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Background: Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium.Methods: Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls.Results: In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate < 0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDRGSEA < 0.001).Conclusion: We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non-invasive biomarker in COPD.Trial Registration: ClinicalTrials.gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.gov registration number NCT00807469 (registration date December 11, 2008). [ABSTRACT FROM AUTHOR]

Background: To investigate if age, gender and smoking are associated with airway wall thickness (AWT) measured by high resolution computed tomography (HRCT) and if higher AWT is associated with lower levels of pulmonary function in healthy current- and never-smokers with a wide age range.Methods: HRCT scans were performed in 99 subjects (48 never- and 51 current-smokers, median age 39 years [IQR 22 - 54], 57% males). The AWT at an internal perimeter of 10 mm (AWT Pi10) was calculated as an overall measurement of AWT, based on all measurements throughout the lungs. Extensive pulmonary function testing was performed in all subjects.Results: Higher age was associated with a lower AWT Pi10 (b = -0.003, p < 0.001). Current-smokers had a higher AWT Pi10 than never-smokers (mean 0.49 mm versus 0.44 mm, p = 0.022). In multivariate analysis, age and current-smoking were independently associated with AWT Pi10 (age b = -0.002, p < 0.001, current-smoking b = 0.041, p = 0.021), whereas gender was not (b = 0.011, p = 0.552). Higher AWT Pi10 was associated with a lower FEV1, FEV1/FVC, FEF25-75 and higher R5, R20 and X5.Conclusions: AWT decreases with higher age, possibly reflecting structural changes of the airways. Additionally, current-smokers have a higher AWT, possibly due to remodeling or inflammation. Finally, higher AWT is associated with a lower level of pulmonary function, even in this population of healthy subjects.Trial Registration: This Study was registered at www.clinicaltrials.gov with number NCT00848406 on 19 February 2009. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by chronic airway inflammation and emphysema, and is caused by exposure to noxious particles or gases, e.g. cigarette smoke. Smoking and oxidative stress lead to accelerated formation and accumulation of advanced glycation end products (AGEs), causing local tissue damage either directly or by binding the receptor for AGEs (RAGE). This study assessed the association of AGEs or RAGE in plasma, sputum, bronchial biopsies and skin with COPD and lung function, and their variance between these body compartments.Methods: Healthy smoking and never-smoking controls (n = 191) and COPD patients (n = 97, GOLD stage I-IV) were included. Autofluorescence (SAF) was measured in the skin, AGEs (pentosidine, CML and CEL) and sRAGE in blood and sputum by ELISA, and in bronchial biopsies by immunohistochemistry. eQTL analysis was performed in bronchial biopsies.Results: COPD patients showed higher SAF values and lower plasma sRAGE levels compared to controls and these values associated with decreased lung function (p <0.001; adjusting for relevant covariates). Lower plasma sRAGE levels significantly and independently predicted higher SAF values (p < 0.001). One SNP (rs2071278) was identified within a region of 50 kB flanking the AGER gene, which was associated with the gene and protein expression levels of AGER and another SNP (rs2071278) which was associated with the accumulation of AGEs in the skin.Conclusion: In COPD, AGEs accumulate differentially in body compartments, i.e. they accumulate in the skin, but not in plasma, sputum and bronchial biopsies. The association between lower sRAGE and higher SAF levels supports the hypothesis that the protective mechanism of sRAGE as a decoy-receptor is impaired in COPD. [ABSTRACT FROM AUTHOR]

Induced lung sputum is a valuable matrix in the study of respiratory diseases. Although the methodology of sputum collection has evolved to a point where it is repeatable and responsive to inflammation, its use in molecular profiling studies is still limited Here, an in-depth lipid profiling of induced lung sputum using high-resolution liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-Q-TOF MS) is described. An enormous complexity in lipid composition could be revealed Over 1500 intact lipids, originating from 6 major lipid classes, have been accurately identified in 120 μL of induced sputum. By number and measured intensity, glycerophospholipids represent the largest lipid class, followed by sphingolipids, glycerolipids, fatty acyls, sterol lipids, and prenol lipids. Several prenol lipids, originating from tobacco, could be detected in the lung sputum of smokers. To illustrate the utility of the methodology in studying respiratory diseases, a comparative lipid screening was performed on lung sputum extracts in order to study the effect of Chronic Obstructive Pulmonary Disease (COPD) on the lung barrier lipidome. Results show that sphingolipid expression in induced sputum significantly differs between smokers with and without COPD. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by ongoing inflammatory and remodeling processes of the airways and lung tissue. Inflammation can be targeted by corticosteroids. However, airway inflammation is generally less responsive to steroids in COPD than in asthma. The underlying mechanisms are yet unclear. This study aimed to assess whether skin corticosteroid insensitivity is associated with COPD and COPD severity using the corticosteroid skin blanching test. Methods: COPD patients GOLD stage I–IV (n = 27, 24, 22, and 16 respectively) and healthy never-smokers and smokers (n = 28 and 56 respectively) were included. Corticosteroid sensitivity was assessed by the corticosteroid skin blanching test. Budesonide was applied in 8 logarithmically increasing concentrations (0–100 μg/ml) on subject's forearm. Assessment of blanching was performed after 7 hours using a 7-point scale (normal skin to intense blanching). All subjects performed spirometry and body plethysmography. Results: Both GOLD III and GOLD IV COPD patients showed significantly lower skin blanching responses than healthy never-smokers and smokers, GOLD I, and GOLD II patients. Their area under the dose-response curve values of the skin blanching response were 586 and 243 vs. 1560, 1154, 1380, and 1309 respectively, p<0.05. Lower FEV1 levels and higher RV/TLC ratios were significantly associated with lower skin blanching responses (p = 0.001 and p = 0.004 respectively). GOLD stage I, II, III and IV patients had similar age and packyears. Conclusions: In this study, severe and very severe COPD patients had lower skin corticosteroid sensitivity than mild and moderate COPD patients and non-COPD controls with comparable age and packyears. Our findings together suggest that the reduced skin blanching response fits with a subgroup of COPD patients that has an early-onset COPD phenotype. [ABSTRACT FROM AUTHOR]

Background: It has been suggested that smoking asthmatics benefit less from corticosteroid treatment than neversmoking asthmatics. We investigated differences in blood and sputum inflammatory profiles between ex-, current-, and never-smokers and assessed their ICS treatment response after 2-week and 1-year treatment. Methods: We analyzed FEV1, PC20 methacholine and PC20 AMP, (differential) cell counts in sputum and blood in ex-, current- and never-smokers at baseline (n=114), after 2-week treatment with fluticasone 500 or 2000 μg/day (n=76) and after 1-year treatment with fluticasone 500 μg/day or a variable dose of fluticasone based on a selfmanagement plan (n=64). Results: A total of 114 patients were included (29 ex-, 30 current- and 55 never-smokers. At baseline, ex- and current-smokers had less eosinophils in sputum and blood than never-smokers. Blood neutrophil counts were higher in current- than in never-smokers. A higher number of cigarettes smoked daily was associated with lower blood and sputum eosinophils. After 2-week ICS treatment, FEV1 %predicted improved less in current-smokers than never-smokers (2.4% versus 8.1%, p=0.010) and ex-smokers tended to improve less than never-smokers (4.1%, p=0.067). In contrast, no differences in ICS treatment response in lung function or inflammatory cells were found between the three groups after 1 year. Conclusions: Ex- and current-smokers have less eosinophils and more neutrophils in their sputum and blood than never-smokers. Although ex- and current-smokers have a reduced short-term corticosteroid treatment response, we did not find a difference in their long-term treatment response. [ABSTRACT FROM AUTHOR]

Summary: Background: Inhaled glucocorticosteroids reduce airway inflammation in asthma patients, thereby improving lung function and reducing airway hyperresponsiveness and symptoms. The response to glucocorticosteroids can be measured with the glucocorticosteroid skin-blanching test. We investigated if asthmatics have a lower skin-blanching response to glucocorticosteroids than non-asthmatic subjects and if asthmatics with airway obstruction have lower skin-blanching response than those without obstruction. Finally, we assessed which clinical and inflammatory parameters influence the variability in skin-blanching response. Methods: We evaluated the skin-blanching response to topical budesonide in a large group of 315 well-characterized asthmatics and their relatives (asthma n = 114, healthy n = 140, other = 61) Results: The skin-blanching scores of the asthma probands and their healthy spouses were not significantly different. The skin-blanching score of patients with FEV1 < 80% predicted was lower than of patients without obstruction. Lower skin-blanching score was significantly associated with lower FEV1 %predicted, higher age, female gender, absence of allergy and summer season, but not with use of inhaled or oral glucocorticosteroids or packyears smoking. Conclusions: Asthmatics do not have lower skin-blanching response to glucocorticosteroids than healthy subjects. Furthermore, lower skin-blanching response to glucocorticosteroids is associated with lower FEV1, female gender, higher age and the absence of allergy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the optimal tracer uptake time, the minimal amount of radioactivity and the inter-observer agreement for 11C-choline positron emission tomography/computed tomography (PET/CT) in patients with primary hyperparathyroidism (pHPT). Methods: Twenty-one patients with biochemically proven pHPT were retrospectively studied after injection of 6.3 ± 1.2 MBq/kg 11C-choline. PET data of the first nine patients, scanned for up to 60 min, were reconstructed in 10-min frames from 10- to 60-min postinjection (p.i.), mimicking varying 11C-choline uptake times. Parathyroid adenoma to background contrast ratios were calculated and compared, using standardized uptake values (SUVs). Data was reconstructed with varying scan durations (1, 2.5, 5, and 10 min) at 20–30-min p.i. (established optimal uptake time), mimicking less administered radioactivity. To establish the minimal required radioactivity, the SUVs in the shorter scan durations (1, 2.5, and 5 min) were compared to the 10-min scan duration to determine whether increased variability and/or statistical differences were observed. Four observers analyzed the 11C-choline PET/CT in four randomized rounds for all patients. Results: SUVpeak of the adenoma decreased from 30 to 40 p.i. onwards. All adenoma/background contrast ratios did not differ from 20- to 30-min p.i. onwards. The SUVs of adenoma in the scan duration of 1, 2.5, and 5 min all differed significantly from the same SUV in the 10-min scan duration (all p = 0.012). However, the difference in absolute SUV adenoma values was well below 10% and therefore not considered clinically significant. The inter-observer analysis showed that the Fleiss' kappa of the 1-min scan were classified as "moderate," while these values were classified as "good" in the 2.5-, 5-, and 10-min scan duration. Observers scored lower certainty scores in the 1- and 2.5-min scans compared to the 5- and 10-min scan durations. Conclusion: The optimal time to start PET/CT scanning in patients with pHPT is 20 min after mean injection of 6.3 MBq/kg 11C-choline, with a recommended scan duration of at least 5 min. Alternatively, the radioactivity dose can be lowered by 50% while keeping a 10-min scan duration without losing the accuracy of 11C-choline PET/CT interpretation. [ABSTRACT FROM AUTHOR]

Rationale: Acute allograft rejection is one of the major complications after lung transplantation, and adequate and early recognition is important. Till now, the reference standard to detect acute rejection is the histopathological grading of transbronchial biopsies (TBBs). Acute rejection is characterised by high levels of activated T lymphocytes. Interleukin-2 (IL-2) binds specifically to high-affinity IL-2 receptors expressed on the cell membrane of activated T lymphocytes. The aim of this proof-of-concept study was to evaluate if non-invasive imaging with 99mTc-HYNIC-IL-2 is able to detect acute rejection after lung transplantation. Methods: 99mTc-HYNIC-IL-2 scintigraphy (static, SPECT/CT of the lungs) was performed shortly before routine transbronchial biopsy (pathology as reference standard). Scans were scored as likely or unlikely for rejection, and semiquantitative analysis (target-to-background ratio) was performed. Results: Thirteen patients were included of which 3 showed acute rejection at transbronchial biopsy; in 2 of these patients (scored as graded 2–3 at pathology), the scan was scored likely for rejection, and in 1 patient (scored grade 1 at pathology), the scan was scored unlikely. No correlation was found between biopsy results and semiquantitative analysis. Conclusion: 99mTc-HYNIC-IL-2 scintigraphy proved to be a good technique to detect grade 2 and 3 acute rejection in a small sample population of patients after lung transplantation. Larger studies are necessary to really show the added value of this non-invasive specific imaging technique over transbronchial biopsy. Alternatively, imaging with the PET tracer 18F-IL-2 may be useful for this purpose. [ABSTRACT FROM AUTHOR]