD patients and controls the percentage of degranulated MC-T and MC-C mast cells was higher in peripheral than in central airways (all p < 0.05), but this was not different between the groups. Conclusion: More MC-T and MC-C in peripheral airways correlate with better lung function in COPD patients. It is yet to determine whether this reflects a protective association of mast cells with COPD pathogenesis, or that other explanations are to be considered. [ABSTRACT FROM AUTHOR]

This article presents the results of randomised studies to see if the genetic polymorphism ADRB2 changes how longacting Β2-agonist therapy in combination with inhaled corticosteroids work in people with asthma. Asthmatics were classified by ADRBS genotype in two studies. Neither study showed any pharmacogenetic effect of the ADRB2 genetic polymorphism on the response to treatment in asthmatic patients. The authors says since they could find no treatment obstacles as a result of the genetic variation, all asthma patients should continue on the combined therapy.

The article discusses the study which assesses the applicability of the forced vital capacity(FVC)/slow inspiratory vital capacity (SVC) ratio as a marker of small airways function in patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX). In the study, the FVC/SVC ratio was analyzed both cross-sectionally and longitudinally in 39 patients with BOS after bilateral LTX and 36 bilateral lung transplant recipients without BOS.

The article presents a study which examines if repeated sputum induction could induce neutrophilic and eosinophilic response. The objective of the study was to investigate the induction and resolution of airway inflammation caused by repeated sputum inductions. The researchers found that sputum inductions could induce neutrophilic response and prolonged eosinophilic inflammatory response in healthy intermittent smokers when repeated within 24 to 48 hours.

Background: Decorin, an extracellular matrix (ECM) proteoglycan, and TGF-β1 are both involved in lung ECM turnover. Decorin and TGF-β1 expression are decreased respectively increased in COPD lung tissue. Interestingly, they act as each other's feedback regulator. We investigated whether single nucleotide polymorphisms (SNPs) in decorin and TGF-β1 underlie accelerated decline in FEV1 and development of COPD in the general population. Methods: We genotyped 1390 subjects from the Vlagtwedde/Vlaardingen cohort. Lung function was measured every 3 years for a period of 25 years. We tested whether five SNPs in decorin (3'UTR and four intron SNPs) and three SNPs in TGF-β1 (3'UTR rs6957, C-509T rs1800469 and Leu10Pro rs1982073), and their haplotypes, were associated with COPD (last survey GOLD stage = II). Linear mixed effects models were used to analyze genotype associations with FEV1 decline. Results: We found a significantly higher prevalence of carriers of the minor allele of the TGF-β1 rs6957 SNP (p = 0.001) in subjects with COPD. Additionally, we found a significantly lower prevalence of the haplotype with the major allele of rs6957 and minor alleles for rs1800469 and rs1982073 SNPs in TGF-β1 in subjects with COPD (p = 0.030), indicating that this association is due to the rs6957 SNP. TGF-β1 SNPs were not associated with FEV1 decline. SNPs in decorin, and haplotypes constructed of both TGF-β1 and decorin SNPs were not associated with development of COPD or with FEV1 decline. Conclusion: Our study shows for the first time that SNPs in decorin on its own or in interaction with SNPs in TGF-β1 do not underlie the disturbed balance in expression between these genes in COPD. TGF-β1 SNPs are associated with COPD, yet not with accelerated FEV1 decline in the general population. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation and airway inflammation, accompanied by decreased health status. It is still unknown which factors are responsible for the impaired health status in COPD. We postulated that airway inflammation negatively contributes to health status in COPD. Methods: In 114 COPD patients (99 male, age: 62 ± 8 yr, 41 [31-55] pack-years, no inhaled or oral corticosteroids, postbronchodilator FEV1: 63 ± 9% pred, FEV1/IVC: 48 ± 9%) we obtained induced sputum and measured health status (St. George's respiratory questionnaire (SGRQ)), postbronchodilator FEV1, hyperinflation (RV/TLC), and airway hyperresponsiveness to methacholine (PC20). Sputum was induced by hypertonic saline and differential cell counts were obtained in 102 patients. Results: Univariate analysis showed that SGRQ total and symptom score were positively associated with % sputum macrophages (r = 0.20, p = 0.05; and r = 0.20, p = 0.04, respectively). Multiple regression analysis confirmed these relationships, providing significant contributions of % sputum macrophages (B = 0.25, p = 0.021) and RV/TLC (B = 0.60, p = 0.002) to SGRQ total score. Furthermore, SGRQ symptom score was associated with % sputum macrophages (B = 0.30, p = 0.03) and RV/TLC (B = 0.48, p = 0.044), whilst SGRQ activity score was associated with % sputum macrophages (B = 0.46, p = 0.002), RV/TLC (B = 0.61, p = 0.015), and PC20 (B = -9.3, p = 0.024). Current smoking and FEV1 were not significantly associated with health status in the multiple regression analysis. Conclusion: We conclude that worse health status in COPD patients is associated with higher inflammatory cell counts in induced sputum. Our findings suggest that airway inflammation and hyperinflation independently contribute to impaired health status in COPD. This may provide a rationale for anti-inflammatory therapy in this disease. [ABSTRACT FROM AUTHOR]

Background. Objective assessment of airway function is important in epidemiologic studies of asthma to facilitate comparison between studies. Airway hyperresponsiveness (AHR), peak expiratory flow (PEF) variability, and bronchodilator reversibility (BR) are widely used as markers of airway lability in such studies. Data from a survey of a population sample of adolescents and young adults (n = 609; 288 males), aged 13–23 years, were analyzed to investigate whether AHR, PEF variability, and BR can be used interchangeably as markers of asthma in an epidemiological setting. Methods. Case history, including self-reported and doctor-diagnosed asthma, smoking habits, and use of asthma medication, was obtained by interview and questionnaire. Lung function, airway responsiveness (positive test: PC 20 FEV 1 20%), BR (positive test: ΔFEV 1 [(FEV 1 max - FEV 1 min)/FEV 1 max) 100]> 10%), blood eosinophil count, and skin prick test reactivity were measured by using standard techniques. Results. The prevalence of a positive test was AHR 16.4%, PEFpos 13.3%, and BRpos 7.2%, respectively; 73.5% of the sample had three negative tests. Among the 74 participants with current self-reported asthma (12.2%), 34 subjects (46%) had more than one positive test. Using AHR as the only objective marker of asthma identified 93% of the participants with current asthma, whereas PEF and BR identified 45% and 10%, respectively. Confining the analysis to participants with only one positive test revealed that 61% of the subjects with isolated AHR had current asthma, whereas none of the subjects with isolated BRpos had asthma, and only one participant with isolated PEFpos had current asthma. Degree of histamine responsiveness was closer associated with other asthma-related factors, including self-reported asthma, use of asthma medication, and level of lung function, than PEF variability and bronchodilator responsiveness. Conclusions. Airway responsiveness to histamine, diurnal peak-flow variability, and bronchodilator reversibility cannot be used interchangeably as objective markers of asthma in epidemiologic studies. On the basis of the present findings, airway hyperresponsiveness to a nonspecific bronchoconstrictor is recommended as the objective marker of asthma-related airway lability. [ABSTRACT FROM AUTHOR]

We have previously reported diminished immunohistochemical staining of decorin in lung tissue from patients with severe emphysema. The aim of this study is to investigate whether this diminished staining is due to a quantitative abnormal production of decorin by pulmonary fibroblasts in vitro. Therefore, we measured decorin (Western blot), collagen type I (ELISA), and fibronectin (ELISA) production by fibroblasts obtained from lung tissue of patients with severe and mild emphysema at basal culture conditions and after modulation with transforming growth factor-ß 1 , basic fibroblast growth factor, and interferon-?. Decorin production at basal culture conditions was significantly higher in fibroblast cultures from patients with severe emphysema compared to fibroblasts from mild emphysema. After stimulation with transforming growth factor-ß 1 and basic fibroblast growth factor, decorin production was significantly more reduced in fibroblast cultures from patients with severe emphysema whereas collagen type I and fibronectin production were not affected. We conclude that decorin production by lung fibroblasts of patients with severe emphysema is dysregulated after modulation with cytokines known to be important in smoking associated inflammation. This dysregulation of decorin production may contribute to the impaired lung tissue repair, present in patients with emphysema, since these alterations in the extracellular matrix may cause diminished cytokine binding and neutralization. [ABSTRACT FROM AUTHOR]

Background: Chronic smoking is the main risk factor for chronic obstructive pulmonary disease. Knowledge on the response to the initial smoke exposures might enhance the understanding of changes due to chronic smoking, since repetitive acute smoke effects may cumulate and lead to irreversible lung damage. Methods: We investigated acute effects of smoking on inflammation in 16 healthy intermittent smokers in an open randomised cross-over study. We compared effects of smoking of two cigarettes on inflammatory markers in exhaled air, induced sputum, blood and urine at 0, 1, 3, 6, 12, 24, 48, 96 and 192 hours and outcomes without smoking. All sputum and blood parameters were log transformed and analysed using a linear mixed effect model. Results: Significant findings were: Smoking increased exhaled carbon monoxide between 0 and 1 hour, and induced a greater decrease in blood eosinophils and sputum lymphocytes between 0 and 3 hours compared to non-smoking. Compared to non-smoking, smoking induced a greater interleukin-8 release from stimulated blood cells between 0 and 3 hours, and a greater increase in sputum lymphocytes and neutrophils between 3 and 12 hours. Conclusion: We conclude that besides an increase in inflammation, as known from chronic smoking, there is also a suppressive effect of smoking two cigarettes on particular inflammatory parameters. [ABSTRACT FROM AUTHOR]

The Dutch hypothesis, formulated in the 1960s, holds that the various forms of airway obstruction are different expressions of a single disease entity. It suggests that genetic factors (eg, airway hyperresponsiveness [AHR] and atopy), endogenous factors (eg, sex and age), and exogenous factors (eg, allergens, infections, and smoking) all play a role in the pathogenesis of chronic nonspecific lung disease. This review finds evidence that AHR and smoking are common risk factors for asthma and COPD. To prove the Dutch hypothesis definitively, however, genetic studies, preferably longitudinal, must be performed. Such studies must include subjects who have airway obstruction that does not necessarily meet the current strict definitions of asthma or COPD (ie, the extremes of these conditions) that are used in clinical studies. [ABSTRACT FROM AUTHOR]

To characterize the possible role of a dysregulated proliferative capacity of pulmonary fibroblasts in insufficient tissue repair in lungs from patients with pulmonary emphysema, the authors undertook in vitro proliferative studies with pulmonary fibroblasts obtained from lung tissue of patients with emphysema. A comparison was made with fibroblasts from control subjects. The authors determined the in vitro proliferative capacity of fibroblasts at basal culture conditions and after modulation with interleukin-1β, interferon-γ, transforming growth factor-β 1 , and basic fibroblast growth factor. Proliferative capacity was determined by measurement of 5-bromo-2-deoxyuridine (BrdU) incorporation. BrdU incorporation by fibroblast cultures from both groups was very similar. Fibroblast cultures from control subjects, however, incorporated more BrdU after incubation with interleukin-1β than cultures from patients with emphysema ( P <.05). On the other hand, transforming growth factor-β 1 decreased incorporation of BrdU stronger in fibroblast cultures from control subjects than from patients with emphysema ( P <.05). Thus, the proliferative capacity of fibroblast cultures isolated from lung tissue of patients with pulmonary emphysema is different from that of control subjects. Although the difference is small, it may be an essential contribution to the development of pulmonary emphysema that only occurs after repeated smoke-induced injury over many years of an individual's life. [ABSTRACT FROM AUTHOR]

Objectives – To investigate the association between asthma and acute bronchitis in adults and to ascertain criteria to help general practitioners (GPs) differentiate between acute bronchitis and asthma. Design – Descriptive study. Setting – Primary health care centre in The Netherlands. Patients – 192 patients, aged 18–75 years, not known to have asthma or other pulmonary diseases, attending their GP with cough persisting for at least 2 weeks. Methods – Patients were considered to have asthma or chronic obstructive pulmonary disease on the basis of a questionnaire on respiratory symptoms, spirometry and methacholine challenge testing. They were classified as having acute bronchitis if, according to international guidelines, coughing was more frequent than normal for at least 2 weeks, but no more than 4 weeks. Furthermore, either expectoration of purulent sputum for a maximum of 2 weeks and/or rhonchi as assessed by auscultation had to be present. By means of logistic regression symptoms, signs and peak expiratory flow measurements were sought to predict which patients with acute bronchitis actually had asthma. Results – Of the 80 (41.7%) subjects with symptoms of acute bronchitis, 29 (36.9%) were patients with asthma. Within the acute bronchitis group, female sex and symptoms of current reported wheeze, reported episodes of attacks of dyspnoea over the last year and symptoms elicited by allergens were of help in identifying patients who actually had asthma. Conclusions – A considerable proportion of the patients presenting with acute bronchitis are actually patients with asthma. The absence or presence of a few symptoms and female sex may help to differentiate between these disorders. [ABSTRACT FROM AUTHOR]

SummaryBackground: Smoking and airway lability, which is expressed by histamine airway hyper-responsiveness, are known risk factors for development of respiratory symptoms. Smoking is also associated with increased mortality risks. We studied whether airway hyper-responsiveness is associated with increased mortality, and whether this risk was independent of smoking and reduced lung function.Methods: We followed up 2008 inhabitants of the communities of Vlagtwedde, Vlaardingen, and Meppel (Netherlands), who had histamine challenge test data, from 1964-72 for 30 years. Follow-up was 99% successful (29 patients lost to follow-up) with 1453 participants alive and 526 deaths (246 died from cardiovascular disease, 54 from lung cancer, and 21 from chronic obstructive pulmonary disease [COPD]).Findings: Mortality from COPD increased with more severe hyper-responsiveness; relative risks of 3.83 (95% CI 0.97-15.1), 4.40 (1.16-16.7), 4.78 (1.27-18.0), 6.69 (1.71-26.1), and 15.8 (3.72-67.1) were associated with histamine thresholds of 32 g/L, 16 g/L, 8 g/L, 4 g/L, and 1 g/L, respectively, compared with no hyper-responsiveness. These risks were adjusted for sex, age, smoking, lung function, body-mass index, positive skin tests, eosinophilia, asthma, and city of residence.Interpretation: Increased histamine airway hyper-responsiveness predicts mortality from COPD. Although this trend was more pronounced in smokers, an increasing proportion of COPD deaths with increasing hyper-responsiveness was also present among individuals who had never smoked. [ABSTRACT FROM AUTHOR]

Investigates whether asthma and chronic bronchitis may share some allergic phenotypes and whether asthmatic individuals who develop chronic bronchitis subsequently have steeper declines in lung function. Differences in characteristics of asthma, chronic bronchitis and emphysema; Presence of bronchodilator response and eosinophilia in chronic bronchitis.

The authors focus on the impact of inhaled corticosteroids (ICS) on immunosuppression. They say that for asthmatics, immunomodulation in the lung with ICS decreased is associated with exacerbations arising from viral infections, improved lung function and better outcomes. They also mention that the high dose of fluticasone and salmeterol reduces exacerbations and improves quality of life.

Background/Objective To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler ® devices by evaluating its protective effect against methacholine-induced bronchoconstriction in stable asthma. Methods In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable mild-to-moderate asthma (FEV 1 ≥80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler ® M2 or Turbuhaler ® M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV 1 (PC 20 ). Patients had a PC 20 methacholine <8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV 1 at all visits (90–110% of enrolment value). Results 60 patients (mean age 31.1 years [range:18–64]; mean FEV 1 92.1% predicted normal [78.4–120.6%]) were randomised to treatment; all completed the study. There was a clear dose–response for both devices. The within-device ratios (1.5 mg:0.5 mg) were 1.79 and 1.87 for Turbuhaler ® M3 and M2, respectively (both p < 0.001). The between-device ratios (M3:M2) were 0.92 (95% CI: 0.75–1.13) for 0.5 mg and 0.88 (95% CI 0.72–1.08) for 1.5 mg. Both confidence intervals lie inside the interval 0.67–1.50, which was the pre-specified condition for equivalent effect. Conclusions Bronchoprotection using a standardised methacholine challenge model proved to be an effective design to elucidate therapeutic equivalence between devices in patients with mild-to-moderate asthma. The findings indicate that patients may switch from one type of Turbuhaler ® to the other without adjustment of therapy. Moreover, they show the robustness and utility of this study design and its suitability for investigating therapeutic equivalence. EudraCT Number 2014-001457-16. Clinicaltrials.gov identifier NCT02322788. [ABSTRACT FROM AUTHOR]

A letter to the editor about the genetic aspects of asthma is presented.

Investigates the genes regulating the immunoglobulin E in asthma and several allergic disorders. Role of IgE in the pathogenesis of asthma and allergic disorders; Identification of 5q31-33 by gene mapping; Prevalence of high IgE levels in individuals with genotypes aaBb aabb.

Background: The rate of lung-function decline in chronic obstructive pulmonary disease (COPD) varies substantially among individuals. We sought to develop and validate an individualized prediction model for forced expiratory volume at 1 second (FEV1) in current smokers with mild-to-moderate COPD.Methods: Using data from a large long-term clinical trial (the Lung Health Study), we derived mixed-effects regression models to predict future FEV1 values over 11 years according to clinical traits. We modelled heterogeneity by allowing regression coefficients to vary across individuals. Two independent cohorts with COPD were used for validating the equations.Results: We used data from 5594 patients (mean age 48.4 yr, 63% men, mean baseline FEV1 2.75 L) to create the individualized prediction equations. There was significant between-individual variability in the rate of FEV1 decline, with the interval for the annual rate of decline that contained 95% of individuals being -124 to -15 mL/yr for smokers and -83 to 15 mL/yr for sustained quitters. Clinical variables in the final model explained 88% of variation around follow-up FEV1. The C statistic for predicting severity grades was 0.90. Prediction equations performed robustly in the 2 external data sets.Interpretation: A substantial part of individual variation in FEV1 decline can be explained by easily measured clinical variables. The model developed in this work can be used for prediction of future lung health in patients with mild-to-moderate COPD.Trial Registration: Lung Health Study - ClinicalTrials.gov, no. NCT00000568; Pan-Canadian Early Detection of Lung Cancer Study - ClinicalTrials.gov, no. NCT00751660. [ABSTRACT FROM AUTHOR]

Background: Bronchial hyperresponsiveness, a risk factor for asthma, consists of a heightened bronchoconstrictor response to a variety of stimuli. The condition has a heritable component and is closely related to serum IgE levels and airway inflammation. The basis for these relations is unknown, as is the mechanism of genetic susceptibility to bronchial hyperresponsiveness. We attempted to define the interrelation between atopy and bronchial hyperresponsiveness and to investigate the chromosomal location of this component of asthma. Methods: We studied 303 children and grandchildren of 84 probands with asthma selected from a homogeneous population in the Netherlands. Ventilatory function, bronchial responsiveness to histamine, and serum total IgE were measured. The association between the last two variables was evaluated. Using analyses involving pairs of siblings, we tested for linkage between bronchial hyperresponsiveness and genetic markers on chromosome 5q31-q33, previously shown to be linked to a genetic locus regulating serum total IgE levels. Results: Serum total IgE levels were strongly correlated (r = 0.65, P<0.01) in pairs of siblings concordant for bronchial hyperresponsiveness (defined as a >20 percent decrease in the forced expiratory volume in one second produced by histamine [threshold dose, <16 mg per milliliter]), suggesting that these traits are coinherited. However, bronchial hyperresponsiveness was not correlated with serum IgE levels (r = 0.04, P>0.10). Analyses of pairs of siblings showed linkage of bronchial hyperresponsiveness with several genetic markers on chromosome 5q, including D5S436 (P<0.001 for a histamine threshold value of ≤16 mg per milliliter). Conclusions: This study demonstrates that a trait for an elevated level of serum total IgE is coinherited with a trait for bronchial hyperresponsiveness and that a gene governing bronchial hyperresponsiveness is located near a major locus that regulates serum IgE levels on chromosome 5q. These findings are consistent with the existence of one or more genes on chromosome 5q31-q33 causing susceptibility to asthma. (N Engl J Med 1995;333:894-900.) [ABSTRACT FROM AUTHOR]

Background Chronic obstructive pulmonary disease (COPD) is a progressive, incurable lung disease characterised by abnormal tissue repair causing emphysema and small airways fibrosis. Since current therapy cannot modify this abnormal repair, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung tissue provides a powerful tool to investigate this. Methods We performed genome-wide gene expression profiling in 581 lung tissue samples from current and ex-smokers with (n=311) and without COPD (n=270). Subsequently, quantitative PCR, western blot and immunohistochemical analyses were performed to validate our main findings Results 112 genes were found to be upregulated in patients with COPD compared with controls, whereas 61 genes were downregulated. Among the most upregulated genes were fibulin-5 (FBLN5), elastin (ELN), latent transforming growth factor β binding protein 2 (LTBP2) and microfibrillar associated protein 4 (MFAP4), all implicated in elastogenesis. Our gene expression findings were validated at mRNA and protein level. We demonstrated higher ELN gene expression in COPD lung tissue and similar trends for FBLN5 and MFAP4, and negative correlations with lung function. FBLN5 protein levels were increased in COPD lung tissue and cleaved, possibly non-functional FBLN5 protein was present. Strong coexpression of FBLN5, ELN, LTBP2 and MFAP4 in lung tissue and in silico analysis indicated cofunctionality of these genes. Finally, colocalisation of FBLN5, MFAP4 and LTBP2 with elastic fibres was demonstrated in lung tissue. Conclusions We identified a clear gene signature for elastogenesis in COPD and propose FBLN5 as a novel player in tissue repair in COPD. [ABSTRACT FROM AUTHOR]

Background and objective We assessed whether co-deposition of a long-acting β2-agonist and a corticosteroid affects their respective transport rates across epithelial cells. Methods Drug particles were deposited on the air-interface culture of Calu-3 cells using a twin-stage impinger. We compared the transport rate of salmeterol and fluticasone across the epithelial cells using commercially available formulations ( Serevent, Flixotide and Seretide). The transepithelial resistance of Calu-3 cells was measured before and after each deposition to monitor epithelial resistance. Results The codeposition of salmeterol and fluticasone had no significant effect on transport of salmeterol through the cell layer. In contrast, the rate of fluticasone propionate transport in presence of salmeterol xinofoate was significantly lower (0.53 ± 0.20%) compared with the single fluticasone formulation (2.36 ± 0.97%). Furthermore, the resistance of the epithelial cells was significantly increased after salmeterol deposition from both single and combination products. Conclusions Our data demonstrate that salmeterol may decrease the permeability of epithelial cells, resulting in slower fluticasone transport across Calu-3 epithelial monolayers. The subsequent increased residence time of fluticasone in the airways could prolong its anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide. Recent genome-wide association studies (GWAS) have identified robust susceptibility loci associated with COPD. However, the mechanisms mediating the risk conferred by these loci remain to be found. The goal of this study was to identify causal genes/variants within susceptibility loci associated with COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed. Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n = 363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case-control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD. [ABSTRACT FROM AUTHOR]

Genome-wide association studies identified single nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine receptors (nAChRs) cluster as a risk factor for nicotine dependency and COPD. We investigated whether SNPs in the nAChR cluster are associated with smoking habits and lung function decline, and if these potential associations are independent of each other. The SNPs rs569207, rs1051730 and rs8034191 in the nAChR cluster were analyzed in the Vlagtwedde-Vlaardingen cohort (n = 1,390) that was followed for 25 years. We used GEE and LME models to analyze the associations of the SNPs with quitting or restarting smoking and with the annual FEV1 decline respectively. Individuals homozygote (CC) for rs569207 were more likely to quit smoking (OR (95%CI) = 1.58 (1.05-2.38)) compared to wild-type (TT) individuals. Individuals homozygote (TT) for rs1051730 were less likely to quit smoking (0.64 (0.42; 0.97)) compared to wild-type (CC) individuals. None of the SNPs was significantly associated with the annual FEV1 decline in smokers and ex-smokers. We show that SNPs in the nAChR region are associated with smoking habits such as quitting smoking, but have no significant effect on the annual FEV1 decline in smokers and ex-smokers, suggesting a potential role of these SNPs in COPD development via smoking habits rather than via direct effects on lung function. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims We investigated whether variants in the serotonin transporter gene ( SLC6A4) influence smoking cessation rates using antidepressant therapy (i.e. bupropion and nortriptyline). Design Pharmacogenetic (secondary) analysis of a randomized, placebo-controlled efficacy trial of bupropion and nortriptyline for smoking cessation. Setting Single-centre study, Maastricht University, the Netherlands. Participants A total of 214 of 255 (84%) current daily smokers participating in a randomized controlled efficacy trial. Measurements Subjects were genotyped for three functional variants in SLC6A4 (5-HTTLPR, STin2, rs25531). Primary outcome measures were prolonged abstinence from weeks 4-12, 4-26 and 4-52. Secondary outcome measures included 7-day point prevalence abstinence at weeks 4, 12, 26 and 52. Findings Carriers of the 5-HTTLPR high-activity L-variant had higher prolonged cessation rates with bupropion than placebo [odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.01-2.05, P = 0.04]. Combining the three variants resulted in increased prolonged cessation rates for both bupropion and nortriptyline among carriers of four to five high-activity variants (bupropion: OR = 2.00, 95% CI = 1.21-3.29, P = 0.01; nortriptyline: OR = 1.91, 95% CI = 1.02-3.56, P = 0.04). Similar results were found for point prevalence abstinence. Conclusions Bupropion and nortriptyline seem to be more effective in smoking cessation among SLC6A4 high-activity variant carriers, probably by blocking the increased serotonin transporter activity, thereby increasing serotonin levels. Prospective studies have to assess if this can improve cessation rates when treatment is targeted at individuals based on their genotypes. [ABSTRACT FROM AUTHOR]

The airway epithelium plays a role in immune regulation during environmental challenge, which is intertwined with its barrier function and capacity to limit submucosal access of environmental factors. In asthma, mucosal barrier function is often compromised, with disrupted expression of the adhesion molecule E-cadherin. Recent progress suggests that E-cadherin contributes to the structural and immunological function of airway epithelium, through the regulation of epithelial junctions, proliferation, differentiation, and production of growth factors and proinflammatory mediators that can modulate the immune response. Here, we discuss this novel role for E-cadherin in mediating the crucial immunological decision between maintenance of tolerance versus induction of innate and adaptive immunity. [Copyright &y& Elsevier]

Abstract: The epidemiological relationship between squamous cell lung cancer (SCC) and chronic obstructive pulmonary disease (COPD), both smoking-related diseases, suggests that they have also a genetic basis. We compared 35 SCC patients with and without COPD with whole-genome gene expression profiles of laser microdissected tissue. Validation of differential expression was performed for 25 genes using quantitative (q)RT-PCR. Subsequently, we performed array-based CGH on the same tumor samples. We found that 374 probes were differentially expressed in SCC from patients with and without COPD. Forty-four probes were derived from genes with mitochondrial functions and 34 probes were located on 5q. All these probes showed a lower expression level in SCC from non-COPD patients. For a random selection of 25 mitochondrial and 5q genes, we confirmed the differential expression by qRT-PCR. Loss of 3p, 5q and 9p was observed, via array-CGH, to be more frequent in SCC from non-COPD patients as compared to SCC from COPD patients. Combination of chromosomal aberrations and the location of the differentially expressed genes showed significant association for loss of the 5q31.2–31.3 region and reduced expression of the 5q genes. In conclusion, a more frequent loss of 5q and a low expression of genes located on 5q in SCC tumors of non-COPD patients compared to tumors from COPD patients was identified suggesting that different oncogenetic pathways are operational in patients with and without COPD. [Copyright &y& Elsevier]

Background. Low mannan-binding lectin (MBL) levels, caused by MBL2 polymorphisms, are suggested to contribute to susceptibility to respiratory tract infections (RTIs), particularly early in life. Large-scale replication of previous associations is needed, however. We investigated the association between MBL2 polymorphisms and the frequency of RTI in a large population-based birth cohort of white children. Methods. The frequency of RTI was prospectively assessed by annual parental questionnaires until children were 4 years of age. Thirteen polymorphisms in MBL2 were determined in 987 Dutch children. Haplotypes, previously shown to be associated with functional levels of MBL, were constructed, and their associations with the frequency of RTI during year 1, year 2, and the first 4 years of life were assessed. High-producing, intermediate-producing, and deficient MBL2 genotypes were defined on the basis of exon 1 and Y/X promoter polymorphisms. Results. No differences were found between investigated polymorphisms and haplotype frequencies in the population as a whole or between the groups with frequent, moderately frequent, or no RTIs reported. Deficient MBL2 genotypes were not associated with an increased risk of RTI (odds ratio, 0.71 [95% confidence interval, 0.25 to 2.05]) during years 1-4 of life. This was also true when year 1 and year 2 were studied separately. Conclusion. These results suggest that, at the population level, MBL2 polymorphisms do not contribute to the risk of questionnaire-reported RTI in white children. [ABSTRACT FROM AUTHOR]

Systemic corticosteroids and additional short-acting ββ2-agonists are commonly used in exacerbations of chronic obstructive pulmonary disease (COPD). In this double-blind study, the combination of a high-dose inhaled corticosteroid with a rapid-onset long-acting ββ2-agonist was evaluated in the treatment of out-patient COPD exacerbations. The primary aim was to compare 14-day treatment effects of budesonide/formoterol to placebo on sputum eosinophils and, secondarily, on other indices of inflammation, forced expiratory flow in one second (FEV1), symptoms, health status, and adverse events. Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, median packyears 38, age 65 years, FEV1 61% predicted), experiencing a COPD exacerbation, were treated at home with budesonide/formoterol (320/9 μg 4 times daily), prednisolone (30 mg daily), or placebo for 14 days. Sputum eosinophils were significantly reduced by budesonide/formoterol (-57%) compared to placebo (+24%) (p = 0.01). Budesonide/formoterol reduced total symptom scores significantly (p = 0.01) compared to placebo. The increase in FEV1 by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p = 0.07). Budesonide/ formoterol treatment did not suppress morning serum cortisol compared to placebo (-16 %; p = 0.50). In conclusion, budesonide/formoterol reduces sputum eosinophils and improves symptoms in the treatment of out-patient COPD exacerbations. [ABSTRACT FROM AUTHOR]

The article assess the safety of sputum induction (SI) during the chronic obstructive pulmonary disease (COPD) exacerbations. The research concluded that SI can be safety carried out in patients with mild-to-moderate COPD who experience an exacerbation. The only independent association was with the larger decrease in FEV1 in the stable phase in a multivariate analysis.

Background: Recent reports indicate that over the next decade rates of chronic obstructive pulmonary disease (COPD) in women will exceed those in men in the western world, though in most jurisdictions, women continue to smoke less compared with men. Whether female adult smokers are biologically more susceptible to COPD is unknown. This study reviewed the available evidence to determine whether female adult smokers have a faster decline in forced expiratory volume in one second (FEV1) compared with male adult smokers and whether age modifies the relationship between cigarette smoke and lung function decline. Methods: A systematic review and a meta-analysis was performed of population-based cohort studies that had a follow-up period of at least 3 years, measured FEV1 on at least two different time points, and presented FEV1 data stratified by gender and smoking status in adults. Results: Of the 646 potentially relevant articles, 11 studies met these criteria and were included in the analyses (N = 55 709 participants). There was heterogeneity in gender-related results across the studies. However, on average current smokers had a faster annual decline rate in FEV1% predicted compared with never and former smokers. Female current smokers had with increasing age a significantly faster annual decline in FEV1% predicted than male current smokers (linear regression analysis, R² = 0.56; p = 0.008). Age did not materially affect the rate of decline in FEV1% predicted in male and female former and never smokers (p = 0.775 and p = 0.326, respectively). Conclusion: As female smokers age, they appear to experience an accelerated decline in FEV1% predicted compared with male smokers. Future research powered specifically on gender-related changes in lung function is needed to confirm these early findings. [ABSTRACT FROM AUTHOR]

Introduction: β-Blockers are known to worsen FEV1 and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring β-blocker treatment. Objective: To determine the effects of β-blockers on AHR (provocative concentration of methacholine causing a 20% fall in FEV1 [PC20]), FEV1, and response to formoterol in patients with COPD. Design: A double-blind, placebo-controlled, randomized, cross-over study. Setting: An ambulatory, hospital outpatient clinic of pulmonary diseases. Patients: Patients with mild-to-moderate irreversible COPD and AHR. Intervention: Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period ≥ 3 days. On day 4 of treatment, FEV1 and PC20 were assessed. Immediately hereafter, formoterol (12 μg) was administered and FEV1 was measured for up to 30 min. Results: PC20 was significantly lower (p < 0.01) with propranolol and metoprolol treatment (geometric means, 2.06 mg/mL and 2.02 mg/mL, respectively) than with placebo (3.16 mg/mL) or celiprolol (3.41 mg/mL). FEV1 deteriorated only after propranolol treatment (2.08 ± 0.31 L) [mean ± SD] compared with placebo (2.24 ± 0.37 L). The fast bronchodilating effect of formoterol was hampered by propranolol (mean increase in FEV1 at 3 min, 6.7 ± 8.9%) but was unaffected by the other β-blockers (16.9 ± 9.8%, 22 ± 11.6%, and 16.9 ± 9.0% for placebo, metoprolol, and celiprolol, respectively). Conclusions: Pulmonary effects did not occur by celiprolol. Only propranolol reduced FEV1 and the bronchodilating effect of formoterol. Both metoprolol and propranolol increased AHR. Thus, different classes of β-blockers have different pulmonary effects. The anticipated beneficial cardiovascular effects of a β-blocker must be weighted against the putative detrimental pulmonary effects, ie, effect on FEV1, AHR, and response to additional β2-agonists. [ABSTRACT FROM AUTHOR]

van den Berg JWK, Slebos D-J, Postma DS, Dijkhuizen B, Koëter GH, Timens W, van der Bij W, Kauffman HF. Feasibility of sputum induction in lung transplant recipients. Clin Transplant 2004 DOI: 10.1111/j.1399-0012.2004.00237.x © Blackwell Munksgaard, 2004 Sputum induction (SI) is nowadays being applied as a non-invasive and safe method to investigate airway inflammation in pulmonary diseases. We investigated the feasibility of SI after lung transplantation (LTX), and compared sputum and bronchoalveolar lavage (BAL) cellular characteristics and interleukin-8 (IL-8) levels. Results were also compared with 11 healthy subjects. SI as performed between 26 and 1947 d after LTX in 19 recipients, was successful in 16 of 22 attempts (73%). Six patients failed to produce sputum after induction, mostly just post-LTX and with having a lower forced expiratory volume in 1 s (FEV1). The success rate in clinically stable patients after the first month post-LTX was 93%. Side-effects were absent. Sputum recovery, viability and squamous cell contamination were comparable between LTX patients and healthy subjects. In the LTX group, total cell counts, neutrophil percentages and IL-8 levels were much higher in SI than BAL (1.6 × 106/mL, 65.5% and 54.2 ng/mL vs. 0.1 × 106/mL, 3.0% and 0.01 ng/mL; p < 0.001). Although LTX-neutrophil percentages in SI and BAL correlated properly ( ρ = 0.72, p = 0.04), both techniques are not interchangeable. We conclude that sputum induction is feasible, well tolerated, and without major side-effects in stable patients after the first month post-LTX. Induced sputum may be a useful tool to study inflammatory changes of the airways after LTX, and because of the large quantity of neutrophils sampled, especially for further studies on the pathogenesis of bronchiolitis obliterans. [ABSTRACT FROM AUTHOR]

Interpretation: When taken as needed, formoterol 4.5 mg provided better asthma control than terbutaline 0.5 mg in patients requiring moderate doses of relief medication despite inhaled corticosteroid treatment. Safety studies should be extended to a wider population of patients with asthma. [ABSTRACT FROM AUTHOR]